Siliang Han,1 Yichao Zhang,1 Zhe Wang,1 Fanchang Kong,2 Junmin Xie11Department of Cardiovascular Medicine, Affiliated Hospital Of Hebei University, Baoding, People’s Republic of China; 2Department of Vascular Surgery, Baoding Vasculitis Hospital, Baoding, People’s Republic of ChinaCorrespondence: Junmin Xie, Department of Cardiovascular Medicine, Affiliated Hospital Of Hebei University, No. 212, Lianchi District, Baoding, Hebei, 071000, People’s Republic of China, Email hsl1990@hbu.edu.cnPurpose: To evaluate the clinical efficacy of a statin therapy strategy guided by Apolipoprotein E (ApoE) gene polymorphism in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).Patients and Methods: In this retrospective study, 263 ACS patients post-PCI were included. The control group (n=120) received standard atorvastatin therapy. The study group (n=143) received a genotype-guided strategy: patients with ApoE E2/E3 genotypes received atorvastatin monotherapy, while those with the E4 genotype received atorvastatin combined with the PCSK9 inhibitor evolocumab. Clinical efficacy, cardiac function parameters, lipid profiles, and quality of life were compared between groups at 1 and 3 months post-treatment.Results: The total effective rate, defined as the combined proportion of patients rated "markedly effective” (complete symptom resolution with a ≥ 2-grade improvement in New York Heart Association [NYHA] functional class) and "effective” (notable symptom improvement with a 1-grade NYHA improvement), was significantly higher in the genotype-guided group than in the control group (92.3% vs 82.5%; P=0.025). At follow-up, the study group showed greater improvements in left ventricular ejection fraction (LVEF) and quality of life scores, and greater reductions in left ventricular dimensions and lipid parameters (including LDL-C) (all P< 0.05). Multivariate logistic regression analysis identified the genotype-guided treatment strategy as an independent protective factor for clinical efficacy (P< 0.05).Conclusion: An ApoE genotype-guided lipid-lowering escalation strategy, in which E4 carriers—who typically respond suboptimally to statin monotherapy and carry a higher residual risk—received add-on PCSK9-inhibitor (evolocumab) therapy, was associated with improved clinical efficacy, cardiac function, and lipid control in ACS patients after PCI. Because the study group received more intensive lipid-lowering therapy, the observed benefits most plausibly reflect the greater treatment intensity achieved through genotype-directed escalation rather than the act of genotyping alone, and require confirmation in prospective randomized trials with longer follow-up.Keywords: pharmacogenomics, precision medicine, dyslipidemia, coronary artery disease, treatment escalation
Cheryl Weiqi Tan,1 Gayatiri Raveentheran,2 Khadijah Rafi’ee,1 Lena Das,3 Mark Jean-Aan Koh,2 Ene-Choo Tan11KK Research Laboratory, KK Women’s & Children’s Hospital, Singapore, Singapore; 2Department of Dermatology, KK Women’s and Children’s Hospital, Singapore, Singapore; 3Rheumatology & Immunology Service, KK Women’s and Children’s Hospital, Singapore, SingaporeCorrespondence: Mark Jean-Aan Koh, Department of Dermatology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore, Email mark.koh.j.a@singhealth.com.sg Ene-Choo Tan, KK Research Laboratory, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore, 229899, Singapore, Email tan.ene.choo@kkh.com.sgBackground: Kikuchi-Fujimoto disease (KFD) is a rare disorder involving necrotizing lymphadenitis which was first described in Japan. The presentations include lymphadenopathy, fever, and leukopenia of unknown cause.Patient: A 2-year-old Malay girl was evaluated and diagnosed with KFD after presenting with prolonged fever and rash. Her parents are not biologically related, but there is a strong family history of KFD on the maternal side of the family. We investigated the genetic profiles of the patient, her mother and grandmother, who also had a history of similar presentations.Methods: High-resolution HLA typing was performed on the family to examine the potential associations with HLA genotypes. Next-generation sequencing using a Mendelian gene panel was performed on the child’s sample, followed by targeted Sanger sequencing of shortlisted variants for the family members.Results: The three affected family members share 14 HLA alleles that are not present in the healthy father, among which five have reported associations with autoimmune inflammatory disorders. Two of them (DQA1*02:01 and DRB1*07:01) were also reported in a pair of affected twins from Australia. In addition to HLA, three rare missense variants in immune-related genes (FGFR3, NRP2 and PCM1) were found to correlate with the presence of symptoms within the family. The three affected members also had at least one of the variants in the C1QC gene (a missense and a 17-nucleotide deletion), which is part of the complement pathway that might be related to KFD.Conclusion: Our study uncovers some HLA alleles and immune gene variants that might be important in the development of KFD. Large-scale sequencing of immune genes may be as important as high-resolution HLA typing in identifying genetic factors contributing to KFD pathogenesis. HLA studies provide risk associations to KFD, while association with variants in immune genes may reveal pathways in the development of KFD.Keywords: histiocytic necrotizing lymphadenitis, HLA, immune genes, genotypes, Kikuchi-Fujimoto disease
