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5 recordsLinked to original sources
PubMed2025

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch®, that employs an algorithm-based CCs analysis. Using EpiSwitch® technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch®CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.

Humans↗
PubMed2026

Genomic Characterization of Classic Adamantinoma, Osteofibrous Dysplasia, and Osteofibrous Dysplasia-like Adamantinoma.

Classic adamantinoma, osteofibrous dysplasia (OFD), and OFD-like adamantinoma are rare bone tumors arising primarily in the tibiae. Their distinction can be challenging; data on their molecular pathogenesis remain limited. We searched our pathology files in 2004-2024 for available cases and performed targeted next-generation sequencing along with whole-genome single-nucleotide polymorphism arrays and 3-dimensional genomics/Hi-C sequencing in selected cases. Our cohort included 3 classic adamantinomas (2 females and 1 male; age, 14-56 years), 5 OFDs (3 females and 2 males; age, 9-25 years), and 2 OFD-like adamantinomas (1 female and 1 male; age, 30-41 years). Of the 10 tumors, 9 arose from the tibiae; 1 classic adamantinoma originated from the radius. The 3 classic adamantinomas harbored multiple copy number gains involving chromosome 7, 8, 10, 12, and/or 19. Focal deletion of chromosome 17, intergenic rearrangement involving FGFR1, and NRAS p.G12D were each present in 1 classic adamantinoma. Of the 5 OFDs, KMT2A p.C2441F, KMT2D p.S1040P, PHOX2B p.G213D, and RIF1 deletion were each present in 1 case; no additional copy number/single-nucleotide variants were identified. Of the 2 OFD-like adamantinomas, one case with tumor clusters visible only on cytokeratin immunostain harbored no variants, whereas another case with tumor clusters visible on light microscopy and cytokeratin/p40 immunostains showed gains of chromosome 7, 8, 19, and 20. By Hi-C, 1 classic adamantinoma harbored an approximately 9 Mb tandem duplication on chromosome 12q, 1 OFD harbored a rearrangement with breakpoints near MECOM and HOOK3, and the OFD-like adamantinoma with tumor clusters visible only on cytokeratin immunostain harbored no structural variant. In conclusion, classic adamantinomas and OFD might be genetically distinct. Classic adamantinomas harbored multiple alterations, including chromosome/arm-level copy number gains, the detection of which could aid their distinction from OFDs. Using genomics as the benchmark, OFD-like adamantinomas might be better delineated by light microscopy or p40 than by cytokeratin immunohistochemistry. These data expanded our molecular understanding of these rare bone tumors.

Humans↗
PubMed2026

AI-Based 3D Heterogeneous Network Model for Functional Prediction of Epigenetics.

Human biology and diseases are the result of constantly evolving processes within an intricately complex molecular network of interactions, such as epigenetic regulation. Epigenetics refers to heritable changes in gene expression that occur without alterations to the underlying DNA sequence. These changes, driven by mechanisms such as DNA methylation, histone modifications, and noncoding RNAs, play critical roles in regulating chromatin structure and gene activity. Epigenetic regulation offers valuable insights into biological systems, and when integrated with sophisticated analyses, it enables us to gain insights into gene regulation and cellular behavior. Here, we describe an artificial intelligence (AI)-based model that is capable of generating 3-dimensional (3D) heterogeneous network by integrating multimodal data for the functional prediction of epigenetic mechanisms, emphasizing its applications in medicine, developmental biology, and personalized therapeutics. Heterogeneous networks in biology are powerful tools for understanding the complex interactions and interdependencies within biological systems. Key advancements in AI and multiomics data integration have propelled this field, offering new insights into disease mechanisms, biomarker discovery, and therapeutic interventions.

Epigenesis, Genetic↗
PubMed1976

Thermophilic and mesophilic enzymes from B. caldotenax and B. stearothermophilus: properties, relationships and formation.

