Proteogenomic characterization of cholangiocarcinoma.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with limited understanding and few effective therapeutic approaches. We aimed at providing a proteogenomic CCA characterization to inform biological processes and treatment vulnerabilities. APPROACH AND RESULTS: Integrative genomic analysis with functional validation uncovered biological perturbations downstream of driver events including DPCR1 , RBM47 mutations, SH3BGRL2 copy number alterations, and FGFR2 fusions in CCA. Proteomic clustering identified three subtypes with distinct clinical outcomes, molecular features, and potential therapeutics. Phosphoproteomics characterized targetable kinases in CCA, suggesting strategies for effective treatment with CDK and MAPK inhibitors. Patients with CCA with HBV infection showed increased antigen processing and presentation (APC) and T cell infiltration, conferring a favorable prognosis compared with those without HBV infection. The characterization of extrahepatic CCA recommended the feasible application of vascular endothelial-derived growth factor inhibitors. Multiomics profiling presented distinctive molecular characteristics of the large bile duct and the small bile duct of intrahepatic CCA. The immune landscape further revealed diverse tumor immune microenvironments, suggesting immune subtypes C1 and C5 might benefit from immune checkpoint therapy. TCN1 was identified as a potential CCA prognostic biomarker, promoting cell growth by enhancing vitamin B12 metabolism. CONCLUSIONS: We characterized the proteogenomic landscape of 217 CCAs with 197 paired normal adjacent tissues and identified their subtypes and potential therapeutic targets. The multiomics analyses with other databases and some functional validations have indicated strategies regarding the clinical, biological, and therapeutic approaches to the management of CCA.

Impact of Duration of Diabetes Mellitus on Long-Term Outcome in Type 2 Diabetic Patients with Primary Percutaneous Coronary Intervention after the First Myocardial Infarction.

BACKGROUND: Diabetes mellitus (DM) increases the risk of mortality in patients with acute myocardial infarction (AMI). The impact of the diabetes duration on the long-term outcome of those with percutaneous coronary intervention (PCI) after the first AMI is unclear. In this study, we evaluated the predictive value of diabetes duration in the occurrence of major adverse cardiovascular and cerebrovascular events (MACCEs). METHODS: A total of 394 type 2 DM patients with PCI after the first AMI were enrolled and were divided into two groups by the diabetes duration: a short-DM group with diabetes duration of <5 years and a long-DM group with a duration of ≥5 years. The clinical endpoint was MACCEs. RESULTS: Multivariate Cox regression analysis found that the diabetes duration was independently associated with increased occurrence of MACCEs (HR: 1.512, 95% CI: 1.033, 2.215, p = 0.034), along with hypertension, Killip class III or IV, creatinine, multivessel disease, and continuous hypoglycemic therapy. After adjusting for the confounding variables, a nested Cox model showed that diabetes duration was still an independent risk factor of MACCEs (HR: 1.963, 95% CI: 1.376, 2.801, p < 0.001). The Kaplan-Meier survival curve illustrated a significantly high risk of MACCEs (HR: 2.045, p < 0.0001) in long-duration DM patients. After propensity score matching, a longer diabetes duration was associated with an increased risk of MACCE occurrence. CONCLUSION: Long-duration diabetes was independently associated with poor clinical outcomes after PCI in patients with their first myocardial infarction. Despite the diabetes duration, continuous hypoglycemic therapy significantly improved long-term clinical outcomes.

[Ginsenoside F1 inhibits cholesterol overload in oxidative-damaged cells through SREBP2/HMGCR pathway].

