Journal Description
Journal of Molecular Pathology
Journal of Molecular Pathology
is an international, peer-reviewed, open access journal on every topic related to modern histopathology and cytopathology, predictive pathology and molecular cytopathology, published quarterly online by MDPI.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, ESCI (Web of Science), CAPlus / SciFinder, and other databases.
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 24.9 days after submission; acceptance to publication is undertaken in 3.8 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: APC discount vouchers, optional signed peer review, and reviewer names published annually in the journal.
Latest Articles
Impact of Gut–Brain Axis on Hepatobiliary Diseases in Fetal Programming
J. Mol. Pathol. 2024, 5(2), 215-227; https://doi.org/10.3390/jmp5020014 - 16 May 2024
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The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially
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The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially in pregnancy, HBD may result in increased maternal and fetal morbidity and mortality. Maternal HBD is a burden to the fetus’s growth, complicates fetal development, and risks the mother’s life. In fetal programming, the maternal mechanism is significantly disturbed by multiple factors (especially diet) that influence the development of the fetus and increase the frequency of metabolic diseases later in life. Additionally, maternal under-nutrition or over-nutrition (especially in high-fat, high-carbohydrate, or protein-rich diets) lead to dysregulation in gut hormones (CCK, GLP-1, etc.), microbiota metabolite production (SCFA, LPS, TMA, etc.), neurotransmitters (POMC, NPY, etc.), and hepatobiliary signaling (insulin resistance, TNF-a, SREBPs, etc.), which significantly impact fetal programming. Recently, biotherapeutics have provided a new horizon for treating HBD during fetal programming to save the lives of the mother and fetus. This review focuses on how maternal impaired hepatobiliary metabolic signaling leads to disease transmission to the fetus mediated through the gut–brain axis.
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Open AccessArticle
Liquid Biopsy Profiling with Multiple Tests in Patients with Metastatic Breast Cancer
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Nikki Higa, Lisa Welter, Liya Xu, Anand Kolatkar, Kelli S. Bramlett, Ole V. Gjoerup, Ryon Graf, Richard S.P. Huang, Rebecca J. Leary, Young Lee, Jeremy G. Perkins, Adam I. Riker, Angad P. Singh, Lorraine Tafra, Carol K. Tweed, Craig D. Shriver, James Hicks and Peter Kuhn
J. Mol. Pathol. 2024, 5(2), 199-214; https://doi.org/10.3390/jmp5020013 - 9 May 2024
Abstract
The chief goal of the Blood Profiling Atlas in Cancer (BloodPAC) consortium is to promote collaborative efforts that support the development and implementation of liquid biopsy tests. Here, we report the results of a pilot study conducted by three BloodPAC members that aimed
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The chief goal of the Blood Profiling Atlas in Cancer (BloodPAC) consortium is to promote collaborative efforts that support the development and implementation of liquid biopsy tests. Here, we report the results of a pilot study conducted by three BloodPAC members that aimed to demonstrate a multisite liquid biopsy testing framework using longitudinal blood specimens from 38 patients with metastatic breast cancer. Three laboratories receiving identical samples from two clinical sites each applied a different targeted sequencing platform to analyze mutations in cell-free DNA (cfDNA). The resulting mutational profiles reflected common breast cancer alterations, including clinically actionable mutations for 40% of hormone- receptor-positive patients. In 12 genes with shared target regions across sequencing panels, perfect inter-assay concordance was also observed for mutations detected above the lowest common assay limit of detection. Whole-genome copy number profiling of cfDNA and circulating tumor cells (CTCs) further revealed marked heterogeneity in copy number alterations and cfDNA tumor fractions across patients. Additionally, comparison of tumor fraction and CTC abundance demonstrated the complementary nature of cfDNA and CTC analyses. Overall, the framework described in this study may serve as a resource for future trials aiming to identify multimodal liquid biopsy biomarkers to guide clinical care.
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(This article belongs to the Collection Feature Papers in Journal of Molecular Pathology)
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Molecular Profiling of H-MSI/dMMR/for Endometrial Cancer Patients: “New Challenges in Diagnostic Routine Practice”
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Riccardo Adorisio, Giancarlo Troncone, Massimo Barberis and Francesco Pepe
J. Mol. Pathol. 2024, 5(2), 187-198; https://doi.org/10.3390/jmp5020012 - 24 Apr 2024
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Endometrial cancer (EC) represents one of the most newly diagnosed cancers across gynecological malignancies. In particular, a plethora of risk factors (both biological and lifestyle-related) drastically impact the incidence rate of novel diagnosis accounting for 8300 cases/year. In the recent era of precision
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Endometrial cancer (EC) represents one of the most newly diagnosed cancers across gynecological malignancies. In particular, a plethora of risk factors (both biological and lifestyle-related) drastically impact the incidence rate of novel diagnosis accounting for 8300 cases/year. In the recent era of precision medicine EC molecular classification, integrating ESGO/ESTRO/ESP guidelines, four distinct diagnostic groups have been established including POLE-mutant (POLE-pos); High-instability MSI (H-MSI)–MMR-deficient (MMR-d); p53-abnormal (p53abn); and non-specific molecular profile (NSMP), also known as p53-wild-type EC patients on the basis of clinically relevant emerging biomarkers. In addition, molecular testing also plays a pivotal role in defining the best therapeutical option. In this scenario, the European Society for Medical Oncology (ESMO) recommended d-MMR/MSI-H status evaluation in the diagnostic workflow of Lynch syndrome or selecting EC patients that could benefit from immune checkpoint inhibitors (ICIs). Although immunohistochemistry (IHC) is considered the gold standard approach for d-MMR profiling, a series of molecular PCR-based techniques have rapidly developed to integrate H-MSI status in routine practice. Here, we technically overviewed the most relevant commercially available diagnostic assays for the determination of the H-MSI/dMMR status in EC patients.
