👤 Quynh Mai Thai

The inhibition of β-site amyloid precursor protein-cleaving enzyme 1 presents a promising therapeutic strategy for treating Alzheimer's disease by reducing amyloid-β (Aβ) production. This paper employed a computational approach that combined machine learning (ML) and atomistic simulations to accelerate the discovery of potential BACE1 inhibitors. Our ML models, trained on a set of ligands with experimental binding affinity, showed high accuracy when tested on a holdout test set. The best model was used to screen more than two million compounds in the CHEMBL33 chemical library to obtain a short list of top-hit compounds, which were further analyzed using molecular docking and fast pulling of ligand (FPL) simulations. The insights into structure and binding energetics obtained from FPL simulations elucidate the stability and interaction mechanisms of the BACE1-ligand bound state, providing data useful for the rational design of novel AD therapeutics. Show less

Apolipoprotein B (APOB) rs676210 polymorphism has been associated with altered lipid metabolism and cardiovascular risk in various populations; however, data from Vietnamese populations remain limited. This study aimed to investigate the association of the APOB rs676210 variant with lipid profiles among Vietnamese individuals newly diagnosed with elevated low-density lipoprotein cholesterol (LDL-C). A cross-sectional study was conducted among 69 Vietnamese adults newly diagnosed with elevated LDL-C (≥130 mg/dL) at a tertiary hospital in Southern Vietnam. Participants were genotyped for APOB rs676210 using real-time polymerase chain reaction (PCR) with allele-specific probes. Lipid profile components, including LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and ApoB, were compared across genotype groups (AA vs GA/GG) and alleles (A vs G). Statistical analyses involved t tests, chi-square tests, and multivariable linear regression adjusted for age, sex, the BMI, and diabetes. P<.05 was considered statistically significant. Of the 69 participants, 32 (46.4%) carried the AA genotype, while 37 (53.6%) carried the GA or the GG genotype. The AA genotype was associated with significantly higher LDL-C (mean 5.19, SD 0.95, vs mean 4.37, SD 0.97, mmol/L; P<.001), non-HDL-C (mean 5.94, SD 1.08, vs mean 5.31, SD 1.22 mmol/L; P=.03), and ApoB (mean 149.5, SD 26.3, vs mean 136.9, SD 15.2, mg/dL; P=.02) and lower HDL-C (mean 1.26, SD 0.31, vs mean 1.44, SD 0.39, mmol/L; P=.03) compared to the GA/GG genotype. Allele-based analysis showed that carriers of the A allele (98/138, 71%) also had higher LDL-C (mean 4.91, SD 1.02, vs mean 4.36, SD 0.97, mmol/L; P=.004) and ApoB (mean 145.6, SD 23.2, vs mean 135.9, SD 16.0, mg/dL; P=.02) than G allele carriers (40/138, 29%). These associations remained significant after multivariate adjustment. APOB rs676210 polymorphism is associated with significant differences in lipid profiles among Vietnamese adults with elevated LDL-C. Specifically, the A allele and the AA genotype confer a more atherogenic profile, suggesting potential utility as a genetic marker in lipid screening and personalized cardiovascular risk management in this population. Show less

Alzheimer's disease (AD) is associated with AChE and BACE1 enzymes. Designing inhibitors for preventing these enzymes can be benefit for AD treatment. In this context, theophylline derivatives were generated to prevent the biological activity of AChE and BACE1. In particular, the potential inhibitory of these compounds was rapidly and accurately estimated Show less

Elevated Lipoprotein(a) [Lp(a)] is a genetic risk factor for cardiovascular diseases affecting 20% of the world's population, with multiple published consensus statements that recommend testing and management strategies. However, elevated Lp(a) remains under-detected and under-treated worldwide. Our qualitative study explored the perspectives of cardiology healthcare professionals regarding the barriers and enablers for Lp(a) detection and management. Guided by Theoretical Domains Framework, we conducted 41 qualitative semi-structured one-on-one interviews in a cardiology department at a high-volume hospital in Singapore from October to December 2023. Healthcare professionals were purposively sampled across role and seniority to include doctors (specialists and interns), specialist nurses and dedicated pharmacists. Through an inductive process, we constructed qualitative codes followed by code-mapping to arrive at higher-order sub-categories, categories, and eventually themes. Analysis revealed 4 themes: rationale for routine testing, barriers to testing and follow-up, enablers of testing and follow-up, and ideal system to enhance patient management. Critical barriers to Lp(a) testing included a perceived lack of guidance in testing and follow-up, and misperception that Lp(a)-mediated cardiovascular risk cannot be managed resulting in low confidence of healthcare professionals to detect and manage elevated Lp(a). Inadequate institutional support to alleviate workload and presumed patient aversion to testing further hindered Lp(a) testing. We identified enablers and strategies to testing and management of Lp(a), notably these were the need for hospital-wide adequate training and education, guidelines and risk management pathways applicable to local settings, integration of Lp(a) testing into existing clinical pathways for high-risk patients, and user-friendly decision aids for healthcare professionals. Effective education for healthcare professionals and optimised clinical workflows may help to address current knowledge gap and implementation barriers in the detection and management of elevated Lp(a) in hospital. Show less

