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Non‐Hodgkin lymphoma (NHL) represents the fourth most common malignant disease among children and adolescents. Current disease classifications, including the most recent World Health Organization (WHO) classification and the International Consensus Classification (ICC), rely on a combination of clinical, epidemiological, histologic, immunophenotypic, and molecular data to define discrete clinicopathologic entities. There is growing evidence that children, adolescents, and young adults (CAYA) with B‐cell NHL display unique clinical and epidemiologic characteristics. This may be explained by distinct age‐related developmental plasticity, immune and haematopoietic repertoires, environmental exposures and social determinants of health, and germline or acquired genetic and molecular features, including those associated with inborn errors of immunity (IEI). Here, we discuss the unique clinical and biological characteristics of several distinct paediatric B‐cell NHL types to indicate a path forward in classification of these CAYA NHL to optimally support multidisciplinary patient care and personalized treatment. We propose a potential “arising in CAYA” classification qualifier to denote the distinct clinicopathologic characteristics of B‐cell NHLs that, otherwise, histologically and immunophenotypically resemble those arising in middle‐aged and older adults. We also discuss how haemopathology diagnoses are evolving to incorporate the most current scientific knowledge into future classification systems of CAYA B‐cell NHL. [ABSTRACT FROM AUTHOR]

ABSTRACT CIC::DUX4 fusion sarcoma represents a rare and aggressive subtype of undifferentiated small round blue cell tumors. We report on a 23‐year‐old African male who developed a rapidly enlarging inferolateral left buttock nodule with ulceration. After debulking excision of the lesion, histologic sections demonstrated sheets and lobules of atypical round blue cells with significant cytologic atypia. Prominent foci of atypical mitotic figures and tissue necrosis were present. Tumoral cells stained strongly and diffusely using MDM2, vimentin, WT1 and CD99 immunohistochemical (IHC) markers. Molecular testing was performed and highlighted CIC::DUX4 gene fusion positivity, making the diagnosis of a CIC::DUX4 sarcoma (CDS). Post‐surgical excision, the patient showed no disease on imaging and underwent five cycles of adjuvant chemotherapy with no recurrence observed at the eight‐month follow‐up. With fewer than 200 cases reported in the literature and somewhat nonspecific clinicopathologic characteristics, CIC::DUX4 sarcoma presents a diagnostic challenge. This case underlines the importance of molecular diagnostics in undifferentiated sarcomas and presents a rare primary cutaneous manifestation of CIC::DUX4 fusion sarcoma. Additionally, we provide a review of the literature to aid in recognition, diagnosis, and treatment of this rare entity. [ABSTRACT FROM AUTHOR]

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC -specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation Database (LOVD) variant database, which included a total of 10,228 unique APC variants. Among the ClinVar and LOVD variants with an initial classification of (likely) benign or (likely) pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUSs were reclassified into clinically meaningful classes, the vast majority as (likely) benign. The total number of VUSs was reduced by 37%. In 24 out of 37 (65%) promising APC variants that remained VUS despite evidence for pathogenicity, a data-mining-driven work-up allowed their reclassification as (likely) pathogenic. These results demonstrated that the application of APC -specific criteria substantially reduced the number of VUSs in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalizable model for other gene- or disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUSs that will benefit from in-depth evidence collection. This subset of APC variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use. [Display omitted] Application of the gene-specific ACMG/AMP variant classification criteria to >10,000 publicly available germline APC variants through a streamlined algorithm reduced the fraction of VUSs by 37%, demonstrating the feasibility of a systematic classification approach in large datasets. This study might serve as a model for other variant interpretation initiatives. [ABSTRACT FROM AUTHOR]

The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology, and variant interpretation. This VCEP made specifications for the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines for the ataxia telangiectasia mutated (ATM) gene according to the ClinGen protocol. These gene-specific rules for ATM were modified from the ACMG/AMP guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar, and re-evaluation with the VCEP's ATM -specific rules resulted in four that were classified as benign, one as likely pathogenic, and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 of the 33 pilot variants were not VUS, leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM. This paper details ACMG/AMP-style guidelines for ataxia telangiectasia mutated (ATM) variant interpretation and shows the results of pilot classifications. Several phenotype-driven rules were omitted or modified due to low-penetrance and commonness of breast cancer. This work aims to harmonize the classification of ATM variants and avoid misinterpretation by using standard rules. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying the neurodevelopmental disorders (NDDs) caused by DDX3X variants remain poorly understood. In this study, we validated that de novo DDX3X variants are enriched in female developmental delay (DD) patients and mainly affect the evolutionarily conserved amino acids based on a meta-analysis of 46,612 NDD trios. We generated a ddx3x deficient zebrafish allele, which exhibited reduced survival rate, DD, microcephaly, adaptation defects, anxiolytic behaviors, social interaction deficits, and impaired spatial recognitive memory. As revealed by single-nucleus RNA sequencing and biological validations, ddx3x deficiency leads to reduced neural stem cell pool, decreased total neuron number, and imbalanced differentiation of excitatory and inhibitory neurons, which are responsible for the behavioral defects. Indeed, the supplementation of L-glutamate or glutamate receptor agonist ly404039 could partly rescue the adaptation and social deficits. Mechanistically, we reveal that the ddx3x deficiency attenuates the stability of the crebbp mRNA, which in turn causes downregulation of Notch signaling and defects in neurogenesis. Our study sheds light on the molecular pathology underlying the abnormal neurodevelopment and behavior of NDD patients with DDX3X mutations, as well as providing potential therapeutic targets for the precision treatment. [ABSTRACT FROM AUTHOR]

Background: The earliest manifestation of alcohol‐associated liver disease (ALD) is steatosis characterized by deposition of fat in specialized organelles called lipid droplets (LDs). While alcohol administration causes a rise in LD numbers in the hepatocytes, little is known regarding their characteristics that allow their accumulation and size to increase. The aim of the present study is to gain insights into underlying pathophysiological mechanisms by investigating the ethanol‐induced changes in hepatic LD proteome as a function of LD size. Methods: Adult male Wistar rats (180–200 g BW) were fed with ethanol liquid diet for 6 weeks. At sacrifice, large‐, medium‐, and small‐sized hepatic LD subpopulations (LD1, LD2, and LD3, respectively) were isolated and subjected to morphological and proteomic analyses. Results: Morphological analysis of LD1‐LD3 fractions of ethanol‐fed rats clearly demonstrated that LD1 contained larger LDs compared with LD2 and LD3 fractions. Our preliminary results from principal component analysis showed that the proteome of different‐sized hepatic LD fractions was distinctly different. Proteomic data analysis identified over 2000 proteins in each LD fraction with significant alterations in protein abundance among the three LD fractions. Among the altered proteins, several were related to fat metabolism, including synthesis, incorporation of fatty acid, and lipolysis. Ingenuity pathway analysis revealed increased fatty acid synthesis, fatty acid incorporation, LD fusion, and reduced lipolysis in LD1 compared to LD3. Overall, the proteomic findings indicate that the increased level of protein that facilitates fusion of LDs combined with an increased association of negative regulators of lipolysis dictates the generation of large‐sized LDs during the development of alcohol‐associated hepatic steatosis. Conclusion: Several significantly altered proteins were identified in different‐sized LDs isolated from livers of ethanol‐fed rats. Ethanol‐induced increases in specific proteins that hinder LD lipid metabolism led to the accumulation and persistence of large‐sized LDs in the liver. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we applied translational informatics for intelligent medicine of acute myeloid leukemia, a type of cancer characterized by disease relapses even after seemingly successful treatments. Treatment failure is associated, at least in part, with the fact that targeting individual proteins often promotes rewiring of relevant networks and re-organization of interactions of, among others, non-targeted proteins to eventually evade single-target therapies. To develop efficient therapies, these dynamics should be taken into account and target whole network modules instead of singleton genes in order to prevent the establishment of compensating signaling circuits. Therefore, we integrated network-based methods, structural pharmacology, and molecular modeling to establish two complementary multitargeting strategies, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. Of note, our study exploits, for the first time, a greedy algorithm to identify optimal combinations of drugs and therapeutic protein targets. Background/Objectives: Acute myeloid leukemia (AML) is characterized by therapeutic failure and long-term risk for disease relapses. As several therapeutic targets participate in networks, they can rewire to eventually evade single-target drugs. Hence, multi-targeting approaches are considered on the expectation that interference with many different components could synergistically hinder activation of alternative pathways and demolish the network one-off, leading to complete disease remission. Methods: Herein, we established a network-based, computer-aided approach for the rational design of drug combinations and de novo agents that interact with many AML network components simultaneously. Results: A reconstructed AML network guided the selection of suitable protein hubs and corresponding multi-targeting strategies. For proteins responsive to existing drugs, a greedy algorithm identified the minimum amount of compounds targeting the maximum number of hubs. We predicted permissible combinations of amiodarone, artenimol, fostamatinib, ponatinib, procaine, and vismodegib that interfere with 3–8 hubs, and we elucidated the pharmacological mode of action of procaine on DNMT3A. For proteins that do not respond to any approved drugs, namely cyclins A1, D2, and E1, we used structure-based de novo drug design to generate a novel triple-targeting compound of the chemical formula C15H15NO5, with favorable pharmacological and drug-like properties. Conclusions: Overall, by integrating network and structural pharmacology with molecular modeling, we determined two complementary strategies with the potential to annihilate the AML network, one in the form of repurposable drug combinations and the other as a de novo synthesized triple-targeting agent. These target–drug interactions could be prioritized for preclinical and clinical testing toward precision medicine for AML. [ABSTRACT FROM AUTHOR]

