Scientific Reports

Our medical research library holds 138 studies published in Scientific Reports (2013–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 138 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: Nature Publishing Group
• Published: 2011 to the present, England
• Language: English
• ISSN: 2045-2322 (electronic)
• Its record in the NLM Catalog

2020s

• Asbestos mineral fibre exposure significantly affects volatile organic compound profiles of mesothelial cell lines in vitro. S. Bonsall, T. Issitt, N. Peake, et al. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is a rare cancer caused by exposure to asbestos, this condition continues to represent a significant diagnostic and therapeutic challenge. Due to the long disease latency, non-invasive diagnostic modalities such as breath analysis may enhance MM early detection by identifying the disease specific pattern of volatile organic compounds (VOCs) in exhaled breath. In this study, solid phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) was used to extract VOCs from the headspace of two mesothelioma cell lines: MSTO-211 H (biphasic mesothelioma) and NCI-H28 (epithelioid mesothelioma) in addition to MET-5a (non-malignant mesothelial cell line), following exposure to asbestos mineral fibers (actinolite, amosite, crocidolite and chrysotile) and a non-asbestos fiber control (wollastonite). Multivariate statistical analysis was applied to identify VOC-based biomarkers associated with asbestos exposure within the cell lines. Data confirms that exposure to mineral fibers (including the non-asbestos fiber control) induces significant alterations in the levels of as many as 24 VOCs in each cell line. This is the first study to investigate the impact of asbestos mineral fiber exposure on the VOC profile of MM cell lines. This may be relevant to studies involving mesothelioma patients, as these VOCs could also serve as indicators of asbestos exposure in individuals who have been exposed to asbestos.

  © 2026. The Author(s).

• Candidate biomarkers to identify mesothelioma patients at risk of developing venous thromboembolism post-surgery. A. Shami-Shah, S. Roth, S.R. Morton, et al. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  Pleural Mesothelioma (PM) is an aggressive cancer that attacks thousands of people every year. One of the common treatments is surgery to remove the tumor. Unfortunately, around 11% of patients die from blood clots post-surgery. Current predictive factors such as C-reactive protein, D-Dimer, and abnormal platelet count lack specificity. To date, no blood-based protein biomarkers have been identified to reliably predict PM patients at risk of developing Venous Thromboembolism (VTE) post-surgery. In this study, we present a set of host-response plasma protein candidate biomarkers that could predict patients at risk of developing VTE. We employed a quantitative mass spectrometry-based proteomics approach integrated with a multilayered, structured, and systematic evaluation of candidate biomarkers in a cohort of 18 patients, comprising six mesothelioma cases, six mesothelioma controls, and six lung cancer controls. This is the first step towards personalized treatment plans for PM patients undergoing surgery. This study’s findings can potentially guide subsequent, larger-scale investigations, highlighting the value of small-scale exploratory research.

• Conditional survival patterns and individualized prognostic prediction in malignant peritoneal mesothelioma. X. Liao, C. Li, M. Huang, et al. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  Malignant peritoneal mesothelioma (MPM) is a rare, aggressive cancer with limited treatment options and extremely poor survival outcomes. Due to the disease's low incidence, large-scale cohort studies to clarify survival outcomes and the impact of treatments like chemotherapy are limited. This study aimed to use conditional survival (CS) analysis to assess survival trends and explore the survival benefits of chemotherapy in MPM patients. Using SEER data (2000-2019), CS analysis was applied to capture survival probabilities conditional on having survived specific durations after diagnosis. Additionally, we used machine learning algorithms, including Random Survival Forest and the least absolute shrinkage and selection operator regression, combined with Cox proportional hazards models, to develop and validate a nomogram model for CS prediction. Propensity score matching (PSM) was conducted to evaluate the effect of chemotherapy on survival. Among 1,549 MPM patients, CS rates improved with time survived post-diagnosis but plateaued later, highlighting the need for early intervention and follow-up. The CS-based nomogram model demonstrated strong predictive performance, with C-index values of 0.701 and 0.717 in the training and validation cohorts, respectively. The model was well-calibrated, with AUC values indicating consistent predictive accuracy. DCA analysis validated the clinical applicability of the model. PSM analysis showed that chemotherapy was associated with longer overall survival. CS analysis provides a time-updated complement to traditional survival estimates and may inform follow-up intensity and patient counseling. The CS-based nomogram offers a useful adjunct to current staging for individualized risk assessment in MPM. Moreover, our study highlighted the potential survival benefit of chemotherapy, though further research is needed to confirm these findings.

  © 2026. The Author(s).

• Dual phase modeling of Chrysotile carcinogenesis from 3D cell transformation to orthotopic tumors. Y. Gao, W. Yu, R. Li, et al. 2026;16(1):2199. PubMed · Publisher · Free full text

  Abstract

  Chrysotile asbestos, a well-established carcinogen, is known to induce various malignant cancers, contributing to an estimated annual death toll of 107,000 individuals due to asbestos-related diseases. While cell and animal models play a crucial role in elucidating the carcinogenic mechanisms of asbestos, existing models are plagued by prolonged experimental durations. In this investigation, we established a novel NIH/3T3 cell model of asbestos-induced malignant transformation using 3D culture techniques, followed by the development of a corresponding mouse model via orthotopic transplantation. Subsequent administration of the HIF-1α inhibitor PX-478 to both models allowed for the assessment of model reliability through the observation of malignant phenotypes and associated protein alterations.

  © 2026. The Author(s).

• Greenstone artifacts in pre-Columbian Costa Rica: from raw material to local and interregional exchanges. C. Hernández-Murillo, S.G. Piedra, S. Salgado, et al. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  Understanding the distribution pattern and relative abundance of the different greenstones used by pre-Columbian societies in the current territory of Costa Rica provides valuable insights into ancient exchange networks. This study examines the role of local and interregional exchange systems involving both locally sourced and allochthonous greenstones in the Greater Nicoya and the Central Caribbean regions. Non-invasive infrared spectroscopy was applied to identify the main mineral phases in 926 objects from 54 archaeological sites, and chemometric analyses were used to distinguish compositional groups and to visualize their spatial distribution. X-ray diffraction was additionally performed on five representative samples, one from each of the most frequent compositional groups, to complement the spectroscopic analysis. The results reveal that each region displays distinct patterns of greenstone use, reflecting differences in access to materials and participation in exchange networks. Data suggests that locally available minerals, such as serpentine, tremolite-actinolite, quartz and other siliceous rocks, were obtained through short-range procurement systems whereas allochthonous allochthonous jadeitite and albitite were involved in long-distance interregional exchange. These findings highlight the coexistence of regional and long-distance networks and demonstrate the key role of jadeite in linking distinct lithic traditions within Costa Rica and beyond.

  © 2026. The Author(s).

• Heritable pulmonary arterial hypertension: new genetic findings and environmental triggers. M. Shaukat, E. Grünig, S. Haas, et al. 2026;16(1):4121. PubMed · Publisher · Free full text

  Abstract

  Our goal was to identify new environmental or genetic causes in heritable pulmonary arterial hypertension (HPAH) families outside the 18 known diagnostics PAH genes. PAH gene panel sequencing was performed for 47 HPAH families which revealed pathogenic variants in 39 families. Five of the remaining families agreed to whole exome sequencing and to fill in a drug and toxin exposure questionnaire. In Family 1 and 2, mother and daughter with HPAH carried a likely pathogenic variant in the CYBA gene and a variant of uncertain significance in the FKBP1A gene, respectively, following ACMG guidelines. In Family 3, we detected a likely pathogenic variant in the PTGR2 gene. These genes could play part in PAH pathogenesis but further functional analyses are required to corroborate these findings. In the remaining two families, we could not identify any plausible genetic cause. However, a father and son with PAH reported exposure to trichloroethylene, asbestos and tramadol in Family 4. In Family 5, two brothers with pulmonary veno-occlusive disease showed occupational toxin exposure. Thus, our findings indicate that not only a genetic predisposition but also environmental triggers should be investigated for HPAH patients.

  © 2026. The Author(s).

• Index-based FT-IR assessment of chrysotile detectability and environmental durability in asbestos cement materials. G.Z. Macher, D. Beke, A. Torma. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  Despite regulatory restrictions, asbestos cement materials remain widely employed among the population, thereby presenting significant environmental and health risks due to their chrysotile asbestos composition and vulnerability to weathering-induced deterioration. This paper explores the environmental durability of asbestos cement products and the detectability of chrysotile fibres using Fourier Transform Infrared spectroscopy, with a focus on an index-based evaluation. The analysis included both environmentally exposed and non-weathered reference samples, categorised into flat sheets, corrugated sheets, and pipes. Key performance indices were developed to assess spectrum matching accuracy, chrysotile fibre detectability, and durability under environmental stress. Results indicate that environmental exposure was associated with higher chrysotile detectability, likely due to surface degradation and increased dusting potential. These findings offer valuable insights for risk assessment and the development of improved monitoring strategies for asbestos-containing materials in various environments. The paper highlights the importance of comprehensive evaluations to understand the environmental behavior and risk profiles of asbestos cement products, which can inform appropriate management approaches for these materials in different applications and settings.

  © 2026. The Author(s).

• Low E-cadherin expression is associated with poor prognosis in pulmonal adenocarcinoma. F. Gehrisch, K.A. Schmid, M. Kluth, et al. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  E-cadherin is a critical cell adhesion molecule with a tumor suppressive role. Reduced membranous E-cadherin expression is considered a central step in the progression and metastatic spread in human cancers. To study the prevalence and potential role of reduced E-cadherin expression in different lung cancer subtypes, E-cadherin expression was analyzed in more than 850 resected lung cancers by IHC in a tissue microarray format. A membranous E-cadherin staining was seen in 779 (96.9%) of the 804 interpretable tumor samples. A loss of E-cadherin expression was slightly more frequent in adenocarcinomas (ACs; 1.1%) than in squamous cell carcinomas (SCCs; 0.0%; p < 0.0001). Among the less common tumor entities, E-cadherin immunostaining was absent in 57.1% of 35 mesotheliomas, but retained in all cases of carcinoid (n = 52), large cell neuroendocrine carcinoma (n = 19), undifferentiated large cell carcinoma (n = 3), carcinosarcoma (n = 2), pleiomorphic carcinoma (n = 11), adenosquamous carcinoma (n = 8), mucoepidermoid carcinoma (n = 1), lymphoepithelial carcinoma (n = 1), and SMARCA4-deficient undifferentiated tumors (n = 1). Reduced E-cadherin immunostaining was significantly linked to advanced pT stage (p = 0.0265) and high grade (p = 0.0351) in ACs. Univariate outcome analysis revealed a significant association between E-cadherin expression and patient survival in all NSCLCs (p < 0.0001) and in ACs (p = 0.0133). It is concluded that loss of E-cadherin expression occurs in only a small subset of NSCLCs, that it is more frequent in ACs compared to SCCs and that reduced E-cadherin expression is linked to poor prognosis and unfavorable histopathological features in ACs. Should targeted therapy become available in the future, a small subset of pulmonary ACs and many mesotheliomas could be candidates for treatment.

• Maintenance pemetrexed after platinum pemetrexed chemotherapy and survival outcomes in malignant pleural mesothelioma in a multicenter real world study. O. Aydin, Z.S. Isleyen, M. Erciyestepe, et al. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive malignancy with poor prognosis, and the role of maintenance therapy after first-line platinum-pemetrexed chemotherapy remains unclear. We conducted a multicenter retrospective study including 96 patients with metastatic or unresectable MPM treated across eight tertiary oncology centers. Eligible patients had received at least four cycles of first-line platinum-pemetrexed and achieved disease control, after which they were either administered maintenance pemetrexed (n = 54) or observed without further treatment (n = 42). Maintenance pemetrexed was associated with significantly prolonged median progression-free survival (15.5 vs. 7.9 months; p < 0.001) and overall survival (22.3 vs. 16.4 months; p = 0.002) compared with observation. Multivariate analyses confirmed maintenance pemetrexed as an independent predictor of improved progression-free survival (HR 2.92; 95% CI 1.81-4.72; p < 0.001) and overall survival (HR 2.10; 95% CI 1.24-3.55; p = 0.005). Non-epithelioid histology was independently associated with worse outcomes. Subgroup analyses demonstrated that the survival benefit of maintenance pemetrexed persisted in patients achieving both partial response and stable disease after first-line chemotherapy. Importantly, maintenance therapy was well tolerated, with no discontinuations due to toxicity, highlighting its feasibility in routine practice. These real-world findings suggest that maintenance pemetrexed may be associated with improved survival outcomes in patients with MPM who achieve disease control after first-line therapy.

  © 2026. The Author(s).

• Mesothelioma location influences the tumour microenvironment and immune checkpoint therapy response in preclinical models. M.L. Orozco Morales, S.M. Lansley, W.L. Chin, et al. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is a cancer derived from mesothelial cells, most commonly arising from the pleura or the peritoneum. Immune checkpoint therapy (ICT) has shown survival benefit for pleural mesothelioma, but little is known about the response in peritoneal mesothelioma. Most preclinical mesothelioma models involve subcutaneous cancer cell implantation, which lacks the relevant tumour microenvironment of peritoneal mesothelioma and does not resemble the clinical presentation. We therefore set out to explore the influence of location on the mesothelioma tumour microenvironment, comparing pleural, peritoneal, and subcutaneous models using identical cell line-derived syngeneic mesotheliomas. We found that the peritoneal location conferred an anti-inflammatory tumour microenvironment, characterised by low IFN, TNFα, and STAT signalling activity, low immune cell infiltration and a gene signature associated with non-response to ICT. ICT was effective in subcutaneous models, but the same cell line-derived tumours were irresponsive when inoculated intraperitoneally. Together, these findings show that peritoneal location is associated with an immune suppressive tumour microenvironment.

• Validation of chemoresistance phenotypes in pleural mesothelioma across 2D, 3D, and in vivo models. H. Shi, S.P. Selvamani, R. Zelei, et al. 2026;16(1). PubMed · Publisher · Free full text

  Abstract

  Pleural mesothelioma (PM) is a highly aggressive cancer with limited treatment efficacy and poor prognosis. Conventional two-dimensional (2D) culture models fail to replicate the tumour microenvironment (TME), limiting their translational relevance. Here, we establish a three-dimensional (3D) spheroid model to investigate chemotherapy resistance across different PM subtypes. Compared to 2D cultures, 3D spheroids display enhanced resistance to cisplatin-pemetrexed, with elevated IC₅₀ values, reduced apoptosis, and altered cell cycle profiles. Seahorse metabolic analysis of 3D spheroids demonstrate a suppressed metabolic phenotype, characterised by reduced oxidative phosphorylation (OCR). However, the glycolytic capacity was not upregulated, consistent with the hypoxic and nutrient-limited conditions observed in mesothelioma lesions. In parallel, molecular profiling identifies subtype-specific miRNA signatures that closely align with patient-derived datasets. Proteomic analysis of 3D cultures identifies upregulation of PI3K/AKT and Notch/VEGF signalling, implicating these pathways in treatment resistance. Histological assessment of xenografts further confirms 3D model fidelity in capturing tumour fibrosis, necrosis, and response to therapy. These findings position the 3D spheroid system as a robust and physiologically relevant platform for modelling drug resistance and guiding therapeutic development in PM.

  © 2026. The Author(s).

• Asbestos exposure assessment for ceiling tile removal using glove bags in small indoor facilities. S.H. Hwang, M. Yun, D.Y. Kim, et al. 2025;15(1):23295. PubMed · Publisher · Free full text

  Abstract

  This study aimed to evaluate the safety of small-scale asbestos dismantling and removal work, especially ceiling tile removal using glove bags (GBs), and to investigate the potential for asbestos dispersion in GBs during ceiling material removal to propose safe work practices and related regulations. Asbestos exposure assessment was conducted at five asbestos-containing ceiling tile dismantling sites nationwide. Air sampling was performed during ceiling tile removal at four points per site: near workers' respiratory tract, at the GB fixed boundary, inside the GB, and within the general work area. Phase contrast microscopy was applied to determine asbestos. The results indicated that airborne asbestos concentrations varied by region, with the highest levels detected inside the GB. Elevated concentrations were also observed near workers' respiratory tract. During ceiling tile removal, asbestos concentrations increased as the number of ceiling tiles removed rose from one to three. Proper sealing of asbestos dust to prevent leakage from the GB is essential, and removing ceiling tiles individually rather than in batches effectively reduces asbestos concentrations.

  © 2025. The Author(s).

• Assessment of asbestos exposure in Kyrgyzstan through analysis of raw and processed materials, air samples and human lung tissue. Z. Kurzhunbaeva, R. Vigliaturo, G.P. Servetto, et al. 2025;15(1):25114. PubMed · Publisher · Free full text

  Abstract

  Asbestos still represents a major public health problem on a global scale. In Central Asia chrysotile is still mined and used, claiming that it is safer with respect to amphibole asbestos within certain concentrations. However, the problem of asbestos exposure in Central Asia and its consequences on human health have been poorly investigated. We analysed, for the first time, samples of raw and wrought material coming from one of the two asbestos-cement industries, currently active, located near the city of Bishkek, the capital of Kyrgyzstan, as well as air samples collected on different sites of Bishkek and Kant and lung tissues taken from the general population during clinical autopsies. Air samples have been analyzed using a scanning electron microscopy (SEM) equipped with energy dispersive spectroscopy (EDS). Heavy air asbestos pollution was detected in Kant (30.2 ff/L), while Bishkek had lower levels. Lung tissue analysis in the general population, carried out using both SEM and transmission electron microscopy (TEM) with EDS, revealed the presence of both chrysotile and amphibole asbestos. Such findings underline that, even in countries where the use of asbestos is allowed based on the presumed pureness of chrysotile used and the lower carcinogenic potential of chrysotile compared to amphibole asbestos, the general population could be exposed also to amphibole asbestos.

  © 2025. The Author(s).

• Bayesian analysis of the rate of spontaneous malignant mesothelioma among BAP1 mutant mice in the absence of asbestos exposure. D.M. Nielsen, M. Hsu, M. Zapata, et al. 2025;15(1):169. PubMed · Publisher · Free full text

  Abstract

  Cancers of the mesothelium, such as malignant mesothelioma (MM), historically have been attributed solely to exposure to asbestos. Recent large scale genetic and genomic functional studies now show that approximately 20% of all human mesotheliomas are causally linked to highly penetrant inherited (germline) pathogenic mutations in numerous cancer related genes. The rarity of these mutations in humans makes it difficult to perform statistically conclusive genetic studies to understand their biological effects. This has created a disconnect between functional and epidemiological studies. However, since the molecular pathogenesis of MM in mice accurately recapitulates that of human disease, this disconnect between functional and epidemiological studies can be overcome by using inbred mouse strains that harbor mutation(s) in genes involved in the disease. Most mouse studies have focused on the effect of asbestos exposure, leaving the effects of genetic mutations in the absence of exposure understudied. Here, using existing peer-reviewed studies, we investigate the rate of spontaneous MM among mice with and without germline genetic mutations, in the absence of asbestos exposure. We leveraged these published data to generate a historical control dataset (HCD) to allow us to improve statistical power and account for genetic heterogeneity between studies. Our Bayesian analyses indicate that the odds of spontaneous MM among germline BAP1 mutant mice is substantially larger than that of wildtype mice. These results support the existing biological study findings that mesotheliomas can arise in the presence of pathogenic germline mutations, independently of asbestos exposure.

  © 2024. The Author(s).

• Carbon monoxide and nitric oxide diffusion capacity of formerly exposed asbestos workers with high-resolution computed tomography in a cross-sectional study. J. Krabbe, D.J. Reimers, N. Otte, et al. 2025;15(1):15380. PubMed · Publisher · Free full text

  Abstract

  Asbestos exposure can induce pulmonary fibrosis known as asbestosis, and pleural thickening, as well as various cancers. Although lung diffusion capacity (DL) including nitric oxide (NO) is assumed to be more sensitive than carbon monoxide (CO), its added value in assessment of pneumoconiosis has not been investigated yet. 371 formerly exposed workers visiting the outpatient clinic for assessment including pulmonary function testing with DL and low-dose high resolution computed tomography between 2018 and 2021 were included. Subgroups were formed depending on findings in low-dose high resolution computed tomography classified according to ICOERD. Receiver operating characteristic curve (ROC) analysis revealed some diagnostic accuracy for DLNO (AUC = 0.73; 95% confidence interval 0.64-0.82) and DLCO (AUC = 0.70; 95% confidence interval 0.60-0.79) regarding asbestosis, but not per unit alveolar volume. DLCO and DLNO correlated strongly with a decreasing score of irregular opacities according to ICOERD (ρDLCO = - 0.87, ρDLNO = - 0.85) but DLNO was also susceptible to emphysema. Although tendencies of a more sensitive detection of diffusion capacity impairment were observed, DLNO was not clearly superior to DLCO in assessment of asbestosis. Based on our findings and considering the lack of availability of DLNO in clinical routine, DLNO does not seem to have added value for clinical assessment of formerly asbestos exposed workers. Future studies should further investigate DLNO including healthy controls and confounders such as emphysema and smoking.

  © 2025. The Author(s).

• CC-chemokine ligand 18, CXC motif chemokine 13 and osteopontin as biomarkers of silicosis and asbestosis: a prospective observational study. N. Wu, C. Xue, S. Yu, et al. 2025;15(1):6819. PubMed · Publisher · Free full text

  Abstract

  Silicosis and asbestosis, distinct forms of pneumoconiosis, manifest progressive interstitial fibrosis due to exposure to silica dust or asbestos fibers. This study aimed to identify potential biomarkers for diagnosing silicosis and asbestosis, while also evaluating disease severity and prognosis. We undertook an prospective observational study involving patients with silicosis or asbestosis. The correlation between baseline CC-chemokine ligand 18 (CCL18), CXC motif chemokine 13 (CXCL13), osteopontin (OPN), periostin, and fibulin-3 and clinical variables was analyzed. Diagnostic sensitivity was evaluated using receiver operating characteristic curves, and correlations between baseline biomarker levels and disease severity were analyzed. Multivariable Cox regression assessed the baseline concentrations' strength in predicting all-cause mortality for silicosis and asbestosis. Of 231 silicosis and 163 asbestosis included in the study, 29 silicosis (12.6%) and 28 (17.2%) asbestosis died within the five years follow-up period. Elevated baseline concentrations of CCL18, CXCL13, and OPN were observed in 231 silicosis patients and 163 asbestosis patients compared to 118 HCs. Diagnostic accuracy for silicosis or asbestosis, in order, was CCL18, OPN, and CXCL13. Combining CCL18, OPN, and CXCL13 enhanced diagnostic accuracy. In silicosis patients, these concentrations were significantly associated with lung function values. However, these biomarkers were not the risk factor for all-cause mortality. CCL18, CXCL13, and OPN stand out as promising biomarkers for diagnosing silicosis and asbestosis. Meanwhile, CCL18, CXCL13, and OPN may be used for the evaluation of silicosis conditions.

  © 2025. The Author(s).

