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Aims: Monogenic diabetes is one of the few examples in metabolic diseases in which a real precision medicine approach can be implemented in daily clinical work. Unfortunately, most of what is known today comes from studies in Whites, thus leaving much uncertainty about the genetics and the clinical presentation of monogenic diabetes in non-Europeans. To fill this gap, we report here two pedigrees from Bangladesh with CEL- and RFX6- diabetes, two rare types of monogenic diabetes which have never been described so far in individuals of the Indian subcontinent. Methods: Next generation, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) were performed. Variants' interpretation was according to the American College of Medical Genetics and Genomics guidelines. Results: In the pedigree with CEL-diabetes, a large and never described deletion of exon 2–11 of CEL (confirmed by MLPA) affecting the entire catalytic domain and being likely pathogenic (LP) was observed in both the proband (who had diabetes at 16) and his mother (diabetes at 31), but not in relatives with normoglycemia. In the pedigree with RFX6-diabetes, a LP protein truncation variant (PTV, p.Tyr192*) in RFX6 was found in both the proband (diabetes at 9) and his mother (diabetes at 30), thus suggesting high heterogeneity in disease onset. Normoglycemic relatives were not available for genetic testing. Conclusions: We report genetic features and clinical presentation of the first two cases of CEL- and RFX6-diabetes from the Indian subcontinent, thus contributing to fill the gap of knowledge on monogenic diabetes in non-Europeans. [ABSTRACT FROM AUTHOR] more...

Background: Cystic fibrosis (CF) is a genetic disorder caused by genetic variant in the cystic fibrosis transmembrane regulator (CFTR) gene that affects around 89,000 people worldwide. Loss of the CFTR chloride channel due to pathogenic variants in the CFTR gene causes obstruction in the exocrine pancreas gland and reduced lung function. Objective: To determine the genotype and phenotype of patients with CF from western India. Materials and Methods: This was a single-center retrospective cross-sectional study conducted in a tertiary care super speciality paediatric hospital of Mumbai, India, comprising patients aged 0 to 18 years visiting a paediatric pulmonology clinic with suspected or confirmed diagnosis of CF. Results: The mean (SD) age of onset of symptoms was 6.8 (10.2) months and the mean (SD) age at diagnosis was 32.5 (50.5) months. The two most common genetic variants found in our patients were c. 1521_1523delCTT (F508del) (n = 21) and c.1367T>C (V456A) (n = 10). There were nine novel genetic variants identified that have not been reported so far. The mean (SD) age of onset of symptoms was 6.8 (10.2) months and mean (SD) age at diagnosis was 32.5 (50.5) months. The most common presenting features were recurrent respiratory infections (83%), malabsorption (79%), and failure to thrive (79%). Sweat chloride testing was conducted to establish the CFTR gene dysfunction and was positive in 79% (46/58) of patients and intermediate in 15% (n = 9/58) of patients. The two most common genetic variants found in our group of patients were c. 1521_1523delCTT (F508del) (n = 21) and c.1367T>C (V456A) (n = 10). There were nine novel genetic variants identified that have not been reported so far. Conclusion: This study adds to the knowledge of genetic diversity in the pathogenic CFTR gene variants causing CF and highlights the importance of sequencing the entire CFTR gene as regional variations in the gene have been documented in India. [ABSTRACT FROM AUTHOR] more...

Managing acute myeloid leukemia (AML) and its critical complications requires understanding the complex interplay between disease biology, treatment strategies, and patient characteristics. Complications like sepsis, acute respiratory failure (ARF), hyperleukocytosis, coagulopathy, tumor lysis syndrome (TLS) and central nervous system (CNS) involvement present unique challenges needing precise evaluation and tailored interventions. Venetoclax-induced TLS and differentiation syndrome (DS) from IDH1/IDH2 or menin inhibitors highlight the need for ongoing research and innovative approaches. As the microbiological landscape evolves and new therapeutic agents emerge, adapting strategies to mitigate harmful pharmacological interactions is crucial. Advances in understanding the genetic profiles of patients with hyperleukocytosis contribute to better-targeted therapeutic strategies. Effective AML management relies on collaborative efforts from hematologists, specialized services, and intensive care units (ICUs). This review analyzes recent data on critical AML complications, identifies areas for further investigation, and proposes ways to advance clinical research and enhance patient care strategies. [ABSTRACT FROM AUTHOR] more...

Nutrition and genetics have individual roles in systemic arterial hypertension (SAH); however, they can interact, influencing the regulation of blood pressure (BP) levels. The aim of this study was to evaluate the available evidence regarding gene–nutrient interactions in modulating BP levels in adults with SAH. The review followed the recommendations of the Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Twelve studies met the inclusion criteria for this review, reporting on 20 genes and 31 single nucleotide polymorphisms (SNPs), with 19 of them associated with BP variations. The most frequently evaluated SNPs were ACE rs4646994 and AT1R rs5186. Among the nutritional interventions, dietary sodium content was the focus of most studies (n = 11). Interactions with sodium consumption were observed for the following SNPs: KDM1A rs587168, EDNRB rs5351, LSS rs2254524, IRS1 rs1801278, KCNK9 rs6997709, ACE rs4646994, GNB3 rs5443, PPARG rs4684847, EDN1 rs5370, BCAT1 rs7961152, IL18 rs5744292, NOS3 rs2070744, and AT1R rs5186. In the presence of a diet rich in fruits and vegetables, moderate alcohol consumption, and reduced sodium intake, the SNP AT2R rs11091046 was associated with a decrease in BP levels. Furthermore, the SNP MTHFR rs1801133 exhibited an interaction with riboflavin supplementation in affecting BP levels. The evidence regarding the interaction between genetics and diet on BP levels remains limited. Among the existing findings, an interaction was observed between sodium, calcium, riboflavin, and specific polymorphisms; however, the underlying mechanisms for these interactions have yet to be identified. Note: This paper is part of the Nutrition Reviews Special Collection on Precision Nutrition. [ABSTRACT FROM AUTHOR] more...

The document explores the impact of genetic profiles and treatment on outcomes and hematological toxicity in CEBPA-mutated AML patients. The study analyzes a cohort of 50 intensively treated patients, focusing on baseline characteristics and treatment details. Results show delayed hematopoietic recovery in CEBPA-mutated patients with additional mutations, suggesting the need to incorporate NGS data for therapeutic management. The study highlights the importance of limiting anthracycline dosage to reduce hematological toxicity and improve treatment adherence in this patient population. [Extracted from the article] more...

Breast cancer (BC) is one of the most common malignancies among women globally, characterized by complex pathogenesis involving various biomarkers present in blood and urine. To enhance understanding of the genetic associations between biomarkers and BC via multidimensional, cross ethnic investigations. Based on GWAS data of 35 blood and urine biomarkers from European populations, we adopted multiple analysis strategies including univariable Mendelian randomization (MR) analysis, reverse MR analysis, sensitivity analysis and multivariate MR to identify potential biomarkers associated with BC risk and survival. Our initial analysis included 122,977 BC and 105,974 controls of European ancestry. Building upon these findings, we conducted cross ethnic validation by applying the same analyses to East Asian populations using data from the IEU GWAS database, which included 5,552 BC and 89,731 controls. This step allowed us to investigate the universality and heterogeneity of our identified biomarkers across different ancestries. Subsequently, utilizing clinical laboratory detection data from multiple regions in China, we performed differential analyses and survival assessments on these potential biomarkers to evaluate their clinical relevance and utility. Notably, we leveraged Luzhou's clinical data to integrate HDL-C with conventional tumor markers (CEA, CA125, CA153) into a machine learning model, comparing its diagnostic efficacy against tumor marker combination. Our study validated associations of ALP, HDL-C, TG, SHBG, and IGF-1 with BC risk, reinforcing the reliability of these findings. Moreover, notable interethnic disparities emerged in the association between HDL-C and BC risk, where in HDL-C demonstrates a contrasting role: acting as a genetic protective agent against BC and suggesting promise as an auxiliary diagnostic marker in East Asian populations, yet inversely, it serves as a genetic dangerous predictor in European populations. Analyzing BC subtypes, we identified associations of HDL-C, TG, SHBG, and CRP with ER+BC, while ER−BC showed associations with GLU, urinary creatinine and microalbuminuria, underscoring subtype-specific genetic characteristics critical for personalized prevention and treatment strategies. Overall, this comprehensive study, by traversing the intricate landscape of genetic associations across ethnic boundaries and employing advanced analytical methodologies, not only uncovers the complex interplay between key biomarkers and BC susceptibility but also highlights the significance of ethnic-specific differences in the role of HDL-C. By enhancing the diagnostic power of a tailored biomarker panel through machine learning, this study contributes to the advancement of precision medicine in BC, offering strategies tailored to the unique genetic profiles and biomarker patterns across diverse populations. [ABSTRACT FROM AUTHOR] more...