Simple Summary: The standard of care for most women with advanced ovarian cancer is primary cytoreduction followed by platinum-based chemotherapy and paclitaxel. However, the use of neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy is not inferior, according to prospective randomized trials. Ovarian cancer has a low mutational load but exhibits a high detection rate of molecular alterations in various genes. It remains unclear whether this is an intrinsic feature of ovarian cancer or if it is due to the administration of a platinum combination during NACT. Our study aimed to determine whether NACT affects the tumor's molecular profile. Any modifications in these areas would need to be identified in the initial therapeutic planning, especially in the era of poly (ADP-ribose) polymerase (PARP) inhibitors. Background: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy is a therapeutic choice for women with advanced ovarian cancer. Whether NACT affects the tumor's molecular profile has not been determined. Methods: This was a retrospective study of patients with advanced-stage epithelial ovarian cancer treated with NACT at oncology departments affiliated with the Hellenic Cooperative Oncology Group (HeCOG). Tumor molecular profiling was performed on formalin-fixed and paraffin-embedded (FFPE) tumor pre- and post-NACT tissues. Homologous recombination deficiency (HRD), tumor-infiltrating lymphocytes (TILs), tumor molecular alterations, and tumor mutational burden (TMB) via next-generation sequencing analysis were assessed. Results: Overall, tumors from 36 patients were assessed, and molecular profiling was evaluated in 20 paired tumor samples. HRD positivity exhibited no significant change between pre- and post-NACT tumors. The BRCA1/2 mutational status remained constant, irrespective of the treatment administration. Pre-NACT tumors tended to exhibit a lower percentage of intratumoral TILs compared to post-NACT tumors (p = 0.004). Differences in the mutation profile between pre- and post-treatment tissue were observed in 33.33% (6/18) of the cases. The mean tumor cell content (TCC) (p-value: 0.0840) and the mean genomic instability score (p-value: 0.0636) decreased slightly numerically after therapy. A moderate inverse relationship was observed between the pre-NACT TMB and the chemotherapy response score (p-value: 0.038), indicating this correlation is statistically significant. Conclusion: This study provides insights into the effect of NACT on the tumor molecular landscape. While BRCA1/2 and HRD status remained stable, an increase in TIL proportion and changes in the mutational profiles were observed post-treatment. [ABSTRACT FROM AUTHOR]

Objective: This study aims to evaluate the clinical management and effectiveness of metagenomic next-generation sequencing (mNGS) in patients with pyogenic spinal infections. Methods: We conducted a retrospective review of 17 patients diagnosed with pyogenic spinal infections and treated at our institution between October 2022 and February 2024. The cohort included 8 males and 9 females, with a mean age of 63.59 ± 10.18 years (range: 41–71 years). The infections comprised 9 epidural abscesses, 6 intervertebral space infections, and 2 deep abscesses. All patients underwent open surgical procedures and mNGS-based bacterial identification using intraoperative pus or tissue specimens, in addition to conventional blood bacterial cultures. Clinical outcomes were assessed using CRP, PCT, WBC inflammatory markers, and VAS scores postoperatively. Results: All 17 patients with pyogenic spinal infections underwent open surgery and mNGS bacterial detection at our institution. Among the 17 patients, mNGS yielded positive results in 14 cases (82.4%), significantly higher than the 5.9% positivity rate of conventional bacterial cultures (p < 0.001). The mNGS test time was notably shorter than conventional cultures (1.0 vs. 5.88 days, p < 0.001). Postoperative antibiotic therapy was adjusted based on mNGS findings. There were significant reductions in postoperative VAS, WBC, PCT, and CRP values compared to preoperative levels (p < 0.01). Conclusion: Metagenomic next-generation sequencing is effective in managing pyogenic spinal infections by facilitating rapid and sensitive detection of pathogens. This technique improves the timeliness and accuracy of diagnosis, highlighting its potential for broader clinical use. [ABSTRACT FROM AUTHOR]

Context.--: Mesothelioma is an uncommon tumor that can be difficult to diagnose. Objective.--: To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. Data sources.--: Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. Conclusions.--: There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions. [ABSTRACT FROM AUTHOR]

Context.--Salivary gland tumors are rare tumor types for which the molecular understanding has resulted in a rapid expansion and shuffling of entities. These changes are reflected in the 5th edition World Health Organization Classification of Head and Neck Tumours (WHO 5th edition), although many nuances still remain. Objective.--To review how molecular alterations have helped recategorize, justify, and reinstate entities into our lexicon as well as defining interrelationships between categories, new entities, and subtypes. Furthermore, newer theranostic applications to molecular phenotype will be summarized. Data Sources.--World Health Organization Classification of Head and Neck Tumours (WHO 3rd through 5th editions), literature review, and personal and institutional experience. Conclusions.--Molecular alterations have helped reclassify, retain, and create new categories by augmenting rather than replacing standard criteria. Key entities that have emerged include sclerosing polycystic adenoma, microsecretory adenocarcinoma, and mucinous adenocarcinoma. Molecular phenotypes solidify the range of morphology in established entities such as mucoepidermoid carcinoma and facilitate connectivity between entities. Molecular characteristics now allow for targeted therapeutic approaches for secretory carcinoma and adenoid cystic carcinoma. [ABSTRACT FROM AUTHOR]

• PM 0.2 exposure induced the disorders of α-syn degradation in mice and astrocytes. • LAMP2-mediated autophagy-lysosome pathway was disturbed and underlied α-syn pathology induced by PM 0.2 exposure. • PP242 improved the disorder of α-syn through TFEB/LAMP2 pathway. Atmospheric particulate matter (PM) exacerbates the risk factor for Alzheimer's and Parkinson's diseases (PD) by promoting the alpha-synuclein (α-syn) pathology in the brain. However, the molecular mechanisms of astrocytes involvement in α-syn pathology underlying the process remain unclear. This study investigated PM with particle size <200 nm (PM 0.2) exposure-induced α-syn pathology in ICR mice and primary astrocytes, then assessed the effects of mammalian target of rapamycin inhibitor (PP242) in vitro studies. We observed the α-syn pathology in the brains of exposed mice. Meanwhile, PM 0.2 -exposed mice also exhibited the activation of glial cell and the inhibition of autophagy. In vitro study, PM 0.2 (3, 10 and 30 µg/mL) induced inflammatory response and the disorders of α-syn degradation in primary astrocytes, and lysosomal-associated membrane protein 2 (LAMP2)-mediated autophagy underlies α-syn pathology. The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3 (LC3II), cathepsin B (CTSB) and lysosomal abundance increased first and then decreased, which might both be a compensatory mechanism to toxic α-syn accumulation induced by PM 0.2. Moreover, with the transcription factor EB (TFEB) subcellular localization and the increase in LC3II, LAMP2, CTSB, and cathepsin D proteins were identified, leading to the restoration of the degradation of α-syn after the intervention of PP242. Our results identified that PM 0.2 exposure could promote the α-syn pathological dysregulation in astrocytes, providing mechanistic insights into how PM 0.2 increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM 0.2 toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