Background:Schizophrenia is considered a neuro-developmental disorder leading to disastrous lifelong disability of the patients and their families. There is a lack of data regarding pharmacogenomics of schizophrenia in Sudan. This study aimed to identify different genes affecting the treatment outcomes in Sudanese patients with schizophrenia. Methods:A case-control study was conducted on seven families having more than one member diagnosed with schizophrenia. This was a small exploratory family-based sequencing study involving 18 affected individuals and 8 controls from seven families. Ethical clearance and informed consent were obtained. Demographic data were collected using a standardized data collection sheet. DNA was extracted from blood samples collected from patients and control groups. Then, whole-exome and genome sequencing were performed. Sixty-six genes associated with schizophrenia, treatment, and treatment resistance were selected from the variant calling file. Variants showing single-nucleotide polymorphisms (SNPs) were identified. These variants were then classified based on their impact on the protein-coding sequence into high- and moderate-impact. Moreover, indel mutations were also identified. Results:Twelve variants of seven genes (COMT, FMO1, LPL, CYP2E1, ABCC1, GRM3, CYP2C9) were identified as genes with impact and potential association with schizophrenia (p-value=0.006632). Forty-three genes had a moderate impact, and they showed a potential association with schizophrenia (p-value=0.0004436). Two variants were indel mutations (CYP2D6, DTNBP1) and showed association with schizophrenia (p-value=0.004741). The p-values were generated from different databases. Conclusion:This exploratory family-based sequencing study identified several potentially relevant pharmacogenomic and schizophrenia-associated variants in Sudanese families, warranting validation in larger and ethnically diverse cohorts.
Purpose:Propofol, a commonly used intravenous sedative in general anesthesia, exhibits significant inter-individual variability in clinical effects; however, the underlying mechanisms remain uncertain. We aimed to assess the association between the UGT1A9 rs13418420 polymorphism and individual propofol response, as assessed by the time required for the bispectral index (BIS) to decrease to 60. Patients and Methods:A total of 75 Chinese female patients undergoing painless abortion, cervical conization, or hysteroscopy under intravenous anesthesia without endotracheal intubation were recruited. Based on bioinformatic analysis and our preliminary sequencing experiments in the Chinese population, UGT1A9 rs13418420 was selected for genotyping and validated using quantitative PCR (qPCR). The primary outcome was the time required for BIS to decrease to 60. Secondary outcomes included the time required for BIS to recover to 80, plasma propofol concentrations measured at 1, 5, 10, and 15 minutes after administration, mean arterial pressure, and heart rate. Results:Our results revealed that patients with the TT genotype of UGT1A9 rs13418420 exhibited a shorter time for BIS to decrease to 60 (P <0.001, adjusted P <0.001) and higher plasma drug concentrations at 15 minutes compared to those with CC and CT genotypes (P=0.026, P=0.032). Linear mixed-effects model analysis of repeated plasma concentration measurements showed a significant time effect (P < 0.001), a trend toward an overall genotype effect (P = 0.063), and no significant genotype-by-time interaction (P = 0.885). No significant differences were observed in recovery-related outcomes among the three genotype groups. Conclusion:Patients carrying the TT genotype of UGT1A9 rs13418420 exhibited a significantly shorter time to BIS 60 and higher plasma propofol concentrations at 15 minutes than those carrying the CC or CT genotypes. No significant differences were observed in recovery-related outcomes among the three genotype groups. These findings suggest that UGT1A9 rs13418420 polymorphism may contribute to inter-individual variability in the onset of propofol-induced anesthesia and warrant further investigation in larger studies.
