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Bipolar disorder is a mood-related disorder, which can be portrayed as extreme shifts in energy, mood, and activity levels which can also be characterized by manic highs and depressive lows that can be often misdiagnosed as unipolar disorder due to primitive diagnostics techniques based on clinical assessments as well as diagnostic complexities arising due to its heterogeneous nature and overlapping symptoms with conditions like schizophrenia. leading to delays in treatment Strong evidence in support of genetic and epigenetic aspects of bipolar disorder, including mechanisms such as compromised hypothalamic-pituitary-adrenal axis, immune-inflammatory imbalances, oxidative stress, and mitochondrial dysfunction are found. Moreover, some previous research has already stated the role of genes like CITED2, NUDT4, and Arl8B in these processes. The primary goal of this study is to investigate the involvement of the genes in exploring and validating their potential as biomarkers for bipolar disorder. In silico tools like MutationTaster, PolyPhen2, SIFT, GTEx, PhenoScanner, and RegulomeDB were used to perform mutational and gene expression analyses. Results revealed potentially dangerous mutations caused in CITED2, NUDT4, and Arl8B, those which can have diverse outcomes. RegulomeDB, GTEx, and PhenoScanner reveal the involvement of these genes in various brain regions highlighting their relevance to bipolar disorder. This analysis suggests the potential utility of CITED2, NUDT4, and Arl8B as diagnostic markers hence shedding light on their roles to elaborate the molecular range of bipolar disorder. The study also contributes to providing valuable insights into the genetic and molecular basis of bipolar disorders.

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Introduction: Double-negative prostate cancer, an androgen receptor-independent prostate cancer without features of neuroendocrine tumors, is refractory to treatment but could be an ideal candidate for individualized treatment. Case presentation: An 85-year-old patient with metastatic castration-resistant prostate cancer without prostate-specific antigen progression presented with local recurrence and liver and lung metastases 6 months after orchiectomy and apalutamide. A liver tumor biopsy led to a diagnosis of double-negative prostate cancer. FoundationOne® CDx showed BRCA2 mutation and high tumor mutation burden. Olaparib and pembrolizumab were administered sequentially, and the patient responded to each treatment for 5 months until radiographic progression. Conclusion: Sequential use of olaparib and pembrolizumab may be effective for double-negative prostate cancer with BRCA2 mutations and high tumor mutation burden.

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Somatic KIT activating mutations drive most gastrointestinal stromal tumors (GISTs). Disease progression eventually develops with first-line imatinib, commonly due to KIT secondary mutations, and different kinase inhibitors have various levels of treatment efficacy dependent on specific acquired resistance mutations. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA tyrosine kinase inhibitor for patients with advanced GIST who received prior treatment with three or more kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11 mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11 + 17/18 mutations detected by circulating tumor DNA.Clinical Trial Registration: NCT05734105 (ClinicalTrials.gov).

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Gastrointestinal stromal tumor (GIST) is rare, but it is the most common mesenchymal tumor (a type of tumor that develops from cells which give rise to soft tissues) of the gastrointestinal tract. The primary treatment for advanced GIST is medication that targets the abnormal mechanisms in cancer cells in order to block tumor growth and spread. Ripretinib is an inhibitor of a protein known as KIT, which is a member of the tyrosine kinase protein family and is involved in the growth of GIST. In a Phase III clinical trial called INTRIGUE, the effects of ripretinib and another receptor tyrosine kinase inhibitor, sunitinib, were compared in patients with advanced GIST previously treated with the drug imatinib. An exploratory analysis from the INTRIGUE trial that characterized baseline circulating tumor DNA in the blood showed a greater clinical benefit with ripretinib versus sunitinib in patients with gene mutations solely occurring in KIT exon 11 + 17 and/or 18 (exon 11 + 17/18). This article describes the rationale and design for a Phase III clinical trial called INSIGHT that will evaluate the benefit of ripretinib compared with sunitinib in patients with advanced GIST whose tumors have mutations in KIT exon 11 and KIT exon 17 and/or 18. Patients will receive ripretinib or sunitinib in 6-week cycles, and investigators will assess survival without cancer progression as the primary outcome, and overall survival, and response of the tumor to these two drugs as secondary outcomes.

