An atlas of genetic effects on cellular composition of the tumor microenvironment.

Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition. We constructed a combined immunQTL map by integrating data from European and Chinese colorectal cancer (CRC) samples. A polygenic risk score that incorporates these immunQTLs and hits on a genome-wide association study outperformed in CRC risk stratification within 447,495 multiethnic individuals. Using large-scale population cohorts, we identified that the immunQTL rs1360948 is associated with CRC risk and prognosis. Mechanistically, the rs1360948-G-allele increases CCL2 expression, recruiting regulatory T cells that can exert immunosuppressive effects on CRC progression. Blocking the CCL2-CCR2 axis enhanced anti-programmed cell death protein 1 ligand therapy. Finally, we have established a database (CancerlmmunityQTL2) to serve the research community and advance our understanding of immunogenomic interactions in cancer pathogenesis.

Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI.

BACKGROUND: In patients with coronary artery disease who are being evaluated for percutaneous coronary intervention (PCI), procedures can be guided by fractional flow reserve (FFR) or intravascular ultrasonography (IVUS) for decision making regarding revascularization and stent implantation. However, the differences in clinical outcomes when only one method is used for both purposes are unclear. METHODS: We randomly assigned 1682 patients who were being evaluated for PCI for the treatment of intermediate stenosis (40 to 70% occlusion by visual estimation on coronary angiography) in a 1:1 ratio to undergo either an FFR-guided or IVUS-guided procedure. FFR or IVUS was to be used to determine whether to perform PCI and to assess PCI success. In the FFR group, PCI was to be performed if the FFR was 0.80 or less. In the IVUS group, the criteria for PCI were a minimal lumen area measuring either 3 mm2 or less or measuring 3 to 4 mm2 with a plaque burden of more than 70%. The primary outcome was a composite of death, myocardial infarction, or revascularization at 24 months after randomization. We tested the noninferiority of the FFR group as compared with the IVUS group (noninferiority margin, 2.5 percentage points). RESULTS: The frequency of PCI was 44.4% among patients in the FFR group and 65.3% among those in the IVUS group. At 24 months, a primary-outcome event had occurred in 8.1% of the patients in the FFR group and in 8.5% of those in the IVUS group (absolute difference, -0.4 percentage points; upper boundary of the one-sided 97.5% confidence interval, 2.2 percentage points; P = 0.01 for noninferiority). Patient-reported outcomes as reported on the Seattle Angina Questionnaire were similar in the two groups. CONCLUSIONS: In patients with intermediate stenosis who were being evaluated for PCI, FFR guidance was noninferior to IVUS guidance with respect to the composite primary outcome of death, myocardial infarction, or revascularization at 24 months. (Funded by Boston Scientific; FLAVOUR ClinicalTrials.gov number, NCT02673424.).

Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms.

BACKGROUND & AIMS: Dysregulation of alternative splicing is implicated in many human diseases, and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms. METHODS: We performed a comprehensive sQTL analysis to identify genetic variants that control messenger RNA splicing across 33 cancer types from The Cancer Genome Atlas and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multi-ethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes. RESULTS: The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. In addition, functionally informed polygenic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese (odds ratio, 1.20; 95% CI, 1.12-1.29; P = 8.82 × 10-7) and European (odds ratio, 1.11; 95% CI, 1.07-1.16; P = 1.13 × 10-7) populations. rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RNA-binding protein PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells. CONCLUSIONS: Our study provides an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk and serving as biomarkers and therapeutic targets.

The prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF): a systematic review and meta-analysis.

