J. Mol. Pathol., Volume 7, Issue 3 (September 2026) – 10 articles

Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, and alterations in cholesterol metabolism may contribute to motor neuron vulnerability. This study investigated CYP7B1 rs121908613 and CYP46A1 rs754203 in relation to ALS susceptibility in a Brazilian case–control study. Methods: The study included 115 patients with ALS and 115 controls. Both variants were genotyped using TaqMan^® allelic discrimination assays. Genetic association analyses were performed under codominant, dominant, recessive, and overdominant inheritance models using Firth penalized logistic regression, with p-values adjusted for multiple testing using the Holm procedure. Sex-stratified analyses and a formal genotype-by-sex interaction test were also performed. Survival and in silico analyses were conducted as complementary exploratory analyses. Results: Genotyping of CYP7B1 rs121908613 revealed no allelic variability. Given the extremely low frequency of this variant in the general population, this finding should be interpreted as a negative result. For CYP46A1 rs754203, the overdominant model showed a nominal association with ALS (OR = 1.94, 95% CI: 1.14–3.34; nominal p = 0.015), but this association did not remain statistically significant after Holm correction (adjusted p = 0.148). In the male subgroup, the overdominant model remained significant after Holm correction (adjusted p = 0.046). However, the genotype-by-sex interaction test was not statistically significant (OR = 2.46, 95% CI: 0.84–7.32; p = 0.101), indicating insufficient evidence to support a sex-specific genetic effect. Hardy–Weinberg equilibrium (HWE) analysis revealed that the ALS group was deviated, therefore associations should be interpreted with caution. (exact p = 0.012). Survival analyses showed no statistically significant differences among CYP46A1 rs754203 genotypes. In silico analyses identified sequence-dependent structural and regulatory predictions that require experimental validation. Conclusions: CYP46A1 rs754203 showed exploratory association signals, including an overdominant effect in the male subgroup after multiple-testing correction. Additionally, the absence of a statistically significant genotype-by-sex interaction did not support sex-dependent evidence. These findings should be considered preliminary and hypothesis-generating and require replication in larger and well-characterized cohorts, together with experimental functional validation. Full article

Age-related macular degeneration (AMD) remains the leading cause of irreversible, severe visual loss among elderly populations in industrialized nations. The clinical spectrum ranges from early forms, characterized by the accumulation of extracellular deposits known as drusen, to advanced, vision-threatening late stages. While anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular AMD is the standard of care, geographic atrophy has remained a progressive condition. Geographic atrophy is a chronic neurodegenerative disease defined pathologically by the concurrent, progressive loss of the retinal pigment epithelium (RPE), the overlying photoreceptors, and the underlying choriocapillaris. Historically, the diagnosis and monitoring of GA relied on color fundus photography, which identified the lesions as sharply demarcated, well-circumscribed round or oval areas of depigmentation through which underlying choroidal vessels became clinically visible. However, the advent of high-resolution multimodal imaging—particularly fundus autofluorescence (FAF) and optical coherence tomography (OCT)—has necessitated a modernization of this terminology. Despite the imaging consensus, the fundamental pathophysiology of GA remains the subject of intense academic and clinical debate. The controversy focuses on identifying the primary cellular culprit responsible for initiating the cascade of degeneration. The “top-down” hypothesis suggests that intracellular metabolic failure, oxidative stress, and senescence within the RPE trigger the secondary dysfunction and death of the adjacent photoreceptors and choriocapillaris. Conversely, the “bottom-up” vascular hypothesis argues that age-related and complement activation–driven hemodynamic insufficiency, ischemic dropout, and structural involution of the choriocapillaris precede RPE dysfunction, creating a hypoxic microenvironment that drives the subsequent epithelial collapse. This narrative review scrutinizes the exact molecular, genetic, and structural mechanisms governing the expansion of geographic atrophy. By dissecting the evidence supporting both the RPE and the choriocapillaris as primary instigators, this analysis explores the paradigm that GA represents a synergistic failure of the outer blood–retinal barrier—a symbiotic trophic unit highly dependent on precise vascular and epithelial crosstalk, tightly regulated complement cascades, and extracellular matrix integrity. Full article