This case describes a situation of mislabeling of specimen pots that led to a malignant diagnosis being attributed to the wrong patient's surgical resection. Short tandem repeat analysis was used to determine which specimen originated from the two patients involved. This report describes a not infrequent scenario for pathologists and how current genetic techniques can be used to resolve issues of patient/tissue identity. [ABSTRACT FROM AUTHOR]

Cancers of the gastrointestinal tract are a major cause of morbidity and mortality globally and, not surprisingly, there has been intense interest in identifying prognostic and predictive markers for new targeted therapies. The cancers of the gastrointestinal tract are unique in so completely exemplifying many of the key features of biomarker profiling across all solid cancers. Firstly, they involve the assessment of many individual biomarkers of many types, with both genomic and proteomic markers requiring assessment for complete profiling. Secondly, the interpretation of one biomarker is often critically dependent on the presence or absence of other biomarkers. And finally, this vast array of testing must be delivered often on very small samples. Here, we review the clinically-validated molecular targets in carcinomas of the esophagus, stomach, colorectum and anal canal, and in gastrointestinal stromal tumors, and discuss a handful of markers which are likely to be of use in the future. [ABSTRACT FROM AUTHOR]

Lymphoblastic lymphoma (LBL) with an early T-cell precursor phenotype has only been rarely reported. Nijmegen breakage syndrome (NBS) is an inherited chromosomal instability disorder with known predisposition to malignancies that is very rare as well. We report a case of early T-precursor LBL (ETP-LBL) in a patient with NBS, a rare combination that has not been reported. We raise the question of whether a chromosomal instability disorder such as NBS increases the propensity for early T-precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL), given that ETP-ALL has been shown to have increased genomic instability compared to T-ALL. [ABSTRACT FROM AUTHOR]

Despite advancements in precision medicine, many cancer patients globally, particularly those in resource-constrained environments, face significant challenges in accessing high-quality molecular testing and targeted therapies. The considerable heterogeneity in molecular testing highlights the urgent need to harmonize practices across Europe and beyond, establishing a more standardized and consistent approach in MP laboratories. Professionals, especially molecular pathologists, must move beyond traditional education to cope with this heterogeneity. This perspective addresses critical issues in molecular pathology (MP), such as limited access to high-quality molecular testing, leading to disparities in cancer treatment, and the consequences of inconsistent practices. Recognizing the necessity for a standardized framework for education to address these issues, educational programs play a pivotal role in updating professionals' skills to achieve standardization in MP. European experts from the Steering Committee, the Pathology Section of the European Union of Medical Specialists, and the European Society of Pathology have proposed creating a comprehensive Master's degree program called the "European Masters in Molecular Pathology" (EMMP). This program emerges as a strategic response to the demand for a specialized and standardized framework for education in MP, catering to professionals who concurrently work and study. The program's design aligns with evidence-based education methods, ensuring effective learning and engagement while integrating computational pathology to analyze complex molecular data, enhance diagnostic accuracy, and improve treatment outcomes. EMMP's structured curriculum, strategic partnerships, and regular updates underscore its significance in standardizing MP practices. Exploring future developments, this perspective delves into technology integration and interdisciplinary collaboration, anticipating ongoing advances and harmonization. Challenges and future directions in MP education are discussed, emphasizing the necessity for dynamic curriculum updates, seamless technology integration, and interdisciplinary cooperation. This perspective underscores EMMP's pivotal role in preparing pathologists for this dynamic field, advocating continuous advancements in education and training to uphold excellence in MP practices and maintain the highest patient care standards. [ABSTRACT FROM AUTHOR]

The article focuses on the ethical, clinical, and regulatory challenges of using molecular diagnostic tests, such as circulating tumor DNA (ctDNA), in cancer care. Topics include the evolving role of ctDNA testing in detecting minimal residual disease, the ethical considerations surrounding early adoption of tests with uncertain clinical benefits, and the responsibility of oncologists in guiding patients through emerging technologies.

This paper discusses the administrative aspects of molecular diagnostics in oncology, including US Food and Drug Administration (FDA) oversight, the regulatory approval process, clinical, and operational workflows, and payment models. Comprehensive molecular testing is important to deliver optimal oncology care and improve patient outcomes. Despite the potential benefits of testing, utilization remains low. The FDA regulatory approval process is reviewed for in vitro diagnostic products, which includes classification into three regulatory classes on the basis of risk. Companion diagnostic devices are used to guide treatment decisions. The clinical and operational challenges associated with molecular testing in oncology are also discussed, including the rapidly evolving landscape of precision oncology, the wide range of biomarker testing options, and complexities of test ordering, interpretation, and result delivery. There is a need for a multifaceted support approach involving education, technology enhancements, and workflow support to overcome these challenges. In terms of payment models, coverage policies between Medicare and commercial payers are compared with differences in coverage criteria, with Medicare focusing on FDA approval or clearance, whereas commercial payers consider additional factors such as National Comprehensive Cancer Network and ASCO guidelines. Commercial payers tend to cover smaller panels on the basis of guideline-recommended biomarkers, whereas coverage for broad tumor profiling is limited. Several strategies can increase the utilization of molecular testing, including integrating test results into electronic medical record platforms, standardizing billing practices, increasing clinical trials, and primary literature supporting the use of molecular testing, educating physicians, and using tumor boards for result interpretation and treatment discussions. [ABSTRACT FROM AUTHOR]

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Cytopathology represents a well established diagnostic approach because of its limited cost, reliability, and minimal invasiveness with respect to other methodologies. The evolving complexity of the different classifications systems and the implementation of ancillary techniques to refine the diagnosis is progressively helping in the risk of malignancy stratification, and the adoption of next‐generation sequencing techniques contributes to enrich this valuable tool with predictive information, which is always more essential in the tailored medicine era. The recent introduction of digital and computational pathology is further boosting the potentialities of cytopathology, aiding in the interpretation of samples to improve the cost effectiveness of large screening programs and the diagnostic efficiency within intermediate/atypical categories. Moreover, the adoption of artificial intelligence tools is promising to complement molecular investigations, representing a stimulating perspective in the cytopathology field. In this work, the authors tried to summarize the multifaceted nature of this complex and evolving field of pathology, synthesizing the most recent advances and providing the young pathologists' perspective on this fascinating world. Cytopathology has evolved significantly in the molecular and computational era, integrating next‐generation sequencing techniques and artificial intelligence tools to enhance diagnostic accuracy and patient care. This evolution is marked by advancements in molecular cytopathology, quality‐control measures, digital techniques, and the promise of artificial intelligence in aiding diagnostics, addressing challenges such as intraobserver and interobserver reproducibility, and the global shortage of pathologists. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Determining the pathogenicity of missense variants in clinical genetic tests for individuals with epilepsy is crucial for guiding personalized treatment. However, achieving a definitive pathogenic classification remains challenging, with most missense variants still classified as variants of uncertain significance (VUS) and with the availability of many computational tools which may provide conflicting predictions. Here, we aim to evaluate the performance of state‐of‐the‐art computational tools in pathogenicity prediction of missense variants in epilepsy‐associated genes. This will assist in selecting the most appropriate tool and critically assess their use in clinical setting.We assessed the performance of nine in silico pathogenicity prediction tools for missense variants in epilepsy‐associated genes on three carefully curated data sets. The first two data sets comprise missense variants in epilepsy associated genes that have been uploaded to ClinVar in the last year and were, therefore, not part of the training set of any of the nine considered tools. These two data sets are based on two different lists of epilepsy‐associated genes and comprise ~700 and ~ 250 missense variants, respectively. The third data set includes ~400 missense variants within epilepsy‐associated genes for which the functional effects have been determined experimentally and are therefore used here to infer pathogenicity. These three data sets represent the best available approximation to blind and independent test sets.Among the nine assessed tools, AlphaMissense (area under the curve [AUC]: .93, .88, and .95) and REVEL (AUC: .93, .88, and .93) showed the best classification performance, also outperforming other tools in the number of classified variants.We show which recently developed prediction tools achieve higher performance in epilepsy‐associated genes and should be integrated, therefore, into the American College of Medical Genetics and Genomics/Association of Molecular Pathology (AGMC/AMP) variant classification process. Periodic reevaluation of genetic test results with newly developed or updated tools should be incorporated into standard clinical practice to improve diagnostic yield and better inform precision medicine. [ABSTRACT FROM AUTHOR]

