Multiple institutions’ research findings using the National Mesothelioma Virtual Bank

Seemran Barapatre; Waqas Amin; Yuhe Gao; Yaming Li; Michael John Becich; Ye Ye

doi:10.12688/f1000research.127060.1

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Multiple institutions’ research findings using the National Mesothelioma Virtual Bank

[version 1; peer review: 1 not approved]

Seemran Barapatre¹, Waqas Amin², Yuhe Gao¹, Yaming Li¹, Michael John Becich¹, Ye Ye¹

Seemran Barapatre¹, Waqas Amin², [...] Yuhe Gao¹, Yaming Li¹, Michael John Becich¹, Ye Ye¹

PUBLISHED 18 Nov 2022

Author details Author details

¹ Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15206, USA
² Clinical and Translational Sciences Institute, Indiana University School of Medicine, indianapolis, IN, 46202, USA

Seemran Barapatre
Roles: Methodology, Writing – Original Draft Preparation

Waqas Amin
Roles: Writing – Review & Editing

Yuhe Gao
Roles: Writing – Review & Editing

Yaming Li
Roles: Writing – Review & Editing

Michael John Becich
Roles: Project Administration, Supervision

Ye Ye
Roles: Project Administration, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Mesothelioma remains an under-researched cancerous disease due to the lack of high-quality patient samples and clinical information especially outcomes and asbestos exposure data. The National Mesothelioma Virtual Bank (NMVB) is a biobank in which mesothelioma annotated biospecimens can be made widely available to the research community. Here, we summarized the significant research findings from 20 publications that utilized the NMVB samples for novel biomarker and therapeutic discoveries. The results showed that the use of the NMVB resource was dispersed among a variety of basic science topics including, but not limited to, biomarkers, abnormal gene expression, and potential therapeutic targets. Positive biomarkers included several miRNAs and antibodies, HMGB1, ATG5, PIAS3, pancytokeratin and GATA3. Genes that had mutations or high/low levels of expression were BAP1, a human control gene of importance in this disease, as well as various cytokines, and checkpoint inhibitors TM4SF1, PKM2, ARHGDIA, COBLL1, WT1, FOXM1, and CD30. Treatments investigated include thiostrepton, interferon-β gene, and Brentuximab. Publications reviewed indicated a significant impact of the NMVB resource utilized in significant studies focusing on biomarker and therapeutic discoveries, which can act as a model for rare diseases, especially in oncology.

Keywords

National Mesothelioma Virtual Bank, Translational Research, Biomarker, Informatics, Rare Disease Biobank, Patient Registries

Corresponding authors: Waqas Amin, Ye Ye

Competing interests: No competing interests were disclosed.

Grant information: This work is funded and supported by the Centers for Disease Control and Prevention (CDC) through an ongoing grant to the National Mesothelioma Virtual Bank or NMVB (U24OH009077).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2022 Barapatre S et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Barapatre S, Amin W, Gao Y et al. Multiple institutions’ research findings using the National Mesothelioma Virtual Bank [version 1; peer review: 1 not approved]. F1000Research 2022, 11:1343 (https://doi.org/10.12688/f1000research.127060.1) First published: 18 Nov 2022, 11:1343 (https://doi.org/10.12688/f1000research.127060.1) Latest published: 28 May 2024, 11:1343 (https://doi.org/10.12688/f1000research.127060.3)

Introduction

Mesothelioma is commonly a cancerous tumor lining pleural and peritoneal surfaces.¹ Environmental exposure to asbestos, a naturally occurring silicate mineral, is the leading cause of mesothelioma.² Other mineral fibers (e.g., erionite, antigorite, actinolite) are known to be carcinogenic as well.²^,³ Asbestos and these other mineral fibers are thought to directly interfere with the cell spindle during human mesothelial cell division, leading to mutations and increased pathogenicity.⁴ The most common symptoms include breathlessness, chest pain, difficulty swallowing, and pleural fluid accumulation; as disease worsens, it leads to death.³ Because mesothelioma is aggressive and fatal (approximately 8–14 months survival after diagnosis³), reduction in exposure and early diagnosis are essential. Biomarkers, especially mesothelin, have been proven useful in malignant pleural mesothelioma (MPM) diagnoses.³ Furthermore, sampling measures (pleural fluid), staging, immunohistochemistry (IHC), histology (epithelial, biphasic, and sarcomatoid) and imaging (chest radiography, CT imaging, PET-CT) can be used as distinguishers between diagnosis and progression of the MPM, as well as among MPM subtypes.⁴ There are both surgical and non-surgical treatment options available to prolong the survival of patients such as chemotherapy, radiotherapy, targeted therapy, surgery, trimodality (consists of surgery, chemotherapy and radiotherapy), and multimodality.³^,⁴ Researchers must uncover and improve treatment options rapidly in order to benefit patients.

It’s challenging and sometimes impossible for biomedical researchers to obtain a sufficient number of mesothelioma patients’ high-quality samples and comprehensive clinical information for analysis. As tissue banking informatics becomes increasingly widespread and improved in collection and storage of human biospecimens, researchers can obtain important results in basic and clinical science research that contribute toward personalized medical approaches in a clinical setting. The National Mesothelioma Virtual Bank (NMVB) (https://mesotissue.org/, last accessed on Oct 17^th, 2022) is the largest US mesothelioma patient registry and offers pleural and peritoneal mesothelioma biospecimens with high-quality data that are critical for effective biomarker identification discovery and personalized medicine research. The NMVB database captures robust clinical data including patient demographics, epidemiology, health assessment survey, pathology, treatment, and outcomes (collecting tissue and blood products for various types of molecular analysis). Researchers can access statistical data for public view (https://data.mesotissue.org/data-page.html), or search the collection of mesothelioma biospecimens via the request fulfilment process (https://mesotissue.org/specimens). As a result, the NMVB serves as a leading resource for mesothelioma biospecimens by providing a sufficient number of mesothelioma cases, standardizing the data and specimen collection method, facilitating the sharing of information through the NMVB database, and addressing the issues of constraint through confidentiality and de-identification.

Starting from 2008, the NMVB collected over 2,000 archived mesothelioma and prospective mesothelioma biospecimens that have been accrued from surgical resections and biopsies, including fresh frozen and blood products. Retrospective collections include clinically collected specimens for diagnostic purposes from surgical and diagnostic biopsies, like paraffin tissue samples. Prospective collections are obtained from clinical visits in which physicians obtain permission for each NMVB study via e-informed consent. These researchers have used novel technologies, such as sequencing techniques, staining techniques (such as fluorescence), and DNA/gene expression analyses, to study potential mesothelioma inhibitors, activators, and therapies.

This manuscript aims to summarize the important research findings of key published studies that have utilized NMVB resources and discuss the future direction of the NMVB. The innovative work discussed in this paper was conducted by a total of 320 scholars from 99 institutions or departments.

Biomarker studies related to mesothelioma

In NMVB-related biomedical studies, there are biomarkers that show substantial evidence of mesothelioma and cancer detection in tumor samples. The expression of MicroRNAs as a biomarker can be utilized to determine stages of tumor progression, as well as to categorize cancer types (lung adenocarcinoma versus mesothelioma).⁵ The subset of RNA through seven major types (miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, miR-429) can reduce protein expression (MYC, JUN, VANGL1, RHOA, ROCK2, WNT5A, or PLCB1), thereby reducing the likelihood of disease.⁵ In prior studies, SV40 has been suggested to contribute to malignant mesothelioma because of its viral capabilities.⁶ A 2010 study⁷ obtained tissues from several institutions, including the NMVB, to observe SV40 miRNA expression within these cells and detected low expression of SV40 miRNAs, indicating that SV40 may not contribute to mesothelioma tumorigenesis. Another 2013 study⁸ further indicated that microRNAs can be investigated in order to understand the change from non-cancerous to cancerous cell. This study found that within several mesothelioma cells, three miRNAs were under expressed (miR-1, miR-206, and miR-133b). Specifically, miR-1 acted as an active malignant pleural mesothelioma tumor suppressor.

Tissue and serum samples were tested in order to establish autoantibodies that could provide accurate recognition of malignant mesothelioma. Although not an all-inclusive list, nine autoantibody biomarkers (PDIA6, MEG3, SDCCAG3, IGHG3, NADH dehydrogenase 1, BACRP11-484D18, CH507-528H12, RP11-413M2) researched within the phage library (T7 MM) fell under that category.⁹ A supposed prognostic marker, PIAS3, prevents mesothelioma growth through the inhibition of STAT3 activity.¹⁰ Researchers found that the tissue cores from NMVB tissue microarray slides had either low or no PIAS3 expression in MM cells.¹⁰ Another biomarker, cytoplasmic and extracellular HMGB1, is a mediator of autophagy. A study from Hawaii Cancer Center¹¹ found that asbestos exposure directly releases HMGB1 and impacts the Beclin 1/PI3K-III complex. HMGB1-mediated autophagy caused the upregulation of phosphorylated Beclin-1, whereas the silencing of HMGB1 caused p-Beclin-1 levels to greatly decrease. Therefore, HMGB1 is likely to cause carcinogenesis through the increased survival of human mesothelial cells. ATG5 was increased in asbestos-exposed individuals, as well.

Interestingly, extracellular vesicles particle (EVP) derived biomarkers are able to distinguish various cancer types. EVP proteins, HSPA8, and CD63 are commonly seen in EVPs. Two other EVP proteins, THBS1 and VCAN, and other less significant biomarkers, such as metabolic enzymes, have the ability to discern between cancer and non-cancer cells.¹² Specific EVP proteomes can aid in the classification of 16 cancer types including but not limited to: breast, lung, pancreatic carcinoma, etc.¹² In a BAP1 study,⁴ researchers found that the most specific marker for MM, adenocarcinoma, and SCC was WT1 nuclear positivity, TTF-1 and Napsin A, and p63 and p40, respectively. Another research study¹³ verified a six-peptide biomarker signature (intercellular adhesion molecule 1, basement membrane-specific heparan sulfate proteoglycan core protein, serum paraoxonase/arylesterase 1, mesothelin, hypoxia up-regulated protein 1, thrombospondin-1) that can be used to detect MPM. Since MPM has a poor prognosis, the tool has the potential to decrease the risk of false negatives when diagnosing individuals. The MPM signature has a higher sensitivity than the SMRP ELISA test.¹³ A case report¹⁴ dealing with a deceased sarcomatoid mesothelioma patient uncovered a loss of p16 cyclin-dependent kinase inhibitor 2A, which is a prominent feature of desmoplastic malignant mesothelioma. Additionally, CK7 and CK5/6 expression is essential in the diagnosis of sarcomatoid mesothelioma. Calretinin, D2-40, and WT-1 are likely elevated in certain central locations (especially the lung). Diffuse sarcomatoid mesothelioma is sensitive for GATA3 expression, but it is improbable that this mesothelioma type will show large levels of TTF-1 and carcinoembryonic antigen. Pleural-based sarcomas are commonly seen to have a loss of pancytokeratin and CD31, a vascular biomarker.

Previously, miRNAs were an essential component of determining the progression of non-cancerous cells to mesothelioma cancerous cells. There has been a transition to studies regarding biomarkers (e.g., PIAS3 and HMGB1) that have a major or minor role in mesothelioma expansion and proliferation. Other biomarkers may be useful in determining variations in the type of mesothelioma and differences between mesothelioma and other cancers of the lung.