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Brassinosteroids (BRs) are an essential group of plant hormones regulating numerous aspects of plant growth, development, and stress responses. BRI1, along with its co-receptor BAK1, are involved in brassinosteroid sensing and early events in the BR signal transduction cascade. Mutational analysis of a particular gene is a powerful strategy for investigating its biochemical role. Molecular genetic studies, predominantly in Arabidopsis thaliana, but progressively in numerous other plants, have identified many mutants of the BRI1 gene and its orthologs to gain insight into its structure and function. So far, the plant kingdom has identified up to 40 bri1 alleles in Arabidopsis and up to 30 bri1 orthologs in different plants. These alleles exhibit phenotypes that are identical in terms of development and growth. Here, we have summarized bri1 alleles in Arabidopsis and its orthologs present in various plants including monocots and dicots. We have discussed the possible mechanism responsible for the specific allele. Finally, we have briefly debated the importance of these alleles in the research field and the agronomically valuable traits they offer to improve plant varieties.

Asunto(s)

Alelos , Proteínas de Arabidopsis , Arabidopsis , Brasinoesteroides , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Brasinoesteroides/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Regulación de la Expresión Génica de las Plantas , Mutación , Transducción de Señal/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo

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Guideline-recommended screening programs exist for only a few cancer types. Although all these programs are understood to lead to reductions in cancer-related mortality, standard-of-care screening tests vary in accuracy, adherence and effectiveness. Recent advances in high-throughput technologies and machine learning have facilitated the development of blood-based multi-cancer cancer early detection (MCED) tests. MCED tests are positioned to be complementary to standard-of-care screening and they may broaden screening availability, especially for individuals who are not adherent with current screening programs and for individuals who may harbor cancers with no available screening options. In this article, we outline some key features that should be considered for study design and MCED test development, provide an example of the developmental pathway undertaken for an emerging multi-biomarker class MCED test and propose a clinical algorithm for an imaging-based diagnostic resolution strategy following MCED testing.

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BACKGROUND: Multi-drug resistant tuberculosis (MDR-TB) results in treatment failure and poor clinical outcomes. This study was carried out with the aim to determine the pattern of drug resistance against Mycobacterium tuberculosis towards first line ATT (anti-tubercular treatment) in sputum smear-positive patients using Line Probe Assay (LPA). METHODS: A cross sectional prospective study was carried out in a tertiary care Hospital of Meerut. A total of 898 sputum samples (on spot and early morning) collected from 449 suspected pulmonary tuberculosis patients as per RNTCP guidelines were screened by microscopy. Decontamination was done by N-acetyl-l-cysteine and sodium hydroxide. Then smear positive samples were subjected to 1st line drug susceptibility testing (DST) using LPA GenoType® MTBDRplus (HAIN Life Science) assay, a molecular method which allows rapid detection of Rifampicin (Rif) and Isoniazid (INH) resistance. RESULTS: The overall burden of MDR TB in this geographical area was 7.9 %. Mono-resistance with Rif alone was around 2.8 %. However, the mono-resistance with INH (inhA gene) and INH (katG gene) was 2.8 % and 1.1 % respectively. Drug resistance of Rif was due to mutations in rpoB gene while resistances to INH were more commonly due to mutation in inhA gene followed by katG gene. TB was more commonly seen in the age group of 30-59 years (43.8 %) and predominantly in males. CONCLUSION: Tuberculosis positivity rate is high in Western Uttar Pradesh. Burden of MDR TB in Western Uttar Pradesh was similar to National data. Line probe assay can be used as a primary method to diagnose multi drug resistant TB as done in present study which can help in earlier initiation of correct therapy.

