Apinya Jusakul

Introduction: Strongyloides stercoralis exacerbates the early stages of chronic kidney disease (CKD) through the disruption of metabolic processes. However, the metabolic consequences of infection and of its resolution after treatment remain poorly characterized. This study explores urinary metabolic changes in patients with early-stage CKD following antiparasitic therapy. Methods: In an exploratory before-and-after longitudinal study design, fifteen patients presenting with concurrent early-stage CKD (stages 1–3) and confirmed strongyloidiasis were monitored at baseline and 17 months following ivermectin anthelmintic treatment. Serum and urine clinical biochemistry assessments were paired with high-resolution untargeted liquid chromatography-quadrupole time-of-flight mass spectrometry (LC/Q-TOF MS) urinary metabolomic profiling executed in both negative and positive ionization modes. Results: Global multivariate analyses did not demonstrate statistically significant separation between pre- and post-treatment urinary metabolomic profiles. However, univariate analyses identified 91 significantly altered urinary mass features following treatment. Among these, thirteen metabolites (twelve decreased and one increased) were identified as potential markers associated with parasite clearance in patients with CKD. Changes in fasting blood sugar, serum creatinine, and estimated glomerular filtration rate (eGFR) were also observed. Notably, urinary 1-O-galloyl-6-O-cinnamoylglucose was negatively correlated with urine creatinine, while sedoheptulose-7-phosphate levels was negatively correlated with serum creatinine. Additionally, urinary ascorbic acid levels increased following treatment, suggesting their potential relevance to kidney function. Pathway analysis indicated disturbances in amino acid and carbohydrate metabolism, particularly glycine/serine metabolism, tyrosine metabolism, and glycolysis, that partially normalized post-treatment. Conclusion: These findings suggest that clearance of S. stercoralis infection was associated with changes in urinary metabolomic profiles in patients with CKD. Kidney function and urinary metabolomic profiles were observed in patients with early-stage CKD and S. stercoralis infection. Further investigations of kidney outcomes following S. stercoralis clearance and of the potential value of strongyloidiasis screening in patients with CKD are warranted.

1. Thiamine, commonly known as vitamin B1, is water-soluble and plays a vital role in energy metabolism and mitochondrial energy production. It is a precursor of thiamine pyrophosphate (TPP), which...

Importance: Suspicious thyroid nodules often prompt avoidable surgeries due to diagnostic uncertainty. Although commercial next-generation sequencing assays improve risk stratification, evidence for locally developed sequencing pipelines remains limited. Objective: To evaluate the diagnostic performance of Burapha University-customized whole-exome sequencing (BUU-WES) using preoperative ultrasound-guided core needle biopsy (CNB) specimens, with postsurgical histopathology as the reference standard. Design: Multicenter prospective diagnostic accuracy study. Setting: Four tertiary-care hospitals in Thailand. Participants: Adults (≥20 years) undergoing thyroid surgery for nodules suspicious on ultrasonography (American College of Radiology Thyroid Imaging Reporting and Data System 4-5) and/or cytology (Bethesda I-V). Intervention: DNA extracted from CNB specimens underwent BUU-WES; variants were interpreted using curated databases and published evidence. Main Outcome and Measures: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy with 95% confidence intervals (CIs). Results: Among 82 participants (82 index nodules), malignancy prevalence was 25.6% (21/82). BUU-WES demonstrated sensitivity of 57.1% (95% CI, 34.0%-78.2%), specificity of 86.9% (95% CI, 75.8%-94.2%), PPV of 60.0% (95% CI, 36.1%-80.9%), and NPV of 85.5% (95% CI, 74.2%-93.1%). In nodules ≥1 cm (n = 71), sensitivity increased to 83.3% (95% CI, 51.6%-97.9%), specificity 89.8% (79.2%-96.2%), with NPV 96.4% (95% CI, 87.5%-99.6%). In indeterminate cytology (Bethesda III/IV), BUU-WES showed moderate diagnostic performance, with sensitivity of 60% and specificity and NPV of 86.4%. The most frequently detected alterations involved BRAF , NRAS , and KRAS . Conclusions: BUU-WES primarily functions as a rule-in test due to its high specificity. Its most clinically relevant application is in indeterminate thyroid nodules (Bethesda III/IV), where it serves as an adjunctive tool for risk stratification. Within this subgroup, diagnostic performance is further optimized in nodules ≥1 cm, where the improved NPV suggests potential rule-out applicability in appropriately selected patients.