Background:Pharmacogenomics (PGx) is increasingly recognised as a cornerstone of personalised medicine, with established recommendations for many commonly prescribed medicines. Despite this, translation into real-world clinical practice remains inconsistent, reflecting persistent implementation and health-system gaps. Objective:To provide a multidisciplinary perspective on the system-level conditions required to normalise PGx within contemporary hospital care, drawing on structured knowledge exchange and priority-setting across clinical, digital and governance domains. Methods:A multidisciplinary knowledge exchange program convened clinicians, pharmacists, genetic services, informatics teams, researchers and health-service leaders across oncology, transplantation, peri-operative care and palliative care. Knowledge was exchanged through presentations, informing the generation and ranking of shared priorities in groups and individually using the Nominal Group Technique. Aggregate scores were calculated, and priorities further refined. Presentation insights were synthesised using a narrative, interpretive approach, to identify cross-cutting translational themes. Results:Eleven shared priorities were identified across four broad critical levers for sustainable integration: (1) computable, reusable PGx data embedded within electronic medical records (EMR); (2) coordinated and equitable testing and prescribing pathways; (3) workforce capability and stewardship; and (4) governance. Equity, access and data sovereignty were highlighted as foundational to responsible scale-up, particularly for First Nations peoples and under-represented communities. Conclusion:Insights from this knowledge-exchange program highlight the feasibility and clinical relevance of PGx, and identify workforce capability, EMR integration, and system-level governance as critical implementation levers of adoption. Coordinated national investment and policy alignment will be central to realising the full value of PGx.
Inflammatory myofibroblastoma tumor (IMT) is a rare mesenchymal neoplasm that develops in the lungs, retroperitoneum, or abdominopelvic region, and is most common in children and adolescents; although IMT usually has a good prognosis, some cases still show local invasion, recurrence, and even distant metastasis. Effective standard treatment for locally advanced or metastatic IMT is limited, but therapy with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) improves the prognosis in some patients with ALK protein expression or ALK gene fusions. This case reports a 39-year-old woman with recurrent fever, cough, sputum, chest tightness, and shortness of breath for more than 2 weeks. Contrast-enhanced computed tomography (CT) revealed a mass in the upper lobe of the right lung with ill-defined borders involving the mediastinum, pleura, and right hilum. Multiple pleural nodules and right-sided pleural effusion were also observed. IMT was diagnosed by lung biopsy, and ALK positive was confirmed by immunohistochemistry. The patient's lung CT was reviewed after 3 weeks of treatment with brigatinib, and the right lung lesion and multiple metastases in the right pleura, hilar region, and mediastinum were significantly smaller than before. Additionally, the right pleural effusion was reduced, and the clinical symptoms were significantly improved compared to prior evaluations. Unlike most IMT cases, this patient's tumor showed highly malignant biology, with pleural metastasis at the initial diagnosis, as well as rapid progression and a favorable response to ALK TKI. Brigatinib represents a potential therapeutic option for the treatment of IMT.
Objective:To examine the association between SLCO1B1 gene polymorphisms and blood lipid metabolism in Tibetan patients with type 2 diabetes mellitus (T2DM) in Yushu, Qinghai, China. Methods:A cross-sectional study enrolled 156 Tibetan T2DM patients (78 normolipidemic and 78 dyslipidemic) admitted to Yushu People's Hospital between September 2022 and December 2023. SLCO1B1 521T>C and 388A>G polymorphisms were genotyped using PCR-RFLP. Results:The 521TC genotype frequency was significantly higher in the dyslipidemia group (30.8% vs. 14.1%, p < 0.05), with elevated triglycerides, total cholesterol, and low-density lipoprotein cholesterol (p < 0.01). Multivariate regression confirmed positive associations. The 388AG and 388GG genotypes were associated with elevated triglycerides (p < 0.05). Conclusion:SLCO1B1 521T>C and 388A>G polymorphisms are significantly associated with dyslipidemia in this high-altitude Tibetan T2DM population, with 521T>C showing stronger predictive potential.