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Mechanisms of Inflammasome Activation and Involvement in Liver Disease
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Ananda Baral
J. Mol. Pathol. 2024, 5(2), 171-186; https://doi.org/10.3390/jmp5020011 - 13 Apr 2024
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The liver is a multi-potent organ with important metabolic, immunological and endocrine functions. Hepatic physiology is maintained at a balanced state via the delicate actions of different liver-resident cells. Among several factors that modulate hepatic physiology, the harmony between the activity of pro-
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The liver is a multi-potent organ with important metabolic, immunological and endocrine functions. Hepatic physiology is maintained at a balanced state via the delicate actions of different liver-resident cells. Among several factors that modulate hepatic physiology, the harmony between the activity of pro- and anti-inflammatory cytokines is a crucial determinant. However, initiation of inflammatory activity can be detrimental if it goes unresolved, leading to severe consequences such as hepatitis, hepatic fibrosis, cirrhosis or even hepatocellular carcinoma (HCC). Different physiological processes can modulate the hepatic microenvironment; one such factor is a cytosolic protein complex called the inflammasome. Inflammasome activation is a consequence of the cellular encounter with pathogens or products of cellular damage. Once activated, inflammasomes promote the maturation of interleukin-1 family cytokines such as IL-1β and IL-18 via activation of caspase-1. These cytokines have a very potent role in modulating hepatic physiology. Various lines of reports suggest that inflammasome activation and IL-1 cytokines play critical roles in liver diseases, including hepatitis, hepatic fibrosis and HCC. Conversely, inhibition of inflammasome activation and/or IL-1 signaling prevents such effects. This review summarizes the mechanisms leading to inflammasome activation and the role it plays in hepatic physiology.
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(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Liver Diseases)
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Open AccessReview
Basal Cell Carcinoma: Diagnosis, Management and Prevention
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Peerzada Umar Farooq Baba, Ashfaq ul Hassan, Junaid Khurshid and Adil Hafeez Wani
J. Mol. Pathol. 2024, 5(2), 153-170; https://doi.org/10.3390/jmp5020010 - 10 Apr 2024
Abstract
Basal cell carcinoma (BCC) is a slow-growing, locally aggressive, rarely metastasizing, low-grade cutaneous neoplasm that arises from the epidermal basal layer and invades the adjoining tissues. It is the most common skin cancer. It is fairly common in fair Caucasians and quite uncommon
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Basal cell carcinoma (BCC) is a slow-growing, locally aggressive, rarely metastasizing, low-grade cutaneous neoplasm that arises from the epidermal basal layer and invades the adjoining tissues. It is the most common skin cancer. It is fairly common in fair Caucasians and quite uncommon in dark-skinned populations. It contributes to 65–75% of cutaneous malignancies in whites and 20–30% in Asian Indians. The most important causal factors appear to be radiation exposure and genetic predisposition. It may present as a nonhealing lesion that occasionally bleeds or as a pruritic lesion with no symptoms. Tumours rarely spread to regional lymph nodes. The clinical appearances and morphology of BCC are diverse. Clinical types include nodular, cystic, superficial, pigmented, morphoeaform, (sclerosing), keratotic and fibroepithelioma of Pinkus. Most of the lesions appear on the head and neck, usually above the line joining the tragus and the angle of the mouth. A biopsy should be performed on all lesions suspected of BCC. The primary aim of treatment is the complete excision of the tumour tissue. Other treatment modalities include cryotherapy, immunomodulatory drugs, laser treatment or locally applicable chemotherapeutic agents. Prevention consists of lifestyle changes such as avoiding sunburn, tanning beds and prolonged direct sun exposure, shade seeking, sunscreen application on the skin, and physical barrier methods such as protective clothing, hats and sunglasses. Regular sunscreen use in childhood and adolescence seems more beneficial than in adulthood.
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Open AccessArticle
Regulation of a Metabolic Gene Signature in Response to Respiratory Viruses and Type I Interferon Signaling
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Chilakamarti V. Ramana
J. Mol. Pathol. 2024, 5(1), 133-152; https://doi.org/10.3390/jmp5010009 - 7 Mar 2024
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Respiratory viruses are the causative agents responsible for seasonal epidemics and occasional pandemic outbreaks and are a leading cause of death worldwide. Type I interferon (IFNα/β) signaling in the lung epithelial cells plays a major role in the innate immunity to respiratory viruses.