The document is a correction notice for an article titled "PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling." The correction addresses errors in Figures 1 and 6 of the original article, specifically related to plot type errors and mislabeling of fluorescence markers. The corrected figures provide data on the expression of PSMD9 in HCC tissues and its association with patient prognosis. The article is licensed under a Creative Commons Attribution 4.0 International License. [Extracted from the article]

AbstractAA amyloidosis is a prototypic example of systemic amyloidosis: it results from the prolonged overproduction of SAA protein produced in response to chronic inflammation. AA amyloidosis primarily affects the kidneys, liver, spleen, gastrointestinal tract, leading to a variety of symptoms. First, this review examines AA amyloidosis in humans, focusing on pathogenesis, clinical presentation, and diagnosis and then in animals. In fact AA amyloidosis is the only systemic amyloidosis that has been largely documented in a remarkable number of vertebrate species: mammals, birds, and fishes, especially in individuals with comorbidities, chronic stress, or held in captivity. Secondly, here, we summarise independent sets of evidence obtained on different animal species, exploring the possible transmissibility of AA amyloidosis especially in crowded or confined populations. Finally, biochemical and structural data on native SAA and on AA amyloid fibrils from human, murine, and cat ex vivo samples are discussed. The available structural data depict a complex scenario, where SAA can misfold forming highly different amyloid assemblies. This review highlights the complexity of AA amyloidosis, emphasising the need for further research into its spread in the animal kingdom, its structural aspects, and pathogenetic mechanisms to evaluate its impact on human and animal health. [ABSTRACT FROM AUTHOR]

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of recurrent glioblastoma. This study addresses the need for non-invasive approaches to map heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We developed BioNet, a biologically-informed neural network, to predict regional distributions of two primary tissue-specific gene modules: proliferating tumor (Pro) and reactive/inflammatory cells (Inf). BioNet significantly outperforms existing methods (p < 2e-26). In cross-validation, BioNet achieved AUCs of 0.80 (Pro) and 0.81 (Inf), with accuracies of 80% and 75%, respectively. In blind tests, BioNet achieved AUCs of 0.80 (Pro) and 0.76 (Inf), with accuracies of 81% and 74%. Competing methods had AUCs lower or around 0.6 and accuracies lower or around 70%. BioNet's voxel-level prediction maps reveal intratumoral heterogeneity, potentially improving biopsy targeting and treatment evaluation. This non-invasive approach facilitates regular monitoring and timely therapeutic adjustments, highlighting the role of ML in precision medicine. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis (CF) is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the distribution of CFTR mutation profiles in sub-tropical Queensland, Australia, and characterise the phenotypes associated with 'rare' CFTR mutation combinations. Methods: We conducted a retrospective observational study to analyse the CFTR mutation profiles of 322 people with CF (pwCF) under the care of a large adult CF centre in Queensland, Australia. Molecular pathology results were available for all identifiable CFTR mutations. The CFTR2 database was utilised to characterise the less common CFTR mutations to define mutation classes and explore associated phenotypic sequelae. Results: In total, eighty-seven different genotypes were identified within our CF cohort, with the most abundant mutation being the F508del mutation, 298/322 (92.5%). Thirty-six pwCF with CFTR mutations are considered to have 'rare' CFTR mutations, and eleven with previously undefined phenotypes. For these eleven pwCF, late diagnosis in adulthood was confirmed in 5/11 pwCF (45.5%) with CFTR modulator therapy only initiated in 5/11 (45.5%). Conclusions: The profile of more common CFTR genotypes within our cohort of adult pwCF living in Queensland, Australia, generally reflects the global predominance of F508del, G542X, G551D, N1303K, and R117H. The phenotypic heterogeneity of disease seen within the eleven pwCF in our cohort with previously undefined CFTR genotypes highlights that rare mutations can also be associated with severe disease and continue to be at risk of delayed diagnosis. Access to CFTR modulator therapies for this group of pwCF remains limited and should remain a research priority. [ABSTRACT FROM AUTHOR]

This study aims to broaden the morphological scope of SDH-deficient renal cell carcinoma and to assist clinicians and pathologists in better understanding this entity to prevent misdiagnosis. This study used immunohistochemistry staining and the first-generation sequencing Sanger method for gene detection. It retrospectively analysed the clinical pathology, molecular characteristics, biological behaviour, and treatment information of one case of SDH-deficient renal cell carcinoma. The patient was a 57-year-old female with right back pain for more than 20 days and had no personal or family history of kidney tumours. In addition, the tumour cells had clear boundaries in morphology, and residual normal renal tubules could be seen around them. There were also ossification and adipose tissue around the tumour centre. The tumour cells were arranged in a glandular tubular and cord-like manner. Vacuolar and eosinophilic inclusion bodies could be observed in the cytoplasm. The nucleus was regular, the chromatin distribution was fine, and there were no obvious nucleoli. They were low-grade nuclei. In addition, no atypical mitosis or necrosis could been found. Furthermore, immunohistochemistry staining showed SDHB-negative and keratin 20 -positive tumour. Meanwhile, the first-generation sequencing also pointed out the presence of SDHB gene mutations in the tumour. After 12 months of follow-up, there was no evidence of disease recurrence in the patient. SDH-deficient renal cell carcinoma is a rare tumour associated with SDH gene germline mutations, and suspected cases should undergo SDHB immunohistochemistry staining. Most SDH-deficient renal cell carcinomas have a good prognosis, but undifferentiated cases require long-term follow-up. [ABSTRACT FROM AUTHOR]

ABSTRACT Melanocytic tumors are a diverse group of lesions and are traditionally classified based on a combination of clinical presentation as well as histological examination. More recently, molecular diagnostics has become an increasingly important part of differentiating different melanocytic lesions in the current WHO standards. This molecular testing, however, can result in unexpected findings. In this report, we describe that molecular testing of a clinical atypical melanocytic lesion showed a mutation in the MAP2K1 gene as well as an unexpected germline mutation in PTPN11, indicative of Noonan syndrome. Based on these findings we concluded that the patient had a MAP2K1 associated melanocytic lesion with Noonan syndrome as an incidental finding. Melanomas are classically not associated with Noonan syndrome. However, we hypothesized that the germline mutations of PTPN11 and the somatic second hit mutation in the MAP2K1 genes might be involved in the formation of the aforementioned lesion. As they are both part of the RAS‐MAPK pathway. Furthermore, with the expansion of molecular diagnostics in melanomas, we expect to find an increase in unexpected (germline) mutations. [ABSTRACT FROM AUTHOR]