Wei Cai, Yi Liang, Li-Na Kang, Ya-Qian Jin, Pan XuDepartment of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, Chongqing, 400000, People’s Republic of ChinaCorrespondence: Pan Xu, Department of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, Chongqing, 400000, People’s Republic of China, Tel +86 023 65714718, Email xpysy123@163.comObjective: This study aimed to characterize the molecular epidemiology of α-/β-thalassemia in Chongqing’s University Town population in the University Town area of Chongqing, China.Methods: A retrospective analysis was conducted on 1012 individuals (comprising 840 females and 172 males, reflecting referral bias rather than biological sex differences) who underwent thalassemia genetic testing between June 2020 and February 2023. Genetic variants were detected using a combination of PCR and flow-through hybridization. Detection rates were compared between sexes using the chi-squared test. Hematological parameters were compared between carriers and a control group using the Mann–Whitney U-test.Results: The heterozygous carrier rates for α- and β-thalassemia were 12.1% and 11.4%, respectively. The overall detection rate was significantly higher in males (30.2%) than in females (22.1%). The predominant α-thalassemia variants were the –SEA deletion and the – 3.7 kb deletion. The most frequent β-thalassemia variants were CD41– 42, CD17, and IVS-II-654. Compared to controls, thalassemia carriers exhibited significantly elevated red blood cell (RBC) count and red cell distribution width (RDW), alongside reduced hemoglobin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC).Conclusion: The spectrum of thalassemia gene variants in this Chongqing population exhibits distinct regional patterns. University Town hosts a young and highly mobile population with diverse regional origins, making it a representative area for epidemiological sampling. Furthermore, standard complete blood count (CBC) testing cannot reliably distinguish thalassemia from iron deficiency anemia. The findings underscore the necessity of widespread genetic screening among newborns, school-aged children, and individuals of reproductive age for early carrier identification. This is crucial for effective genetic counseling, reproductive risk assessment, and the prevention of severe thalassemia births in the region.Keywords: thalassemia, molecular epidemiology, genetic variants, carrier screening, reproductive risk assessment
Purpose: Drug-drug-gene interactions can alter drug exposure and thereby increase the risk of clinically relevant outcomes, such as concentration-dependent toxicity (eg, tacrolimus toxicity in the context of altered CYP3A4/5 activity) or reduced treatment effectiveness. Despite their emerging relevance in clinical research, drug-drug-gene interactions remain understudied and are often ignored in clinical practice. Our objective was to assess the risk of phenoconversion by identifying potential drug-drug-gene interactions involving the transporters OATP1B1 and BCRP and the enzymes CYP2B6 and CYP3A4/5 in the Swiss population. Patients and Methods: Using claims data from the Helsana basic health insurance, we identified all persons of all ages with at least one drug claim between 2017 and 2021 and with Helsana basic health insurance coverage for at least one full year. For the five-year analysis, only persons with insurance for the entire five-year period were included. Within this study population, we assessed and ranked the frequency of potential drug-drug-gene interactions of a pharmacogenetic substrate and an inhibitor/inducer of OATP1B1, BCRP, CYP2B6, or CYP3A4/5. Potential drug-drug-gene interactions were defined as the co-occurrence of a pharmacogenetic substrate and an inhibitor/inducer within a 30-or 5-days window. Results: During the entire five-year period, 18'523 (2.1%) and 12'645 (1.4%) individuals were exposed to potential drug-drug-gene interactions using the 30-day and 5-day windows, respectively. Potential drug-drug-gene interactions most frequently involved CYP3A4/5 (81.0% and 85.3%), followed by CYP2B6 (10.9% and 8.7%) and OATP1B1 (8.7% and 13.3%). The top three drug classes involved were nervous system drugs (75.1%), cardiovascular drugs (10.6%), and dermatologicals (4.0%). Quetiapine ranked first in the number of involved drug pairs, with quetiapine-metamizole being the predominant drug pair. Conclusion: In Switzerland, two out of 100 persons taking drugs metabolized or transported by OATP1B1, BCRP, CYP2B6, and CYP3A4/5 are at potential risk of phenoconversion, predominantly involving CYP3A4/5. These findings quantify real-world phenoconversion potential at the population level and underscore the need for outcome-and genotype-linked studies to determine clinical relevance. As this study was not designed to assess clinical outcomes, future genotype-and outcome-linked investigations are required to determine the actual impact on adverse drug reactions or treatment effectiveness.
