Genex Systems (United States)

Ornithine transcarbamylase (OTC) deficiency can present during the neonatal period, infancy, or adulthood. Late-onset phenotypes are influenced by residual enzyme activity and OTC gene expression. The objective of this study was to assess the pathogenicity of a rare promoter region variant, c.-106C>A. We reviewed three independent pedigrees harboring the c.-106C>A variant. Retrospective chart reviews were conducted for 16 affected males to evaluate biochemical and clinical features. Functional OTC enzyme data were obtained from the liver biopsy of three affected males. The median age of diagnosis for symptomatic males was 15 years (range: 0.08-55). All 21 heterozygous females have been asymptomatic to date. Of the 16 hemizygous males, seven have experienced at least one episode of hyperammonemia, and eight have remained asymptomatic. The proband from Family A presented at age 55, with a peak ammonia level of 694 μmol/L. His OTC activity was 8.2 μmol/g liver/min (control: 94.9 μmol/g liver/min). The proband from Family B presented at age 15 with an ammonia level of 1568 μmol/L and later died from cerebral edema. His OTC activity was 2.2 μmol/g liver/min (control: 73.2 μmol/g liver/min). The proband from Family C presented at age 24 with hyperammonemia and later died following withdrawal of care. His liver punch biopsy OTC enzyme activity was measured to be 0 μmol/g liver/min (control range: 25-31.7 μmol/g liver/min). For most affected males, ammonia scavenger therapy has successfully prevented recurrent decompensation. The combined biochemical, clinical, and enzymatic data strongly support the pathogenicity of the c.-106C>A OTC promoter region variant in late-onset OTC deficiency.

Background:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent condition characterized by fat build-up in the liver and ranges from benign steatosis to progression to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and end-stage liver disease including hepatocellular carcinoma, representing a significant cause of chronic liver disease globally.1,2 Current treatment options are limited, primarily relying on lifestyle modifications, highlighting an urgent need for novel therapeutic strategies.Methods:A Cell Painting-style high-content screening phenotypic assay was employed using the PH5CH8 human hepatocyte cell line to identify small molecules capable of modulating induced hepatic steatosis. The Plex Research artificial intelligence (AI) platform was utilized for target deconvolution of the lead hit compound, α-terthienyl. In vivo efficacy was assessed in a diet-induced obesity (DIO) C57BL/6J mouse model of MASLD. Biochemical assays and molecular docking simulations were performed to validate predicted target interactions.Results:Phenotypic screening identified 15 chemical probes/drugs that elicit dose-responsive inhibition of steatosis, and 16 that exacerbate steatosis, which could contribute to worsening of the disease clinically. α-terthienyl, a plant-derived natural product, was identified as a potent and non-toxic inhibitor of steatosis in PH5CH8 cells with an EC50 of 106 nM. In vivo, α-terthienyl administration to diet-induced obesity (60% fat diet) mice significantly reduced hepatic steatosis histologically, improved glucose tolerance, and favorably modulated serum biomarkers including ALT and AST. AI-driven analysis predicted dipeptidyl peptidase 4 (DPP-IV) and 17-beta hydroxysteroid dehydrogenase 13 (HSD17β13) as potential molecular targets of α-terthienyl. Biochemical inhibition of DPP-IV was observed and an oxidized α-terthienyl analog inhibited HSD17β13. Molecular docking supported these predictions, indicating binding to DPP-IV and HSD17β13.Conclusion:This study demonstrates the successful application of phenotypic screening integrated with AI-driven target deconvolution to identify compounds and drugs that ameliorate or exacerbate hepatic steatosis. α-terthienyl was identified as a novel modulator of hepatic steatosis with in vivo efficacy in a MASLD model. Our findings suggest a dual-target mechanism involving DPP-IV and HSD17β13, potentially engaged by the parent compound and its metabolite, respectively, offering a promising polypharmacological approach for MASLD treatment.

The cover image is based on the article Succinic Acid Production by Engineered Mannheimia succiniciproducens and Its Use in Chemoenzymatic Poly(Butylene Succinate) Synthesis by Ji Yeon Kim et al., https://doi.org/10.1002/bit.70072.