Abnormal gene expression in mesothelioma

An important factor of mesothelioma and other cancer types is the modification or increase/decrease of gene expression. BAP1 plays a pivotal role in regulating gene expression in malignant mesothelioma.⁴^,¹⁴^,¹⁵ Out of 70 malignant mesothelioma (MM) biopsies (embedded tissue slides) in this research, BAP1 was mutated in 60% of the specimens.¹⁵ Not surprisingly, there is a loss of BAP1 expression in 50% of biphasic mesotheliomas and 25% of sarcomatoid mesotheliomas.¹⁴ In addition, BAP1 can be utilized in order to distinguish between non-small lung carcinoma and malignant mesothelioma (MM).⁴ Due to prior records of immunohistochemical (IHC) differentiation causing difficulty when discriminating between non-small lung carcinoma and MM, this specific study⁴ aimed to investigate BAP1 immunostaining as an accurate diagnosis predictor between the two cancer forms. Overall, there was a greater lack of BAP1 nuclear staining in MM as compared to non-small lung carcinomas (in which it was extremely rare).

Another publication¹⁶ focuses on the varying levels of the human control gene in mesothelioma tissues. Out of the 45 independent mesothelioma samples from the NMVB, 42 tissues were observed to have high levels of this particular gene. In contrast, Merkel cell polyomavirus (MCPyV) was either never seen or detected at extremely low levels in all tissues. In 2020, researchers have studied the Bloom Syndrome (BLM) gene through multiple experiments in mesothelioma patients’ samples and animal models.¹⁷ BLM is a helicase enzyme that aids in DNA replication and the repair of DNA damage. There are two BLM mutations: biallelic BLM mutations and inactivating germline BLM heterozygous mutations. Biallelic mutations of the Bloom Syndrome gene cause Bloom Syndrome, leading to the risk of developing cancer because of chromosomal instability, the disruption of cell-cycle processes, and decreased p53-mediated apoptosis. Heterozygous BLM mutations lead to a truncated BLM protein. In a few experiments, the researchers found that some mesothelioma patients contained harmful BLM mutations. Another experiment regarding BLM-silencing human mesothelial cells found reduced caspase-3 levels, and therefore, reduced apoptosis in human mesothelial (HM) cells and reduced levels of phosphorylated histone γ-H2A.X involved in DNA repair. The researchers further conducted a mice experiment and observed an increase in M1 macrophages and levels of TNF-α, IL-1β, IL-3, IL-10, and IL-12(p70) for BLM heterozygous mutated mice compared to WT mice. These cytokines are linked to carcinogenesis.

A gene expression test study¹⁸ developed a potential molecular algorithm that could replace the current MPM staging system (which has issues of validity and comprehension). In this examination, samples undergo clinical tests that assess the expression of genes. Utilizing MPM-matched frozen and formalin-fixed, paraffin-embedded (FFPE) samples, a gene expression score (GES) was confirmed to provide prognostic information about different patient conditions. The expression of four genes (TM4SF1, PKM2, ARHGDIA, and COBLL1) and three ratios (TM4SF1/PKM2, TM4SF1/ARHGDIA, and COBLL1/ARHGDIA) are used in this score, which can allow for a more accurate reading in addition to current staging systems. Cells contain complicated interactions between cell surface receptors and transcriptional factors, leading to gene expressions that dictate the cell’s specific and wide-ranging functions. A SPaRTAN model is utilized to decipher the connections between cell surface receptors and transcriptional factors, which are then used as predictions for future transcriptional factor (TF) activity.¹⁹ The model includes a bilinear regression algorithm that learns an interaction matrix. SPaRTAN was applied to malignant peritoneal (MPeM) and pleural mesothelioma (MPM) tumors to obtain and analyze the regulatory states of CD8+ T cells. A portion of the MPeM CD8+ T cell population that was tested had high PD-1, TIM3. And TOGIT (checkpoint inhibitors) expression. A portion of the MPM CD8+ T cell population had the same results, indicating exhausted CD8+ T cells in these tumors. BCL3 activity was found in MPeM CD8+ T cells when PD-1 was present, but not in MPM CD8+ T cells.

Overall, BAP1 plays an essential role in affecting malignant mesothelioma – showing a reduction in gene expression in these BAP1 studies. Similarly, abnormal expression levels of certain genes (e.g., human control gene and BLM gene) may be indicators of mesothelioma. Researchers have constructed systems, such as the SPaRTAN and GES score, to understand cell activity.

Therapeutic targets for mesothelioma treatment

Researchers have determined numerous therapeutic targets and potential inhibitory substances or molecules that could aid in the treatment of mesothelioma. There are two therapeutic targets, FOXM1 protein and CD30, that can decrease cell growth. Researchers observed that Forkhead box M1 (FOXM1) was present in the majority of human malignant mesothelioma cells (>50%).²⁰ The protein, FOXM1, controls gene expression in the cell cycle (specifically S phase entry to mitosis), which assists in cell progression. CD30 is a cytokine receptor that aids in the regulation of apoptosis, which means that the presence of the gene in mesothelioma cells should be high.²¹ To counter tumor progression, researchers utilized thiostrepton (TS) to inhibit this specific protein. TS disables peroxiredoxin 3 (PRX3) by increasing mitochondrial oxidant production, leading to the decrease of the FOXM1 protein and CD30 that cause cell death.²⁰ As a result, FOXM1 and CD30 have the capability of being a therapeutic target and TS could be a therapeutic strategy. Researchers, in 2015, observed the intensity of immunostaining using tissue microarray slides from the NMVB and applied brentuximab vedotin to target CD30 antigens.²¹ After subsequent analyses, CD30 mRNA expression was abnormally high in mesothelioma tissues, giving further evidence that the receptor could be a therapeutic target in the future. And brentuximab Vedotin does impact the activity of CD30, leading to decreased cell growth and survivability.

Furthermore, there are two widely known non-surgical treatments, chemotherapy and radiation therapy, that are involved in decreasing size and morbidity with MPM. Unfortunately, studies have shown that malignant pleural mesothelioma is not as affective. A University of Pennsylvania Medical Center study²² hypothesized that a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma cells because the virus is normally an oncolytic agent. Forty-eight mesothelioma tumors were obtained from the NMVB for various treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses.

These studies have established FOXM1 and CD30 as therapeutic targets, and thiostrepton and brentuximab vedotin as therapeutic strategies that decrease cell stability. Additionally, the treatment of VSV vectors containing the Interferon-β gene serves as a cell progression inhibitor, as well.

Cases in which the usage of tumor samples aided in the determination of potential biomarkers, gene expression, and therapeutic factors for general mesothelioma and/or differentiating mesothelioma subtypes are summarized in Table 1.

Table 1. Summary of research sample and research findings of NMVB-related studies.

Category	Research samples used in the study (not limited to samples from NMVB, may include samples from other resources)	Research findings	Publication
Biomarkers in tumor samples	100 mesothelioma tumor samples: 77 mesothelioma tumor samples (NMVB) and 23 (Brigham and Women’s hospital) 32 adenocarcinoma tumor samples (National Disease Research Interchange)	Specifically, these 7 major types of microRNA, miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, miR-429, can lead to the reduction of MYC, JUN, VANGL1, RHOA, ROCK2, WNT5A, or PLCB1 expression that is commonly found in mesothelioma.	⁶
	28 nonmalignant biopsies, 20 pleural biopsies from lung adenocarcinoma patients and 94 mesothelioma tumor samples (made up of 42 epithelioid, 18 biphasic, 10 sarcomatoid, and 24 non-histologically defined mesothelioma patients)	SV40 is not a useful biomarker of mesothelioma.	⁷
	(unknown number) tumor samples from NMVB, 28 tumors (University of Minnesota Cancer Center), 6 patient’s normal parietal pleura without malignancies of any kind (Tissue Bank at Stanford Center), MPM cell lines (epithelial and sarcomatoid) (National Caner Institute)	miR-1 acts as an active MPM tumor suppressor.	⁸
	5 tissue and 215 serum samples (NMVB)	9 autoantibody biomarkers (PDIA6, MEG3, SDCCAG3, IGHG3, NADH dehydrogenase 1, BACRP11-484D18, CH507-528H12, RP11-413M2) in tissue and serum samples within the phage library (T7 MM) could provide accurate recognition of malignant mesothelioma	⁹
	NMVB tissue microarray slides (does not state the exact amount)	Low PIAS3 expression in MM cells. PIAS3 prevents mesothelioma growth through the inhibition of STAT3 activity.	¹⁰
	29 serum samples from individuals with 4+ years of continuous exposure to asbestos fibers and mesothelial HMGB1-cKO mice	HMGB1 and ATG5 are biomarkers likely to cause carcinogenesis.	¹¹
	497 normal and cancer-associated human and murine-derived samples	Extracellular vesicle and particle biomarkers are able to distinguish various cancer types through two main proteins (HSPA8 and CD63) and other less expressed proteins (such as THBS1 and VCAN).	¹²
	213 MPM patients and 189 Asbestos-exposed patients	Intercellular adhesion molecule 1, basement membrane-specific heparan sulfate proteoglycan core protein, serum paraoxonase/arylesterase 1, mesothelin, hypoxia up-regulated protein 1, and thrombospondin-1 are biomarkers that can detect MPM.	¹³
	1 sarcomatoid mesothelioma patient	There was positivity for pancytokeratin and GATA3. Additionally, there was a loss of CDKN2A and negativity for calretinin, D2-40, HBME and WT-1.	¹⁴
Changes of gene expression	32 primary lung adenocarcinomas, 13 primary lung SCC and 35 MM biopsies (20 epithelial, 8 biphasic, and 7 sarcomatoid)	MM has a lack of nuclear staining for BAP1 and non-small lung carcinoma has a positive BAP1 staining. The most specific marker for MM, adenocarcinoma, and SCC was WT1 nuclear positivity, TTF-1 & Napsin A, and p63 and p40, respectively.	⁴
	70 MM biopsies (embedded tissues slides)	BAP1 is mutated in 60% of the specimens, playing a pivotal role in regulating gene expression.	¹⁵
	45 independent mesothelioma samples	42 tissues were observed to have high levels of the human control gene. In contrast, merkel cell polyomavirus was either never seen or detected at extremely low levels in all tissues.	¹⁶
	122 pleural and peritoneal mesothelioma patients and germline DNA of 10 patients with mesothelioma	The cytokines, TNF-α, IL-1β, IL-3, IL-10, and IL-12(p70) are linked to carcinogenesis. BLM mutations can impact processes of the cell and proteins leading to cell death.	¹⁷
	73 patients with FFPE biopsy specimens and clinically documented evidence of surgical resection of the tumor with diagnosis of histologic subtype	As part of the GES system, the expression of four genes (TM4SF1, PKM2, ARHGDIA, and COBLL1) and three-ratios (TM4SF1/PKM2, TM4SF1/ARHGDIA, and COBLL1/ARHGDIA) are used for a more accurate patient condition reading.	¹⁸
	Tumor samples	High PD-1, TIM3, and TIGIT checkpoint inhibitors expression in some populations of MPeM and MPM CD8+ T cells.	¹⁹
Therapeutic targets and potential inhibitory substances	Tissue microarrays (included duplicate paraffin-embedded sections for 46 tumors)	FOXM1 allows for cell progression. In turn, thiostrepton can be used to interfere with PRX3 in FOXM1 protein and cause cell death.	²⁰
	83 mesothelioma specimens	CD30 levels are high in mesothelioma cells. Brentuximab vedotin targets CD30 antigens.	²¹
	48 mesothelioma tumors	Interferon- β prevent the lysis of mesothelioma cells when incorporate into a VSV vector, which is a virus that is normally an oncolytic agent.	²²