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Respiratory viruses are the causative agents responsible for seasonal epidemics and occasional pandemic outbreaks and are a leading cause of death worldwide. Type I interferon (IFNα/β) signaling in the lung epithelial cells plays a major role in the innate immunity to respiratory viruses. Gene signatures are a set of differentially expressed genes in a particular disease or condition and are used to diagnose, monitor, and predict disease progression. These signatures can be used to identify regulatory modules and gene regulatory networks (GRNs) in mammalian signal transduction pathways. Considerable progress has been made in the identification of type I interferon-regulated gene signatures in the host response to respiratory viruses, including antiviral, immunomodulatory, apoptosis, and transcription factor signatures. Respiratory virus infections and host defenses require a dramatic change in the metabolic flux of macromolecules involved in nucleotide, lipid, and protein metabolism. The profiling of IFN-stimulated metabolic genes induced in the host response to several respiratory viruses led to the identification of a common gene signature in human lung epithelial cells and in the lungs of mouse models of respiratory virus infection. The regulation of the metabolic gene signature was correlated with the induction of IFN-beta (IFN-β) and IFN-inducible transcription factors at the RNA level in lung epithelial cells. Furthermore, the gene signature was also detected in response to bacterial lipopolysaccharide-induced acute lung injury. A protein interaction network analysis revealed that metabolic enzymes interact with IFN-regulated transcription factors and members of the unfolded protein response (UPR) to form a module and potentially regulate type I interferon signaling, constituting a feedback loop. In addition, components of the metabolic gene expression signature were differentially regulated in the lung tissues of COVID-19 patients compared with healthy controls. These results suggest that the metabolic gene signature is a potential therapeutic target for the treatment of respiratory virus infections and inflammatory diseases.
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Open AccessReview
The Role of IRF8 Polymorphisms in Systemic Sclerosis Development and Pathogenesis
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Anna Mennella, Giuseppe Ocone, Katia Stefanantoni and Loredana Frasca
J. Mol. Pathol. 2024, 5(1), 120-132; https://doi.org/10.3390/jmp5010008 - 2 Mar 2024
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Systemic sclerosis (SSc) is a rare autoimmune disease whose molecular mechanisms are not yet fully understood. There is no definitive cure, and the main causes of death are pulmonary fibrosis and pulmonary arterial hypertension. Here, we focus on the interferon regulators factor 8
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Systemic sclerosis (SSc) is a rare autoimmune disease whose molecular mechanisms are not yet fully understood. There is no definitive cure, and the main causes of death are pulmonary fibrosis and pulmonary arterial hypertension. Here, we focus on the interferon regulators factor 8 (IRF8), a factor involved in the type I interferon (IFN-I) signature, which is present in about half of SSc patients. Variants of this factor may play a role in autoimmunity, but little is known regarding the role of IRF8 in SSc pathogenesis. We carried out a literature search to address the association between the IRF8 factor and SSc susceptibility and clinical manifestations. The current studies appear to confirm a possible association between the alteration of the gene for IRF8 and SSc susceptibility. A link between IRF8 mutations and expression of a pro-fibrotic phenotype at the cellular level also emerges. Additional investigations are needed to confirm the role of IRF8 in SSc. However, IRF8 is worth consideration as a possible new disease marker of fibrosis in SSc patients.
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Open AccessReview
Oxidative Stress and ROS Link Diabetes and Cancer
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Homer S. Black
J. Mol. Pathol. 2024, 5(1), 96-119; https://doi.org/10.3390/jmp5010007 - 1 Mar 2024
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Type 2 diabetes mellitus (T2DM) accounts for one-sixth of deaths globally, whereas cancer is the second leading cause of death in the U.S. T2DM is a known risk factor for many cancers. Reactive oxygen species (ROS)-altered metabolic and signaling pathways link T2DM to
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Type 2 diabetes mellitus (T2DM) accounts for one-sixth of deaths globally, whereas cancer is the second leading cause of death in the U.S. T2DM is a known risk factor for many cancers. Reactive oxygen species (ROS)-altered metabolic and signaling pathways link T2DM to cancer. These reprogrammed metabolic and signaling pathways contribute to diabetic complications, impact the redox balance (oxidative stress), and have differential roles in the early and late stages of cancer. A respiratory chain that is highly reduced (as under hyperglycemic conditions) or if reduced cofactors accumulate, ROS are greatly elevated. ROS may cause mutations in mitochondrial DNA (mtDNA) that result in further ROS elevations. The amplification of ROS results in the activation of PKC, an overarching signaling pathway that activates MAPK with a subsequent regulation in several factors that result in pathophysiological manifestations of T2DM and cancer. An upregulation in PKC leads to a deregulation in NF-kß, which regulates the PKB/P13/Akt pathway and orchestrates the cell survival, growth, proliferation, and glucose metabolism manifested in cancer. It also affects Insulin Receptor Substrate (IRS-1), decreasing insulin-stimulated glucose transport and glucose uptake, disrupting subsequent cell signaling pathways contributing to the development of T2DM. Dyslipidemia is a hallmark of T2DM and cancer. ROS-induced lipid peroxidation leads to systemic inflammation, producing inflammatory prostaglandins, cytokines, and chemokines that result in tumor proliferation, rapid tumor growth, and modulation of immunity. The dual role of ROS in the early and late stages of cancer makes antioxidant therapy precarious and may be responsible for controversial results. A system that delivers an antioxidant directly to mitochondria may be useful in inhibiting the formation of ROS early during the pre-diabetic stage, whereas antioxidant therapy must be halted in later stages to retard metastasis.
