Mahidol University's Institutional Repository
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Recent Submissions
The impact of neutralizing anti-IFN-γ autoantibodies on GBP5 expression and monocyte dysfunction in adult-onset immunodeficiency
(2025-01-01) Sornsuwan K.; Juntit O.a.; Thongheang K.; Wongsawat E.; Tayapiwatana C.; Yasamut U.; Sornsuwan K.; Mahidol University
Anti-interferon gamma (IFN-γ) autoantibodies (AIGAs) are linked to opportunistic infections in adult-onset immunodeficiency (AOID). These autoantibodies, particularly those recognizing the C-terminal linear epitope (P128–143) and B27 epitope, block IFN-γ functions in monocytes, contributing to disease. In a retrospective analysis of residual plasma from 45 AOID patients, we confirmed the presence of AIGAs by indirect ELISA and evaluated their capacity to neutralize IFN-γ–induced MHC-II expression. All samples showed neutralizing capability, with varying epitope recognition: 10 samples had AIGAs which recognize both epitopes, 7 had B27 epitope-recognizing AIGAs, 12 had P128–143 epitope-recognizing AIGAs, and 16 had neither. Inhibition levels ranged from 36.5 % to 91.6 %. Five representative samples containing at least B27 epitope-recognizing AIGAs could inhibit guanylate binding protein 5 (GBP5) expression, crucial for pathogen killing. Additionally, high levels of neutralizing AIGAs persisted in patients with active and stable diseases. Overall, the data underscore the relationship between neutralizing AIGA levels, population characteristics, and persistence of AIGAs with monocyte dysfunction and disease outcome.
Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study☆
(2025-01-01) Fizazi K.; Clarke N.W.; De Santis M.; Uemura H.; Fay A.P.; Karadurmus N.; Kwiatkowski M.; Alvarez-Fernandez C.; Jiang S.; Sotelo M.; Parslow D.; Oliveira N.; Kwon T.G.; Ye D.; Boudewijns S.; Danchaivijitr P.; Rooney C.; Gresty C.; Yeste-Velasco M.; Logan J.; George D.J.; Fizazi K.; Mahidol University
Background: In metastatic hormone-sensitive prostate cancer (mHSPC), phosphatase and tensin homolog (PTEN) deficiency results in phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway activation, providing an independent proliferative drive, which cannot be suppressed by androgen receptor pathway inhibitors (ARPIs), resulting in worse outcomes. Dual inhibition of PI3K/AKT and AR pathways with capivasertib and abiraterone may delay progression and improve disease outcomes. Patients and methods: In CAPItello-281 (NCT04493853), patients with PTEN-deficient mHSPC (diagnostic cut-off: ≥90% viable malignant cells with no specific cytoplasmic PTEN immunohistochemistry staining) received capivasertib or placebo (1 : 1) plus abiraterone, prednisone/prednisolone, and androgen deprivation therapy (ADT). The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS); overall survival (OS) was a key secondary endpoint. Post hoc exploratory subgroups at increasing PTEN cut-off thresholds were also assessed. Results: 25.3% (1519/6003) of patients with valid tumor test results had PTEN-deficient tumors. In the randomized PTEN-deficient population, a statistically significant improvement in rPFS was observed with capivasertib plus abiraterone (n = 507, median 33.2 months) versus placebo plus abiraterone [n = 505, 25.7 months; hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.66-0.98, P = 0.034]. Post hoc rPFS analyses for loss of PTEN cut-offs of ≥95%, ≥99%, and 100% showed that the capivasertib plus abiraterone arm performed consistently across cut-offs, but the placebo plus abiraterone arm performed progressively worse as the cut-off for the degree of PTEN loss was increased, resulting in a numerically improved treatment effect. In the overall population studied, the HR for OS (26.4% maturity) was 0.90, 95% CI 0.71-1.15, P = 0.401. The most common adverse events (AEs) for capivasertib plus abiraterone were diarrhea (51.9%; 8.0% placebo plus abiraterone), hyperglycemia (38.0%; 12.9%), and rash (35.4%; 7.0%). Deaths associated with an AE were reported in 36 (7.2%) and 26 (5.2%) patients in the capivasertib plus abiraterone and placebo plus abiraterone arms, respectively. Conclusions: Capivasertib plus abiraterone improves rPFS versus placebo plus abiraterone in PTEN-deficient mHSPC, on a background of ADT, with a 7.5-month improvement in median rPFS. AE profile was consistent with that of the individual agents. Patients with PTEN-deficient mHSPC benefit from dual blockade of the PI3K/AKT and AR pathways with capivasertib plus abiraterone.