Biomedical informatics research in NMVB

Through the process of continuously enriching the research cohort of mesothelioma patients and providing samples and research data to external institutions, the NMVB team has also been upgrading NMVB infrastructure using state-of-art informatics techniques and sharing our experience in peer-reviewed articles.²³^,²⁴ We developed a multidisciplinary approach to conduct honest broker service efficiently and effectively, sharing our practical experience in Ref. 23. Using mesothelioma as an example, we have developed and deployed common data elements for tissue banks for translational research in cancer, which is generalizable to other types of cancers.²⁴

Furthermore, the NMVB team has been using NMVB data to conduct internal scientific research. We explored the potential of using automated image analysis in the evaluation of mesothelioma tissue microarray, which matched the performance of manual scoring by pathologists.²⁵ This result indicates that an automated image analysis approach may be a reproducible, objective, and accurate way for the immunohistochemical assessment of biomarker expression. In a cancer history classification study,²⁶ we applied Natural Language Processing (NLP), a modern Artificial Intelligence technique, to automatically classify personal and family history from free-text medical reports of mesothelioma patients, with a high accuracy. In another study,²⁷ we conducted a retrospective review of the NMVB cohort, and identified factors influencing malignant mesothelioma survival, including age (younger than 45), gender (female), epithelioid histological subtype, staging (I), peritoneal occurrence, and having the combined treatment of surgical therapy with chemotherapy. Moreover, for malignant pleural mesothelioma, we developed a novel computational algorithm that automatically discovered 364 potential protein-protein interactions, of which five interactions (BAP1-PARP3, KDR-ALB, PDGFRA-ALB, CUTA-HMGB1, and CUTA-CLPS) were validated experimentally; our comparative transcriptiome analysis identified five potentially repurposable drugs targeting the interactome proteins (cabazitaxel, primaquine, pyrimethamine, trimethroprim, and gliclazide).²⁸ To share our findings with the whole research community, we make the discovered interactions publicly available through Wiki-MPM (https://hagrid.dbmi.pitt.edu/wiki-MPM/, last accessed on July 31^st, 2022). Realizing the computational approach may be more needed by rare types, we further applied similar techniques on malignant peritoneal mesothelioma and identified 417 novel protein-protein interactions.²⁹

Discussion

With regard to research findings using NMVB, there was a high number of publications that investigated and examined specific genes’ roles in mesothelioma, such as IFN-β, BAP1, and PIAS3, and pre-existing or current cancer/mesothelioma therapies, such as HDACi panobinostat, CRS, and HIPEC. In addition, there were publications related solely to the development and utilization of NMVB as a significant resource. Many publications had some positive scientific findings that allowed for possible therapies to aid in mesothelioma or cancer treatment including (but not limited to) delivery of type I IFNs, carcumin, brentuximab vedotin, panobinostat, and CRS/HIPEC. There were also gene markers that were not related to or did not provide enough information for lung inflammation, cancer, or mesothelioma, such as MCPyV DNA and CRP. When comparing mesothelioma and lung adenocarcinoma, there were certain miRNA traits that varied, indicating that miRNAs can act as potential biomarkers. The NMVB has been proven to a robust biobanking resource to support the fundamental domain of biomedical science, including molecular and genetic epidemiology, molecular pathology and pharmacogenomics.

The NMVB was cited in 879 publications in 2021 compared to 676 publications in 2020 (a nearly 30% increase). NMVB is on track for over 1000 citations in CY2022, establishing that the bank is important in sharing genomic data and specimens. There are many NMVB publications from the users of the resource that focus on biomarker development, of which some are previously discussed in this publication.

The NMVB plans to improve its system on including which specimen types and related annotation by taking mesothelioma researchers’ feedback and expand the reach of its database in the upcoming years. Currently, there are nine collaborating institutions that are a part of the NMVB, including New York University, University of Pittsburgh/UPMC, University of Pennsylvania, Roswell Park Cancer Institute, Mount Sinai School of Medicine (currently inactive), Baylor College of Medicine, Fox Chase Cancer Center, Temple University and University of Maryland (https://mesotissue.org/about/, last accessed on July 31^th, 2022). Additionally, NMVB hopes to make use of international networks like MesoNet (France), the United Kingdom Biobank and the Italian Mesothelioma Biobank to obtain far-reaching and increased data from mesothelioma patients that can be accessed by researchers.³⁰

The NMVB is making efforts with the CDC and MedMorph to create advanced infrastructure and refined tools that can enhance data extraction of asbestos exposure and occupational health data. With so many years of practical experience, the team leaders of NMVB actively joined a nationwide workshop discussing the potential usefulness and feasibility of national mesothelioma registry.³¹ Moving forward, the NMVB is working with an epidemiology and occupational health expert and gain knowledge through the CDC NIOSH to enhance the investigation of occupational history and the exposure that may contribute to mesothelioma.

Lastly, the NMVB utilizes a communications plan involving the NMVB website, mass mailings to users, and presentations at national meetings. The NMVB website contains links to the CTSA, NIH, NCI, Office of Biospecimen and Biorepository Research, National Center for Biotechnology Information, the Cancer Genome Atlas Project and dozens of other biorepository and relevant organizational websites. These supply information about mesothelioma, biospecimens, and other specimens via a searchable database. Letters and/or e-mails are sent to investigators and their cancer research coordinators that have published articles in mesothelioma research in the recent past as well as investigators that have received or applied for Mesothelioma Foundation research grant funding. NMVB is always present and markets the resource especially at the Mesothelioma Applied Research Foundation’s annual symposium, the International Mesothelioma Interest Group’s every other year meeting, the AACR meeting and other research meetings. The NMVB will have outreach efforts, such as increasing the awareness of the NMVB resource, increasing education about the function NMVB and how it is operated, providing information about scientific advances facilitated by NMVB, and learning from the affected communities about the disease especially through active participation at the International Symposium on Malignant Mesothelioma (Mesothelioma Foundation sponsored annual meeting).

Conclusions

The NMVB has aided in biomarker, gene expression, and therapeutic target studies. NMVB plans to improve its resources and system allowing for future researchers to make widespread use of the data and specimens within the database. It is essential that the NMVB dataset continues to expand and play a pivotal role in cancer research, especially for possible treatments/phenomena that target NMVB specimens and aid in inhibiting tumor growth in certain cells.

Data availability

No data are associated with this article.

Acknowledgements

We thank Schwenk, Melissa Dawn for setting up the NMVB research paper Google scholar webpage: https://scholar.google.com/.

References

1. Sekido Y: Molecular pathogenesis of malignant mesothelioma. Carcinogenesis. 2013; 34: 1413–1419. Publisher Full Text
2. Roggli VL: Measuring EMPs in the lung what can be measured in the lung: Asbestiform minerals and cleavage fragments. Toxicol. Appl. Pharmacol. 2018; 361: 14–17. PubMed Abstract | Publisher Full Text
3. Bibby AC, Tsim S, Kanellakis N, et al.: Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment. Eur. Respir. Rev. 2016; 25: 472–486. PubMed Abstract | Publisher Full Text
4. Carbone M, Shimizu D, Napolitano A, et al.: Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma. Oncotarget. 2016; 7: 59314–59321. PubMed Abstract | Publisher Full Text
5. Gee GV, Koestler DC, Christensen BC, et al.: Downregulated microRNAs in the differential diagnosis of malignant pleural mesothelioma. Int. J. Cancer. 2010; 127: 2859–2869. PubMed Abstract | Publisher Full Text
6. Vilchez RA, Butel JS: Emergent human pathogen simian virus 40 and its role in cancer. Clin. Microbiol. Rev. 2004; 17: 495–508, table of contents. PubMed Abstract | Publisher Full Text
7. Gee G, Stanifer M, Christensen B, et al.: SV40 associated miRNAs are not detectable in mesotheliomas. Br. J. Cancer. 2010; 103: 885–888. PubMed Abstract | Publisher Full Text
8. Xu Y, Zheng M, Merritt RE, et al.: miR-1 induces growth arrest and apoptosis in malignant mesothelioma. Chest. 2013; 144: 1632–1643. PubMed Abstract | Publisher Full Text
9. Zhang X, Shen W, Dong X, et al.: Identification of novel autoantibodies for detection of malignant mesothelioma. PLoS One. 2013; 8: e72458. PubMed Abstract | Publisher Full Text
10. Dabir S, Kluge A, Kresak A, et al.: Low PIAS3 Expression in Malignant Mesothelioma Is Associated with Increased STAT3 Activation and Poor Patient Survival. Clin. Cancer Res. 2014; 20: 5124–5132. PubMed Abstract | Publisher Full Text
11. Xue J, Patergnani S, Giorgi C, et al.: Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy. Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 25543–25552. PubMed Abstract | Publisher Full Text
12. Hoshino A, Kim HS, Bojmar L, et al.: Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers. Cell. 2020; 182: 1044–1061.e18. PubMed Abstract | Publisher Full Text
13. Cerciello F, Choi M, Sinicropi-Yao SL, et al.: Verification of a Blood-Based Targeted Proteomics Signature for Malignant Pleural Mesothelioma. Cancer Epidemiol. Biomark. Prev. 2020; 29: 1973–1982. PubMed Abstract | Publisher Full Text
14. Burke A, Legesse T: Nivolumab-Induced Peritonitis With Mesothelial Hyperplasia Mimicking Metastatic Mesothelioma. AJSP: Rev. Rep. 2022; 27: 98–102. Publisher Full Text
15. Nasu M, Emi M, Pastorino S, et al.: High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma. J. Thorac. Oncol. 2015; 10: 565–576. PubMed Abstract | Publisher Full Text
16. Bhatia K, Modali R, Goedert JJ: Merkel cell polyomavirus is not detected in mesotheliomas. J. Clin. Virol. 2010; 47: 196–198. PubMed Abstract | Publisher Full Text
17. Bononi A, Goto K, Ak G, et al.: Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma. Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 33466–33473. PubMed Abstract | Publisher Full Text
18. De Rienzo A, Cook RW, Wilkinson J, et al.: Validation of a Gene Expression Test for Mesothelioma Prognosis in Formalin-Fixed Paraffin-Embedded Tissues. J. Mol. Diagn. 2017; 19: 65–71. PubMed Abstract | Publisher Full Text
19. Ma X, Somasundaram A, Qi Z, et al.: SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators. Nucleic Acids Res. 2021; 49: 9633–9647. PubMed Abstract | Publisher Full Text
20. Newick K, Cunniff B, Preston K, et al.: Peroxiredoxin 3 Is a Redox-Dependent Target of Thiostrepton in Malignant Mesothelioma Cells. PLoS One. 2012; 7: e39404. PubMed Abstract | Publisher Full Text
21. Dabir S, Kresak A, Yang M, et al.: CD30 is a potential therapeutic target in malignant mesothelioma. Mol. Cancer Ther. 2015; 14: 740–746. PubMed Abstract | Publisher Full Text
22. Saloura V, Wang LC, Fridlender ZG, et al.: Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-beta for use in malignant pleural mesothelioma: heterogeneity in interferon responsiveness defines potential efficacy. Hum. Gene Ther. 2010; 21: 51–64. PubMed Abstract | Publisher Full Text
23. Dhir R, Patel AA, Winters S, et al.: A multidisciplinary approach to honest broker services for tissue banks and clinical data. Cancer. 2008; 113: 1705–1715. PubMed Abstract | Publisher Full Text
24. Mohanty SK, Mistry AT, Amin W, et al.: The development and deployment of Common Data Elements for tissue banks for translational research in cancer - an emerging standard based approach for the Mesothelioma Virtual Tissue Bank. BMC Cancer. 2008; 8: 91. PubMed Abstract | Publisher Full Text
25. Amin W, Srinivasan M, Song SY, et al.: Use of automated image analysis in evaluation of Mesothelioma Tissue Microarray (TMA) from National Mesothelioma Virtual Bank. Pathol. Res. Pract. 2014; 210: 79–82. PubMed Abstract | Publisher Full Text
26. Wilson RA, Chapman WW, Defries SJ, et al.: Automated ancillary cancer history classification for mesothelioma patients from free-text clinical reports. J. Pathol. Inform. 2010; 1: 24. PubMed Abstract | Publisher Full Text
27. Amin W, Linkov F, Landsittel DP, et al.: Factors influencing malignant mesothelioma survival: a retrospective review of the National Mesothelioma Virtual Bank cohort. F1000Res. 2018; 7: 1184. PubMed Abstract | Publisher Full Text
28. Karunakaran KB, Yanamala N, Boyce G, et al.: Malignant Pleural Mesothelioma Interactome with 364 Novel Protein-Protein Interactions. Cancers (Basel). 2021; 13. PubMed Abstract | Publisher Full Text
29. Karunakaran KB, Ganapathiraju MK: Malignant Peritoneal Mesothelioma Interactome with 417 Novel Protein-Protein Interactions.2021; 6. Publisher Full Text
30. van Gerwen M , Alpert N, Flores R, et al.: An overview of existing mesothelioma registries worldwide, and the need for a US Registry. Am. J. Ind. Med. 2020; 63: 115–120. PubMed Abstract | Publisher Full Text
31. Cummings KJ, Becich MJ, Blackley DJ, et al.: Workshop summary: Potential usefulness and feasibility of a US National Mesothelioma Registry. Am. J. Ind. Med. 2020; 63: 105–114. PubMed Abstract | Publisher Full Text