• Characterization of talc deposits in ultramafic rocks of Gebel El Maiyit and its economic feasibility. I.A. Salem, S.M. Aly, A. Shebl, et al. 2025;15(1):14361. PubMed · Publisher · Free full text

  Abstract

  A comprehensive, multiscale investigation, integrating remote sensing, mineralogy, whole rock chemistry, Electron Microprobe (EMP), and stable isotopes (oxygen-18O and carbon-13C), was undertaken to assess the feasibility of talc deposits and their host serpentinite at Gebel El-Maiyit in the Eastern Desert of Egypt. Sentinel 2 remote sensing images were applied to discriminate talc from serpentinites followed by geochemical study of serpentinites using RO`/SiO2 ratios, AFM diagram and MgO versus SiO2 relationship indicates a peridotite origin formed at low temperature Alpine type. Our study revealed that talc deposit has a varied mineralogical composition and according to the predominant talc and gangue minerals three main types have been distinguished: 1- pure talc, 2- tremolite talc and 3- chlorite talc. Paragenetically, talc is derived from serpentine minerals, tremolite and chlorite. The latter is formed at about 231 °C. The chemical data of talc deposit reveals that the summation of talc components (SiO2 + MgO + H2O) is 92.68%, while that of impurity oxides (Al2O3 + CaO + Fe2O3 + FeO) is 5.56%. The carbon13C) and oxygen18O) contents of pure magnesite revealed that the pure phase of Gebel El-Maiyit was formed at low temperature (around 100 °C) while magnesite contained in talc carbonate rock was formed at high temperature (140-175 °C). In terms of source fluids, the metamorphic and /or magmatic water was supposed to be the main fluids which are circulated during the hydrothermal alteration. Although S and P are very minor components in all the talc ore types of the considered area and do not affect their industrial use. Copper (Cu) was not detected. Iron (Fe) and manganese (Mn) concentrations are significantly high, necessitating treatment to reduce these elements for the ore to be suitable as an electrical insulator. Arsenic (As) levels are consistently below 5 ppm, indicating the ore's potential use in the cosmetic industry without further processing.

  © 2025. The Author(s).

• Detection of asbestos-based cement rooftops in conflict-affected settings using EnMAP hyperspectral data: a research article. J.E. Shepherd, E. Sagi, G. Zagron, et al. 2025;15(1):24166. PubMed · Publisher · Free full text

  Abstract

  In volatile, conflict-affected regions, rapidly mapping asbestos-cement rooftops is critical to mitigate health risks from airborne fibres. Over a 4-month field campaign (Nov 2023-Apr 2024), we partnered with the Israel Space Agency and Ministry of Environmental Protection to acquire disturbance-free field spectra at multiple Kibbutzim, Moshavim and cities, using an ASD FieldSpec 4 High-Res with both the SoilPro® apparatus and contact probe to build a comprehensive spectral library (Sup Figs. 5-14). Leveraging EnMAP Level 2A hyperspectral imagery (17 May 2024), we applied MNF noise reduction, precise co-registration, and cloud/shadow masking before executing eight supervised classifiers; Linear Spectral Unmixing, Support Vector Machine, Spectral Angle Mapper, Adaptive Coherence Estimator, Mahalanobis Distance, Maximum Likelihood, Spectral Information Divergence, and Matched Filtering, in an iterative filtering cascade. Exhaustive ground-truth surveys across villages and cities achieved an 86% positive match rate despite urban complexity and security-driven coordinate restrictions. This integrative workflow combining rigorous field calibration, multi-algorithm spectral filtering, and exhaustive validation, demonstrates that orbit-based hyperspectral data can reliably map asbestos hazards at scale, guiding timely emergency response and long-term remediation in high-risk settings.

  © 2025. The Author(s).

• Determining factors affecting the accuracy of SEM-EDX data-based quantitative chemical analysis for identifying naturally occurring individual carcinogenic erionite fibers. W.W. Fan, A.F. Gualtieri, A. Hamilton, et al. 2025;15(1):25316. PubMed · Publisher · Free full text

  Abstract

  Erionite is a fibrous zeolite classified as a Group 1 carcinogen and may pose a significant public health hazard when aerosolized into individual respirable-sized fibers. SEM-EDXA has been widely used to identify individual erionite fibers in environmental samples as it combines morphological imaging with elemental analysis. However, the reliability of SEM-EDXA data when applied to the quantitative chemical analysis of individual erionite fibers rather than bulk samples remains uncertain. This study analyzed 325 individual erionite fibers (obtained from a bulk sample with high-purity) across a range of fiber widths and four commonly used sample preparation methods, using two different SEM-EDS systems. SEM-EDXA results were compared with previously acquired EPMA reference data from the bulk sample to assess analytical accuracy. Systematic overestimations of Si and Mg and underestimations of Al, K, and Ca were observed. Framework elements (Si and Al) exhibited relatively stable detection in fibers > 0.5 μm. However, preparation methods-deionized water dispersion and hydrogen peroxide digestion-introduced greater variability, likely due to ion exchange and cation mobilization. Despite the purity of the erionite bulk sample, none of the analyzed individual fibers fully met the established quantitative chemical criteria for erionite identification. These results highlight the need for pre-calibration with erionite standards and the application of correction index to improve SEM-EDX accuracy, and subsequent confirmation of mineralogy using TEM-SAED, when determining whether individual fibers found in airborne samples are erionite.

  © 2025. The Author(s).

• Disentangling the effects of various risk factors and trends in lung cancer mortality. X. Wu, J. Zhang, Y. Yoshida. 2025;15(1):8719. PubMed · Publisher · Free full text

  Abstract

  Lung cancer is a leading cause of mortality in oncological classifications, yet the impact of various risk factors on lung cancer mortality (LCM) in non-smokers remains unclear. This study aims to weigh out the diverse impact of multiple risk factors on LCM rates and identify trends in LCM rates worldwide. We initially employed Random Forest Tree (RFT) and Gradient Boosting Regression (GBR) to identify common primary factors influencing LCM. After eliminating four common primary factors, a comparative analysis between partial and Pearson correlations was conducted to filter out significant factors in the correlations between risk factors and LCM rates across 204 countries from 2005 to 2019. The findings show that excluding the impacts of occupational exposure to arsenic, smoking, residential radon, occupational exposure to silica, occupational exposure to asbestos, high systolic blood pressure, secondhand smoke, child wasting, and alcohol use had a considerably greater impact on LCM than particular matter pollution (PM2.5). Furthermore, a Multiple Joinpoint Regression analysis identified increasing trends of LCM rates in the 142 countries (e.g., China and India); decreasing trends in 38 countries (e.g., Denmark and Norway), and stable trends in 24 countries (e.g., Sudan, Mali, and Australia). This research suggests that in addition to considering the effects of occupational exposure to arsenic, smoking, residential radon, and occupational exposure to silica on LCM rates, occupational exposure to asbestos, high systolic blood pressure, secondhand smoke, child wasting, and alcohol use should be considered in lung cancer prevention strategies, especially in countries with increasing trends of LCM rates.

  © 2025. The Author(s).

• Evaluating therapeutic plasma exchange and protease inhibitors as mechanisms to reduce soluble mesothelin. K.E.R. Smith, J.R. Ayers-Ringler, J.J. Orme, et al. 2025;15(1):13174. PubMed · Publisher · Free full text

  Abstract

  Cell surface mesothelin (MSLN) can be solubilized and released into the systemic circulation. The resulting soluble MSLN (sMSLN) may interfere with therapies targeting surface MSLN. We investigated the effects of sMSLN on anetumab, an antibody-based therapy against MSLN, anetumab ravtansine, an antibody drug conjugate, and mechanisms to decrease sMSLN. Whole blood samples were collected before and after one plasma volume of therapeutic plasma exchange (TPE). sMSLN levels were measured with ELISA assays in matched pre- and post-TPE plasma samples, and anetumab-immunoprecipitated samples. We also used protease inhibitors (PIs) as a mechanism to stabilize surface MSLN, then evaluated the cytotoxic effects of anetumab ravtansine. Our findings indicate that sMSLN sequesters and may impair the efficacy of this anti-MSLN antibody based on results showing that anetumab decreases the concentration of MSLN in plasma (p < 0.05) and reduced cytotoxicity of anetumab ravtansine in the presence of recombinant MSLN in cell lines, a surrogate for sMSLN. TPE consistently reduced sMSLN (p < 0.05) with an average decrease of 43.6% (15.4 ng/mL). Surface MSLN stabilization was inconsistently observed with PIs. Overall, sMSLN could represent a predictive biomarker for MSLN directed therapies. TPE may be more reliable than PIs to reduce sMSLN and ultimately restore sensitivity to these therapies in patients with high sMSLN.

  © 2025. The Author(s).

• Evaluation of the genotoxic and transformation potential induced by asbestos compared to cleavage fragments. S. La Maestra, G.M. Militello, S. Alberti, et al. 2025;15(1):3613. PubMed · Publisher · Free full text

  Abstract

  The World Health Organization has confirmed that asbestos fibres are carcinogenic, claiming that asbestos-related diseases should be eradicated worldwide. Actinolite, amosite, anthophyllite, chrysotile, crocidolite, and tremolite are regulated asbestiform mineral phases. However, in nature, asbestos minerals occur either in a fibrous and asbestiform (original morphology characterized by high length-to-width ratio and provided of high tensile strength and flexibility) or fibrous but not asbestiform appearance. This study used human epithelial cancer cells (A549) and a mouse fibroblast cell line (Balb/c 3T3) to compare the genotoxic and carcinogenic effects of a sample of amphibole asbestos with samples of fibrous not asbestiform named cleavage fragments (CV) obtained by grinding non-asbestiform amphiboles. The results showed that exposure of alveolar lung cells to asbestos and elongated mineral particles, in the habit of cleavage fragments (CF) derived from the grinding of non-asbestiform amphiboles and serpentines, causes cytotoxic effects, oxidative stress and genotoxic damage. Moreover, CF obtained from an actinolite schist induces a transformation effect in the Balb/c 3T3 model. Together, these findings highlight the importance of considering CF as a potential threat to human health since it can cause genotoxic damage by triggering cellular transformation processes that overlap with the mechanisms involved in the carcinogenesis processes of asbestos.

  © 2025. The Author(s).

• Investigating the influence of urban land use on asbestos concentration and identifying the most vulnerable areas in Shiraz, Iran. S. Norzaee, S. Darvishali, M. Farzadkia, et al. 2025;15(1):27591. PubMed · Publisher · Free full text

  Abstract

  This study investigated asbestos fiber concentrations and associated health risks in Shiraz over a period of one year and examined their relationship with various land use factors. Samples were analyzed using phase-contrast microscopy (PCM), and health effects were assessed using the EPA's IRIS method. We examined the relationship between asbestos fiber concentrations and road network density, population, number of bus stations, and green space. The results showed that 10% of the sampling sites in Shiraz had low asbestos fiber concentrations, 20% had medium concentrations, 60% had high concentrations, and 10% had very high concentrations. The mean ELCR for asbestos inhalation was 1.44 × 10-4, indicating a cancer risk for 1.44 out of every 10,000 people. The highest ELCR values were found in the west, near the Shiraz Ring expressway, and in the southeast, near high-traffic areas. Additionally, no positive correlation was found between asbestos concentrations and population, bus stations, or green space, but there was a significant positive correlation with road network density. Motor vehicle traffic is the primary source of asbestos pollution, posing a significant health risk. Traffic control measures and replacing asbestos in brake pads with alternative materials are necessary to reduce pollution in Shiraz.

  © 2025. The Author(s).

• Mesothelioma cell heterogeneity identified by single cell RNA sequencing. L. Wu, Z. Wang, A. Zia, et al. 2025;15(1):8725. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma cell heterogeneity encompasses diverse morphological and molecular characteristics observed within tumors, significantly impacting disease progression, treatment outcomes, and the development of targeted therapies. This heterogeneity has long posed challenges for accurate diagnosis and effective treatment, but understanding its complexities offers the potential for novel diagnostic modalities and therapeutic interventions. This study employed single-cell RNA sequencing (scRNA-seq) to investigate mesothelioma cell heterogeneity from various sources, including cell culture (CC), peritoneal lavage (Lav) from the tumor microenvironment, and circulating tumor cells (CTC) in murine models. Gene set enrichment analysis was used to identify distinct gene signatures for each subpopulation. The results revealed unique characteristics for mesothelioma cells depending on their origin. In the CC group, up-regulated genes were primarily involved in tumor cell cycle control, proliferation, and apoptosis. In the CTC group, up-regulated genes were associated with cancer cell stemness. The Lav group showed up-regulated genes facilitating interactions between tumor cells and the microenvironment, such as epithelial-mesenchymal transition and immune responses mediated by IFN-α and IFN-γ. Some pathways were shared among all tumor cells, suggesting the potential for transitioning between functional states under specific conditions. This may be the first study to explore circulating mesothelioma cell heterogeneity using scRNA-seq. The distinct gene signatures identified in each mesothelioma cell subpopulation likely play critical roles in tumor initiation and progression, offering potential novel targets for therapeutic intervention. These findings could help inform the development of more effective, personalized treatments for mesothelioma, ultimately improving patient outcomes.

  © 2025. The Author(s).

• Numerical simulation of heat dissipation characteristics in PWR high-pressure coolant pipes during cold shutdown. F. Tang, W. Wang, Y. Luo, et al. 2025;15(1):41685. PubMed · Publisher · Free full text

  Abstract

  Under cold shutdown conditions, the heat dissipation performance of the high-pressure coolant pipeline critically impacts pressurized water reactor (PWR) safety by governing residual heat removal efficiency. To quantify key drivers of thermal behavior during stagnant coolant operation, a high-fidelity thermal-hydraulic model is established by using the REALP5 MOD3.2 code. Systematic parametric analyses evaluate radiation effects and insulation-environment interactions through three dimensions. The results show that under stagnant coolant and zero-wind conditions, radiation contributes 90% of total heat transfer in the high-pressure coolant pipeline in the vertical direction, yielding a larger coolant temperature drop (ΔT) of 6.12 K over 86,400 s compared to the no-radiation model. Pipeline heat dissipation exhibits an inverse relationship with insulation cotton thickness but scales positively with material thermal conductivity. Within 800,000 s, when the insulation cotton thickness(δ) is reduced from 15 to 5 mm, the coolant temperature drops by nearly 18 K. This means that for every 10 mm reduction in the thickness of insulation cotton(δ), the heat dissipation efficiency increases by 40%. The coolant temperature drop (ΔT) of the pipe with asbestos insulation (thermal conductivity λ = 0.046W /(m·K)) reaches 43.98 K, which is 53.1% higher than that of the pipe with ultra-fine glass fiber cotton insulation(ΔT = 28.72 K) (thermal conductivity λ = 0.022W /(m·K)). Ambient temperature and airflow velocity exhibit inverse and positive correlations with coolant temperature drop (ΔT), the coolant temperature is reduced by 12.51 K more than the ambient temperature of 10℃ and 30℃. For every 1℃ decrease in ambient temperature, the temperature drop increases by 0.625 K. When the airflow velocity is 0.5 m/s compared to 0.1 m/s, the coolant temperature drops by 1.65 K more. This paper pioneers a high-fidelity thermo-hydraulic model of the main coolant pipeline of PWR under the stagnation condition after cold shutdown, which advances the theoretical framework of heat dissipation such as natural convection in the external environment and provides a quantitative safety margin for the removal of waste heat from the core. Further, it guides the design of insulation cotton material and the thickness of the high-pressure coolant pipeline and delivers predictive tools for the optimization of the heat dissipation strategy after cold shutdown.

  © 2025. The Author(s).

• Pleural mesothelioma incidence and use of systemic treatment decreased during the COVID-19 pandemic in The Netherlands. I. Smesseim, L.H. Douma, J.A. Burgers, et al. 2025;15(1):25677. PubMed · Publisher · Free full text

  Abstract

  Pleural mesothelioma (PM) is a lethal cancer often linked to asbestos exposure. The COVID-19 pandemic caused a global health crisis, raising concerns about its impact on cancer diagnoses and treatments. In response to the immense pressures on the healthcare system caused by the COVID-19 pandemic, many countries advised prioritizing essential healthcare services while postponing or suspending care considered non-emergent to prevent overburdening healthcare systems. This study assesses the impact of COVID-19 on the incidence, treatment, and overall survival of PM patients in the Netherlands between 2018 and 2022. Data were collected from the Netherlands Cancer Registry for 2,629 PM patients. Incidence, treatment patterns, and survival rates were analyzed using statistical methods, including Kruskal-Wallis and log-rank tests. PM incidence dropped 13.2% in 2020 during the pandemic, with a 58.8% increase in patients receiving best supportive care and a decline in chemotherapy use (from 39.4% to 32.0%). In 2021, diagnoses rebounded (+ 15.2%), and immunotherapy use rose following its approval. However, no significant difference in overall survival was found between 2018 and 2022. COVID-19 led to a temporary decline in PM diagnoses and systemic treatments in 2020, followed by recovery in 2021. Despite these changes, overall survival rates remained stable.

  © 2025. The Author(s).

• Postmarketing safety evaluation of pemetrexed using FAERS and JADER databases. L. Lv, X. Wu, Y. Ren, et al. 2025;15(1):18738. PubMed · Publisher · Free full text

  Abstract

  Pemetrexed, a multi-target antifolate chemotherapeutic widely used in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), is associated with various adverse drug events (ADEs), some of which may be underrecognized in clinical trials. This study conducted a comprehensive pharmacovigilance analysis using two major spontaneous reporting systems-FAERS (2004Q1-2024Q3) and JADER (2007Q1-2024Q3)-to evaluate pemetrexed-related ADEs. Disproportionality analysis was performed using four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). Time-to-onset (TTO) patterns were assessed using Weibull distribution modeling. A total of 12,026 and 4,522 pemetrexed-related ADE reports were retrieved from FAERS and JADER, respectively. The most frequently reported ADEs included hematologic toxicities (anemia, neutropenia, thrombocytopenia), gastrointestinal disorders (nausea, vomiting, diarrhea), and renal impairment. Strong safety signals were consistently identified for these events. Notably, novel ADE signals such as hepatobiliary injury, endocrine dysfunction, and thromboembolic events were observed in both databases. Subgroup analyses revealed sex- and age-specific ADE patterns, with younger patients and males showing distinct toxicity profiles. Sensitivity analysis excluding combination therapies confirmed the robustness of primary signals. TTO analysis revealed that most ADEs occurred within the first two months after pemetrexed initiation, with a median TTO of 27 days and a predominance of early failure patterns (Weibull β < 1), highlighting the importance of close monitoring during early treatment. Rare but severe ADEs, including myocarditis, sepsis, cholestasis, and pseudocellulitis, were identified, several of which are not currently listed in official drug labeling. This study provides a comprehensive safety assessment of pemetrexed, confirming known toxicities and identifying new safety signals. Continuous pharmacovigilance is essential to optimize its clinical use and improve patient safety.

  © 2025. The Author(s).

• The impact of asbestos cement pollution in irrigation water on physiological and germination characteristics of Trifolium pratense, Medicago sativa, and Solanum lycopersicum seeds. G.Z. Macher, A. Torma, D. Beke. 2025;15(1):16265. PubMed · Publisher · Free full text

  Abstract

  This paper investigates how plants respond to stress caused by asbestos cement products in irrigation water. It presents a thorough evaluation of the exposure and risk factors for plants, water, and soil when exposed to these materials. The experimental results provide empirical evidence of plant stress responses based on physiological and germination parameters. The research is motivated by concerns about environmental contamination from asbestos cement in irrigation water, which can be toxic to plants and lead to soil pollution, negatively impacting vegetation and soil quality. When exposed to asbestos in water, plants experience toxic stress that can inhibit photosynthesis, nutrient uptake, and germination. Asbestos can also adversely affect cell division and metabolism, risking plant growth, reproduction, and overall health, as well as making them more susceptible to disease and pests under environmental stress. The paper examines the impact on germination and physiological parameters of Trifolium pratense, Medicago sativa, and Solanum lycopersicum, particularly how they were affected by pre-established concentrations of irrigation water mixed with asbestos cement during a controlled germination experiment. The research methodology was developed in the absence of established global practices, standards, and methods, creating an opportunity for further methodological advancement. The findings could serve as a situational analysis for professionals in environmental plant protection and analytical fields.

  © 2025. The Author(s).

• The presence of pleural effusion is an independent prognostic factor in patients with malignant pleural mesothelioma. H. Wang, R. Yang, D. Liu, et al. 2025;15(1):392. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare form of thoracic malignancy with a poor prognosis. Pleural effusion (PE) occurs in the majority of patients with MPM; however, its impact on MPM outcomes remains controversial. We searched for eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database, and clinicopathological information and outcomes were collected. Cox proportional hazard regression analyses were utilized to evaluate the association of PE and other factors with overall survival (OS) and cancer-specific survival (CSS) in patients with MPM. A total of 4185 patients were extracted from the SEER database from 2000 to 2021. The median age of the cohort was 73 years, with a predominance of male patients and epithelioid MPM as the main histological subtype. Univariate Cox regression revealed associations between PE, age, sex, marital status, histology, stage, and treatment with both OS and CSS. Besides, multivariate analyses indicated that PE was independently associated with poorer OS and CSS in patients with MPM, regardless of age, sex, histology, stage, and treatment. Subgroup analyses suggested that PE has a remarkable impact on patients undergoing surgery. PE might serve as an independent prognostic factor in patients with MPM, especially in surgery recipients. Consequently, the development of pleural effusion in these patients should receive increased attention. Future studies are needed to validate these findings, particularly concerning the effect of PE in other clinical settings, such as immunotherapy.

  © 2024. The Author(s).

• Water quality index assessment of toxicity in direct and roofs runoff rainwater in industrial and remote areas of Eastern Nigeria. E.S. Nicholas, C.C. Okudo, P.O. Ukoha. 2025;15(1):36068. PubMed · Publisher · Free full text

  Abstract

  Rainwater may be contaminated by leaching from roofing materials and industrial activities, rendering it unsuitable for potable use. In this study, the physico-chemical, microbiological and heavy metals parameters were investigated in harvested rainwater quality from various roof types in the urban and rural areas of Enugu State, Nigeria, between April-July, 2018. Metal compositions of asbestos, corrugated iron, Cameroun zinc, Stone-coated tiles and long span aluminium were also assessed. Thirty-six (36) harvested rainwater samples were forwarded to the laboratory after determination of pH, temperature, TDS and electrical conductivity at the point of collection. Titration, Electrometric and spectrophotometric methods of analysis were used. Results were compared with the WHO, USEPA and NSDWQ water quality standards. The weighted arithmetic method was obtained for the assessment of the water quality index. Results for heavy metals (mg/L) gave values which ranged from 0.00 to 0.20, metal concentrations (mg/kg) of digested roofs gave 0.00-63.78, and other parameters gave 6.50-7.60 for pH and Escherichia coli (no detection). The obtained results met the national and global standards except for a few samples. The WQI gave values which ranged from 3.00 to 78.46 and were rated excellent to very poor water quality. It was concluded that harvested rainwater should be treated before drinking.

  © 2025. The Author(s).