Background: Recent pan-cancer transcriptome analyses have identified ENST00000453316 as a cancer biomarker candidate, showing consistent and significant deregulation across multiple cancer types. Methods: This study investigated the transcript as a regulatory RNA in cancer-associated processes and its potential as a biomarker using a bioinformatics approach. Results: In silico characterization classified ENST00000453316 as a non-coding transcript with regulatory features and stable structure. Curated annotations documented the binding of 21 RNA-binding proteins across the transcript region, with core spliceosomal factors at the unique splice junction and cytoplasmic 3′-end factors at the terminal exon, in agreement with the sequence-based predictions. Promoter analysis revealed a TATA-less, CpG-poor region with multiple putative transcriptional regulator binding sites. Its expression was higher in most solid tumor types analyzed, with minimal expression in non-tumor tissues, indicating a tumor-associated pattern. Discrimination between tumor and adjacent non-tumor tissue within TCGA was good in five of the ten tissue types with sufficient adjacent-normal samples, with the area under the ROC curve reaching 0.82 in the lung, 0.78 in the bladder and 0.71–0.75 in the colon, breast and stomach, but close to chance in the kidney, thyroid and prostate. Conclusions: These results suggest that ENST00000453316 is a cancer-associated, promoter-driven non-coding transcript with potential regulatory relevance. Despite its revised annotation, it exemplifies how alternative promoter usage generates biologically and clinically meaningful transcripts contributing to tumor-specific gene regulation. Future experimental validation is needed to confirm the role of ENST00000453316 as a functional regulatory RNA and assess its clinical potential as a cancer biomarker. Full article

Non-small cell lung cancer (NSCLC) represents most lung cancer diagnoses worldwide and remains a leading cause of cancer-related mortality. The advent of precision oncology has transformed the therapeutic landscape of NSCLC through the identification of druggable genetic alterations, enabling the use of targeted therapies with significant clinical benefit. However, the reported prevalence of these alterations varies widely across studies and populations, raising important questions about the underlying determinants of such discrepancies. In this context, molecular epidemiology provides a framework to understand the distribution of genomic alterations and their interplay with demographic, clinical, and methodological factors. This narrative review examines the spectrum of druggable genetic alterations in NSCLC and critically analyzes the sources of variability in their reported frequencies. We discuss geographic and ethnic differences, particularly between East Asian, European, and North American populations, as well as the influence of smoking status, environmental exposures, histologic subtypes, and sex-related factors. Furthermore, we explore how disease stage and sample source may contribute to heterogeneity in molecular profiles. A substantial focus is placed on methodological sources of discrepancy, including differences in molecular testing platforms, analytical sensitivity and limits of detection, tissue versus liquid biopsy approaches, tumor heterogeneity, and gene panel design. Finally, emerging trends in the field, such as the use of ultra-large genomic datasets, real-world evidence, multi-omics integration, and artificial intelligence, alongside ongoing efforts toward standardization of molecular testing, are discussed. Full article

Background: Unexplained cytopenia represents a common diagnostic challenge in clinical haematology, reflecting either benign conditions or early manifestations of myeloid neoplasms. Methods: In this retrospective cross-sectional study, we analysed 557 patients with cytopenia who underwent initial diagnostic evaluation. The diagnostic performance of the initial morphological assessment of the bone marrow and ancillary studies excluding genetic analyses was evaluated against a genetically supported reference diagnosis established by a multidisciplinary haematology tumour board. We examined the extent to which the initial morphological assessment could reliably detect or rule out myeloid neoplasia. The analysis was performed for the entire cohort and stratified by specific myeloid neoplasm entities. Results: In the overall cohort, the initial morphological assessment of the bone marrow showed high diagnostic performance (sensitivity, 0.864; specificity, 0.934). The misclassification analysis revealed more false negatives than false positives (31 vs. 21), with no significant asymmetry. In the entity-specific analysis, a sensitivity of 1.0 was observed for acute myeloid leukaemia, with a reduced specificity (0.400). Myelodysplastic neoplasms exhibited a higher rate of false-negative findings, whereas myelodysplastic/myeloproliferative overlap neoplasms were characterised by very high sensitivity (0.982) and limited specificity (0.632). A comparable diagnostic pattern was observed for myelofibrotic neoplasms. Conclusions: Initial morphological assessment demonstrates high overall diagnostic performance in cytopenia but shows important variation across individual entities. These findings highlight the need to consider entity-specific limitations and the role of genetic confirmation in the diagnostic work-up of specific entities. Full article