Deconvolution of the On-Target Activity of Plasmepsin V Peptidomimetics in Plasmodium falciparum Parasites
(2025-12-12) Su W.; Nguyen W.; Siddiqui G.; Dziekan J.M.; Marapana D.; Penington J.S.; Mehra S.; Razook Z.; McCann K.; Ngo A.; Jarman K.E.; Barry A.E.; Papenfuss A.T.; Gilson P.R.; Creek D.J.; Cowman A.F.; Sleebs B.E.; Dans M.G.; Su W.; Mahidol University
Plasmepsin V (PMV), an essential aspartyl protease, plays a critical role during the asexual blood stage of infection of Plasmodium by enabling the export of parasite proteins into the host red blood cell. This export is vital for parasite survival and pathogenesis, making PMV an attractive target for antimalarial drug development. Peptidomimetic inhibitors designed to mimic the natural substrate of PMV have demonstrated potent parasite-killing activity by blocking protein export. While these compounds have been instrumental in validating PMV as a bona fide antimalarial target, inconsistencies between their biochemical potency and cellular activity have raised questions regarding their precise mechanism of action. In this study, we employed chemoproteomic approaches, including solvent-induced protein precipitation and intact-cell thermal profiling, to demonstrate PMV target engagement by the peptidomimetics. To further support these findings, we generated parasite lines exhibiting reduced sensitivity to peptidomimetics. Through whole-genome sequencing of these parasite lines, a single nucleotide variant within the pmv gene was revealed. This mutation was later validated using reverse genetics, confirming its role in mediating resistance. Together, these data provide strong evidence that the peptidomimetics exert their antimalarial activity by directly targeting PMV. These findings further support the potential of PMV as a validated and promising target for future antimalarial drug development.
Effects of Hot-Air Drying Conditions on Quality Attributes of Meat and Shell of Dried Shrimp
(2025-12-01) Lin Z.; Zhang Z.; Zheng Z.; Hou R.; Zhang Y.; Zheng B.; Sriboonvorakul N.; Hu J.; Lin Z.; Mahidol University
Maintaining desirable texture, color, and flavor during hot-air drying is crucial for improving the commercial value of dried shrimp. This study aims to address the limitations of previous research on hot-air drying of shrimp, which focused solely on the meat. The objective is to simultaneously investigate the dual effects of hot-air drying conditions on the textural and physicochemical properties of both the shrimp shell and meat. This provides a theoretical foundation for preserving the optimal texture, color, and flavor of dried shrimp snack products. After drying and separation, the textural and physicochemical properties of the two components were comprehensively evaluated, including hardness, crispness, chewiness, springiness, color (L*, a*, b*), rehydration rate, sensory attributes, and odor characteristics. Furthermore, to elucidate the complex interrelationships among these variables, two predictive models were established: a Partial Least Squares Regression (PLSR) model and an Artificial Neural Network (ANN) model optimized using the Levenberg–Marquardt algorithm. The PLSR model achieved a calibration accuracy of R2 = 0.38 and a validation accuracy of R2 = 0.32, whereas the optimized LM-ANN model exhibited markedly superior predictive capability (R2Training = 0.99, R2Validation = 0.98), effectively capturing nonlinear associations between drying parameters and quality attributes of both meat and shell. Finally, a user-oriented prediction module was established based on the optimized ANN model, allowing flexible input of variables and prediction of quality outcomes. This integrated framework may provide a novel approach for modeling and optimizing the hot-air drying process of shrimp, offering practical guidance for quality control and texture customization of dried shrimp products.
Impacts of polymorphisms in drug-metabolizing enzyme and transporter genes on irinotecan toxicity and efficacy in Thai colorectal cancer patients
(2025-12-01) Akarapredee N.; Atasilp C.; Sukasem C.; Jinda P.; Sukprasong R.; Jensuriyarkun J.; Wongjitjanyong S.; Satapornpong P.; Vanwong N.; Akarapredee N.; Mahidol University
Introduction Irinotecan is a chemotherapy agent commonly prescribed for metastatic colorectal cancer but often leads to neutropenia. Variations in genes encoding drug-metabolizing enzymes and transporters may affect the toxicity and effectiveness of irinotecan. This study aimed to examine the impact of these genetic polymorphisms on irinotecan outcomes in Thai colorectal cancer patients. Methods The study retrospectively analyzed 41 metastatic colorectal cancer patients treated with irinotecan-based chemotherapy. Genotyping was conducted for 23 single nucleotide polymorphisms in genes including UGT1A1, CYP3A4, CYP3A5, CES1, ABCB1, ABCC2, ABCC5, ABCG1, ABCG2, and SLCO1B1.Toxicity and efficacy were assessed, with statistical significance set at a Bonferroni-corrected P value<0.002. Results In terms of toxicity, UGT1A1*6 was significantly associated with both all-grade and severe neutropenia in the first cycle (p<0.001) and severe neutropenia in the second cycle (p<0.002). Lower absolute neutrophil count was observed among intermediate and poor UGT1A1 metabolizers (p<0.001). The ABCC2 -24C>T variant was linked to all-grade neutropenia in the second cycle (p=0.001). For efficacy, patients with the wild-type UGT1A1*6 had longer progression-free survival (PFS) (p<0.002). Additionally, the SLCO1B1 521T>C variant was associated with improved PFS (p<0.002). Conclusion UGT1A1*6 and ABCC2 -24C>T variants emerge as potential predictors of irinotecan-induced neutropenia, while UGT1A1*6 and SLCO1B1 521T>C may serve as markers of prolonged PFS in Thai patients. Validation through larger prospective studies is essential to confirm and refine these genetic associations.