• A multi-disciplinary approach for uranium exploration using remote sensing and airborne gamma-ray spectrometry data in the Gebel Duwi area, Central Eastern Desert, Egypt. M.A.E. Hegab. 2024;14(1):19739. PubMed · Publisher · Free full text

  Abstract

  Uranium exploration plays a pivotal role in meeting global energy demands and advancing nuclear technology. This study presents a comprehensive approach to uranium exploration in the Gebel Duwi area of the Central Eastern Desert of Egypt, utilizing remote sensing and airborne gamma-ray spectrometric data. Multispectral remote sensing techniques, including Principal Component Analysis (PCA), Minimum Noise Fraction (MNF), and Band Ratioing (BR), are employed to identify lithological units and hydrothermal alteration zones associated with uranium deposition, such as iron oxides, argillic, propylitic, and phyllic alterations. Additionally, airborne gamma-ray spectrometry data provide insights into the spatial distribution of radioelements, including uranium (eU), thorium (eTh), and potassium (K), as well as radioelement ratios (eU/eTh, eU/K, and eTh/K). The uranium migration index map (eU-(eTh/3.5)) and the F-parameter map (K*(eU/eTh)) have been generated to investigate the movement of uranium within various geological zones and characterize anomalous uranium concentrations. Statistical analyses, including mean (X), standard deviation (S), and coefficient of variability (C.V.), are conducted to identify uranium-rich zones. The integration of these datasets enables the generation of a uranium potential map highlighting areas of elevated concentrations indicative of uranium mineralization. Field observations and mineralogical analyses of collected samples validate our findings, confirming the presence of minerals associated with uranium mineralization in mapped high-potential areas. The significance of minerals like Fe-Chlorite, Fe-Mg-Chlorite, ferrihydrite, goethite, calcite, muscovite, dolomite, actinolite, vermiculite, and gypsum in indicating potential uranium mineralization processes underscores the importance of our results.

  © 2024. The Author(s).

• An integrated multicriteria decision making framework for the selection of waste cement dust filled automotive brake friction composites. T. Singh. 2024;14(1):6817. PubMed · Publisher · Free full text

  Abstract

  This work discusses selecting optimal brake friction composite alternatives based on an integrated MABAC (multi-attributive border approximation area comparison) and AHP (analytic hierarchy process) approach. Therefore, non-asbestos automotive brake friction composites containing varying proportions of cement dust (50 to 0 wt%) and barium sulfate (0 to 50 wt%) were developed and tribo-evaluated on a Krauss machine following European regulations. Composite made up of 30 wt% cement dust and 20 wt% barium sulfate had the highest friction coefficient (0.361), lowest variability coefficient (0.598), and maximum recovery (123.27%). The composite with the least fading (15.36%) included 50 wt% cement dust, whereas the composite with the lowest wear (9.10 g) and the least frictional fluctuations (0.271) contained 50 wt% barium sulfate. By AHP, the friction coefficient (0.1989), fade (0.1696), recovery (0.1551), and wear (0.1412) were selected as the essential criteria in the performance assessment. Based on the MABAC ranking evaluation, the composite comprises 20 wt% barium sulfate and 30 wt% cement dust has the best tribological profile, whereas the composites of solely cement dust or barium sulfate have the poorest tribological profile. The acquired ranking results were confirmed using other decision-making models and subjected to sensitivity analysis to demonstrate their robustness.

  © 2024. The Author(s).

• Antigen targeting and anti-tumor activity of a novel anti-CD146 212Pb internalizing alpha-radioimmunoconjugate against malignant peritoneal mesothelioma. K. Lindland, M.M. Malenge, R.G. Li, et al. 2024;14(1):25941. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma, a highly aggressive cancer that primarily affects the serosal membranes, has limited therapeutic options, particularly for cavitary tumors, such as peritoneal and pleural malignant mesothelioma. Intracavitary administration of a radioimmunoconjugate to locally target mesothelioma cancer cells has been proposed as a treatment. CD146, upregulated in mesothelioma but not in healthy tissues, is a promising therapeutic target. This study characterized CD146 expression and binding/internalization kinetics of the CD146-targeting antibody OI-3 coupled with 212Pb (212Pb-TCMC-OI-3) in human mesothelioma cells. Flow cytometry showed that both chimeric (chOI-3) and murine (mOI-3) antibodies rapidly bound and internalized within 1-6 h in MSTO-211H cells. 212Pb-TCMC-chOI-3 exhibited 3.1- to 13.7-fold and 3.1- to 8.5-fold increased internalized 212Pb and 212Bi atoms per cell at 2 and 24 h, respectively, compared to isotype control, underscoring enhanced internalization efficiency. Intraperitoneal administration of 212Pb-TCMC-mOI-3 to mice with intraperitoneal MSTO-211H xenografts improved median survival by a ratio of 1.3 compared to non-binding 212Pb-TCMC-mIgG1. The ability of 212Pb-TCMC-mOI-3 to target and inhibit the growth of intraperitoneal mesothelioma xenografts supports targeted radionuclide therapy's efficacy for metastatic peritoneal mesothelioma. This study highlights the potential of localized CD146-targeted radioimmunotherapy for malignant mesothelioma, offering a new avenue for improving patient outcomes.

  © 2024. The Author(s).

• CDK12 is a potential biomarker for diagnosis, prognosis and immunomodulation in pan-cancer. K.Q. Lu, Z.L. Li, Q. Zhang, et al. 2024;14(1):6574. PubMed · Publisher · Free full text

  Abstract

  Cell cycle-dependent protein kinase 12 (CDK12) plays a key role in a variety of carcinogenesis processes and represents a promising therapeutic target for cancer treatment. However, to date, there have been no systematic studies addressing its diagnostic, prognostic and immunological value across cancers. Here, we found that CDK12 was significantly upregulated in various types of cancers, and it expression increased with progression in ten cancer types, including breast cancer, cholangiocarcinoma and colon adenocarcinoma. Moreover, the ROC curves indicated that CDK12 showed diagnostic value in eight cancer types. High CDK12 expression was associated with poor prognosis in eight types of cancer, including low-grade glioma, mesothelioma, melanoma and pancreatic cancer. Furthermore, we conducted immunoassays to explore the exact mechanisms underlying CDK12-induced carcinogenesis, which revealed that increased expression of CDK12 allowed tumours to evade immune surveillance and upregulate immune checkpoint genes. Additionally, mutational studies have shown that amplification and missense mutations are the predominant mutational events affecting CDK12 across cancers. These findings establish CDK12 as a significant biological indicator of cancer diagnosis, prognosis, and immunotherapeutic targeting. Early surveillance and employment of CDK12 inhibitors, along with concomitant immunotherapy interventions, may enhance the clinical outcomes of cancer patients.

  © 2024. The Author(s).

• Characterizing soluble immune checkpoint molecules and TGF-β1,2,3 in pleural effusion of malignant pleural mesothelioma. R. Okita, T. Senoo, Y. Mimura-Kimura, et al. 2024;14(1):15947. PubMed · Publisher · Free full text

  Abstract

  The clinical impact of soluble molecules in pleural effusion (PE) is unclear in patients with malignant pleural mesothelioma (MPM). In this single-center, retrospective, observational study, we assessed soluble forms of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and PD-1 ligand 1 (PD-L1) using enzyme-linked immunosorbent assays; three TGF-β isoforms were measured via multiplex assay in PE of patients with fibrinous pleuritis (FP) or MPM, to assess relationships between the levels of six molecules, clinicopathological characteristics, and efficacy of immune checkpoint inhibitors. Soluble forms of CTLA-4, PD-L1, PD-1, TGF-β1, TGF-β2, and TGF-β3 were variably produced in PE of FP (n = 34) and MPM (n = 79); we found significant relationships between the six molecules and clinicopathological features. Although none of the three soluble immune checkpoint molecules showed diagnostic or prognostic effects in patients with MPM, TGF-β2 level in PE is a useful differential diagnostic marker between FP and MPM. Both TGF-β1 and TGF-β3 levels are promising prognostic markers for MPM. Moreover, we found that higher baseline levels of PD-1 soluble forms predicted the response to anti-PD1 monotherapy. Our findings identify novel diagnostic, prognostic, and predictive biomarkers for anti-PD1 therapy in patients with MPM.

  © 2024. The Author(s).

• Chemotherapy increases CDA expression and sensitizes malignant pleural mesothelioma cells to capecitabine treatment. D. Karatkevich, T. Losmanova, P. Zens, et al. 2024;14(1):18206. PubMed · Publisher · Free full text

  Abstract

  The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.

  © 2024. The Author(s).

• Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma. C.S. Cleeland, K.N. Keating, B. Cuffel, et al. 2024;14(1):14839. PubMed · Publisher · Free full text

  Abstract

  We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79-0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

  © 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

• Magnesium and silicon recovery from chrysotile asbestos waste of the deposit Zhitikara, Kazakhstan. R.A. Shayakhmetova, A.A. Mukhametzhanova, D.N. Akbayeva, et al. 2024;14(1):31866. PubMed · Publisher · Free full text

  Abstract

  Waste generated during asbestos manufacturing contains substantial quantities of iron, nickel, magnesium, and silicon. The existing techniques for processing chrysotile-asbestos waste (CAW) cannot fully recover these elements. Therefore this paper presents a hydrometallurgical method for processing the CAW of the Zhitikara deposit in the Kostanay region of Kazakhstan. Batch reactors are used in both laboratory and pilot experiments, and initial trials are conducted in a recently constructed industrial Ti reactor at the Kostanay Minerals JSC plant in the Kostanay region of Zhitikara. The primary benefits of the industrial reactor include operation without excessively grinding the feedstock and creation of a pulp with enhanced filtration properties. A moderate agitation speed (10 rpm) helps ensure a consistent pulp density and prevent the production of silica gel. Optimal leaching conditions are determined as a fraction size of CAW between - 1.25 and 0.25 mm, hydrochloric acid concentration of 18 wt%, temperature of ~ 85-90 °C, pressure of 1 atmosphere, and duration of 2 h. An investigation of the process kinetics reveals that diffusion is the rate-controlling step. Further, the activation energies are determined to be 54.4 kJ.mol- 1, and the leaching rates of Mg, Fe, and Ni under these conditions are 96.0, 87.8, and 81.3%, respectively. Washing and recycling water enhances helps to increase the recovery of magnesium chloride. Implementing pilot-scale hydrometallurgical processing of CAW can effectively address environmental issues that pose a threat to human health and provide commercial advantages.

  © 2024. The Author(s).

• Pollution of the environment and building interiors during asbestos removal as a result of lack of negative pressure in the working areas. A. Obmiński. 2024;14(1):21185. PubMed · Publisher · Free full text

  Abstract

  The paper presents examples of the consequences of the lack of negative pressure in the work zone during asbestos removal. The asbestos fibre concentrations generated in those work zones were relatively low. This was due to the leakage in barriers restricting the work zone. Therefore the asbestos content in the outside air, near the renovated rooms was increasing. In the cases discussed, these works resulted in short-term pollution of the building's outdoor air to a depth of up to 15 m. Such contamination can cover the entire interior of the building. This may lead to long-term retention of asbestos fibre in the facility, despite the completion of asbestos removal. For example, non-friable asbestos-cement sheets removal in those work conditions increased indoor air by contamination up to 3000 f/m3 (outside the work zone). In the case of removing friable asbestos inside the building type "LIPSK", indoor air contamination locally was up 21,000-51,000 f/m3, and outside the work zone to 18,000-28,900 f/m3. These values are above the average concentration of asbestos fibres in the same type of buildings (< 300-400 f/m3) in regular use.

  © 2024. The Author(s).

• Risk assessment and source analysis of heavy metals in soil around an asbestos mine in an arid plateau region, China. X. Li, D. Ding, W. Xie, et al. 2024;14(1):7552. PubMed · Publisher · Free full text

  Abstract

  Asbestos is widely used in construction, manufacturing, and other common industrial fields. Human activities such as mining, processing, and transportation can release heavy metals from asbestos into the surrounding soil environment, posing a health hazard to the mining area's environment and its surrounding residents. The purpose of the present study was to determine the extent of ecological and human health damage caused by asbestos pollution, as well as the primary contributors to the contamination, by examining a large asbestos mine and the surrounding soil in China. The level of heavy metal pollution in soil and sources were analyzed using methods such as the geo-accumulation index (Igeo), potential ecological risk index (RI), and positive matrix factorization (PMF) model. A Monte Carlo simulation-based health risk model was employed to assess the health risks of heavy metals in the study area's soil to human beings. The results showed that the concentrations of As, Pb, Cr, Cu, and Ni in the soil were 1.74, 0.13, 13.31, 0.33, and 33.37 times higher than the local soil background values, respectively. The Igeo assessment indicated significant accumulation effects for Ni, Cr, and As. The RI evaluation revealed extremely high comprehensive ecological risks (RI ≥ 444) in the vicinity of the waste residue heap and beneficiation area, with Ni exhibiting strong individual potential ecological risk (Eir ≥ 320). The soil health risk assessment demonstrated that As and Cr posed carcinogenic risks to adults, with mean carcinogenic indices (CR) of 1.56E - 05 and 4.14E - 06, respectively. As, Cr, and Cd posed carcinogenic risks to children, with mean CRs of 1.08E - 04, 1.61E - 05, and 2.68E - 06, respectively. Cr also posed certain non-carcinogenic risks to both adults and children. The PMF model identified asbestos contamination as the primary source of heavy metals in the soil surrounding the asbestos mining area, contributing to 79.0%. According to this study, it is recommended that management exercise oversight and regulation over the concentrations of Ni, Cr, Cd, and As in the soil adjacent to asbestos mines, establish a designated control zone to restrict population activities, and locate residential zones at a safe distance from the asbestos mine production zone.

  © 2024. The Author(s).

• The lncRNAs Gas5, MALAT1 and SNHG8 as diagnostic biomarkers for epithelial malignant pleural mesothelioma in Egyptian patients. D.M. Elkahwagy, C.J. Kiriacos, M.E. Sobeih, et al. 2024;14(1):4823. PubMed · Publisher · Free full text

  Abstract

  Long noncoding RNAs have been shown to be involved in a myriad of physiological and pathological pathways. To date, malignant pleural mesothelioma (MPM) is considered an extremely aggressive cancer. One reason for this is the late diagnosis of the disease, which can occur within 30-40 years of asbestos exposure. There is an immense need for the development of new, sensitive, inexpensive and easy methods for the early detection of this disease other than invasive methods such as biopsy. The aim of this study was to determine the expression of circulating lncRNAs in mesothelioma patient plasma to identify potential biomarkers. Ten previously identified lncRNAs that were shown to be aberrantly expressed in mesothelioma tissues were selected as candidates for subsequent validation. The expression of the ten selected candidate lncRNAs was verified via quantitative PCR (qPCR) in human plasma samples from mesothelioma patients versus healthy controls. The expression levels of circulating GAS5, SNHG8 and MALAT1 were significantly greater in plasma samples from patients than in those from controls. The ROC analysis of both MALAT1 and SNHG8 revealed 88.89% sensitivity and 66.67% specificity. The sensitivity of these markers was greater than that of GAS5 (sensitivity 72.22% and specificity 66.67%). The regression model for GAS5 was statistically significant, while that for SNHG8 and MALAT1 was not significant due to the small sample size. The area under the curve (AUC) of the three ROC curves was acceptable and significant: 0.7519 for GAS5, 0.7352 for SNHG8 and 0.7185 for MALAT1. This finding confirmed their ability to be used as markers. The three lncRNAs were not affected by age, sex or smoking status. The three lncRNAs showed great potential as independent predictive diagnostic biomarkers. Although the prediction model for MALAT1 did not significantly differ, MALAT1 was significantly expressed in patients more than in controls (p = 0.0266), and the recorded sensitivity and specificity were greater than those of GAS5.

  © 2024. The Author(s).

• Transcriptomic analysis-guided assessment of precision-cut tumor slices (PCTS) as an ex-vivo tool in cancer research. S. Trivedi, C. Tilsed, M. Liousia, et al. 2024;14(1):11006. PubMed · Publisher · Free full text

  Abstract

  With cancer immunotherapy and precision medicine dynamically evolving, there is greater need for pre-clinical models that can better replicate the intact tumor and its complex tumor microenvironment (TME). Precision-cut tumor slices (PCTS) have recently emerged as an ex vivo human tumor model, offering the opportunity to study individual patient responses to targeted therapies, including immunotherapies. However, little is known about the physiologic status of PCTS and how culture conditions alter gene expression. In this study, we generated PCTS from head and neck cancers (HNC) and mesothelioma tumors (Meso) and undertook transcriptomic analyses to understand the changes that occur in the timeframe between PCTS generation and up to 72 h (hrs) in culture. Our findings showed major changes occurring during the first 24 h culture period of PCTS, involving genes related to wound healing, extracellular matrix, hypoxia, and IFNγ-dependent pathways in both tumor types, as well as tumor-specific changes. Collectively, our data provides an insight into PCTS physiology, which should be taken into consideration when designing PCTS studies, especially in the context of immunology and immunotherapy.

  © 2024. The Author(s).

• A novel pH sensitive theranostic PLGA nanoparticle for boron neutron capture therapy in mesothelioma treatment. J. Sforzi, A. Lanfranco, R. Stefania, et al. 2023;13(1):620. PubMed · Publisher · Free full text

  Abstract

  This study aims to develop poly lactic-co-glycolic acid (PLGA) nanoparticles with an innovative imaging-guided approach based on Boron Neutron Capture Therapy for the treatment of mesothelioma. The herein-reported results demonstrate that PLGA nanoparticles incorporating oligo-histidine chains and the dual Gd/B theranostic agent AT101 can successfully be exploited to deliver a therapeutic dose of boron to mesothelioma cells, significantly higher than in healthy mesothelial cells as assessed by ICP-MS and MRI. The selective release is pH responsive taking advantage of the slightly acidic pH of the tumour extracellular environment and triggered by the protonation of imidazole groups of histidine. After irradiation with thermal neutrons, tumoral and healthy cells survival and clonogenic ability were evaluated. Obtained results appear very promising, providing patients affected by this rare disease with an improved therapeutic option, exploiting PLGA nanoparticles.

  © 2023. The Author(s).

• A risk-based soft sensor for failure rate monitoring in water distribution network via adaptive neuro-fuzzy interference systems. M. Gheibi, R. Moezzi, H. Taghavian, et al. 2023;13(1):12200. PubMed · Publisher · Free full text

  Abstract

  Water Distribution Networks (WDNs) are considered one of the most important water infrastructures, and their study is of great importance. In the meantime, it seems necessary to investigate the factors involved in the failure of the urban water distribution network to optimally manage water resources and the environment. This study investigated the impact of influential factors on the failure rate of the water distribution network in Birjand, Iran. The outcomes can be considered a case study, with the possibility of extending to any similar city worldwide. The soft sensor based on the Adaptive Neuro-Fuzzy Inference System (ANFIS) was implemented to predict the failure rate based on effective features. Finally, the WDN was assessed using the Failure Modes and Effects Analysis (FMEA) technique. The results showed that pipe diameter, pipe material, and water pressure are the most influential factors. Besides, polyethylene pipes have failure rates four times higher than asbestos-cement pipes. Moreover, the failure rate is directly proportional to water pressure but inversely related to the pipe diameter. Finally, the FMEA analysis based on the knowledge management technique demonstrated that pressure management in WDNs is the main policy for risk reduction of leakage and failure.

  © 2023. The Author(s).

• Asbestos exposure as an additional risk factor for small duct intrahepatic cholangiocarcinoma: a pilot study. F. Vasuri, M. Deserti, A.G. Corradini, et al. 2023;13(1):2580. PubMed · Publisher · Free full text

  Abstract

  Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy, recently classified in small duct and large duct morphological subtypes. Growing evidence suggests asbestos as a putative risk factor for iCCA, albeit no correlation between asbestos and iCCA morphology has been investigated so far. The aim of the present study was to assess the relationship between asbestos exposure and iCCA morphological subtype. Forty patients with surgically removed iCCA were prospectively enrolled: asbestos exposure was assessed according to the Italian National Mesothelioma Register questionnaire. From the surgical iCCA specimens the main histopathological variables were collected, including the small duct (sd-iCCA, 32 patients) and large duct subtypes (ld-iCCA, 8 patients). Five sd-iCCA cases had a definite/probable occupational exposure to asbestos, while no cases of ld-iCCA were classified as being occupationally exposed (definite/probable). Other kind of asbestos exposure (i.e. possible occupational, familial, environmental) were recorded in 16 sd-iCCA and 3 ld-iCCA. Cases with unlikely exposure to asbestos were 11 sd-iCCA (35.5%) and 5 ld-iCCA (62.5%). In conclusion, these findings seem to indicate that sd-iCCA might be more frequently associated to asbestos exposure rather than ld-iCCA, suggesting that asbestos fibres might represent a parenchymal, rather than a ductal risk factor for iCCA. This pilot study must be confirmed by further case-control studies or large independent cohorts.

  © 2023. The Author(s).

• Asbestos-related cancer in naval personnel: findings from participants in the British nuclear tests 1952-1967. R.T. Gun, G.M. Kendall. 2023;13(1):18842. PubMed · Publisher · Free full text

  Abstract

  Asbestos-containing materials (ACM) were present in British and Australian naval vessels throughout the twentieth century. The aim of this study was to identify and quantify the incidence of cancer in naval personnel from onboard asbestos exposure. Subjects were four cohorts of subjects who had served in the armed forces of the United Kingdom and Australia in the 1950s and 1960s. All cohorts had previously been studied, three of them in relation to radiation exposures from British nuclear testing. Comparisons of SIRs between services were made to identify cancers attributable to asbestos exposure. Excess mesotheliomas were found in naval personnel in all cohorts. In all but one cohort the lung cancer incidence was highest in navy personnel. Comparison of other smoking-related conditions indicated that the excess in navy personnel was not smoking-related. The relatively high SIRs for mesothelioma and the occurrence of deaths from asbestosis were indicative of high levels of asbestos exposure, with an expectation of cases of asbestos-related lung cancer. The findings are consistent with the occurrence of significant excesses of mesotheliomas. In addition, notwithstanding some inconsistencies in the results between the cohorts, we estimated that approximately 27% of lung cancers in Australian seamen and 12% in British seamen were related to onboard asbestos exposure.

  © 2023. The Author(s).

• Cisplatin exhibits superiority over MMC as a perfusion agent in a peritoneal mesothelioma patient specific organoid HIPEC platform. S.D. Forsythe, R.A. Erali, N. Edenhoffer, et al. 2023;13(1):11640. PubMed · Publisher · Free full text

  Abstract

  Peritoneal mesothelioma (PM) is a rare malignancy with poor prognosis, representing about 10-15% of all mesothelioma cases. Herein we apply PM patient-derived tumor organoids (PTOs) in elucidating personalized HIPEC responses to bypass rarity of disease in generating preclinical data. Specimens were obtained from PM patients undergoing cytoreductive surgery with HIPEC. PTOs were fabricated with tumor cells suspended in ECM-hydrogel and treated with HIPEC regimen parameters. Viability and characterization analyses were performed post-treatment. Treatment efficacy was defined as ≥ 50% viability reduction and p < 0.05 compared to controls. From October 2020 to November 2022, 17 tumors from 7 patients were biofabricated into organoids, with 16/17 (94.1%) sites undergoing comparative 37° and 42° treatments with cisplatin and mitomycin C (MMC). Hyperthermic cisplatin and MMC enhanced cytotoxicity which reduced treatment viability by 25% and 22%, respectively, compared to normothermia. Heated cisplatin displayed the greatest cytotoxicity, with efficacy in 12/16 (75%) tumors and an average viability of 38% (5-68%). Heated MMC demonstrated efficacy in 7/16 (43.8%) tumors with an average treatment viability of 51% (17-92.3%). PTOs fabricated from distinct anatomic sites exhibited site-specific variability in treatment responses. PM PTOs exhibit patient and anatomic location treatment responses suggestive of underlying disease clonality. In PM organoids cisplatin is superior to MMC in HIPEC.

  © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

• Comparison of the effects of use, protection, improper renovation and removal of asbestos products on the example of typical old office buildings in Poland. A. Obmiński. 2023;13(1):13577. PubMed · Publisher · Free full text

  Abstract

  The study focused on old, German building types "LIPSK" and "BERLIN" used in Poland, since the 1960s in Eastern Europe. The different operations on buildings were analysed: protection and maintenance of asbestos products, asbestos removal and inadvertent damage to asbestos as a result of building renovation. Measurements of respirable (countable) asbestos fibres in the air were carried out using the PCOM + PLM method and SEM-EDS. In the case of the accidental destruction of products, initial contamination was ≈7000 f/m3. After 16 weeks from the end of the activity and 20 days of extreme ventilation, contamination decreased to about 500 f/m3. At the same time, in similar rooms, without extreme ventilation, the pollution was above 4000 f/m3. The average increase in pollution in a dozen or so similar buildings, after asbestos removal in places beyond the work zones, ranged from ≈ 1700-2700 f/m3 and lasted for one or two years. These buildings, used without ACM destruction or after product impregnation, have maintained low asbestos contamination < 300 f/m3 for more than 10-20 years. So, due to the easy release of asbestos that occurs with any ACM removal and the increased risk of occupant exposure, these works are often inappropriate for the buildings in question.

  © 2023. Springer Nature Limited.

• Development of a prognostic nomogram for patients with malignant mesothelioma with bone metastasis. A. Yang, B. Tang, X. Liu, et al. 2023;13(1):10789. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is a rare aggressive tumor, and bone metastasis often occurs in later stages of this disease. This study aimed to establish a nomogram to predict the prognosis of bone metastasis of patients with MM. Data from the Surveillance, Epidemiology, and End Results database were screened and retrieved. This study included 311 patients with MM with bone metastases. Prognostic factors were analyzed using the Kaplan-Meier method and Cox proportional hazards model. A nomogram for overall survival (OS) was established and evaluated using statistically significant prognostic factors, and cancer-specific survival (CSS) analysis was performed to investigate its prognostic factors. In addition, the metastasis patterns of patients with MM were investigated, and the effects of different sites of metastasis on survival were compared using the Kaplan-Meier method. Age, sex, histological type, and chemotherapy were identified as the independent risk factors for OS. The 1-, 2-, and 3-year areas under the curve of the nomogram were 0.792, 0.774, and 0.928, and 0.742, 0.733, and 0.733 in the training and validation sets, respectively. Compared to OS, histological type, radiotherapy, and chemotherapy were independent risk factors for CSS. Different metastatic sites in MM have significantly different effects on prognosis.

  © 2023. The Author(s).

• Epigenetic investigation into circulating microRNA 197-3p in sera from patients affected by malignant pleural mesothelioma and workers ex-exposed to asbestos. G. Di Mauro, F. Frontini, E. Torreggiani, et al. 2023;13(1):6501. PubMed · Publisher · Free full text

  Abstract

  The epigenetic role of microRNAs is established at both physiological and pathological levels. Dysregulated miRNAs and their targets appear to be a promising approach for innovative anticancer therapies. In our previous study, circulating miR-197-3p tested dysregulated in workers ex-exposed to asbestos (WEA). Herein, an epigenetic investigation on this circulating miRNA was carried out in sera from malignant pleural mesothelioma (MPM) patients. MiR-197-3p was quantified in MPM (n = 75) sera and comparatively analyzed to WEA (n = 75) and healthy subject (n = 75) sera, using ddPCR and RT-qPCR techniques. Clinicopathological characteristics, occupational, non-occupational information and overall survival (OS) were evaluated in correlation studies. MiR-197-3p levels, analyzed by ddPCR, were significantly higher in MPM than in WEA cohort, with a mean copies/µl of 981.7 and 525.01, respectively. Consistently, RT-qPCR showed higher miR-197-3p levels in sera from MPM with a mean copies/µl of 603.7, compared to WEA with 336.1 copies/µl. OS data were significantly associated with histologic subtype and pleurectomy. Circulating miR-197-3p is proposed as a new potential biomarker for an early diagnosis of the MPM onset. Indeed, miR-197-3p epigenetic investigations along with chest X-ray, computed tomography scan and spirometry could provide relevant information useful to reach an early and effective diagnosis for MPM.

  © 2023. The Author(s).

• Formation of giant iron oxide-copper-gold deposits by superimposed episodic hydrothermal pulses. I. Del Real, M. Reich, A.C. Simon, et al. 2023;13(1):12041. PubMed · Publisher · Free full text

  Abstract

  Iron oxide-copper-gold (IOCG) deposits are a globally important source of copper, gold and critical commodities. Despite their relevance, IOCG deposits remain an ill-defined clan, with a range of characteristics that has complicated development of the general genetic model. Here we focus on the Candelaria IOCG deposit in Chile and reveal that by using micro-textural and compositional variations in actinolite, a common alteration mineral found in many IOCG deposits, we can constrain the evolution of these systems. We demonstrate that Candelaria formed by the superposition of at least two pulses of mineralization with a late Cu-rich event overprinting and superimposed over an early, and probably higher temperature, iron oxide-apatite (IOA) mineralization event. These distinct pulses were likely caused by episodic injections of magmatic-hydrothermal fluids from crystallizing magmas at depth. Our data provide empirical evidence of grain-to-deposit scale compositional and potentially temperature changes in an IOCG system. The results support the use of actinolite chemistry as a novel approach to understand the formation of IOCG deposits and a potential tool for vectoring in exploration.

  © 2023. The Author(s).

• Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition. M. Zhao, L. Li, C.H. Kiernan, et al. 2023;13(1):15678. PubMed · Publisher · Free full text

  Abstract

  Cytotoxic CD8 + T cell (CTL) exhaustion is driven by chronic antigen stimulation. Reversing CTL exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. We, therefore, investigated whether modulating chronic antigen stimulation and T-cell receptor (TCR) signaling with an IL2-inducible T-cell kinase (ITK) inhibitor, could confer ICB responsiveness to ICB resistant solid tumors. In vivo intermittent treatment of 3 ICB-resistant solid tumor (melanoma, mesothelioma or pancreatic cancer) with ITK inhibitor significantly improved ICB therapy. ITK inhibition directly reinvigorate exhausted CTL in vitro as it enhanced cytokine production, decreased inhibitory receptor expression, and downregulated the transcription factor TOX. Our study demonstrates that intermittent ITK inhibition can be used to directly ameliorate CTL exhaustion and enhance immunotherapies even in solid tumors that are ICB resistant.

  © 2023. Springer Nature Limited.

• Pleural fluid microbiota as a biomarker for malignancy and prognosis. B. Kwok, B.G. Wu, I.F. Kocak, et al. 2023;13(1):2229. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.

  © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

• Preoperative neutrophil-to-lymphocyte ratio correlates with PD-L1 expression in immune cells of patients with malignant pleural mesothelioma and predicts prognosis. R. Okita, N. Kawamoto, M. Okada, et al. 2023;13(1):5263. PubMed · Publisher · Free full text

  Abstract

  We assessed the prognostic value of five complex inflammatory and nutritional parameters, namely neutrophil-to-lymphocyte ratio (NLR), prognostic nutritional index (PNI), C-reactive protein-to-NLR ratio (C/NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) using data from patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP). Moreover, the correlation between these five parameters and programmed cell death protein 1 ligand-1 (PD-L1) expression in the tumor microenvironment was evaluated. This study included consecutive MPM patients who underwent EPP. The histological subtype of the eligible patients (n = 61) correlated with all five parameters. Moreover, the PD-L1 expression scores for immune cells correlated with NLR and PLR, and the PD-L1 expression scores for both tumor cells and immune cells were inversely correlated with both PNI and LMR. Univariate analysis elucidated that NLR, PNI, and C/NLR were predictors of 5-year overall survival (OS), and multivariate analysis revealed that NLR was an independent predictor of 5-year OS, suggesting that NLR is a preoperative, prognostic factor for patients with MPM who are scheduled for EPP. To the best of our knowledge, this is the first study to evaluate the prognostic potentials of NLR, PNI, C/NLR, PLR, and LMR simultaneously in patients with MPM who underwent EPP.

  © 2023. The Author(s).

• Preparation and characterization of different micro/nano structures on the surface of bredigite scaffolds. C. Qin, D. Che, D. Liu, et al. 2023;13(1):9072. PubMed · Publisher · Free full text

  Abstract

  The preparation of controllable micro/nano structures on the surface of the bredigite scaffold is expected to exhibit the same support and osteoconductive capabilities as living bone. However, the hydrophobicity of the white calciμm silicate scaffold surface restricts the adhesion and spreading of osteoblasts. Furthermore, during the degradation process of the bredigite scaffold, the release of Ca2+ results in an alkaline environment around the scaffold, which inhibits the growth of osteoblasts. In this study, the three-dimensional geometry of the Primitive surface in the three-periodic minimal surface with an average curvature of 0 was used as the basis for the scaffold unit cell, and a white hydroxyapatite scaffold was fabricated via photopolymerization-based 3D printing. Nanoparticles, microparticles, and micro-sheet structures with thicknesses of 6 μm, 24 μm, and 42 μm, respectively, were prepared on the surface of the porous scaffold through a hydrothermal reaction. The results of the study indicate that the micro/nano surface did not affect the morphology and mineralization ability of the macroporous scaffold. However, the transition from hydrophobic to hydrophilic resulted in a rougher surface and an increase in compressive strength from 45 to 59-86 MPa, while the adhesion of the micro/nano structures enhanced the scaffold's ductility. In addition, after 8 days of degradation, the pH of the degradation solution decreased from 8.6 to around 7.6, which is more suitable for cell growth in the hμman body. However, there were issues of slow degradation and high P element concentration in the degradation solution for the microscale layer group during the degradation process, so the nanoparticle and microparticle group scaffolds could provide effective support and a suitable environment for bone tissue repair.

  © 2023. The Author(s).

• Targeting BAP1 with small compound inhibitor for colon cancer treatment. M. Kang, S.G. Park, S.A. Lee, et al. 2023;13(1):2264. PubMed · Publisher · Free full text

  Abstract

  BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase. The gene encoding BAP1 is mutated in various human cancers, including mesothelioma, uveal melanoma and renal cell carcinoma. BAP1 plays roles in many cancer-related cellular functions, including cell proliferation, cell death, and nuclear processes crucial for genome stability, such as DNA repair and replication. While these findings suggest that BAP1 functions as a tumor suppressor, recent data also suggest that BAP1 might play tumor-promoting roles in certain cancers, such as breast cancer and hematopoietic malignancies. Here, we show that BAP1 is upregulated in colon cancer cells and tissues and that BAP1 depletion reduces colon cancer cell proliferation and tumor growth. BAP1 contributes to colon cancer cell proliferation by accelerating DNA replication and suppressing replication stress and concomitant apoptosis. A recently identified BAP1 inhibitor, TG2-179-1, which seems to covalently bind to the active site of BAP1, exhibits potent cytotoxic activity against colon cancer cells, with half-maximal inhibitory concentrations of less than 10 μM, and inhibits colon tumor growth. TG2-179-1 exerts cytotoxic activity by targeting BAP1, leading to defective replication and increased apoptosis. This work therefore shows that BAP1 acts oncogenically in colon cancer and is a potential therapeutic target for this cancer. Our work also suggests that TG2-179-1 can be developed as a potential therapeutic agent for colon cancer.

  © 2023. The Author(s).

• A panel of emerging EMT genes identified in malignant mesothelioma. L. Wu, S. Amjad, H. Yun, et al. 2022;12(1):1007. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MESO) is a highly aggressive cancer with poor prognosis. Epithelial-mesenchymal transition (EMT) is a critical process in malignancies involved in tumor angiogenesis, progression, invasion and metastasis, immunosuppressive microenvironment and therapy resistance. However, there is a lack of specific biomarkers to identify EMT in MESO. Biphasic MESO with dual phenotypes could be an optimal model to study EMT process. Using a powerful EMTome to investigate EMT gene signature, we identified a panel of EMT genes COL5A2, ITGAV, SPARC and ACTA2 in MESO. In combination with TCGA database, Timer2.0 and other resources, we observed that overexpression of these emerging genes is positively correlated with immunosuppressive infiltration, and an unfavorable factor to patient survival in MESO. The expression of these genes was confirmed in our patients and human cell lines. Our findings suggest that these genes may be novel targets for therapeutics and prognosis in MESO and other types of cancers.

  © 2022. The Author(s).

• Analysis of the correlation between Zeste enhancer homolog 2 (EZH2) mRNA expression and the prognosis of mesothelioma patients and immune infiltration. K. Fan, C.L. Zhang, B.H. Zhang, et al. 2022;12(1):16583. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma lies one of the most malignant tumors, in which the identification of the corresponding biomarkers is extremely critical. This study aims to investigate the prognostic value of enhancer homolog 2 (EZH2) mRNA expression in mesothelioma patients accompanied with its immune infiltration analysis. Gene expression, clinical information and enrichment analysis were obtained based on the Cancer Genome Atlas (TCGA), the immune infiltration analysis and bioinformatics analysis were performed. Clinical information and gene expression were obtained from 86 patients with mesothelioma based on TCGA database. Survival analysis, GSEA enrichment analysis, and immune infiltration analysis of EZH2 expression were carried out using R (version 3.6.3) (statistical analysis and visualization). The correlation of EZH2 expression with immune cell infiltration in mesothelioma was analyzed according to the TIMER database (Fig. https://cistrome.shinyapps.io/timer/ ). A univariate and multivariate analysis of general data obtained from the TCGA database was performed, involving age, gender, stage, pathological type, and whether they had received radiotherapy, the results indicated the association of high expression of EZH2 with poor prognosis in mesothelioma patients, with the worse prognosis in the High group (HR = 2.75, 95% CI 1.68-4.52, P < 0.010). Moreover, ROC curves showed that EZH2 expression predicted 1-year survival with an AUC of 0.740, 2-year survival with an AUC of 0.756, and 3-year survival with an AUC of 0.692, suggesting a robust predictive effect of EZH2 expression on prognosis. KEGG pathway analysis indicated five pathways showing the strongest positive correlation with EZH2 expression: cell cycle, DNA replication, Cell adhesion molecules cams, Primary immuno deficiency, Tsate transduction, and five pathways showing the strongest negative correlation with EZH2 expression: Glycolysis gluconeogenesis, Drug metabolism, cytochrome P450, retinol metabolism, fatty acid metabolism ribosome. We investigated the correlation between EZH2 expression and the level of immune infiltration in mesothelioma tissues. The results indicated that EZH2 expression played a critical role in immune infiltration, of which the high expression was correlated with the reduced number of NK cells, Mast cells, and Th17 cells. Moreover, mesothelioma patients with high EZH2 expression differ from those with low EZH2 expression in their tumor immune microenvironment. EZH2, as a new prognostic biomarker for mesothelioma, contributes to elucidating how changes in the immune environment promote the development of mesothelioma. Further analysis, EZH2 may serve as a biological test to predict the prognosis of mesothelioma.

  © 2022. The Author(s).

• Carbonation and serpentinization of diopsidite in the Altun Mountains, NW China. D. Zhou, S. Cao, J. Liu, et al. 2022;12(1):21361. PubMed · Publisher · Free full text

  Abstract

  Mineral carbonation of mafic-ultramafic rocks has been highlighted as a promising way for permanent carbon capture and storage. Carbonatization involves the release of Ca, Mg and Fe from silicate minerals by dissolution and reaction in the aqueous phase to form stable carbonate minerals. Diopside is one of the most abundant mafic minerals in the lithosphere and contributes a portion of Mg and Ca to surface weathering. Here, we present detailed processes of the carbonation-coupled serpentinization of diopsidite from the Yushishan Nb-Ta deposit in the Altun Mountain, northwest China. Diopsidite is the prograde metamorphic product of siliceous dolomitic marble by full decarbonation process. Retrograde serpentinization and carbonation of diopsidite lead to the addition of CO2, H2O, light rare earth elements and fluid-mobile elements but the loss of SiO2. The diopsides are replaced by calcite and chrysotile by mineral alteration to form pseudomorphic textures. Dissolution-precipitation processes significantly affect diopside serpentinization and carbonation. The carbonation of diopside-rich rocks may be suitable for permanent CO2 storage.

  © 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

• Dysregulation of microRNAs and tRNA-derived ncRNAs in mesothelial and mesothelioma cell lines after asbestiform fiber exposure. V. Filetti, A. La Ferlita, A. Di Maria, et al. 2022;12(1):9181. PubMed · Publisher · Free full text

  Abstract

  Experimental evidence demonstrated that fluoro-edenite (FE) can develop chronic respiratory diseases and elicit carcinogenic effects. Environmental exposure to FE fibers is correlated with malignant pleural mesothelioma (MPM). An early diagnosis of MPM, and a comprehensive health monitoring of the patients exposed to FE fibers are two clinical issues that may be solved by the identification of specific biomarkers. We reported the microRNA (miRNA) and transfer RNA-derived non coding RNA (tRNA-derived ncRNA) transcriptome in human normal mesothelial and malignant mesothelioma cell lines exposed or not exposed to several concentration FE fibers. Furthermore, an interactive mesothelioma-based network was derived by using NetME tool. In untreated condition, the expression of miRNAs and tRNA-derived ncRNAs in tumor cells was significantly different with respect to non-tumor samples. Moreover, interesting and significant changes were found after the exposure of both cells lines to FE fibers. The network-based pathway analysis showed several signaling and metabolic pathways potentially involved in the pathogenesis of MPM. From papers analyzed by NetME, it is clear that many miRNAs can positively or negatively influence various pathways involved in MPM. For the first time, the analysis of tRNA-derived ncRNAs molecules in the context of mesothelioma has been made by using in vitro systems. Further studies will be designed to test and validate their diagnostic potential in high-risk individuals' liquid biopsies.

  © 2022. The Author(s).

• Effects of inhalable gene transfection as a novel gene therapy for non-small cell lung cancer and malignant pleural mesothelioma. M. Ichikawa, N. Muramatsu, W. Matsunaga, et al. 2022;12(1):8634. PubMed · Publisher · Free full text

  Abstract

  Gene therapy using vectors has attracted attention in recent years for the treatment of cancers caused by gene mutations. Besides, new treatments are imperative for lung cancer, including non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), due to its high mortality. We developed a minimally invasive and orally inhalable tumor suppressor gene drug (SFD-p16 and SFD-p53) with non-viral vectors for lung cancer treatment by combining tumor suppressor genes with an inhalant powder that can deliver active ingredients directly to the lung. We used NSCLC (A549 and H1299) and MPM (H2052) cell lines in an air-liquid interface culture. Transfection of A549 and H2052 cells with SFD-p16 significantly increased p16 mRNA expression levels and decreased cell proliferation in both cell lines. Similar results were obtained with transfection of H1299 with the inhalable gene drug SFD-p53. In an in vivo experiment, a mouse model of lung cancer with orthotopically transplanted luciferase-expressing A549 cells was subjected to intratracheal insufflation of SFD-p16. Consequently, SFD-p16 effectively and directly affected lung cancer. This study suggests that inhalable gene drugs are effective treatments for NSCLC and MPM. We expect inhalable gene drugs to present a novel gene therapy agent for lung cancer that patients can self-administer.

  © 2022. The Author(s).

• Nanoscale transformations of amphiboles within human alveolar epithelial cells. R. Vigliaturo, M. Jamnik, G. Dražić, et al. 2022;12(1):1782. PubMed · Publisher · Free full text

  Abstract

  Amphibole asbestos is related to lung fibrosis and several types of lung tumors. The disease-triggering mechanisms still challenge our diagnostic capabilities and are still far from being fully understood. The literature focuses primarily on the role and formation of asbestos bodies in lung tissues, but there is a distinct lack of studies on amphibole particles that have been internalized by alveolar epithelial cells (AECs). These internalized particles may directly interact with the cell nucleus and the organelles, exerting a synergistic action with asbestos bodies (AB) from a different location. Here we document the near-atomic- to nano-scale transformations induced by, and taking place within, AECs of three distinct amphiboles (anthophyllite, grunerite, "amosite") with different Fe-content and morphologic features. We show that: (i) an Fe-rich layer is formed on the internalized particles, (ii) particle grain boundaries are transformed abiotically by the internal chemical environment of AECs and/or by a biologically induced mineralization mechanism, (iii) the Fe-rich material produced on the particle surface does not contain large amounts of P, in stark contrast to extracellular ABs, and (iv) the iron in the Fe-rich layer is derived from the particle itself. Internalized particles and ABs follow two distinct formation mechanisms reaching different physicochemical end-states.

  © 2022. The Author(s).

• RhoA and vigilin are candidates for immunohistochemical markers for epithelioid malignant mesothelioma. T. Hiratsuka, T. Yamamoto, A. Yoshizawa, et al. 2022;12(1):18519. PubMed · Publisher · Free full text

  Abstract

  Diagnostic markers of malignant mesothelioma (MM) have been extensively investigated. Immunohistochemistry (IHC) markers, such as calretinin, have been used for pathologic diagnosis. However, more diagnostic markers are required to improve the specificity and sensitivity of pathologic diagnosis. This study proposed two proteins as diagnostic markers for epithelioid MM. One is RhoA, an MM mutation-susceptible locus-derived protein, and another is vigilin, a lung small cell carcinoma marker. IHC was performed using 93 MM (epithelioid, 71 cases; sarcomatoid, 13 cases; and biphasic, 9 cases), 64 lung adenocarcinoma (LAC), 60 lung squamous cell carcinoma (LSC), and 14 normal mesothelial (NM) tissues. The majority of epithelioid MM cases were positive for both RhoA and vigilin, whereas both IHCs showed lower stainability in biphasic and sarcomatoid MM. Besides, both IHCs showed significantly higher stainability for RhoA and vigilin in epithelioid MM than in LAC and LSC (p < 0.05). Chi-square tests showed that both RhoA and vigilin IHC positive rate in epithelioid MM was not significantly different from that of calretinin (p > 0.05). In the differential diagnosis of MM from lung cancer, the accuracy and specificity of RhoA, vigilin, and calretinin staining were almost equivalent. Further, H-score test showed that there was no significant difference between RhoA versus calretinin and vigilin versus calretinin in IHC positivity in epithelioid MM (p > 0.05). In conclusion, RhoA and vigilin may be candidates for immunohistochemical markers for epithelioid MM.

  © 2022. The Author(s).

• The natural reduction of threat in selected systems of old buildings containing asbestos. A. Obmiński. 2022;12(1):2580. PubMed · Publisher · Free full text

  Abstract

  The aim of this study was to measure changes in asbestos dust concentrations over extended use in old building systems. Buildings from different systems during their service lifetimes and after asbestos removal were tested. Asbestos dust concentrations decreased in all building systems due to air exchange and other phenomena in the absence of new active dust sources. Currently, with proper use of those buildings, average values of dust concentrations did not exceed 300-400 f/m3 with a downward trend to < 300 f/m3. The results of these studies were obtained with a modified optical microscopy technique, verified by SEM and TEM methods. The graphical trends in concentration changes over longer periods illustrate the potency of opposing factors reducing and increasing indoor air pollution. If removal asbestos work was not carried out carefully, single measurements conducted in the short-term and mandated immediately after asbestos removal may not detect hazards that appear over time. Monitoring buildings over longer periods allows detection of significant contamination changes. In many cases, the minimal air contamination undermines the desirability of removing asbestos in old buildings.