OBJECTIVE: To investigate the inhibitory mechanisms of ginsenoside F1 on hydrogen peroxide induced cholesterol metabolism disorder and oxidative stress in HepG2 cells. METHODS: 1, 1-diphenyl-2-picrylhydrazyl(DPPH) and oxygen radical absorbance capacity(ORAC) tests were used to detect the scavenging effect of ginsenoside F1 on nitrogen and oxygen free radicals. HepG2 cells were treated with 400 µmol/L hydrogen peroxide and pretreated with 10, 20 and 40 µmol/L ginsenoside F1. Mitochondrial membrane potential(MMP) and total cholesterol levels were detected by JC-1 method and cholesterol kit, respectively. The protein expression levels of sterol-regulatory element binding proteins(SREBP2)and 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMGCR) in cholesterol synthesis pathway were detected by Western blot. RESULTS: The DPPH clearance rate of ginsenoside F1 was much lower than that of 6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid(Trolox), but the ORAC capability of ginsenoside F1 was stronger, which was comparable to Trolox. The MMP and protein expression of SREBP2 were significantly decreased in injured group(P<0.05). The cholesterol and protein expression of HMGCR were significantly increased(P<0.05). Whereas, compared with the injured group, the MMP and protein expression of SREBP2 were significantly increased after 10, 20 and 40 µmol/L ginsenoside F1 pretreatment of injured cells(P<0.05). The cholesterol level and protein expression of HMGCR were significantly lower than injured group with concentration-dependent decreases(P<0.05). CONCLUSION: Ginsenoside F1 can protect against hydrogen peroxide induced oxidative stress in HepG2 cells by inhibiting oxygen free radicals and protecting mitochondria. And its mechanism may be related to the intervention of SREBP2/HMGCR pathway in regulating cellular cholesterol anabolism.

Effects of Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting on Clinical Outcomes in Patients with Reduced Ejection Fraction Heart Failure and Coronary Heart Disease: A Meta-Analysis.

OBJECTIVE: To clarify the effects of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on the clinical outcomes of patients with coronary heart disease (CHD) complicated with reduced ejection fraction heart failure (HFrEF) through meta-analysis. METHODS: Three major literature databases - PubMed, Web of Science, and Cochrane - were searched by search terms and the literature retrieval time was publications dating from January 2007 to December 2021. To search for observational studies and randomized controlled trials (RCT) comparing the efficacy of PCI and CABG in patients with CHD and HFrEF, the abstract or full text of the literature was read and the final included literature was determined, according to inclusion and exclusion criteria. The quality of the included literature was evaluated using the Ottawa scale and data extraction was further completed. Data analysis was made using RevMan5.4 and R4.1 software; relevant forest plots and funnel plots were made, according to the extracted data. Egger's test was used to evaluate whether the data had publication bias. Outcomes were the major adverse cardiovascular events (MACE). RESULTS: A total of 10 studies were included and 11,032 subjects were included, made up of 5,521 cases of PCI and 5,511 cases of CABG. The results showed no significant difference between the two groups in cardiac mortality (CM) (RR=1.13, 95% CI 0.98-1.30, P = 0.10) and in overall all-cause mortality (ACM) (RR=1.12, 95% CI 0.92-1.37, P = 0.25). In the subgroup analysis of ACM, in the subgroups with left ventricular ejection fraction (LVEF) less than 35% and exceeding 35% and less than 50% (RR=1.12, 95% CI 0.92-1.37, P = 0.25) between the two groups, there was no statistical difference. However, among other MACE, compared with the PCI group, the CABG group had a lower risk of MACE (RR=1.58, 95%CI 1.49-1.70, P < 0.00001), myocardial infarction (MI) (RR=1.99, 95% CI 1.02-3.88, P = 0.04), heart failure (HF) (RR=1.29, 95% CI 1.17-1.43, P < 0.00001) and revascularization (RR=2.74, 95% CI 1.93-3.90, P < 0.00001). Finally in the CABG group, the risk of stroke or transient ischemic attack (TIA) was higher (RR=0.71, 95% CI 0.58-0.86, P = 0.0006) than the PCI group. CONCLUSIONS: The mortality rates of PCI and CABG were similar in patients with CHD complicated with HFrEF. Compared with PCI, CABG had a lower incidence of MACE, MI, HF, and revascularization, and a higher incidence of stroke or TIA.

Integrated Strategy for Large-Scale Investigation on Protein Core Fucosylation Stoichiometry Based on Glycan-Simplification and Paired-Peaks-Extraction.