Inactivating mutations in BAP1 (BRCA1-associated protein 1) are prevalent in many aggressive cancers of high global concern, including cholangiocarcinoma, mesothelioma, uveal melanoma, and renal cell carcinoma. However, research on BAP1 has been predominantly focused on single cancer types, lacking comprehensive pancancer studies that could uncover universal molecular mechanisms and therapeutic vulnerabilities. Our pancancer study uses K-ε-GG ubiquitin remnant motif pulldown coupled with mass spectrometry to comprehensively map the landscape of proteins deubiquitinated by BAP1. Combined with transcriptomics and functional assays, we uncover previously unrecognized roles of BAP1 in enhancing global genome nucleotide excision repair (GG-NER) by modulating the deubiquitination dynamics of three GG-NER DNA damage recognition proteins, DDB1, RAD23B, and COPS7B. We also identify LSD1 (lysine-specific histone demethylase 1) and PARP1 [poly(ADP-ribose) polymerase 1] as synthetic lethal partners of BAP1 through high-throughput drug inhibitor screening. Integrative analysis using ChIP sequencing, ATAC sequencing, and transcriptomics demonstrates the colocalization of BAP1, LSD1, and PARP1 on chromatin loci, with LSD1 promoting chromatin relaxation to facilitate efficient transcription-coupled NER (TC-NER) in addition to GG-NER, whereas PARP1 facilitates lesion recognition of both TC-NER and GG-NER. Combined inhibition of LSD1 and PARP1, using SP2509/SP2577 and olaparib, respectively, synergistically hinders NER, induces apoptosis, reduces tumor burden, and prolongs the survival of multiple BAP1-deficient pancancer in vitro models and in vivo xenografts. In conclusion, our results provide a deubiquitination landscape of BAP1; elucidate the mechanisms of action of BAP1, LSD1, and PARP1 in pancancers; and describe a promising combination therapeutic strategy applicable across multiple cancers with BAP1 mutations.

Cholangiocarcinoma (CCA) is a highly aggressive cancer of the biliary tract, distinguished by significant intratumoral heterogeneity (ITH), which contributes to therapy resistance and unfavorable clinical outcomes. Traditional genome profiling has revealed recurring driver changes in CCA; yet, genomic data alone fails to elucidate functional pathway activation, adaptive signaling, and the diverse treatment responses reported among tumor locations and disease subtypes. This review analyses the use of integrated sequencing technologies, proteogenomics, and phosphoproteomics to systematically characterize intratumoral heterogeneity in cholangiocarcinoma and convert molecular diversity into therapeutically applicable discoveries. We present evidence that the combination of genomic sequencing and mass spectrometry–based proteomics facilitates the direct correlation of genetic mutations with protein expression, post-translational modifications, and signaling system activity. Phosphoproteomic profiling specifically offers functional insights into kinase-driven networks that dictate tumor aggressiveness, therapeutic susceptibility, and adaptive resistance mechanisms, which cannot be anticipated only from DNA-level analysis. We propose that integrating proteogenomic and phosphoproteomic analyses into diagnostic and therapeutic assessments can enhance molecular classification, reveal subtype- and region-specific therapeutic dependencies, and guide rational combination treatment strategies, based on recent extensive proteogenomic studies and functional proteomic investigations in CCA. Pathway-level analysis of intratumoral heterogeneity provides a framework for selecting targeted medicines, predicting resistance, and informing personalized treatment strategies in CCA. The combination of sequencing, proteogenomics, and phosphoproteomics is essential for advancing precision oncology in cholangiocarcinoma. The implementation of this multi-layered analytical approach may better patient classification, refine therapy choices, and eventually improve clinical outcomes for individuals with this particular heterogeneous cancer.