  © 2022. The Author(s).

• Asbestos bodies count and morphometry in bulk lung tissue samples by non-invasive X-ray micro-tomography. F. Bardelli, F. Brun, S. Capella, et al. 2021;11(1):10608. PubMed · Publisher · Free full text

  Abstract

  The number of the Asbestos Bodies (AB), i.e. asbestos that developed an iron-protein coating during its permanence in biological tissues, is one of the most accessible markers of asbestos exposure in individuals. The approaches developed to perform AB count in biological tissues are based on the manual examination of tissue digests or histological sections by means of light or electron microscopies. Although these approaches are well established and relatively accessible, manual examination is time-consuming and can be reader-dependent. Besides, approximations are applied because of the limitations of 2D readings and to speed up manual counts. In addition, sample preparation using tissue digests require an amount of tissue that can only be obtained by invasive surgery or post-mortem sampling. In this paper, we propose a new approach to AB counting based on non-destructive 3D imaging, which has the potential to overcome most of the limitations of conventional approaches. This method allows automating the AB count and determining their morphometry distribution in bulk tissue samples (ideally non-invasive needle biopsies), with minimal sample preparation and avoiding approximations. Although the results are promising, additional testing on a larger number of AB-containing biological samples would be required to fully validate the method.

• Circulating microRNA-197-3p as a potential biomarker for asbestos exposure. F. Frontini, I. Bononi, E. Torreggiani, et al. 2021;11(1):23955. PubMed · Publisher · Free full text

  Abstract

  Asbestos is considered the main cause of diseases in workers exposed to this mineral in the workplace as well as an environmental pollutant. The association between asbestos and the onset of different diseases has been reported, but asbestos exposure specific biomarkers are not known. MicroRNAs (miRNAs) are small, single-strand, non-coding RNAs, with potential value as diagnostic, prognostic, and predictive markers in liquid biopsies. Sera collected from workers ex-exposed to asbestos (WEA) fibers were compared with sera from healthy subjects (HS) of similar age, as liquid biopsies. The expression of the circulating miRNA 197-3p was investigated employing two different highly analytical PCR methods, i.e. RT-qPCR and ddPCR. MiR-197-3p levels were tested in sera from WEA compared to HS. MiR-197-3p tested dysregulated in sera from WEA (n = 75) compared to HS (n = 62). Indeed, miR-197-3p was found to be 2.6 times down-regulated in WEA vs. HS (p = 0.0001***). In addition, an inverse correlation was detected between miR-197-3p expression level and cumulative asbestos exposure, being this miRNA down-regulated 2.1 times in WEA, with high cumulative asbestos exposure, compared to WEA with low exposure (p = 0.0303*). Circulating miR-197-3p, found to be down regulated in sera from WEA, is proposed as a new potential biomarker of asbestos exposure.

  © 2021. The Author(s).

• CLDN15 is a novel diagnostic marker for malignant pleural mesothelioma. M. Watanabe, T. Higashi, K. Ozeki, et al. 2021;11(1):12554. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is a cancer with a poor survival rate. It is difficult to diagnose mesotheliomas because they show a variety of histological patterns similar to those of various other cancers. However, since currently used positive markers for mesotheliomas may show false positives or false negatives, a novel mesothelial positive marker is required. In the present study, we screened 25 claudins and found that claudin-15 is expressed in the mesothelial cells. We made new rat anti-human claudin-15 (CLDN15) monoclonal antibodies that selectively recognize CLDN15, and investigated whether CLDN15 is a good positive marker for malignant pleural mesotheliomas (MPMs) using MPM tissue samples by immunohistochemistry and semi-quantification of the expression level using an immunoreactive score (IRS) method. Of 42 MPM samples, 83% were positive for CLDN15. The positive ratio was equal to or greater than other positive markers for MPMs including calretinin (81%), WT-1 (50%), and D2-40 (81%). In 50 lung adenocarcinoma sections, four cases were positive for CLDN15 and the specificity (92%) was comparable with other markers (90-100%). Notably, CLDN15 was rarely detected in 24 non-mesothelial tumors in the tissue microarray (12/327 cases). In conclusion, CLDN15 can be used in the clinical setting as a positive marker for MPM diagnosis.

• County-level longitudinal clustering of COVID-19 mortality to incidence ratio in the United States. N. Vahabi, M. Salehi, J.D. Duarte, et al. 2021;11(1):3088. PubMed · Publisher · Free full text

  Abstract

  As of November 12, 2020, the mortality to incidence ratio (MIR) of COVID-19 was 5.8% in the US. A longitudinal model-based clustering system on the disease trajectories over time was used to identify "vulnerable" clusters of counties that would benefit from allocating additional resources by federal, state and county policymakers. County-level COVID-19 cases and deaths, together with a set of potential risk factors were collected for 3050 U.S. counties during the 1st wave of COVID-19 (Mar25-Jun3, 2020), followed by similar data for 1344 counties (in the "sunbelt" region of the country) during the 2nd wave (Jun4-Sep2, 2020), and finally for 1055 counties located broadly in the great plains region of the country during the 3rd wave (Sep3-Nov12, 2020). We used growth mixture models to identify clusters of counties exhibiting similar COVID-19 MIR growth trajectories and risk-factors over time. The analysis identifies "more vulnerable" clusters during the 1st, 2nd and 3rd waves of COVID-19. Further, tuberculosis (OR 1.3-2.1-3.2), drug use disorder (OR 1.1), hepatitis (OR 13.1), HIV/AIDS (OR 2.3), cardiomyopathy and myocarditis (OR 1.3), diabetes (OR 1.2), mesothelioma (OR 9.3) were significantly associated with increased odds of being in a more vulnerable cluster. Heart complications and cancer were the main risk factors increasing the COVID-19 MIR (range 0.08-0.52% MIR↑). We identified "more vulnerable" county-clusters exhibiting the highest COVID-19 MIR trajectories, indicating that enhancing the capacity and access to healthcare resources would be key to successfully manage COVID-19 in these clusters. These findings provide insights for public health policymakers on the groups of people and locations they need to pay particular attention while managing the COVID-19 epidemic.

• Efficacy of chemotherapy for malignant pleural mesothelioma according to histology in a real-world cohort. S. Cedres, J.D. Assaf, P. Iranzo, et al. 2021;11(1):21357. PubMed · Publisher · Free full text

  Abstract

  CheckMate 743 trial demonstrated survival benefit of immunotherapy in first line in MPM with some differences in the efficacy of chemotherapy according to histology. The objective of this study is to characterize the impact of chemotherapy according to histology in patients diagnosed with MPM at our institution. Clinical records of all MPM patients diagnosed at Vall d'Hebron University Hospital between November 2002 and April 2020 were reviewed. Associations between clinical variables and outcomes were assessed with Cox regression models. Survival data were calculated by the Kaplan-Meier method. 189 patients were included with 76% of tumors classified as epithelioid subtype. First line chemotherapy was offered to 85% of patients. Median survival in overall population was 21.3 months (95% CI 17.2-24.3). We found that patients with epithelioid tumors had better overall survival (OS) and progression free survival (PFS). Median OS of epithelioid patients treated with first line chemotherapy was 26.7 months versus 15.0 months in non-epithelioid patients (HR 2.25 CI 95% 1.4-3.4; p < 0.001). Median PFS for patients with epithelioid tumors treated with chemotherapy was 4.8 months versus 3.6 months in non-epithelioid (HR 1.5 CI 95% 1.0-2.3; p = 0.03). The improvement of outcomes in patients with epithelioid histology was detected in patients treated with cisplatin or carboplatin. Histology was not a predictive factor for the platinum agent sensitivity (p of interaction PFS = 0.09, p of interaction OS = 0.65). In our series, patients with non-epithelioid tumors presented worse prognosis. Although epithelioid tumors exposed to cisplatin had higher PFS, histology was not a clear predictor of chemotherapy efficacy.

  © 2021. The Author(s).

• Identification of distinct immune landscapes using an automated nine-color multiplex immunofluorescence staining panel and image analysis in paraffin tumor tissues. E.R. Parra, J. Zhai, A. Tamegnon, et al. 2021;11(1):4530. PubMed · Publisher · Free full text

  Abstract

  Immune profiling is becoming a vital tool for identifying predictive and prognostic markers for translational studies. The study of the tumor microenvironment (TME) in paraffin tumor tissues such as malignant pleural mesothelioma (MPM) could yield insights to actionable targets to improve patient outcome. Here, we optimized and tested a new immune-profiling method to characterize immune cell phenotypes in paraffin tissues and explore the co-localization and spatial distribution between the immune cells within the TME and the stromal or tumor compartments. Tonsil tissues and tissue microarray (TMA) were used to optimize an automated nine-color multiplex immunofluorescence (mIF) panel to study the TME using eight antibodies: PD-L1, PD-1, CD3, CD8, Foxp3, CD68, KI67, and pancytokeratin. To explore the potential role of the cells into the TME with this mIF panel we applied this panel in twelve MPM cases to assess the multiple cell phenotypes obtained from the image analysis and well as their spatial distribution in this cohort. We successful optimized and applied an automated nine-color mIF panel to explore a small set of MPM cases. Image analysis showed a high degree of cell phenotype diversity with immunosuppression patterns in the TME of the MPM cases. Mapping the geographic cell phenotype distribution in the TME, we were able to identify two distinct, complex immune landscapes characterized by specific patterns of cellular distribution as well as cell phenotype interactions with malignant cells. Successful we showed the optimization and reproducibility of our mIF panel and their incorporation for comprehensive TME immune profiling into translational studies that could refine our ability to correlate immunologic phenotypes with specific patterns of cells distribution and distance analysis. Overall, this will improve our ability to understand the behavior of cells within the TME and predict new treatment strategies to improve patient outcome.

• Insights on the deep carbon cycle from the electrical conductivity of carbon-bearing aqueous fluids. G. Manthilake, M. Mookherjee, N. Miyajima. 2021;11(1):3745. PubMed · Publisher · Free full text

  Abstract

  The dehydration and decarbonation in the subducting slab are intricately related and the knowledge of the physical properties of the resulting C-H-O fluid is crucial to interpret the petrological, geochemical, and geophysical processes associated with subduction zones. In this study, we investigate the C-H-O fluid released during the progressive devolatilization of carbonate-bearing serpentine-polymorph chrysotile, with in situ electrical conductivity measurements at high pressures and temperatures. The C-H-O fluid produced by carbonated chrysotile exhibits high electrical conductivity compared to carbon-free aqueous fluids and can be an excellent indicator of the migration of carbon in subduction zones. The crystallization of diamond and graphite indicates that the oxidized C-H-O fluids are responsible for the recycling of carbon in the wedge mantle. The carbonate and chrysotile bearing assemblages stabilize dolomite during the devolatilization process. This unique dolomite forming mechanism in chrysotile in subduction slabs may facilitate the transport of carbon into the deep mantle.

• Integrated genomics point to immune vulnerabilities in pleural mesothelioma. A. Nastase, A. Mandal, S.K. Lu, et al. 2021;11(1):19138. PubMed · Publisher · Free full text

  Abstract

  Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

  © 2021. The Author(s).

• Integrative pan-cancer analysis of MEK1 aberrations and the potential clinical implications. Z. Zhou, B. Peng, J. Li, et al. 2021;11(1):18366. PubMed · Publisher · Free full text

  Abstract

  Alterations of mitogen-activated protein kinase kinase 1 (MEK1) are commonly associated with tumorigenesis, and MEK1 is thought to be a suitable targeted therapy for various cancers. However, abnormal MEK1 alterations and their relevant clinical implications are unknown. Our research comprehensively analyzed the MEK1 alteration spectrum and provided novel insight for targeted therapies. There were 7694 samples covering 32 types of cancer from The Cancer Genome Atlas (TCGA) database. They were used to conduct an integrative analysis of MEK1 expression, alterations, functional impacts and clinical significance. There was a dramatic difference in the alteration frequency and distribution and clinical implications in 32 types of cancer from the TCGA. Skin cutaneous melanoma (SKCM) has the most alterations and has therapeutic targets located in the protein kinase domain, and the growing expression of SKCM is positively related to patient prognosis. MEK1 expression in lung adenocarcinoma (LUAD), kidney renal papillary cell carcinoma (KIRP), esophageal carcinoma (ESCA) and liver hepatocellular carcinoma (LIHC) is decreased, which is associated with better prognosis, while MEK1 expression in thymoma (THYM), stomach adenocarcinoma (STAD), kidney renal clear cell carcinoma (KIRC), testicular germ cell tumors (TGCTs) and head and neck squamous cell carcinoma (HNSC) is increased, which is associated with better prognosis. Mesothelioma (MESO) has the second highest alterations but has no therapy targets. This study provided a great and detailed interpretation of MEK1 expression, alterations and clinical implications in 32 types of cancer and reminded us to fill the gap in MEK1 research from a new perspective.

  © 2021. The Author(s).

• Occurrence and characterization of tremolite asbestos from the Mid Atlantic Ridge. D. Di Giuseppe, N. Perchiazzi, D. Brunelli, et al. 2021;11(1):6285. PubMed · Publisher · Free full text

  Abstract

  Tremolite is one of the most common amphibole species and, in the fibrous form (i.e., characterized by crystals/particles consisting of fibres with length > 5 µm, width < 3 µm and aspect ratio > 3), one of the six asbestos minerals. Until now the attention of crystallographers has focused only on samples from continental environment. Here we report the first chemical and structural data of a tremolite asbestos found along the Mid Atlantic Ridge (MAR) at the eastern intersection of the Romanche Transform Fault (Equatorial MAR). Tremolite is associated with chlorite and lizardite and was formed through the green shale facies lower than zeolite in a predominantly fluid system. MAR tremolite asbestos shows very slight deviations from the ideal crystal structure of tremolite. Differences in cation site partitioning were found with respect to tremolite asbestos from ophiolitic complexes, attributed to the different chemical-physical conditions during the mineral formation. In particular, oceanic tremolite asbestos is enriched in Al and Na, forming a trend clearly distinct from the continental tremolites.

• Significance of secretory leukocyte peptidase inhibitor in pleural fluid for the diagnosis of benign asbestos pleural effusion. T. Kishimoto, Y. Kojima, N. Fujimoto. 2021;11(1):12965. PubMed · Publisher · Free full text

  Abstract

  Secretory leukocyte peptidase inhibitor (SLPI) is a biomarker present in the respiratory tract that protects against tissue destruction and aids in wound healing. We examined whether SLPI in pleural effusion can be used to distinguish benign asbestos pleural effusion (BAPE) from early-stage malignant pleural mesothelioma (MPM) and other diseases. We measured the levels of SLPI, hyaluronic acid (HA), soluble mesothelin-related peptides (SMRP), CCL2, galectin-3, and CYFRA21-1 in 51 patients with BAPE, 37 patients with early-stage MPM, 77 patients with pleural effusions due to non-small-cell lung cancer (LCa), and 74 patients with other pleural effusions. SLPI levels in the pleural fluid of patients with BAPE were significantly lower than those in patients with MPM, LCa, and other pleural effusions (p < 0.0001). The area under the curve (AUC) for SLPI's ability to distinguish BAPE from MPM was 0.902, with a sensitivity of 82.4% and a specificity of 86.5%. This AUC was not only favourable but was better than the AUC for the ability of CYFRA21-1 to distinguish BAPE (0.853). The combination of SLPI and CYFRA21-1 achieved an AUC of 0.965 for the differentiation between BAPE and MPM. Pleural fluid SLPI as well as CYFRA21-1 and HA is useful as a biomarker to diagnose BAPE, which needs to be distinguished from early-stage MPM.

• Study on the adsorption properties of methyl orange by natural one-dimensional nano-mineral materials with different structures. L. Wu, X. Liu, G. Lv, et al. 2021;11(1):10640. PubMed · Publisher · Free full text

  Abstract

  Methyl orange (MO) is a common anionic azo dye that is harmful to the environment and biology, so it must be treated innocuously before it can be discharged. Adsorption is an effective method to remove anionic dyes. Nanotube mineral is a natural one-dimensional adsorption material, and its unique morphology and structure endow it with good adsorption capacity. Although there are many related studies, there is a lack of in-depth discussions on the influence of nanotube's composition and structure on the adsorption of dyes and other pollutants. In this paper, two kinds of natural one-dimensional silicate minerals [halloysite nanotubes (HNTs) and chrysotile nanotubes (ChNTs)] with similar morphology but slightly different compositions and crystal structures were used as adsorbents, and MO solution was used as simulate pollutants. It is the first time to discuss in depth the influence of the composition and structure of nanotube minerals on their charge properties and the adsorption performance of methyl orange dyes. It is found that HNTs and ChNTs have different adsorption capacity due to the difference of electronegativity between Al3+ and Mg2+ in the crystal, so they possess negative and positive charges respectively in near-neutral solution, which leads to the adsorption capacity of MO by ChNTs with positive charges which is greater than that of HNTs.

• Surface and bulk modifications of amphibole asbestos in mimicked gamble's solution at acidic PH. A. Pacella, P. Ballirano, M. Fantauzzi, et al. 2021;11(1):14249. PubMed · Publisher · Free full text

  Abstract

  This study aimed at investigating the surface modifications occurring on amphibole asbestos (crocidolite and tremolite) during leaching in a mimicked Gamble's solution at pH of 4.5 and T = 37 °C, from 1 h up to 720 h. Results showed that the fibre dissolution starts with the release of cations prevalently allocated at the various M- and (eventually) A-sites of the amphibole structure (incongruent dissolution). The amount of released silicon, normalized to fibre surface area, highlighted a leaching faster for the crocidolite sample, about twenty times higher than that of tremolite. Besides, the fast alteration of crocidolite promotes the occurrence of Fe centres in proximity of the fibre surface, or possibly even exposed, particularly in the form of Fe(II), of which the bulk is enriched with respect to the oxidized surface. Conversely, for tremolite fibres the very slow fibre dissolution prevents the underlying cations of the bulk to be exposed on the mineral surface, and the iron oxidation, faster than the leaching process, significantly depletes the surface Fe(II) centres initially present. Results of this work may contribute to unravel possible correlations between surface properties of amphibole asbestos and its long-term toxicity.

  © 2021. The Author(s).

• Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression. S. Busacca, Q. Zhang, A. Sharkey, et al. 2021;11(1):7434. PubMed · Publisher · Free full text

  Abstract

  We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

• Attenuation of oxidative stress and chromosomal aberrations in cultured macrophages and pulmonary cells following self-sustained high temperature synthesis of asbestos. S. La Maestra, R.T. Micale, M. Ferretti, et al. 2020;10(1):8581. PubMed · Publisher · Free full text

  Abstract

  Inhalation of asbestos fibres can cause lung and pleural diseases in humans and constitutes a severe public health threat worldwide. The aim of the present study was to assess the biological effects induced in both pulmonary cells (A549) and monocyte/macrophage (RAW 264.7) cell lines by combustion slags obtained from asbestos through a self-sustained high-temperature synthesis (SHS) reaction. The SHS reaction involves rapid thermal treatment and displays great ability to neutralise asbestos. Cytotoxicity, redox status imbalance, lipid peroxide production, DNA strand breaks (comet assay) and chromosomal aberrations (cytokinesis block micronucleus test) were evaluated in cells exposed either to untreated asbestos fibres or to grinded SHS-generated slags of different granulometry, tested in cultured cells at varying doses and for varying exposure times. Our results show that asbestos fibres cause redox status imbalance, especially in monocyte/macrophage cell lines. Moreover, they promote lipid peroxidation and trigger genomic alterations. When the cells were exposed to slag powders, which are the products of SHS asbestos treatment, generation of lipid peroxides and induction of DNA strand breaks still persisted, due to the high content in iron and other metals detected in these samples. However, there was an attenuation of redox status imbalance and an absence of chromosomal aberrations, which probably reflects the loss of the asbestos fibrous structure following SHS reaction, as demonstrated by electron microscopy analyses. In conclusions, SHS-treated asbestos wastes can potentially have deleterious health effects due to the oxidative stress induced by inhaled powders but they loose the asbestos ability to induce chromosomal alterations.

• Characteristics of asbestos fibers in lung tissue from occupational and environmental asbestos exposure of lung cancer patients in Busan, Korea. H.S. Jung, E.K. Park, J.S. Cha, et al. 2020;10(1):20359. PubMed · Publisher · Free full text

  Abstract

  The Asbestos Injury Relief Act in Korea requires that asbestos exposure be assessed through clinical examination and chest computed tomography (CT). However, a more specific measurement of asbestos characteristics in the lung tissue may be appropriate. We aimed to investigate the asbestos burden and characterize asbestos fibers in patients with lung cancer and ultimately assess the relationship between occupational and environmental asbestos exposure and lung cancer in Korea. We evaluated 37 lung cancer patients (LCPs) from Busan. The factors affecting asbestos burden in LCPs were analyzed using a multiple regression analysis. History of asbestos exposure (environmental/occupational), male sex, and old age were the main factors affecting asbestos burden in lung tissues of LCPs. These factors had an approximate 37% adjusted coefficient of determination. There was a significant difference in the length of asbestos fibers (4.06-37.6 µm vs. 4.26-91.7 µm) and aspect ratio (4.5-151.9 vs. 5.6-735.6) between those who were occupationally exposed to asbestos and those who were environmentally exposed (P < 0.01). Therefore, both environmental/occupational exposure to asbestos should be strongly managed to reduce the risk of lung cancer, and exposure should be assessed according to the characteristics of asbestos fibers in the lung tissue.

• Impact of metallothionein-knockdown on cisplatin resistance in malignant pleural mesothelioma. S. Borchert, P.M. Suckrau, R.F.H. Walter, et al. 2020;10(1):18677. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor with dismal prognosis. Platinum-based chemotherapy is regularly used as part of multimodality therapy. The expression of metallothioneins (MT) has been identified as a reason for cisplatin resistance, which often leads to early therapy failure or relapse. Thus, knockdown of MT expression may improve response to cisplatin treatment. The MT gene- and protein expression of the MPM-cell lines MSTO-211H, NCI-H2052 and NCI-H2452 and the human fibroblast cell line MRC-5, as well as their sensitivity to cisplatin treatment have been evaluated. Knockdown of MT1A, 1B and 2A expression was induced by RNA interference. MT expression was measured using quantitative real-time PCR. An in vitro Assay based on enzyme activity was used to detect cell viability, necrosis and apoptosis before and after incubation with cisplatin. MT2A gene expression could be detected in all MPM cell lines, showing the highest expression in NCI-H2452 and NCI-H2052, whereas gene expression levels of MT1A and MT1B were low or absent. The immunohistochemically protein expression of MT-I/II reflect MT2A gene expression levels. Especially for MSTO-211H cell presenting low initial MT2A levels, a strong induction of MT2A expression could be observed during cisplatin treatment, indicating a cell line-specific and platin-dependent adaption mechanism. Additionally, a MT2A-dependent cellular evasion of apoptosis during cisplatin could be observed, leading to three different MT based phenotypes. MSTO-211H cells showed lower apoptosis rates at an increased expression level of MT2A after cisplatin treatment (from sixfold to fourfold). NCI-H2052 cells showed no changes in MT2A expression, while apoptosis rate is the highest (8-12-fold). NCI-H2452 cells showed neither changes in alteration rate of MT2A expression nor changes in apoptosis rates, indicating an MT2A-independent resistance mechanism. Knockdown of MT2A expression levels resulted in significantly induced apoptotic rates during cisplatin treatment with strongest induction of apoptosis in each of the MPM cell lines, but in different markedness. A therapeutic meaningful effect of MT2A knockdown and subsequent cisplatin treatment could be observed in MSTO-211H cells. The present study showed MT2A to be part of the underlying mechanism of cisplatin resistance in MPM. Especially in MSTO-211H cells we could demonstrate major effects by knockdown of MT2A expression, verifying our hypothesis of an MT driven resistance mechanism. We could prove the inhibition of MT2A as a powerful tool to boost response rates to cisplatin-based therapy in vitro. These data carry the potential to enhance the clinical outcome and management of MPM in the future.