Core fucosylation (CF) is a special form of N-glycosylation and plays an important role in pathological and biological processes. Increasing efforts in this area are focused on the identification of CF glycosites, whereas evidence showed that the stoichiometry of CF occupancy is functionally important. Here, an integrated strategy based on "Glycan-Simplification and Paired-Peaks-extraction" (GSPPE) for detecting large-scale stoichiometries of CF was developed. After HILIC enrichment of intact glycopeptides, sequential cleavages by endoglycosidases H and endoglycosidases F3 were performed to generate simplified glycopeptide forms (SGFs), i.e., peptide-GlcNAc (pep-HN) and peptide-GlcNAc-Fucose (pep-CF). These paired SGFs were found to be eluted consecutively on a reversed-phase chromatography column, which allowed us to obtain peak areas of SGF pairs, even if only one of the peaks was captured by the mass spectrometer (MS), by introducing the Paired-Peaks-Extraction algorithm. Thus, the missing value dilemma of random data-dependent MS/MS acquisition was reduced and the stoichiometry of site-specific CF could be calculated. We systematically evaluated the feasibility of this strategy using standard glycoproteins and then explored urinary samples from healthy individuals and hepatocellular carcinoma (HCC) patients. In total, 1449 highly reliable core fucose glycosites and their corresponding CF stoichiometries were obtained. Dozens of glycosites that differed significantly in the urine of healthy individuals and HCC patients were disclosed. The developed approach and program presented here may promote studies on core fucosylation and lead to a deeper understanding of their dysregulation in physiological- or pathological processes.

Site-Specific and Quantitative N-Glycan Heterogeneity Analysis of the Charge Isomers of an Anti-VEGF Recombinant Fusion Protein by High-Resolution Two-Dimensional Gel Electrophoresis and Mass Spectrometry.

Glycan modification prompts important concerns about the quality control of biopharmaceutical production. Conbercept is a multiglycosylated recombinant fusion protein drug approved for the treatment of age-related macular degeneration (AMD). With 14 N-glycosites in the molecule and 7 N-glycosites in the monomer, the charge isomer separation and characterization of conbercept pose great challenges due to its enormous heterogeneities. The batch-to-batch stability on the charge isomer distribution and the possible causation of the pattern necessitate the development of effective analytical approaches. Here, the immobilized pH gradient (IPG)-based two-dimensional gel electrophoresis (2-DE) approach was first optimized to achieve high-resolution, high-reproducible separation and preparation of charge isomers. Then, combined with the quantitative analysis strategy of site-specific N-glycan heterogeneity based on the diagnostic MS2 ion (peptides+GlcNAc, Y1 ions) of glycopeptides, an integrated approach for the quantitation of site-specific N-glycan heterogeneities among charge isomers was established. Finally, the quantitation of site-specific N-glycoforms in each of the 2-DE resolved spots were performed, and the results showed that the sialylation tends to increase for gel spots located in the acidic regions. This study provides an effective approach to separate the charge isomers of the heavily glycosylated protein drugs, and to quantitatively explore the site-specific N-glycans dynamics along with the different charge isomers.

rAAV9-Mediated MEK1 Gene Expression Restores Post-conditioning Protection Against Ischemia Injury in Hypertrophic Myocardium.

PURPOSE: We investigated whether increased expression of activated mitogen-activated protein kinase (MAPK) kinases 1 (MEK1) restores ischemic post-conditioning (IPostC) protection in hypertrophic myocardium following ischemia/reperfusion (I/R) injury. METHODS: C57Bl/6 mice received recombinant adeno-associated virus type 9 (rAAV9)-mediated activated MEK1 gene delivery systemically, then following the induction of cardiac hypertrophy via transverse aortic constriction for 4 weeks. In a Langendorff model, hypertrophic hearts were subjected to 40 min/60 min I/R or with IPostC intervention consisting of 6 cycles of 10 s reperfusion and 10 s no-flow before a 60-min reperfusion. Hemodynamics, infarct size (IS), myocyte apoptosis and changes in expression of reperfusion injury salvage kinase (RISK) pathway were examined. RESULTS: rAAV9-MEK1 gene delivery led to a 4.3-fold and 2.7-fold increase in MEK1 mRNA and protein expression in the heart versus their control values. I/R resulted in a larger IS in hypertrophic than in non-hypertrophic hearts (52.3 ± 4.7% vs. 40.0 ± 2.5%, P < 0.05). IPostC mediated IS reduction in non-hypertrophic hearts (27.6 ± 2.6%, P < 0.05), while it had no significant effect in hypertrophic hearts (46.5 ± 3.1%, P=NS) compared with the IS in non-hypertrophic or hypertrophic hearts subjected to I/R injury only, respectively. Hemodynamic decline induced by I/R was preserved by IPostC in non-hypertrophic hearts but not in hypertrophic hearts. rAAV9-MEK1 gene delivery restored IPostC protection in hypertrophic hearts evidenced by reduced IS (32.0 ± 2.8% vs. 46.5 ± 3.1%) and cardiac cell apoptosis and largely preserved hemodynamic parameters. These protective effects were associated with significantly increased phosphorylation of ERK1/2 and ribosomal protein S6 kinases (p70S6K), but it had no influence on Akt and glycogen synthase kinase-3ß. CONCLUSION: These results demonstrated that rAAV9-mediated activated MEK1 expression restores IPostC protection in the hypertrophic heart against I/R injury through the activation of ERK pathway.

