Background: Investigating the genetic basis of adaptation to environmental stresses, such as hypoxia, can enhance our understanding of human biology and resilience. High-altitude adaptation provides a valuable model for studying the genetic mechanisms of the hypoxic response. Indeed, most known loci associated with hypoxic adaptation have been identified in indigenous mountain populations; however, research on elite climbers remains limited. In our previous study, we conducted exome sequencing of experienced mountaineers and identified two pathogenic variants in the RTEL1 and COL6A1 genes, both of which are linked to respiratory failure. These findings encouraged this study, which conducted exome sequencing to explore genetic variation in a larger cohort. Methods: We performed exome sequencing for a cohort of 114 mountaineers with varying levels of experience. Variant calling was performed in the sequencing data using a pipeline based on the Genome Analysis Toolkit (GATK) v.4.1.9. Annotated variants were used to identify rare and common variants with possible effects on high-altitude adaptation. Results: The analysis did not identify any common adaptive variants in these individuals; however, nine variants were identified as potentially relevant to high-altitude adaptation and climbing performance. These included novel variants in the EPAS1 and EGLN1 genes, which may have a positive effect under hypoxic conditions, as well as variants in TCAP, F5, GP1BA, and other genes involved in muscle activity and blood coagulation. Conclusions: This study identified rare variants in the EPAS1 and EGLN1 genes, which had previously been associated with high-altitude adaptation. Additionally, we describe several potentially pathogenic variants in genes not previously linked to hypoxia, highlighting the value of studying elite mountaineers as a unique cohort for broader interpretation of genetic variation.
Background: Epstein–Barr virus (EBV) is a well-known cause of infectious mononucleosisand it has also been linked to the development of various malignant tumors. EBV can be classified into two genotypes based on EBNA-2 and EBNA-3 polymorphisms, with further subclassification predominantly based on BNLF-1 and EBNA-1 variations. Currently, EBV subtyping has not been performed using EBER genes. Thus, this study aimed to determine EBV subtypes in various malignant tumors and to assess the potential of EBER polymorphisms for EBV classification. Methods: DNA was isolated from tissue samples of patients diagnosed with classical Hodgkin lymphoma (cHL), angioimmunoblastic T cell lymphoma (AITL), and nasopharyngeal carcinoma (NPC). Specific fragments of the BNLF-1, EBNA-1, EBNA-3C, and EBER genes were amplified, and population sequencing was conducted. Results: Based on EBNA-3C sequences, all tumor samples were genotype EBV-1, whereas the BNLF-1, EBNA-1, and EBER sequences indicated that the tumor tissues were infected with different EBV subtypes. The B95-8 subtype predominated in cHL, whereas North Carolina and P-ala were the most frequent subtypes in NPC. In addition, we propose a newly designed algorithm for EBER-based subclassification, which showed that the subtype Cro2 is more frequently present in cHL and AITL than in NPC. Conclusion: The results of this study show characteristic pattern of EBV diversity based on the EBNA-3C, EBNA-1, and BNLF-1 gene sequences, as well as the EBER promoter sequence in AITL, NPC, and cHL cohorts specific for the Caucasian population of southeastern Europe; however, these results may not relate to the distribution of EBV variants in other geographic areas.
Interfamilial hybridization between American paddlefish (Polyodon spathula) and Acipenserid (sturgeon) species produces viable hybrid offspring. However, the potential fertility of these hybrids is a critical issue for understanding sex determination mechanisms within Acipenseriformes, as well as for aquaculture and species conservation programs. Investigating the fertility of such hybrids requires an integrative focus on the genetic basis of sex determination and gonadal differentiation. Based on current knowledge of sturgeon sex determination systems, the fundamental genetic framework for gonadal development is assumed to be at least partially retained in Polyodon–Acipenserid hybrids. Nevertheless, the meiotic processes governing gametogenesis may be affected by chromosomal or regulatory incompatibilities. To date, the available evidence does not indicate complete disruption of meiosis. However, further cytogenetic and molecular analyses are needed to clarify the extent of functional gametogenesis and the reproductive potential of these hybrids.