Massive hepatocellular carcinoma (HCC) is not suitable for radical surgery due to the factors of high tumor burden and poor postoperative liver function tolerance. There are few reports on the conversion therapy for HCC with insufficient future liver remnant (FLR) volume using a combination of two - stage hepatectomy (TSH), hepatic arterial infusion chemotherapy (HAIC), and lenvatinib - sintilimab. We report a case of a 62-year-old male with massive HCC (81mm×11.5mm×95mm). At the initial diagnosis, the ratio of his FLR to standard liver volume (SLV) was 34%. After multidisciplinary team (MDT) discussion, the patient decided to undergo conversion therapy. After three formal cycles (9 weeks) of conversion therapy, the FLR/SLV ratio increased to 65%, and then right hepatectomy was performed. The lesion achieved a partial response (PR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. The second hepatectomy was successfully performed, and there was no recurrence during the 36-month postoperative follow-up. In this case, portal vein ligation (PVL) surgery, HAIC, and targeted immunotherapy contributed to the conversion therapy of HCC through different dimensions, including mechanical blood flow blockage, local chemotherapy, and immune regulation, laying the foundation for the safety of radical surgery and long-term postoperative survival.
Objective:To construct and externally validate a multi-omics nomogram that uses only routine clinicopathological variables to predict tumor mutational burden (TMB), microsatellite instability (MSI), NTRK/PIK3CA mutation status and overall survival (OS) in colorectal cancer (CRC). Methods:TCGA data (n=398) served as the training set and 120 consecutive CRC patients who underwent radical resection at Yuebei People's Hospital formed the prospective validation set. After z-score normalization, 21demographic, clinical and pathological features were screened for multicollinearity (VIF<5) and redundancy via least absolute shrinkage and selection operator (LASSO) regression with 10-fold cross-validation. Optimal hyper-parameters for each algorithm were tuned by nested 10-fold grid search. Four machine-learning algorithms, logistic regression (LR), support-vector machine (SVM), decision tree (DT) and random forest (RF), were compared by area under the receiver-operating-characteristic curve (AUC), F1 score and decision-curve analysis. The best model was externally validated and calibrated with bootstrapping. Results:The results showed that the TMB prediction model included in the MSI index had the best power when constructed by the RF method, with an area under the ROC curve value of 0.9597. For the MSI state prediction model which includes three indicators of TMB, had the best power when constructed by RF method, with AUC value of 0.8225. The NTRK and PIK3CA gene status prediction model, which included three indicators of TMB and MSI status, had the best power when constructed using the RF method. Conclusion:The prediction model constructed in this study can help clinicians quickly identify high-risk patients and provide a basis for formulating a reasonable treatment plan. Further optimization of the model and expansion of the sample size are required to verify its power in the future.
Post-translational modifications (PTMs) of histones and non-histones are significant epigenetic modifications in humans, including acetylation, methylation, phosphorylation, glycosylation, and ubiquitination. These modifications regulate chromatin structure and gene expression, enabling proteins to perform their normal biological functions within cells and maintain stable expression. It is also closely related to the development process of liver diseases and plays an important role in the pathological processes of liver cancer, liver fibrosis, alcoholic fatty liver disease and non-alcoholic fatty liver disease. This article reviews the roles and pathway mechanisms mediated by post-translational modifications of histones and non-histones in these liver diseases, and briefly outlines how traditional Chinese medicine (TCM) can intervene in liver diseases by modulating protein post-translational modifications, providing new strategies for future prevention and treatment of liver diseases.