PURPOSE: Metastatic spread of non–small cell lung cancer (NSCLC) to the brain is a commonly occurring and challenging clinical problem, often resulting in patient mortality. Systemic therapies including immunotherapy have modest efficacy in treating brain metastases. Moreover, the local immune environment of brain metastases remains poorly described. This study aims to understand the genomic and immune landscape of NSCLC brain metastases. METHODS: A total of 3,060 patients with NSCLC sequenced with the Strata Select assay on the Strata Oncology Platform were analyzed. Genomic alterations, tumor mutation burden (TMB), PD-L1 expression, and immune gene expression were compared across different tissue sites and histologies and within brain metastases. RESULTS: A significant increase in TMB was observed in the brain metastasis samples compared with nonbrain metastasis samples. Mutations in TP53 , KRAS , and CDKNA2A were more prevalent within the brain metastasis cohort compared with other tissue locations. In addition, PD-L1 expression was significantly decreased within brain metastasis samples compared with other sites. The overall immune landscape within the brain metastasis samples was largely reduced compared with primary lung samples. However, an immune-enriched brain metastasis cohort was identified with higher expressions of PD-L1 and other immune-related genes. CONCLUSION: The overall TMB is increased within brain metastases compared with primary lung and other metastasis sites and is associated with a markedly diminished overall immune landscape. The identification of an immune-enriched brain metastasis subgroup suggests potential heterogeneity within the brain metastasis patient cohort, which might have implications for the development of targeted therapies. [ABSTRACT FROM AUTHOR] more...

Introduction: The Bacillus cereus group encompasses a complex group of closely related pathogenic and non-pathogenic bacterial species. Key members include B. anthracis , B. cereus , and B. thuringiensis organisms that, despite genetic proximity, diverge significantly in morphology and pathogenic potential. Taxonomic challenges persist due to inconsistent classification methods, particularly for B. cereus isolates that resemble B. anthracis in genetic clustering. Methods: This study investigated B. cereus group isolates from blood smears of animal carcasses in Kruger National Park, uncovering an unusual isolate with B. cereus features based on classical microbiological tests yet B. anthracis -like genomic similarities with an Average Nucleotide Identity (ANI) of ≥95%. Using comparative genomics, pan-genomics and whole genome Single Nucleotide Polymorphism (wgSNP) analysis, a total of 103 B. cereus group genomes were analyzed, including nine newly sequenced isolates from South Africa and a collection of isolates that showed some classification discrepancies, thus classified as "anomalous." Results and discussion: Of the 36 strains identified as B. anthracis in GenBank, 26 clustered phylogenetically with the four confirmed B. anthracis isolates from South Africa and shared 99% ANI. Isolates with less than 99% ANI alignment to B. anthracis exhibited characteristics consistent with B. cereus and/or B. thuringiensis , possessing diverse genetic profiles, insertion elements, resistance genes, and virulence genes features, contrasting with the genetic uniformity of typical B. anthracis. The findings underscore a recurrent acquisition of mobile genetic elements within B. cereus and B. thuringiensis , a process infrequent in B. anthracis. Conclusion: This study highlights the pressing need for standardized taxonomic criteria in B. cereus group classification, especially as anomalous isolates emerge. This study supports the existing nomenclature framework which offers an effective solution for classifying species into genomospecies groups. We recommend isolates with ANI ≥99% to standard reference B. anthracis be designated as typical B. anthracis in GenBank to maintain taxonomic clarity and precision. [ABSTRACT FROM AUTHOR] more...

Introduction: Thyroid cancer (THCA) is the most common endocrine tumor. Research on Cell Senescence Associated Genes (CSAGs), which impact many cancers, remains limited in the THCA field. Methods: In this study, we downloaded THCA sample data from several public databases and selected a set of CSAGs for subsequent analysis. Differential expression genes (DEGs) obtained through differential analysis were intersected with prognostic genes identified by Cox regression analysis to explore the correlation among these crossed genes. We constructed a prognostic model using the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm and verified its efficacy. Kaplan-Meier survival curves were plotted, and Receiver Operating Characteristic (ROC) curves rigorously confirmed the accuracy of model predictions. Results: To evaluate the predictive power of prognostic models across different phenotypic traits, we performed survival analysis, Gene Set Enrichment Analysis (GSEA), and immune-related differential analysis. Differences in tumor mutation burden (TMB) and treatment response between high-risk and low-risk patient groups were also analyzed. Finally, the predictive effect of our model on immunotherapy response was validated, showing promising results for THCA patients. Discussion: Our study enhances the understanding of THCA cell senescence and provides new therapeutic insights. The proposed model not only accurately predicts patient survival but also reveals factors related to immunotherapy response, offering new perspectives for personalized medicine. [ABSTRACT FROM AUTHOR] more...

Background: Primary cardiomyopathies are major causes of heart failure, placing a substantial burden on both individuals and society. Revealing its genetic profiles can lead to a better understanding of the mechanism and is critical for disease prevention and treatment. Method: Primary cardiomyopathy patients were enrolled and whole exome sequence was conducted to analyze their genetic profiles. Retrospective clinical information extraction and analysis of sequence data were implemented. Results: A total of 77 primary cardiomyopathy patients were enrolled, comprising 65 patients with dilated cardiomyopathy (DCM) and 12 with hypertrophic cardiomyopathy (HCM). Among the DCM patients, 13 variants classified as pathogenic (P) or likely pathogenic (LP) were identified in 12 patients (18.46%), predominantly in genes associated with the nuclear envelope and sarcomere. Among HCM patients, 6 P/LP variants were discovered in 6 (50%) patients. Taking variants of uncertain significance (VUS) into consideration, an analysis of the association between the number of variants carried by patients and their clinical characteristics revealed that DCM patients with more than one variant had a higher proportion of hyperuricemia. Conclusions: We map a comprehensive profile of primary cardiomyopathy in Chinese population and, for the first time, identify a possible association between hyperuricemia and the number of genetic variants carried by DCM patients. [ABSTRACT FROM AUTHOR] more...

Pendred syndrome and autosomal recessive non-syndromic hearing loss, type 4 (DFNB4), are associated with mutations in SLC26A4 that encodes the anion transporter SLC26A4 (pendrin). SLC26A4 is expressed in mitochondria-rich cells of the endolymphatic sac, spindle and root cells in the cochlear lateral wall, transitional cells in the vestibular organs, follicular cells in the thyroid, and type B intercalated cells in the kidney. This study aimed to assess the gene profiles of murine Slc26a4-expressing cells to better understand the regulatory mechanisms and functions of SLC26A4. Publicly available murine single-cell or single-nucleus RNA-sequencing (RNA-seq) datasets from the endolymphatic sac, cochlear lateral wall, utricle, kidney, airway, epididymis, and salivary glands were collected. After quality control, principal component analysis and clustering, distinct cell populations were identified, and differentially expressed genes (DEGs) were analyzed. The datasets were integrated for comparison across multiple tissues and organs. The results revealed no shared genetic profile among inner ear Slc26a4-expressing cells, with Slc26a4 being the only shared DEG, suggesting that regulatory genes may include low expression transcripts, splicing variants, or long non-coding RNAs undetectable by single-cell analysis. Comparative analysis within the ionocyte family identified distinct DEGs such as Insrr and Hmx2 in Slc26a4-expressing cells from the endolymphatic sac and kidneys, potentially significant in ion homeostasis and SLC26A4 regulation. This study highlights the specificity and complexity of SLC26A4 expression and highlights the challenges and limitations of single-cell analysis. Future research should address regulatory elements such as low-expression genes, splicing variants, and non-coding RNAs to enhance our understanding of SLC26A4 regulation across various cellular contexts. [ABSTRACT FROM AUTHOR] more...

After centuries of decline and protracted bottlenecks, the peninsular Italian wolf population has naturally recovered. However, an exhaustive comprehension of the effects of such a conservation success is still limited by the reduced availability of historical data. Therefore, in this study, we morphologically and genetically analyzed historical and contemporary wolf samples, also exploiting the optimization of an innovative bone DNA extraction method, to describe the morphological variability of the subspecies and its genetic diversity during the last 30 years. We obtained high amplification and genotyping success rates for tissue, blood and also petrous bone DNA samples. Multivariate, clustering and variability analyses confirmed that the Apennine wolf population is genetically and morphologically well-distinguishable from both European wolves and dogs, with no natural immigration from other populations, while its genetic variability has remained low across the last three decades, without significant changes between historical and contemporary specimens. This study highlights the scientific value of well-maintained museum collections, demonstrates that petrous bones represent reliable DNA sources, and emphasizes the need to genetically long-term monitor the dynamics of peculiar wolf populations to ensure appropriate conservation management actions. [ABSTRACT FROM AUTHOR] more...

Sialidosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the NEU1 gene, resulting in deficient neuraminidase-1 activity and the subsequent accumulation of sialylated compounds in lysosomes. This review comprehensively analyzes the genetic and clinical heterogeneity associated with sialidosis, emphasizing the distinction between the milder type I form and the more severe type II form. Over 90 pathogenic NEU1 variants, predominantly missense mutations, have been identified, highlighting significant phenotypic diversity. Advancements in genomic sequencing technologies have facilitated the identification of known and novel mutations, with population-specific insights elucidating ethnic variability in symptomatology and genetic profiles. Recent case studies, including a novel compound heterozygous variant, further illustrate the complexity of the genotype–phenotype correlations. Emerging therapeutic approaches, such as enzyme replacement therapy and adeno-associated virus-mediated gene therapy, demonstrate promising potential for restoring neuraminidase-1 function and improving outcomes in preclinical models. This review emphasizes the critical role of genetic analysis in diagnosis and management while advocating for continued research into the molecular mechanisms underlying sialidosis to enable the development of targeted, personalized treatments. [ABSTRACT FROM AUTHOR] more...

Background: Dilated cardiomyopathy (DCM) can be an inherited condition related to premature sudden cardiac death (SCD). Pathogenic variants in some genes, like LMNA, SCN5A, FLNC or RBM20, have been linked to an increased risk of SCD. Although genetic study can help to stratify the arrhythmic risk, there are no specific guidelines for RBM20 carriers' management. We aimed to evaluate the genetic profile and clinical features of all DCM patients with pathogenic variants in RBM20.Methods: We identified all carriers of pathogenic variants in RBM20 in a single national center that specializes in inherited cardiac conditions. Forensic and molecular autopsies provided crucial information. Results: We identified a large family with inherited DCM due to RBM20 p.Arg636Cy and several SCDs. The proband was a 37-year-old male who suffered an unexpected SCD despite presenting a mild DCM phenotype with normal left ventricular ejection fraction. Family screening identified four other carriers, who were asymptomatic, but presented concealed mild DCM phenotypes. Family history revealed that six other relatives (two of them obligate carriers) had also suffered sudden deaths at young ages. Conclusions: We present an informative family with DCM, due to RBM20 p.Arg636Cys, and high rates of SCD, even in members with mild DCM phenotypes. ICD implantation to prevent SCD should be carefully evaluated in all RBM20 p.Arg636Cys carriers. Moreover, the frequent development of AF and HF progression requires specific awareness. [ABSTRACT FROM AUTHOR] more...

Simple Summary: This study reviews targeted therapies in veterinary medicine, focusing on how specific treatments can improve animal care by addressing the underlying causes of disease. The research highlights the role of genetics, environment, and other factors that influence the effectiveness of treatments in different species, with the main aim of exploring how individual differences—such as genetic and environmental factors—affect an animal's response to therapies. By understanding these variations, veterinarians can formulate individualised treatment plans to ensure optimal outcomes. The study highlights the importance of comparing the responses of different species to therapies, helping to identify potential risks and benefits. This knowledge will help to refine treatment strategies and ensure the safety and efficacy of therapies for different animal populations. The results highlight the need for further research to improve our understanding of the interplay between biology and environment in determining therapeutic success. The knowledge gained from this research could contribute to the advancement of veterinary medicine, the promotion of animal health, and the development of new opportunities for the creation of more targeted therapies that benefit both animals and humans, thus improving overall healthcare. This literature review explores the impact of molecular, genetic, and environmental factors on the efficacy of targeted therapies in veterinary medicine. Relevant studies were identified through systematic searches of PubMed, Web of Science, Scopus, and ScienceDirect using keywords such as "species-specific treatment strategies", "signalling pathways", "epigenetic and paragenetic influences", "targeted therapies", "veterinary medicine", "genetic variation", and "free radicals and oxidative stress". Inclusion criteria included studies focusing on species-specific therapeutic responses, genetic influences, and oxidative stress. To ensure that only the most recent and relevant evidence was included, only peer-reviewed publications from the last two decades were considered. Each study selected for analysis was critically appraised, with a particular emphasis on methodological quality, experimental design, and scientific contribution to the understanding of how environmental and biological factors influence therapeutic outcomes. A special emphasis was placed on studies that used a comparative, cross-species approach to assess variability in therapeutic responses and potential adverse effects. The review synthesises evidence on the role of epigenetic and paragenetic factors and highlights the importance of cross-species studies to understand how environmental and biological factors influence treatment outcomes. By highlighting genetic variation, oxidative stress, and individual species differences, the review argues for personalised and species-specific therapeutic approaches. The review emphasises that such an approach would improve veterinary care and inform future research aimed at optimising targeted therapies, ultimately leading to better animal health and treatment efficacy. A key contribution of the review is its emphasis on the need for more personalised treatment protocols that take into account individual genetic profiles and environmental factors; it also calls for a greater integration of cross-species studies. [ABSTRACT FROM AUTHOR] more...

Simple Summary: The objective was to understand the improvement in clinical parameters in piglets where different modified live vaccines (MLVs) against porcine reproductive and respiratory syndrome (PRRS) were administered. We conducted the study in the field with a large group of piglets and three different MLVs, assessing both safety and efficacy parameters. We found that different MLVs can be used at different stages of production if needed without adverse impacts on production and that there are differences in safety and efficacy between MLVs. This study was conducted to evaluate the protective efficacy of modified live vaccines (MLVs) against porcine reproductive and respiratory syndrome (PRRS) in nursery pigs in a worst case scenario where MLV does not match the genetic profile of the field isolate, different MLVs are used for sows and piglets, and piglets are naturally exposed to genetically distinct heterologous PRRS virus (PRRSV) isolates. We divided 76,075, 2-week-old piglets from a seropositive sow herd vaccinated with US1-MLV into four groups. US1-MLV, US2-MLV, and US3-MLV groups were vaccinated with PRRSV-2 MLV including Ingelvac® PRRS MLV (Boehringer Ingelheim, Ingelheim am Rhein, Germany), HP-PRRSV-2 based MLV (Harbin Veterinary Research Institute, CAAS, Harbin, China), and Prime Pac® PRRS (MSD Animal Health, Rahway, NJ, USA), respectively. The NonVac group was left unvaccinated. At 0, 14, 28, and 56 days post-vaccination (DPV), sera were assayed for the presence of PRRSV-specific antibodies using ELISA and serum neutralization (SN), and PRRSV RNA using PCR. Average daily gain (ADG) and survival rates were compared between treatment groups. The results demonstrated vaccinated groups significantly improved in ADG compared to the non-vaccinated control group. Only US1-MLV and US3-MLV were able to significantly reduce mortality associated with field PRRSV infection in nursery pigs. Pigs vaccinated with US3-MLV displayed significantly lower mortality and higher ADG compared to all other groups. Field isolates were isolated and genetically compared to all three MLV vaccines at the start of the trial. The MLV with closest genetic similarity to the field isolate was US2-MLV by ORF5 gene comparison. This provided the lowest protection judging by ADG improvement and mortality reduction, as compared to US1-MLV and US3-MLV. Separately, strains of Thai PRRSV-2 isolates collected in 2017, 2019, and 2020 in the study area were investigated for evolutionary changes. Over time, we observed a shift in PRRSV-2 isolates from lineage 8.7 to lineage 1. The field isolates found shared 82.59–84.42%, 83.75–85.74%, and 84.25–85.90% nucleotide identity with the US1-MLV, US3-MLV and US2-MLV based vaccine, respectively. Our findings suggest genetic similarity between field viruses and vaccine strains should not be used as a predictor of field performance. We found that zootechnical performance of piglets was best in US3-MLV, despite sows being treated with a different vaccine The results also support that different MLVs can be used at different stages of production. Finally, we concluded that the shift from lineage 8.7 to lineage 1 was due to shifts in the worldwide prevalence of PRRSV isolates during that period of time and not due to vaccine recombination between isolates. Overall, MLV vaccine selection should be based on production performance and safety profile. [ABSTRACT FROM AUTHOR] more...