[Corncornin-3-O-glucoside mediates the NF-κB pathway to inhibit H_2O_2-induced apoptosis].

OBJECTIVE: To study the anti-apoptotic effect of cyanidin-3-O-glucoside(C3 G) on H_2O_2-induced injury in human embryonic kidney(HEK)-293 cells. METHODS: Hydrogen peroxide induced injury of HEK-293 cell was used as the research object. HEK-293 cells were pretreated with different concentrations of C3 G(1. 25, 5, 20 µmol/L). The anti-apoptotic effects of C3 G on injured cells were examined by the release rates of LDH and mitochondrial membrane potential(MMP). Western blot and qRT-PCR were used to detect the protein expression and mRNA expression of NF-κB P65. RESULTS: The result showed that the release rate of LDH was increased, MMP was decreased, the protein and mRNA of P65 was increased after H_2O_2 inducing. Whereas, the release rates of LDH were significantly lower than that of the injured group after 1. 25, 5, 20 µmol/L C3 G pretreatment of injured cells(P<0. 05). The MMP of C3 G group was significantly higher than injured group with concentration-dependent increases. The proteins and mRNA of P65 were also significantly lower than that of injured group(P<0. 05). CONCLUSION: Cyanidin-3-O-glucoside shows anti-apoptotic effect on H_2O_2-induced injury in HEK-293 cell. The mechanisms of anti-apoptotic effects may be to achieve by protecting cell biofilms, and inhibiting the activity of NF-κB signaling pathway.

Monocyte to high-density lipoprotein cholesterol ratio as long-term prognostic marker in patients with coronary artery disease undergoing percutaneous coronary intervention.

BACKGROUND: The relation between monocyte to high-density lipoprotein cholesterol ratio (MHR) and coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains controversial. The present study aims to assess the prognostic value of MHR in patients with CAD who underwent PCI. METHODS: A total of 673 CAD patients were retrospectively enrolled and divided into four groups according to MHR values. Multivariate Cox regression analysis was performed to study the effects of different variables to clinical outcomes reported as major adverse cardiac events (MACE) and all-cause mortality (ACM). RESULTS: In a multivariate Cox analysis, after adjustment of other confounders, MHR was found to be an independent predictor of ACM (HR: 3.655; 95% CI: 1.170-11.419, P = 0.026) and MACE (HR =2.390, 95% CI 1.379-4.143, p < 0.002). Having a MHR in the third and fourth quartile were associated with a 2.83-fold and 3.26 -flod increased risk of MACE. CONCLUSIONS: MHR is an independent predictor of ACM and MACE in CAD patients undergoing PCI.

Development of a sensitive Luminex xMAP-based microsphere immunoassay for specific detection of Iris yellow spot virus.