Objective: In this study, we examined the effectiveness of hyperbaric oxygen (HBO) therapy in ameliorating cognitive deficits in mice with Alzheimer's disease (AD), while also assessing its impact on the autophagic pathway within the context of AD. Methods: 20 double-transgenic mice expressing the amyloid precursor protein and presenilin 1 (APP/PS1) were purposefully selected and randomly assigned to groups A and B. Concurrently, 20 C57BL/6 mice were chosen and randomly categorized into groups C and D, each consisting of 10 mice. Mice in groups B and D received HBO treatment. The Morris water maze assay was used to assess changes in mouse behavior. Immunohistochemistry techniques were used to quantify the expression levels of amyloid-beta 42 (Ab42) and microtubuleassociated protein 1A/1B-light chain 3 (LC3) in hippocampal tissues, while western blot analysis was used to investigate the levels of LC3-II, p62, phosphoinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) proteins within hippocampal tissues. Results: Mice allocated to group B exhibited reduced escape latency and prolonged dwell time in the target quadrant compared to other groups. Histological examination revealed conspicuous plaque-like deposits of Ab42 in the hippocampal tissues of mice in groups A and B. Group B displayed diminished Ab42-positive reactants and augmented microtubule-associated protein 1A/1B-LC3-positive reactants compared to group A. LC3-positive reactants were also detected in the hippocampal tissues of mice in groups C and D, surpassing the levels observed in groups A and B. Furthermore, group B demonstrated significantly lower expression of mTOR protein and markedly higher expression of LC3-II protein in mouse hippocampal tissues when compared to group A (P < 0.05). Conversely, there were no significant disparities noted in PI3K and p62 protein expression between groups B and A. Notably, no discernible discrepancies were observed in the expression levels of mTOR, PI3K, LC3-II, and p62 proteins between groups C and D within mouse hippocampal tissues. Conclusion: HBO treatment demonstrates efficacy in enhancing cognitive function in mice with AD and holds promise as a potential therapeutic intervention for AD by facilitating the activation of the mTOR pathwaymediated autophagy. [ABSTRACT FROM AUTHOR]

Background: Bartonella species are fastidious, intracellular bacteria responsible for an expanding array of human pathologies. Most are considered to be transmitted by direct inoculation with infected bodily fluids from a mammalian reservoir species or vector-transmitted through a variety of arthropod species and their excrement. However, there are mounting reports of infection in the absence of documented animal or vector contact. A variety of Bartonella species have been documented in conditions affecting both the peripheral and central nervous systems. More common conditions, including neuroretinitis, are often associated with Bartonella henselae. However, Bartonella quintana, the agent of trench fever, as well as emerging pathogens related to rodent reservoir species, B. grahamii and B. elizabethae, have also been documented. Encephalitis and encephalopathy, also most often associated with B. henselae, have been reported with B. quintana, B. washoensis (ground squirrels) and B. vinsonii subsp. vinsonii (voles) infections. Bartonella infections have also been associated with peripheral neuropathies, such as cranial nerve paresis and neuropathic pain, including infection with less commonly encountered species such as Bartonella koehlerae. Recently, molecular diagnostic testing revealed that DNA from Bartonella spp. was found to be more prevalent in blood of patients with neuropsychiatric disorders such as schizophrenia and psychoses compared to healthy controls. Methods: A systematic literature search was conducted on PubMed, Google Scholar and Web of Science. Search terms included Bartonella and specific neurological conditions and focused on peer-reviewed case reports published after 2012 pursuant to a prior review, with limited exceptions for conditions not previously covered. Published diagnostic testing, serology, molecular testing or pathology, were necessary for inclusion, except for one case which had clinical and epidemiological evidence consistent with diagnosis along with follow-up. Results: Neurobartonelloses included neuralgic amyotrophy, complex regional pain syndrome, chronic inflammatory demyelinating polyneuropathy, cranial nerve paralysis, Guillain-Barré syndrome, peripheral vasculitic polyneuropathy, acute transverse myelopathy, neuroretinitis, encephalitis/encephalopathy, cerebral vasculitis/aneurysm and neuropsychiatric conditions. Conclusions: The breadth of reported symptoms and clinical syndromes associated with an increasing number of Bartonella species continues to expand. Increased clinical awareness of this important zoonotic pathogen is necessary to advance One Health among the medical and veterinary communities. [ABSTRACT FROM AUTHOR]

Purpose: Trop family proteins, including epithelial cell adhesion molecule (EpCAM) and Trop-2, have garnered attention as potential therapeutic and diagnostic targets for various malignancies. This study aimed to elucidate the clinicopathological significance of these proteins in gastric carcinoma (GC) and to reinforce their potential as biomarkers for patient stratification in targeted therapies. Materials and Methods: Immunohistochemical (IHC) analyses of EpCAM and Trop-2 were performed on GC and precancerous lesions, following rigorous orthogonal validation of the antibodies to ensure specificity and sensitivity. Results: Strong membranous staining (3+) for Trop-2 was observed in 49.3% of the GC cases, whereas EpCAM was strongly expressed in almost all cases (93.2%), indicating its widespread expression in GC. A high Trop-2 expression level, characterized by an elevated H-score, was significantly associated with intestinal type by Lauren classification, gastric mucin type, presence of lymph node metastasis, human epidermal growth factor receptor 2-positivity, and Epstein–Barr virus (EBV)-positivity. Patients with a high Trop-2 expression level exhibited poorer survival outcomes on univariate and multivariate analyses. High EpCAM expression levels were prevalent in differentiated histologic type, microsatellite instability–high, and EBV-negative cancer, and were correlated with high densities of CD3 and CD8 T cells and elevated combined positive score for programmed death-ligand 1. Conclusions: These results highlight the differential expression of Trop-2 and EpCAM and their prognostic implications in GC. The use of meticulously validated antibodies ensured the reliability of our IHC data, thereby offering a robust foundation for future therapeutic strategies targeting Trop family members in GC. [ABSTRACT FROM AUTHOR]

The role of P2X ionotropic receptors in the behavior of purinergic signaling on pathophysiological processes has been widely studied. In recent years, the important participation of P2X receptors in physiological and pathological processes, such as energy metabolism, characteristic inflammatory responses of the immune system, and nociceptive activity in response to pain stimuli, has been noted. Here, we explore the molecular characteristics of the P2X receptors and the use of the different agonist and antagonist agents recently described, focusing on their potential as new therapeutic targets in the treatment of diseases with emphasis on obesity, diabetes, and some of the complications derived from these pathologies. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a heterogeneous disease characterized by significant global mortality and incidence rates. Annually, approximately 1 million cases of BC are diagnosed worldwide, with over 170,000 classified as triple-negative. Triple-negative breast cancer (TNBC) is a particularly aggressive subtype lacking targeted therapeutic options, which contributes to poorer outcomes compared to other BC subtypes. The five-year survival rate for patients with TNBC is roughly 30% lower than that for patients with other subtypes. TNBC treatment options are limited to surgery, radiotherapy, and chemotherapy. There is a critical need for the development of targeted therapies. Enhancing early detection through effective diagnostic and prognostic biomarkers can significantly improve survival rates. This review explores recent advancements in clinically relevant proteomic, genetic, and metabolomic biomarkers for TNBC, highlighting their potential roles as prognostic, diagnostic, and predictive markers that could facilitate personalized treatment approaches. [ABSTRACT FROM AUTHOR]