Simple Summary: This study investigates Brucella ceti infections in marine mammals stranded along the Lisbon and Tagus Valley coast from 2022 to mid-2024, reporting the first evidence of this zoonotic agent in Portuguese waters. Among 59 animals, B. ceti was isolated in 5.1% of dolphins, with a higher PCR-based detection rate (23.7%), suggesting an underestimation of infection prevalence. Genetic analysis revealed links to Atlantic strains, supporting host-adapted lineages in dolphins. Key findings include virulence genes (bspE, btpB, virB7, vceA) and antimicrobial resistance genes (mprF, bepC-G), highlighting pathogenic potential. The findings emphasize the need for further research and surveillance to understand and manage infection risks. This study investigates Brucella ceti infection in marine mammals stranded along the Lisbon and Tagus Valley coast between 2022 and mid-2024, marking the first report of Brucella presence in Portuguese waters. Out of 59 examined marine mammals, B. ceti was isolated in three common dolphins (5.1%), a prevalence rate consistent with previous studies from other coastlines. PCR-based detection indicated a higher infection rate (23.7%), suggesting an underestimation of the prevalence of B. ceti infection in this population. Multi-locus Sequence Typing (MLST) and Multiple-Locus Variable-Number Tandem-Repeat Analysis (MLVA) revealed distinct genetic profiles and close relationships to B. ceti strains from the Atlantic, supporting the hypothesis of specific host-adapted lineages in dolphins. Virulence genes, including those for host interaction (bspE, btpB) and intracellular survival (virB7, vceA), were consistent across isolates, highlighting the pathogenic potential. Additionally, antimicrobial resistance (AMR) genes, such as mprF and efflux proteins (bepC-G), were also identified. These findings underscore the need for further research and surveillance to understand B. ceti transmission, host range, and impacts on Atlantic cetaceans, as well as to develop effective diagnostic and management strategies to mitigate infection risks in marine environments. [ABSTRACT FROM AUTHOR] more...

Abnormalities in structural-functional connectivity (SC-FC) coupling have been identified globally in patients with major depressive disorder (MDD). However, investigations have neglected the variability and hierarchical distribution of these abnormalities across different brain regions. Furthermore, the biological mechanisms that underlie regional SC-FC coupling patterns are not well understood. We enrolled 182 patients with MDD and 157 healthy control participants and quantified the intergroup differences in regional SC-FC coupling. Extreme gradient boosting (XGBoost), support vector machine, and random forest models were constructed to assess the potential of SC-FC coupling as biomarkers for MDD diagnosis and symptom prediction. Then, we examined the link between changes in regional SC-FC coupling in patients with MDD, neurotransmitter distributions, and gene expression. We observed increased regional SC-FC coupling in the default mode network (t 337 = 3.233) and decreased coupling in the frontoparietal network (t 337 = −3.471) in patients with MDD compared with healthy control participants. XGBoost (area under the receiver operating characteristic curve = 0.853), support vector machine (area under the receiver operating characteristic curve = 0.832), and random forest (p <.05) models exhibited good prediction performance. The alterations in regional SC-FC coupling in patients with MDD were correlated with the distributions of 4 neurotransmitters (p <.05) and expression maps of specific genes. These enriched genes were implicated in excitatory neurons, inhibitory neurons, cellular metabolism, synapse function, and immune signaling. These findings were replicated on 2 brain atlases. This work enhances our understanding of MDD and paves the way for the development of additional targeted therapeutic interventions. [ABSTRACT FROM AUTHOR] more...

The article "Elucidating Gene Dependencies and Mutations of Chordoma" published in the Journal of Neurological Surgery. Part B. Skull Base discusses the importance of understanding gene dependencies and mutations in chordoma, a rare bone cancer. The study identifies critical genes like TBXT, EXTL1, and COL9A2, as well as dependencies on IL17RA, HLA-DQB2, FZD3, and GABBR2, shedding light on the complex biology of chordoma development. By analyzing these genetic factors, surgeons can personalize treatment approaches, leading to more effective surgical interventions and improved outcomes for chordoma patients. [Extracted from the article] more...

Indian yaks (Bos grunniens) have experienced a significant decline in their population in recent years, primarily due to reduced economic returns from bovid products and the lack of mainstream markets for yak milk and meat. This decline has led to a decreased interest among younger generations in continuing the tradition of nomadic yak herding. To establish effective conservation strategies and improvement plans, it is imperative to conduct in-depth studies on these animals, uncovering their genetic intricacies and identifying key genomic variants associated with adaptive traits. The present study focuses on whole-genome sequencing data from diverse Indian yak populations to elucidate the genomic adaptations associated with high-altitude hypoxia tolerance, physiological resilience, coat color variations, and skeletal modifications. Despite the critical role of yaks in these regions, the comprehensive genetic structure and evolutionary dynamics of these animals remain largely unexplored. Through comparative analyses using interpopulation statistical methodologies, including Fixation Index (FST) and Nucleotide Diversity Ratio (θπ), we examined the genetic makeup of Arunachali, Himachali, and Ladakhi yak populations alongside the Chinese Jinchuan yak. This analysis identified genomic loci subjected to selective pressures, revealing a suite of candidate genes indicative of adaptation to distinct environmental niches. Our integration of FST and θπ analyses highlighted substantial genetic signatures of selection, particularly in the Ladakhi yak, which exhibits enhanced adaptation to high-altitude environments. Notably, Ladakhi yaks demonstrated enriched pathways associated with altitude adaptation, underscoring their superior resilience compared to other Indian yak breeds. Comparative analyses between Indian and Chinese yaks unveiled distinctive genetic profiles, with Chinese yaks showing enrichment in pathways associated with tameness and domestication. These findings provide valuable insights into the molecular underpinnings of high-altitude adaptation and the diverse selective forces shaping the genomes of yak populations. Our study will contribute crucial knowledge on the genetic relationships between Indian yak populations, which is essential for the conservation of this native germplasm. [ABSTRACT FROM AUTHOR] more...

Background/Objectives: Vedolizumab (VDZ) is the new monoclonal drug targeting α4β7 integrin for patients with moderate/severe IBD. Between 30 and 45% of patients fail to respond to VDZ after 14–16 weeks of treatment. The aim of the study was to explore the genetic profile of vedolizumab-treated Arab IBD patients in Saudi Arabia to identify the potential biomarkers to differentiate the responders from non-responders. Methods: A cohort of 16 patients with IBD, including 4 with Crohn's disease and 12 with ulcerative colitis, were recruited. Following 16 weeks of VDZ treatment, nine were found to be responders and seven non-responders. Blood samples were collected for the whole exome sequencing of DNA from all patients. The variants in the whole-exome sequencing data were analyzed with a variety of bioinformatics tools and databases, such as Polyphen2, Mutation Taster, CADD, FATHMM, Open Target Platform, TOPPFun, STRING, and GTEx. Results: More than 1.6 million variants from 16 samples were analyzed. The rare variant analysis prioritized NOD2, IL23, IL10, IL27, and TRAF1 genes in non-responders. NOD2, IL23, IL10, IL27, and TRAF1 were found to be the significant IBD risk factors in multiple genome-wide association studies, and their pro-inflammatory activity might contribute to the inherent resistance to VDZ. Rare variants of CARD9, TYK2, IL4, and NLRP1 genes present in VDZ responders enhance the anti-inflammatory/immune modulation effects. Conclusions: This investigation is the first to apply whole-exome sequencing to identify the potential drug response biomarkers for the IBD drug VDZ in Saudi Arabia. [ABSTRACT FROM AUTHOR] more...

Background: Escherichia coli (E. coli) O157:H7, associated with diarrhea, poses a global health risk. In Ethiopia, where diarrhea is common, there is limited knowledge about these resistant strains and a lack of data on Extended-Spectrum β-Lactamase (ESBL) and carbapenemase production. Understanding the prevalence of antimicrobial resistance genes associated with ESBL and carbapenems is crucial for addressing diarrheal disease. This study aimed to investigate the genetic profile of ESBL and carbapenemase coding gene carriage in E. coli O157:H7 from clinical stool samples and evaluate antimicrobial susceptibility patterns. Methods: A total of twenty-nine bacterial isolates obtained from diarrheal patients were subjected to conventional culture and phenotypic (Kirby Bauer disc diffusion method) testing for antimicrobial resistance. Additionally, screening for the production of ESBL (combined disk method) and carbapenemase (modified carbapenem inactivation method) was conducted. Isolates that tested positive for ESBL and carbapenemase production were further analyzed, targeting five genes (blaNDM, blaKPC, blaCTX−M, blaTEM, and blaSHV) associated with ESBL and carbapenemase production. Data analysis was performed using SPSS version 27.0, employing logistic regression and descriptive statistics. Results: We analyzed a total of 27 isolates that were ESBL-positive and 12 isolates that were found to produce carbapenemase phenotypically. These isolates were obtained from clinical stool samples and (9/27) 33.3% of the isolates were from under five years children, predominantly from urban areas, and those that have contact with domestic animals. Genes coding ESBL were found in (19/27) 70.4% of the isolates, the most predominant being blaCTX−M and blaTEM. Eight isolates carried blaKPC, but none had blaNDM, while five isolates carried both blaCTX−M and blaTEM genes. blaSHV-carrying isolates showed phenotypic resistance to ampicillin and cephalosporins, while blaKPC-carrying isolates exhibited resistance to ampicillin, carbapenems, and tetracycline. Conclusion: This study identifies a significant prevalence of multidrug resistance in E. coli O157:H7, which can be attributed to the presence of resistance genes coding for ESBL and carbapenem production. Key factors contributing to this resistance, such as urban environments, children under the age of five, and domestic animal ownership, have been emphasized. Additionally, this research underscores the urgent need for enhanced surveillance and targeted interventions to address this pressing public health concern. [ABSTRACT FROM AUTHOR] more...

Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine is effective for unresectable locally advanced PDAC. This study aimed to identify patient characteristics predictive of CIRT response. We utilized a panel of human PDAC cell lines with diverse genetic profiles to determine their sensitivity to CIRT compared to γ-rays, assessing relative biological effectiveness (RBE) at 10% survival, which ranged from 1.96 to 3.04. Increased radiosensitivity was linked to impaired DNA double-strand break (DSB) repair, particularly in cell lines with deficiencies in the homologous recombination (HR) repair pathway and/or elevated genomic instability from replication stress. Furthermore, pretreatment with the HR inhibitor B02 significantly enhanced CIRT sensitivity in a radioresistant PDAC cell line when irradiated in the spread-out Bragg peak but not at the entry position of the beam. These findings suggest that PDAC tumors with HR pathway mutations or high replication stress are more likely to benefit from CIRT while minimizing normal tissue toxicity. [ABSTRACT FROM AUTHOR] more...

Obesity is a global epidemic associated with chronic inflammation, oxidative stress, and metabolic disorders. Bariatric surgery is a highly effective intervention for sustained weight loss and the improvement of obesity-related comorbidities. However, post-surgery nutritional deficiencies, including vitamin E, remain a concern. This study investigates the role of single-nucleotide polymorphisms (SNPs) in genes related to vitamin E transport and bioavailability in determining vitamin E levels post bariatric surgery. A cohort of 140 patients with obesity undergoing bariatric surgery was analyzed. Serum vitamin E levels were measured before and one year after surgery, and SNPs in genes associated with vitamin E transport and metabolism were genotyped using PCR, DHPLC, and sequencing methods. Associations between SNPs, haplotypes, and vitamin E levels were statistically evaluated. Significant associations were observed between the APOE rs7412 SNP and serum vitamin E levels. The rare T allele was linked to lower vitamin E levels post surgery, with an increased frequency in patients with severe deficiency (<11.6 μmol/L). Haplotype analysis of APOE revealed that the ε2 haplotype (T-T) was strongly associated with vitamin E deficiency. Other SNPs, including CD36 rs1761667, SCARB1 rs4238001, and ABCA1 rs4149314, were also linked to changes in vitamin E levels, suggesting that an impaired bioavailability and transport can be the reason for low vitamin E levels post surgery. Genetic polymorphisms in APOE, CD36, SCARB1, and ABCA1 significantly influence vitamin E status after bariatric surgery. These findings highlight the importance of personalized supplementation strategies considering patients' genetic profiles to mitigate the risk of vitamin E deficiency and related complications. [ABSTRACT FROM AUTHOR] more...

Glioblastoma is the deadliest primary brain tumor, largely due to inevitable recurrence of the disease after treatment. While most recurrences are local, patients rarely present with a new discontiguous focus of glioblastoma. Little is currently known about the genetic profile of discontiguous recurrences. In our institutional database, we identified 22 patients with targeted exome sequencing of pairs of initial and recurrent IDH-wildtype glioblastoma. Recurrences were classified as contiguous or discontiguous based on the presence or absence of T2 FLAIR signal connection to the initial site of disease on MRI. Exome analysis revealed shared driver and passenger mutations between discontiguous recurrences and initial tumors, supporting a common origin. Discontiguous recurrences were more likely to be hypermutated compared to contiguous recurrences (p = 0.038). Analysis of 2 glioblastoma cases with discontiguous recurrence at a collaborating institution also exhibited hypermutation. In conclusion, discontiguous glioblastoma recurrences share a common origin with the initial tumor and are more likely to be hypermutated than contiguous recurrences. [ABSTRACT FROM AUTHOR] more...

Simple Summary: Endometrial cancer is becoming more common, and current treatments do not work well for everyone. The study aims to understand how genetic changes drive this type of cancer and how these insights can improve treatment. It explores key genetic mutations and how they influence the development of cancer, with the goal of helping to classify the disease more precisely and design targeted therapies that are tailored to individual patients. By connecting genetics to clinical care, this research could lead to earlier diagnoses, better treatment options, and improved survival rates. It also sets the stage for future studies, giving the scientific community a clearer roadmap to enhance cancer care. Endometrial cancer (EC), a prevalent gynecological malignancy, presents significant challenges due to its genetic complexity and heterogeneity. The genomic landscape of EC is underpinned by genetic alterations, such as mutations in PTEN, PIK3CA, and ARID1A, and chromosomal abnormalities. The identification of molecular subtypes—POLE ultramutated, microsatellite instability (MSI), copy number low, and copy number high—illustrates the diverse genetic profiles within EC and underscores the need for subtype-specific therapeutic strategies. The integration of multi-omics technologies such as single-cell genomics and spatial transcriptomics has revolutionized our understanding and approach to studying EC and offers a holistic perspective that enhances the ability to identify novel biomarkers and therapeutic targets. The translation of these multi-omics findings into personalized medicine and precision oncology is increasingly feasible in clinical practice. Targeted therapies such as PI3K/AKT/mTOR inhibitors have demonstrated the potential for improved treatment efficacy tailored to specific genetic alterations. Despite these advancements, challenges persist in terms of variability in patient responses, the integration of genomic data into clinical workflows, and ethical considerations. This review explores the genomic underpinnings of EC, from genes to clinical practice. It highlights the ongoing need for multidisciplinary research and collaboration to address the complexities of EC and improve diagnosis, treatment, and patient outcomes. [ABSTRACT FROM AUTHOR] more...

Simple Summary: Myeloproliferative neoplasms (MPNs) represent a subset of blood cancers, a member of which is chronic neutrophilic leukemia (CNL). This entity is very rare in comparison to the more common MPNs. The increased usage of next-generation sequencing (NGS) has increased our diagnostic and prognostic ability regarding this entity. There is no specified treatment approach for CNL; however, there are clinical trials that show promising results and experimental drugs that are being investigated to reach a unified treatment approach. This review aims to comprehensively review this rare entity in terms of epidemiology, diagnosis, pathogenesis, and treatment. CNL is a rare subtype of MPNs characterized by persistent neutrophilia, bone marrow hypercellularity, and specific genetic mutations, particularly in the CSF3R gene. Advances in molecular diagnostics have greatly enhanced our understanding of CNL, distinguishing it from other myeloproliferative disorders and refining diagnostic criteria. This review provides an updated overview of CNL, focusing on breakthroughs in genetic profiling, including novel mutations with potential prognostic value and implications for targeted therapy. We discuss current management strategies, emphasizing the role of JAK inhibitors, allogeneic stem cell transplantation, and evolving investigational treatments. Challenges in early diagnosis, therapeutic resistance, and future directions in research are also addressed, underscoring the need for a personalized medicine approach to improve outcomes for patients with CNL. [ABSTRACT FROM AUTHOR] more...

Background: Syndromic genetic disorders affecting vision can also cause hearing loss, and Usher syndrome is by far the most common etiology. However, many other conditions can present dual sensory impairment. Accurate diagnosis is essential for providing patients with genetic counseling, prognostic information, and appropriate resources. This study aimed to describe the genetic profile of combined inherited deaf-blindness in Portugal. Methods: This was a cross-sectional study conducted at a tertiary hospital in Portugal. Patients were identified through the national, web-based inherited retinal dystrophies registry (IRD-PT, retina.com.pt). Demographics, clinical, and genetic data were retrieved from individual patient records. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for solved cases. Results: Eighty-four patients (58.3% males; mean age 40.0 ± 17.9 years) from 71 families were included. Usher syndrome was the most frequent etiology (71.4%) followed by Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract syndrome (6.0%), Autosomal dominant optic atrophy plus (4.8%) and cone-rod dystrophy and hearing loss (4.8%). Other less frequent etiologies included Alport syndrome (2.4%), Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (2.4%), Heimler syndrome (2.4%), Senior-Loken syndrome (1.2%), Waardenburg syndrome (1.2%), Maternally inherited diabetes and deafness (1.2%), and Stickler syndrome (1.2%). The overall diagnostic yield of deleterious variants in our deaf–blind cohort was 73.2%. A total of 55 genetic variants were identified across 16 different genes; 11 of these variants are novel and herein reported for the first time. Conclusions: This is the first study to describe the genetic profile of patients with dual sensory impairment in Portugal, highlighting the genetic heterogeneity associated with inherited deaf-blindness. Usher syndrome was the most prevalent cause in this cohort. Nevertheless, several other less frequent causes must also be considered. This study showed a high diagnostic yield and reported 11 novel genetic variants, thereby contributing to expand the mutational spectrum of these conditions. [ABSTRACT FROM AUTHOR] more...