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Open AccessArticle
Comparing Classifications from Multiple Variant Annotation Software Solutions Using Real-World Next Generation Sequencing Data from Oncology Testing
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Roy Khalife, Tara M. Love, Lara Sucheston-Campbell, Michael J. Clark, Helle Sorensen, Shuba Krishna and Anthony Magliocco
J. Mol. Pathol. 2024, 5(1), 81-95; https://doi.org/10.3390/jmp5010006 - 1 Mar 2024
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Variant annotation is an important step in deciphering the functional impact of genomic variants and their association with diseases. In this study, we analyzed 80 pan-cancer cases that underwent comprehensive genomic testing and compared the auto-classified variant tiers among four globally-available software solutions
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Variant annotation is an important step in deciphering the functional impact of genomic variants and their association with diseases. In this study, we analyzed 80 pan-cancer cases that underwent comprehensive genomic testing and compared the auto-classified variant tiers among four globally-available software solutions for variant interpretation from Roche, SOPHiA GENETICS, QIAGEN, and Genoox. The results revealed striking differences in tier classifications, which are believed to be a result of several factors, including subjectivity in the AMP/ASCO/CAP guidelines, threshold settings for variant allele frequencies and population allele frequencies, as well as variation in disease ontologies. Although the software tools described here provide a time-saving and repeatable process for interpretation of genomic data, it is crucial to understand the nuances and various settings for these solutions, as they can strongly influence variant tier classifications and downstream management.
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Open AccessArticle
Delving into the Role of Receptor-like Tyrosine Kinase (RYK) in Cancer: In Silico Insights into Its Diagnostic and Prognostic Utility
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Jessica Alejandra Zapata-García, Luis Felipe Jave-Suárez and Adriana Aguilar-Lemarroy
J. Mol. Pathol. 2024, 5(1), 66-80; https://doi.org/10.3390/jmp5010005 - 6 Feb 2024
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The RYK gene encodes a receptor-like tyrosine kinase crucial for several biological processes, including development, tissue homeostasis, and cancer. This study utilized data from the Cancer Genome Atlas Project (TCGA) to evaluate RYK expression at both mRNA and protein levels in various cancers,
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The RYK gene encodes a receptor-like tyrosine kinase crucial for several biological processes, including development, tissue homeostasis, and cancer. This study utilized data from the Cancer Genome Atlas Project (TCGA) to evaluate RYK expression at both mRNA and protein levels in various cancers, determine its prognostic significance, and explore its involvement in cancer-related signaling pathways. Elevated levels of RYK mRNA were identified in cholangiocarcinoma (CHOL), pancreatic adenocarcinoma (PAAD), glioblastoma multiforme (GBM), lung squamous cell carcinoma (LUSC), brain lower grade glioma (LGG), head and neck squamous cell carcinoma (HNSC), liver hepatocellular carcinoma (LICH), esophageal carcinoma (ESCA), and colon adenocarcinoma (COAD), while RYK protein levels were observed to be increased in colon adenocarcinoma (COAD), GBM, LICH, cervical and endocervical adenocarcinoma (CESC), and breast invasive carcinoma (BRCA). Additionally, RYK overexpression correlated with poorer prognosis in several cancers, including PAAD, LICH, BRCA, ESCA, COAD, and CESC. Furthermore, RYK showed a positive correlation with the upregulation of multiple receptors and coreceptors in the WNT signaling pathway in various types of cancer. In terms of cancer-related signaling pathways, RYK was found to potentially interact with DNA damage, TSC/mTOR, PI3K/AKT, EMT, RTK, RAS/MAPK, ER hormone, AR hormone, and the cell cycle. This study provides new and previously unreported insights into the role of RYK in cancer biology.
