Pharmacogenomics & Personalized Medicine最新文献

Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.

Introduction: Clopidogrel is an antiplatelet prodrug primarily prescribed to prevent or treat acute coronary syndrome (ACS) or acute ischemic stroke (IS), polymorphisms of genes encoding cytochrome P-450 (CYP) and P-glycoprotein transporter, could affect the efficiency of clopidogrel absorption and biotransformation, especially during the first critical hours following its administration.

Methods: The present study was designed to investigate the potential association of clopidogrel responsiveness and 14 polymorphisms in the genes encoding the CYPs (CYP2C9, 2C19, 3A4, 3A5, 1A2, and 2B6), the ATP binding cassette subfamily B member 1 (ABCB1). Platelet aggregation activity was measured after 8h of 300mg clopidogrel administration for fifty-five ACS patients.

Results: There was no significant association between polymorphism of the studied CYPs and clopidogrel responsiveness (P>0.05). The frequency of the ABCB1 3435 T allele in clopidogrel non-responders was higher (78.9%) compared to responders (52.8%), but this difference was not significant (P=0.057). Demographic characteristics, comorbidities, concomitant treatments were not associated with clopidogrel response.

Discussion: There was no effect of the studied genetic variations and demographic factors on the platelet activity of clopidogrel in Moroccan ACS patients.

Background: Mutations in Myosin Binding Protein C (MYBPC3) are one of the most frequent causes of cardiomyopathies in the world, but not much data are available in India.

Methods: We carried out targeted direct sequencing of MYBPC3 in 115 hypertrophic (HCM) and 127 dilated (DCM) cardiomyopathies against 197 ethnically matched healthy controls from India.

Results: We detected 34 single nucleotide variations in MYBPC3, of which 19 were novel. We found a splice site mutation [(IVS6+2T) T>G] and 16 missense mutations in Indian cardiomyopathies [5 in HCM; E258K, T262S, H287L, R408M, V483A: 4 in DCM; T146N, V321L, A392T, E393K and 7 in both HCM and DCM; L104M, V158M, S236G, R272C, T290A, G522E, A626V], but those were absent in 197 normal healthy controls. Interestingly, we found 7 out of 16 missense mutations (V158M, E258K, R272C, A392T, V483A, G522E, and A626V) in MYBPC3 were altering the evolutionarily conserved native amino acids, accounted for 8.7% and 6.3% in HCM and DCM, respectively. The bioinformatic tools predicted that those 7 missense mutations were pathogenic. Moreover, the co-segregation of those 7 mutations in families further confirmed their pathogenicity. Remarkably, we also identified compound mutations within the MYBPC3 gene of 6 cardiomyopathy patients (5%) with more severe disease phenotype; of which, 3 were HCM (2.6%) [(1. K244K + E258K + (IVS6+2T) T>G); (2. L104M + G522E + A626V); (3. P186P + G522E + A626V]; and 3 were DCM (2.4%) [(1. 5'UTR + A392T; 2. V158M+G522E; and 3.V158M + T262T + A626V].

Conclusion: The present comprehensive study on MYBPC3 has revealed both single and compound mutations in MYBPC3 and their association with disease in Indian Population with Cardiomyopathies. Our findings may perhaps help in initiating diagnostic strategies and eventually recognizing the targets for therapeutic interventions.

Purpose: According to the World Health Organization, Saudi Arabia ranks seventh worldwide in the number of patients with diabetes mellitus. To our knowledge, no research has addressed the potential of noncoding RNA as a diagnostic and/or management biomarker for patients with type 2 diabetes mellitus (T2DM) living in high-altitude areas. This study aimed to identify molecular biomarkers influencing patients with T2DM living in high-altitude areas by analyzing lncRNA and mRNA.

Patients and methods: RNA sequencing and bioinformatics analyses were used to identify significantly expressed lncRNAs and mRNAs in T2DM and healthy control groups. Coding potential was analyzed using coding-noncoding indices, the coding potential calculator, and PFAM, and the lncRNA function was predicted using Pearson's correlation. Differentially expressed transcripts between the groups were identified, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the biological functions of both lncRNAs and mRNAs.

Results: We assembled 1766 lncRNAs in the T2DM group, of which 582 were novel. This study identified three lncRNA target genes (KLF2, CREBBP, and REL) and seven mRNAs (PIK3CD, PIK3R5, IL6R, TYK2, ZAP70, LAMTOR4, and SSH2) significantly enriched in important pathways, playing a role in the progression of T2DM.