Background: Drug response prediction can infer the relationship between an individual's genetic profile and a drug, which can be used to determine the choice of treatment for an individual patient. Prediction of drug response is recently being performed using machine learning technology. However, high-throughput sequencing data produces thousands of features per patient. In addition, it is difficult for researchers to know which algorithm is appropriate for prediction as various regression and feature selection algorithms exist. Methods: We compared and evaluated the performance of 13 representative regression algorithms using Genomics of Drug Sensitivity in Cancer (GDSC) dataset. Three analyses was conducted to show the effect of feature selection methods, multiomics information, and drug categories on drug response prediction. Results: In the experiments, Support Vector Regression algorithm and gene features selected with LINC L1000 dataset showed the best performance in terms of accuracy and execution time. However, integration of mutation and copy number variation information did not contribute to the prediction. Among the drug groups, responses of drugs related with hormone-related pathway were predicted with relatively high accuracy. Conclusion: This study can help bioinformatics researchers design data processing steps and select algorithms for drug response prediction, and develop a new drug response prediction model based on the GDSC or other high-throughput sequencing datasets. [ABSTRACT FROM AUTHOR] more...

Background: Sepsis and shock are common complications of necrotising soft tissue infections (NSTI). Sepsis encompasses different endotypes that are associated with specific immune responses. Hyperbaric oxygen (HBO2) treatment activates the cells oxygen sensing mechanisms that are interlinked with inflammatory pathways. We aimed to identify gene expression patterns associated with effects of HBO2 treatment in patients with sepsis caused by NSTI, and to explore sepsis-NSTI profiles that are more receptive to HBO2 treatment. Methods: An observational cohort study examining 83 NSTI patients treated with HBO2 in the acute phase of NSTI, fourteen of whom had received two sessions of HBO2 (HBOx2 group), and another ten patients (non-HBO group) who had not been exposed to HBO2. Whole blood RNA sequencing and clinical data were collected at baseline and after the intervention, and at equivalent time points in the non-HBO group. Gene expression profiles were analysed using machine learning techniques to identify sepsis endotypes, treatment response endotypes and clinically relevant transcriptomic signatures of response to treatment. Results: We identified differences in gene expression profiles at follow-up between HBO2-treated patients and patients not treated with HBO2. Moreover, we identified two patient endotypes before and after treatment that represented an immuno-suppressive and an immune-adaptive endotype respectively, and we characterized the genetic profile of the patients that transition from the immuno-suppressive to the immune-adaptive endotype after treatment. We discovered one gene MTCO2P12 that distinguished individuals who altered their endotype in response to treatment from non-responders. Conclusion: The global gene expression pattern in blood changed in response to HBO2 treatment in a direction associated with clinical biochemistry improvement, and the study provides potential novel biomarkers and pathways for monitoring HBO2 treatment effects and predicting an HBO2 responsive NSTI-sepsis profile. Trial registration: Biological material was collected during the INFECT study, registered at ClinicalTrials.gov (NCT01790698) 04/02/2013. [ABSTRACT FROM AUTHOR] more...

Introduction Ovarian cancer is a leading cause of cancer mortality globally due to late-stage diagnosis and limited treatment options. PARP inhibitors have shown promise as effective treatments for recurrent and various stages of ovarian cancer. Aim of the Study This study reviews the efficacy and application of PARP inhibitors in ovarian cancer treatment over the past 15 years, focusing on literature from the PubMed database post-2009 and considering FDA and EMA guidelines. Review methods A literature review was conducted using the PubMed database, focusing on studies published after 2009. The review also incorporated recommendations from the FDA and the European Medicines Agency regarding the use of PARP inhibitors in ovarian cancer treatment. Results The findings highlight the substantial impact of PARP inhibitors on ovarian cancer treatment, improving PFS and overall outcomes. Olaparib, niraparib, and rucaparib have become integral to ovarian cancer management, offering effective options for patients with BRCA mutations or homologous recombination deficiencies. These inhibitors have been validated in multiple clinical trials, underscoring their robustness and effectiveness. Combination therapies, such as olaparib with bevacizumab, further enhance therapeutic outcomes, showcasing the potential for synergistic effects. Summary PARP inhibitors represent a significant advancement in ovarian cancer treatment, offering improved survival outcomes for patients with specific genetic profiles. Their integration into standard care protocols underscores their importance and efficacy, providing valuable therapeutic options in the fight against ovarian cancer. [ABSTRACT FROM AUTHOR] more...

Background: Patient-derived lung cancer organoids (PD-LCOs) demonstrate exceptional potential in preclinical testing and serve as a promising model for the multimodal management of lung cancer. However, certain lung cancer cells derived from patients exhibit limited capacity to generate organoids due to inter-tumor or intra-tumor variability. To overcome this limitation, we have created an in vitro system that employs mesenchymal stromal cells (MSCs) or fibroblasts to serve as a supportive scaffold for lung cancer cells that do not form organoids. Methods: We successfully established an MSCs/fibroblast co-culture system to form LCOs. We analyzed the morphological and histological similarities between LCOs co-cultured with fibroblast and primary lung cancer lesions through HE and IF staining. We evaluated whether LCOs co-cultured with fibroblast retained the original genetic mutations of their source tumors based on WES. RNA sequencing was used to analyze the differences in gene expression profiles between LCOs co-cultured with fibroblast and paracancerous organoids (POs). Importantly, we have successfully validated the impact of Kindlin-2 on the regulation of MSCs in organoid formation through lentiviral vector-mediated interference or overexpression of kindlin-2. Results: Our findings demonstrate that the addition of MSCs/fibroblasts to three tumor samples, initially incapable of forming organoids by traditional methods, successfully facilitated the cultivation of tumor organoids. Importantly, these organoids co-cultured with fibroblast faithfully recapitulate the tissue morphology of original lung tumors and replicate the genetic profile observed in the parental tumors even after prolonged in vitro culture. Moreover, drug responses exhibited by these organoids co-cultured with MSCs/fibroblasts are consistent with those observed in the original tumors. Mechanistically, we have also identified kindlin-2 as a crucial regulator linking extracellular matrix (ECM) and mitochondria that influence MSC/fibroblast-mediated support for tumor organoid formation. Conclusion: The results obtained from our research enhance the understanding of the mechanisms implicated in the formation of tumor organoids and aid in creating stronger patient-specific tumor organoid models. This advancement supports the refinement of personalized drug response assessments for use in clinical settings. [ABSTRACT FROM AUTHOR] more...

Background: Sarcoglycanopathies (SGPs) are limb-girdle muscular dystrophies (LGMDs) that can be classified into four types, LGMDR3, LGMDR4, LGMDR5, and LGMDR6, caused by mutations in the genes, SGCA, SGCB, SGCG, and SGCD, respectively. SGPs are relatively rare in Japan. This study aims to profile the genetic variants that cause SGPs in Japanese patients. Methods: Clinical course and pathological findings were retrospectively reviewed in Japanese patients with SGP. Genetic analyses were performed using a combination of targeted resequencing with a hereditary muscle disease panel, whole genome sequencing, multiplex ligation-dependent probe amplification, and long-read sequencing. The structures of transcripts with aberrant splicing were also determined by RT-PCR, RNA-seq, and in silico prediction. Results: We identified biallelic variants in SGC genes in 53 families, including three families with LGMDR6, which had not been identified in Japan so far. SGCA was the most common causative gene, accounting for 56% of cases, followed by SGCG, SGCB, and SGCD, at 17%, 21%, and 6%, respectively. Missense variants in SGCA were very frequent at 78.3%, while they were relatively rare in SGCB, SGCG, and SGCD at 11.1%, 18.2%, and 16.6%, respectively. We also analyzed the haplotypes of alleles carrying three variants found in multiple cases: c.229C > T in SGCA, c.325C > T in SGCB, and exon 6 deletion in SGCG; two distinct haplotypes were found for c.229C > T in SGCA, while each of the latter two variants was on single haplotypes. Conclusions: We present genetic profiles of Japanese patients with SGPs. Haplotype analysis indicated common ancestors of frequent variants. Our findings will support genetic diagnosis and gene therapy. [ABSTRACT FROM AUTHOR] more...