• In vitro and in vivo BNCT investigations using a carborane containing sulfonamide targeting CAIX epitopes on malignant pleural mesothelioma and breast cancer cells. D. Alberti, A. Michelotti, A. Lanfranco, et al. 2020;10(1):19274. PubMed · Publisher · Free full text

  Abstract

  This study aims at merging the therapeutic effects associated to the inhibition of Carbonic Anhydrase IX (CAIX), an essential enzyme overexpressed by cancer cells including mesothelioma and breast cancer, with those ones brought by the application of Boron Neutron Capture Therapy (BNCT). This task was pursued by designing a sulfonamido-functionalised-carborane (CA-SF) that acts simultaneously as CAIX inhibitor and boron delivery agent. The CAIX expression, measured by Western blot analysis, resulted high in both mesothelioma and breast tumours. This finding was exploited for the delivery of a therapeutic dose of boron (> 20 μg/g) to the cancer cells. The synergic cytotoxic effects operated by the enzymatic inhibition and neutron irradiation was evaluated in vitro on ZL34, AB22 and MCF7 cancer cells. Next, an in vivo model was prepared by subcutaneous injection of AB22 cells in Balb/c mice and CA-SF was administered as inclusion complex with a β-cyclodextrin oligomer. After irradiation with thermal neutrons tumour growth was evaluated for 25 days by MRI. The obtained results appear very promising as the tumour growth was definitively markedly lower in comparison to controls and the CAIX inhibitor alone. This approach appears promising and it call consideration for the design of new therapeutic routes to cure patients affected by this disease.

• Multicellular contractility contributes to the emergence of mesothelioma nodules. J. Tarnoki-Zach, P. Stockhammer, D.G. Isai, et al. 2020;10(1):20114. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) has an overall poor prognosis and unsatisfactory treatment options. MPM nodules, protruding into the pleural cavity may have growth and spreading dynamics distinct that of other solid tumors. We demonstrate that multicellular aggregates can develop spontaneously in the majority of tested MPM cell lines when cultured at high cell density. Surprisingly, the nodule-like aggregates do not arise by excessive local cell proliferation, but by myosin II-driven cell contractility. Prominent actin cables, spanning several cells, are abundant both in cultured aggregates and in MPM surgical specimens. We propose a computational model for in vitro MPM nodule development. Such a self-tensioned Maxwell fluid exhibits a pattern-forming instability that was studied by analytical tools and computer simulations. Altogether, our findings may underline a rational for targeting the actomyosin system in MPM.

• Overexpression of fibulin-3 in tumor tissue predicts poor survival of malignant mesothelioma patients from hand-spinning asbestos exposed area in eastern China. Z. Jiang, W. Shen, S. Ying, et al. 2020;10(1):20373. PubMed · Publisher · Free full text

  Abstract

  Fibulin-3 is an extracellular matrix glycoprotein widely expressed in various tissues. Tissue fibulin-3 expression have never been reported in association with prognosis of mesothelioma. Hence, we sought to determine the association between fibulin-3 expression and mesothelioma survival. We made a tissue microarray, which was comprised of cancer and normal tissue from mesothelioma patients (n = 82) during the period 1998-2017 in China. Fibulin-3 and HGMB1 expression were analyzed by immunohistochemistry method. Kaplan-Meier method and Cox proportional hazard models were used for analyzing survival data. Overall, 61 cases (74.4%) were female; 90.2% were of epithelioid type; the median overall survival time was 12.5 months. Fibulin-3 and HMGB1 were highly expressed in tumor tissue rather than adjacent tissue. The expression of fibulin-3 in tissue was correlated with that of HMGB1 (r = 0.32, P = 0.003). High expression of fibulin-3 in tumor tissue could predict poor survival in patients with mesothelioma (P = 0.02). This remained true in a multivariate model, with a significant hazard ratio of 1.91. We demonstrated that fibulin-3 in tumor tissue was a novel biomarker of poor survival of mesothelioma, suggesting it may be a relevant target for therapeutic intervention.

• Predicting Aedes aegypti infestation using landscape and thermal features. C. Lorenz, M.C. Castro, P.M.P. Trindade, et al. 2020;10(1):21688. PubMed · Publisher · Free full text

  Abstract

  Identifying Aedes aegypti breeding hotspots in urban areas is crucial for the design of effective vector control strategies. Remote sensing techniques offer valuable tools for mapping habitat suitability. In this study, we evaluated the association between urban landscape, thermal features, and mosquito infestations. Entomological surveys were conducted between 2016 and 2019 in Vila Toninho, a neighborhood of São José do Rio Preto, São Paulo, Brazil, in which the numbers of adult female Ae. aegypti were recorded monthly and grouped by season for three years. We used data from 2016 to 2018 to build the model and data from summer of 2019 to validate it. WorldView-3 satellite images were used to extract land cover classes, and land surface temperature data were obtained using the Landsat-8 Thermal Infrared Sensor (TIRS). A multilevel negative binomial model was fitted to the data, which showed that the winter season has the greatest influence on decreases in mosquito abundance. Green areas and pavements were negatively associated, and a higher cover of asbestos roofs and exposed soil was positively associated with the presence of adult females. These features are related to socio-economic factors but also provide favorable breeding conditions for mosquitos. The application of remote sensing technologies has significant potential for optimizing vector control strategies, future mosquito suppression, and outbreak prediction.

• Prognostic role of radiological peritoneal cancer index in malignant peritoneal mesothelioma: national cohort study. S.A.S. Salo, E. Lantto, E. Robinson, et al. 2020;10(1):13257. PubMed · Publisher · Free full text

  Abstract

  Malignant peritoneal mesothelioma (MPeM) is a rare cancer of the mesothelial cells of the peritoneum. Computed tomography (CT) is considered the standard for first-line imaging of MPeM, diagnosis and risk stratification remains challenging. Peritoneal cancer index (PCI), as assessed by CT, is utilized in the prognostic assessment of other malignant intra-abdominal conditions; however, there is limited data concerning the utility of PCI in the diagnosis and workup of MPeM. We studied a retrospective cohort of all patients diagnosed with MPeM from 2000 to 2012 in Finland. CT and magnetic resonance imaging (MRI) were reviewed and scored by an experienced and blinded, board-certified abdominal radiologist. Additional clinical data and outcomes were obtained from Finnish Cancer Registry (FCR), the Workers' Compensations Center (WCC), and Statistics Finland (SF). Abdominal CT or MRI was available for 53 of 90 patients. The median radiographic PCI was 25. PCI score was correlated with overall survival (p = 0.004, Exp(B) = 1.064, 95% CI 1.020-1.110). PCI score ≥ 30 was associated with worse survival (p = 0.002), while PCI ≤ 19 was associated with improved overall survival (p = 0.001). Our study indicates that radiological PCI is prognostic in MPeM and should be assessed during radiographic workup and integrated into clinical decision-making.

• Proteasomal degradation of polycomb-group protein CBX6 confers MMP-2 expression essential for mesothelioma invasion. K. Sakai, T. Nishiuchi, S. Tange, et al. 2020;10(1):16678. PubMed · Publisher · Free full text

  Abstract

  The aggressive invasiveness of malignant mesothelioma limits cancer therapy, however, the molecular mechanisms underlying the invasiveness remain largely unknown. Here we found that the matrix metalloproteinase-2 (MMP-2) was required for the invasion of mesothelioma cells in the collagen matrix and the gene expression of MMP-2 was correlated with the invasive phenotype. The MMP-2 gene expression was regulated by DNA and histone methylation around the transcription start site, implicating the involvement of the polycomb repressive complex (PRC). Knockdown of PRC component chromobox 6 (CBX6) promoted MMP-2 expression and invasion of mesothelioma cells. Transcriptome analysis suggested that CBX6 regulates sets of genes involved in cancer cell migration and metastasis. In invasive but not non-invasive cells, CBX6 was constantly unstable owing to ubiquitination and protein degradation. In human tissues, CBX6 localized in the nuclei of normal mesothelium and benign mesothelioma, but the nuclear staining of CBX6 was lost in malignant mesothelioma. These results suggest involvement of proteasomal degradation of CBX6 in mesothelioma progression.

• Tumour cell PD-L1 expression is prognostic in patients with malignant pleural effusion: the impact of C-reactive protein and immune-checkpoint inhibition. B. Ghanim, A. Rosenmayr, P. Stockhammer, et al. 2020;10(1):5784. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural effusion (MPE) confers dismal prognosis and has limited treatment options. While immune-checkpoint inhibition (ICI) proved clinical efficacy in a variety of malignancies, data on the prognostic role of PD-L1 in MPE is scarce. We retrospectively studied PD-L1 tumour proportion score and Ki-67 index in pleural biopsies or cytologies from 123 patients (69 lung cancer, 25 mesothelioma, and 29 extrathoracic primary malignancies). Additionally, the impact of C-reactive protein (CRP) and platelet count was also analysed. Median overall survival (OS) after MPE diagnosis was 9 months. Patients with PD-L1 positive tumours (≥1%) had significantly shorter OS than patients with negative PD-L1 status (p = 0.031). CRP and Ki-67 index were also prognostic and remained independent prognosticators after multivariate analysis. Interestingly, Ki-67 index and CRP influenced the prognostic power of PD-L1. Finally, patients receiving ICI tended to have a longer median OS and CRP - but not PD-L1 - was a significant prognosticator in this subgroup. In summary, histological and circulating biomarkers should also be taken into account as potential biomarkers in ICI therapy and they may have an impact on the prognostic power of PD-L1. Our findings might help personalizing immune-checkpoint inhibition for patients with MPE and warrant further prospective validation.

• YAP Activity is Not Associated with Survival of Uveal Melanoma Patients and Cell Lines. Y.J. Kim, S.C. Lee, S.E. Kim, et al. 2020;10(1):6209. PubMed · Publisher · Free full text

  Abstract

  Recent experimental studies have demonstrated an essential role for the Hippo-Yes-associated protein (YAP) pathway in GNAQ/GNA11-induced tumorigenesis in uveal melanoma (UM). However, the association between YAP activity and clinical outcomes remains elusive. We investigated possible associations between YAP activity and clinicopathological features including survival outcomes in patients with UM using The Cancer Genome Atlas (TCGA) cohort and our local cohort. We estimated YAP activity by mRNA expression levels, Gene Set Variation Analysis (GSVA) for the TCGA cohort, and immunohistochemical YAP staining for the local cohort. In the TCGA cohort, most clinicopathological features including tumor stage, mitotic counts, mutation of genes, and tumor sizes did not significantly differ between low and high YAP activity groups. In the local cohort, YAP nuclear-positive staining was observed in 30 (42%) of 72 patients with primary UM. UM-specific survival was not significantly different between tumors with low and high YAP activities. Unlike mesothelioma cells harboring a mutation of negative regulators of YAP, the survival of multiple UM cell lines was not significantly reduced by YAP/TAZ depletion. Our results suggest that the effect of YAP on development, growth, and invasion of UM in actual patients is less than previously demonstrated in experimental studies.

2010s

• Exosomal miR-16-5p as a target for malignant mesothelioma. P.B. Munson, E.M. Hall, N.H. Farina, et al. 2019;9(1):11688. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is an asbestos-induced cancer arising on the mesothelial surface of organ cavities. MM is essentially incurable without a means of early diagnosis and no successful standard of care. These facts indicate a deep chasm of knowledge that needs to be filled. Our group recently delved into MM tumor biology from the perspective of exosome-contained microRNAs (miRNAs). We discovered that the most abundant miRNAs in MM cancer exosomes were tumor suppressors, particularly miR-16-5p. This observation lead us to hypothesize that MM cells preferentially secreted tumor-suppressor miRNAs via exosomes. Through separate avenues of potential therapeutic advance, we embarked on an innovative strategy to kill MM tumor cells. We employed small molecule inhibitors to block exosome secretion, thereby reducing miR-16-5p exosome loss and replenishing cellular miR-16-5p leading to reduced tumorigenic capacity and miR-16-5p target oncoproteins CCND1 and BCL2. Additionally, we force-fed MM tumor exosomes back to MM tumor cells, which led to cell death, and a reduction in the same oncoproteins. We recapitulated these results with direct transfection of miR-16-5p, confirmed that this is a cancer-cell specific effect, and elucidated a part of the miR-16-5p mechanism of exosome loading.

• On the mechanism of the electrophysiological changes and membrane lesions induced by asbestos fiber exposure in Xenopus laevis oocytes. A. Bernareggi, G. Conte, A. Constanti, et al. 2019;9(1):2014. PubMed · Publisher · Free full text

  Abstract

  The so-called amphibole asbestos fibers are enriched with mineral iron ions, able to stimulate ROS production. We recently reported that crocidolite asbestos was able to interact with the cell membranes of Xenopus laevis oocytes, to alter their electrical membrane properties. Here, we found that applied iron ions (Fe3+) or H2O2 (for ROS generation) mimicked these effects, suggesting that at least one effect of iron-containing asbestos fiber exposure was mediated by ROS production. Furthermore, combined Fe3+ and H2O2 acted synergistically, producing a membrane effect stronger than that induced by these factors alone. Similar to crocidolite, these changes peaked within 30 minutes of incubation and vanished almost completely after 120 min. However, in the presence of cytochalasin D, which inhibits membrane actin repair mechanisms, crocidolite or applied Fe3+/H2O2 invariably produced oocyte cell death. While the electrophysiological modifications induced by crocidolite suggested a modification of an intrinsic chloride ion channel, the morphological appearance of the treated oocytes also indicated the formation of membrane "pores"; the effects of asbestos exposure may therefore consist of multiple (not necessarily exclusive) underlying mechanisms. In conclusion, using Xenopus oocytes allowed us for the first time, to focus on a specific membrane effect of crocidolite asbestos exposure, which deserves to be tested also on human lung cell lines. Much available evidence suggests that asbestos fibers damage cells through the production of ROS. Our present data confirm that crocidolite fibers can indeed trigger ROS-mediated damaging effects in the oocyte cell membrane, provided iron ions and H2O2 are available for ROS production.

• The human tubal lavage proteome reveals biological processes that may govern the pathology of hydrosalpinx. E. Yohannes, A.A. Kazanjian, M.E. Lindsay, et al. 2019;9(1):8980. PubMed · Publisher · Free full text

  Abstract

  Hydrosalpinx, the blockage of fallopian tubes, can result from pelvic inflammatory disease. Hydrosalpinx is a cause of infertility and negatively impacts in vitro fertilization. To better understand the pathobiology of hydrosalpinx, we compared the proteome of lavages from disease vs. healthy fallopian tubes. Results indicate a disruption of redox homeostasis and activation of the complement system, immune cell infiltration, and phagocytosis; pathways that may drive tubal injury. To our surprise among the most prominent proteins with hydrosalpinx was mesothelin (MSLN), which until now has only been associated with epithelial malignancies. Analogous to mesothelioma and ovarian carcinoma, a significant increase of MSLN was detected in plasma from patients with hydrosalpinx. This finding suggests MSLN may provide clinical diagnosis in lieu of the current approaches that require invasive imaging. Importantly, these findings implicate MSLN in a benign disease, indicating that the activation and role of MSLN is not restricted to cancer.

• Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy. T. Riedel, S. Cavin, H. van den Bergh, et al. 2018;8(1):10263. PubMed · Publisher · Free full text

  Abstract

  Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.

• Clay-induced DNA breaks as a path for genetic diversity, antibiotic resistance, and asbestos carcinogenesis. E. González-Tortuero, J. Rodríguez-Beltrán, R. Radek, et al. 2018;8(1):8504. PubMed · Publisher · Free full text

  Abstract

  Natural clays and synthetic nanofibres can have a severe impact on human health. After several decades of research, the molecular mechanism of how asbestos induces cancer is not well understood. Different fibres, including asbestos, can penetrate cell membranes and introduce foreign DNA in bacterial and eukaryotic cells. Incubating Escherichia coli under friction forces with sepiolite, a clayey material, or with asbestos, causes double-strand DNA breaks. Antibiotics and clays are used together in animal husbandry, the mutagenic effect of these fibres could be a pathway to antibiotic resistance due to the friction provided by peristalsis of the gut from farm animals in addition to horizontal gene transfer. Moreover, we raise the possibility that the same mechanism could generate bacteria diversity in natural scenarios, playing a role in the evolution of species. Finally, we provide a new model on how asbestos may promote mutagenesis and cancer based on the observed mechanical genotoxicity.

• Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma. E.R. Gamazon, M.R. Trendowski, Y. Wen, et al. 2018;8(1):733. PubMed · Publisher · Free full text

  Abstract

  Pemetrexed is indicated for non-small cell lung carcinoma and mesothelioma, but often has limited efficacy due to drug resistance. To probe the molecular mechanisms underlying chemotherapeutic response, we performed mRNA and microRNA (miRNA) expression profiling of pemetrexed treated and untreated lymphoblastoid cell lines (LCLs) and applied a hierarchical Bayesian method. We identified genetic variation associated with gene expression in human lung tissue for the most significant differentially expressed genes (Benjamini-Hochberg [BH] adjusted p < 0.05) using the Genotype-Tissue Expression data and found evidence for their clinical relevance using integrated molecular profiling and lung adenocarcinoma survival data from The Cancer Genome Atlas project. We identified 39 miRNAs with significant differential expression (BH adjusted p < 0.05) in LCLs. We developed a gene expression based imputation model of drug sensitivity, quantified its prediction performance, and found a significant correlation of the imputed phenotype generated from expression data with survival time in lung adenocarcinoma patients. Differentially expressed genes (MTHFD2 and SUFU) that are putative targets of differentially expressed miRNAs also showed differential perturbation in A549 fusion lung tumor cells with further replication in A549 cells. Our study suggests pemetrexed may be used in combination with agents that target miRNAs to increase its cytotoxicity.

• Identification of mesothelioma-specific sialylated epitope recognized with monoclonal antibody SKM9-2 in a mucin-like membrane protein HEG1. R. Matsuura, H. Kaji, A. Tomioka, et al. 2018;8(1):14251. PubMed · Publisher · Free full text

  Abstract

  The anti-mesothelioma mAb SKM9-2 recognizes the sialylated protein HEG homolog 1 (HEG1). HEG1 is a 400 kDa mucin-like membrane protein found on mesothelioma. SKM9-2 can detect mesothelioma more specifically and sensitively than other antibodies against current mesothelioma markers; therefore, SKM9-2 would be likely useful for the precise detection and diagnosis of malignant mesothelioma. In the present study, we investigated the epitope of SKM9-2. We analyzed the binding of SKM9-2 to truncated HEG1 and candidate epitope-fused glycosylphosphatidylinositol-anchor proteins. The epitope of SKM9-2 was identified as an O-glycosylated region, 893-SKSPSLVSLPT-903, in HEG1. An alanine scanning assay of the epitope showed that SKM9-2 bound to a simple epitope in HEG1, and the SKxPSxVS sequence within the epitope was essential for SKM9-2 recognition. Mass spectrometry analysis and lectin binding analysis of soluble epitope peptides indicated that the SKM9-2 epitope, in which Ser897 was not glycosylated, contained two disialylated core 1 O-linked glycan-modified serine residues, Ser893 and Ser900. Neuraminidase treatment analysis also confirmed that the epitope in mesothelioma cells contained a similar glycan modification. The specific detection of mesothelioma with SKM9-2 can thus be performed by the recognition of sialylated glycan modification in the specific region of HEG1.

• In vitro acellular dissolution of mineral fibres: A comparative study. A.F. Gualtieri, S. Pollastri, N. Bursi Gandolfi, et al. 2018;8(1):7071. PubMed · Publisher · Free full text

  Abstract

  The study of the mechanisms by which mineral fibres promote adverse effects in both animals and humans is a hot topic of multidisciplinary research with many aspects that still need to be elucidated. Besides length and diameter, a key parameter that determines the toxicity/pathogenicity of a fibre is biopersistence, one component of which is biodurability. In this paper, biodurability of mineral fibres of social and economic importance (chrysotile, amphibole asbestos and fibrous erionite) has been determined for the first time in a systematic comparative way from in vitro acellular dissolution experiments. Dissolution was possible using the Gamble solution as simulated lung fluid (pH = 4 and at body temperature) so to reproduce the macrophage phagolysosome environment. The investigated mineral fibres display very different dissolution rates. For a 0.25 μm thick fibre, the calculated dissolution time of chrysotile is in the range 94-177 days, very short if compared to that of amphibole fibres (49-245 years), and fibrous erionite (181 years). Diffraction and SEM data on the dissolution products evidence that chrysotile rapidly undergoes amorphization with the formation of a nanophasic silica-rich fibrous metastable pseudomorph as first dissolution step whereas amphibole asbestos and fibrous erionite show minor signs of dissolution even after 9-12 months.

• In vitro patient-derived 3D mesothelioma tumor organoids facilitate patient-centric therapeutic screening. A.R. Mazzocchi, S.A.P. Rajan, K.I. Votanopoulos, et al. 2018;8(1):2886. PubMed · Publisher · Free full text

  Abstract

  Variability in patient response to anti-cancer drugs is currently addressed by relating genetic mutations to chemotherapy through precision medicine. However, practical benefits of precision medicine to therapy design are less clear. Even after identification of mutations, oncologists are often left with several drug options, and for some patients there is no definitive treatment solution. There is a need for model systems to help predict personalized responses to chemotherapeutics. We have microengineered 3D tumor organoids directly from fresh tumor biopsies to provide patient-specific models with which treatment optimization can be performed before initiation of therapy. We demonstrate the initial implementation of this platform using tumor biospecimens surgically removed from two mesothelioma patients. First, we show the ability to biofabricate and maintain viable 3D tumor constructs within a tumor-on-a-chip microfluidic device. Second, we demonstrate that results of on-chip chemotherapy screening mimic those observed in subjects themselves. Finally, we demonstrate mutation-specific drug testing by considering the results of precision medicine genetic screening and confirming the effectiveness of the non-standard compound 3-deazaneplanocin A for an identified mutation. This patient-derived tumor organoid strategy is adaptable to a wide variety of cancers and may provide a framework with which to improve efforts in precision medicine oncology.

• Induction of protein citrullination and auto-antibodies production in murine exposed to nickel nanomaterials. B.M. Mohamed, N.T. Boyle, A. Schinwald, et al. 2018;8(1):679. PubMed · Publisher · Free full text

  Abstract

  Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity.