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Version 3

VERSION 3 PUBLISHED 18 Nov 2022

Author details Author details

Seemran Barapatre
Roles: Methodology, Writing – Original Draft Preparation

Waqas Amin
Roles: Writing – Review & Editing

Yuhe Gao
Roles: Writing – Review & Editing

Yaming Li
Roles: Writing – Review & Editing

Michael John Becich
Roles: Project Administration, Supervision

Ye Ye
Roles: Project Administration, Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

This work is funded and supported by the Centers for Disease Control and Prevention (CDC) through an ongoing grant to the National Mesothelioma Virtual Bank or NMVB (U24OH009077).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (3)

version 3

Revised

Published: 28 May 2024, 11:1343

https://doi.org/10.12688/f1000research.127060.3

version 2

Revised

Published: 11 Sep 2023, 11:1343

https://doi.org/10.12688/f1000research.127060.2

version 1

Published: 18 Nov 2022, 11:1343

https://doi.org/10.12688/f1000research.127060.1

© 2022 Barapatre S et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Barapatre S, Amin W, Gao Y et al. Multiple institutions’ research findings using the National Mesothelioma Virtual Bank [version 1; peer review: 1 not approved]. F1000Research 2022, 11:1343 (https://doi.org/10.12688/f1000research.127060.1)

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Open Peer Review

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Reviewer Report 08 Dec 2022

Emanuela Felley-Bosco, Laboratory of Molecular Oncology, Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland

Not Approved

https://doi.org/10.5256/f1000research.139528.r156174

The National Mesothelioma Virtual Bank (NMVB) is led by the collaborative effort of the Departments of Biomedical Informatics and Pathology at the University of Pittsburgh, and is funded by a grant from the National Institute of Occupational Health and Safety of the Centers for Disease Control and Prevention. The authors state that the aim is to summarize in this review research from 20 publications that included NMVB samples.

This work is of potential interest since it analyzes the output of an effort to assemble a large collection of mesothelioma, which is a rare disease, for the benefit of scientists’ community. However, the manuscripts needs a large amount of revision and would benefit from the addition in the co-authors of a scientist with deep biology understanding, which would complement bioinformatics skills of the other authors.

Major:
General comments:

The focus is to summarize research in biomarker and therapeutic discovery research. It might help the reader if the strategy used for the selection of the studies would be indicated. Indeed, there are according to the homepage of NMVB 60 publications/preprints (merging preprints and publications). In the Table there are 9 studies in the category biomarkers, 6 studies in the category gene expression and 3 studies for therapeutic targets. The total is 18 studies. The bioinformatics analysis studies are not included in the Table, so it is not clear how clear how they are considered.
Text and table reference numbers do not match, adding to the confusion. E.g. reference 5 in text corresponds to reference 6 in the table.
The manuscript would benefit of a more clear structure. For example separating studies based on NMVB plasma vs. tissue, and weighting by sample number, i.e. when only a single sample is analyzed this has not the same impact compared to the study of several samples.
Data should not be just mentioned but it is necessary to have some comments and critical assessments. If not it will look rather like a list, decreasing its interest. E.g. the two sentences starting “Tissue and serum samples were…..…….category” would be more informative if the authors could comment of what they think about antibodies against MEG3, which is non-coding RNA.
English should be more reader friendly as well. A sentence like “In NMVB-related biomedical studies, there are biomarkers that show substantial evidence of mesothelioma and cancer detection in tumor samples“ is not easy. It might be better to change to “NMVB samples have allowed to discover biomarkers for mesothelioma detection”. What may mean “cancer detection in tumor samples” is not evident. There are several other difficult sentences, I would advise a copy edit of the article.

Specific comments:

The sentence “the subset of RNA through seven major types…” needs to be changed. The authors refer to a study where differential expression of miRNA was investigated and predicted targets discussed. The data should be reported so with no overstatement about likelihood of the disease.
SV40 was not “suggested to contribute to malignant mesothelioma because of its viral capabilities” but because large T antigen of SV40 binds e.g. p53 tumor suppressor gene. This is a very precise mechanism and not a general viral capability, whatever this may mean.
Tone down the sentence “Therefore, HMGB1 is likely to cause carcinogenesis”.
The whole paragraph starting with “Interestingly, extracellular…” misses to forward the message of that study in the context of mesothelioma.
What do the authors mean when they write. “In a BAP1 study…”?
Be more precise when reporting data in reference 13: serum samples, enriched using glycoprotein capture etc...
What does mean the sentence: “There has been a transition…”?
What does mean the sentence ”varying levels of the human control gene in mesothelioma”? How do the authors imagine a reader may understand? Why should readers understand the interest of checking Merkel cell polyoma virus?
What is the message of the paragraph starting: “Overall, BAP1…”?
CD30: the authors could comment that positivity in tumor samples was variable, and could represent a target for antibody-drug conjugates on in a fraction of samples…
Thiostrepton had been first used in breast cancer cells where it was shown to decrease the expression of FOXM1 (Kwok JM, et al Mol Cancer Ther 2008;7:2022–32) and the authors should mention this reference. Then they should comment on reasons why FOXM1 inhibiting antibiotics are not suitable for use in humans.
The whole paragraph: “Furthermore, there are two widely known non-surgical treatments, chemotherapy and radiation therapy, that are involved in decreasing size and morbidity with MPM. Unfortunately, studies have shown that malignant pleural mesothelioma is not as affective. A University of Pennsylvania Medical Center study hypothesized that a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma cells because the virus is normally an oncolytic agent. Forty-eight mesothelioma tumors were obtained from the NMVB forvarious treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses” requires a copy edit.
There is an obvious interest in discussing the integration of the several biobanks/registries existing worldwide. However it might be useful also to integrate bioinformatics analysis. The authors should mention https://www.wikipathways.org/index.php/Pathway:WP5087, which is a resource publicly available and continues to be under development and curation by the community, enabling the scientists in mesothelioma to actively participate in the prioritization of shared biological knowledge.

Is the topic of the review discussed comprehensively in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Partly
Are the conclusions drawn appropriate in the context of the current research literature?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: fundamental and translational research in mesothelioma

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

CITE

Report a concern

Author Response 16 Nov 2023

Yuhe Gao, Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, 15206, USA

16 Nov 2023

Author Response
The National Mesothelioma Virtual Bank (NMVB) is led by the collaborative effort of the Departments of Biomedical Informatics and Pathology at the University of Pittsburgh, and is funded by a ... Continue reading
The National Mesothelioma Virtual Bank (NMVB) is led by the collaborative effort of the Departments of Biomedical Informatics and Pathology at the University of Pittsburgh, and is funded by a grant from the National Institute of Occupational Health and Safety of the Centers for Disease Control and Prevention. The authors state that the aim is to summarize in this review research from 20 publications that included NMVB samples.

This work is of potential interest since it analyzes the output of an effort to assemble a large collection of mesothelioma, which is a rare disease, for the benefit of scientists’ community. However, the manuscripts needs a large amount of revision and would benefit from the addition in the co-authors of a scientist with deep biology understanding, which would complement bioinformatics skills of the other authors.

--We invited Dr. Uma Chandran, who has a deep biology understanding and solid background, as our co-author. With her help of review and edits, we largely resolved the comments from the reviewer and the self-noticed problem in our previous manuscript.

Major:
General comments:

The focus is to summarize research in biomarker and therapeutic discovery research. It might help the reader if the strategy used for the selection of the studies would be indicated. Indeed, there are according to the homepage of NMVB 60 publications/preprints (merging preprints and publications). In the Table there are 9 studies in the category biomarkers, 6 studies in the category gene expression and 3 studies for therapeutic targets. The total is 18 studies. The bioinformatics analysis studies are not included in the Table, so it is not clear how clear how they are considered.

Added bioinformatics analysis studies in Table 1.

Text and table reference numbers do not match, adding to the confusion. E.g. reference 5 in text corresponds to reference 6 in the table.

Changed, now they match.

The manuscript would benefit of a more clear structure. For example separating studies based on NMVB plasma vs. tissue, and weighting by sample number, i.e. when only a single sample is analyzed this has not the same impact compared to the study of several samples.

Ranked them based on the samples size, and added a platform column in Table 1.

English should be more reader friendly as well. A sentence like “In NMVB-related biomedical studies, there are biomarkers that show substantial evidence of mesothelioma and cancer detection in tumor samples“ is not easy. It might be better to change to “NMVB samples have allowed to discover biomarkers for mesothelioma detection”. What may mean “cancer detection in tumor samples” is not evident. There are several other difficult sentences, I would advise a copy edit of the article.

Have copy edit of the whole article with writing tutors.

Specific comments:

The sentence “the subset of RNA through seven major types…” needs to be changed. The authors refer to a study where differential expression of miRNA was investigated and predicted targets discussed. The data should be reported so with no overstatement about likelihood of the disease.

Revised

SV40 was not “suggested to contribute to malignant mesothelioma because of its viral capabilities” but because large T antigen of SV40 binds e.g. p53 tumor suppressor gene. This is a very precise mechanism and not a general viral capability, whatever this may mean.

Changed to “SV40 has been suggested to contribute to malignant mesothelioma as its large tumor antigen, which binds to cellular tumor suppressor proteins, have been demonstrated in MME”.

Tone down the sentence “Therefore, HMGB1 is likely to cause carcinogenesis”.

Changed to “Therefore, HMGB1 is likely to encourage cell transformation by saving asbestos-damaged human mesothelial cells.”

The whole paragraph starting with “Interestingly, extracellular…” misses to forward the message of that study in the context of mesothelioma.

Added one sentence starting with “More importantly..” to declare the context of mesothelioma.

What do the authors mean when they write. “In a BAP1 study…”?

Was meaning, in a study focusing on BAP1, while now changed to: ” In a study aiming to seek novel biomarkers for distinguishing malignancies, ⁴researchers found that the lack of nuclear BAP1 stain can differentiate MM from lung carcinomas.”

Be more precise when reporting data in reference 13: serum samples, enriched using glycoprotein capture etc...