Background/Objectives: The blood–brain barrier (BBB) remains a major obstacle to effective gene therapy for neurological disorders by limiting delivery of viral vectors, nanoparticles, and biologics to the central nervous system. Multiple strategies have been developed to transiently disrupt or bypass the BBB, including focused ultrasound (FUS) with microbubbles, osmotic agents, biochemical modulators, and receptor-mediated transport systems. Among these approaches, FUS-mediated BBB opening has emerged as the most spatially precise and clinically advanced strategy. Methods: This narrative review synthesizes recent preclinical and clinical literature on BBB microdisruption technologies for central nervous system gene therapy, with primary emphasis on FUS combined with microbubbles. We review BBB physiology, gene delivery platforms, the development of FUS technologies, optimization parameters, and translational evidence across neurological diseases from animal models through early-phase human studies. Results: FUS-mediated BBB opening has emerged as the leading method for transient barrier modulation. Preclinical studies in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, glioblastoma, amyotrophic lateral sclerosis, and lysosomal storage disorders demonstrate enhanced gene delivery, increased transgene expression, and improved functional outcomes. Large-animal studies and early clinical trials indicate that BBB opening is reversible, spatially controlled, and generally well tolerated. Clinical investigations have demonstrated successful delivery of therapeutic agents across neurological indications, with preliminary efficacy signals including improved drug penetration, metabolic changes, and potential survival benefits. Optimization of acoustic parameters, microbubble characteristics, and real-time cavitation monitoring remains critical for maximizing safety and therapeutic efficacy. Conclusions: BBB microdisruption, particularly through FUS with microbubbles, represents a transformative platform for central nervous system gene therapy. Continued research is needed to standardize treatment protocols, characterize long-term safety, and facilitate broader clinical translation. Full article

Both SARS-CoV-2 infection and COVID-19 vaccination have been associated with renal complications. In the context of SARS-CoV-2 infection, kidney injury is primarily attributed to a complex interplay of systemic immune dysregulation and vascular damage. Severe infection triggers a cytokine-mediated inflammatory response characterized by elevated levels of pro-inflammatory mediators, resulting in systemic hemodynamic instability, increased capillary permeability, and renal hypoperfusion, ultimately leading to acute tubular injury. In addition, virus-induced endothelial activation promotes a prothrombotic state, microvascular injury, and further impairment of renal perfusion. Collectively, these processes converge to produce acute kidney injury (AKI) and, in severe or prolonged cases, may contribute to chronic tubulointerstitial damage and progressive renal dysfunction. In contrast, renal manifestations following COVID-19 vaccination are relatively uncommon and are thought to arise primarily from immune-mediated dysregulation rather than direct cytopathic effects. Reported cases include minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis (FSGS), acute interstitial nephritis and other glomerulopathies, which present as either new-onset disease or relapses. These lesions are thought to result from transient immune activation following vaccination, including T-cell stimulation and altered humoral responses, which may trigger or unmask an underlying susceptibility to renal injury. Careful post-vaccination monitoring in high-risk populations may be warranted, and further molecular and population-level studies are needed to elucidate the underlying mechanisms and refine risk assessment. Full article

Background/Objectives: PgRMC1 is a progesterone-binding protein often overexpressed in breast cancer, correlating with tumor progression and chemoresistance. Identifying predictive markers for neoadjuvant chemotherapy (NAC) response is crucial for guiding therapeutic decisions. This study examines PgRMC1 expression in breast cancer tissues and its correlation with clinicopathological characteristics and NAC response. Methods: PgRMC1 expression in normal and cancerous breast tissues was evaluated via immunohistochemistry (IHC). Expression of ER, PgR, HER2, AR, and PGRMC1 mRNA was determined by qPCR in 112 patients. A separate 44-patient neoadjuvant chemotherapy (NAC) cohort was assessed for intrinsic subtypes (pretreatment biopsies) alongside PgRMC1 IHC expression and pathological response (post-NAC surgical specimens). In vitro chemoresistance and qPCR analyses were performed in breast cancer cell lines following PgRMC1 overexpression or siRNA-mediated knockdown. Results: PgRMC1 expression was detected in breast cancer tissue, while no immunoreactivity was observed in normal breast tissue. PGRMC1 mRNA expression levels were significantly higher in luminal and HER2 subtypes. In the distinct cohort of patients treated with NAC, those with a poorer pathological response had significantly higher PgRMC1 expression than those with a good response. In vitro, forced overexpression of PgRMC1 in two breast cancer cell lines, MCF7 and MDA-MB-468, significantly reduced chemosensitivity. Overexpression of PgRMC1 modulated the expression of epithelial and differentiation markers, including CDH1, AR, KRT19, and GATA3. Conclusions: PgRMC1 may contribute to chemoresistance and serves as a candidate biomarker for assessing neoadjuvant chemotherapy sensitivity. Full article