To date, studies on the prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF) have not been summarized and analyzed as a whole. We conducted this systematic review and meta-analysis to assess the prevalence of CMD in patients with HFpEF. The PubMed, Cochrane, and Embase databases were searched from dates of inception until May 1, 2023. The primary outcome was the prevalence of CMD in patients with HFpEF, and values of CMD prevalence were pooled using a random-effects model. In total, 10 studies involving 1267 patients, including 822 with HFpEF and 445 without HFpEF, were included. The pooled prevalence of CMD in patients with HFpEF was 71% (95% CI, 0.63-0.79). In the subgroup analysis, the prevalence of CMD was 79% (95% CI, 0.71-0.87) by invasive measurement and 66% (95% CI, 0.54-0.77) by noninvasive measurement and 67% (95% CI, 0.52-0.82) with CFR < 2.0 and 75.0% (95% CI, 0.71-0.79) with CFR < 2.5. The prevalence of endothelium-independent CMD and endothelium-dependent CMD was 62% (95% CI, 0.53-0.72) and 50% (95% CI, 0.19-0.81), respectively. The prevalence of CMD was 74% (95% CI = 0.69-0.79) and 66% (95% CI = 0.41-0.90) in prospective and retrospective studies, respectively. Compared with the control group, patients with HFpEF had a significantly lower CFR (MD = - 1.28, 95% CI = - 1.82 to - 0.74, P < 0.01) and a higher prevalence of CMD (RR = 2.21, 95% CI = 1.52 to 3.20, P < 0.01). Qualitative analysis demonstrated that CMD might be associated with poor clinical outcomes in patients with HFpEF. In conclusion, this is the first systematic review and meta-analysis of all studies reporting the prevalence of CMD in patients with HFpEF. Our study demonstrates that CMD is common in patients with HFpEF and might be associated with poor clinical outcomes in these patients. Clinicians should attach importance to CMD in the diagnosis and treatment of HFpEF. The number of studies in this field is relatively small. Therefore, more high-quality studies are needed to explore the diagnostic and prognostic value of CMD and the potential role of CMD as a therapeutic target in patients with HFpEF.

Results from a real-world study: a novel glycosyltransferase risk score for prognosis, tumor microenvironment phenotypes and immunotherapy in bladder cancer.

BACKGROUND: Although immunotherapy shows tremendous potential in the treatment of bladder cancer (BLCA), the overall prognosis and response rates to immunotherapy in BLCA remain suboptimal. METHODS: We performed an extensive evaluation of glycosyltransferase expression patterns in BLCA patients by analyzing 210 glycosyltransferase-related genes. Subsequently, we established correlations between these glycosyltransferase patterns, prognosis, and tumor microenvironment (TME) phenotypes. To offer personalized patient assessments, we developed a glycosyltransferase risk score that accurately predicts prognosis, TME phenotypes, and molecular subtypes. Importantly, we developed a RNA-seq cohort, named Xiangya cohort, to validate our results. RESULTS: Two distinct patterns of glycosyltransferase expression were identified, corresponding to inflamed and noninflamed TME phenotypes, and demonstrated the potential to predict prognosis. We developed and validated a comprehensive risk score that accurately predicted individual patient prognosis in the TCGA-BLCA cohort. Additionally, we constructed a nomogram that integrated the risk score with several key clinical factors. Importantly, this risk score was successfully validated in external cohorts, including the Xiangya cohort and GSE48075. Furthermore, we discovered a positive correlation between this risk score and tumor-infiltrating lymphocytes in both the TCGA-BLCA and Xiangya cohorts, suggesting that patients with a higher risk score exhibited an inflamed TME phenotype and were more responsive to immunotherapy. Finally, we observed that the high and low risk score groups were consistent with the luminal and basal subtypes of BLCA, respectively, providing further validation of the risk score's role in the TME in terms of molecular subtypes. CONCLUSIONS: Glycosyltransferase patterns exhibit distinct TME phenotypes in BLCA. Our comprehensive risk score provides a promising approach for prognostic prediction and assessment of immunotherapy efficacy, offering valuable guidance for precision medicine.

Emergence of a clinical Salmonella enterica serovar 1,4,[5], 12: i:-isolate, ST3606, in China with susceptibility decrease to ceftazidime-avibactam carrying a novel blaCTX-M-261 variant and a blaNDM-5.

