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Results for “molecular pathology”

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At least 19 recordsLinked to original sources
PubMed1978

Molecular biology and molecular pathology of a newly described molecular disease--tyrosinemia II (the Richner-Hanhart syndrome).

A deficiency of hepatic tyrosine aminotransferase in humans is responsible for a syndrome of keratitis, palmar and plantar erosions and hyperkeratosis and mental retardation. Serum tyrosine increases due to the enzymatic deficiency leads to the deposition of tyrosine crystals in the eye and cornea. This deposition and possible lysosomal activation leads to inflammation in the cornea and the skin. The syndrome can be reproduced in animals who are fed a high tyrosine diet. The interaction of tyrosine crystals with membrane-bound particles can be studied in vitro with lysosomes and erythrocytes.

Amino Acid Metabolism, Inborn Errors↗
PubMed1976

[Molecular pathology and the problem of bodily integrity].

The paper is devoted to general and special (local) problems in pathology. The author lays particular stress on the fact that, despite the achievements of molecular biology, a solution of many principal problems of pathogenesis of various diseases in man, regularities of his adaptation to diverse environmental factors, etc., can be achieved only by a synthetic insight into the whole complex of factual material seen from the standpoint of the organism as an integrated system functioning on the basis of general regulatory mechanisms, many elements of which remain still unknown. Establishing of the latter is one of the most important and most complicated present-day challenges of biology and medicine.

Molecular Biology↗
PubMed1976

[Collagen metabolism and mineralization of uremic bone--aspects of the molecular pathology of renal osteodystrophy].

Importance sequelae of uremia are hormonal changes in calcium homeostasis combined with chronic calcium imbalance causing structural alteration and functional insufficiency of bone. Morphological findings of the so called renal osteodystrophy are osteomalacia, osteitis fibrosa and osteoporosis. Osteitis fibrosa and abnormal skeletal metabolism (changes of collagen turnover, insufficient maturation of stable bone crystals) impair the mechanical qualities of bone. Probably the uremia per se influences the collagen metabolism; additional factors such as secondary hyperparathyroidism and deficiency of vitamin D3 are discussed.

Animals↗
PubMed2026

Pediatric intracranial inflammatory myofibroblastic tumor harboring DCTN1::ALK fusion: a case report with radiologic-pathologic-molecular correlation.

Central nervous system inflammatory myofibroblastic tumors are rare; pediatric DCTN1::ALK fusion cases are exceptionally uncommon. Here, we present an eight-year-old boy who presented with headache, vomiting, and a rapidly enlarging right frontal scalp mass. An MRI showed a dural, extra-axial lesion with mass effect. Histology confirmed IMT, and ALK immunohistochemistry was positive; next-generation sequencing (NGS) identified DCTN1 (exon 1-27)-ALK (exon 20-29) fusion, and FISH confirmed ALK rearrangement (33/100 nuclei). Genomic metrics showed tumor mutational burden (TMB) of 0.94/Mb, microsatellite stability, and CNV burden of 2.1%. He underwent near total resection followed by alectinib; to our knowledge, this is the first reported young pediatric (<10&#xa0;years old) CNS IMT with this fusion.

Humans↗
PubMed2026

Salivary duct carcinoma- contemporary nuts and bolts from pathologist perspective.

INTRODUCTION: Salivary gland carcinomas are highly heterogeneous malignancies that present a complex variety of histological features and distinct clinical behaviors, with salivary duct carcinoma (SDCa) as the most clinically severe and aggressive subtype. The standard of care for these patients is a combined approach of surgery followed by radiotherapy. The aggressive clinical course of SDCa is primarily driven by frequent disease recurrences and systemic spread. AREAS COVERED: The publication of WHO 5th Classification of Head and Neck tumors has sparked a surge in research targeting SDCa. Owing to the highly aggressive behavior of the tumor, most literature heavily emphasizes the molecular pathology of SDCa.A systematic literature search was conducted using the PubMed with the following search terms: salivary duct carcinoma AND pathology OR updates OR molecular OR signaling pathway OR gene expression OR mutation OR oncogene OR tumor suppressor OR DNA methylation OR tumor microenvironment. Results were limited to primary research articles in English language. EXPERT OPINION: This article outlines key advancements in SDCa morphology, molecular pathology, and targeted therapies. Patient management in precision oncology will be fundamentally transformed by the classification of new morphologic subtypes, the discovery of molecular biomarkers, and an enhanced comprehension of tumor microenvironment.