Background: The cytochrome P450 family 3 subfamily A polypeptide 5 (CYP3A5) gene plays an important role in renal function through its product’s involvement in metabolizing endogenous substances and drugs, including immunosuppressants used following kidney transplantation. A single-nucleotide polymorphism, CYP3A5*3 (rs776746), produces a non-functional variant that may influence progression of chronic kidney disease (CKD) by impairing renal filtration. However, the frequency of the CYP3A5*3 allele in the Thai population and its association with renal parameters remain underexplored. This study aimed to determine the prevalence of CYP3A5 polymorphisms and their association with renal function. Methods: We investigated the distribution of CYP3A5 polymorphisms in 329 northeastern Thai participants, including 205 CKD patients and 124 healthy controls. Genotyping was performed using the TaqMan allelic discrimination assay. Renal function parameters were assessed and compared between CYP3A5*1 and CYP3A5*3 allele carriers. Results: In the entire cohort, the allele frequency of CYP3A5*3 was 63.2%, with genotype frequencies of CYP3A5*1/*1 (16.7%), CYP3A5*1/*3 (40.1%), and CYP3A5*3/*3 (43.2%). There was no significant difference in the CYP3A5 allele frequencies between CKD and control groups. CYP3A5*3 carriers exhibited significantly lower eGFR, urine creatinine and serum creatinine clearance and higher UACR compared to CYP3A5*1 carriers. After adjusting for confounders, CYP3A5*3 remained significantly associated with reduced urine creatinine. Conclusion: This study highlights a high prevalence of CYP3A5 polymorphisms in the northeastern Thai population. The association of the CYP3A5*3 allele with renal function parameters underscores the need for further research into the mechanisms by which CYP3A5 affects kidney function, which could inform personalized CKD management strategies.

Background/Aim: Cholangiocarcinoma (CCA) is an aggressive hepatobiliary malignancy characterized by genomic heterogeneity. KRAS mutations play a significant role in influencing patient prognosis and guiding therapeutic decision-making. This study aimed to determine the prevalence and prognostic significance of KRAS mutations in CCA, asses the detection of KRAS G12/G13 mutations in plasma cell-free DNA (cfDNA), and evaluate the prognostic value of KRAS G12/G13 mutant allele frequency (MAF) in cfDNA in relation to clinicopathological data and patient survival. Materials and Methods: A retrospective analysis of 937 CCA patients was performed using data from cBioPortal to examine KRAS mutation profiles and their association with survival. Plasma from 101 CCA patients was analyzed for KRAS G12/G13 mutations in the cfDNA using droplet digital PCR, and the results were compared with tissue-based sequencing from 78 matched samples. Results: KRAS driver mutations were found in 15.6% of patients, with common variants being G12D (37.0%), G12V (24.0%) and Q61H (8.2%). Patients harboring KRAS mutations exhibited decreased overall and recurrence-free survival. KRAS G12/G13 mutations were detected in 14.9% of cfDNA samples, showing moderate concordance with tissue sequencing, and achieving 80% sensitivity and 93% specificity. Elevated KRAS G12/G13 MAF in cfDNA, combined with high CA19-9 levels, correlated with poorer survival outcomes. Conclusion: The presence of KRAS mutations was associated with poor survival in CCA, underscoring the importance of KRAS mutations as prognostic markers. The detection of KRAS mutations in cfDNA demonstrated potential as a promising non-invasive alternative for mutation detection and, when combined with CA19-9 levels, may improve prognostic efficacy in CCA.