Artificial intelligence (AI) has significantly impacted various fields, including oncology. This comprehensive review examines the current applications and future prospects of AI in lung cancer research and treatment. We critically analyze the latest AI technologies and their applications across multiple domains, including genomics, transcriptomics, proteomics, metabolomics, immunomics, microbiomics, radiomics, and pathomics in lung cancer research. The review elucidates AI's transformative role in enhancing early detection, personalizing treatment strategies, and accelerating therapeutic innovations. We explore AI's impact on precision medicine in lung cancer, encompassing early diagnosis, treatment planning, monitoring, and drug discovery. The potential of AI in analyzing complex datasets, including genetic profiles, imaging data, and clinical records, is discussed, highlighting its capacity to provide more accurate diagnoses and tailored treatment plans. Additionally, we examine AI's potential in predicting patient responses to immunotherapy and forecasting survival rates, particularly in non-small cell lung cancer (NSCLC). The review addresses technical challenges facing AI implementation in lung cancer care, including data quality and quantity issues, model interpretability, and ethical considerations, while discussing potential solutions and emphasizing the importance of rigorous validation. By providing a comprehensive analysis for researchers and clinicians, this review underscores AI's indispensable role in combating lung cancer and its potential to usher in a new era of medical breakthroughs, ultimately aiming to improve patient outcomes and quality of life. [ABSTRACT FROM AUTHOR] more...

The results from the analysis of 12 polymorphic microsatellite loci in Holstein cattle from a number of regions of Russia and other countries are presented. The mean number of alleles per locus was found to be 5.43 ± 0.19 with the range of 4–13 alleles and the mean number of effective alleles was 3.26 ± 0.11. A list of 29 most frequent alleles was compiled. Twenty-two private alleles were identified, and their frequencies were in the range of 0.004–0.033. It was demonstrated that the number of locally distributed alleles in Russian herds was higher than in the animals reared in other countries. The mean level of observed heterozygosity for all loci reached 0.681 ± 0.017 and varied in the range of 0.65–0.78 with the fixation index of –0.131 ± 0.005. The genetic distances between the herds reared in Russia were <0.074. The herds of cows were found to divide into two clusters. One cluster included the animals from three oblasts of Russia, along with the bulls from Germany and the Netherlands, and the other cluster included the animals from two regions that were close to the bulls from Canada, USA, and the United Kingdom. At the same time, the bulls from Denmark and Finland were found in a separate cluster. The objective of the present study was to assess the allele pool of Holstein cattle reared in Russia and determine genetic profile of the breed using STR markers. [ABSTRACT FROM AUTHOR] more...

The article discusses the evolving understanding of radioiodine-refractory thyroid cancer (RAI-R DTC) and the need to redefine it in light of novel redifferentiation therapies. It highlights the limitations of current definitions, the evidence supporting redefinition, and proposes a new framework for defining RAI-R DTC. The proposed new definition views radioiodine sensitivity as a continuum, incorporates genetic and molecular markers, allows for heterogeneity within patients, and considers the potential for response to redifferentiation therapies. Adopting a new definition could have significant implications for patient care, regulatory considerations, and educational programs, but it also presents challenges in implementation and validation. [Extracted from the article] more...

Atlantic sturgeon Acipenser oxyrinchus oxyrinchus is widely distributed along the Atlantic coast of North America, with spawning populations extending from the St. Lawrence River, Quebec to the St. Marys River, Georgia-Florida. At one time, Atlantic sturgeon supported lucrative fisheries on adults within rivers where they spawned and on subadults and adults within coastal waters. Because of decimated population sizes, Atlantic sturgeon in U.S. waters are now federally protected as five Distinct Population Segments (DPS) under the U.S. Endangered Species Act. While juvenile Atlantic sturgeon are resident within their natal rivers, subadults and adults are highly migratory in coastal waters and often occur in non-natal estuaries, exposing them to a variety of anthropogenic threats outside of their natal estuaries, including bycatch. To most effectively protect the smallest and most vulnerable populations, a method is needed to accurately identify the population origin of individual specimens and their aggregations outside of their natal systems. In this study, microsatellite DNA analysis was used to identify the genetic population structure of Atlantic sturgeon across 13 reference populations. Their genetic profiles then were used to identify the population origin of individuals collected from six coastal locales and one non-natal estuary. All 13 reference collections harbored genetically distinct, and in some cases more than one, population of Atlantic sturgeon. The Hudson River was by far the largest contributor to the overall coastal and non-natal estuarine collections, at 35.3%. The contributions of the other reference populations varied considerably between < 1.0% (York, Edisto, Savannah, and Satilla rivers) to 15.6% (Saint John River) and 12.9% (James River) and appeared unrelated to their estimated population sizes. These results suggest that migratory behavior in marine waters varies greatly among Atlantic sturgeon populations, and should assist resource managers assess the effects of anthropogenic stressors on sturgeon outside of their individual natal river or DPS. [ABSTRACT FROM AUTHOR] more...

The integration of drug molecular representations into predictive models for Drug Response Prediction (DRP) is a standard procedure in pharmaceutical research and development. However, the comparative effectiveness of combining these representations with genetic profiles for DRP remains unclear. This study conducts a comprehensive evaluation of the efficacy of various drug molecular representations employing cutting-edge machine learning models under various experimental settings. Our findings reveal that the inclusion of molecular representations from either PubChem fingerprints or SMILES can significantly enhance the performance of DRPs when used in conjunction with deep learning models. However, the optimal choice of drug molecular representation can vary depending on the predictive model and the specific DRP task. The insights derived from our study offer useful guidance on selecting the most suitable drug molecular representations for constructing efficient predictive models for DRPs, aiding for drug repurposing, personalized medicine, and new drug discovery. [ABSTRACT FROM AUTHOR] more...

• Some limited studies have indicated a correlation between driver gene mutations and organ-specific metastasis. Our research tried to expore the genomic characteristics and molecular mechanisms underlying adrenal metastases in lung adenocarcinoma. • EGFR mutations, especially rare variants (G724A, L747P, Q701 L, G719C, V769 L and S768I), exhibited significant less enrichment in the adrenal metastases (AM) group (P <0.001). • ALK mutations in the AM group correlated with shorter overall survival (P <0.001). KRAS mutations in the early synchronous adrenal metastases group were also associated with shorter OS (P <0.001). The aim of this study was to examine the genomic characteristics and explore the molecular mechanisms underlying adrenal metastases in lung adenocarcinoma. 57 patients diagnosed with lung adenocarcinoma (LUAD) and adrenal metastases (AM) were enrolled, alongside 33 controls diagnosed with non-adrenal metastases (non-AM) at the time of diagnosis. The primary lung cancer tissue sample were analyzed using next-generation sequencing. The molecular and clinical features were correlated with clinical outcomes. TP53, EGFR and KRAS were the most frequently mutated gene in both groups. EGFR mutations, especially rare variants (G724A, L747P, Q701 L, G719C, V769 L and S768I), exhibited significant enrichment in the non-AM group (P <0.001). An elevated age-related signature in the group of patients with AM, whereas the non-AM group exhibited a higher BRCA signature. Potential prognostic biomarkers such as KEAP1, LRP1B, NOTCH1 and RET mutations were detected in the non-AM group, while ALK mutations in the AM group correlated with shorter overall survival (P <0.001). KRAS mutations in the early synchronous adrenal metastases group were also associated with shorter OS (P <0.001). The analysis of 425 tumor genes in 29 patients with adrenal metastases showed significant enrichment in pathways associated with invasion and metastasis, including TNF signaling pathway and TGF-β signaling pathway. Patients without EGFR mutations in LUAD need to be more concerned about adrenal metastases. Meanwhile, patients with adrenal metastases harboring ALK or KRAS mutations have a poor prognosis and require more aggressive treatment. The TNF and TGF-β pathways might be associated with adrenal metastasis. [ABSTRACT FROM AUTHOR] more...

In forensic genetics, sometimes formalin-fixed paraffin-embedded (FFPE) biopsy material taken during life is the only biological sample available for individual identification or paternity testing. In most cases, this biological tissue is characterized by the presence of tumor cells characterized by instability and loss of heterozygosity of microsatellites (MSI/LOH) compared to the DNA present in cells of normal tissue.In this case report, two FFPE samples from the same male subject were available for genetic investigation: one sample with colorectal cancer tissue and the other with normal tissue (no cancerous histopathological features). The comparison of the genetic profiles obtained from DNA extracted from the two tissues showed in the tumor tissue the presence of three genomic instability phenomena affecting FGA, CSF1P0, D21S2055 loci, located on three distinct autosomal chromosomes, and one duplication phenomenon affecting the DYS438. Therefore, due to the MSI/LOH phenomena, the genetic profile acquired from the tumor tissue was distorted and thus generated a fictitious genetic profile, not corresponding to the subject's real one (normal tissue free of tumor cells). [ABSTRACT FROM AUTHOR] more...

