👤 Hoang Dang Khoa Ta

Plozasiran (Redemplo), a novel small interfering RNA (siRNA) therapeutic targeting the hepatic biosynthesis of apolipoprotein C-III (APOC3), is approved by the US FDA for treating familial chylomicronemia syndrome (FCS), a disease of rare prevalence that presents with extremely elevated levels of serum triglycerides (TG) leading to a higher risk of acute pancreatitis. Plozasiran is also in Phase 3 development to treat the broader indication of severe hypertriglyceridemia. Population pharmacodynamic (PD) analysis of plozasiran was conducted on serially measured serum APOC3 and TG levels in the FCS patients participating in the pivotal Phase 3 study by employing a cascading kinetic-PD model that described the inhibitory effect of plozasiran on the synthesis of APOC3, which in turn decreases serum TG levels. The estimated IC Show less

α-synucleinopathies are clinically and biologically heterogeneous disorders lacking reliable biomarkers to assist with early diagnosis, disease progression, patient stratification, and therapeutic targeting. Genetic variation is known to impact biomarker levels, influencing their utility and interpretation in research and clinical settings. We aimed to identify common genetic modulators of biomarker levels implicated in α-synucleinopathy pathogenesis. Genome-wide association studies (GWASs) were conducted on 63 CSF, plasma, and urine biomarkers in 581 individuals from the Parkinson's Progression Markers Initiative (PPMI). Analyses were adjusted for age, sex, disease status, and principal components. PD- and DLB-risk loci associations were separately assessed for each GWAS. We confirm strong associations between urine bis(monoacylglycerol)phosphate (BMP) isoforms and the variants The present study reveals established and novel genetic modulators of potential α-synucleinopathy biomarkers, demonstrating that genetic background significantly shapes biomarker levels. These genetic influences should be accounted for when conducting biomarker-based research, clinical trials, or therapeutic development to ensure accurate interpretation and improve their translational relevance. Show less

Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition. Traditional genetic testing is typically conducted on the proband only, with family members undergoing Sanger sequencing, which may overlook other pathogenic variants. This study explores the gene sequencing strategy in a three-generation family based on genetic carrier status and examines the relationship between phenotypic characteristics and genotype. High-throughput second-generation sequencing was performed on the proband to analyze HCM-related pathogenic genes. Subsequently, the identified pathogenic variants were validated by Sanger sequencing in the proband and family members. Clinical, electrocardiographic, and echocardiographic assessments were conducted for family members. Second-generation sequencing of the proband (III7) revealed a pathogenic variant MYBPC3-P453Lfs. Initially, no HCM-related pathogenic variants were detected in another patient (III11), prompting additional sequencing of III11, which identified the MYH7-G823E pathogenic variant. Both patients had severe left ventricular outflow tract obstruction. Sanger sequencing showed that five family members carried both mutations. Among them, three died suddenly before age 40, one required an implantable cardioverter defibrillator for arrhythmias, and one developed HCM before adulthood. Cardiac magnetic resonance imaging (MRI) of patients carrying both mutations showed myocardial fibrosis of 32.75%, significantly higher than the 6.98% observed in patients carrying only one mutation. In families with varying HCM phenotypes, second-generation sequencing should be considered for all members. In this family, carrying one variant led to outflow tract obstruction, while carrying both variants resulted in severe disease, including sudden death and early onset. Cardiac MRI is crucial for assessing the severity of the disease within the family. Show less

Glioblastoma (GBM) is one of the most progressive and prevalent cancers of the central nervous system. Identifying genetic markers is therefore crucial to predict prognosis and enhance treatment effectiveness in GBM. To this end, we obtained gene expression data of GBM from TCGA and GEO datasets and identified differentially expressed genes (DEGs), which were overlapped and used for survival analysis with univariate Cox regression. Next, the genes' biological significance and potential as immunotherapy candidates were examined using functional enrichment and immune infiltration analysis. Eight prognostic-related DEGs in GBM were identified, namely Show less

The development and progression of colorectal cancer (CRC) involve changes in genetic and epigenetic levels of oncogenes and/or tumor suppressors. In spite of advances in understanding of the molecular mechanisms involved in CRC, the overall survival rate of CRC still remains relatively low. Thus, more research is needed to discover and investigate effective biomarkers and targets for diagnosing and treating CRC. The roles of long non-coding RNAs (lncRNAs) participating in various aspects of cell biology have been investigated and potentially contribute to tumor development. Our recent study also showed that CRNDE was among the top 20 upregulated genes in CRC clinical tissues compared to normal colorectal tissues by analyzing a Gene Expression Omnibus (GEO) dataset (GSE21815). Although CRNDE is widely reported to be associated with different types of cancer, most studies of CRNDE were limited to examining regulation of its transcription levels, and in-depth mechanistic research is lacking. In the present study, CRNDE was found to be significantly upregulated in CRC patients at an advanced TNM stage, and its high expression was correlated with poor outcomes of CRC patients. In addition, we found that knocking down CRNDE could reduce lipid accumulation through the miR-29b-3p/ANGPTL4 axis and consequently induce autophagy of CRC cells. Show less