HER 2↗
PubMed2026

Distinct periarticular muscle transcriptomes: inflammation in rheumatoid arthritis versus metabolic dysregulation in osteoarthritis.

OBJECTIVES: Periarticular skeletal muscle abnormalities are recognised in rheumatoid arthritis (RA) and osteoarthritis (OA), but their divergent molecular pathologies are poorly defined. This study aimed to elucidate and directly compare the transcriptomic profiles of periarticular muscle in patients with RA and OA. METHODS: We performed bulk RNA sequencing of periarticular skeletal muscle samples collected during total joint arthroplasty from RA (n=6) and OA (n=4) patients. Differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), pathway enrichment, and gene set variation analyses were conducted to identify disease-specific molecular features and their clinical associations. RESULTS: The two conditions showed fundamentally distinct profiles. RA muscle exhibited a pronounced inflammatory signature, characterised by upregulation of cytokine-responsive genes including FOS, EGR1, and CXCL2, and enrichment of tumour necrosis factor-&#x3b1; and interleukin-6 (IL-6)/JAK-STAT3 signalling. In contrast, OA muscle was characterised by metabolic dysregulation, with upregulation of genes linked to adipogenesis (PCK1, SFRP4) and significant enrichment of epithelial-to-mesenchymal transition (EMT) signalling. These divergent profiles were further supported by WGCNA, which identified distinct modules reflecting heightened innate immune and complement activation in RA, and disrupted metabolic processes in OA. Notably, in RA, the IL-2-STAT5 signalling pathway was unique among those tested in showing a strong positive correlation with DAS28-ESR (r=0.94, p=0.019). CONCLUSIONS: This study reveals distinct molecular pathologies in the periarticular muscle of RA and OA. RA muscle shows an intense inflammatory profile potentially linked to cachexia, whereas OA muscle displays features of metabolic disease and pro-fibrotic remodelling.

Humans↗
PubMed2025

HCSeeker: A classification tool for human genetic variant hot and cold spots designed for PM1 and benign criteria in the ACMG-AMP guideline.

PURPOSE: The PM1 criterion, which states that a variant is located in a mutational hot spot and/or critical and well-established functional domain without benign variation (such as the active site of an enzyme), is considered moderate evidence for assessing its pathogenicity. Although guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology are widely adopted, the PM1 criterion remains limited from lacking a reliable database of variant hot spots. Compared with hot spots, cold spots are neglected by the guidelines. To improve variant classification, we suggest including cold spots for supporting benign classifications. Consequently, we have developed the HCSeeker to provide data support for PM1 and the "Benign" criteria. METHODS: HCSeeker uses the Kernel Density Estimation and the Expectation-Maximization algorithm to identify hot- and cold-spot regions. RESULTS: Through HCSeeker, we identified 988 hot spots and 682 cold spots across 889 genes and provided a public database (http://www.genemed.tech/hcseeker/) for researchers and clinicians to query variant locations, facilitating the application of American College of Medical Genetics and Genomics and the Association for Molecular Pathology PM1 or "Benign" criteria. CONCLUSION: We developed the HCSeeker tool, which can effectively identify variant hot and cold spots within genes to enhance the interpretability of gene variants.

Humans↗
PubMed2026

Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.