We introduce a sizable (n = 34) whole-genome dataset on Armenians, a population inhabiting the region in West Asia known as the Armenian highlands. Equipped with this genetic data, we conducted a whole-genome study of Armenians and deciphered their fine-scale population structure and complex demographic history. We demonstrated that the Armenian populations from western, central, and eastern parts of the highlands are relatively homogeneous. The Sasun, a population in the south that had been argued to have received a major genetic contribution from Assyrians, was instead shown to have derived its slightly divergent genetic profile from a bottleneck that occurred in the recent past. We also investigated the debated question on the genetic origin of Armenians and failed to find any significant support for historical suggestions by Herodotus of their Balkan-related ancestry. We checked the degree of continuity of modern Armenians with ancient inhabitants of the eastern Armenian highlands and detected a genetic input into the region from a source linked to Neolithic Levantine Farmers at some point after the Early Bronze Age. Additionally, we cataloged an abundance of new mutations unique to the population, including a missense mutation predicted to cause familial Mediterranean fever, an autoinflammatory disorder highly prevalent in Armenians. Thus, we highlight the importance of further genetic and medical studies of this population. A whole-genome study of Armenians shows homogeneous genetic structure across the region, with a recent bottleneck explaining the distinctiveness of the Sasun population. Our findings reject the Balkan theory for the origin of Armenians, instead revealing genetic input from a Levantine source in the region after the Early Bronze Age. [ABSTRACT FROM AUTHOR] more...

Simple Summary: Due to the complex heterogeneity, inherent high invasiveness, and high recurrence rate of gliomas, the prognosis for patients is extremely unfavorable, especially in the case of glioblastoma. Extensive tumor resection can enhance patient prognosis; however, the diffuse infiltrative growth and malignant characteristics of glioma pose challenges in achieving complete tumor resection. Therefore, we present a review of advanced multi-parameter quantitative MRI applications at the biological level in terms of the cellular, blood perfusion, and cerebrovascular response to explore its feasibility in assessing the complex intra-tumoral heterogeneity and visualizing the extent of peri-tumoral invasion, while providing guidance for future research and clinical implementation. Magnetic resonance imaging (MRI) currently serves as the primary diagnostic method for glioma detection and monitoring. The integration of neurosurgery, radiation therapy, pathology, and radiology in a multi-disciplinary approach has significantly advanced its diagnosis and treatment. However, the prognosis remains unfavorable due to treatment resistance, inconsistent response rates, and high recurrence rates after surgery. These factors are closely associated with the complex molecular characteristics of the tumors, the internal heterogeneity, and the relevant external microenvironment. The complete removal of gliomas presents challenges due to their infiltrative growth pattern along the white matter fibers and perivascular space. Therefore, it is crucial to comprehensively understand the molecular features of gliomas and analyze the internal tumor heterogeneity in order to accurately characterize and quantify the tumor invasion range. The multi-parameter quantitative MRI technique provides an opportunity to investigate the microenvironment and aggressiveness of glioma tumors at the cellular, blood perfusion, and cerebrovascular response levels. Therefore, this review examines the current applications of advanced multi-parameter quantitative MRI in glioma research and explores the prospects for future development. [ABSTRACT FROM AUTHOR] more...

Despite extensive experience with influenza surveillance in humans in Senegal, there is limited knowledge about the actual situation and genetic diversity of avian influenza viruses (AIVs) circulating in the country, hindering control measures and pandemic risk assessment. Therefore, as part of the "One Health" approach to influenza surveillance, we conducted active AIV surveillance in two live bird markets (LBMs) in Dakar to better understand the dynamics and diversity of influenza viruses in Senegal, obtain genetic profiles of circulating AIVs, and assess the risk of emergence of novel strains and their transmission to humans. Cloacal swabs from poultry and environmental samples collected weekly from the two LBMs were screened by RT-qPCR for H5, H7, and H9 AIVs. Subsequently, a subset of H9-positive samples was selected for whole sequencing. From December 2023 to October 2024, 499 samples were tested, and AIV was detected in 58.3% of them. Among these, A/H9N2 was the only subtype detected in both markets, with a detection rate of 47.7% (82/172) in Thiaroye and 35.3% (42/119) in Tilene, resulting in an overall positivity rate of 42.6% (124/291). Genome sequencing of 22 A/H9N2 isolates, including 11 poultry drinking water samples, 7 carcass wash water samples, 3 fecal samples, and 1 cloacal swab, yielded 7 complete and 15 partial genomic sequences. Phylogenetic analyses of the resulting sequences showed that the A/H9N2 isolates obtained in this study formed a monophyletic cluster and were closely related to the Senegalese human strain (A/Senegal/0243/2019) identified through the national influenza sentinel surveillance program. These strains were also closely related to the A/H9N2 viruses of the G1 lineage circulating in neighboring countries, suggesting cross-border transmission. The A/H9N2 strains carried the low pathogenicity RSSR/GLF motif at the HA cleavage site and possessed several key amino acid mutations, including HA-I155T and HA-Q226L, which are associated with human host adaptation, PB2-T105V, PB2-A661T, and PB2-A588V, which are linked to the human-to-human transmission and increased polymerase activity, NS2-T14M, NS2-M100I, NS1-I106M, NS1-V222M, NS1-E223A, NS1-I226V, NS1-E227G, and NS1-P228S, which are known to alter virulence (increased or reduced) in humans or mice, and M2-S31N, which promotes drug resistance. Seven potential N-glycosylation sites were predicted in the HA protein and six in the NA protein. The selection pressure analysis revealed that the A/H9N2 isolates were primarily under neutral evolution or purifying selection pressure. Overall, our findings highlight the potential for cross-species transmission of Senegalese A/H9N2 viruses, emphasizing the need for sustained monitoring of these viruses in both animal and human populations. [ABSTRACT FROM AUTHOR] more...

Psychotropic drugs are vital in psychiatry, aiding in the management of mental health disorders. Their use requires an understanding of their pharmacological properties, therapeutic applications, and potential side effects. Ongoing research aims to improve their efficacy and safety. Biomarkers play a crucial role in understanding and predicting memory decline in psychotropic drug users. A comprehensive understanding of biomarkers, including neuroimaging, biochemical, genetic, and cognitive assessments, is essential for developing targeted interventions and preventive strategies. In this narrative review, we performed a comprehensive search on PubMed and Google using review-specific terms. Clinicians should use a multifaceted approach, including neurotransmitter analysis, neurotrophic factors, miRNA profiling, and cognitive tasks for early intervention and personalized treatment. Anxiolytics' mechanisms involve various neurotransmitter systems and emerging targets. Research on biomarkers for memory decline in anxiolytic users can lead to early detection and intervention, enhancing clinical practices and aligning with precision medicine. Mood stabilizer users can benefit from early detection of memory decline through RNA, neurophysiological, and inflammatory biomarkers, promoting timely interventions. Performance-enhancing drugs may boost athletic performance in the short term, but their long-term health risks and ethical issues make their use problematic. Long-term use of psychotropic performance enhancers in athletes shows changes in biomarkers of cognitive decline, necessitating ongoing monitoring and intervention strategies. Understanding these genetic influences on memory decline helps pave the way for personalized approaches to prevent or mitigate cognitive deterioration, emphasizing the importance of genetic screening and early interventions based on an individual's genetic profile. Future research should focus on refining these biomarkers and protective measures against cognitive deterioration. Overall, a comprehensive understanding of biomarkers in psychotropic drug users is essential for developing targeted interventions and preventive strategies. [ABSTRACT FROM AUTHOR] more...

Pharmacogenetics (PGx) aims to optimize drug treatment outcomes by using a patient's genetic profile for individualized drug and dose selection. Currently, reactive and pretherapeutic single-gene PGx tests are increasingly applied in clinical practice in several countries and institutions. With over 95% of the population carrying at least one actionable PGx variant, and with drugs impacted by these genetic variants being in common use, pretherapeutic or preemptive PGx panel testing appears to be an attractive option for better-informed drug prescribing. Here, we discuss the current state of PGx panel testing and explore the potential for clinical implementation. We conclude that available evidence supports the implementation of pretherapeutic PGx panel testing for drugs covered in the PGx guidelines, yet identification of specific patient populations that benefit most and cost-effectiveness data are necessary to support large-scale implementation. [ABSTRACT FROM AUTHOR] more...