PURPOSE: The detection rate of Salmonella enterica serovar 1,4,[5], 12: i: - (S. 1,4,[5], 12: i: -) has increased as the most common serotype globally. A S. 1,4,[5], 12: i: - strain named ST3606 (sequence type 34), isolated from a fecal specimen of a child with acute diarrhea hospitalized in a tertiary hospital in China, was firstly reported to be resistant to carbapenem and ceftazidime-avibactam. The aim of this study was to characterize the whole-genome sequence of S. 1,4,[5], 12: i: - isolate, ST3606, and explore its antibiotic resistance genes and their genetic environments. METHODS: The genomic DNA of S. 1,4,[5], 12: i: - ST3606 was extracted and performed with single-molecule real-time sequencing. Resistance genes, plasmid replicon type, mobile elements, and multilocus sequence types (STs) of ST3606 were identified by ResFinder 3.2, PlasmidFinder, OriTfinder database, ISfinder database, and MLST 2.0, respectively. The conjugation experiment was utilized to evaluate the conjugation frequency of pST3606-2. Protein expression and enzyme kinetics experiments of CTX-M were performed to analyze hydrolytic activity of a novel CTX-M-261 enzyme toward several antibiotics. RESULTS: Single-molecule real-time sequencing revealed the coexistence of a 109-kb IncI1-Iα plasmid pST3606-1 and a 70.5-kb IncFII plasmid pST3606-2. The isolate carried resistance genes, including blaNDM-5, sul1, qacE, aadA2, and dfrA12 in pST3606-1, blaTEM-1B, aac(3)-lld, and blaCTX-M-261, a novel blaCTX-M-1 family member, in pST3606-2, and aac(6')-Iaa in chromosome. The blaCTX-M-261 was derived from blaCTX-M-55 by a single-nucleotide mutation 751G>A leading to amino acid substitution of Val for Met at position 251 (Val251Met), which conferred CTX-M increasing resistance to ceftazidime verified by antibiotics susceptibility testing of transconjugants carrying pST3606-2 and steady-state kinetic parameters of CTX-M-261. pST3606-1 is an IncI1-α incompatibility type that shares homology with plasmids of pC-F-164_A-OXA140, pE-T654-NDM-5, p_dm760b_NDM-5, and p_dmcr749c_NDM-5. The conjugation experiment demonstrated that pST3606-2 was successfully transferred to the Escherichia coli recipient C600 with four modules of OriTfinder. CONCLUSION: Plasmid-mediated horizontal transfer plays an important role in blaNDM-5 and blaCTX-M-261 dissemination, which increases the threat to public health due to the resistance to most ß-lactam antibiotics. This is the first report of blaCTX-M-261 and blaNDM-5 in S. 1,4,[5], 12: i: -. The work provides insights into the enzymatic function and demonstrates the ongoing evolution of CTX-M enzymes and confirms urgency to control resistance of S. 1,4,[5], 12: i: -.

Quantitative Flow Ratio-Derived Index of Microcirculatory Resistance as a Novel Tool to Identify Microcirculatory Function in Patients with Ischemia and No Obstructive Coronary Artery Disease.

BACKGROUND: Coronary microvascular disease (CMVD) is associated with adverse cardiovascular outcomes. However, there is no reliable and noninvasive quantitative diagnostic method available for CMVD. The use of a pressure wire to measure the index of microcirculatory resistance (IMR) is possible, but it has inevitable practical restrictions. We hypothesized that computation of the quantitative flow ratio could be used to predict CMVD with symptoms of ischemia and no obstructive coronary artery disease (INOCA). METHODS: We retrospectively assessed the diagnostic efficiency of the quantitative flow ratio-derived index of microcirculatory resistance (QMR) in 103 vessels from 66 patients and compared it with invasive IMR using the thermodilution technique. RESULTS: Patients were divided into the CMVD group (41/66, 62.1%) and non-CMVD group (25/66, 37.9%). Pressure wire IMR measurements were made in 103 coronary vessels, including 44 left descending arteries, 18 left circumflex arteries, and 41 right coronary arteries. ROC curve analysis showed a good diagnostic performance of QMR for all arteries (area under the curve = 0.820, 95% confidence interval 0.736-0.904, p < 0.001) in predicting microcirculatory function. The optimal cut-off for QMR to predict microcirculatory function was 266 (sensitivity: 82.9%, specificity: 72.6%, and diagnostic accuracy: 76.7%). CONCLUSION: QMR is a promising tool for the assessment of coronary microcirculation. The assessment of the IMR without the use of a pressure wire may enable more rapid, convenient, and cost-effective assessment of coronary microvascular function.