• Iron-related toxicity of single-walled carbon nanotubes and crocidolite fibres in human mesothelial cells investigated by Synchrotron XRF microscopy. F. Cammisuli, S. Giordani, A. Gianoncelli, et al. 2018;8(1):706. PubMed · Publisher · Free full text

  Abstract

  Carbon nanotubes (CNTs) are promising products in industry and medicine, but there are several human health concerns since their fibrous structure resembles asbestos. The presence of transition metals, mainly iron, in the fibres seems also implicated in the pathogenetic mechanisms. To unravel the role of iron at mesothelial level, we compared the chemical changes induced in MeT-5A cells by the exposure to asbestos (crocidolite) or CNTs at different content of iron impurities (raw-SWCNTs, purified- and highly purified-SWCNTs). We applied synchrotron-based X-Ray Fluorescence (XRF) microscopy and soft X-ray imaging (absorption and phase contrast images) to monitor chemical and morphological changes of the exposed cells. In parallel, we performed a ferritin assay. X-ray microscopy imaging and XRF well localize the crocidolite fibres interacting with cells, as well as the damage-related morphological changes. Differently, CNTs presence could be only partially evinced by low energy XRF through carbon distribution and sometimes iron co-localisation. Compared to controls, the cells treated with raw-SWCNTs and crocidolite fibres showed a severe alteration of iron distribution and content, with concomitant stimulation of ferritin production. Interestingly, highly purified nanotubes did not altered iron metabolism. The data provide new insights for possible CNTs effects at mesothelial/pleural level in humans.

• MUC4 immunohistochemistry is useful in distinguishing epithelioid mesothelioma from adenocarcinoma and squamous cell carcinoma of the lung. A.S. Mawas, V.J. Amatya, K. Kushitani, et al. 2018;8(1):134. PubMed · Publisher · Free full text

  Abstract

  The differential diagnosis of epithelioid mesothelioma from lung adenocarcinoma and squamous cell carcinoma requires the positive and negative immunohistochemical markers of mesothelioma. The IMIG guideline has suggested the use of Calretinin, D2-40, WT1, and CK5/6 as mesothelial markers, TTF-1, Napsin-A, Claudin 4, CEA as lung adenocarcinoma markers p40, p63, CK5/6, MOC-31 as squamous cell markers. However, use of other immunohistochemical markers is still necessary. We evaluated 65 epithelioid mesotheliomas, 60 adenocarcinomas, and 57 squamous cell carcinomas of the lung for MUC4 expression by immunohistochemistry and compared with the previously known immunohistochemical markers. MUC4 expression was not found in any of 65 cases of epithelioid mesothelioma. In contrast, MUC4 expression was observed in 50/60(83.3%) cases of lung adenocarcinoma and 50/56(89.3%) cases of lung squamous cell carcinoma. The negative MUC4 expression showed 100% sensitivity, 86.2% specificity and accuracy rate of 91.2% to differentiate epithelioid mesothelioma from lung carcinoma. The sensitivity, specificity, and accuracy of MUC4 are comparable to that of previously known markers of lung adenocarcinoma and squamous cell carcinoma, namely CEA, Claudin 4 and better than that of MOC-31. In conclusion, MUC4 immunohistochemistry is useful for differentiation of epithelioid mesothelioma from lung carcinoma, either adenocarcinoma or squamous cell carcinoma.

• Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo. C. Li, V. Rezov, E. Joensuu, et al. 2018;8(1):10070. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is an aggressive cancer with poor prognosis. It is characterized by prominent extracellular matrix, mesenchymal tumor cell phenotypes and chemoresistance. In this study, the ability of pirfenidone to alter mesothelioma cell proliferation and migration as well as mesothelioma tumor microenvironment was evaluated. Pirfenidone is an anti-fibrotic drug used in the treatment of idiopathic pulmonary fibrosis and has also anti-proliferative activities. Mesothelioma cell proliferation was decreased by pirfenidone alone or in combination with cisplatin. Pirfenidone also decreased significantly Transwell migration/invasion and 3D collagen invasion. This was associated with increased BMP pathway activity, decreased GREM1 expression and downregulation of MAPK/ERK and AKT/mTOR signaling. The canonical Smad-mediated TGF-β signaling was not affected by pirfenidone. However, pirfenidone blocked TGF-β induced upregulation of ERK and AKT pathways. Treatment of mice harboring mesothelioma xenografts with pirfenidone alone did not reduce tumor proliferation in vivo. However, pirfenidone modified the tumor microenvironment by reducing the expression of extracellular matrix associated genes. In addition, GREM1 expression was downregulated by pirfenidone in vivo. By reducing two major upregulated pathways in mesothelioma and by targeting tumor cells and the microenvironment pirfenidone may present a novel anti-fibrotic and anti-cancer adjuvant therapy for mesothelioma.

• Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin - a case-control comparison nested into a prospective cohort of asbestos-exposed workers. G. Johnen, K. Burek, I. Raiko, et al. 2018;8(1):14321. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is strongly associated with a previous asbestos exposure. To improve timely detection of MM in asbestos workers, better screening tools - like minimally-invasive biomarkers - are desirable. Between 2008 and 2018 2,769 patients with benign asbestos-related diseases were recruited to participate in annual screens. Using a nested case-control design the protein markers calretinin and mesothelin were determined by enzyme-linked immunosorbent assays in prediagnostic plasma samples of 34 MM cases as well as 136 matched controls from the cohort. Conditional on a pre-defined specificity of 98% for calretinin and 99% for mesothelin the markers reached individual sensitivities of 31% and 23%, respectively, when including the incident cases with samples taken between one and 15 months before diagnosis. The combination of both markers increased the sensitivity to 46% at 98% specificity. Marker complementation increased with earlier sampling. The marker combination improves the sensitivity of the individual markers, indicating a useful complementation and suggesting that additional markers may further improve the performance. This is the first prospective cohort study to evaluate a detection of MM by calretinin and its combination with mesothelin up to about a year before clinical diagnosis. Whether an earlier diagnosis will result in reduced mortality has yet to be demonstrated.

• Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma. T. Klikovits, P. Stockhammer, V. Laszlo, et al. 2017;7(1):16456. PubMed · Publisher · Free full text

  Abstract

  Only limited information is available on the role of complement activation in malignant pleural mesothelioma (MPM). Thus, we investigated the circulating and tissue levels of the complement component 4d (C4d) in MPM. Plasma samples from 55 MPM patients, 21 healthy volunteers (HV) and 14 patients with non-malignant pleural diseases (NMPD) were measured by ELISA for C4d levels. Tissue specimens from 32 patients were analyzed by C4d immunohistochemistry. Tumor volumetry was measured in 20 patients. We found no C4d labeling on tumor cells, but on ectopic lymphoid structures within the tumor stroma. Plasma C4d levels did not significantly differ between MPM, HV or NMPD. Late-stage MPM patients had higher plasma C4d levels compared to early-stage (p = 0.079). High circulating C4d was associated with a higher tumor volume (p = 0.047). Plasma C4d levels following induction chemotherapy were significantly higher in patients with stable/progressive disease compared to those with partial/major response (p = 0.005). Strikingly, patients with low C4d levels at diagnosis had a significantly better overall survival, confirmed in a multivariate cox regression model (hazard ratio 0.263, p = 0.01). Our findings suggest that circulating plasma C4d is a promising new prognostic biomarker in patients with MPM and, moreover, helps to select patients for surgery following induction chemotherapy.

• Clinical-pharmacogenetic models for personalized cancer treatment: application to malignant mesothelioma. K. Goričar, V. Kovač, V. Dolžan. 2017;7:46537. PubMed · Publisher · Free full text

  Abstract

  Large interindividual differences in treatment outcome are observed in cancer patients undergoing chemotherapy. Our aim was to develop and validate clinical-pharmacogenetic prediction models of gemcitabine/cisplatin or pemetrexed/cisplatin treatment outcome and develop an algorithm for genotype-based treatment recommendations in malignant mesothelioma (MM). We genotyped 189 MM patients for polymorphisms in gemcitabine, pemetrexed and cisplatin metabolism, transport and drug target genes and DNA repair pathways. To build respective clinical-pharmacogenetic models, pharmacogenetic scores were assigned by rounding regression coefficients. Gemcitabine/cisplatin model was based on training group of 71 patients and included CRP, histological type, performance status, RRM1 rs1042927, ERCC2 rs13181, ERCC1 rs3212986, and XRCC1 rs25487. Patients with higher score had shorter progression-free (PFS) and overall survival (P < 0.001). This model's sensitivity was 0.615 and specificity 0.812. In independent validation group of 66 patients the sensitivity and specificity were 0.667 and 0.641, respectively. Pemetrexed/cisplatin model was based on 57 patients and included CRP, MTHFD1 rs2236225, and ABCC2 rs2273697. Patients with higher score had worse response and shorter PFS (P < 0.001). This model's sensitivity was 0.750 and specificity 0.607. In independent validation group of 20 patients the sensitivity and specificity were 0.889 and 0.500, respectively. The proposed algorithm based on these models could enable the choice of the most effective chemotherapy for 85.5% of patients and lead to improved treatment outcome in MM.

• Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism. C. De Santi, O. Melaiu, A. Bonotti, et al. 2017;7(1):3140. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive human cancer and miRNAs can play a key role for this disease. In order to broaden the knowledge in this field, the miRNA expression was investigated in a large series of MPM to discover new pathways helpful in diagnosis, prognosis and therapy. We employed nanoString nCounter system for miRNA profiling on 105 MPM samples and 10 healthy pleura. The analysis was followed by the validation of the most significantly deregulated miRNAs by RT-qPCR in an independent sample set. We identified 63 miRNAs deregulated in a statistically significant way. MiR-185, miR-197, and miR-299 were confirmed differentially expressed, after validation study. In addition, the results of the microarray analysis corroborated previous findings concerning miR-15b-5p, miR-126-3p, and miR-145-5p. Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS) and identified a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism respectively. In silico analyses with DIANA-microT-CDS highlighted 5 putative targets in common between two miRNAs. With the present work we showed that the pattern of miRNAs expression is highly deregulated in MPM and that a 2-miRNA signature can be a new useful tool for prognosis in MPM.

• HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target for malignant mesothelioma. S. Tsuji, K. Washimi, T. Kageyama, et al. 2017;7:45768. PubMed · Publisher · Free full text

  Abstract

  The absence of highly specific markers for malignant mesothelioma (MM) has served an obstacle for its diagnosis and development of molecular-targeting therapy against MM. Here, we show that a novel mucin-like membrane protein, sialylated protein HEG homolog 1 (HEG1), is a highly specific marker for MM. A monoclonal antibody against sialylated HEG1, SKM9-2, can detect even sarcomatoid and desmoplastic MM. The specificity and sensitivity of SKM9-2 to MM reached 99% and 92%, respectively; this antibody did not react with normal tissues. This accurate discrimination by SKM9-2 was due to the recognition of a sialylated O-linked glycan with HEG1 peptide. We also found that gene silencing of HEG1 significantly suppressed the survival and proliferation of mesothelioma cells; this result suggests that HEG1 may be a worthwhile target for function-inhibition drugs. Taken together, our results indicate that sialylated HEG1 may be useful as a diagnostic and therapeutic target for MM.

• Human canonical CD157/Bst1 is an alternatively spliced isoform masking a previously unidentified primate-specific exon included in a novel transcript. E. Ferrero, N. Lo Buono, S. Morone, et al. 2017;7(1):15923. PubMed · Publisher · Free full text

  Abstract

  CD157/Bst1 is a dual-function receptor and β-NAD+-metabolizing ectoenzyme of the ADP-ribosyl cyclase family. Expressed in human peripheral blood neutrophils and monocytes, CD157 interacts with extracellular matrix components and regulates leukocyte diapedesis via integrin-mediated signalling in inflammation. CD157 also regulates cell migration and is a marker of adverse prognosis in epithelial ovarian cancer and pleural mesothelioma. One form of CD157 is known to date: the canonical sequence of 318 aa from a 9-exon transcript encoded by BST1 on human chromosome 4. Here we describe a second BST1 transcript, consisting of 10 exons, in human neutrophils. This transcript includes an unreported exon, exon 1b, located between exons 1 and 2 of BST1. Inclusion of exon 1b in frame yields CD157-002, a novel proteoform of 333 aa: exclusion of exon 1b by alternative splicing generates canonical CD157, the dominant proteoform in neutrophils and other tissues analysed here. In comparative functional analyses, both proteoforms were indistinguishable in cell surface localization, specific mAb binding, and behaviour in cell adhesion and migration. However, NAD glycohydrolase activity was detected in canonical CD157 alone. Comparative phylogenetics indicate that exon 1b is a genomic innovation acquired during primate evolution, pointing to the importance of alternative splicing for CD157 function.

• Mantle hydration along outer-rise faults inferred from serpentinite permeability. K. Hatakeyama, I. Katayama, K.I. Hirauchi, et al. 2017;7(1):13870. PubMed · Publisher · Free full text

  Abstract

  Recent geophysical surveys indicate that hydration (serpentinization) of oceanic mantle is related to outer-rise faulting prior to subduction. The serpentinization of oceanic mantle influences the generation of intermediate-depth earthquakes and subduction water flux, thereby promoting arc volcanism. Since the chemical reactions that produce serpentinite are geologically rapid at low temperatures, the flux of water delivery to the reaction front appears to control the lateral extent of serpentinization. In this study, we measured the permeability of low-temperature serpentinites composed of lizardite and chrysotile, and calculated the lateral extent of serpentinization along an outer-rise fault based on Darcy's law. The experimental results indicate that serpentinization extends to a region several hundred meters wide in the direction normal to the outer-rise fault in the uppermost oceanic mantle. We calculated the global water flux carried by serpentinized oceanic mantle ranging from 1.7 × 1011 to 2.4 × 1012 kg/year, which is comparable or even higher than the water flux of hydrated oceanic crust.

• Microplastics in eviscerated flesh and excised organs of dried fish. A. Karami, A. Golieskardi, Y.B. Ho, et al. 2017;7(1):5473. PubMed · Publisher · Free full text

  Abstract

  There is a paucity of information about the occurrence of microplastics (MPs) in edible fish tissues. Here, we investigated the potential presence of MPs in the excised organs (viscera and gills) and eviscerated flesh (whole fish excluding the viscera and gills) of four commonly consumed dried fish species (n = 30 per species). The MP chemical composition was then determined using micro-Raman spectroscopy and elemental analysis with energy-dispersive X-ray spectroscopy (EDX). Out of 61 isolated particles, 59.0% were plastic polymers, 21.3% were pigment particles, 6.55% were non-plastic items (i.e. cellulose or actinolite), while 13.1% remained unidentified. The level of heavy metals on MPs or pigment particles were below the detection limit. Surprisingly, in two species, the eviscerated flesh contained higher MP loads than the excised organs, which highlights that evisceration does not necessarily eliminate the risk of MP intake by consumers. Future studies are encouraged to quantify anthropogenic particle loads in edible fish tissues.

• New insights on the biomineralisation process developing in human lungs around inhaled asbestos fibres. F. Bardelli, G. Veronesi, S. Capella, et al. 2017;7:44862. PubMed · Publisher · Free full text

  Abstract

  Once penetrated into the lungs of exposed people, asbestos induces an in vivo biomineralisation process that leads to the formation of a ferruginous coating embedding the fibres. The ensemble of the fibre and the coating is referred to as asbestos body and is believed to be responsible for the high toxicological outcome of asbestos. Lung tissue of two individuals subjected to prolonged occupational exposure to crocidolite asbestos was investigated using synchrotron radiation micro-probe tools. The distribution of K and of elements heavier than Fe (Zn, Cu, As, and Ba) in the asbestos bodies was observed for the first time. Elemental quantification, also reported for the first time, confirmed that the coating is highly enriched in Fe (~20% w/w), and x-ray absorption spectroscopy indicated that Fe is in the 3+ oxidation state and that it is present in the form of ferritin or hemosiderin. Comparison of the results obtained studying the asbestos bodies upon removing the biological tissue by chemical digestion and those embedded in histological sections, allowed unambiguously distinguishing the composition of the asbestos bodies, and understanding to what extent the digestion procedure altered their chemical composition. A speculative model is proposed to explain the observed distribution of Fe.

• Particles of different sizes and shapes induce neutrophil necroptosis followed by the release of neutrophil extracellular trap-like chromatin. J. Desai, O. Foresto-Neto, M. Honarpisheh, et al. 2017;7(1):15003. PubMed · Publisher · Free full text

  Abstract

  The human body is exposed to a wide range of particles of industrial, environmental or internal origin such as asbestos, alum, silica or crystals of urate, calcium phosphate, calcium oxalate, cystine or cholesterol. Phagocytic clearance of such particles involves neutrophils and macrophages. Here we report that neutrophils encountering such particles of diverse sizes and shapes undergo necrotic cell death, a process associated with the formation of neutrophil extracellular trap (NET)-like extracellular DNA. In human neutrophils receptor-interacting protein kinase (RIPK)-1 inhibition with necrostatin-1s or mixed lineage kinase domain-like (MLKL) inhibition with necrosulfonamide abrogated cell death and associated-neutrophil extracellular DNA release induced by all of the aforementioned particles. Similar results were obtained with Mlkl-deficient mice neutrophils for all particles in vitro. Furthermore, Mlkl-deficient mice lacked tophus formation upon injection of MSU crystals into subcutaneous air pouches. These findings imply that nano- or microparticle-induced neutrophil extracellular DNA release is the consequence of neutrophil necroptosis, a regulated form of cell necrosis defined by RIPK1-RIPK3-MLKL signaling. Interestingly, this finding was consistent across different particle sizes and shapes. The RIPK1-RIPK3-MLKL signaling pathway may represent a potential therapeutic target in nano- or microparticle-related diseases (crystallopathies).

• Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis. F. Cerruti, G. Jocollè, C. Salio, et al. 2017;7(1):17626. PubMed · Publisher · Free full text

  Abstract

  Based on promising results in preclinical models, clinical trials have been performed to evaluate the efficacy of the first-in-class proteasome inhibitor bortezomib towards malignant pleural mesothelioma (MPM), an aggressive cancer arising from the mesothelium of the serous cavities following exposure to asbestos. Unexpectedly, only minimal therapeutic benefits were observed, thus implicating that MPM harbors inherent resistance mechanisms. Identifying the molecular bases of this primary resistance is crucial to develop novel pharmacologic strategies aimed at increasing the vulnerability of MPM to bortezomib. Therefore, we assessed a panel of four human MPM lines with different sensitivity to bortezomib, for functional proteasome activity and levels of free and polymerized ubiquitin. We found that highly sensitive MPM lines display lower proteasome activity than more bortezomib-resistant clones, suggesting that reduced proteasomal capacity might contribute to the intrinsic susceptibility of mesothelioma cells to proteasome inhibitors-induced apoptosis. Moreover, MPM equipped with fewer active proteasomes accumulated polyubiquitinated proteins, at the expense of free ubiquitin, a condition known as proteasome stress, which lowers the cellular apoptotic threshold and sensitizes mesothelioma cells to bortezomib-induced toxicity as shown herein. Taken together, our data suggest that an unfavorable load-versus-capacity balance represents a critical determinant of primary apoptotic sensitivity to bortezomib in MPM.

• Risk of other Cancers in Families with Melanoma: Novel Familial Links. C. Frank, J. Sundquist, A. Hemminki, et al. 2017;7:42601. PubMed · Publisher · Free full text

  Abstract

  A family history of cutaneous melanoma ('melanoma') is a well-established risk factor for melanoma. However, less is known about the possible familial associations of melanoma with other discordant cancers. A risk for discordant cancer may provide useful information about shared genetic and environmental risk factors and it may be relevant background data in clinical genetic counseling. Using the Swedish Family-Cancer Database, we assessed the relative risk (RR) for any cancer in families with increasing numbers of first-degree relatives diagnosed with melanoma, including multiple melanoma, and in reverse order RR for melanoma in families of multiple discordant cancers. Close to 9% of melanoma was familial; among these 92% were in 2-case families and 8% in families with 3 cases or more. Cancers that were associated with melanoma, in at least two independent analyses, included breast, prostate, colorectal, skin and nervous system cancers. Other associations included cancer of unknown primary, acute myeloid leukemia/myelofibrosis and Waldenström macroglobulinemia/myeloma. Significant results, which appear biologically plausible, were also obtained for rare nasal melanoma and mesothelioma. Although small samples sizes and multiple comparisons were of concern, many of the above associations were internally consistent and provide new diverse leads for discordant familial association of melanoma.

• Spatial and molecular resolution of diffuse malignant mesothelioma heterogeneity by integrating label-free FTIR imaging, laser capture microdissection and proteomics. F. Großerueschkamp, T. Bracht, H.C. Diehl, et al. 2017;7:44829. PubMed · Publisher · Free full text

  Abstract

  Diffuse malignant mesothelioma (DMM) is a heterogeneous malignant neoplasia manifesting with three subtypes: epithelioid, sarcomatoid and biphasic. DMM exhibit a high degree of spatial heterogeneity that complicates a thorough understanding of the underlying different molecular processes in each subtype. We present a novel approach to spatially resolve the heterogeneity of a tumour in a label-free manner by integrating FTIR imaging and laser capture microdissection (LCM). Subsequent proteome analysis of the dissected homogenous samples provides in addition molecular resolution. FTIR imaging resolves tumour subtypes within tissue thin-sections in an automated and label-free manner with accuracy of about 85% for DMM subtypes. Even in highly heterogeneous tissue structures, our label-free approach can identify small regions of interest, which can be dissected as homogeneous samples using LCM. Subsequent proteome analysis provides a location specific molecular characterization. Applied to DMM subtypes, we identify 142 differentially expressed proteins, including five protein biomarkers commonly used in DMM immunohistochemistry panels. Thus, FTIR imaging resolves not only morphological alteration within tissue but it resolves even alterations at the level of single proteins in tumour subtypes. Our fully automated workflow FTIR-guided LCM opens new avenues collecting homogeneous samples for precise and predictive biomarkers from omics studies.

• Surface reactivity of amphibole asbestos: a comparison between crocidolite and tremolite. G.B. Andreozzi, A. Pacella, I. Corazzari, et al. 2017;7(1):14696. PubMed · Publisher · Free full text

  Abstract

  Among asbestos minerals, fibrous riebeckite (crocidolite) and tremolite share the amphibole structure but largely differ in terms of their iron content and oxidation state. In asbestos toxicology, iron-generated free radicals are largely held as one of the causes of asbestos malignant effect. With the aim of clarifying i) the relationship between Fe occurrence and asbestos surface reactivity, and ii) how free-radical generation is modulated by surface modifications of the minerals, UICC crocidolite and fibrous tremolite from Maryland were leached from 1 day to 1 month in an oxidative medium buffered at pH 7.4 to induce redox alterations and surface rearrangements that may occur in body fluids. Structural and chemical modifications and free radical generation were monitored by HR-TEM/EDS and spin trapping/EPR spectroscopy, respectively. Free radical yield resulted to be dependent on few specific Fe2+ and Fe3+ surface sites rather than total Fe content. The evolution of reactivity with time highlighted that low-coordinated Fe ions primarily contribute to the overall reactivity of the fibre. Current findings contribute to explain the causes of the severe asbestos-induced oxidative stress at molecular level also for iron-poor amphiboles, and demonstrate that asbestos have a sustained surface radical activity even when highly altered by oxidative leaching.