Added “isolating N-linked glycoproteins to enrich serum proteome and decrease analytical complexity” to describe ref 13.

What does mean the sentence: “There has been a transition…”?

Changed to “There have been some novel directions…”

What does mean the sentence ”varying levels of the human control gene in mesothelioma”? How do the authors imagine a reader may understand? Why should readers understand the interest of checking Merkel cell polyoma virus?

Deleted this statement, added description on MCPyV and SV40 and their relationships to mesothelioma.

What is the message of the paragraph starting: “Overall, BAP1…”?

Changed to “In MM studies, BAP1..”. Was trying to identify the role of BAP1 in existing MM studies.

The whole paragraph: “Furthermore, there are two widely known non-surgical treatments, chemotherapy and radiation therapy, that are involved in decreasing size and morbidity with MPM. Unfortunately, studies have shown that malignant pleural mesothelioma is not as affective. A University of Pennsylvania Medical Center study hypothesized that a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma cells because the virus is normally an oncolytic agent. Forty-eight mesothelioma tumors were obtained from the NMVB forvarious treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses” requires a copy edit.

Revised as “There are two widely known non-surgical treatments to MM, chemotherapy and radiation therapy, however studies have shown that these treatments are not effective enough with malignant pleural mesothelioma. A University of Pennsylvania Medical Center study ²²has proposed an oncolytic viral therapy. Researchers hypothesized that, normally functioning as an oncolytic agent, a vesicular stomatitis virus (VSV) vector that incorporated an Interferon- β gene could effectively prevent the growth of lysis mesothelioma. In the study, 48 mesothelioma tumors were obtained from the NMVB for various treatments (hIFN -β, IFN- β ELISA, IFN -β bioassay ). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses.”

There is an obvious interest in discussing the integration of the several biobanks/registries existing worldwide. However it might be useful also to integrate bioinformatics analysis. The authors should mention https://www.wikipathways.org/index.php/Pathway:WP5087, which is a resource publicly available and continues to be under development and curation by the community, enabling the scientists in mesothelioma to actively participate in the prioritization of shared biological knowledge.

Added existing biobanks/registries both worldwide and in US in discussion part.
The National Mesothelioma Virtual Bank (NMVB) is led by the collaborative effort of the Departments of Biomedical Informatics and Pathology at the University of Pittsburgh, and is funded by a grant from the National Institute of Occupational Health and Safety of the Centers for Disease Control and Prevention. The authors state that the aim is to summarize in this review research from 20 publications that included NMVB samples.

This work is of potential interest since it analyzes the output of an effort to assemble a large collection of mesothelioma, which is a rare disease, for the benefit of scientists’ community. However, the manuscripts needs a large amount of revision and would benefit from the addition in the co-authors of a scientist with deep biology understanding, which would complement bioinformatics skills of the other authors.

--We invited Dr. Uma Chandran, who has a deep biology understanding and solid background, as our co-author. With her help of review and edits, we largely resolved the comments from the reviewer and the self-noticed problem in our previous manuscript.

Major:
General comments:

The focus is to summarize research in biomarker and therapeutic discovery research. It might help the reader if the strategy used for the selection of the studies would be indicated. Indeed, there are according to the homepage of NMVB 60 publications/preprints (merging preprints and publications). In the Table there are 9 studies in the category biomarkers, 6 studies in the category gene expression and 3 studies for therapeutic targets. The total is 18 studies. The bioinformatics analysis studies are not included in the Table, so it is not clear how clear how they are considered.

Added bioinformatics analysis studies in Table 1.

Text and table reference numbers do not match, adding to the confusion. E.g. reference 5 in text corresponds to reference 6 in the table.

Changed, now they match.

The manuscript would benefit of a more clear structure. For example separating studies based on NMVB plasma vs. tissue, and weighting by sample number, i.e. when only a single sample is analyzed this has not the same impact compared to the study of several samples.

Ranked them based on the samples size, and added a platform column in Table 1.

English should be more reader friendly as well. A sentence like “In NMVB-related biomedical studies, there are biomarkers that show substantial evidence of mesothelioma and cancer detection in tumor samples“ is not easy. It might be better to change to “NMVB samples have allowed to discover biomarkers for mesothelioma detection”. What may mean “cancer detection in tumor samples” is not evident. There are several other difficult sentences, I would advise a copy edit of the article.

Have copy edit of the whole article with writing tutors.

Specific comments:

The sentence “the subset of RNA through seven major types…” needs to be changed. The authors refer to a study where differential expression of miRNA was investigated and predicted targets discussed. The data should be reported so with no overstatement about likelihood of the disease.

Revised

SV40 was not “suggested to contribute to malignant mesothelioma because of its viral capabilities” but because large T antigen of SV40 binds e.g. p53 tumor suppressor gene. This is a very precise mechanism and not a general viral capability, whatever this may mean.

Changed to “SV40 has been suggested to contribute to malignant mesothelioma as its large tumor antigen, which binds to cellular tumor suppressor proteins, have been demonstrated in MME”.

Tone down the sentence “Therefore, HMGB1 is likely to cause carcinogenesis”.

Changed to “Therefore, HMGB1 is likely to encourage cell transformation by saving asbestos-damaged human mesothelial cells.”

The whole paragraph starting with “Interestingly, extracellular…” misses to forward the message of that study in the context of mesothelioma.

Added one sentence starting with “More importantly..” to declare the context of mesothelioma.

What do the authors mean when they write. “In a BAP1 study…”?

Was meaning, in a study focusing on BAP1, while now changed to: ” In a study aiming to seek novel biomarkers for distinguishing malignancies, ⁴researchers found that the lack of nuclear BAP1 stain can differentiate MM from lung carcinomas.”

Be more precise when reporting data in reference 13: serum samples, enriched using glycoprotein capture etc...

Added “isolating N-linked glycoproteins to enrich serum proteome and decrease analytical complexity” to describe ref 13.

What does mean the sentence: “There has been a transition…”?

Changed to “There have been some novel directions…”

What does mean the sentence ”varying levels of the human control gene in mesothelioma”? How do the authors imagine a reader may understand? Why should readers understand the interest of checking Merkel cell polyoma virus?

Deleted this statement, added description on MCPyV and SV40 and their relationships to mesothelioma.

What is the message of the paragraph starting: “Overall, BAP1…”?

Changed to “In MM studies, BAP1..”. Was trying to identify the role of BAP1 in existing MM studies.

The whole paragraph: “Furthermore, there are two widely known non-surgical treatments, chemotherapy and radiation therapy, that are involved in decreasing size and morbidity with MPM. Unfortunately, studies have shown that malignant pleural mesothelioma is not as affective. A University of Pennsylvania Medical Center study hypothesized that a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma cells because the virus is normally an oncolytic agent. Forty-eight mesothelioma tumors were obtained from the NMVB forvarious treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses” requires a copy edit.

Revised as “There are two widely known non-surgical treatments to MM, chemotherapy and radiation therapy, however studies have shown that these treatments are not effective enough with malignant pleural mesothelioma. A University of Pennsylvania Medical Center study ²²has proposed an oncolytic viral therapy. Researchers hypothesized that, normally functioning as an oncolytic agent, a vesicular stomatitis virus (VSV) vector that incorporated an Interferon- β gene could effectively prevent the growth of lysis mesothelioma. In the study, 48 mesothelioma tumors were obtained from the NMVB for various treatments (hIFN -β, IFN- β ELISA, IFN -β bioassay ). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses.”

There is an obvious interest in discussing the integration of the several biobanks/registries existing worldwide. However it might be useful also to integrate bioinformatics analysis. The authors should mention https://www.wikipathways.org/index.php/Pathway:WP5087, which is a resource publicly available and continues to be under development and curation by the community, enabling the scientists in mesothelioma to actively participate in the prioritization of shared biological knowledge.

Added existing biobanks/registries both worldwide and in US in discussion part.
Competing Interests: No competing interests were disclosed. Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 16 Nov 2023

Yuhe Gao, Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, 15206, USA

16 Nov 2023

Author Response
The National Mesothelioma Virtual Bank (NMVB) is led by the collaborative effort of the Departments of Biomedical Informatics and Pathology at the University of Pittsburgh, and is funded by a ... Continue reading
The National Mesothelioma Virtual Bank (NMVB) is led by the collaborative effort of the Departments of Biomedical Informatics and Pathology at the University of Pittsburgh, and is funded by a grant from the National Institute of Occupational Health and Safety of the Centers for Disease Control and Prevention. The authors state that the aim is to summarize in this review research from 20 publications that included NMVB samples.

This work is of potential interest since it analyzes the output of an effort to assemble a large collection of mesothelioma, which is a rare disease, for the benefit of scientists’ community. However, the manuscripts needs a large amount of revision and would benefit from the addition in the co-authors of a scientist with deep biology understanding, which would complement bioinformatics skills of the other authors.

--We invited Dr. Uma Chandran, who has a deep biology understanding and solid background, as our co-author. With her help of review and edits, we largely resolved the comments from the reviewer and the self-noticed problem in our previous manuscript.

Major:
General comments:

The focus is to summarize research in biomarker and therapeutic discovery research. It might help the reader if the strategy used for the selection of the studies would be indicated. Indeed, there are according to the homepage of NMVB 60 publications/preprints (merging preprints and publications). In the Table there are 9 studies in the category biomarkers, 6 studies in the category gene expression and 3 studies for therapeutic targets. The total is 18 studies. The bioinformatics analysis studies are not included in the Table, so it is not clear how clear how they are considered.

Added bioinformatics analysis studies in Table 1.

Text and table reference numbers do not match, adding to the confusion. E.g. reference 5 in text corresponds to reference 6 in the table.

Changed, now they match.

The manuscript would benefit of a more clear structure. For example separating studies based on NMVB plasma vs. tissue, and weighting by sample number, i.e. when only a single sample is analyzed this has not the same impact compared to the study of several samples.

Ranked them based on the samples size, and added a platform column in Table 1.

English should be more reader friendly as well. A sentence like “In NMVB-related biomedical studies, there are biomarkers that show substantial evidence of mesothelioma and cancer detection in tumor samples“ is not easy. It might be better to change to “NMVB samples have allowed to discover biomarkers for mesothelioma detection”. What may mean “cancer detection in tumor samples” is not evident. There are several other difficult sentences, I would advise a copy edit of the article.

Have copy edit of the whole article with writing tutors.

Specific comments:

The sentence “the subset of RNA through seven major types…” needs to be changed. The authors refer to a study where differential expression of miRNA was investigated and predicted targets discussed. The data should be reported so with no overstatement about likelihood of the disease.

Revised

SV40 was not “suggested to contribute to malignant mesothelioma because of its viral capabilities” but because large T antigen of SV40 binds e.g. p53 tumor suppressor gene. This is a very precise mechanism and not a general viral capability, whatever this may mean.

Changed to “SV40 has been suggested to contribute to malignant mesothelioma as its large tumor antigen, which binds to cellular tumor suppressor proteins, have been demonstrated in MME”.

Tone down the sentence “Therefore, HMGB1 is likely to cause carcinogenesis”.

Changed to “Therefore, HMGB1 is likely to encourage cell transformation by saving asbestos-damaged human mesothelial cells.”

The whole paragraph starting with “Interestingly, extracellular…” misses to forward the message of that study in the context of mesothelioma.

Added one sentence starting with “More importantly..” to declare the context of mesothelioma.

What do the authors mean when they write. “In a BAP1 study…”?

Was meaning, in a study focusing on BAP1, while now changed to: ” In a study aiming to seek novel biomarkers for distinguishing malignancies, ⁴researchers found that the lack of nuclear BAP1 stain can differentiate MM from lung carcinomas.”