Background: Neuroblastoma (NB) is the most common extracranial solid tumor among pediatric cancers and accounts for approximately 15% of childhood cancer-related deaths. Neurotrophic receptor tyrosine kinases (NTRKs) are genes that play critical roles in the development and function of the nervous system. Therefore, elucidating the role of NTRKs in NB is important for both understanding basic biological mechanisms and developing novel therapeutic approaches. Specifically, NTRK fusions are being investigated as potential biomarkers and therapeutic targets for targeted therapy strategies. The tumor-agnostic TRK inhibitors larotrectinib and entrectinib are used to treat advanced or metastatic solid tumors with NTRK gene fusions. Accordingly, this study aimed to investigate the clinical significance of NTRK1, NTRK2, and NTRK3 point mutations, gene fusions, and protein expression, and to assess the effectiveness of these in guiding targeted therapy decisions in NB. Methods: This study investigated pan-TRK expression, point mutations, and fusions in the NTRK1, NTRK2, and NTRK3 genes using next-generation sequencing (NGS) on paraffin-embedded blocks from 173 patients diagnosed with NB. Findings were analyzed in SPSS 29.0 using clinical data, MYCN amplification, and 11q deletion status, with Pearson correlation analysis applied at the p < 0.05 significance level. Results: Immunohistochemistry (IHC) for NTRK revealed that 67.9% of cases were NTRK-positive. NGS analysis identified NTRK1 missense point mutations in 20 cases, NTRK2 in 9 cases, and NTRK3 in 9 cases. In addition, 5 fusions were detected in 4 of the 103 patients who underwent fusion analysis. Conclusions: Owing to the presence of neural tissue, NTRKs are highly positive in IHC, making these genes unsuitable as biomarkers for assessing NTRK inhibitor sensitivity and resistance, which are tissue-agnostic drugs. The observed low fusion rate is consistent with the literature, and the significance of the numerous point mutations identified as agnostic markers warrants further investigation. NTRK expression, fusion, and point mutations were not associated with clinical parameters or survival.
Systemic lupus erythematosus (SLE), a complex autoimmune disease, affects multiple tissues and organs, presenting substantial challenges for both diagnosis and treatment. Both innate and adaptive immune cells are involved in the intricate pathophysiology of SLE. The characteristics of SLE include the production of autoantibodies and the formation of immune complexes that accumulate within the vasculature, leading to organ damage. Although progress in understanding the pathogenesis of SLE has lagged behind that of other autoimmune rheumatic diseases, recent findings have highlighted promising therapeutic targets and raised the prospect of personalized treatment strategies. This narrative review was conducted through a comprehensive analysis of recent literature focused on the pathogenesis, diagnosis, and treatment of SLE. Prospective experimental and clinical studies with well-documented results were selected for analysis. Diagnostic biomarkers were evaluated for their sensitivity, specificity, and correlation with disease activity indices, such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Therapeutic agents, including monoclonal antibodies, interferon, and interleukin inhibitors, as well as emerging small molecules, were assessed based on clinical trial outcomes and potential future applicability in clinical practice. Several promising biomarkers, such as pentraxin 3 (PTX3), S100 calcium-binding protein A8 (S100A8), B cell differentiation factor (BCDF), interferon gamma-induced protein 10 (IP-10), urinary activated leukocyte cell adhesion molecule (ALCAM), vascular cell adhesion molecule 1 (VCAM-1), and platelet factor 4 (PF4), have shown strong correlations with disease activity and lupus nephritis (LN). Among treatments, monoclonal antibodies, such as belimumab and anifrolumab, are already approved by the United States Food and Drug Administration. Meanwhile, others, including obinutuzumab and sifalimumab, have demonstrated encouraging results in Phase II trials. These developments reflect growing potential for precision diagnostics and targeted therapy in SLE. Recent advances in understanding the immunological underpinnings of SLE have led to the identification of sensitive and specific biomarkers, as well as novel biologics, which may overcome the limitations of traditional therapies. Biomarkers such as PTX3 and S100A8 can facilitate early diagnosis and may also predict treatment efficacy, offering the foundation for tailored therapeutic strategies. The continued evaluation of emerging biologics, particularly those targeting B cells and the interferon pathway, holds promise for enhancing disease management and improving long-term patient outcomes.