BACKGROUND: Iris yellow spot virus (IYSV) is an Orthotospovirus that infects most Allium species. Very few approaches for specific detection of IYSV from infected plants are available to date. We report the development of a high-sensitive Luminex xMAP-based microsphere immunoassay (MIA) for specific detection of IYSV. RESULTS: The nucleocapsid (N) gene of IYSV was cloned and expressed in Escherichia coli to produce the His-tagged recombinant N protein. A panel of monoclonal antibodies (MAbs) against IYSV was generated by immunizing the mice with recombinant N protein. Five specific MAbs (16D9, 11C6, 7F4, 12C10, and 14H12) were identified and used for developing the Luminex xMAP-based MIA systems along with a polyclonal antibody against IYSV. Comparative analyses of their sensitivity and specificity in detecting IYSV from infected tobacco leaves identified 7F4 as the best-performed MAb in MIA. We then optimized the working conditions of Luminex xMAP-based MIA in specific detection of IYSV from infected tobacco leaves by using appropriate blocking buffer and proper concentration of biotin-labeled antibodies as well as the suitable ratio between the antibodies and the streptavidin R-phycoerythrin (SA-RPE). Under the optimized conditions the Luminex xMAP-based MIA was able to specifically detect IYSV with much higher sensitivity than conventional enzyme-linked immunosorbent assay (ELISA). Importantly, the Luminex xMAP-based MIA is time-saving and the whole procedure could be completed within 2.5 h. CONCLUSIONS: We generated five specific MAbs against IYSV and developed the Luminex xMAP-based MIA method for specific detection of IYSV in plants. This assay provides a sensitive, high-specific, easy to perform and likely cost-effective approach for IYSV detection from infected plants, implicating potential broad usefulness of MIA in plant virus diagnosis.

Sequential fragment ion filtering and endoglycosidase-assisted identification of intact glycopeptides.

Detailed characterization of glycoprotein structures requires determining both the sites of glycosylation as well as the glycan structures associated with each site. In this work, we developed an analytical strategy for characterization of intact N-glycopeptides in complex proteome samples. In the first step, tryptic glycopeptides were enriched using ZIC-HILIC. Secondly, a portion of the glycopeptides was treated with endoglycosidase H (Endo H) to remove high-mannose (Man) and hybrid N-linked glycans. Thirdly, a fraction of the Endo H-treated glycopeptides was further subjected to PNGase F treatment in 18O water to remove the remaining complex glycans. The intact glycopeptides and deglycosylated peptides were analyzed by nano-RPLC-MS/MS, and the glycan structures and the peptide sequences were identified by using the Byonic or pFind tools. Sequential digestion by endoglycosidase provided candidate glycosites information and indication of the glycoforms on each glycopeptide, thus helping to confine the database search space and improve the confidence regarding intact glycopeptide identification. We demonstrated the effectiveness of this approach using RNase B and IgG and applied this sequential digestion strategy for the identification of glycopeptides from the HepG2 cell line. We identified 4514 intact glycopeptides coming from 947 glycosites and 1011 unique peptide sequences from HepG2 cells. The intensity of different glycoforms at a specific glycosite was obtained to reach the occupancy ratios of site-specific glycoforms. These results indicate that our method can be used for characterizing site-specific protein glycosylation in complex samples. Graphical abstract Through integrating the information of intact glycopeptide, fragment ions filters and endoglycosidase digestion, the reliability of the identification could be significantly improved. We quantified the site-specific glycoforms occupancy ratios through the MS response signaling of each glycopeptide at the same time.

FrzA gene protects cardiomyocytes from H2O2-induced oxidative stress through restraining the Wnt/Frizzled pathway.

BACKGROUND: Lately, there is accumulating evidence that the Wnt/Frizzled pathway is reactivated after myocardial infarction, the inhibition of the pathway is beneficial since it reduce of myocardial apoptosis and prevents heart failure. FrzA/Sfrp-1, a secreted frizzled-related protein and antagonist for the wnt/frizzled pathway. We assessed the hypothesis that FrzA protects cardiomyocytes from H2O2-Induced Oxidative damage through the inhibition of Wnt/Frizzled pathway activity. METHODS: We used a recombinant AAV9 vector to deliver FrzA gene into neonatal rat ventricle myocytes and developed an oxidative stress model using H2O2. The cell vitality was measured by MTT colorimetric assay. Western blot and RT-PCR were used to evaluate the expressions of Dvl-1, ß-catenin, c-Myc, Bax and Bcl-2. Flow cytometry analysis of cardiomyocytes apoptosis. RESULTS: We confirmed that Wnt/frizzled pathway is involved in H2O2-induced apoptosis in cardiomyocytes. Compared with controls, H2O2 induced the upregulation of Dvl-1, ß-catenin, and c-Myc. FrzA suppressed the expression of Dvl-1, ß-catenin, c-Myc and the activity of the Wnt/frizzled pathway. Furthermore, FrzA over-expression decreased the apoptotic rate, and the Bax/Bcl-2 ratio in cardiomyocytes treated with H2O2. CONCLUSIONS: FrzA, through the inhibition of Wnt/Frizzled pathway activity reduced H2O2-induced cardiomyocytes apoptosis and could be a potential therapeutic target for prevention of cardiac oxidative damage.