Conclusion: To the best of our knowledge, this comprehensive study is the first to explore the applicability of certain lncRNAs as diagnostic or management biomarkers for T2DM in females in Taif City, Saudi Arabia through the genome-wide identification of lncRNA and mRNA profiling using RNA seq and bioinformatics analysis. Our findings could help in the early diagnosis of T2DM and in designing effective therapeutic targets.

Purpose: Chromosomal abnormalities represent genomic signatures linked to cancer prognosis and responses to chemotherapy, immunotherapy, and drug resistance. This study aimed to investigate the impact of chromosome copy number variants (CNVs) on the efficacy of tyrosine kinase inhibitors (TKIs) in EGFR-mutated non-small cell lung cancer (NSCLC) patients, as well as its prognostic implications for progression-free survival (PFS) and overall survival (OS) in EGFR wild-type patients.

Methods: A total of 110 patients with advanced NSCLC were enrolled in this study and categorized into EGFR-mutated and wild-type groups. Utilizing next-generation sequencing (NGS) technology, we assessed 24 genes and chromosome CNVs associated with lung cancer pathways in patients' tissue samples.

Results: Within the EGFR-mutated group, patients with a gain in Chr 1p13.3-p13.1 exhibited poor TKI responses, a high relapse rate, and shortened PFS (P = 0.002). Conversely, EGFR-mutated patients with a gain in 14q31.1-q31.3 demonstrated favorable TKI responses and relatively extended PFS (P = 0.005). Among EGFR wild-type patients, the presence of 7q31.1-q31.31 CNV emerged as an independent factor influencing both PFS and OS (P = 0.013, P = 0.004). Notably, patients with a gain in 7q31.1-q31.31 exhibited prolonged PFS and OS. Additionally, independent prognostic significance for OS in EGFR wild-type patients was observed for CNVs in 9q21.31-q22.2 and 11p11.11-q12.1 regions (P = 0.001). Patients with gains in these regions experienced extended OS, while losses were predictive of poorer outcomes.

Conclusion: Our results suggested that chromosomal copy number variation is a practical indicator for predicting the response of EGFR-targeted therapy and prognosis for NSCLC patients.

Background: N-acetyltransferase 2 (NAT2) enzyme is a Phase II drug-metabolizing enzyme that metabolizes different compounds. Genetic variations in NAT2 can influence the enzyme's activity and potentially lead to the development of certain diseases.

Aim: This study aimed to investigate the association of NAT2 variants with the risk of Type II diabetes mellitus (T2DM) and the lipid profile among Jordanian patients.

Methods: We sequenced the whole protein-coding region in NAT2 using Sanger's method among a sample of 45 Jordanian T2DM patients and 50 control subjects. Moreover, we analyzed the lipid profiles of the patients and examined any potential associations with NAT2 variants.

Results: This study revealed that the heterozygous NAT2*13 C/T genotype is significantly (P = 0.03) more common among T2DM (44%) than non-T2DM subjects (23.5%). Furthermore, the frequency of homozygous NAT2*13 T/T genotype was found to be significantly higher (P = 0.03) among T2DM patients (26.7%) compared to that of non-T2DM subjects (11%). The heterozygous NAT2*7 G/A genotype was exclusively observed in T2DM patients (11.1%) and absent in the control non-T2DM group. Moreover, among T2DM patients, those with a homozygous NAT2*11 T/T genotype exhibited significantly higher levels of triglycerides (381.50 ± 9.19 ng/dL) with a P value of 0.01 compared to those with heterozygous NAT2*11 C/T (136.23 ± 51.12 ng/dL) or wild-type NAT2*11 C/C (193.65 ± 109.89 ng/dL) genotypes. T2DM patients with homozygous NAT2*12 G/G genotype had a significantly (P = 0.04) higher triglyceride levels (275.67 ± 183.42 ng/dL) than the heterozygous NAT2*12 A/G (140.02 ± 49.53 ng/dL) and the wild NAT2*12 A/A (193.65 ± 109.89 ng/dL).

Conclusion: The finding in this study suggests that the NAT2 gene is a potential biomarker for the development of T2DM and changes in triglyceride levels among Jordanians. However, it is important to note that our sample size was limited; therefore, further clinical studies with a larger cohort are necessary to validate these findings.

