Pharmacogenomics & Personalized Medicine最新文献

Introduction: GPR176, an orphan G protein-coupled receptor (GPCR), is essential for the progression of gastrointestinal cancers. However, it is still unclear how GPR176 affects tumor immunity and patient prognosis in gastric cancer (GC).

Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were searched in this investigation to assess the expression patterns of GPR176 in GC tissues and normal gastric mucosa. The findings were further verified using immunohistochemical tests and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). The Kaplan-Meier method, univariate logistic regression, and Cox regression were then used to investigate the relationship between GPR176 and clinical traits. Additionally, the potential correlation between GPR176, immune checkpoint genes, and immune cell infiltration levels was investigated.

Results: As per the research findings, GC tissues had higher levels of GPR176 than normal tissues. Additionally, individuals with high expression of GPR176 had a worse 10-year overall survival (OS), in contrast with those having a low expression of GPR176 (p < 0.001). The OS of GC can be predicted using a validated nomogram model. The expression of GPR176 demonstrated a negative correlation with CD8+ T cells. When compared to the low-expression group of GPR176, Tumor Immune Dysfunction and Exclusion (TIDE) analysis demonstrated that the high-expression group had a considerably higher risk of immune evasion. A remarkable difference (variation) was observed in the levels of GPR176 expression across both groups, ie, low and high-risk groups, as determined by the immune phenomenon scores (IPS) immunotherapy assessment.

Conclusion: By examining GPR176 from various biological perspectives, it was determined that GPR176 can act as a predictive biomarker for poor patient prognosis in GC. Additionally, it was observed that GPR176 is capable of suppressing the proliferation of CD8+ T cells and facilitating immune evasion.

Introduction: Many circRNAs, such as circRNA-0076906 and circRNA-0134944, have been reported to participate in the pathogenesis of osteoporosis via sponging miRNAs in postmenopausal female patients. In this study, we aimed to study potential signaling pathways underlying the role of certain circRNAs, miRNAs and their target genes in the pathogenesis of osteoporotic fracture in postmenopausal females.

Methods: Quantitative real-time PCR was performed to analyze the expression of circRNAs, miRNAs and their targets genes. Luciferase assays were carried out to explore the regulatory relationship between circ_0076906/miR-548i/OGN and circ_0134944/miR-630/TLR4.

Results: Osteoporosis and fracture were positively correlated to the expression of circ_0134944, miR-548i and TLR4, but negatively correlated to the expression of circ_0076906, miR-630 and OGN in the peripheral blood and bone tissue samples of postmenopausal women. Luciferase activities of wild-type circ_0076906 and OGN were inhibited by miR-548i, and the luciferase activities of wild-type circ_0134944 and TLR4 were suppressed by miR-630 in MG-63 and U-2 OS cells. Inhibition of circ_0076906 expression in MG-63 and U-2 OS cells activated the expression of miR-548i and inhibited the expression of OGN. Moreover, the overexpression of circ_0134944 in MG-63 and U-2 OS cells suppressed the expression of miR-630 and enhanced the expression of TLR4.

Conclusion: This study implied that the dysregulation of circRNA-0076906 and circRNA-0134944 modulated their specific signaling and thus contributed to the severity of osteoporosis, increasing the risk of osteoporotic fracture.

Background: Circular RNAs (circRNAs) are strong modulators of tumor pathology. Herein, our goal was to examine the plasma hsa_circ_0052184 content among colorectal cancer (CRC) patients, and assess its association with patient clinicopathological profile and diagnostic values.

Methods: Overall, we collected 228 presurgical CRC and 146 normal plasma samples from The First People's Hospital of Wenling. Circulating hsa_circ_0052184 levels were assessed via qRT-PCR, and the diagnostic prediction was conducted with the receiver operating characteristic (ROC) curve.

Results: Relative to healthy controls, CRC patients exhibited markedly enhanced circulating hsa_circ_0052184 levels, which were closely correlated with advanced stage of disease and worse outcome. Based on our uni- (UA) and multivariate assessments (MA), elevated hsa_circ_0052184 levels were a stand-alone predictor of poor prognosis. The ROC curve depicted an area under the curve (AUC) for CRC diagnosis to be 0.9072.

Conclusion: Circulating hsa_circ_0052184 is a potential bioindicator of CRC outcome.

Introduction: Transarterial chemoembolization (TACE) is the commonly used therapy of unresectable hepatocellular carcinoma (HCC), though the prognosis of different TACE-treated HCC patients varies, which may be due to the heterogeneity of HCC tumors caused by genetic variants and epigenetic changes such as RNA editing. There is dysregulated RNA adenosine-to-inosine (A-to-I) editing in HCC and RNA-edited genes are involved in the epigenetic process. It remains unclear how genetic variants of RNA editing genes affect the prognosis of HCC cases treated by TACE.