[The optimal cutoff point of waist-to-hip ratio for screening Uyghur population aged 35 years and over at high-risk of cardiovascular diseases in Xinjiang].

OBJECTIVE: To explore the appropriate waist-to-hip ratio (WHR) cutoffs to identify people at high risk of cardiovascular disease of Uygur population aged 35 years and over in Xinjiang. METHODS: The cardiovascular risk survey (CRS) in Xinjiang was conducted from October 2007 to March 2010, using 4-stagestratified random sampling method and 14 618 representative participated this survey, and the questionnaire survey, anthropometric data, blood pressure, serum total cholesterol, triglyceride, low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) and fasting glucose were measured. A total of 4 657 participants aged 35 years and over with complete anthropometric data were analyzed. The sensitivity, specificity and distance on the receiver operating characteristic (ROC) curve of different WHR levels predicting risk factors of cardiovascular disease were calculated. The analysis method of ROC curve was used to determine the optimum cut-off point of WHR predicting risk factors of cardiovascular disease. RESULTS: (1) There were significantly differences in prevalence of hypertension, diabetes mellitus, hypercholesterolemia, low HDL-C level, and hypertriglyceridemia between WHR < 0.75,0.75 ≤ WHR < 0.80,0.80 ≤ WHR < 0.85,0.85 ≤ WHR < 0.90,0.90 ≤ WHR < 0.95,0.95 ≤ WHR < 1.00, WHR ≥ 1.00 in male participants (P < 0.01 or 0.05), LDL-C level was similar among groups in males (P = 0.139). There were significantly differences in prevalence of hypertension, diabetes mellitus, hypercholesterolemia and hypertriglyceridemia between WHR < 0.75,0.75 ≤ WHR < 0.80,0.80 ≤ WHR < 0.85,0.85 ≤ WHR < 0.90,0.90 ≤ WHR < 0.95,0.95 ≤ WHR < 1.00, WHR ≥ 1.00 in female participants (all P < 0.01), and there were no significantly differences in prevalence of high LDL-C level and low HDL-C level among groups in females (both P > 0.05). (2) ROC analysis for hypertension, dyslipidemia, diabetes and ≥ 2 of these risk factors suggested a WHR cutoff of 0.92 for men and 0.90 for women as the optimal cutoff value for predicting high risk of cardiovascular disease of Uygur population aged 35 years and over in Xinjiang. CONCLUSION: Higher WHR cutoffs are needed for screening people at high risk of cardiovascular disease among Uygur population aged 35 years and over in Xinjiang.

Optimal cutoff of the waist-to-hip ratio for detecting cardiovascular risk factors among Han adults in Xinjiang.