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Open AccessArticle
A Novel Single-Tube Next Generation Sequencing Assay for B-Cell Receptor Clonality Testing
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Landon Pastushok, Shrutii Sarda, Karen Mochoruk, Wayne Hill, Loni T. Pickle, Michelle Toro, Carolina Gonzalez, Stephanie Ostresh, Timothy J. Looney, Chenchen Yang, Julie Stakiw, Mark J. Bosch, Hadi Goubran, C. Ronald Geyer, Geoffrey M. Lowman and John F. DeCoteau
J. Mol. Pathol. 2024, 5(1), 45-65; https://doi.org/10.3390/jmp5010004 - 2 Feb 2024
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B-cell neoplasms possess clonal B-cell receptor rearrangements (BCR clonotype lineages) that can be identified by sequencing the B-cell repertoire for use in diagnostics, risk stratification, and high-sensitivity monitoring. BCR somatic hypermutation (SHM) can result in clonality detection failure from point mutations in PCR
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B-cell neoplasms possess clonal B-cell receptor rearrangements (BCR clonotype lineages) that can be identified by sequencing the B-cell repertoire for use in diagnostics, risk stratification, and high-sensitivity monitoring. BCR somatic hypermutation (SHM) can result in clonality detection failure from point mutations in PCR primer binding regions, often necessitating splitting samples into multiple reactions which increases test costs, turnaround times, and sample requirements. We evaluated the Oncomine BCR Pan-Clonality Assay, a novel single-tube PCR reaction that simultaneously amplifies all BCR loci for next-generation DNA sequencing, using neoplastic B-cell lines and clinical research samples from multiple myeloma (MM) patients, a plasma cell neoplasm associated with high SHM levels. The assay showed a linear detection range down to 1 ng of clonal DNA input, sensitivity to 10−6 in a polyclonal background, and high reproducibility. Clonotype lineages were identified in 42/45 (93%) MM samples. Ion Reporter software packaged with the assay permitted straightforward identification of MM subgroups. As expected, SHM was identified in 94% of MM cases, but several unexpected subgroups were identified including biased IGHV3-11 or IGHV4-34 usage in 20% of MM samples, and two cases with very low levels of SHM. Evidence of intraclonal diversity/ongoing SHM was identified in 18% of samples, suggesting a possible germinal center origin for some MM cases. The single-tube Oncomine BCR Pan-Clonality assay efficiently detects BCR clonotype lineages at rates comparable to existing multiple reaction assays and permits their characterization for cell of origin studies and lymphoma classification.
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Open AccessArticle
AI-Enhanced Blood Cell Recognition and Analysis: Advancing Traditional Microscopy with the Web-Based Platform IKOSA
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Manuel Campos-Medina, Aiden Blumer, Patrick Kraus-Füreder, Michael Mayrhofer-Reinhartshuber, Philipp Kainz and Johannes A. Schmid
J. Mol. Pathol. 2024, 5(1), 28-44; https://doi.org/10.3390/jmp5010003 - 25 Jan 2024
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Microscopy of stained blood smears is still a ubiquitous technique in pathology. It is often used in addition to automated electronic counters or flow cytometers to evaluate leukocytes and their morphologies in a rather simple manner and has low requirements for resources and
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Microscopy of stained blood smears is still a ubiquitous technique in pathology. It is often used in addition to automated electronic counters or flow cytometers to evaluate leukocytes and their morphologies in a rather simple manner and has low requirements for resources and equipment. However, despite the constant advances in microscopy, computer science, and pathology, it still usually follows the traditional approach of manual assessment by humans. We aimed to extend this technique using AI-based automated cell recognition methods while maintaining its technical simplicity. Using the web platform IKOSA, we developed an AI-based workflow to segment and identify all blood cells in DAPI-Giemsa co-stained blood smears. Thereby, we could automatically detect and classify neutrophils (young and segmented), lymphocytes, eosinophils, and monocytes, in addition to erythrocytes and platelets, in contrast to previously published algorithms, which usually focus on only one type of blood cell. Furthermore, our method delivers quantitative measurements, unattainable by the classical method or formerly published AI techniques, and it provides more sophisticated analyses based on entropy or gray-level co-occurrence matrices (GLCMs), which have the potential to monitor changes in internal cellular structures associated with disease states or responses to treatment. We conclude that AI-based automated blood cell evaluation has the potential to facilitate and improve routine diagnostics by adding quantitative shape and structure parameters to simple leukocyte counts of classical analysis.
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Open AccessArticle
Human Metastatic Melanoma Cell Lines Panel for In Vitro and In Vivo Investigations
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Ekaterina N. Kosobokova, Nadezhda A. Kalinina, Ksenia M. Konoplina, Anastasiia A. Malchenkova, Alexandra E. Evdokimova, Marina V. Piniugina, Irina I. Khan, Ilya A. Kislyak, Anna A. Basharina, Anna N. Grishanina, Anna A. Rudakova, Pavel O. Varaksa, Maria A. Baryshnikova, Vadim S. Pokrovsky, Tatiana A. Bogush and Vyacheslav S. Kosorukov
J. Mol. Pathol. 2024, 5(1), 11-27; https://doi.org/10.3390/jmp5010002 - 8 Jan 2024
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The melanoma origin of cell lines obtained from the axillary lymph node (mel Kas, mel Pet, and mel Lap from patients with a verified diagnosis) was confirmed by the detection of the Melan A melanocyte marker expression. A hyperdiploid (2n+) for the mel
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The melanoma origin of cell lines obtained from the axillary lymph node (mel Kas, mel Pet, and mel Lap from patients with a verified diagnosis) was confirmed by the detection of the Melan A melanocyte marker expression. A hyperdiploid (2n+) for the mel Kas line; near-diploid (2n), and in some cells near-tertaploid (4n), and even hypo-octaploid (8n) set (172–179 chromosomes) in the mel Pet cell line; and a hypotetraploid (4n−) for the mel Lap line were detected by karyotypic analysis. All three cell lines are tumorigenic; however, mel Pet demonstrates tumor growth in Balb/c nude mice only in the presence of matrigel. All three lines showed a high expression of TUBB3 and PD-L1 markers, while ERa was low (minimum for mel Pet). Significant differences in the expression level were shown for the Cyt molecular marker. In the transplantation of cells to Balb/c nude mice, a stable expression level is observed only for TUBB3. For the rest of the markers, a decrease in their expression level of varying degrees was noted when the cells were growing in solid tumors in vivo. Mutations were detected in oncogenes (BRAF, EZH2, KIT, KRAS, NRAS, ROS1) and tumor suppressor genes (CDKN2A, FAT4, KMT2C, LRP1B, PTEN, PTPRB, TP53). The detailed characterization of the cell lines makes them valuable for various scientific and regulatory experiments, particularly those involving preclinical data on antiproliferative drugs for malignant melanoma or investigations into melanoma cell properties and progression.