The triglyceride glucose index was nonlinearly associated with all-cause mortality in diabetic patients.

BACKGROUND AND AIM: The TyG index has been linked with cardiometabolic diseases. Our study aimed to investigate the specific relationship between the triglyceride and glucose index (TyG) and both all-cause and cardiovascular mortality in diabetic patients. METHODS AND RESULTS: We enrolled 3120 participants with diabetes from the National Health and Nutrition Examination Survey. The TyG index was calculated using the formula ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Hazard ratios (HRs) of TyG associated with mortality risk were assessed using Cox proportional hazard regression models. Over a follow-up period of 10.8 thousand person-years, we observed 768 all-cause deaths and 155 cardiovascular deaths. Compared to the reference quartile, the multivariate-adjusted hazard ratios and 95% confidence intervals for all-cause mortality were 1.02 (1.01-1.05; p = 0.008) in the fourth quartile. Dose-response analysis revealed a non-linear association. However, no significant associations were found between the TyG index and cardiovascular mortality. CONCLUSIONS: The TyG index exhibited a non-linear association with the risk of all-cause mortality in diabetic patients.

Multimodal MRI-based radiomics models for the preoperative prediction of lymphovascular space invasion of endometrial carcinoma.

PURPOSE: To evaluate the predictive capabilities of MRI-based radiomics for detecting lymphovascular space invasion (LVSI) in patients diagnosed with endometrial carcinoma (EC). MATERIALS AND METHODS: A retrospective analysis was conducted on 160 female patients diagnosed with EC. The radiomics model including T2-weighted and dynamic contrast-enhanced MRI (DCE-MRI) images was established. Additionally, a conventional MRI model, which incorporated MRI-reported FIGO stage, deep myometrial infiltration (DMI), adnexal involvement, and vaginal/parametrial involvement, was established. Finally, a combined model was created by integrating the radiomics signature and conventional MRI characteristics. The predictive performance was validated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curves. A stratified analysis was conducted to compare the differences between the three models by Delong test. RESULTS: In predicting LVSI, the radiomics model outperformed the clinical model in the training cohort (AUC: 0.899 vs. 0.8862) but not in the test cohort (AUC: 0.812 vs. 0.8758). The combined model demonstrated superior performance in both the training and test cohorts (training cohort: AUC = 0.934, 95% CI: 0.8807-0.9873; testing cohort: AUC = 0.905, 95% CI: 0.7679-1). CONCLUSIONS: The combined model exhibited utility in preoperatively predicting LVSI in patients with EC, offering potential benefits for clinical decision-making.

The Roles of Circular RNAs in Ischemic Stroke through Modulating Neuroinflammation.

Ischemic stroke (IS) remains a serious threat to human health. Neuroinflammatory response is an important pathophysiological process after IS. Circular RNAs (circRNAs), a member of the non-coding RNA family, are highly expressed in the central nervous system and widely involved in regulating physiological and pathophysiological processes. This study reviews the current evidence on neuroinflammatory responses, the role of circRNAs in IS and their potential mechanisms in regulating inflammatory cells, and inflammatory factors affecting IS damage. This review lays a foundation for future clinical application of circRNAs as novel biomarkers and therapeutic targets.

The Prognostic Value of Advanced Lung Cancer Inflammation Index in Elderly Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