Be more precise when reporting data in reference 13: serum samples, enriched using glycoprotein capture etc...

Added “isolating N-linked glycoproteins to enrich serum proteome and decrease analytical complexity” to describe ref 13.

What does mean the sentence: “There has been a transition…”?

Changed to “There have been some novel directions…”

What does mean the sentence ”varying levels of the human control gene in mesothelioma”? How do the authors imagine a reader may understand? Why should readers understand the interest of checking Merkel cell polyoma virus?

Deleted this statement, added description on MCPyV and SV40 and their relationships to mesothelioma.

What is the message of the paragraph starting: “Overall, BAP1…”?

Changed to “In MM studies, BAP1..”. Was trying to identify the role of BAP1 in existing MM studies.

The whole paragraph: “Furthermore, there are two widely known non-surgical treatments, chemotherapy and radiation therapy, that are involved in decreasing size and morbidity with MPM. Unfortunately, studies have shown that malignant pleural mesothelioma is not as affective. A University of Pennsylvania Medical Center study hypothesized that a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma cells because the virus is normally an oncolytic agent. Forty-eight mesothelioma tumors were obtained from the NMVB forvarious treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses” requires a copy edit.

Revised as “There are two widely known non-surgical treatments to MM, chemotherapy and radiation therapy, however studies have shown that these treatments are not effective enough with malignant pleural mesothelioma. A University of Pennsylvania Medical Center study ²²has proposed an oncolytic viral therapy. Researchers hypothesized that, normally functioning as an oncolytic agent, a vesicular stomatitis virus (VSV) vector that incorporated an Interferon- β gene could effectively prevent the growth of lysis mesothelioma. In the study, 48 mesothelioma tumors were obtained from the NMVB for various treatments (hIFN -β, IFN- β ELISA, IFN -β bioassay ). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses.”

There is an obvious interest in discussing the integration of the several biobanks/registries existing worldwide. However it might be useful also to integrate bioinformatics analysis. The authors should mention https://www.wikipathways.org/index.php/Pathway:WP5087, which is a resource publicly available and continues to be under development and curation by the community, enabling the scientists in mesothelioma to actively participate in the prioritization of shared biological knowledge.

Added existing biobanks/registries both worldwide and in US in discussion part.
The National Mesothelioma Virtual Bank (NMVB) is led by the collaborative effort of the Departments of Biomedical Informatics and Pathology at the University of Pittsburgh, and is funded by a grant from the National Institute of Occupational Health and Safety of the Centers for Disease Control and Prevention. The authors state that the aim is to summarize in this review research from 20 publications that included NMVB samples.

This work is of potential interest since it analyzes the output of an effort to assemble a large collection of mesothelioma, which is a rare disease, for the benefit of scientists’ community. However, the manuscripts needs a large amount of revision and would benefit from the addition in the co-authors of a scientist with deep biology understanding, which would complement bioinformatics skills of the other authors.

--We invited Dr. Uma Chandran, who has a deep biology understanding and solid background, as our co-author. With her help of review and edits, we largely resolved the comments from the reviewer and the self-noticed problem in our previous manuscript.

Major:
General comments:

The focus is to summarize research in biomarker and therapeutic discovery research. It might help the reader if the strategy used for the selection of the studies would be indicated. Indeed, there are according to the homepage of NMVB 60 publications/preprints (merging preprints and publications). In the Table there are 9 studies in the category biomarkers, 6 studies in the category gene expression and 3 studies for therapeutic targets. The total is 18 studies. The bioinformatics analysis studies are not included in the Table, so it is not clear how clear how they are considered.

Added bioinformatics analysis studies in Table 1.

Text and table reference numbers do not match, adding to the confusion. E.g. reference 5 in text corresponds to reference 6 in the table.

Changed, now they match.

The manuscript would benefit of a more clear structure. For example separating studies based on NMVB plasma vs. tissue, and weighting by sample number, i.e. when only a single sample is analyzed this has not the same impact compared to the study of several samples.

Ranked them based on the samples size, and added a platform column in Table 1.

English should be more reader friendly as well. A sentence like “In NMVB-related biomedical studies, there are biomarkers that show substantial evidence of mesothelioma and cancer detection in tumor samples“ is not easy. It might be better to change to “NMVB samples have allowed to discover biomarkers for mesothelioma detection”. What may mean “cancer detection in tumor samples” is not evident. There are several other difficult sentences, I would advise a copy edit of the article.

Have copy edit of the whole article with writing tutors.

Specific comments:

The sentence “the subset of RNA through seven major types…” needs to be changed. The authors refer to a study where differential expression of miRNA was investigated and predicted targets discussed. The data should be reported so with no overstatement about likelihood of the disease.

Revised

SV40 was not “suggested to contribute to malignant mesothelioma because of its viral capabilities” but because large T antigen of SV40 binds e.g. p53 tumor suppressor gene. This is a very precise mechanism and not a general viral capability, whatever this may mean.

Changed to “SV40 has been suggested to contribute to malignant mesothelioma as its large tumor antigen, which binds to cellular tumor suppressor proteins, have been demonstrated in MME”.

Tone down the sentence “Therefore, HMGB1 is likely to cause carcinogenesis”.

Changed to “Therefore, HMGB1 is likely to encourage cell transformation by saving asbestos-damaged human mesothelial cells.”

The whole paragraph starting with “Interestingly, extracellular…” misses to forward the message of that study in the context of mesothelioma.

Added one sentence starting with “More importantly..” to declare the context of mesothelioma.

What do the authors mean when they write. “In a BAP1 study…”?

Was meaning, in a study focusing on BAP1, while now changed to: ” In a study aiming to seek novel biomarkers for distinguishing malignancies, ⁴researchers found that the lack of nuclear BAP1 stain can differentiate MM from lung carcinomas.”

Be more precise when reporting data in reference 13: serum samples, enriched using glycoprotein capture etc...

Added “isolating N-linked glycoproteins to enrich serum proteome and decrease analytical complexity” to describe ref 13.

What does mean the sentence: “There has been a transition…”?

Changed to “There have been some novel directions…”

What does mean the sentence ”varying levels of the human control gene in mesothelioma”? How do the authors imagine a reader may understand? Why should readers understand the interest of checking Merkel cell polyoma virus?

Deleted this statement, added description on MCPyV and SV40 and their relationships to mesothelioma.

What is the message of the paragraph starting: “Overall, BAP1…”?

Changed to “In MM studies, BAP1..”. Was trying to identify the role of BAP1 in existing MM studies.

The whole paragraph: “Furthermore, there are two widely known non-surgical treatments, chemotherapy and radiation therapy, that are involved in decreasing size and morbidity with MPM. Unfortunately, studies have shown that malignant pleural mesothelioma is not as affective. A University of Pennsylvania Medical Center study hypothesized that a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma cells because the virus is normally an oncolytic agent. Forty-eight mesothelioma tumors were obtained from the NMVB forvarious treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses” requires a copy edit.

Revised as “There are two widely known non-surgical treatments to MM, chemotherapy and radiation therapy, however studies have shown that these treatments are not effective enough with malignant pleural mesothelioma. A University of Pennsylvania Medical Center study ²²has proposed an oncolytic viral therapy. Researchers hypothesized that, normally functioning as an oncolytic agent, a vesicular stomatitis virus (VSV) vector that incorporated an Interferon- β gene could effectively prevent the growth of lysis mesothelioma. In the study, 48 mesothelioma tumors were obtained from the NMVB for various treatments (hIFN -β, IFN- β ELISA, IFN -β bioassay ). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses.”

There is an obvious interest in discussing the integration of the several biobanks/registries existing worldwide. However it might be useful also to integrate bioinformatics analysis. The authors should mention https://www.wikipathways.org/index.php/Pathway:WP5087, which is a resource publicly available and continues to be under development and curation by the community, enabling the scientists in mesothelioma to actively participate in the prioritization of shared biological knowledge.

Added existing biobanks/registries both worldwide and in US in discussion part.
Competing Interests: No competing interests were disclosed. Close
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Version 3

VERSION 3 PUBLISHED 18 Nov 2022

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	1	2	3
Version 3 (revision) 28 May 24		read	read
Version 2 (revision) 11 Sep 23		read
Version 1 18 Nov 22	read

Emanuela Felley-Bosco, University Hospital Zurich, Zurich, Switzerland
Brooke Mossman, University of Vermont College of Medicine, Burlington, USA
Claire W. Michael, University Hospitals Cleveland Medical Center/Case Western Reserve University, Cleveland, USA

Omid Savari, Case Western Reserve University, Cleveland, USA

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Reviewer Report

7 Views

31 Dec 2024 | for Version 3

Claire W. Michael, University Hospitals Cleveland Medical Center/Case Western Reserve University, Cleveland, USA

Omid Savari, Case Western Reserve University, Cleveland, Ohio, USA

7 Views Cite this report Responses(0)

Not Approved

This article examined and summarized the study findings from the studies that used NMVB resources. The NMVB (National Mesothelioma Virtual Bank) is led by the Department of Biomedical Informatics and Pathology at the University of Pittsburgh, and its mission is to support research that will assist patients with mesothelioma. The current effort to describe the research findings is crucial to understanding the efficacy of the NMVB database, however I believe this review requires considerable modifications.

Lack of fluency and clarity: This summary provides results of over 100 studies which utilized NMVB, however only conclusions of those studies are provides in inconsistent and fragmented statements. To fully grasp each section, the reader must refer to the original sources several times.
Absence of inclusion and exclusion criteria: NMVB data was used in 110 published articles; however, the authors only identified 34 of these studies as "key published studies" in their review, failing to specify their inclusion and exclusion criteria.
Providing merely raw data: It is challenging to draw any conclusions because the data from numerous studies are presented without any statistical analysis.
Practical implications: several biomarkers have been presented, but their clinical utility is not explained in any depth. At the conclusion of this essay, we remain uncertain about the sensitivity and specificity of each test and the methods for their evaluation.

Input from a thoracic pathologist is required because many NMVB researches have examined genes and markers for prognostic or diagnostic purposes that can be used in thoracic pathology. This report would benefit greatly from a review and revision by a thoracic pathologist with experience in mesothelioma

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Yes
Is the review written in accessible language?

Partly
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Cytopathology, immunostaining, mesothelioma

We confirm that we have read this submission and believe that we have an appropriate level of expertise to state that we do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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Reviewer Report

12 Views

10 Jul 2024 | for Version 3

Brooke Mossman, Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA

12 Views Cite this report Responses(0)

Approved

Regarding my previous comment #3 in the Introduction, Paragraph #1, please omit statement “inducing the mutation.” at end of sentence. This makes no sense.

Regarding my previous comment #7, please rewrite the sentence “Utilizing algorithms such as the SPaRTAN and GES scores to understand cell activation”. It is an incomplete sentence.

