Pharmacogenomics & Personalized Medicine最新文献

Objective: To investigate the role of the TopBP1 interacting checkpoint and replication regulator (TICRR) in cutaneous melanoma (CM) as a prognostic biomarker and therapeutic target.

Methods: TICRR expression in tumour samples was explored using the TCGA and the GTEx database. The Kaplan-Meier survival curve, nomogram model and risk score curve were established to evaluate the prognostic role of TICRR in CM. Tissue samples of CM patients were obtained to validate the TICRR expression further. Several experiments in vitro were conducted to investigate the effect of TICRR upon CM aggressiveness and to explore underlying mechanisms.

Results: TICRR was overexpressed in CM tissue and was correlated with poor prognosis of CM patients. The knockdown of TICRR decreased the proliferation, migration, and invasion of CM cells, whereas overexpression produced the opposite effect. Furthermore, TICRR suppression substantially attenuated the activation of PI3K/AKT/mTOR signalling, while the PI3K/AKT inhibitor LY294002 could partially reverse the aggressiveness-enhancing effect induced by TICRR overexpression. It was further confirmed that TICRR was closely related to immune cell infiltration activities by using immune infiltration and immunofluorescence analysis.

Conclusion: TICRR overexpression may enhance CM aggressiveness by activating the PI3K/Akt/mTOR pathway and promoting immune infiltration. TICRR was verified as a potential prognostic biomarker and therapeutic target for CM.

Purpose: This study aimed to investigate the expression of Acyl-CoA thioesterase 8 (ACOT8) in breast cancer (BC) and its association with clinicopathological characteristics, patient survival, and immune infiltration.

Methods: We conducted a comprehensive analysis of ACOT8 mRNA differential expression across various cancer types, followed by survival analysis. We focused on BC, where ACOT8 expression was evaluated at both the mRNA and protein levels using online databases, qRT-PCR, and immunohistochemistry. Associations between ACOT8 expression and clinicopathological parameters were assessed using different databases. Additionally, we investigated the prognostic significance of ACOT8 in BC patients by analyzing various cohorts and databases. Furthermore, we predicted a potential signaling pathway and identified miR-1-3p as a possible upstream regulator of ACOT8. Finally, the relationship between ACOT8 and immune system infiltration, as well as immune checkpoint molecules, was examined.

Results: Our findings demonstrated upregulated ACOT8 mRNA and protein levels in BC. Elevated ACOT8 expression correlated positively with various clinicopathological characteristics, indicating an unfavorable prognosis for patients. Functional enrichment analysis suggested ACOT8 involvement in lipid metabolism, mitochondrial components, and ribosomal functions. Moreover, we identified connections between ACOT8 and immune system markers, immune cell infiltration, and immune checkpoints.

Conclusion: This study provides compelling evidence for ACOT8 upregulation in BC and its association with clinicopathological features and patient outcomes. Additionally, our findings suggest that targeting ACOT8 and immune checkpoints might enhance the effectiveness of immunotherapy in BC patients.

Background: Lung cancer is the leading cause of cancer deaths worldwide, primarily due to lung adenocarcinoma (LUAD). However, the heterogeneity of programmed cell death results in varied prognostic and predictive outcomes. This study aimed to develop an LUAD evaluation marker based on cuproptosis-related lncRNAs.

Methods: First, transcriptome data and clinical data related to LUAD were downloaded from the Cancer Genome Atlas (TCGA), and cuproptosis-related genes were analyzed to identify cuproptosis-related lncRNAs. Univariate, LASSO, and multivariate Cox regression analyses were conducted to construct cuproptosis-associated lncRNA models. LUAD patients were categorized into high-risk and low-risk groups using prognostic risk values. Kaplan-Meier analysis, PCA, GSEA, and nomograms were employed to evaluate and validate the results.