Background: The advancements in artificial intelligence (AI) technology for image recognition were propelling molecular pathology research into a new era. Objective: To summarize the hot spots and research trends in the field of molecular pathology image recognition. Methods: Relevant articles from January 1st, 2010, to August 25th, 2023, were retrieved from the Web of Science Core Collection. Subsequently, CiteSpace was employed for bibliometric and visual analysis, generating diverse network diagrams illustrating keywords, highly cited references, hot topics, and research trends. Results: A total of 110 relevant articles were extracted from a pool of 10,205 articles. The overall publication count exhibited a rising trend each year. The leading contributors in terms of institutions, countries, and authors were Maastricht University (11 articles), the United States (38 articles), and Kather Jacob Nicholas (9 articles), respectively. Half of the top ten research institutions, based on publication volume, were affiliated with Germany. The most frequently cited article was authored by Nicolas Coudray et al. accumulating 703 citations. The keyword "Deep learning" had the highest frequency in 2019. Notably, the highlighted keywords from 2022 to 2023 included “microsatellite instability”, and there were 21 articles focusing on utilizing algorithms to recognize microsatellite instability (MSI) in colorectal cancer (CRC) pathological images. Conclusion: The use of DL is expected to provide a new strategy to effectively solve the current problem of time-consuming and expensive molecular pathology detection. Therefore, further research is needed to address issues, such as data quality and standardization, model interpretability, and resource and infrastructure requirements. [ABSTRACT FROM AUTHOR]

Copper is a vital trace element in oxidized and reduced forms. It plays crucial roles in numerous biological events such as redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy, and immune modulation. Maintaining the balance of copper in the body is essential because its deficiency and excess can be harmful. Abnormal copper metabolism has a two-fold impact on the development of tumors and cancer treatment. Cuproptosis is a form of cell death that occurs when there is excessive copper in the body, leading to proteotoxic stress and the activation of a specific pathway in the mitochondria. Research has been conducted on the advantageous role of copper ionophores and chelators in cancer management. This review presents recent progress in understanding copper metabolism, cuproptosis, and the molecular mechanisms involved in using copper for targeted therapy in cervical cancer. Integrating trace metals and minerals into nanoparticulate systems is a promising approach for controlling invasive tumors. Therefore, we have also included a concise overview of copper nanoformulations targeting cervical cancer cells. This review offers comprehensive insights into the correlation between cuproptosis-related genes and immune infiltration, as well as the prognosis of cervical cancer. These findings can be valuable for developing advanced clinical tools to enhance the detection and treatment of cervical cancer. [ABSTRACT FROM AUTHOR]

Endometrial carcinoma is a heterogeneous group of malignancies characterized by distinct histopathological features and genetic underpinnings. The 2020 WHO classification has provided a comprehensive framework for the categorization of endometrial carcinoma. However, it has not fully addressed the spectrum of uncommon entities that are currently not recognized by the 2020 WHO and have only been described in the form of small case series and case reports. These neoplasms represent a real diagnostic challenge for pathologists; furthermore, their therapeutic management still remains controversial and information regarding tumor prognosis is very limited. This review aims to elucidate these lesser-known variants of endometrial carcinoma. We discuss the challenges of identifying these rare subtypes and the molecular alterations associated with them. Furthermore, we propose the need for expanded classification systems that include these variants to enhance clinical outcomes and research efforts. We believe that a better histological typing characterization of these entities may lead to more reproducible and accurate diagnoses and more personalized treatments. By raising awareness of these rare entities, we also hope to encourage further investigation and integration into clinical practice to improve patient care in endometrial carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: There has recently been an interest in drugs that work across the pan-cancer spectrum and show antitumor activity based on biomarkers rather than histology. In this article, we discuss one of these biomarkers, NTRK fusions, which, if present, can predict sensitivity to treatment with inhibitors of the NTRK molecular pathway. Currently, there are three drugs that have been approved by the United States Food and Drug Administration (FDA) in patients with NTRK fusions, regardless of the tumor tissue of origin. These are larotrectinib, entrectinib, and repotrectinib. Herein, we discuss what NTRK fusions are and how to detect them, alongside data on each drug, from a clinical perspective. NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition of normal NTRK can be a concern. Also, on- and off-target resistance mechanisms can arise during therapy with TRK inhibitors, but they can be addressed with the use of combination therapy and next-generation TRK inhibitors. More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric cancer (GC) represents a major global health challenge, ranking as the second leading cause of cancer-related deaths. The high mortality rate is primarily due to late-stage diagnoses, which limit effective treatment options. Recent research emphasizes the development of targeted therapies and radiation immunotherapy as promising alternatives to traditional approaches. The review authors summarize recent advancements in targeted therapies for gastric cancer, focusing on both laboratory and clinical studies. They explore targeted approaches that have shown potential for improving diagnostic accuracy and treatment effectiveness. The findings of this paper may significantly impact the research community by highlighting the importance of personalized medicine in gastric cancer treatment. By identifying specific molecular targets and utilizing nanotechnology for drug delivery, these advancements aim to enhance treatment efficacy while minimizing systemic toxicity. Overall, the review suggests the potential for improved prognosis and treatment strategies through targeted therapies and precision medicine. Gastric cancer (GC) is the second most common cause of cancer-related death worldwide and a serious public health concern. This high death rate is mostly caused by late-stage diagnoses, which lead to poor treatment outcomes. Radiation immunotherapy and targeted therapies are becoming increasingly popular in GC treatment, in addition to surgery and systemic chemotherapy. In this review, we have focused on both in vitro and in vivo research, which presents a summary of recent developments in targeted therapies for gastric cancer. We explore targeted therapy approaches, including integrin receptors, HER2, Claudin 18, and glutathione-responsive systems. For instance, therapies targeting the integrin receptors such as the αvβ3 and αvβ5 integrins have shown promise in enhancing diagnostic precision and treatment efficacy. Furthermore, nanotechnology provides novel approaches to targeted drug delivery and imaging. These include glutathione-responsive nanoplatforms and cyclic RGD peptide-conjugated nanoparticles. These novel strategies seek to reduce systemic toxicity while increasing specificity and efficacy. To sum up, the review addresses the significance of personalized medicine and advancements in gastric cancer-targeted therapies. It explores potential methods for enhancing gastric cancer prognosis and treatment in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Nasopharyngeal carcinoma (NPC) is a head and neck cancer that is mainly found in Southeast Asia and North Africa. Most patients with NPC are diagnosed at an advanced stage, which increases the risk of recurrence and metastasis. A cohort of 41 NPC tumor samples from Morocco and North Africa were analyzed using shotgun proteomics. Within the cohort, three proteomically defined clusters were identified. We also examined sex and stage differences from a proteomic perspective. In total, 59 and 26 differentially abundant proteins were identified between male and female patients and patients with early and advanced stages within the cohort. Data were then compared to 21 healthy controls from a prior study. Across the two datasets, 6532 proteins were identified, of which 1507 proteins were differentially abundant between patients and controls. Differentially abundant proteins between tumor and healthy samples included PI3K, MAPK, BCL2, and PPIA proteins, which are involved in various biological pathways related to cell proliferation and growth. This study lays a foundation for both mechanistic and biomarker studies into NPC in Morocco and North African populations. Background: Nasopharyngeal carcinoma (NPC) is a distinct cancer of the head and neck that is highly prevalent in Southeast Asia and North Africa. Though an extensive analysis of environmental and genetic contributors has been performed, very little is known about the proteome of this disease. A proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tissues can provide valuable information on protein expression and molecular patterns for both increasing our understanding of the disease and for biomarker discovery. To date, very few NPC proteomic studies have been performed, and none focused on patients from Morocco and North Africa. Methods: Label-free Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) was used to perform a proteomic analysis of FFPE tissue samples from a cohort of 41 NPC tumor samples of Morocco and North Africa origins. The LC-MS/MS data from this cohort were analyzed alongside 21 healthy controls using MaxQuant 2.4.2.0. A differential expression analysis was performed using the MSstats package in R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations were carried out using the DAVID bioinformatic tool. Results: 3341 proteins were identified across our NPC cases, revealing three main clusters and five DEPs with prognostic significance. The sex disparity of NPC was investigated from a proteomic perspective in which 59 DEPs were found between males and females, with significantly enriched terms associated with the immune response and gene expression. Furthermore, 26 DEPs were observed between patients with early and advanced stages of NPC with a significant cluster related to the immune response, implicating up-regulated DEPs such as IGHA, IGKC, and VAT1. Across both datasets, 6532 proteins were quantified between NPC patients and healthy controls. Among them, 1507 differentially expressed proteins (DEPs) were observed. GO and KEGG pathway analyses showed enriched terms of DEPs related to increased cellular activity, cell proliferation, and survival. PI3K and MAPK proteins as well as RAC1 BCL2 and PPIA were found to be overexpressed between cancer tissues and healthy controls. EBV infection was also one of the enriched pathways implicating its latent genes like LMP1 and LMP2 that activate several proteins and signaling pathways including NF-Kappa B, MAPK, and JAK-STAT pathways. Conclusion: Our findings unveil the proteomic landscape of NPC for the first time in the Moroccan population. These studies additionally may provide a foundation for identifying potential biomarkers. Further research is still needed to help develop tools for the early diagnosis and treatment of NPC in Moroccan and North African populations. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) associated with portal vein thrombosis (PVT) represents an advanced stage of the tumor, with a subsequently poor prognosis and reduced therapeutic perspectives. These patients could present severe complications such as ascites, metastases, an increase in portal hypertension and potentially fatal gastrointestinal bleeding. The intricate molecular patterns at the basis of the development of TVP could also represent possible biomarkers in the early detection of patients at high risk of PVT. Hepatocellular carcinoma (HCC) represents the sixth most diagnosed cancer worldwide and is the second leading cause of cancer-related death in the world. The association of HCC and portal vein thrombosis (PVT) represents an advanced stage of the tumor. PVT has a prevalence of about 25–50% in HCC, determining poor prognosis and a remarkable reduction in therapeutic perspectives in these patients, leading to severe complications such as ascites, metastasis, an increase in portal hypertension and potentially fatal gastrointestinal bleeding. The aim of this review is to evaluate the molecular mechanisms that are at the basis of PVT development, trying to evaluate possible strategies in the early detection of patients at high risk of PVT. [ABSTRACT FROM AUTHOR]