BACKGROUND: Missense variants are frequently classified as variants of uncertain significance (VUS) according to the guidelines of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology (ACMG/AMP). Consequently, disease relevance remains elusive, impeding molecular genetic diagnostics, patients` and family genetic counseling, and identification of patients eligible for clinical trials. Functional studies are critical for resolving the clinical significance of VUS. CNGA1 encodes the main subunit of the rod cyclic nucleotide-gated (CNG) channel, a vital component of the phototransduction cascade. Variants in CNGA1 are a rare cause of autosomal recessive retinitis pigmentosa and a phase I/II gene augmentation trial (NCT06291935) is currently ongoing highlighting the necessity to differentiate benign from pathogenic variants. METHODS: CNGA1 missense variants compiled from retinal disease patient cohorts, public databases and literature were functionally investigated using a medium-throughput aequorin-based assay and in vitro minigene splice assays for predicted exonic spliceogenic variants. Functional data were correlated with the in silico prediction of five variant effect predictors (VEPs) and applied to support or revise variants' ACMG/AMP classification. RESULTS: Data mining revealed 86 missense CNGA1 variants - including three novel - most of them lacking functional data; 65.1% of the variants were initially classified as VUS. The aequorin-based assay showed that 72.1% of tested variants significantly impaired CNG channel function and were classified as functionally abnormal, while 23.3% were functionally normal and 5% remained functionally uncertain. Correlation of the functional data with in silico predictions identified AlphaMissense and CPT-1 to be the most suitable tools for assessing CNGA1 missense variants. Using in vitro minigene splice assays, two putative missense variants were shown to induce missplicing. Based on the functional findings, 62.1% of the variants initially classified as VUS were re-categorized as likely pathogenic or likely benign. Furthermore, 93.3% of the variants initially classified as likely pathogenic showed an effect on CNGA1 channel function, confirming their disease relevance and supporting their reclassification as pathogenic. CONCLUSION: This study represents the first comprehensive functional assessment of disease-associated CNGA1 missense variants, thus significantly advancing the understanding of their disease relevance and improving molecular genetic diagnostics in patients.

Humans↗
PubMed2026

Whole-Exome Sequencing in a Consanguinity-Enriched South Indian Retinitis Pigmentosa Cohort: Diagnostic Yield and Molecular Spectrum.

PURPOSE: To determine the molecular diagnostic yield, variant spectrum, inheritance architecture, and influence of consanguinity on whole-exome sequencing outcomes in a South Indian retinitis pigmentosa (RP) cohort. DESIGN: Prospective, registry-based cohort study. SUBJECTS: A total of 113 affected participants were enrolled through the Aravind Registry for Inherited Diseases of the Eye, including 109 unrelated probands and 4 affected relatives from already represented families. Primary analyses were restricted to the 109 unrelated probands. METHODS: Whole-exome sequencing was performed using a clinical exome workflow. Variants were interpreted using American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and cases were categorized as solved, possibly solved, inconclusive, or unsolved using prespecified inheritance-aware rules. MAIN OUTCOME MEASURES: Molecular diagnostic yield, distribution of implicated genes and variant classes, inheritance architecture, and diagnostic yield stratified by consanguinity status. RESULTS: Among the 109 unrelated probands, mean age at testing was 39.3 &#xb1; 14.1 years and 58.7% were male. Whole-exome sequencing identified 186 distinct rare variants across 92 inherited retinal disease genes, including 26 pathogenic and 33 likely pathogenic variants. A molecular diagnosis was established in 50 of 109 probands (45.9%), including 42 solved and 8 possibly solved cases; 45 (41.3%) were inconclusive and 14 (12.8%) remained unsolved, including 4 (3.7%) in whom no candidate variant was identified. EYS, USH2A, and ADGRV1 were the most frequently implicated genes. Autosomal recessive (AR) disease predominated (44/50, 88.0%). Consanguineous AR cases were exclusively homozygous (17/17); notably, 68.0% of nonconsanguineous AR cases were also homozygous (P = 0.013). Diagnostic yield was higher in consanguineous probands (51.4% vs. 41.7%), without reaching significance. Recurrent alleles included an established South Asian founder variant (MFSD8 c.1361T>C) and candidate founder alleles in EYS (c.4321C>T) and ADGRV1 (c.14329C>T). CONCLUSIONS: Whole-exome sequencing established a molecular diagnosis in nearly half of this South Indian RP cohort and revealed a predominantly recessive, homozygosity-enriched architecture shaped by consanguinity. These findings define a region-specific variant landscape to support clinical interpretation, genetic counseling, and future trial enrollment in this underrepresented population. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.

Consanguinity↗