Background: Proteasome 26S subunit ATPase 2 (PSMC2) is a part of the 19S regulatory complex, which catalyzes the unfolding and transport of substrates into the 20S proteasome. Our previous research demonstrated that PSMC2 participates in the tumorigenesis and progression of pancreatic cancer (PC). However, no systematic analysis has been conducted to conclude its expression pattern and correlation with tumor immunity.

Aim: To investigate the expression level of PSMC2 in PC, its prognostic value and its relationship with tumor immunity.

Methods: In numerous public and internal cohorts, the expression, prognostic significance, and immunological connections of PSMC2 in PC were investigated. Additionally, using data from The Cancer Genome Atlas (TCGA), a pan-cancer analysis was carried out to examine PSMC2's immunological assocaition, and the predictive power of PSMC2 for immunotherapy was also evaluated in numerous public cohorts.

Results: PSMC2 was overexpressed in tumor tissues and linked to unfavorable prognosis in PC. PSMC2 was not only positively correlated with TIICs, also positively correlated with immune checkpoints in PC. In addition to PC, PSMC2 was expected to be an indicator of high immunogenicity in most cancer types. Importantly, PSMC2 could predict the immunotherapeutic responses in various cancer types, including urothelial carcinoma and breast cancer.

Conclusion: From PC to pan-cancer analysis, we report that PSMC2 is a novel prognostic biomarker in multiple cancer types. PSMC2 is related to the immuno-hot phenotype and predicts the outcome of immunotherapy. Therefore, the current study emphasizes that cancer patients with high PMSC2 expression should actively receive immunotherapy to improve their prognosis.

Background: Gamma-aminobutyric acid (GABA) plays an important role in tumorigenesis and progression. Despite this, the role of Reactome GABA receptor activation (RGRA) on gastric cancer (GC) remains unclear. This study was intended to screen RGRA-related genes in GC and investigate their prognostic value.

Methods: GSVA algorithm was used to assess the score of RGRA. GC patients were divided into two subtypes based on the median score of RGRA. GSEA, functional enrichment analysis, and immune infiltration analysis were performed between the two subgroups. Then, differentially expressed analysis, and weighted gene co-expression network analysis (WGCNA) were used to identify RGRA-related genes. The prognosis and expression of core genes were analyzed and validated in the TCGA database, GEO database, and clinical samples. ssGSEA and ESTIMATE algorithms were used to assess the immune cell infiltration in the low- and high-core genes subgroups.

Results: High-RGRA subtype had a poor prognosis and activated immune-related pathways, as well as an activated immune microenvironment. ATP1A2 was identified to be the core gene. The expression of ATP1A2 was associated with the overall survival rate and tumor stage, and its expression was down-regulated in GC patients. Furthermore, ATP1A2 expression was positively correlated with the level of immune cells, including B cells, CD8 T cells, cytotoxic cells, DC, eosinophils, macrophages, mast cells, NK cells, and T cells.

Conclusion: Two RGRA-related molecular subtypes were identified that could predict the outcome in GC patients. ATP1A2 was a core immunoregulatory gene and was associated with prognosis and immune cell infiltration in GC.

Type 1 diabetes (T1D) management has been revolutionized with the development and routine utilization of continuous glucose monitoring (CGM). CGM technology has allowed for the ability to track dynamic glycemic fluctuations and trends over time allowing for optimization of medical therapy and the prevention of dangerous hypoglycemic events. This review details currently-available real-time and intermittently-scanned CGM devices, clinical benefits, and challenges of CGM use, and current guidelines supporting its use in the clinical care of patients with T1D. We additionally describe future issues that will need to be addressed as CGM technology continues to evolve.

Situs inversus totalis (SIT) is a rare congenital condition in which abdominal and thoracic organs are transposed from normal positions. Two-stage hepatectomy (TSH) combined with translational therapy for hepatocellular carcinoma (HCC) with SIT has been rarely reported. We report a 41-year-old man with giant hepatocellular carcinoma (71 mm × 55 mm × 51 mm) whose future residual liver (FLR) and standard liver volume (SLV) ratio at first diagnosis was 37.4%. Preoperative volume assessment of portal vein ligation (PVL) revealed inadequate hypertrophy of FLR. After a multidisciplinary group discussion (MDT), the patient decided to follow conversion therapy. Three months later, ratio of the FLR/SLV increased from 37.4% to 71% after operation, which met the surgical requirements. Second hepatectomy, right lobectomy was successful. There was no recurrence after six months of follow-up. In our case, conversion therapy appears to be effective in maintaining residual liver hyperplasia, reducing tumor load, and preventing tumor progression in patients with large HCC during TSH.