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Antituberculosos , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , India/epidemiología , Masculino , Femenino , Adulto , Estudios Transversales , Persona de Mediana Edad , Estudios Prospectivos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/epidemiología , Pruebas de Sensibilidad Microbiana , Adulto Joven , Esputo/microbiología , Análisis Mutacional de ADN , Rifampin/uso terapéutico , Rifampin/farmacología , Isoniazida/uso terapéutico , Isoniazida/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Proteínas Bacterianas/genética , Adolescente , Oxidorreductasas/genética , Mutación , Catalasa

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When designing live-attenuated respiratory syncytial virus (RSV) vaccine candidates, attenuating mutations can be developed through biologic selection or reverse-genetic manipulation and may include point mutations, codon and gene deletions, and genome rearrangements. Attenuation typically involves the reduction in virus replication, due to direct effects on viral structural and replicative machinery or viral factors that antagonize host defense or cause disease. However, attenuation must balance reduced replication and immunogenic antigen expression. In the present study, we explored a new approach in order to discover attenuating mutations. Specifically, we used protein structure modeling and computational methods to identify amino acid substitutions in the RSV nonstructural protein 1 (NS1) predicted to cause various levels of structural perturbation. Twelve different mutations predicted to alter the NS1 protein structure were introduced into infectious virus and analyzed in cell culture for effects on viral mRNA and protein expression, interferon and cytokine expression, and caspase activation. We found the use of structure-based machine learning to predict amino acid substitutions that reduce the thermodynamic stability of NS1 resulted in various levels of loss of NS1 function, exemplified by effects including reduced multi-cycle viral replication in cells competent for type I interferon, reduced expression of viral mRNAs and proteins, and increased interferon and apoptosis responses.

Asunto(s)

Aprendizaje Automático , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Proteínas no Estructurales Virales , Replicación Viral , Humanos , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/inmunología , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Vacunas contra Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/genética , Virus Sincitial Respiratorio Humano/genética , Virus Sincitial Respiratorio Humano/inmunología , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/genética , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones por Virus Sincitial Respiratorio/virología , Infecciones por Virus Sincitial Respiratorio/inmunología , Sustitución de Aminoácidos , Mutación , Línea Celular

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Proteins are constantly undergoing folding and unfolding transitions, with rates that determine their homeostasis in vivo and modulate their biological function. The ability to optimize these rates without affecting overall native stability is hence highly desirable for protein engineering and design. The great challenge is, however, that mutations generally affect folding and unfolding rates with inversely complementary fractions of the net free energy change they inflict on the native state. Here we address this challenge by targeting the folding transition state (FTS) of chymotrypsin inhibitor 2 (CI2), a very slow and stable two-state folding protein with an FTS known to be refractory to change by mutation. We first discovered that the CI2's FTS is energetically taxed by the desolvation of several, highly conserved, charges that form a buried salt bridge network in the native structure. Based on these findings, we designed a CI2 variant that bears just four mutations and aims to selectively stabilize the FTS. This variant has >250-fold faster rates in both directions and hence identical native stability, demonstrating the success of our FTS-centric design strategy. With an optimized FTS, CI2 also becomes 250-fold more sensitive to proteolytic degradation by its natural substrate chymotrypsin, and completely loses its activity as inhibitor. These results indicate that CI2 has been selected through evolution to have a very unstable FTS in order to attain the kinetic stability needed to effectively function as protease inhibitor. Moreover, the CI2 case showcases that protein (un)folding rates can critically pivot around a few key residues-interactions, which can strongly modify the general effects of known structural factors such as domain size and fold topology. From a practical standpoint, our results suggest that future efforts should perhaps focus on identifying such critical residues-interactions in proteins as best strategy to significantly improve our ability to predict and engineer protein (un)folding rates.