1) The adaptive system of thermophilic bacteria, as demonstrated with B. caldotenax, seems to be suitable to produce thermophilic and mesophilic enzymes for comparative studies. 2) If it may be assumed that the extensive homologies in the N-terminal sequences of the LDHs also extend over the entire polypeptide chain, comparison of these sequences together with investigation on the 3-dimensional structure offer the possibility of elucidating those structural details which may be responsible for thermostability and the other thermophilic properties. However, the difficulty still remains that the latter may be obscured by differences not related to thermostability etc. Neverthless it may be hoped that comparison of the full sequences of not only the LDHs but also of a sufficient number of other enzymes of the same system will yield such details. 3) A further interesting goal with respect to the mechanism of enzyme adaptation would be reached if the differences in amino acid sequence of thermophilic and mesophilic LDH enzymes would throw light on the type of the amino acids always being exchanged. Here from the very hypothetical point of view the question arises as to whether the bacterial cell during the metabolic adaptation process or even by mutation/selection is able to modify just those few amino acid residues thermodynamically important for thermostability. Alternatively: does there exist a "rule" by which certain amino acid residues are invariably exchanged on a change for thermophilic to mesophilic enzymes? 4) Problems not mentioned here arise with B. stearothermophilus, which can be adapted poorly via the spores or on intermediate temperatures. Of great importance, but also a special problem in these studies on thermophilic and mesophilic enzymes produced by the same bacterium are a) the characterization of the thermophilic (70 degrees or 55 degrees) and mesophilic (37 degrees) bacterial variants (in respect to type), b) the control of homogeneity of the bacterial culture (contamination, mixed population), c) proof of the genetic identity of the 70 degrees- (55 degrees-) and 37 degrees -variant of B. caldotenax and B. stearothermophilus, which differ greatly in their phenotypes, for example in their metabolism, cell- or colony merphology. The taxonomical-biochemical identity or also the identity of morphology of the sporangia, since this should be an expression of the temperature dependent phenotype, cannot be used unconditionally as criteria of identity. Criteria such as the presence of identical enzymes in both variants or the identity of the genome (use of genetic markers, anlaysis of the DNA) are more reliable. Experiments with both variants of B. caldotenax demonstrated an identically high content of cytosine plus guanine in their DNA: 62.2% in the thermophilic DNA and 66.8% in the mesophilic DNA. In the thermophilic B. stearothermophilus the C+G content of the DNA was 56.5% and in the mesophilic variant 57.1%...

Adaptation, Physiological↗
PubMed2026

The use of 3-dimensional (3D) printing in teaching musculoskeletal oncology for medical undergraduates.

INTRODUCTION: The approach to integrating relevant anatomy in the medical curriculum has been debated for many years. Current literature has explored the broad impact of 3D printing in medical education. However, there is little evidence on 3D printing for the teaching of musculoskeletal oncology (MSO). This is a self-controlled case series (SCCS) study that aims to analyse the effectiveness of 3D printed models in MSO in enhancing the learning experience, engagement and understanding of clinical and surgical anatomy for medical students. METHOD: A cross-sectional cohort study involving 75 clinical year medical students across 3 years from 2 medical schools that rotated through a single teaching hospital's orthopaedic department. Participants first viewed a set of computed-tomography (CT) images of a large pelvic osteosarcoma from a free open-source database, the Cancer Genome Atlas Sarcoma Collection (TCGA-SARC). A standardised 10-minute pre-intervention questionnaire which comprised 15 questions categorised by: 4 questions in 'anatomical knowledge', 7 questions in 'spatial awareness', 4 questions in 'surgical planning and complications', was administered to assess the baseline knowledge in their interpretation of the pathology via CT images only. Next, a 3D-printed model of the pelvic osteosarcoma, which included colour-coded adjacent structures, was provided as an adjunct to answer the same questionnaire. This concluded with a 5-point Likert scale feedback survey to gauge their perspectives and experience. RESULTS: The mean scores comparing their pre- and post-intervention assessment questionnaire increased by +1.34 from 8.15 (SD = 1.85) to 9.49 (SD = 1.7) (p < 0.001). The final year students had the greatest improvement of +1.54 from 8.00 (SD = 1.89) to 9.54 (SD = 1.59) (p = 0.004). There was no significant difference between the scores amongst the 2 medical schools. 91% of students agreed that the 3D model had helped them further their understanding of the anatomy of the sarcoma and 87% would want 3D printing models to augment their learning in anatomy. Baseline weaker students demonstrated significantly greater improvement in scores compared with baseline stronger students (mean difference +2.04 vs +0.30, p < 0.001). CONCLUSION: 3D printing is an effective teaching adjunct for musculoskeletal oncology surgical anatomy for medical undergraduates and could be used to enhance their understanding and learning experience. 3D models could be integrated in the teaching curriculum of surgical anatomy for undergraduate students.

Humans↗