This study is significant as it discovered deep proteomic signatures for the highly aggressive and malignant metaplastic breast cancer (MCB) which is now considered a fifth subtype based upon its remarkable intra-tumoral heterogeneity that illustrates its unique cell plasticity. To efficiently analyze formalin-fixed paraffin-embedded (FFPE) breast tissues from patients with different breast cancer subtypes and disease-free individuals, we optimized a novel workflow in which we combined paraffinization and Folch extraction. We identified and confidently quantified ∼6,000 protein groups. We were able to find robust changes in extracellular matrix (ECM) with cancer, even though no ECM enrichments were performed. Interestingly, despite the relatively small human cohort size (42 patients), distinct protein signatures emerged throughout all cancer subtypes - common and unique - with remarkable statistical significance for many cancer-relevant proteins and pathways. This Pilot study indicates the hypothesis that an altered stroma can dictate epithelial tumor cell fate. We also observed that MBC was characterized by an especially immunosuppressed tumor environment. We do note the limitation of the relatively small cohort size of our study, and in the future additional patient cohorts will be needed to further validate our findings.

BackgroundNeurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented.MethodsProband-only or trio exome sequencing was performed on DNA samples obtained from affected individuals and available family members. The variant prioritisation process focused on identifying rare deleterious variants. International collaboration aided in the identification of additional affected individuals.ResultsWe identified 13 patients from 8 families of Ashkenazi Jewish origin who all carried the same homozygous frameshift variant in SGSM3 gene. The variant was predicted to cause a loss of function, potentially leading to impaired protein structure or function. The variant co-segregated with the disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature.ConclusionsAn Ashkenazi Jewish homozygous founder variant in SGSM3 was discovered in individuals with NDDs and short stature. This finding establishes a connection between another member of the RAS family and NDDs. Additional research is needed to uncover the specific molecular mechanisms by which SGSM3 influences neurodevelopmental processes and the regulation of growth.

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.

funcionalidade dessa regio, contribuindo para uma recuperao mais suave. Durante o ps-operatrio, as intervenes fisioteraputicas desempenham um papel integral na adaptao e recuperao das mulheres trans.

Germline genetic testing is recommended by practice guidelines for patients diagnosed with cancer to enable genetically targeted treatment and identify relatives who may benefit from personalized cancer screening and prevention. To describe the prevalence of germline genetic testing among patients diagnosed with cancer in California and Georgia between 2013 and 2019. Observational study including patients aged 20 years or older who had been diagnosed with any type of cancer between January 1, 2013, and March 31, 2019, that was reported to statewide Surveillance, Epidemiology, and End Results registries in California and Georgia. These patients were linked to genetic testing results from 4 laboratories that performed most germline testing for California and Georgia. The primary outcome was germline genetic testing within 2 years of a cancer diagnosis. Testing trends were analyzed with logistic regression modeling. The results of sequencing each gene, including variants associated with increased cancer risk (pathogenic results) and variants whose cancer risk association was unknown (uncertain results), were evaluated. The genes were categorized according to their primary cancer association, including breast or ovarian, gastrointestinal, and other, and whether practice guidelines recommended germline testing. Among 1 369 602 patients diagnosed with cancer between 2013 and 2019 in California and Georgia, 93 052 (6.8%) underwent germline testing through March 31, 2021. The proportion of patients tested varied by cancer type: male breast (50%), ovarian (38.6%), female breast (26%), multiple (7.5%), endometrial (6.4%), pancreatic (5.6%), colorectal (5.6%), prostate (1.1%), and lung (0.3%). In a logistic regression model, compared with the 31% (95% CI, 30%-31%) of non-Hispanic White patients with male breast cancer, female breast cancer, or ovarian cancer who underwent testing, patients of other races and ethnicities underwent testing less often: 22% (95% CI, 21%-22%) of Asian patients, 25% (95% CI, 24%-25%) of Black patients, and 23% (95% CI, 23%-23%) of Hispanic patients (P < .001 using the χ2 test). Of all pathogenic results, 67.5% to 94.9% of variants were identified in genes for which practice guidelines recommend testing and 68.3% to 83.8% of variants were identified in genes associated with the diagnosed cancer type. Among patients diagnosed with cancer in California and Georgia between 2013 and 2019, only 6.8% underwent germline genetic testing. Compared with non-Hispanic White patients, rates of testing were lower among Asian, Black, and Hispanic patients.