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Mutación , Pliegue de Proteína , Estabilidad Proteica , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Modelos Moleculares , Cinética , Conformación Proteica , Péptidos

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Intellectual disability (ID) is a progressive disorder that affects around 1-3% of the world's population. The heterogeneity of intellectual disability makes it difficult to diagnose as a complete disease. Genetic factors and major mutations play a noticeable role in the development and progression of ID. There is a high need to explore novel variants that may lead to new insights into the progressive aspects of ID. In the current course of study, 31 samples of ID from different studies available on GEO (GSE77742, GSE74263, GSE90682, GSE98476, GSE108887, GSE145710, and PRJEB21964) datasets were taken for the study. These datasets were analyzed for differential gene expression and single nucleotide polymorphism (SNPs). The SNPs of high impact were compared with the differentially expressed genes. Comparison leads to the identification of the priority gene ie NPR3 gene. The identified priority gene further was evaluated for the effect of the mutation using a Mutation Taster. Structure comparison analysis of the wild and mutated proteins of the NPR3 gene was further carried out by UCSF Chimera. Structural analysis reveals the anomalies in protein expression affecting the regulations of the NPR3 gene. These findings identified a novel nonsense mutation (E222*) in the downregulated NPR3 gene that leads to anomalies in the regulation of its protein expression. This missense mutation reveals a major role in causing ID. Our study concludes that the decrease in the expression of the NPR3 gene causes delayed sensory, motor, and physiological functions of the human brain leading to neurodevelopmental delay that causes ID.

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The COVID-19 pandemic led to a large global effort to sequence SARS-CoV-2 genomes from patient samples to track viral evolution and inform public health response. Millions of SARS-CoV-2 genome sequences have been deposited in global public repositories. The Canadian COVID-19 Genomics Network (CanCOGeN - VirusSeq), a consortium tasked with coordinating expanded sequencing of SARS-CoV-2 genomes across Canada early in the pandemic, created the Canadian VirusSeq Data Portal, with associated data pipelines and procedures, to support these efforts. The goal of VirusSeq was to allow open access to Canadian SARS-CoV-2 genomic sequences and enhanced, standardized contextual data that were unavailable in other repositories and that meet FAIR standards (Findable, Accessible, Interoperable and Reusable). In addition, the Portal data submission pipeline contains data quality checking procedures and appropriate acknowledgement of data generators that encourages collaboration. From inception to execution, the portal was developed with a conscientious focus on strong data governance principles and practices. Extensive efforts ensured a commitment to Canadian privacy laws, data security standards, and organizational processes. This Portal has been coupled with other resources like Viral AI and was further leveraged by the Coronavirus Variants Rapid Response Network (CoVaRR-Net) to produce a suite of continually updated analytical tools and notebooks. Here we highlight this Portal, including its contextual data not available elsewhere, and the 'Duotang', a web platform that presents key genomic epidemiology and modeling analyses on circulating and emerging SARS-CoV-2 variants in Canada. Duotang presents dynamic changes in variant composition of SARS-CoV-2 in Canada and by province, estimates variant growth, and displays complementary interactive visualizations, with a text overview of the current situation. The VirusSeq Data Portal and Duotang resources, alongside additional analyses and resources computed from the Portal (COVID-MVP, CoVizu), are all open-source and freely available. Together, they provide an updated picture of SARS-CoV-2 evolution to spur scientific discussions, inform public discourse, and support communication with and within public health authorities. They also serve as a framework for other jurisdictions interested in open, collaborative sequence data sharing and analyses.