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Open AccessArticle
Novel Approach to Proficiency Testing Highlights Key Practice Variations in Cancer Biomarker Delivery
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Kassandra R. Bisson, Jennifer R. Won, Andrea Beharry, Michael D. Carter, Shaan Dudani, John G. Garratt, Jonathan M. Loree, Stephanie Snow, Stephen Yip and Brandon S. Sheffield
J. Mol. Pathol. 2024, 5(1), 1-10; https://doi.org/10.3390/jmp5010001 - 5 Jan 2024
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Biomarkers are fundamental to modern oncology practice, forming a close link to pathology practice. Pathology results must be accurate, timely, comprehensive, and comprehendible. External proficiency testing is a key tool in maintaining biomarker quality. Here, we demonstrate the feasibility and utility of a
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Biomarkers are fundamental to modern oncology practice, forming a close link to pathology practice. Pathology results must be accurate, timely, comprehensive, and comprehendible. External proficiency testing is a key tool in maintaining biomarker quality. Here, we demonstrate the feasibility and utility of a novel end-to-end proficiency testing exercise exploring accuracy, turnaround time, and communication. Challenge specimens were made using resected colon cancer tissue, each paired with a fictional clinical vignette, and distributed to participants who were asked to provide all molecular testing required and return a final report for each case upon completion. Reports were redistributed to an assessor team including medical oncologists, each of whom was asked to recommend a systemic therapy based on each lab’s biomarker report. Participants were graded based on their ability to guide oncologists to the correct treatment. Eight laboratories participated. Three laboratories were found to have suboptimal results, two leading oncologists to incorrect therapeutic prescriptions, and one withdrawn. Turnaround time ranged from 6 to 86 days (median 24). Substantial qualitative reporting differences were identified. This study demonstrates the feasibility of end-to-end proficiency testing. The approach provides considerable value beyond analytic accuracy, including specimen management, turnaround time, and communication of results. Results suggest that reporting differences may lead to treatment disparities. This style of quality assurance will help reinforce good practices critical to the delivery of precision cancer care.
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Open AccessReview
DRP1 Regulation as a Potential Target in Hypoxia-Induced Cerebral Pathology
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Evgenia N. Fedorova, Anna V. Egorova, Dmitry N. Voronkov, Natalia M. Mudzhiri, Tatiana I. Baranich, Valeria V. Glinkina, Alexey I. Krapivkin, Ilgar S. Mamedov and Vladimir S. Sukhorukov
J. Mol. Pathol. 2023, 4(4), 333-348; https://doi.org/10.3390/jmp4040027 - 9 Dec 2023
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The following review considers current concepts concerning the characteristics of DRP1-related mitochondrial division in brain cells during hypoxic-ischemic pathology. The functional role of DRP1 in neurons and astroglia in cerebral ischemia conditions was analyzed. We discuss the potential for regulating DRP1 activity through
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The following review considers current concepts concerning the characteristics of DRP1-related mitochondrial division in brain cells during hypoxic-ischemic pathology. The functional role of DRP1 in neurons and astroglia in cerebral ischemia conditions was analyzed. We discuss the potential for regulating DRP1 activity through the selective inhibitor of mitochondrial fission, mdivi-1. The article also presents data on DRP1 involvement in astro- and microglia-mediated intercellular mitochondrial transport. Understanding of the molecular mechanisms responsible for mitochondrial fission during hypoxic-ischemic exposure will allow us to consider DRP1 as an effective therapeutic target for treating conditions with a hypoxic component.
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Open AccessReview
The Role of Macrophages in Cardiac Function and Disease
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Nella Prevete and Daniela Sorriento
J. Mol. Pathol. 2023, 4(4), 318-332; https://doi.org/10.3390/jmp4040026 - 7 Dec 2023
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A tight association between inflammation and cardiac damage has been extensively recognized. In this review, we will focus on macrophages as key players in the physiology and pathology of the heart and on their role in the functional crosstalk between inflammation and heart
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A tight association between inflammation and cardiac damage has been extensively recognized. In this review, we will focus on macrophages as key players in the physiology and pathology of the heart and on their role in the functional crosstalk between inflammation and heart disease. In the steady state, macrophages contribute to the homeostasis of cardiac tissue. Indeed, cardiac resident macrophages promote coronary development and tissue homeostasis, favor electric conduction in cardiomyocytes, and contribute to mitochondrial quality control. However, macrophages also take part in adverse cardiac events contributing to the development or the progression of several pathologic conditions. Infiltrating cells derived from circulating monocytes contribute to tissue injury through the release of inflammatory cytokines and catecholamines. In particular, the present review will discuss the role of macrophages in heart failure, atherosclerosis, and anthracycline-dependent cardiotoxicity. Prolonged inflammatory response and increased apoptotic cell death sustained by chronic activation of the transcription factor NFκB are the basis of heart failure pathogenesis. Here, we will discuss the involvement of NFκB signaling in macrophage-dependent cardiac damage and its use as a therapeutic target in the treatment of cardiovascular pathologies.