Results: 7 cuproptosis-related lncRNAs were identified, and a risk model was created. High-risk tumors exhibited cuproptosis-related gene alterations in 95.54% of cases, while low-risk tumors showed alterations in 85.65% of cases, mainly involving TP53. The risk value outperformed other clinical variables and tumor mutation burden as a predictor of 1-, 3-, and 5-year overall survival. The cuproptosis-related lncRNA-based risk model demonstrated high validity for LUAD evaluation, potentially influencing individualized treatment approaches. Expression analysis of four candidate cuproptosis-related lncRNAs (AL606834.1, AL161431.1, AC007613.1, and LINC02835) in LUAD tissues and adjacent normal tissues revealed significantly higher expression levels of AL606834.1 and AL161431.1 in LUAD tissues, positively correlating with tumor stage, lymph node metastasis, and histopathological grade. Conversely, AC007613.1 and LINC02835 exhibited lower expression levels, negatively correlating with these factors. High expression of AL606834.1 and AL161431.1 indicated poor prognosis, while low expression of AC007613.1 and LINC02835 was associated with unfavorable outcomes. Univariate and multivariate analyses confirmed these lncRNAs as independent risk factors for LUAD prognosis.

Conclusion: The 4 cuproptosis-related (lncRNAsAL606834.1, AL161431.1, AC007613.1, and LINC02835) can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.

Objective: Regimens of S-1-based adjuvant chemotherapy are of great significance in attenuating recurrence risk in postoperative patients with gastric cancer (GC). Kinase insert-domain receptor (KDR) gene plays an essential role in tumor growth and metastasis. This study aimed to investigate the implication of KDR genotyping on the therapeutic outcomes of patients with gastric cancer (GC) who received S-1-based adjuvant chemotherapy.

Methods: A total of 169 postoperative GC with pathological staging of II and III and no metastasis who received S-1-based adjuvant chemotherapy were included retrospectively. Peripheral blood specimens were collected and prepared for KDR genotyping and KDR mRNA expression. Correlation between KDR genotype status and prognosis was performed using Kaplan-Meier survival analysis, and multivariate analysis was ultimately adopted using Cox regression analysis.

Results: Median disease-free survival (DFS) of the 169 patients with GC was 5.1 years [95% confidence interval (CI): 4.25-5.95] and median overall survival (OS) was 6.7 years (95% CI: 5.44-7.96). Rs2071559 was located at the upstream region, and the prevalence among 169 patients with GC was as follows: AA genotype in 104 cases (61.5%), AG genotype in 57 cases (33.7%), and GG genotype in 8 cases (4.7%), yielding a minor allele frequency of 0.22, which was consistent with Hardy-Weinberg equilibrium (P=0.958). Median DFS of patients with AA and AG/GG genotypes was 6.0 years and 4.0 years, respectively (P=0.002). Additionally, patients with the AA genotype had longer OS than those with the AG/GG genotype [median OS: not reached (NR) vs 5.5 years, P=0.011]. Additionally, KDR mRNA expression was significantly higher in patients with the AG/GG genotype than that in those with the AA genotype (P<0.001).

Conclusion: Rs2071559 in KDR gene might be a promising biomarker for evaluating the recurrence risk and OS of patients with GC who received S-1-based adjuvant chemotherapy. This conclusion should be confirmed in randomized clinical trials.

Objective: This study aimed to discern the association between PLP2 expression, its biological significance, and the extent of immune infiltration in human GBM.

Methods: Utilizing the GEPIA2 and TCGA databases, we contrasted the expression levels of PLP2 in GBM against normal tissue. We utilized GEPIA2 and LinkedOmics for survival analysis, recognized genes co-expressed with PLP2 via cBioPortal and GEPIA2, and implemented GO and KEGG analyses. The STRING database facilitated the construction of protein-protein interaction networks. We evaluated the relationship of PLP2 with tumor immune infiltrates using ssGSEA and the TIMER 2.0 database. An IHC assay assessed PLP2 and PDL-1 expression in GBM tissue, and the Drugbank database aided in identifying potential PLP2-targeting compounds. Molecular docking was accomplished using Autodock Vina 1.2.2.

Results: PLP2 expression was markedly higher in GBM tissues in comparison to normal tissues. High PLP2 expression correlated with a decrease in overall survival across two databases. Functional analyses highlighted a focus of PLP2 functions within leukocyte. Discrepancies in PLP2 expression were evident in immune infiltration, impacting CD4+ T cells, neutrophils, myeloid dendritic cells, and macrophages. There was a concomitant increase in PLP2 and PD-L1 expression in GBM tissues, revealing a link between the two. Molecular docking with ethosuximide and praziquantel yielded scores of -7.441 and -4.295 kcal/mol, correspondingly.