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Clostridioides difficile endolysin (Ecd09610) consists of an unknown domain at its N terminus, followed by two catalytic domains, a glucosaminidase domain and endopeptidase domain. X-ray structure and mutagenesis analyses of the Ecd09610 catalytic domain with glucosaminidase activity (Ecd09610CD53) were performed. Ecd09610CD53 was found to possess an α-bundle-like structure with nine helices, which is well conserved among GH73 family enzymes. The mutagenesis analysis based on X-ray structures showed that Glu405 and Asn470 were essential for enzymatic activity. Ecd09610CD53 may adopt a neighboring-group mechanism for a catalytic reaction in which Glu405 acted as an acid/base catalyst and Asn470 helped to stabilize the oxazolinium ion intermediate. Structural comparisons with the newly identified Clostridium perfringens autolysin catalytic domain (AcpCD) in the P1 form and a zymography analysis demonstrated that AcpCD was 15-fold more active than Ecd09610CD53. The strength of the glucosaminidase activity of the GH73 family appears to be dependent on the depth of the substrate-binding groove.

Asunto(s)

Dominio Catalítico , Clostridioides difficile , Endopeptidasas , Clostridioides difficile/enzimología , Clostridioides difficile/genética , Cristalografía por Rayos X , Endopeptidasas/química , Endopeptidasas/metabolismo , Endopeptidasas/genética , Modelos Moleculares , Hexosaminidasas/química , Hexosaminidasas/genética , Hexosaminidasas/metabolismo , Mutagénesis , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Mutagénesis Sitio-Dirigida , Dominios Proteicos

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[This corrects the article DOI: 10.3389/fonc.2023.1206768.].

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Hepatitis B virus (HBV) vaccine is composed of the purified hepatitis B surface antigen (HBsAg) that is produced by recombinant DNA technology. The neutralizing antibodies induced by vaccination target mainly the "a" determinant, aa124-147, of the outer viral envelope (HBsAg). In the present work, we demonstrate a case study for vaccinated patient that is infected with a vaccine escape HBV strain (Eg200). Characterization of the isolate Eg200 showed that it belongs to the genotype D and an uncommon sub-genotype in Egypt; D9. The DNA sequence encoding HBsAg was sequenced. Mutational analysis of the HBsAg showed a double mutation in the "a" determinant of this HBV isolate; T125M and P127T. However, such substitutions were found to be conserved to the detected serotype, ayw3, of Eg200 isolate. This case report indicates that continuous characterization of breakthrough vaccine escape strains of HBV is essential to develop the immunization strategies against HBV infection.

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Virus de la Hepatitis B , Hepatitis B , Humanos , Antígenos de Superficie de la Hepatitis B/genética , Anticuerpos contra la Hepatitis B , Vacunas contra Hepatitis B/genética , Mutación , ADN Viral/genética

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Dementia is a syndrome that can cause a number of progressive illnesses that affect memory, thinking, and ability to perform everyday tasks. Alzheimer's disease (AD) is the most common cause of dementia and represents a major public health problem. AD is a progressive disease, where in early stages there is mild memory loss and in late-stage patient loses the ability to carry on a conversation. AD (for which there is no exact cause and cure known so far) is the sixth leading cause of deaths in the United States. Every 68 second someone develops AD. This study focuses on protein structure modeling of genes presenilin 1 and 2 ( PSEN1 and PSEN2 ) and their mutated forms (Asn141Tyr found in Chinese family, Gly34Ser identified in a Japanese patient, and Arg62Cys & Val214Leu identified in the Korean patients). It also involves wild and mutant type comparison, protein interaction studies, docking and phylogenetic history based on representative ortholog species and also sheds insight into the comparative evolutionary rates of coding sequence across various orthologs. This study gives a time and cost-effective analysis of genes ( PSEN1 and PSEN2 ) underlying AD and genetic alterations that drive development and causes of disease.