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Open AccessArticle
Assessing the Impact of Melanin Content on the Reliability of the Idylla™ BRAF Mutation Test
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Sam D. Parsons, Kate Murphy and Alison Finall
J. Mol. Pathol. 2023, 4(4), 307-317; https://doi.org/10.3390/jmp4040025 - 29 Nov 2023
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Aims: This study aims to investigate the potential influence of melanin content on the performance of the Idylla™ BRAF Mutation Test. Specifically, we assess whether melanin levels in samples impact the test’s reliability, thereby validating its clinical utility in accelerating melanoma diagnosis and
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Aims: This study aims to investigate the potential influence of melanin content on the performance of the Idylla™ BRAF Mutation Test. Specifically, we assess whether melanin levels in samples impact the test’s reliability, thereby validating its clinical utility in accelerating melanoma diagnosis and potentially improving patient prognosis. Methods: We conducted a retrospective analysis of 98 confirmed melanoma samples collected between February 2020 and November 2020. Formalin-fixed paraffin-embedded (FFPE) slides were evaluated by two independent observers using light microscopy to categorise samples into three groups based on melanin content (no, low, or high) following a standardised system. The samples underwent the Idylla™ BRAF Mutation Test and were compared with results obtained from next-generation sequencing (NGS). Results: Quantification cycle (Cq) values were utilised to assess for interference from melanin levels on the Idylla™ BRAF Mutation Test results. Statistical analyses revealed no significant differences in Cq values based on melanin content categories. Furthermore, analysis of polymerase chain reaction PCR curves did not indicate any notable influence of melanin. Discordant results with NGS are discussed. Conclusions: The study demonstrates that melanin content in samples does not significantly affect the performance of the Idylla™ BRAF Mutation Test. These results provide robust evidence supporting the confident application of the test in clinical settings, even for samples with high melanin content. The ability to obtain rapid on-site results holds promising potential in guiding timely and appropriate treatment decisions, thereby contributing to improved patient prognosis. What is already known on this topic—Prior research conducted by Petty et al. (2020) including 23 melanoma samples suggested that melanin does not significantly interfere with the Idylla™ BRAF Mutation Test by stating they were concordant with reference laboratory testing. What this study adds—This current study builds upon prior research with a larger sample size of 98. In addition to examining concordance between the Idylla™ BRAF Mutation Test and next generation sequencing, this study examines PCR curves and effect on Cq values, providing more robust evidence that melanin content in FFPE samples does not have a significant impact on the accuracy of the Idylla™ BRAF Mutation Test. How this study might affect research, practice or policy—The additional evidence base provided by this study is valuable for researchers, clinicians, and policymakers, as it supports the integration of the Idylla™ BRAF Mutation Test as a rapid and accurate method for detecting these mutations in melanoma patients.
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Open AccessReview
STING-Associated Vasculopathy with Onset in Infancy: A Review Focusing on Pathophysiology and Treatment Options
by
Konstantinos Drougkas, Roubini Smerla, Charalampos Skarlis and Clio P. Mavragani
J. Mol. Pathol. 2023, 4(4), 294-306; https://doi.org/10.3390/jmp4040024 - 13 Nov 2023
Abstract
STING-associated vasculopathy with onset in infancy (SAVI) is a rare type Ι interferonopathy caused by gain of function mutations in an encoding stimulator of interferon genes (STING) protein 1. SAVI is characterized by neonatal or infantile-onset systemic inflammation, mainly affecting peripheral cutaneous blood
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STING-associated vasculopathy with onset in infancy (SAVI) is a rare type Ι interferonopathy caused by gain of function mutations in an encoding stimulator of interferon genes (STING) protein 1. SAVI is characterized by neonatal or infantile-onset systemic inflammation, mainly affecting peripheral cutaneous blood vessels, skin, and lungs. The main disease manifestations include recurrent febrile episodes, cough, dyspnea, and failure to thrive, in association with progressive interstitial lung disease, polyarthritis, and cold-induced red violet plaques or papules on fingers, knees, toes, heels, nasal tip, and ears that can lead to distal ulcerations, skin necrosis, tissue loss, and autoamputation. For the management of SAVI, JAK inhibitors can be a valuable therapeutic intervention that hampers disease progression, while conventional immunosuppressive treatments have shown minimal efficacy. This review aims to describe the underlying pathophysiologic mechanisms of SAVI, highlighting the main clinical manifestations and discussing the current treatment approaches.