Tuberculosis (TB) continues to be a significant health challenge in India, which necessitates accurate and personalized therapeutic strategies for its successful treatment. Polymorphisms in the N-acetyltransferase-2 (NAT2) enzyme, involved in metabolism of a first-line drug, isoniazid (INH), for treatment of TB, have three acetylation phenotypes (slow, intermediate, or fast) that influence drug efficacy, toxicity and treatment outcomes. This article is presented as a narrative review of current research retrieved from PubMed, Scopus, and Google Scholar, focusing on studies related to NAT2 polymorphisms, pharmacogenomics, and tuberculosis therapy. The selected literature was reviewed to address the biological importance of the acetylation process and the development of DNA-based methods for genotyping of the NAT2 gene and discussion of their clinical applications, as well as the effect of NAT2 phenotypes on the treatment outcomes of TB. In addition, how highly genetic diversity in Indian populations necessitates the development of simplified and personalized medication therapy using population-based NAT2 phenotyping approaches is discussed. The need for nationwide mapping of NAT2 variants and the deployment of rapid, cost-effective genotyping platforms, especially in resource-limited endemic settings, are also emphasized. Moreover, how combining NAT2 profiling with additional pharmacogenetic markers may lead to a comprehensive framework for TB treatment optimization is also discussed. It is envisioned that integration of all of these approaches under NAT2-guided therapy in India's National TB Elimination Programme (NTEP) might change the dynamics of TB management in India.
Objective:To assess the clinical outcomes of osimertinib combined with platinum-based chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and to describe associated changes in angiogenesis-related and tumor marker levels. Methods:A retrospective analysis was performed on 112 NSCLC patients with EGFR-sensitive mutations treated from June 2018 to October 2020. Patients received either pemetrexed plus cisplatin (control group, n=56) or the same regimen with osimertinib (experimental group, n=56). Evaluation parameters included objective response rate (ORR), disease control rate (DCR), vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events. Results:ORR was comparable between groups (P>0.05), whereas the experimental group showed a significantly higher DCR (P<0.05). Post-treatment VEGF, Ang-2, CEA, and CYFRA21-1 levels decreased in both groups, with greater reductions observed in the experimental group (P<0.05). Median follow-up was 18.8 months. The experimental group demonstrated longer median PFS (15.7 vs 10.6 months, χ2=18.337, P<0.001) and OS (24.6 vs 17.5 months, χ2=24.679, P<0.001). The incidence of adverse reactions did not differ significantly between groups (P>0.05). Conclusion:In this retrospective cohort, the addition of osimertinib to platinum-based chemotherapy was associated with improved disease control and prolonged survival, along with greater reductions in angiogenesis-related and tumor marker levels, without increasing treatment-related toxicity.
Background:Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor with very poor prognosis for patients. Ferroptosis, as a novel cell death mechanism, brings a new direction for PAAD therapeutic research. Methods:Ferroptosis-related differentially expressed genes were identified by bioinformatic analysis of the FerrDb, TCGA, and GTEx databases. A series of analyses, including functional enrichment, protein-protein interaction (PPI) networking, survival analysis, and immune infiltration profiling, were performed to screen for and characterize hub genes. Subsequently, the expression of key hubs-NFE2L2 (NRF2), TGFB1, and TP53-was validated in PDAC patient tissues and cell lines using qRT-PCR and Western blot. Their biological functions were investigated via shRNA-mediated knockdown in BxPC-3 cells, followed by assays for cell migration (wound healing, transwell) and ferroptosis (ROS, MDA, GSH/GSSG). Results:Bioinformatic analysis identified 221 ferroptosis-related DEGs. NFE2L2, TGFB1, and TP53 emerged as core hub genes whose high expression correlated with poor patient survival and specific immune infiltration patterns. Experimental validation confirmed that NRF2, TGFβ1, and TP53 proteins were significantly upregulated in PDAC tissues compared to adjacent normal tissues. Functionally, knockdown of NFE2L2 and TGFB1 suppressed PDAC cell migration, whereas TP53 knockdown enhanced it. Inversely, NFE2L2 knockdown promoted ferroptosis (increased ROS and MDA, decreased GSH), while knockdown of both TGFB1 and TP53 inhibited ferroptosis. Conclusion:TP53, TGFB1, and NRF2 are key ferroptosis-related regulators in PAAD, influencing tumor progression, ferroptosis sensitivity, and immune contexture. These findings provide new insights and potential targets for ferroptosis-based therapies in PAAD.