Conclusion: PLP2's upregulation in GBM may adversely influence the lifespan of GBM patients. The involvement of PLP2 in pathways linked to leukocyte function is suggested. The positive correlation between PLP2 and PD-L1 could provide insights into PLP2's role in glioma modulation. Our research hints at PLP2's potential as a therapeutic target for GBM, with ethosuximide and praziquantel emerging as potential treatment candidates, especially emphasizing the potential of these compounds in GBM treatment targeting PLP2.

Antiplatelet therapy is the cornerstone of antithrombotic prevention in patients with established atherosclerosis, since it has been proven to reduce coronary, cerebrovascular, and peripheral thrombotic events. However, the protective effect of antiplatelet agents is counterbalanced by an increase of bleeding events that impacts on patients' mortality and morbidity. Over the last years, great efforts have been made toward personalized antithrombotic strategies according to the individual bleeding and ischemic risk profile, aiming to maximizing the net clinical benefit. The development of risk scores, consensus definitions, and the new promising artificial intelligence tools, as well as the assessment of platelet responsiveness using platelet function and genetic testing, are now part of an integrated approach to tailored antithrombotic management. Moreover, novel strategies are available including dual antiplatelet therapy intensity and length modulation in patients undergoing myocardial revascularization, the use of P2Y₁₂ inhibitor monotherapy for long-term secondary prevention, the implementation of parenteral antiplatelet agents in high-ischemic risk clinical settings, and combination of antiplatelet agents with low-dose factor Xa inhibitors (dual pathway inhibition) in patients suffering from polyvascular disease. This review summarizes the currently available evidence and provides an overview of the principal risk-stratification tools and antiplatelet strategies to inform treatment decisions in patients with cardiovascular disease.

Hepatocellular carcinoma (HCC) recurrence, which encompasses both true recurrence resulting from cancer spread and de novo tumors developing within the same cancer-prone liver, presents a complication in approximately 70% of cases within a 5-year timeframe. The efficacy of neoadjuvant therapy for recurrence after hepatectomy for hepatocellular carcinoma is still unclear. We report a case of recurrent massive advanced hepatocellular carcinoma with pathological complete remission was treated by continuous hepatic arterial infusion chemotherapy (HAIC) and sequential transcatheter arterial embolization (TAE) combined with secondary operation. One month after resection, the patient recurred (massive type 141mm×76mm). After 4 times of HAIC sequential TAE conversion therapy, the tumor shrank significantly (70mm×29mm), alpha-fetoprotein(AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels decreased significantly, residual liver volume[left half liver accounted for 39.85% of standard liver volume(left half liver + right anterior lobe) accounted for 80.17% of standard liver volume] and Indocyanine green 15-minute retention(ICG R15 8.0%) complies with surgical requirement.The second operation was performed, and the tumor was completely resected after hepatic blood flow occlusion Requirement. The postoperative pathological results showed complete remission (PCR) of the tumor, and no recurrence was found during the follow-up of 16 months. In this case, HAIC sequential TAE conversion therapy has good short-term effect on patients with postoperative recurrence of hepatocellular carcinoma, tumor burden is significantly reduced, the second surgery pathology achieves complete remission, safety and tolerance, it is worthy of study and promotion.

Background: Long noncoding RNAs (LncRNAs) have been revealed to involve in cervical cancer (CC) developing. The current study was designed to explore the association of SNPs (rs217727, rs2366152, rs1859168, rs10505477) located in the lncRNA H19, HOTAIR, HOTTIP and CASC8 genes with the risk of CC in a Chinese Han population.

Methods: Four SNPs were selected and genotyped in 1426 participants (274 CIN patients, 448 CC patients, and 704 healthy control individuals) using MassArray. The association of these SNPs with susceptibility to CC was evaluated.

Results: Significant differences in allelic distribution of rs217727 were observed in the comparison of CC with control (P = 0.001), indicating the risk of rs217727-A allele in CC (OR = 1.33; 95% CI: 1.12-1.58). The inheritance model analysis revealed that 2AA+GA genotype represented a certain risk of CC (P = 0.001, OR = 1.35; 95% CI: 1.13-1.62). The stratified analysis revealed a risk of the rs217727-A allele for cervical squamous cell carcinoma (SCC) (P = 0.002, OR = 1.33; 95% CI: 1.11-1.60).

Conclusion: rs217727 in lncRNA H19 exhibited a significant correlation with CC susceptibility, particularly SCC, and A/A genotype of this SNP might present as a risk in CC.