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(This article belongs to the Collection Feature Papers in Journal of Molecular Pathology)
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Open AccessReview
Mitochondrial Dynamics in Ovarian Cancer: Pathophysiology and Therapeutic Implications
by
Hiroshi Kobayashi, Chiharu Yoshimoto, Sho Matsubara, Hiroshi Shigetomi and Shogo Imanaka
J. Mol. Pathol. 2023, 4(4), 275-293; https://doi.org/10.3390/jmp4040023 - 6 Nov 2023
Abstract
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Background: Ovarian cancer is often characterized by aggressive growth and chemoresistance, leading to a poor prognosis. The energy and nutrient acquisition through metabolic reprogramming has been reported to facilitate cancer cell proliferation, invasion, and metastasis. Therefore, a therapeutic strategy to consider is to
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Background: Ovarian cancer is often characterized by aggressive growth and chemoresistance, leading to a poor prognosis. The energy and nutrient acquisition through metabolic reprogramming has been reported to facilitate cancer cell proliferation, invasion, and metastasis. Therefore, a therapeutic strategy to consider is to rewire energy metabolism. Mitochondrial dynamics have a profound impact on the metabolic profiles. In this review, we summarize the current understanding of the molecular mechanisms governing mitochondrial dynamics and their impact on cell proliferation and invasion and discuss future perspectives for therapeutic strategies and research directions. Methods: A search was conducted for literature published up to 30 June 2023 using the online databases PubMed and Google Scholar in this narrative literature review. Results: Mitochondria are essential for regulating metabolic reprogramming to meet the increasing energy demand for rapid cancer cell proliferation and invasion. A metabolic switch from OXPHOS to glycolysis may promote invasion, and OXPHOS-driven metabolism may be associated with proliferation, chemoresistance, and stemness. Many ovarian cancer cells are known to favor glycolysis over OXPHOS, but the opposite takes place in the subpopulation of cancer cells. The preference for glycolysis versus OXPHOS in ovarian cancer cells may be determined by histopathologic types, the unique genetic profile of energy metabolism, and intrinsic (e.g., oncogenic signaling) and extrinsic (e.g., nutritional status and hypoxia) factors. Conclusions: Preclinical studies suggest that mitochondrial dynamics regulators have therapeutic potential in ovarian cancer, but some factors limit their beneficial effects.
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Open AccessBrief Report
Technical Validation of a Fully Integrated NGS Platform in the Real-World Practice of Italian Referral Institutions
by
Caterina De Luca, Francesco Pepe, Gianluca Russo, Mariantonia Nacchio, Pasquale Pisapia, Maria Russo, Floriana Conticelli, Lucia Palumbo, Claudia Scimone, Domenico Cozzolino, Gianluca Gragnano, Antonino Iaccarino, Giancarlo Troncone and Umberto Malapelle
J. Mol. Pathol. 2023, 4(4), 259-274; https://doi.org/10.3390/jmp4040022 - 31 Oct 2023
Abstract
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Aims: To date, precision medicine has played a pivotal role in the clinical administration of solid-tumor patients. In this scenario, a rapidly increasing number of predictive biomarkers have been approved in diagnostic practice or are currently being investigated in clinical trials. A pitfall
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Aims: To date, precision medicine has played a pivotal role in the clinical administration of solid-tumor patients. In this scenario, a rapidly increasing number of predictive biomarkers have been approved in diagnostic practice or are currently being investigated in clinical trials. A pitfall in molecular testing is the diagnostic routine sample available to analyze predictive biomarkers; a scant tissue sample often represents the only diagnostical source of nucleic acids with which to conduct molecular analysis. At the sight of these critical issues, next-generation sequencing (NGS) platforms emerged as referral testing strategies for the molecular analysis of predictive biomarkers in routine practice, but the need for highly skilled personnel and extensive working time drastically impacts the widespread diffusion of this technology in diagnostic settings. Here, we technically validate a fully integrated NGS platform on diagnostic routine tissue samples previously tested with an NGS-based diagnostic workflow by a referral institution. Methods: A retrospective series of n = 64 samples (n = 32 DNA, n = 32 RNA samples), previously tested using a customized NGS assay (SiRe™ and SiRe fusion), was retrieved from the internal archive of the University of Naples Federico II. Each sample was tested by adopting an Oncomine Precision Assay (OPA), which is able to detect 2769 molecular actionable alterations [hotspot mutations, copy number variations (CNV) and gene fusions] on fully integrated NGS platforms (Genexus, Thermo Fisher Scientific (Waltham, MA, USA). The concordance rate between these technical approaches was determined. Results: The Genexus system successfully carried out molecular analysis in all instances. A concordance rate of 96.9% (31 out of 32) was observed between the OPA and SiRe™ panels both for DNA- and RNA-based analysis. A negative predictive value of 100% and a positive predictive value of 96.9% (62 out of 64) were assessed. Conclusions: A fully automatized Genexus system combined with OPA (Thermo Fisher Scientific) may be considered a technically valuable, time-saving sequencing platform to test predictive biomarkers in diagnostic routine practice.
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