Solid tumour tissue has traditionally been used for cancer molecular diagnostics. Recently, biomarker assessment in blood or liquid biopsies has become relevant because it allows genotyping in a less invasive and costly manner. In addition, it is a very useful technique in cases with insufficient tumour samples. Recent data have shown that this method can provide the baseline molecular characteristics of the tumour and resistance changes that emerge during cancer treatment. In terms of diagnostic application, the platforms available for clinical use in lung cancer focus on the isolation and detection of circulating DNA (ctDNA) and generally cover a limited number of mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS) and BRAF, as well as anaplastic lymphoma kinase (ALK) rearrangements. In parallel, there are plasma genotyping platforms based on next-generation sequencing (NGS) techniques, which are much broader in scope, allowing multiple genes to be studied simultaneously in a more efficient manner. More recently, promising research scenarios for liquid biopsy have emerged, such as its utility for early diagnosis and evaluation of minimal residual disease after oncological treatment. In light of these advances, knowledge of the benefits and limitations of liquid biopsy, as well as awareness of emerging information on new indications for this technique in non-small cell lung cancer (NSCLC), are of paramount importance in developing more effective management strategies for patients with this neoplasm. [ABSTRACT FROM AUTHOR]

Since the World Health Organization (WHO) 2016 revision, the number of molecular markers required for diffuse gliomas has increased, placing a burden on clinical practice. We have established an in‐house, molecular diagnostic platform using Senshin‐Iryo, a feature of Japan's unique healthcare system, and partially modified the analysis method in accordance with the WHO 2021 revision. Herein, we review over a total 5 years of achievements using this platform. Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity (LOH) on 1p/19q and chromosomes 10 and 17, and MGMT methylation were combined into a set that was submitted to Senshin‐Iryo as "Drug resistance gene testing for anticancer chemotherapy" and was approved in August 2018. Subsequently, in October 2021, Sanger sequencing for the TERT promoter mutation was added to the set, and LOH analysis was replaced with multiplex ligation‐dependent probe amplification (MLPA) to analyze 1p/19q codeletion and newly required genetic markers, such as EGFR, PTEN, and CDKN2A from WHO 2021. Among the over 200 cases included, 54 were analyzed after the WHO 2021 revision. The laboratory has maintained a diagnostic platform where molecular diagnoses are confirmed within 2 weeks. Initial expenditures exceeded the income from patient copayments; however, it has gradually been reduced to running costs alone and is approaching profitability. After the WHO 2021 revision, diagnoses were confirmed using molecular markers obtained from Senshin‐Iryo in 38 of 54 cases (70.1%). Among the remaining 16 patients, only four (7.4%) were diagnosed with diffuse glioma, not elsewhere classified, which was excluded in 12 cases where glioblastoma was confirmed by histopathological diagnosis. Our Senshin‐Iryo trial functioned as a salvage system to overcome the transition period between continued revisions of WHO classification that has caused a clinical dilemma in the Japanese healthcare system. [ABSTRACT FROM AUTHOR]

Bovine mastitis is a complex infectious disease that develops in the mammary gland, predominantly caused by a bacterial infection of mammary tissue. Genetic variability of mastitis is well established and depends upon different quantitative trait loci (QTL) related to mastitis resistance or susceptibility. The susceptibility is often attributed to single-nucleotide polymorphisms (SNPs) in the variable cow breed genomes. Several global investigative attempts have resulted in studies mapping mastitis to the variations in the relevant genes. Reports have been attributed to dramatic genetic expression changes in Toll-Like Receptor 4 (TLR4) genes in mastitis-positive cows. However, the mechanism behind this variable genetic expression of TLR4 genes has been studied poorly. The present study aims to investigate SCM through various screening tests like somatic cell count (SCC), electric conductivity (EC), pH, and California mastitis test (CMT) in milk samples. This study also aims to investigate possible mechanisms behind this variable expression of TLR4 by comparative SNP evaluation and transcriptional factor profile mining. So that the important genetic mutations and effects thereof can be exploited in selecting specific breeds with higher mastitis resistance and milk yield. Seventy Holstein Frisian (HF) crossbred dairy cows were selected in the present study. The animals were screened based on various diagnostic tests (SCC, pH, EC, and CMT). Blood samples (5 mL) were collected for extraction of DNA followed by amplification of PPR1 and PPR2 of the promoter region and 5′UTR of the bovine TLR4 gene using specific primers. Sanger's enzymatic DNA sequencing technique sequenced the amplified PCR products. Further, the identification of SNPs was done through various bioinformatic tools used in this study. The findings of the present study revealed that CMT, EC, pH, and SCC could be used for the early detection of subclinical mastitis. In the present study, a significant increase in the EC, pH, and SCC in milk samples of animals affected with SCM was found in comparison to the healthy animals. The present study also revealed 16 SNPs falling in TLR4 promoter and 5′ untranslated region (5′UTR) sequences in mastitis-positive genotypes compared to reference genomes. The study also investigates the potential transcriptional factor program deployed in response to variable mastitis development resistance. In the present study, the allelic and genotype frequencies of all SNP variants in the three regions viz., PPR1, PPR2, and 5′UTR, were the same indicating the absence of heterozygous condition at the respective loci. The present study has wide applicability for researchers developing mastitis-resistant breeding programs and the data generated may aid in the selection of better genetic breeds. The transcription factor binding profiles can serve as concrete leads about the studies on bovine mastitis at the molecular level and may also aid global research groups working on transcription factor (TF)-based molecular pathology of mastitis. [ABSTRACT FROM AUTHOR]

DSP‐cardiomyopathy has recently been recognised as a specific type of cardiomyopathy. Using an in‐house Mendelian disease registry, we aimed to identify probands with likely pathogenic or pathogenic DSP variants. We detected these variants in 4.8% and 77.8% of genotype‐positive probands referred for dilated and non‐dilated left ventricular cardiomyopathy (NDLVC), respectively. We identified six Slovenian probands with the DSP:c.3793G>T and characterised them along with further eight of their relatives at the molecular and phenotypic level. Medical records revealed NDLVC with arrhythmia in six individuals (five probands, one relative; 33 ± 14 years; three males, three females). All had subepicardial late gadolinium enhancement on cardiac MRI (CMRI), and five received an ICD. Four individuals (one proband, three relatives; 48 ± 14 years; all female) had no ECG and/or cardiac abnormalities on CMRI detected. Our analysis presents a Slovenian‐specific molecular pathology of DSP cardiomyopathy, delineates the clinical manifestation of DSP:c.3793C>T, and thereby improves the understanding of the clinical outcomes associated with truncating DSP variants. [ABSTRACT FROM AUTHOR]