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations. Show less

The goal of these studies is to discover novel urinary biomarkers of lupus nephritis (LN). Urine from systemic lupus erythematosus (SLE) patients was interrogated for 1000 proteins using a novel, quantitative planar protein microarray. Hits were validated in an independent SLE cohort with inactive, active non-renal (ANR) and active renal (AR) patients, in a cohort with concurrent renal biopsies, and in a longitudinal cohort. Single-cell renal RNA sequencing data from LN kidneys were examined to deduce the cellular origin of each biomarker. Screening of 1000 proteins revealed 64 proteins to be significantly elevated in SLE urine, of which 17 were ELISA validated in independent cohorts. Urine Angptl4 (area under the curve (AUC)=0.96), L-selectin (AUC=0.86), TPP1 (AUC=0.84), transforming growth factor-β1 (TGFβ1) (AUC=0.78), thrombospondin-1 (AUC=0.73), FOLR2 (AUC=0.72), platelet-derived growth factor receptor-β (AUC=0.67) and PRX2 (AUC=0.65) distinguished AR from ANR SLE, outperforming anti-dsDNA, C3 and C4, in terms of specificity, sensitivity and positive predictive value. In multivariate regression analysis, urine Angptl4, L-selectin, TPP1 and TGFβ1 were highly associated with disease activity, even after correction for demographic variables. In SLE patients with serial follow-up, urine L-selectin (followed by urine Angptl4 and TGFβ1) were best at tracking concurrent or pending disease flares. Importantly, several proteins elevated in LN urine were also expressed within the kidneys in LN, either within resident renal cells or infiltrating immune cells, based on single-cell RNA sequencing analysis. Unbiased planar array screening of 1000 proteins has led to the discovery of urine Angptl4, L-selectin and TGFβ1 as potential biomarker candidates for tracking disease activity in LN. Show less

Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide association studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT variation. This may open new avenues of investigation into human ocular traits and their relationship to the risk of vision disorders. Show less

For settings with limited laboratory capacity, 2013 World Health Organization (WHO) guidelines recommend targeted HIV-1 viral load (VL) testing to identify virological failure. We previously developed and validated a clinical prediction score (CPS) for targeted VL testing, relying on clinical, adherence and laboratory data. While outperforming the WHO failure criteria, it required substantial calculation and review of all previous laboratory tests. In response, we developed four simplified, less error-prone and broadly applicable CPS versions that can be done 'on the spot'. Findings From May 2010 to June 2011, we validated the original CPS in a non-governmental hospital in Phnom Penh, Cambodia applying the CPS to adults on first-line treatment >1 year. Virological failure was defined as a single VL >1000 copies/ml. The four CPSs included CPS1 with 'current CD4 count' instead of %-decline-from-peak CD4; CPS2 with hemoglobin measurements removed; CPS3 having 'decrease in CD4 count below baseline value' removed; CPS4 was purely clinical. Score development relied on the Spiegelhalter/Knill-Jones method. Variables independently associated with virological failure with a likelihood ratio ≥ 1.5 or ≤ 0.67 were retained. CPS performance was evaluated based on the area-under-the-ROC-curve (AUROC) and 95% confidence intervals (CI). The CPSs were validated in an independent dataset. A total of 1490 individuals (56.6% female, median age: 38 years (interquartile range (IQR 33-44)); median baseline CD4 count: 94 cells/µL (IQR 28-205), median time on antiretroviral therapy 3.6 years (IQR 2.1-5.1)), were included. Forty-five 45 (3.0%) individuals had virological failure. CPS1 yielded an AUROC of 0.69 (95% CI: 0.62-0.75) in validation, CPS2 an AUROC of 0.68 (95% CI: 0.62-0.74), and CPS3, an AUROC of 0.67 (95% CI: 0.61-0.73). The purely clinical CPS4 performed poorly (AUROC-0.59; 95% CI: 0.53-0.65). Simplified CPSs retained acceptable accuracy as long as current CD4 count testing was included. Ease of field application and field accuracy remains to be defined. Show less