Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

Prognostic significance of triglyceride-glucose index in acute coronary syndrome patients without standard modifiable cardiovascular risk factors.

BACKGROUND: A significant percentage of patients with acute coronary syndrome (ACS) without standard modifiable cardiovascular risk factors (SMuRFs) are being identified. Nonetheless, the prognostic influence of the TyG index on adverse events in this type of patient remains unexplored. The aim of this study was to assess the prognostic value of the TyG index among ACS patients without SMuRFs for predicting adverse outcomes. METHODS: This study involved 1140 consecutive patients who were diagnosed with ACS without SMuRFs at Beijing Anzhen Hospital between May 2018 and December 2020 and underwent coronary angiography. Each patient was followed up for a period of 35 to 66 months after discharge. The objective of this study was to examine major adverse cardiac and cerebrovascular events (MACCE), which included all-cause mortality, non-fatal myocardial infarction, non-fatal ischemic stroke, as well as ischemia-driven revascularization. RESULTS: During the median follow-up period of 48.3 months, 220 (19.3%) MACCE events occurred. The average age of the participants was 59.55 ± 10.98 years, and the average TyG index was 8.67 ± 0.53. In the fully adjusted model, when considering the TyG index as either a continuous/categorical variable, significant associations with adverse outcomes were observed. Specifically, for each 1 standard deviation increase in the TyG index within the highest TyG index group, there was a hazard ratio (HR) of 1.245 (95% confidence interval CI 1.030, 1.504) for MACCE and 1.303 (95% CI 1.026, 1.653) for ischemia-driven revascularization (both P < 0.05), when the TyG index was analyzed as a continuous variable. Similarly, when the TyG index was examined as a categorical variable, the HR (95% CI) for MACCE in the highest TyG index group was 1.693 (95% CI 1.051, 2.727) (P < 0.05) in the fully adjusted model, while the HR (95% CI) for ischemia-driven revascularization was 1.855 (95% CI 0.998, 3.449) (P = 0.051). Additionally, the TyG index was found to be associated with a poor prognosis among the subgroup. CONCLUSION: The TyG index is correlated with poor prognosis in patients with ACS without SMuRFs, suggesting that it may be an independent predictive factor of adverse events among these individuals.

The prognostic role of remnant cholesterol in Asian menopausal women received percutaneous coronary intervention with acute coronary syndrome.

BACKGROUND: Remnant cholesterol (RC) exert a significant influence on atherosclerotic cardiovascular disease development. However, the prognostic implications of RC in menopausal women received percutaneous coronary intervention (PCI) who experiencing acute coronary syndrome (ACS) remain uncertain. METHODS: RC was derived by subtracting the sum of high-density lipoprotein cholesterol and low-density lipoprotein cholesterol from the total cholesterol. Kaplan-Meier survival and Cox regression analysis were employed for assessing the correlation between continuous RC levels and composite and individual adverse events in Q1-Q4 quartiles. Receiver operator characteristic (ROC) curves, derived from Cox regression, were employed for analyzing the relationship between RC and both composite and individual adverse events. RESULTS: 1505 consecutive menopausal women who underwent PCI and diagnosed with ACS were included. Kaplan-Meier survival analysis demonstrated a progressive reduction in composite adverse event survival rates across the four groups, observed in both the general population and among diabetic individuals, as RC values increased (Log-rank P < 0.001). The analysis of multivariate Cox regression indicated RC remained independently associated with both composite and individual adverse events. ROC analysis showed that RC enhanced the area under the curve both in total and diabetic populations for composite adverse events. CONCLUSION: Among menopausal women diagnosed with ACS who underwent PCI, heightened levels of RC were found to be independently correlated with an increased occurrence of adverse events.

The combined predictive power of the atherogenic index of plasma and serum glycated albumin for cardiovascular events in postmenopausal patients with acute coronary syndrome after percutaneous coronary intervention.

BACKGROUND: Glycated Albumin (GA) and atherogenic index of plasma (AIP) are two important biomarkers that respectively reflect lipid and glucose levels. Previous research has revealed their roles in cardiovascular diseases (CVD) and diabetes. However, their combined predictive ability in forecasting cardiovascular events (CVE) after percutaneous coronary intervention (PCI) among postmenopausal acute coronary syndrome (ACS) patients remains insufficiently studied. METHODS: Based on the levels of AIP (AIP-L and AIP-H) and GA (GA-L and GA-H), four groups were used to categorize the patients. The CVE assessed included cardiac death, nonfatal myocardial infarction (MI) and nonfatal stroke. To evaluate the relationship between AIP, GA, and CVE, multivariate Cox regression analyses were performed. RESULTS: 98 patients (7.5%) experienced CVE during follow-up. AIP and GA were revealed as strong independent predictors of CVE through multivariate analysis (AIP: HR 3.324, 95%CI 1.732-6.365, P = 0.004; GA: HR 1.098, 95% CI 1.023-1.177, P = 0.009). In comparison to those in the initial group (AIP-L and GA-L), the fourth group (AIP-H and GA-H) of patients exhibited the greatest CVE risk (HR 2.929, 95% CI 1.206-5.117, P = 0.018). Derived from the model of baseline risk, the combination of AIP + GA significantly enhanced the AUC, meanwhile combining AIP and GA levels maximized prognostic accuracy in the baseline risk model. CONCLUSIONS: This study found that the combined measurement of AIP and GA significantly enhanced the predictive capability for CVE following PCI in postmenopausal ACS patients. By integrating these two biomarkers, it became possible to more accurately identify high-risk individuals and provided clinicians with new predictive tools for postmenopausal ACS patients in risk assessment and management.