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With the explosion in knowledge about the molecular landscape of lymphoid malignancies and the increasing availability of high throughput techniques, molecular diagnostics in hematopathology has moved from isolated marker studies to a more comprehensive approach, integrating results of multiple genes analyzed with a variety of techniques on the DNA and RNA level. Although diagnosis of lymphoma still relies on the careful integration of clinical, morphological, phenotypic, and, if necessary molecular features, and only few entities are defined strictly by genetic features, genetic profiling has contributed profoundly to our current understanding of lymphomas and shaped the two current lymphoma classifications, the International Consensus Classification and the fifth edition of the WHO classification of lymphoid malignancies. In this review, the current state of the art of molecular diagnostics in lymphoproliferations is summarized, including clonality analysis, mutational studies, and gene expression profiling, with a focus on practical applications for diagnosis and prognostication. With consideration for differences in accessibility of high throughput techniques and cost limitations, we tried to distinguish between diagnostically relevant and in part disease-defining molecular features and optional, more extensive genetic profiling, which is usually restricted to clinical studies, patients with relapsed or refractory disease or specific therapeutic decisions. Although molecular diagnostics in lymphomas currently is primarily done for diagnosis and subclassification, prognostic stratification and predictive markers will gain importance in the near future.

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Linfoma , Patología Molecular , Humanos , Pronóstico , Linfoma/diagnóstico , Linfoma/genética , Linfoma/patología , Perfilación de la Expresión Génica , Mutación

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Objective:To screen m6A modification-related genes, and to establish a prognostic model in patients with FLT3 mutated acute myeloid leukemia(AML), especially in older patients and to evaluate the prognostic efficiency of the model.Methods:Gene expression omnibus(GEO)datasets were used to analyze abnormally expressed m6A enzymes and reading proteins in FLT3 mutated AML; Correlation analysis was used to screen m6A modified-related genes in expression profiles.By integrating TCGA and BEAT data, 83 FLT3 mutated AML patients were included, and 32 of them were older than 60 years.Univariate Cox analysis and Lasso regression were conducted to construct the risk model.Kaplan-Meier curve and time-dependent receiver operating characteristic curve(tROC)were used to evaluate the prognostic efficiency of the model; subgroup analysis was conducted in the older patients.The concordance index(C-index)and calibration curve were used to evaluate the discrimination and accuracy of the model.Results:14 m6A modification enzymes or reading proteins were abnormally expressed in patients with FLT3 mutated AML.Correlation analysis filtered out 2 476 m6A related genes in expression profile.In TCGA and BEAT integrated data, univariate Cox analysis identified 132 prognostic genes.Lasso regression selected seven candidate genes to establish the prognostic risk model, including AKAP9, AVEN, DMCA1, DPYD, FAR2, GPHN and SPECC1L.Kaplan-Meier curve showed that high-risk group of the model had significantly shorter overall survival with a hazard ratio( HR)of 5.08(95% CI: 2.54-10.14, P<0.001).The area under the curve(AUC)in tROC for 1-year survival was 0.83; the C-index of risk model was 0.737.In older patients, the hazard ratio( HR)of the risk model for 1-year overall survival was 3.40(95% CI: 1.25-9.24, P=0.017)with an AUC of 0.79. Conclusions:The risk model based on m6A modified-related genes has some predictive value in assessing the prognosis of patients with FLT3 mutated AML, especially indicative to prognosis prediction in the elderly.

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Objective:To identify pathogenic genes in 3 cases of piebaldism, and to explore the genotype-phenotype relationships in piebaldism.Methods:Clinical data were collected from 3 patients with piebaldism and their parents at the Department of Dermatology, Henan Provincial People′s Hospital from January 2019 to December 2021. Peripheral blood samples were obtained from them and 100 unrelated healthy controls, and DNA was extracted. Whole-exome sequencing technology was used to screen genetic variation sites, and then Sanger sequencing was performed for verification. The deleteriousness of genetic variants was evaluated by using pathogenicity analysis software tools.Results:Case 1: a 23-year-old male patient presented with white patches on the forehead, chest, and abdomen for 23 years, and his parents had no similar symptoms; case 2: a 1-year- and 5-month-old male infant presented with white patches on the forehead and abdomen for 1 year, and his parents had no similar symptoms; case 3: a 6-year-old male child presented with white patches on the forehead and limbs for 6 years, and his parents had no similar clinical manifestations. Genetic testing showed that a missense mutation c.2033T>C (p.L678P) in exon 14 of the KIT gene, a splice site mutation c.2485-1G>C in exon 18 of the KIT gene, and a heterozygous missense mutation c.2346C>G (p.F782L) in exon 16 of the KIT gene were identified in the case 1, 2, 3 respectively, but no above mutations were identified in the patients′ parents or 100 unrelated healthy controls. The 3 genetic variants were all novel pathogenic mutations, and all were deleterious mutations.Conclusions:Three novel pathogenic mutations in the KIT gene were identified in the 3 cases of piebaldism, namely c.2033T>C (p.L678P), c.2485-1G>C, and c.2346C>G (p.F782L). It was further verified that the severity of piebaldism was closely related to the type and location of KIT gene mutations.