This study aimed to investigate the predictive value of advanced lung cancer inflammation index (ALI) for major adverse cardiovascular events (MACEs) in elderly patients with acute coronary syndrome (ACS).A total of 586 ACS patients undergoing percutaneous coronary intervention (PCI) over 65 years old between January 2017 and December 2018 were retrospectively collected. The patients were divided into two groups by the optimal cutoff value of ALI. Spearman rank correlation coefficient was used to evaluate the correlation between ALI and the Global Registry of Acute Coronary Events (GRACE). Time-dependent receiver operating characteristic (ROC) curves, Cox survival analysis, and Kaplan Meier curves were used to assess the predictive value of ALI for MACEs.Spearman's nonparametric test revealed a moderate correlation between ALI and the GRACE (r: -0.417, P < 0.001). Time-dependent ROC curves showed that the area under the curve for ALI was 0.751 (95% CI, 0.699-0.798) in predicting MACEs, higher than Geriatric Nutritional Risk Index (0.531, 95% CI 0.435-0.627) and Prognostic Nutritional Index (0.590, 95% CI 0.505-0.676), and for combined diagnostic models (ALI + GRACE) was 0.913, (95% CI 0.875 - 0.942, P < 0.001). Multivariate Cox analysis demonstrated that ALI (HR: 0.974, 95% CI: 0.952-0.996, P = 0.017) was an independent risk factor for MACEs. Kaplan Meier survival analysis showed that the cumulative incidence of MACEs was significantly higher in elderly ACS patients with lower ALI (log-rank test, P < 0.001).ALI could be a nutrition-inflammation indicator with independent predictive value for long-term MACEs of elderly ACS patients after PCI.

[Meta-analysis and trial sequential analysis of Shenshao Capsules in treatment of angina pectoris in coronary heart disease].

The efficacy and safety of Shenshao Capsules in combination with conventional western medicine for the treatment of angina pectoris in coronary heart disease were systematically evaluated. Computer search of seven databases, including CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, and Cochrane Library, was conducted to identify randomized controlled trial(RCT) on Shenshao Capsules for the treatment of angina pectoris in coronary heart disease up to December 2023. According to inclusion and exclusion criteria, articles were screened, and data was extracted. Cochrane bias risk assessment tool 2.0(RoB 2.0) was used to evaluate the quality of the included articles. Meta-analysis was performed by RevMan 5.4 and Stata/SE 15.1 software, and evidence quality was rated by the GRADE system. TSA 0.9.5.10 beta software was used for the trial sequential analysis(TSA). Twelve RCTs, with a total of 1 128 participants(567 in the experimental group and 561 in the control group), were included. Meta-analysis showed that Shenshao Capsules + conventional western medicine significantly improved clinical efficacy(RR=1.20, 95%CI[1.15, 1.26], P<0.000 01) and electrocardiogram efficacy(RR=1.16, 95%CI[1.04, 1.30], P=0.01), reduced the frequency of weekly angina pectoris attacks(MD=-2.85, 95%CI[-5.27,-0.43], P=0.02), daily angina pectoris attacks(MD=-0.30, 95%CI[-0.57,-0.03], P=0.03) and the duration of angina pectoris attacks(RR=-2.28, 95%CI[-3.44,-1.12], P=0.000 1). There was no statistically significant difference in adverse reactions between the two groups(RR=1.33, 95%CI[0.71, 2.51], P=0.37). TSA indicated that the cumulative evidence for clinical efficacy exceeded the traditional boundary but did not exceed the TSA boundary, suggesting a potential false positive result. According to GRADE assessment, except for clinical efficacy, which was rated as low-quality evidence, the remaining outcomes were rated as very low-quality evidence. The results indicate that Shenshao Capsules + conventional western medicine may have certain advantages in improving clinical efficacy and electrocardiographic efficacy, reducing the frequency and duration of angina pectoris attacks. However, due to the limitations of this study, more rigorous and high-quality RCT is needed to validate its efficacy and safety.

[Evidence map of clinical research on Chinese patent medicines for post-acute myocardial infarction heart failure].