Methods: In this study, we examined 28 potentially functional single-nucleotide polymorphisms (SNPs) of four RNA editing genes (ADARB1, ADAR, ADARB2 and AIMP2) in two independent TACE patient cohorts.

Results: We found that ADARB1 rs1051367 and rs2253763 polymorphisms were markedly associated with the prognosis of HCC cases who received TACE in both cohorts. In HCC cells, the rs2253763 C-to-T change in ADARB1 3'-untranslated region attenuated its binding with miR-542-3p and allele-specifically elevated ADARB1 levels. Consistent with this, patients carrying the rs2253763 C allele showed reduced ADARB1 expression in cancer tissues and notably shorter survival after TACE therapy in comparison with individuals with the T allele. Ectopic ADARB1 profoundly enhanced the efficacy of oxaliplatin, one of the common TACE chemotherapeutic drugs.

Discussion: Our findings highlighted the value of ADARB1 polymorphisms as prognostic markers in TACE therapy for HCC patients. Notably, our findings revealed that targeting the ADARB1 enzyme may be a promising therapeutic strategy in combination with TACE for HCC cases.

Introduction: Homocysteine (Hcy) concentration has been reported to be associated with ischemic stroke. In this study, we aimed to investigate the potential of plasma Hcy in the prediction of post-ischemic hyperperfusion in AIS patients, which was diagnosed with the single-photon emission computed tomography (SPECT) method.

Methods: A total of 112 ischemic stroke patients were recruited in this study. According to whether the patients were subjected to post-ischemic hyperperfusion, all recruited subjects were divided into a post-ischemic hyperperfusion (+) group (N=48) and post-ischemic hyperperfusion (-) group (N=64). The basic demographical data, clinicopathological data and laboratory biochemical data were collected and compared. Level of homocysteine (Hcy) and cystatin-C (Cys-C) and their potential as predictive biomarker are also investigated.

Results: No significant differences were spotted between the post-ischemic hyperperfusion group (+) and post-ischemic hyperperfusion (-) group in respect to the basic demographical and clinicopathological data. And the serum Hcy levels were lower in the post-ischemic hyperperfusion (+) group. Moreover, ROC analysis indicated significant relationships between Hcy levels and the onset of post-ischemic hyperperfusion.

Conclusion: In conclusion, we validated that the plasma Hcy concentration can be used as a predictive biomarker of SPECT-evaluated post-ischemic hyperperfusion in patients suffering from acute ischemic stroke.

Background and aims: It is crucial to provide healthcare personnel with the necessary knowledge and understanding of genetic testing and pharmacogenomics. The purpose of this study is to assess the knowledge, attitudes, views, and considerations of Community pharmacists (CPs) about pharmacogenomics and genetics.

Methods and materials: A cross-sectional web-based study was conducted among practicing pharmacists Between January and February of 2022. Participants were recruited through a convenient sampling technique. A total of 23 item questionnaires were used to assess the Knowledge Attitudes, Views, and Considerations toward Pharmacogenomics among pharmacists.

Results: The mean age of the CPs were 28.45±7.29(Std). Among the CPs, 38.4% (98 of 255) of them were correctly identified human chromosomes, and the majority of them 73.3% knew that adverse reactions can be caused by genetic changes in the human body. A total of 194 CPs agreed that certain drugs can be affected by genetic changes in the patient. In this study, one-third (33%) of the CPs were found to have good knowledge, while most (66.3%) of the CPs were found poor knowledge of pharmacogenomics and genetics. Furthermore, the knowledge score is significantly different concerning the qualification of the CPs (p=0.0001).

Conclusion: The current findings, demonstrated a majority of the CPs found a lack of knowledge and understanding regarding pharmacogenomics and its perspectives, there is a need to increase awareness among CPs to reduce the knowledge gap of pharmacogenomics and genetics.

The introduction of genomic sequencing technologies into routine newborn screening programs in some form is not only inevitable but also already occurring in some settings. The question is therefore not "if" but "when and how" genomic newborn screening (GNBS) should be implemented. In April 2022, the Centre for Ethics of Paediatric Genomics held a one-day symposium exploring ethical issues relating to the use of genomic sequencing in a range of clinical settings. This review article synthesises the panel discussion and presents both the potential benefits of wide-scale implementation of genomic newborn screening, as well as its practical and ethical issues, including obtaining appropriate consent, and health system implications. A more in-depth understanding of the barriers associated with implementing genomic newborn screening is critical to the success of GNBS programs, both from a practical perspective and also in order to maintain public trust in an important public health initiative.