Background and Aims Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. Methods We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. Results Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18–66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAF N486_P490 (29.6%), BRAF V600E (18.5%), and MAP2K1 (14.8%). Outcomes After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550–7.388, P  = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P  = .010) correlated with superior PFS versus chemotherapy. Conclusions In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy. [ABSTRACT FROM AUTHOR]

Background. Since the ants play a key role in transmitting microorganisms, it is important to identify the fungal species isolated from the external surfaces of ants caught from hospitals. Therefore, the present study aimed to identify the fungal species isolated from the external surfaces of ants caught from Babol hospitals. Methods. Ants were collected by trapping inside sterile tubes and were washed with normal saline for 20 seconds. Then, 100 μL of the resulting solution was cultured in Sabouraud Dextrose Agar (SDA) medium and incubated for one week at 35C°. Macroscopic, microscopic, and RFLP-PCR molecular techniques were employed to confirm the grown isolates. Results. A total of 79 fungal isolates including 47 isolates of hyaline fungi (59.49%) and 32 isolates of black fungi (40.51%) were obtained from 63 captured ants. Out of 47 cultured fungi, 15 fungi (31.91%) were Aspergillus niger and 15 (31.91%) were A. flavus, 12 (25.53%) were A. fumigatus and 5 isolates were Penicillium (10.63%). Conclusion. Taking into account the increasing number of immunocompromised patients, outbreak of COVID-19 in recent years, and numerous reports about the invasive fungal diseases among COVID-19 patients, it was found necessary to control the ants as carriers of these organisms. Practical Implications. It was necessary to control these insects effectively in order to prevent the increasing prevalence of the fungal diseases among the hospitalized people. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) Classification of Tumours (WCT) is a widely used resource for medical professionals and researchers. The upcoming sixth edition (WCT-6) is currently being planned and will build upon the fifth edition (WCT-5) based on user feedback and new research evidence. The aim of WCT-6 is to improve the classification framework, content, and image quality, as well as address evidence gaps. The subcommittees for WCT-6 will address various issues, such as the impact of molecular-based classifications in regions without access to molecular diagnostics and the integration of computational pathology. The WCT-6 series will be published in late 2025, with three volumes initially planned. The WCT is recognized as the global authority in tumor classification and continues to adapt to the challenges of tumor diagnosis. [Extracted from the article]

Many skin diseases begin with inflammatory changes on a molecular level. To develop a more thorough understanding of skin pathology and to identify new targets for therapeutic advancements, molecular mechanisms of inflammation in the context of skin disease should be studied. Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). This review seeks to summarize recent developments in our understanding of inflammatory processes in skin disease and to highlight opportunities for therapeutic advancements. With a focus on publications within the past 5 years (2019–2024), the databases PubMed and EBSCOhost were used to search for peer-reviewed papers regarding inflammatory molecular mechanisms and skin disease. Several themes of research interest regarding inflammatory processes in skin disease were determined through extensive review and were included based on their relative representation in current research and their focus on therapeutic potential. Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease. [ABSTRACT FROM AUTHOR]

Rationale: Sphingomyelins (SMs) and resulting metabolic products serve important functional and cell signaling roles and can act as potential biomarkers and therapeutic targets in many pathological disorders. SMs each contain a sphingoid base, an amide‐linked fatty acyl chain, and a phosphocholine headgroup. Despite these simple building blocks, variations and modifications of both the sphingoid base and the fatty acyl chain result in a diverse array of structurally complicated SM compounds. Conventional tandem mass spectrometry (MS/MS) using the collision‐induced dissociation (CID) method only provides limited structural information, necessitating other tools to unravel the structural complexity of these lipids. Methods: We utilize electron‐induced dissociation (EID) and sequential CID/EID approaches to elucidate detailed structural features of SMs. Integrating the CID/EID method into an imaging MS workflow enables accurate identification of SMs directly from kidney tissue. Results: The application of EID enables identification of SMs at the molecular species level, identifying the sphingosine base and the amide‐linked fatty acyl chains. Furthermore, removal of the phosphocholine headgroup via CID followed by sequential EID in an MS3 analysis (CID/EID) enhances the structural information obtained. CID/EID provides diagnostic fragmentation patterns revealing the hydroxylation site and double bond position in both the sphingosine base and amide‐linked fatty acyl chains. Conclusions: Detailed structural information of SMs from synthetic standards and biological tissue samples is obtained using an alternative electron‐based dissociation method. Accurate characterization of SMs promises to better inform studies of tissue biochemistry, lipid metabolism, and molecular pathology. [ABSTRACT FROM AUTHOR]

Some forms of Sjögren's syndrome (SS) follow a clinical course accompanied by systemic symptoms caused by lymphocyte infiltration and proliferation in the liver, kidneys, and other organs. To better understand the clinical outcomes of SS, here we used minor salivary gland tissues from patients and examine their molecular, biological, and pathological characteristics. A retrospective study was performed, combining clinical data and formalin-fixed paraffin-embedded (FFPE) samples from female patients over 60 years of age who underwent biopsies at Okayama University Hospital. We employed direct digital RNA counting with nCounter® and multiplex immunofluorescence analysis with a PhenoCycler™ on the labial gland biopsies. We compared FFPE samples from SS patients who presented with other connective tissue diseases (secondary SS) with those from stable SS patients with symptoms restricted to the exocrine glands (primary SS). Secondary SS tissues showed enhanced epithelial damage and lymphocytic infiltration accompanied by elevated expression of autophagy marker genes in the immune cells of the labial glands. The close intercellular distance between helper T cells and B cells positive for autophagy-associated molecules suggests accelerated autophagy in these lymphocytes and potential B cell activation by helper T cells. These findings indicate that examination of FFPE samples from labial gland biopsies can be an effective tool for evaluating molecular histological differences between secondary and primary SS through multiplexed analysis of gene expression and tissue imaging. [ABSTRACT FROM AUTHOR]

Background: Sensorineural hearing loss (SNHL) is a clinically and genetically heterogeneous group of disorders of the auditory system. SNHL can occur as a symptom in more than 400 syndromes, and mutations in more than 150 genes can lead to SNHL. Mutations in the GJB2 and GJB6 genes are among the most common causes of SNHL worldwide. Mutations in Cadherin 23 (CDH23) can cause Usher syndrome and/or non-syndromic hearing loss (NSHL). Material and methods: In this study, the Whole Exome Sequencing (WES) was used to detect the cause of hearing loss in a large consanguineous Iranian family with two patients. All family members underwent a thorough Genotype–phenotype correlation assessment and co-segregation analysis to understand the inheritance pattern within the family. The candidate variants were further confirmed by Sanger sequencing. In addition, in silico analysis was performed to predict the functional impact of the variants; the interpretation of the variants was performed in accordance with the American College of Medical Genetics (ACMG) guidelines. Results: WES results identified two novel variants, a homozygous missense variant in CDH23 (c.2961T > G) and a heterozygous splice site variant in OTOGL that was compatible with the autosomal recessive pattern of inheritance. Bioinformatics studies confirmed the pathogenic effects of novel variants. The c.2961T > G variant was classified as likely pathogenic. Conclusions: The novel identified variant in the CDH23 was the cause of congenital profound progressive form of HL. Samples were not available from the second family to distinguish which variant is responsible for the molecular pathology of the disease. Further studies and functional examinations are suggested for investigating the role of OTOGL: c. 1863-1G > T in deafness. [ABSTRACT FROM AUTHOR]