• The mechanism of iron binding processes in erionite fibres. A. Pacella, C. Cremisini, E. Nardi, et al. 2017;7(1):1319. PubMed · Publisher · Free full text

  Abstract

  Fibrous erionite-Na from Rome (Oregon, USA) was K-exchanged and characterized from the structural point of view. In addition, the modifications experienced after contact with a Fe(II) source were investigated for evaluating if the large potassium ions, blocking off nearly all the erionite cavity openings, might prevent the Fe(II) binding process, which is currently assumed to be one of the reasons of the toxicity of erionite. The K-exchanged sample had a 95% reduction of the BET surface area indicating that it behaves as a mesoporous material. Exchanged K is segregated at K2 and at OW sites commonly occupied by H2O. The latter K cations provide a relevant contribution to the reduction of the surface area. Surprisingly, despite the collapse of its surface area the sample preserves the tendency to bind Fe(II). Therefore, yet in the case of a peculiar and potentially hostile structural environment the Fe(II) ion-exchange process has essentially the same kinetics observed in a typical erionite sample. This is a clear evidence of the very limited effect of the chemical composition of erionite on the Fe(II) binding process and reasonably it does not play a significant role in its toxicity.

• 3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors. S. Giordano, L. Morosi, P. Veglianese, et al. 2016;6:37027. PubMed · Publisher · Free full text

  Abstract

  Mass Spectrometry Imaging (MSI) is a widespread technique used to qualitatively describe in two dimensions the distribution of endogenous or exogenous compounds within tissue sections. Absolute quantification of drugs using MSI is a recent challenge that just in the last years has started to be addressed. Starting from a two dimensional MSI protocol, we developed a three-dimensional pipeline to study drug penetration in tumors and to develop a new drug quantification method by MALDI MSI. Paclitaxel distribution and concentration in different tumors were measured in a 3D model of Malignant Pleural Mesothelioma (MPM), which is known to be a very heterogeneous neoplasm, highly resistant to different drugs. The 3D computational reconstruction allows an accurate description of tumor PTX penetration, adding information about the heterogeneity of tumor drug distribution due to the complex microenvironment. The use of an internal standard, homogenously sprayed on tissue slices, ensures quantitative results that are similar to those obtained using HPLC. The 3D model gives important information about the drug concentration in different tumor sub-volumes and shows that the great part of each tumor is not reached by the drug, suggesting the concept of pseudo-resistance as a further explanation for ineffective therapies and tumors relapse.

• A Subset of Malignant Mesothelioma Tumors Retain Osteogenic Potential. S.M. Lansley, B. Pedersen, C. Robinson, et al. 2016;6:36349. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is an aggressive serosal tumor associated with asbestos exposure. We previously demonstrated that mesothelial cells differentiate into cells of different mesenchymal lineages and hypothesize that osseous tissue observed in a subset of MM patients is due to local differentiation of MM cells. In this study, the capacity of human and mouse MM cells to differentiate into osteoblast-like cells was determined in vitro using a functional model of bone nodule formation and in vivo using an established model of MM. Human and murine MM cell lines cultured in osteogenic medium expressed alkaline phosphatase and formed mineralized bone-like nodules. Several human and mouse MM cell lines also expressed a number of osteoblast phenotype markers, including runt-related transcription factor 2 (RUNX2), osteopontin, osteonectin and bone sialoprotein mRNA and protein. Histological analysis of murine MM tumors identified areas of ossification within the tumor, similar to those observed in human MM biopsies. These data demonstrate the ability of MM to differentiate into another mesenchymal cell type and suggest that MM cells may contribute to the formation of the heterologous elements observed in MM tumors.

• Erionite-Na upon heating: dehydration dynamics and exchangeable cations mobility. P. Ballirano, A. Pacella. 2016;6:22786. PubMed · Publisher · Free full text

  Abstract

  Erionite is a fibrous zeolite significantly more tumorigenic than crocidolite asbestos upon inhalation. In recent years, several papers have been published aimed at characterizing from the crystal-chemical point of view erionite fibres. As their toxicity has been ascribed to Fe acquired within the human body, studies aimed at characterizing the iron topochemistry have also been published, suggesting a possible important role played by the ionic exchange properties and cations mobility of this zeolite on developing carcinogenicity. Here we report the analysis results of the thermal behaviour of erionite-Na, which has been found to deviate significantly from that of erionite-K. This result is in contrast with the current scientific view that differences in weighted ionic potential, Si/Al ratio and size of exchangeable cations result in significantly different thermal behaviours, all those parameters being nearly identical or very similar in both species. The different mobility of the extraframework cations observed in erionite samples with dissimilar chemistry is of particular interest within the frame of the hypothesis that their biological activity could depend, apart from surface interactions, also on bulk effects.

• Fine needle aspirate flow cytometric phenotyping characterizes immunosuppressive nature of the mesothelioma microenvironment. P.H. Lizotte, R.E. Jones, L. Keogh, et al. 2016;6:31745. PubMed · Publisher · Free full text

  Abstract

  With the emergence of checkpoint blockade and other immunotherapeutic drugs, and the growing adoption of smaller, more flexible adaptive clinical trial designs, there is an unmet need to develop diagnostics that can rapidly immunophenotype patient tumors. The ability to longitudinally profile the tumor immune infiltrate in response to immunotherapy also presents a window of opportunity to illuminate mechanisms of resistance. We have developed a fine needle aspirate biopsy (FNA) platform to perform immune profiling on thoracic malignancies. Matching peripheral blood, bulk resected tumor, and FNA were analyzed from 13 mesothelioma patients. FNA samples yielded greater numbers of viable cells when compared to core needle biopsies. Cell numbers were adequate to perform flow cytometric analyses on T cell lineage, T cell activation and inhibitory receptor expression, and myeloid immunosuppressive checkpoint markers. FNA samples were representative of the tumor as a whole as assessed by head-to-head comparison to single cell suspensions of dissociated whole tumor. Parallel analysis of matched patient blood enabled us to establish quality assurance criteria to determine the accuracy of FNA procedures to sample tumor tissue. FNA biopsies provide a diagnostic to rapidly phenotype the tumor immune microenvironment that may be of great relevance to clinical trials.

• Heterogeneity of paclitaxel distribution in different tumor models assessed by MALDI mass spectrometry imaging. S. Giordano, M. Zucchetti, A. Decio, et al. 2016;6:39284. PubMed · Publisher · Free full text

  Abstract

  The penetration of anticancer drugs in solid tumors is important to ensure the therapeutic effect, so methods are needed to understand drug distribution in different parts of the tumor. Mass spectrometry imaging (MSI) has great potential in this field to visualize drug distribution in organs and tumor tissues with good spatial resolution and superior specificity. We present an accurate and reproducible imaging method to investigate the variation of drug distribution in different parts of solid tumors. The method was applied to study the distribution of paclitaxel in three ovarian cancer models with different histopathological characteristics and in colon cancer (HCT116), breast cancer (MDA-MB-231) and malignant pleural mesothelioma (MPM487). The heterogeneous drug penetration in the tumors is evident from the MALDI imaging results and from the images analysis. The differences between the various models do not always relate to significant changes in drug content in tumor homogenate examined by classical HPLC analysis. The specificity of the method clarifies the heterogeneity of the drug distribution that is analyzed from a quantitative point of view too, highlighting how marked are the variations of paclitaxel amounts in different part of solid tumors.

• Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells. R. Mezzapelle, E. Rrapaj, E. Gatti, et al. 2016;6:22850. PubMed · Publisher · Free full text

  Abstract

  Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment.

• Intrapleural Adenoviral-mediated Endothelial Cell Protein C Receptor Gene Transfer Suppresses the Progression of Malignant Pleural Mesothelioma in a Mouse Model. S. Keshava, L.V. Rao, U.R. Pendurthi. 2016;6:36829. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer with a high mortality rate as it responds poorly to standard therapeutic interventions. Our recent studies showed that expression of endothelial cell protein C receptor (EPCR) in MPM cells suppresses tumorigenicity. The present study was aimed to investigate the mechanism by which EPCR suppresses MPM tumor growth and evaluate whether EPCR gene therapy could suppress the progression of MPM in a mouse model of MPM. Measurement of cytokines from the pleural lavage showed that mice implanted with MPM cells expressing EPCR had elevated levels of IFNγ and TNFα compared to mice implanted with MPM cells lacking EPCR. In vitro studies demonstrated that EPCR expression renders MPM cells highly susceptible to IFNγ + TNFα-induced apoptosis. Intrapleural injection of Ad.EPCR into mice with an established MPM originating from MPM cells lacking EPCR reduced the progression of tumor growth. Ad.EPCR treatment elicited recruitment of macrophages and NK cells into the tumor microenvironment and increased IFNγ and TNFα levels in the pleural space. Ad.EPCR treatment resulted in a marked increase in tumor cell apoptosis. In summary, our data show that EPCR expression in MPM cells promotes tumor cell apoptosis, and intrapleural EPCR gene therapy suppresses MPM progression.

• MINDEC-An Enhanced Negative Depletion Strategy for Circulating Tumour Cell Enrichment. M. Lapin, K. Tjensvoll, S. Oltedal, et al. 2016;6:28929. PubMed · Publisher · Free full text

  Abstract

  Most current methods of circulating tumour cell (CTC) enrichment target the epithelial protein EpCAM, which is commonly expressed in adenocarcinoma cells. However, such methods will not recover the fraction of CTCs that have a non-epithelial phenotype due to epithelial-mesenchymal transition. For phenotype-independent CTC enrichment, we developed a new enhanced negative depletion strategy-termed MINDEC-that is based on multi-marker (CD45, CD16, CD19, CD163, and CD235a/GYPA) depletion of blood cells rather than targeted enrichment of CTCs. Here we validated the performance of MINDEC using epithelial and mesenchymal cancer cell lines, demonstrating a mean recovery of 82 ± 10%, high depletion (437 ± 350 residual white blood cells (WBCs)/mL peripheral blood), linearity between spiked and recovered cells (correlation coefficient: r = 0.995), and a low detection limit (≥1 cell recovered in all four replicates spiked with 3 cells). For clinical validation of this method, we enumerated CTCs in peripheral blood samples from patients with metastatic pancreatic cancer, detecting CTCs in 15 of 21 blood samples (71%) from 9 patients. The promising performance of the MINDEC enrichment strategy in our study encourages validation in larger clinical trials.

• PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma. R. Kanteti, J.J. Riehm, I. Dhanasingh, et al. 2016;6:32992. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth. Treatment of MPM cells with these inhibitors also significantly decreased cell migration, and the combination of them was synergistic. Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase. Using a PDX mouse model, we showed that a combination of crizotinib with BKM120 was highly synergetic in inhibiting MPM tumor growth. In conclusion our findings suggest that dual inhibition of PI3K and MET pathway is an effective strategy in treating MPM as compared to a single agent.

• Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo. D.W. Greening, H. Ji, M. Chen, et al. 2016;6:32643. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets.

• Two-Step Delivery: Exploiting the Partition Coefficient Concept to Increase Intratumoral Paclitaxel Concentrations In vivo Using Responsive Nanoparticles. A.H. Colby, R. Liu, M.D. Schulz, et al. 2016;6:18720. PubMed · Publisher · Free full text

  Abstract

  Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of peritoneal cancers, including mesothelioma, ovarian, and pancreatic cancer, which regularly employ regimens of intravenous and/or intraperitoneal chemotherapy (e.g., gemcitabine, cisplatin, pemetrexed, and paclitaxel) with limited results. Here, we show that a "two-step" nanoparticle (NP) delivery system may address this limitation. This two-step approach involves the separate administration of NP and drug where, first, the NP localizes to tumor. Second, subsequent administration of drug then rapidly concentrates into the NP already stationed within the target tissue. This two-step method results in a greater than 5-fold increase in intratumoral drug concentrations compared to conventional "drug-alone" administration. These results suggest that this unique two-step delivery may provide a novel method for increasing drug concentrations in target tissues.

• Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma. F.E. Lennon, G.C. Cianci, R. Kanteti, et al. 2016;6:24578. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma (MM), is an intractable disease with limited therapeutic options and grim survival rates. Altered metabolic and mitochondrial functions are hallmarks of MM and most other cancers. Mitochondria exist as a dynamic network, playing a central role in cellular metabolism. MM cell lines display a spectrum of altered mitochondrial morphologies and function compared to control mesothelial cells. Fractal dimension and lacunarity measurements are a sensitive and objective method to quantify mitochondrial morphology and most importantly are a promising predictor of response to mitochondrial inhibition. Control cells have high fractal dimension and low lacunarity and are relatively insensitive to mitochondrial inhibition. MM cells exhibit a spectrum of sensitivities to mitochondrial inhibitors. Low mitochondrial fractal dimension and high lacunarity correlates with increased sensitivity to the mitochondrial inhibitor metformin. Lacunarity also correlates with sensitivity to Mdivi-1, a mitochondrial fission inhibitor. MM and control cells have similar sensitivities to cisplatin, a chemotherapeutic agent used in the treatment of MM. Neither oxidative phosphorylation nor glycolytic activity, correlated with sensitivity to either metformin or mdivi-1. Our results suggest that mitochondrial inhibition may be an effective and selective therapeutic strategy in mesothelioma, and identifies mitochondrial morphology as a possible predictor of response to targeted mitochondrial inhibition.

• Where is iron in erionite? A multidisciplinary study on fibrous erionite-Na from Jersey (Nevada, USA). A.F. Gualtieri, N.B. Gandolfi, S. Pollastri, et al. 2016;6:37981. PubMed · Publisher · Free full text

  Abstract

  Fibrous erionite is a mineral fibre of great concern but to date mechanisms by which it induces cyto- and geno-toxic damage, and especially the role of iron associated to this zeolite species, remain poorly understood. One of the reasons is that we still don't know exactly where iron is in natural erionite. This work is focused on fibrous erionite-Na from Jersey (Nevada, USA) and attempts to draw a general model of occurrence of iron in erionite and relationship with toxicity mechanisms. It was found that iron is present as 6-fold coordinated Fe3+ not part of the zeolite structure. The heterogeneous nature of the sample was revealed as receptacle of different iron-bearing impurities (amorphous iron-rich nanoparticles, micro-particles of iron oxides/hydroxides, and flakes of nontronite). If iron is not part of the structure, its role should be considered irrelevant for erionite toxicity, and other factors like biopersistence should be invoked. An alternative perspective to the proposed model is that iron rich nano-particles and nontronite dissolve in the intracellular acidic environment, leaving a residue of iron atoms at specific surface sites anchored to the windows of the zeolite channels. These sites may be active later as low nuclearity groups.

• A Deep Look Into Erionite Fibres: an Electron Microscopy Investigation of their Self-Assembly. R. Matassa, G. Familiari, M. Relucenti, et al. 2015;5:16757. PubMed · Publisher · Free full text

  Abstract

  The exposure of humans to erionite fibres of appropriate morphology and dimension has been unambiguously linked to the occurrence of Malignant Mesothelioma. For this reason, a detailed morpho-structural investigation through Electron Microscopy techniques has been performed on erionite samples collected at two different localities, Durkee (ED) and Rome (ER), Oregon, USA. The sample from Rome has been also investigated after a prolonged leaching with Gamble's solution (ER4G) in order to evaluate the possible occurrence of morpho-structural modifications induced by this Simulated-Lung-Fluid (SLF). Here we report how the micrometric erionite fibres evolve in irregular ribbon- or rod-like bundles as a function of different nano-structural features. The reasons for the observed morphological variability have been explained by considering the structural defects located at ED surface fibrils (bi-dimensional ribbons) and the presence of nontronite, an iron-bearing clay mineral embedding the ER fibrils (mono-dimensional rods). ER4G shows a decrease in width of the rod-like fibres due to their partial digestion by SLF leaching, which synchronously dissolves nontronite. The reported results represent a valuable background toward the full comprehension of the morphological mechanisms responsible for potentially damage of lung tissue through the potential relocation of fibers to extrapulmonary sites, increasing the carcinogenic risk to humans.

• Diagnostic accuracy of calretinin for malignant mesothelioma in serous effusions: a meta-analysis. D. Li, B. Wang, H. Long, et al. 2015;5:9507. Meta-analysis PubMed · Publisher · Free full text

  Abstract

  Numerous studies have investigated the utility of calretinin in differentiating malignant mesothelioma (MM) from metastatic carcinoma (MC) in serous effusions. However, the results remain controversial. The aim of this study is to determine the overall accuracy of calretinin in serous effusions for MM through a meta-analysis of published studies. Publications addressing the accuracy of calretinin in the diagnosis of MM were selected from the Medline (Ovid), PubMed, the Cochrane Library Database and the Web of Science. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratio (LR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve. Statistical analysis was performed by Meta-Disc 1.4 and STATA 12.0 softwares. 18 studies met the inclusion criteria and the summary estimating for calretinin in the diagnosis of MM were: sensitivity 0.91 (95%CI: 0.87-0.94), specificity 0.96 (95%CI: 0.95-0.96), positive likelihood ratio (PLR) 14.42 (95%CI: 7.92-26.26), negative likelihood ratio (NLR) 0.1 (95%CI: 0.05-0.2) and diagnostic odds ratio 163.03 (95%CI: 54.62-486.63). The SROC curve indicated that the maximum joint sensitivity and specificity (Q-value) was 0.92; the area under the curve was 0.97. Our findings suggest that calretinin may be a useful diagnostic tool for confirming MM in serous effusions.

• Differential protein folding and chemical changes in lung tissues exposed to asbestos or particulates. L. Pascolo, V. Borelli, V. Canzonieri, et al. 2015;5:12129. PubMed · Publisher · Free full text

  Abstract

  Environmental and occupational inhalants may induce a large number of pulmonary diseases, with asbestos exposure being the most risky. The mechanisms are clearly related to chemical composition and physical and surface properties of materials. A combination of X-ray fluorescence (μXRF) and Fourier Transform InfraRed (μFTIR) microscopy was used to chemically characterize and compare asbestos bodies versus environmental particulates (anthracosis) in lung tissues from asbestos exposed and control patients. μXRF analyses revealed heterogeneously aggregated particles in the anthracotic structures, containing mainly Si, K, Al and Fe. Both asbestos and particulates alter lung iron homeostasis, with a more marked effect in asbestos exposure. μFTIR analyses revealed abundant proteins on asbestos bodies but not on anthracotic particles. Most importantly, the analyses demonstrated that the asbestos coating proteins contain high levels of β-sheet structures. The occurrence of conformational changes in the proteic component of the asbestos coating provides new insights into long-term asbestos effects.

• Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations. W.J. Lesterhuis, C. Rinaldi, A. Jones, et al. 2015;5:12298. PubMed · Publisher · Free full text

  Abstract

  Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade. Network analysis of gene expression profiling data from responding versus non-responding tumours was employed to identify modules associated with response. Targeting the modules via selective modulation of hub genes or alternatively by using repurposed pharmaceuticals selected on the basis of their expression perturbation signatures dramatically enhanced the efficacy of CTLA4 blockade in this model. Our approach provides a powerful platform to repurpose drugs, and define contextually relevant novel therapeutic targets.

• New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma. Y.F. Zhang, Y. Phung, W. Gao, et al. 2015;5:9928. PubMed · Publisher · Free full text

  Abstract

  Mesothelin is an emerging cell surface target in mesothelioma and other solid tumors. Most antibody drug candidates recognize highly immunogenic Region I (296-390) on mesothelin. Here, we report a group of high-affinity non-Region I rabbit monoclonal antibodies. These antibodies do not compete for mesothelin binding with the immunotoxin SS1P that binds Region I of mesothelin. One pair of antibodies (YP218 and YP223) is suitable to detect soluble mesothelin in a sandwich ELISA with high sensitivity. The new assay can also be used to measure serum mesothelin concentration in mesothelioma patients, indicating its potential use for monitoring patients treated with current antibody therapies targeting Region I. The antibodies are highly specific and sensitive in immunostaining of mesothelioma. To explore their use in tumor therapy, we have generated the immunotoxins based on the Fv of these antibodies. One immunotoxin (YP218 Fv-PE38) exhibits potent anti-tumor cytotoxicity towards primary mesothelioma cell lines in vitro and an NCI-H226 xenograft tumor in mice. Furthermore, we have engineered a humanized YP218 Fv that retains full binding affinity for mesothelin-expressing cancer cells. In conclusion, with their unique binding properties, these antibodies may be promising candidates for monitoring and treating mesothelioma and other mesothelin-expressing cancers.

• Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer. B.D. Ferguson, Y.H. Carol Tan, R.S. Kanteti, et al. 2015;5:10641. PubMed · Publisher · Free full text

  Abstract

  Lung cancer outcomes remain poor despite the identification of several potential therapeutic targets. The EPHB4 receptor tyrosine kinase (RTK) has recently emerged as an oncogenic factor in many cancers, including lung cancer. Mutations of EPHB4 in lung cancers have previously been identified, though their significance remains unknown. Here, we report the identification of novel EPHB4 mutations that lead to putative structural alterations as well as increased cellular proliferation and motility. We also conducted a bioinformatic analysis of these mutations to demonstrate that they are mutually exclusive from other common RTK variants in lung cancer, that they correspond to analogous sites of other RTKs' variations in cancers, and that they are predicted to be oncogenic based on biochemical, evolutionary, and domain-function constraints. Finally, we show that EPHB4 mutations can induce broad changes in the kinome signature of lung cancer cells. Taken together, these data illuminate the role of EPHB4 in lung cancer and further identify EPHB4 as a potentially important therapeutic target.

• Establishing a panel of chemo-resistant mesothelioma models for investigating chemo-resistance and identifying new treatments for mesothelioma. A.L. Hudson, C. Weir, E. Moon, et al. 2014;4:6152. PubMed · Publisher · Free full text

  Abstract

  Mesothelioma is inherently chemo-resistant with only 50% of patients responding to the standard of care treatments, and consequently it has a very grim prognosis. The aim of this study was to establish a panel of chemo-resistant mesothelioma models with clinically relevant levels of resistance as tools for investigating chemo-resistance and identifying new treatments for mesothelioma. Chemo-resistant cell lines were established in vitro and characterized in vivo using syngeneic Fischer rats. Tumors derived from all chemo-resistant cell lines were immunohistochemically classified as mesothelioma. Homozygous deletion of p16(INK4A)/p14(ARF) and increased expression of several ATP-binding cassette transporters were demonstrated, consistent with findings in human mesothelioma. Further, the acquisition of chemo-resistance in vitro resulted in changes to tumor morphology and overall survival. In conclusion, these models display many features corresponding with the human disease, and provide the first series of matched parental and chemo-resistant models for in vitro and in vivo mesothelioma studies.

• The interaction of asbestos and iron in lung tissue revealed by synchrotron-based scanning X-ray microscopy. L. Pascolo, A. Gianoncelli, G. Schneider, et al. 2013;3:1123. PubMed · Publisher · Free full text

  Abstract

  Asbestos is a potent carcinogen associated with malignant mesothelioma and lung cancer but its carcinogenic mechanisms are still poorly understood. Asbestos toxicity is ascribed to its particular physico-chemical characteristics, and one of them is the presence of and ability to adsorb iron, which may cause an alteration of iron homeostasis in the tissue. This observational study reports a combination of advanced synchrotron-based X-ray imaging and micro-spectroscopic methods that provide correlative morphological and chemical information for shedding light on iron mobilization features during asbestos permanence in lung tissue. The results show that the processes responsible for the unusual distribution of iron at different stages of interaction with the fibres also involve calcium, phosphorus and magnesium. It has been confirmed that the dominant iron form present in asbestos bodies is ferritin, while the concurrent presence of haematite suggests alteration of iron chemistry during asbestos body permanence.

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