Competing Interests

Am a member of the review team for NMVB

Reviewer Expertise

Mechanisms of mesothelioma development and therapy.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

22 Views

29 Apr 2024 | for Version 2

Brooke Mossman, Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA

22 Views Cite this report Responses(1)

Approved With Reservations

This is an important review that cites the findings of key published studies using the services of the NMVB, a critical resource for mechanistic and therapeutic investigations on human malignant mesotheliomas (MMs). Also described are the services, materials available, and access of specimens as well as the participation of multiple investigators conducting clinical and basic scientific research. Minor revisions are needed:
1) Introduction, Para. #1, line 2. "Environmental" should be changed to "Occupational" as this is consistent with the published literature and quoted articles. Moreover, asbestos is " a group of" naturally occurring silicate minerals.
2) Introduction, Para. #1, line 3-4. it is stated that other mineral fibers including antigorite and actinolite "are known to be carcinogenic as well^2,3." In fact, actinolite is an asbestos type and antigorite can occur in several mineralogic forms. Neither citation (nor a PubMed search) classifies antigorite as a carcinogen, and the cited reference by Roggli² (Table 1) lists fluoro-edenite, balangeroite and winchite instead as fibers with potential to cause MMs.
3) Introduction, Para #1, line 4-6. This sentence should be omitted as it is based on outdated studies (1980s and 1990s) showing that long fibers of a variety of types interact with the cell spindle in cells in vitro. The idea that asbestos fibers physically interact with DNA to induce aneuploidy or mutations is inconsistent with results by MacCorkle et al.[1] and conclusions by Carbone et al [2]. The authors here cite reference 4 in support of their statement which is a paper on nuclear BAP1 staining in differential diagnosis of MM (?). In fact, MM is a primarily epigenetically regulated disease involving interaction between cell surface receptors, protein cascades affecting transcription factors, gene expression, and loss of tumor suppressor gene function.
4) Introduction, Para #2, line 5. Please change to "a valuable resource" (no s).
5) Under the section "Biomarker studies related to mesothelioma", EVP should be defined in line 2 and in lines 2-3,"of" should be inserted after "seven types ". This sentence should be rewritten for clarity. In the second to last line of the paragraph on miRNAs, the word "filed" should be changed to "failed".
6) The heading of the next section should be corrected to "Extracellular Vesicles and Particles (EVP).
7) In the section, Abnormal gene expression in mesothelioma, Para # 3, line 3 "In this examination,..." and the last sentence of Para #3 needs to be rewritten for clarification. Also note that the last sentence in this paragraph is incomplete.

Is the topic of the review discussed comprehensively in the context of the current literature?

Yes
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Yes
Are the conclusions drawn appropriate in the context of the current research literature?

Yes

References

1. MacCorkle RA, Slattery SD, Nash DR, Brinkley BR: Intracellular protein binding to asbestos induces aneuploidy in human lung fibroblasts.Cell Motil Cytoskeleton. 2006; 63 (10): 646-57 PubMed Abstract | Publisher Full Text
2. Carbone M, Adusumilli PS, Alexander HR, Baas P, et al.: Mesothelioma: Scientific clues for prevention, diagnosis, and therapy.CA Cancer J Clin. 2019; 69 (5): 402-429 PubMed Abstract | Publisher Full Text

Competing Interests

Dr. Mossman has used materials from the NMVB in her NIH-funded research and has reviewed research requests by others for materials from the NMVB.

Reviewer Expertise

Mechanisms of mesothelioma development and therapy.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response

29 Jun 2024

Yuhe Gao, Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, 15206, USA

1) Introduction, Para. #1, line 2. "Environmental" should be changed to "Occupational" as this is consistent with the published literature and quoted articles. Moreover, asbestos is " a group of" naturally occurring silicate minerals.
Resolved.

2) Introduction, Para. #1, line 3-4. it is stated that other mineral fibers including antigorite and actinolite "are known to be carcinogenic as well2,3." In fact, actinolite is an asbestos type and antigorite can occur in several mineralogic forms. Neither citation (nor a PubMed search) classifies antigorite as a carcinogen, and the cited reference by Roggli2 (Table 1) lists fluoro-edenite, balangeroite and / winchite instead as fibers with potential to cause MMs.
Resolved.

3) Introduction, Para #1, line 4-6. This sentence should be omitted as it is based on outdated studies (1980s and 1990s) showing that long fibers of a variety of types interact with the cell spindle in cells in vitro. The idea that asbestos fibers physically interact with DNA to induce aneuploidy or mutations is inconsistent with results by MacCorkle et al.[1] and conclusions by Carbone et al [2]. The authors here cite reference 4 in support of their statement which is a paper on nuclear BAP1 staining in differential diagnosis of MM (?). In fact, MM is a primarily epigenetically regulated disease involving interaction between cell surface receptors, protein cascades affecting transcription factors, gene expression, and loss of tumor suppressor gene function.
Deleted that statement, revised as “Previous studies from the 1980s and 1990s suggested that long fibers of various types interact with the cell spindle in vitro inducing the mutation³². However, mesothelioma is primarily an epigenetically regulated disease that results from interactions between cell surface receptors, protein cascades influencing transcription factors, gene expression, and the loss of tumor suppressor gene function.”

4) Introduction, Para #2, line 5. Please change to "a valuable resource" (no s).
Resolved.

5) Under the section "Biomarker studies related to mesothelioma", EVP should be defined in line 2 and in lines 2-3,"of" should be inserted after "seven types ". This sentence should be rewritten for clarity. In the second to last line of the paragraph on miRNAs, the word "filed" should be changed to "failed".
Resolved. Revised the sentences to “Researchers have discovered that seven types of RNA—miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-205, and miR-429—are significantly downregulated in MPM compared to lung adenocarcinoma.5 Additionally, they identified that key downstream modulators, such as MYC and JUN, as well as effectors like VANGL1, RHOA, ROCK2, WNT5A, and PLCB1 of the Wnt pathway, are redundantly targeted by these downregulated miRNAs. This reduction in miRNA expression leads to the dysregulation of the Wnt pathway, which is a crucial process in the development of MPM.”

6) The heading of the next section should be corrected to "Extracellular Vesicles and Particles (EVP).
Resolved.

7) In the section, Abnormal gene expression in mesothelioma, Para # 3, line 3 "In this examination,..." and the last sentence of Para #3 needs to be rewritten for clarification. Also note that the last sentence in this paragraph is incomplete.
Resolved. Added “combining lymph node status and histologic subtype” to illustrate “clinical tests”, and rephrased the last sentence.

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Competing Interests

No competing interests were disclosed.

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Reviewer Report

32 Views

08 Dec 2022 | for Version 1

Emanuela Felley-Bosco, Laboratory of Molecular Oncology, Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland

32 Views Cite this report Responses(1)

Not Approved

The focus is to summarize research in biomarker and therapeutic discovery research. It might help the reader if the strategy used for the selection of the studies would be indicated. Indeed, there are according to the homepage of NMVB 60 publications/preprints (merging preprints and publications). In the Table there are 9 studies in the category biomarkers, 6 studies in the category gene expression and 3 studies for therapeutic targets. The total is 18 studies. The bioinformatics analysis studies are not included in the Table, so it is not clear how clear how they are considered.
Text and table reference numbers do not match, adding to the confusion. E.g. reference 5 in text corresponds to reference 6 in the table.
The manuscript would benefit of a more clear structure. For example separating studies based on NMVB plasma vs. tissue, and weighting by sample number, i.e. when only a single sample is analyzed this has not the same impact compared to the study of several samples.
Data should not be just mentioned but it is necessary to have some comments and critical assessments. If not it will look rather like a list, decreasing its interest. E.g. the two sentences starting “Tissue and serum samples were…..…….category” would be more informative if the authors could comment of what they think about antibodies against MEG3, which is non-coding RNA.
English should be more reader friendly as well. A sentence like “In NMVB-related biomedical studies, there are biomarkers that show substantial evidence of mesothelioma and cancer detection in tumor samples“ is not easy. It might be better to change to “NMVB samples have allowed to discover biomarkers for mesothelioma detection”. What may mean “cancer detection in tumor samples” is not evident. There are several other difficult sentences, I would advise a copy edit of the article.

Specific comments:

The sentence “the subset of RNA through seven major types…” needs to be changed. The authors refer to a study where differential expression of miRNA was investigated and predicted targets discussed. The data should be reported so with no overstatement about likelihood of the disease.
SV40 was not “suggested to contribute to malignant mesothelioma because of its viral capabilities” but because large T antigen of SV40 binds e.g. p53 tumor suppressor gene. This is a very precise mechanism and not a general viral capability, whatever this may mean.
Tone down the sentence “Therefore, HMGB1 is likely to cause carcinogenesis”.
The whole paragraph starting with “Interestingly, extracellular…” misses to forward the message of that study in the context of mesothelioma.
What do the authors mean when they write. “In a BAP1 study…”?
Be more precise when reporting data in reference 13: serum samples, enriched using glycoprotein capture etc...
What does mean the sentence: “There has been a transition…”?
What does mean the sentence ”varying levels of the human control gene in mesothelioma”? How do the authors imagine a reader may understand? Why should readers understand the interest of checking Merkel cell polyoma virus?
What is the message of the paragraph starting: “Overall, BAP1…”?
CD30: the authors could comment that positivity in tumor samples was variable, and could represent a target for antibody-drug conjugates on in a fraction of samples…
Thiostrepton had been first used in breast cancer cells where it was shown to decrease the expression of FOXM1 (Kwok JM, et al Mol Cancer Ther 2008;7:2022–32) and the authors should mention this reference. Then they should comment on reasons why FOXM1 inhibiting antibiotics are not suitable for use in humans.
The whole paragraph: “Furthermore, there are two widely known non-surgical treatments, chemotherapy and radiation therapy, that are involved in decreasing size and morbidity with MPM. Unfortunately, studies have shown that malignant pleural mesothelioma is not as affective. A University of Pennsylvania Medical Center study hypothesized that a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma cells because the virus is normally an oncolytic agent. Forty-eight mesothelioma tumors were obtained from the NMVB forvarious treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses” requires a copy edit.
There is an obvious interest in discussing the integration of the several biobanks/registries existing worldwide. However it might be useful also to integrate bioinformatics analysis. The authors should mention https://www.wikipathways.org/index.php/Pathway:WP5087, which is a resource publicly available and continues to be under development and curation by the community, enabling the scientists in mesothelioma to actively participate in the prioritization of shared biological knowledge.

Is the topic of the review discussed comprehensively in the context of the current literature?

Partly
Are all factual statements correct and adequately supported by citations?

Partly
Is the review written in accessible language?

Partly
Are the conclusions drawn appropriate in the context of the current research literature?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

fundamental and translational research in mesothelioma

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Responses (1)

Author Response

16 Nov 2023

Yuhe Gao, Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, 15206, USA

The focus is to summarize research in biomarker and therapeutic discovery research. It might help the reader if the strategy used for the selection of the studies would be indicated. Indeed, there are according to the homepage of NMVB 60 publications/preprints (merging preprints and publications). In the Table there are 9 studies in the category biomarkers, 6 studies in the category gene expression and 3 studies for therapeutic targets. The total is 18 studies. The bioinformatics analysis studies are not included in the Table, so it is not clear how clear how they are considered.
- Added bioinformatics analysis studies in Table 1.
Text and table reference numbers do not match, adding to the confusion. E.g. reference 5 in text corresponds to reference 6 in the table.
- Changed, now they match.
The manuscript would benefit of a more clear structure. For example separating studies based on NMVB plasma vs. tissue, and weighting by sample number, i.e. when only a single sample is analyzed this has not the same impact compared to the study of several samples.
- Ranked them based on the samples size, and added a platform column in Table 1.
English should be more reader friendly as well. A sentence like “In NMVB-related biomedical studies, there are biomarkers that show substantial evidence of mesothelioma and cancer detection in tumor samples“ is not easy. It might be better to change to “NMVB samples have allowed to discover biomarkers for mesothelioma detection”. What may mean “cancer detection in tumor samples” is not evident. There are several other difficult sentences, I would advise a copy edit of the article.
- Have copy edit of the whole article with writing tutors.