An evidence map was established to comprehensively sort out the clinical research in the treatment of post-acute myocardial infarction heart failure(P-AMI-HF) with Chinese patent medicines, so as to reveal the distribution of evidence in this field. CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library, and EMbase were searched for the randomized controlled trial(RCT), systematic reviews/Meta-analysis, and guidelines/consensus in this field. The evidence was analyzed and displayed in the form of a combination of text, charts, bubble charts, and bar charts, and the quality of RCT, systematic reviews/Meta-analysis, and guidelines/consensus were evaluated by RoB 1.0, AMSTAR2, and AGREE Ⅱ, respectively. A total of 163 RCTs, 4 systematic reviews/Meta-analysis, 1 network Meta-analysis, 2 observational studies, and 5 guidelines/consensus were included. In recent years, the total number of publications in this field has shown an upward trend. There were a variety of Chinese patent medicines in the treatment of P-AMI-HF, among which Shenfu Injection received the most attention. The clinical RCT and systematic reviews/Meta-analysis generally had poor quality, and the RCT mostly had a small size, a single center, and a short cycle. The outcome indicators mainly included cardiac function indicators, myocardial injury markers, total response rate, hemodynamic indicators, and safety indicators, while the characteristic efficacy indicators of TCM received insufficient attention. The development processes of some guidelines/consensus lack standardization, which compromised their authority and rationality. Chinese patent medicines have advantages in the treatment of P-AMI-HF, while there are also problems, which remain to be solved by more high-quality evidence. That is, more large-sample and multi-center clinical studies should be carried out in the future, and the formulation process of relevant systematic reviews/Meta-analysis and guideline/consensus should be standardized and the quality of evidence should be improved. In this way, the effectiveness and safety of Chinese patent medicines in the treatment of P-AMI-HF can be explored.

HSPA12A was identified as a key driver in colorectal cancer GWAS loci 10q26.12 and modulated by an enhancer-promoter interaction.

Although genome-wide association studies (GWASs) have identified over 100 colorectal cancer (CRC) risk loci, an understanding of causal genes or risk variants and their biological functions in these loci remain unclear. Recently, genomic loci 10q26.12 with lead SNP rs1665650 was identified as an essential CRC risk loci of Asian populations. However, the functional mechanism of this region has not been fully clarified. Here, we applied an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk loci 10q26.12. Notably, HSPA12A had the most significant effect among the identified genes and functioned as a crucial oncogene facilitating cell proliferation. Moreover, we conducted an integrative fine-mapping analysis to identify putative casual variants and further explored their association with CRC risk in a large-scale Chinese population consisting of 4054 cases and 4054 controls and also independently validated in 5208 cases and 20,832 controls from the UK biobank cohort. We identified a risk SNP rs7093835 in the intron of HSPA12A that was significantly associated with an increased risk of CRC (OR 1.23, 95% CI 1.08-1.41, P = 1.92 × 10-3). Mechanistically, the risk variant could facilitate an enhancer-promoter interaction mediated by the transcriptional factor (TF) GRHL1 and ultimately upregulate HSPA12A expression, which provides functional evidence to support our population findings. Collectively, our study reveals the important role of HSPA12A in CRC development and illustrates a novel enhancer-promoter interaction module between HSPA12A and its regulatory elements rs7093835, providing new insights into the etiology of CRC.

CancerImmunityQTL: a database to systematically evaluate the impact of genetic variants on immune infiltration in human cancer.

Tumor-infiltrating immune cells as integral component of the tumor microenvironment are associated with tumor progress, prognosis and responses to immunotherapy. Genetic variants have been demonstrated to impact tumor-infiltrating, underscoring the heritable character of immune landscape. Therefore, identification of immunity quantitative trait loci (immunQTLs), which evaluate the effect of genetic variants on immune cells infiltration, might present a critical step toward fully understanding the contribution of genetic variants in tumor development. Although emerging studies have demonstrated the determinants of germline variants on immune infiltration, no database has yet been developed to systematically analyze immunQTLs across multiple cancer types. Using genotype data from TCGA database and immune cell fractions estimated by CIBERSORT, we developed a computational pipeline to identify immunQTLs in 33 cancer types. A total of 913 immunQTLs across different cancer types were identified. Among them, 5 immunQTLs are associated with patient overall survival. Furthermore, by integrating immunQTLs with GWAS data, we identified 527 immunQTLs overlapping with known GWAS linkage disequilibrium regions. Finally, we constructed a user-friendly database, CancerImmunityQTL (http://www.cancerimmunityqtl-hust.com/) for users to browse, search and download data of interest. This database provides an informative resource to understand the germline determinants of immune infiltration in human cancer and benefit from personalized cancer immunotherapy.