BACKGROUND: The optimal cutoff of the waist-to-hip ratio (WHR) among Han adults in Xinjiang, which is located in the center of Asia, is unknown. We aimed to examine the relationship between different WHRs and cardiovascular risk factors among Han adults in Xinjiang, and determine the optimal cutoff of the WHR. METHODS: The Cardiovascular Risk Survey was conducted from October 2007 to March 2010. A total of 14618 representative participants were selected using a four-stage stratified sampling method. A total of 5757 Han participants were included in the study. The present statistical analysis was restricted to the 5595 Han subjects who had complete anthropometric data. The sensitivity, specificity, and distance on the receiver operating characteristic (ROC) curve in each WHR level were calculated. The shortest distance in the ROC curves was used to determine the optimal cutoff of the WHR for detecting cardiovascular risk factors. RESULTS: In women, the WHR was positively associated with systolic blood pressure, diastolic blood pressure, and serum concentrations of serum total cholesterol. The prevalence of hypertension and hypertriglyceridemia increased as the WHR increased. The same results were not observed among men. The optimal WHR cutoffs for predicting hypertension, diabetes, dyslipidemia and ≥ two of these risk factors for Han adults in Xinjiang were 0.92, 0.92, 0.91, 0.92 in men and 0.88, 0.89, 0.88, 0.89 in women, respectively. CONCLUSIONS: Higher cutoffs for the WHR are required in the identification of Han adults aged ≥ 35 years with a high risk of cardiovascular diseases in Xinjiang.

Prevalence, awareness, treatment and control of dyslipidemia among adults in northwestern China: the cardiovascular risk survey.

AIM: The aim of this study was to estimate the prevalence, awareness, treatment, and control of dyslipidemia in Xinjiang, China. METHOD: Stratified sampling method was used to select a representative sample of the general population including Chinese Han, Uygur, and Kazak in this geographic area. Seven cities were chosen. Based on the government records of registered residences, one participant was randomly selected from each household. The eligibility criterion for the study was ≥ 35 years of age. RESULTS: A total of 14,618 participants (5,757 Han, 4,767 Uygur, and 4,094 Kazak), were randomly selected from 26 villages in 7 cities. The prevalence of dyslipidemia was 52.72% in the all participants. The prevalence of dyslipidemia was higher in Han than that in the other two ethnic (58.58% in Han, 48.27% in Uygur, and 49.60% in Kazak, P < 0.000). The prevalence of dyslipidemia was higher in men than that in women (56.4% vs. 49.3%, P < 0.000). Among the participants with dyslipidemia, the proportion of those who aware, treat, control of dyslipidemia were 53.67%, 22.51%, 17.09% in Han, 42.19%, 27.78%, 16.20% in Uygur, 37.02%, 21.11%, 17.77% in Kazak. CONCLUSION: Dyslipidemia is highly prevalent in Xinjiang. The proportion of participants with dyslipidemia who were aware, treated, and controlled is unacceptably low. These results underscore the urgent need to develop national strategies to improve the prevention, detection, and treatment of dyslipidemia in Xinjiang.

An analysis of the door-to-balloon time in STEMI patients in an underdeveloped area of China: a single-centre analysis.

OBJECTIVES: This study was conducted to break the door-to-balloon time (DTBT) into constituent elements, and compared which components prolonged markedly. We identified the factors that significantly prolonged the DTBT in an underdeveloped area of China. METHODS: The patients were included from January 2008 to December 2010 in 301 consecutive patients presenting with STEMI in our hospital. We analysed the components of total DTB times, such as 'Diagnosis time', 'Cardiologist consultation time', 'Explain the patient's condition time', 'Transferring time', 'Preparation of the catheterisation laboratory (CL) time', and determined which factors significantly prolonged the DTBT potentially. RESULTS: The median DTBT of all patients was 134 (98-186) min. The group was divided by the DTBT into two: ≤120 min and >120 min. In the ≤120 min group, more patients (68.1%) presented to our hospital during working hours (p=0.000), whereas in the >120 min group, more patients (63.2%) presented out of hours (p=0.000). More patients (49.3%) presented when the interventionist was on site (p=0.000) in the ≤120 min group. In the >120 min group, the times for consultation by the cardiologist and explaining the patient's condition to the family prolonged markedly, as compared to the ≤120 min group (p=0.000) when the interventionist was off-duty (OR=4.050, p=0.000) and presentation during non-working hours (OR=3.334, p=0.000) were significant predictors of >120 min DTB times. CONCLUSIONS: In our centre, the time of consultation by the cardiologists and explaining the patient's condition to the family accounted for most of the delay in reperfusion. A lack of interventionists usually resulted in a delay during non-working hours in the CL. Several measures should be taken involving asking emergency department physicians to awake CL directly, sending the patients' information to the cardiologists, popularising medical knowledge to the citizens, and increasing the numbers of interventionists qualified to carry out primary percutaneous coronary intervention, should be developed to shorten the DTBT.