Specific comments:

The sentence “the subset of RNA through seven major types…” needs to be changed. The authors refer to a study where differential expression of miRNA was investigated and predicted targets discussed. The data should be reported so with no overstatement about likelihood of the disease.
- Revised
SV40 was not “suggested to contribute to malignant mesothelioma because of its viral capabilities” but because large T antigen of SV40 binds e.g. p53 tumor suppressor gene. This is a very precise mechanism and not a general viral capability, whatever this may mean.
- Changed to “SV40 has been suggested to contribute to malignant mesothelioma as its large tumor antigen, which binds to cellular tumor suppressor proteins, have been demonstrated in MME”.
Tone down the sentence “Therefore, HMGB1 is likely to cause carcinogenesis”.
- Changed to “Therefore, HMGB1 is likely to encourage cell transformation by saving asbestos-damaged human mesothelial cells.”
The whole paragraph starting with “Interestingly, extracellular…” misses to forward the message of that study in the context of mesothelioma.
- Added one sentence starting with “More importantly..” to declare the context of mesothelioma.
What do the authors mean when they write. “In a BAP1 study…”?
- Was meaning, in a study focusing on BAP1, while now changed to: ” In a study aiming to seek novel biomarkers for distinguishing malignancies, ⁴researchers found that the lack of nuclear BAP1 stain can differentiate MM from lung carcinomas.”
Be more precise when reporting data in reference 13: serum samples, enriched using glycoprotein capture etc...
- Added “isolating N-linked glycoproteins to enrich serum proteome and decrease analytical complexity” to describe ref 13.
What does mean the sentence: “There has been a transition…”?
- Changed to “There have been some novel directions…”
What does mean the sentence ”varying levels of the human control gene in mesothelioma”? How do the authors imagine a reader may understand? Why should readers understand the interest of checking Merkel cell polyoma virus?
- Deleted this statement, added description on MCPyV and SV40 and their relationships to mesothelioma.
What is the message of the paragraph starting: “Overall, BAP1…”?
- Changed to “In MM studies, BAP1..”. Was trying to identify the role of BAP1 in existing MM studies.
The whole paragraph: “Furthermore, there are two widely known non-surgical treatments, chemotherapy and radiation therapy, that are involved in decreasing size and morbidity with MPM. Unfortunately, studies have shown that malignant pleural mesothelioma is not as affective. A University of Pennsylvania Medical Center study hypothesized that a vesicular stomatitis virus (VSV) vector that incorporated an Interferon-β gene could effectively prevent the growth of lysis mesothelioma cells because the virus is normally an oncolytic agent. Forty-eight mesothelioma tumors were obtained from the NMVB forvarious treatments (hIFN-β, IFN-β ELISA, IFN-β bioassay). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses” requires a copy edit.
- Revised as “There are two widely known non-surgical treatments to MM, chemotherapy and radiation therapy, however studies have shown that these treatments are not effective enough with malignant pleural mesothelioma. A University of Pennsylvania Medical Center study ²²has proposed an oncolytic viral therapy. Researchers hypothesized that, normally functioning as an oncolytic agent, a vesicular stomatitis virus (VSV) vector that incorporated an Interferon- β gene could effectively prevent the growth of lysis mesothelioma. In the study, 48 mesothelioma tumors were obtained from the NMVB for various treatments (hIFN -β, IFN- β ELISA, IFN -β bioassay ). As presumed, the delivery of genes results in a decrease of lysis activity and an increase in antitumor immune responses.”
There is an obvious interest in discussing the integration of the several biobanks/registries existing worldwide. However it might be useful also to integrate bioinformatics analysis. The authors should mention https://www.wikipathways.org/index.php/Pathway:WP5087, which is a resource publicly available and continues to be under development and curation by the community, enabling the scientists in mesothelioma to actively participate in the prioritization of shared biological knowledge.
- Added existing biobanks/registries both worldwide and in US in discussion part.

View more View less

Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

[1] 1. Sekido Y: Molecular pathogenesis of malignant mesothelioma. Carcinogenesis. 2013; 34: 1413–1419. Publisher Full Text

[2] 2. Roggli VL: Measuring EMPs in the lung what can be measured in the lung: Asbestiform minerals and cleavage fragments. Toxicol. Appl. Pharmacol. 2018; 361: 14–17. PubMed Abstract | Publisher Full Text

[3] 3. Bibby AC, Tsim S, Kanellakis N, et al.: Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment. Eur. Respir. Rev. 2016; 25: 472–486. PubMed Abstract | Publisher Full Text

[4] 4. Carbone M, Shimizu D, Napolitano A, et al.: Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma. Oncotarget. 2016; 7: 59314–59321. PubMed Abstract | Publisher Full Text

[5] 5. Gee GV, Koestler DC, Christensen BC, et al.: Downregulated microRNAs in the differential diagnosis of malignant pleural mesothelioma. Int. J. Cancer. 2010; 127: 2859–2869. PubMed Abstract | Publisher Full Text

[6] 6. Vilchez RA, Butel JS: Emergent human pathogen simian virus 40 and its role in cancer. Clin. Microbiol. Rev. 2004; 17: 495–508, table of contents. PubMed Abstract | Publisher Full Text

[7] 7. Gee G, Stanifer M, Christensen B, et al.: SV40 associated miRNAs are not detectable in mesotheliomas. Br. J. Cancer. 2010; 103: 885–888. PubMed Abstract | Publisher Full Text

[8] 8. Xu Y, Zheng M, Merritt RE, et al.: miR-1 induces growth arrest and apoptosis in malignant mesothelioma. Chest. 2013; 144: 1632–1643. PubMed Abstract | Publisher Full Text

[9] 9. Zhang X, Shen W, Dong X, et al.: Identification of novel autoantibodies for detection of malignant mesothelioma. PLoS One. 2013; 8: e72458. PubMed Abstract | Publisher Full Text

[10] 10. Dabir S, Kluge A, Kresak A, et al.: Low PIAS3 Expression in Malignant Mesothelioma Is Associated with Increased STAT3 Activation and Poor Patient Survival. Clin. Cancer Res. 2014; 20: 5124–5132. PubMed Abstract | Publisher Full Text

[11] 11. Xue J, Patergnani S, Giorgi C, et al.: Asbestos induces mesothelial cell transformation via HMGB1-driven autophagy. Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 25543–25552. PubMed Abstract | Publisher Full Text

[12] 12. Hoshino A, Kim HS, Bojmar L, et al.: Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers. Cell. 2020; 182: 1044–1061.e18. PubMed Abstract | Publisher Full Text

[13] 13. Cerciello F, Choi M, Sinicropi-Yao SL, et al.: Verification of a Blood-Based Targeted Proteomics Signature for Malignant Pleural Mesothelioma. Cancer Epidemiol. Biomark. Prev. 2020; 29: 1973–1982. PubMed Abstract | Publisher Full Text

[14] 14. Burke A, Legesse T: Nivolumab-Induced Peritonitis With Mesothelial Hyperplasia Mimicking Metastatic Mesothelioma. AJSP: Rev. Rep. 2022; 27: 98–102. Publisher Full Text

[15] 15. Nasu M, Emi M, Pastorino S, et al.: High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma. J. Thorac. Oncol. 2015; 10: 565–576. PubMed Abstract | Publisher Full Text

[16] 16. Bhatia K, Modali R, Goedert JJ: Merkel cell polyomavirus is not detected in mesotheliomas. J. Clin. Virol. 2010; 47: 196–198. PubMed Abstract | Publisher Full Text

[17] 17. Bononi A, Goto K, Ak G, et al.: Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma. Proc. Natl. Acad. Sci. U. S. A. 2020; 117: 33466–33473. PubMed Abstract | Publisher Full Text

[18] 18. De Rienzo A, Cook RW, Wilkinson J, et al.: Validation of a Gene Expression Test for Mesothelioma Prognosis in Formalin-Fixed Paraffin-Embedded Tissues. J. Mol. Diagn. 2017; 19: 65–71. PubMed Abstract | Publisher Full Text

[19] 19. Ma X, Somasundaram A, Qi Z, et al.: SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators. Nucleic Acids Res. 2021; 49: 9633–9647. PubMed Abstract | Publisher Full Text

[20] 20. Newick K, Cunniff B, Preston K, et al.: Peroxiredoxin 3 Is a Redox-Dependent Target of Thiostrepton in Malignant Mesothelioma Cells. PLoS One. 2012; 7: e39404. PubMed Abstract | Publisher Full Text

[21] 21. Dabir S, Kresak A, Yang M, et al.: CD30 is a potential therapeutic target in malignant mesothelioma. Mol. Cancer Ther. 2015; 14: 740–746. PubMed Abstract | Publisher Full Text

[22] 22. Saloura V, Wang LC, Fridlender ZG, et al.: Evaluation of an attenuated vesicular stomatitis virus vector expressing interferon-beta for use in malignant pleural mesothelioma: heterogeneity in interferon responsiveness defines potential efficacy. Hum. Gene Ther. 2010; 21: 51–64. PubMed Abstract | Publisher Full Text

[23] 23. Dhir R, Patel AA, Winters S, et al.: A multidisciplinary approach to honest broker services for tissue banks and clinical data. Cancer. 2008; 113: 1705–1715. PubMed Abstract | Publisher Full Text

[24] 24. Mohanty SK, Mistry AT, Amin W, et al.: The development and deployment of Common Data Elements for tissue banks for translational research in cancer - an emerging standard based approach for the Mesothelioma Virtual Tissue Bank. BMC Cancer. 2008; 8: 91. PubMed Abstract | Publisher Full Text

[25] 25. Amin W, Srinivasan M, Song SY, et al.: Use of automated image analysis in evaluation of Mesothelioma Tissue Microarray (TMA) from National Mesothelioma Virtual Bank. Pathol. Res. Pract. 2014; 210: 79–82. PubMed Abstract | Publisher Full Text

[26] 26. Wilson RA, Chapman WW, Defries SJ, et al.: Automated ancillary cancer history classification for mesothelioma patients from free-text clinical reports. J. Pathol. Inform. 2010; 1: 24. PubMed Abstract | Publisher Full Text

[27] 27. Amin W, Linkov F, Landsittel DP, et al.: Factors influencing malignant mesothelioma survival: a retrospective review of the National Mesothelioma Virtual Bank cohort. F1000Res. 2018; 7: 1184. PubMed Abstract | Publisher Full Text

[28] 28. Karunakaran KB, Yanamala N, Boyce G, et al.: Malignant Pleural Mesothelioma Interactome with 364 Novel Protein-Protein Interactions. Cancers (Basel). 2021; 13. PubMed Abstract | Publisher Full Text

[29] 29. Karunakaran KB, Ganapathiraju MK: Malignant Peritoneal Mesothelioma Interactome with 417 Novel Protein-Protein Interactions.2021; 6. Publisher Full Text

[30] 30. van Gerwen M , Alpert N, Flores R, et al.: An overview of existing mesothelioma registries worldwide, and the need for a US Registry. Am. J. Ind. Med. 2020; 63: 115–120. PubMed Abstract | Publisher Full Text

[31] 31. Cummings KJ, Becich MJ, Blackley DJ, et al.: Workshop summary: Potential usefulness and feasibility of a US National Mesothelioma Registry. Am. J. Ind. Med. 2020; 63: 105–114. PubMed Abstract | Publisher Full Text

Multiple institutions’ research findings using the National Mesothelioma Virtual Bank

Abstract

Keywords

Introduction

Biomarker studies related to mesothelioma

Abnormal gene expression in mesothelioma

Therapeutic targets for mesothelioma treatment

Table 1. Summary of research sample and research findings of NMVB-related studies.

Biomedical informatics research in NMVB

Discussion

Conclusions

Data availability

Acknowledgements

References

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