Background: Tight junctions are major components of apical junction complexes and are crucial for the maintenance of cell polarity, healthy tissue architecture, adhesion, and permeability. These junctions include the claudin family of transmembrane proteins, which act as paracellular barriers to regulate selective permeability. Abnormal claudin expression disturbs cell adhesions and is associated with cancer through promoting cell invasion, migration, and metastasis. Claudin 6 (CLDN6) overexpression, in particular, is linked to several types of cancer with malignant phenotypes. The present study aimed to investigate the association between CLDN6 protein expression and its copy number variations (CNVs) with clinicopathological features and survival outcomes of ovarian cancer (OC) patients. Methods: A total of 114 formalin-fixed paraffin-embedded blocks from primary OC patients were used to construct tissue microarray slides. Automated immunostaining was used to assess CLDN6 protein expression levels, and next-generation knowledge discovery platforms were used to further evaluate CLDN6 CNV levels using The Cancer Genome Atlas open-source data. The relationships between CLDN6 CNVs and tumor stage, overall survival, disease-specific survival (DSS), and disease-free survival (DFS) were investigated. Results: This study demonstrated that CLDN6 had a mixed membranous-cytoplasmic expression pattern. The cytoplasmic expression of CLDN6 was significantly associated with tumor stage (p = 0.05), tumor size (p = 0.04), and recurrence (p = 0.05). In Univariate analysis, Kaplan–Meier analysis demonstrated that CLDN6 expression was significantly correlated with DFS (p = 0.01). OC patients with lower cytoplasmic CLDN6 expression levels lived longer and had lower recurrence rates. These findings were further confirmed through CLDN6 CNVs analysis, where OC with lower CLDN6 cytoplasmic expression positively correlated with longer DFS and DSS. No independent prognosticator was found when using Cox-regression multivariate analysis (p > 0.05). Conclusions: These results suggest CLDN6 as an interesting prognosticator to identify OC patients at a higher risk of recurrence in order to provide personalized management, alleviate the burden of this disease on women’s health, and improve their survival outcomes. Full article

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia and is increasingly driven by cardiometabolic disease, including type 2 diabetes mellitus (T2DM), obesity, and insulin resistance. These conditions promote atrial electrical instability and a permissive substrate through mitochondrial dysfunction, oxidative stress, inflammation, calcium-handling abnormalities, and profibrotic signaling, culminating in atrial fibrosis and conduction heterogeneity. Metformin, the foundational glucose-lowering therapy for T2DM, exerts pleiotropic actions that intersect with these upstream pathways. Beyond glycemic control, metformin induces mild mitochondrial complex I modulation with reduction of reverse electron transfer-derived reactive oxygen species, activates adenosine monophosphate (AMP) activated protein kinase, and attenuates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated cytokine signaling; experimental data further suggest favorable effects on adiponectin–sarcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA) 2a-dependent calcium cycling, connexin expression, small-conductance Ca²⁺-activated K+ channel remodeling, lipid handling, and transforming growth factor-β (TGF)-β-associated fibrotic remodeling. Observational cohort studies have reported associations between metformin exposure and a modest reduction in incident AF, particularly with longer treatment duration and in higher-risk metabolic phenotypes; device-based surveillance cohorts support a preventive association for new-onset AF rather than reduction of established AF burden. Data after catheter ablation suggest improved freedom from recurrence in metformin-treated patients, whereas evidence in postoperative AF is largely neutral, likely reflecting distinct acute mechanisms. Collectively, metformin may be best conceptualized as a potential substrate-modifying, upstream therapy candidate; however, confounding, exposure misclassification, and heterogeneity in comparators limit causal inference, underscoring the need for prospective randomized trials with AF endpoints. In practice, integration with comprehensive risk-factor modification (blood pressure, weight, sleep apnea, and glycemic optimization) remains essential when considering AF prevention strategies. Full article