PARP inhibitors (PARPi) are the maintenance therapy after first line platinum-based chemotherapy for patients with advanced epithelial ovarian cancer (EOC) with germline and pathogenic somatic BRCA1/2 mutations. However, as with chemotherapy, patients can develop resistance to PARPi. The selective pressure generated by heterogeneous somatic BRCA mutations may give rise to chemotherapy or PARPi resistant tumors. Here, we present the case of a patient harboring a pathogenic p.Glu143* (c.427G>T) somatic BRCA1 mutation conferring resistance to olaparib following cytoreductive surgery and platinum-based chemotherapy. We ordered a plasma ctDNA analysis (tissue biopsy of recurrent lesions was contraindicated due to their anatomical location) to figure out the possible resistance mechanism. Analysis of ctDNA did not detect the pathogenic somatic BRCA1 p.Glu143* (c.427G>T) mutation seen before. The tumor cells harboring the pathogenic BRCA1 mutation were probably eliminated by the platinum-based chemotherapy, leaving only those without BRCA mutations to proliferate.

Background: Invasion and metastasis led to poor prognosis and death of clear cell renal cell carcinoma (ccRCC) patients. The deoxynucleotidyl transferase terminal interacting protein 1 (DNTTIP1) was reported to promote multiple tumor progression. However, there is no research about DNTTIP1 in ccRCC.

Methods: Kaplan-Meier survival analysis, multivariate analysis demonstrated the prognostic indicator in overall survival (OS) and disease-free survival (DFS) of ccRCC with DNTTIP1 expression in the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC). Receiver operator characteristic (ROC) curve analyzed diagnostic ability of DNTTIP1 in TCGA-KIRC and validation dataset. The quantitative real-time polymerase chain reaction (qRT-PCR) detected the DNTTIP1 expression in renal cancer tissues, and the Office of Cancer Clinical Proteomics Research (CPTAC) verified the protein expression of DNTTIP1. Moreover, nomogram predicted the role of DNTTIP1 in ccRCC patient. Single-sample Gene Set Enrichment Analysis (SsGSEA) and GSEA evaluated the pathogenesis role of DNTTIP1 in TCGA-KIRC.

Results: DNTTIP1 expression was higher in ccRCC tumor tissues. High expression of DNTTIP1 was associated with poor OS (HR = 1.618, P < 0.0001), and poor DFS (HR = 1.789, P < 0.0001). SsGSEA and GSEA showed DNTTIP1 was associated with hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, G2M checkpoint. DNTTIP1 had a positive correlation with EMT biomarkers in ccRCC, and might be an effective target for ccRCC.

Conclusion: This study provided that higher expression of DNTTIP1 predicted poor prognosis in ccRCC, and DNTTIP1 might be a novel detection biomarker and therapeutic target of tumor malignant in the future.

Introduction and objective: The mitogen-activated protein kinase (MAPK) pathway is inhibited by the pan-target inhibitor Anlotinib, which induces tumor cell death. In addition to the common apoptosis and necrosis, there is also a pyroptosis mode of cancer cell death in recent years, which is mainly manifested by the cleavage of gasdermin proteins (GSDMs). Gasdermin B (GSDMB) participates in the progression and outcome of bladder cancer. The efficacy and mechanism of Anlotinib in the treatment of GSDMB-positive bladder tumors have not been studied to date.

Methods: The relationship between GSDMB expression and tumor stage, overall survival rate, immunotherapy response, tumor recurrence and progression rate was analyzed from the TCGA bladder cancer database. Anlotinib was used to treat GSDMB-positive bladder cancer in mice followed by flow analysis of the secretion of inflammatory factors related to pyroptosis and the level of anti-tumor factors. Western blot analysis detected which MAPK and MEK signal transduction pathways.

Results: TCGA data analysis showed that the overall survival rate of bladder cancer patients with high GSDMB expression was better than that of patients with low GSDMB expression. In vivo experiments showed that Anlotinib was more effective in the treatment of GSDMB-positive bladder cancer than GSDMB-negative bladder cancer. Anlotinib can increase the secretion of antitumor-related factors in GSDMB-positive bladder cancer such as TNF-a and CD107a. In addition, Anlotinib also induced an increase in GSDMB protein expression. Anlotinib treatment of GSDMB-positive bladder cancer decreased AKT and MEK protein expression, which were involved in Anlotinib signal transduction pathway.

Conclusion: Anlotinib has a strong antitumor effect on GSDMB-positive bladder tumors. This effect is mainly achieved by anlotinib stimulating the secretion of relevant antitumor factors by lymphocytes. The PI3K/AKT and MEK signal transduction pathways were inhibited by Anlotinib in bladder cancer expressing GSDMB protein.