Assessing the effects of organizational support, psychological capital, organizational identification on job performance among nurses: a structural equation modeling approach.

BACKGROUND: The job performance of individual employees determines the overall performance of an organization, and organizational support is known as an important resource at the organizational level to enhance job performance. Although nursing scholars have confirmed the crucial role of organizational support in enhancing job performance, there are no studies on whether psychological capital and organizational identification mediate the association between organizational support and job performance. The purpose of this study is to investigate the influence of organizational support, psychological capital, and organizational identification on nurses' job performance. METHODS: A cross-sectional survey was conducted among 455 nurses from 21 public hospitals in China. Instruments were perceived organizational support scale, task performance scale, contextual performance scale, Nurse Psychological Capital Questionnaire, and Organizational Identification Questionnaire. Survey data were analyzed using SPSS and AMOS, and hypotheses were tested using path model analysis. RESULTS: Nurses' perceived organizational support, psychological capital, organizational identification, and task/contextual performance were positively correlated in every two variables. Psychological capital played an important mediating role in perceived organizational support and task/contextual performance, as well as organizational identification. The multi-mediating effect of psychological capital and organizational identification on the relationship between organizational support and task/contextual performance were 0.14 and 0.25, respectively. CONCLUSIONS: There was a positive correlation between organizational support and job performance among nurses. Psychological support, organizational identification and contextual performance played a chain mediation role in the relationship between organizational support on task performance in nurses. Nursing managers should pay more attention to enhancing nurses' psychological capital and organizational identification through effective interventions to improve nurses' job performance.

Yttrium chloride induces ferroptosis in cardiomyocytes via iron accumulation and triggers cardiac lipid peroxidation and inflammation that cause heart adverse events in mice.

The growing presence of yttrium (Y) in the environment raises concern regarding its safety and toxicity. However, limited toxicological data are available to determine cardiotoxicity of Y and its underlying mechanisms. In the present study, yttrium chloride (YCl3) intervention with different doses was performed in male Kunming mice for the toxicological evaluation of Y in the heart. After 28 days of intragastric administration, 500 mg/kg·bw YCl3 induces iron accumulation in cardiomyocytes, and triggers ferroptosis through the glutathione peroxidase 4 (GPX4)/glutathione (GSH)/system Xc- axis via the inhibition of Nrf2 signaling pathway. This process led to cardiac lipid peroxidation and inflammatory response. Further RNA sequencing transcriptome analysis found that many genes involved in ferroptosis and lipid metabolism-related pathways were enriched. The ferroptosis induced by YCl3 in cardiomyocytes ultimately caused cardiac injury and dysfunction in mice. Our findings assist in the elucidation of the potential subacute cardiotoxicity of Y3+ and its underlying mechanisms.

[Correlation of mitochondrial tRNA variants with coronary heart disease in a Chinese pedigree].

OBJECTIVE: To explore the correlation of mitochondrial DNA (mtDNA) variants and coronary heart disease (CHD) in a Chinese pedigree and the possible molecular mechanisms. METHODS: A Chinese pedigree featuring matrilineal inheritance of CHD who visited Hangzhou First People's Hospital in May 2022 was selected as the study subject. Clinical data of the proband and her affected relatives was collected. By sequencing the mtDNA of the proband and her pedigree members, candidate variants were identified through comparison with wild type mitochondrial genes. Conservative analysis among various species was conducted, and bioinformatics software was used to predict the impact of variants on the secondary structure of tRNA. Real-time PCR was carried out to determine the copy number of mtDNA, and a transmitochondrial cell line was established for analyzing the mitochondrial functions, including membrane potential and ATP level. RESULTS: This pedigree had contained thirty-two members from four generations. Among ten maternal members, four had CHD, which yielded a penetrance rate of 40%. Sequence analysis of proband and her matrilineal relatives revealed the presence of a novel m.4420A>T variant and a m.10463T>C variant, both of which were highly conserved among various species. Structurally, the m.4420A>T variant had occurred at position 22 in the D-arm of tRNAMet, which disrupted the 13T-22A base-pairing, while the m.10463T>C variant was located at position 67 in the acceptor arm of tRNAArg, a position critical for steady-state level of the tRNA. Functional analysis revealed that patients with the m.4420A>T and m.10463T>C variants exhibited much fewer copy number of mtDNA and lower mitochondrial membrane potential (MMP) and ATP contents (P < 0.05), which were decreased by approximately 50.47%, 39.6% and 47.4%, respectively. CONCLUSION: Mitochondrial tRNAMet 4420A>T and tRNAArg 10463T>C variants may underlay the maternally transmitted CHD in this pedigree, which had shown variation in mtDNA homogeneity, age of onset, clinical phenotype and other differences, suggesting that nuclear genes, environmental factors and mitochondrial genetic background have certain influence on the pathogenesis of CHD.