The responses to Antihypertensive drugs vary among patients. The renal and muscular processes of blood flow regulation in peripheral blood vessels depend on the genetic and physiological constitution. Here, we present a case of an elderly female patient who experienced several phases of hypertensive emergencies during supervised training sessions. Hypertension treatment with different ACE inhibitors was discontinued because of severe side effects or simply no effect. Genotyping of ACE and ACTN3 gene polymorphisms helped find adequate antihypertensive treatment after all other approaches failed. The measured ACTN3-RR genotype indicated the possibility of a higher proportion of fast-twitch muscle fibers. This type of muscle fiber contributes to the generation of a high muscle force, which can compress the vascular bed more during physical work than slow muscle fibers. Therefore, a beta-blocker was used for treatment, allowing better vasodilative capacity. As reported by the patient, this pharmaceutical alone helped treat hypertensive emergencies adequately. Therefore, we believe that genetic information can help to identify optimal pharmaceutical treatments a problem that is highly prevalent in elderly subjects.
Objective:To evaluate the potential and efficacy of hepatic artery infusion chemotherapy combined with the PD-1/CTLA-4 bispecific antibody cadonilimab and the multi-kinase inhibitor donafenib in conversion therapy for unresectable hepatocellular carcinoma (uHCC) with Vp4-type portal vein tumor thrombus(PVTT). Methods:We present a case report of a 41-year-old male diagnosed with diffuse hepatocellular carcinoma (HCC) in the right lobe of the liver and tumor thrombus involving the main portal vein. Following multidisciplinary team evaluation, the patient received conversion therapy consisting of hepatic artery infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin, in combination with cadonilimab and donafenib. Results:Post-treatment imaging demonstrated marked regression of intrahepatic tumors and complete resolution of the portal vein tumor thrombus. Serum alpha-fetoprotein (AFP) levels normalized, and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels showed a significant decline. Subsequently, a radical right hepatectomy was successfully performed, and postoperative pathological examination confirmed complete response. The patient experienced an uneventful recovery and remained free of tumor recurrence during the one-year follow-up period. Conclusion:The integrative treatment strategy combining HAIC with cadonilimab and donafenib demonstrates considerable promise as a conversion approach for patients with traditionally unresectable HCC with Vp4-type PVTT. This regimen may substantially improve oncological outcomes and enable curative resection. This case provides compelling evidence to support further clinical investigation of this multimodal therapeutic combination.
Background:Berberine (BBR), a key compound in Coptis chinensis, has broad pharmacological properties, though its specific Crohn's disease (CD) targets and mechanisms are undefined. Materials and Methods:We employed network pharmacology, mendelian randomization (MR), molecular docking, and molecular dynamics simulations to identify potential target genes. Next, we assessed the efficacy of BBR in vitro and in vivo. Results:HSP90AA1 and MAPK14 were identified as potential target genes of BBR in the treatment of CD. In vitro experiments revealed that BBR downregulated LPS-induced HSP90AA1, MAPK14, and TNF-α while restoring tight junction proteins (ZO-1, Occludin, Claudin-1, JAM-A). Both HSP90AA1 inhibitor (17-AAG) and MAPK14 inhibitor (SB203580) significantly mitigated the reduction in ZO-1, Occludin, Claudin-1, and JAM-A expression caused by LPS. Furthermore, in vivo experiments revealed that BBR treatment effectively alleviated weight loss, the disease activity index (DAI), and colon shortening in a model of DSS-treated mice. BBR also ameliorated pathological changes in the colon, repaired goblet cells, reduced the expression of HSP90AA1, MAPK14, and TNF-α, and increased the expression of ZO-1, Occludin, Claudin-1, and JAM-A. Conclusion:BBR inhibits the expression of HSP90AA1 and MAPK14 both in vitro and in vivo, thereby facilitating the repair of the intestinal mucosal barrier.