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BACKGROUND AND OBJECTIVES: An important requirement for a hepatitis B surface antigen (HBsAg) screening assay is reliable detection of HBsAg mutant forms, especially in blood donation. Here we investigate and describe the case of an isolated false-negative result of commercial serology HBsAg screening assay of a blood donor. MATERIALS AND METHODS: The current donation was routinely tested for HBsAg and hepatitis B virus (HBV) DNA in the mini-pool mode nucleic acid testing (MP-NAT of six samples), and further evaluated by individual donation ID-NAT. Finally, it was quantified and sequenced. All previous donations were found to have negative HBsAg and HBV DNA, as also the subsequent sample taken 3 months after the marked donation. RESULTS: The current donation of the 53-year-old unvaccinated female with 14 previous donations was initially HBsAg negative and HBV DNA (MP-NAT) positive. Further testing showed HBsAg positive using other HBV serological assays, antibodies to HBV core antigen immunoglobulin M positive and HBV DNA ID-NAT positive, and contained 200 IU/mL of HBV DNA. The implicated donation carried genotype D strains, subtype ayw2 (F83S, V96A, V190A, L193S, I195T, L213S, F220L). The mutations in three positions, namely amino acids T118A, P120T, and P127T, were proven subsequently. CONCLUSION: This unique mutation combination near the target epitope of one of the immunoassay monoclonals is a possible cause of the reduced analytical sensitivity of the serology assay.

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BACKGROUND: SMYD2 is a protein of the SET and MYND domain-containing family SMYD. It can methylate the lysine residue of various histone and nonhistone cancer-related proteins and plays a critical role in tumorigenesis. Although emerging evidence supports the association of SMYD2 in the progression of cancers, but its definitive effect is not yet clear. Therefore, further study of the gene in relation with cancer progression needs to be conducted. In the current study, investigators used TCGA data to determine the potential carcinogenic effect of SMYD2 in 11 cancer types. The transcriptional expression, survival rate, mutations, enriched pathways, and Gene Ontology of the SMYD2 were explored using different bioinformatics tools and servers. In addition, we also examined the correlation between SMYD2 gene expression and immunocyte infiltration in multiple cancer types. RESULTS: Findings revealed that higher expression of SMYD2 was significantly correlated with cancer incidents. In CESC and KIRC, the mRNA expression of SMYD2 was significantly correlated with overall survival (OS). In BRCA, KIRC, COAD, and HNSC, the mRNA expression of SMYD2 was significantly correlated with disease-free survival (DFS). We detected 15 missense, 4 truncating, 4 fusions, and 1 splice type of mutation. The expression of SMYD2 was significantly correlated with tumor purity and immunocyte infiltration in six cancer types. The gene GNPAT was highly associated with SMYD2. Significant pathways and Gene Ontology (GO) terms for co-expressed genes were associated to various processes linked with cancer formation. CONCLUSION: Collectively, our data-driven results may provide reasonably comprehensive insights for understanding the carcinogenic effect of SMYD2. It suggests that SMYD2 might be used as a significant target for identifying new biomarkers for various human tumors.