Role of Circular RNAs in Atherosclerosis through Regulation of Inflammation, Cell Proliferation, Migration, and Apoptosis: Focus on Atherosclerotic Cerebrovascular Disease.

Atherosclerosis (AS) is a disease dangerous to human health and the main pathological cause of ischemic cardiovascular diseases. Although its pathogenesis is not fully understood, numerous basic and clinical studies have shown that AS is a chronic inflammatory disease existing in all stages of atherogenesis. It may be a common link or pathway in the pathogenesis of multiple atherogenic factors. Inflammation is associated with AS complications, such as plaque rupture and ischemic cerebral infarction. In addition to inflammation, apoptosis plays an important role in AS. Apoptosis is a type of programmed cell death, and different apoptotic cells have different or even opposite roles in the process of AS. Unlike linear RNA, circular RNA (circRNA) a covalently closed circular non-coding RNA, is stable and can sponge miRNA, which can affect the stages of AS by regulating downstream pathways. Ultimately, circRNAs play very important roles in AS by regulating inflammation, apoptosis, and some other mechanisms. The study of circular RNAs can provide new ideas for the prediction, prevention, and treatment of AS.

Aspirin Alone Versus Dual Antiplatelet Therapy after Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

BACKGROUND: The current American College of Cardiology and American Heart Association (ACC/AHA) guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 6 months followed by lifelong aspirin after transcatheter aortic valve replacement (TAVR). However, studies that have DAPT with aspirin following TAVR have questioned this recommendation as DAPT has been associated with more bleeding events compared to aspirin. We performed a systematic review and meta-analysis of all the RCTs comparing DAPT (aspirin plus clopidogrel) with aspirin alone as antithrombotic treatment following transcatheter aortic valve replacement. METHODS: The databases of Embase, PubMed, and Cochrane library were searched from inception to Oct 1, 2020, and randomized controlled trials (RCTs) reporting aspirin plus clopidogrel with aspirin alone as antithrombotic treatment after TAVI were included. Revman 5.3 was used to conduct the analysis. RESULTS: After screening 152 articles, four studies involving 1086 patients (541 patients in the aspirin group and 545 patients in the DAPT group) were included. The results demonstrated that, at 30 days follow-up, compared with DAPT, aspirin was not associated with a statistically significant difference in the rate of bleeding events (RR = 1.22, 95% CI 0.62 to 2.39, P = 0.57), all-cause mortality (RR = 1.21, 95% CI 0.52 to 2.84, P = 0.66), stroke (RR = 0.81, 95% CI 0.24 to 2.79, P = 0.74), and MI (RR = 4.00, 95% CI 0.45 to 35.22, P = 0.21). However, at the 6 to 12 months follow-up, DAPT appeared to increase the risk of bleeding events compared with aspirin alone (RR = 1.67, 95% CI 1.24 to 2.24, P < 0.001), and there was no significant difference in the rate of all-cause mortality (RR = 0.89, 95% CI 0.53 to 1.48, P = 0.65), stroke (RR = 1.04, 95% CI 0.57 to 1.92, P = 0.90), and MI (RR = 1.65, 95% CI 0.52 to 5.26, P = 0.40) among the two groups. CONCLUSIONS: Our systematic review and meta-analysis suggested that aspirin alone could decrease the risk of bleeding and was not associated with higher risk of mortality, stroke or myocardial infarction compared with DAPT.