Background:Genetic polymorphisms in the genes encoding enzymes and proteins in drug metabolism, transport, and response can significantly impact enzymatic activity and overall pharmacokinetics and pharmacodynamics, leading to inter-individual and inter-population differences in drug efficacy and safety. The prevalence of pharmacogenomic variants often differs among populations due to unique evolutionary and demographic factors. By studying the genetic variation within 100 pharmacogenes in the Kinh Vietnamese population, a relatively underexplored group in pharmacogenomic research, we aim to provide insights into the population-specific pharmacogenomic landscape. Materials and Methods:100 healthy people were recruited for peripheral blood donation after getting consents. Genomic DNA from participants was sequenced at coding regions of 100 pharmacogenes. Sequence reads were qualified, and variants were called using Genome analysis toolkit (GATK) followed with variant processing. Very important variants were characterized. Genetic distance using pairwise fixation index and allele frequencies comparison between the Kinh population and 25 populations of the 1000 Genome Project were analyzed. Results:689 variants were called with 652 SNPs and 37 indels including 371 missense-, 266 synonymous-, 30 frameshift-, 14 stop-gain-, 2 stop-lost-, 3 in-frame insertion-, 2 in-frame deletion- and 1 protein variant. There are 59 novel variants (8.6%) present in 39/100 genes in which 13 variants are labeled with damaging phenotype. 28 VIP variants were obtained from these regions. Allele frequencies of variants are mostly similar with East Asians, but different from Africans. Remarkably, variants rs1801280 and rs1208 (NAT2), rs2231142 (ABCG2), rs2306283 (SCLO1B1) and rs4148323 (UGT1A1) distribute significantly between Kinh people and all other populations. Conclusion:The prevalence of pharmacogenomic variants of 100 pharmacogenes was obtained for Kinh Vietnamese people, in which 28 variants were characterized as very important variants. Kinh Vietnamese shows close genetic distance with East Asians but far from Africans. The variants with distinguished distribution in Kinh people were also highlighted.
Objective:Atrial septal defect (ASD) is a common congenital heart defect with incompletely understood genetic underpinnings, particularly in specific ethnic groups. This study aimed to identify novel genetic variants related to ASD within the Tibetan population using whole exome sequencing (WES). Methods:Genomic DNA was extracted from blood samples of 17 Tibetan ASD patients. WES was performed using the Illumina HiSeq platform. After rigorous filtering, detection, and annotation of single nucleotide variations (SNVs) and insertion-deletions (InDels), potentially pathogenic variants were prioritized. Functional impact predictions were conducted using SIFT, PolyPhen V2, MutationTaster, and CADD databases to identify variants likely contributing to ASD etiology. Results:We identified nine high-confidence candidate variants in Tibetan ASD patients, including rs145116532 (ALKAL1, c.287G >A: p. R96Q), rs374798430 (AVL9, c.1267G >A: p.D423N), rs138933092 (C5, c.4432C >T: p.R1478W), rs141638421 (CRYAB, c.470G>A: p.R157H), rs147287319 (DOCK8, c.989G>A: c.1193G>A: p.R330Q, p.R398Q), rs141616597 (NTN3, c.1243C>T: p.R415C), rs117506395 (PIWIL1, c.2207C>T: p.T736M), rs142533677 (PLEKHG4, c.2246G>A: p.R749Q), and rs118203532 (TSC1, c.1460C>G: p.S487C). Function annotation further suggested potential associations of C5, CRYAB, PIWIL1, and TSC1 with congenital heart diseases. Conclusion:This first WES-based study of Tibetan ASD patients reveals population-specific genetic determinants. The nine novel candidate variants, particularly in C5, CRYAB, PIWIL1, and TSC1, provide preliminary insights into ASD etiology in high-altitude populations and highlight potential targets for future diagnostic biomarker development.