Proteogenomic insights into the biology and treatment of pan-melanoma.

Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.

Sequential Inhibition of PARP and BET as a Rational Therapeutic Strategy for Glioblastoma.

PARP inhibitors (PARPi) hold substantial promise in treating glioblastoma (GBM). However, the adverse effects have restricted their broad application. Through unbiased transcriptomic and proteomic sequencing, it is discovered that the BET inhibitor (BETi) Birabresib profoundly alters the processes of DNA replication and cell cycle progression in GBM cells, beyond the previously reported impact of BET inhibition on homologous recombination repair. Through in vitro experiments using established GBM cell lines and patient-derived primary GBM cells, as well as in vivo orthotopic transplantation tumor experiments in zebrafish and nude mice, it is demonstrated that the concurrent administration of PARPi and BETi can synergistically inhibit GBM. Intriguingly, it is observed that DNA damage lingers after discontinuation of PARPi monotherapy, implying that sequential administration of PARPi followed by BETi can maintain antitumor efficacy while reducing toxicity. In GBM cells with elevated baseline replication stress, the sequential regimen exhibits comparable efficacy to concurrent treatment, protecting normal glial cells with lower baseline replication stress from DNA toxicity and subsequent death. This study provides compelling preclinical evidence supporting the development of innovative drug administration strategies focusing on PARPi for GBM therapy.

Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma.

Soft tissue sarcoma is a broad family of mesenchymal malignancies exhibiting remarkable histological diversity. We portray the proteomic landscape of 272 soft tissue sarcomas representing 12 major subtypes. Hierarchical classification finds the similarity of proteomic features between angiosarcoma and epithelial sarcoma, and elevated expression of SHC1 in AS and ES is correlated with poor prognosis. Moreover, proteomic clustering classifies patients of soft tissue sarcoma into 3 proteomic clusters with diverse driven pathways and clinical outcomes. In the proteomic cluster featured with the high cell proliferation rate, APEX1 and NPM1 are found to promote cell proliferation and drive the progression of cancer cells. The classification based on immune signatures defines three immune subtypes with distinctive tumor microenvironments. Further analysis illustrates the potential association between immune evasion markers (PD-L1 and CD80) and tumor metastasis in soft tissue sarcoma. Overall, this analysis uncovers sarcoma-type-specific changes in proteins, providing insights about relationships of soft tissue sarcoma.

Prevalence of major cardiovascular risk factors and adverse risk profiles among three ethnic groups in the Xinjiang Uygur Autonomous Region, China.

BACKGROUND: Prevalence of cardiovascular disease (CVD) risk factors have been scarcely studied in Xinjiang, a multi-ethnic region. METHODS: Multi-ethnic, cross-sectional cardiovascular risk survey study in Xinjiang, including individuals of Uygur (n = 4695), Han (n = 3717) and Kazakh (n = 3196) ethnicities, aged 35-74 years. Analyses involved 11,608 participants with complete data enrolled between October 2007 and March 2010. RESULTS: There were differences in age-standardized prevalence of CVD risk factors between the three groups (all P < 0.001). Hypertension, obesity and smoking rates were higher among Kazakh (54.6%, 24.5%, and 35.8%, respectively). Dyslipidemia prevalence was higher among Uygur (54.3%), and diabetes prevalence was higher among Hans (7.1%). Age-standardized prevalence of adverse CVD risk profiles was different across different ethnicities. Compared with the Han participants, the Uygur and Kazakh had more CVD risk factors (P < 0.001). Compared with the Han participants, the adjusted odds ratios of 1, 2, and ≥3 risk factors profiles for Kazakh and Uygur participants were higher (all P < 0.001). CONCLUSIONS: The present study showed the pervasive burden of CVD risk factors in all participant groups in the Xinjiang region. Three major ethnic groups living in Xinjiang had striking differences in the prevalence of major CVD risk factors and adverse risk profiles. Ethnic-specific strategies should be developed to prevent CVD in different ethnic groups, as well as to develop strategies to prevent future development of adverse CVD risk factors at a younger age.