The clinical role of combined circulating complement C1q and AIP for CAD with LDL-C level below 1.8mmol/L.

BACKGROUND: In the past few years, circulating complement C1q involvement in atherosclerosis has garnered growing research interest in addition to the emerging recognition of the novel lipid marker named atherogenic index of plasma (AIP). Nevertheless, among patients experiencing low-density lipoprotein cholesterol (LDL-C) levels less than 1.8mmol/L, the interplay between C1q combined with the AIP for coronary artery disease (CAD) is ambiguous. METHODS: Patients were stratified into a non-CAD and CAD group according to their coronary angiography. The association between C1q in conjunction with the AIP and CAD was explored using restricted cubic spline analyses and logistic regression models. To assess how it predicted, a receiver operating characteristic analysis was undertaken. RESULTS: A total of 7270 patients comprised 1476 non-CAD patients and 5794 patients diagnosed with CAD were analyzed. A comparison of the two groups showed that the C1q levels were notably higher compared to the CAD group, while AIP exhibited an inverse trend. Across quartiles of C1q, the AIP demonstrated a decline with increasing C1q levels, and significant differences were observed between the groups. A correlation analysis underscored a notable negative correlation between the two variables. Univariate and multivariate logistic regression analyses revealed significant associations between CAD and the C1q quartile groups/AIP. Furthermore, compared with the Q4 group, a decrease in the C1q levels corresponded to an escalation in CAD risk, with the odds ratio rising from 1.661 to 2.314. CONCLUSIONS: In conclusion, there appears to be a notable positive correlation between the combination of C1q with the AIP and CAD.

The relation between atherogenic index of plasma and cardiovascular outcomes in prediabetic individuals with unstable angina pectoris.

BACKGROUND: The atherogenic index of plasma (AIP) is a novel biomarker associated with atherosclerosis, and an important risk factor for atherosclerosis, but its relation with cardiovascular prognosis in prediabetic patients with unstable angina pectoris (UAP) is still uncertain. METHODS: This study included 1096 prediabetic patients with UAP who were subjected to follow-up for a maximum of 30 months, with cardiac death, refractory angina, and non-fatal myocardial infarction (MI) being the primary cardiovascular endpoints. RESULTS: A significantly increased AIP was observed for the group with primary cardiovascular endpoints. Kaplan-Meier curves corresponding to these endpoints revealed pronounced differences between these two AIP groups (Log-rank P < 0.001). Multivariate Cox proportional hazards analyses highlighted AIP as being independent related to this primary endpoint (HR 1.308, 95% CI: 1.213-1.412, P < 0.001). AIP addition to the baseline risk model improved the prediction of the primary endpoint (AUC: baseline model, 0.622, vs. baseline model + AIP, 0.739, P < 0.001). CONCLUSIONS: AIP could be used to predict cardiovascular events in prediabetic individuals with UAP.

Serum Uric Acid and Hyperuricemia Associate with Coronary Artery Disease among Postmenopausal Women.

Background: Serum uric acid (SUA) levels has been considered a possible risk factor for coronary artery disease (CAD) for many years. Since SUA levels are greatly affected by medications, diet, and metabolism, the association between SUA and CAD has been controversial for centuries. While, the state of hyperuricemia (HUA) has been proven to have a negative impact on CAD in previous studies, there are still few clinical and epidemiological studies of HUA in CAD. In particular, evidence of this association is limited in postmenopausal women. This study explored the influence of SUA levels and HUA on CAD in this demographic group. Methods: In total, 5435 postmenopausal women were allocated to either a non-CAD group (n = 2021) or a CAD group (n = 3414). Regression analyses, including generalized linear models (GLM), correlation analysis, comparison between stratified groups, and analysis by use of diuretics were carried out on data obtained in this study. Results: SUA and HUA were found to associate significantly with CAD by univariate logistic regression analysis. In addition, GLM showed nonlinear response of CAD probability with increasing level of SUA. In multivariate analysis, we found that SUA and HUA were independently related to CAD. Correlation analysis showed that SUA and HUA both correlated positively with CAD (p < 0.001). By comparing the stratified age groups, we found that the differences among the age groups were significant (p < 0.05). Conclusions: SUA and HUA were shown to be independently associated with CAD among postmenopausal women.

Mesenchymal stem cell-exosome-mediated matrix metalloproteinase 1 participates in oral leukoplakia and carcinogenesis by inducing angiogenesis.

BACKGROUND: In the malignant progression of oral leukoplakia (OLK) to oral squamous cell carcinoma (OSCC), the density of microvessels and expression of angiogenesis-related molecules increases. Emerging evidence indicates that mesenchymal stem cells (MSCs) play an indispensable role in the tumor microenvironment. However, the role and mechanism of action of oral MSCs in inducing angiogenesis remain unclear. Therefore, it is necessary to explore the molecules and mechanisms that play a role in the tissue microenvironment. METHODS: Exosomes were collected from normal oral mucosa (N-Exo), OLK (OLK-Exo), and OSCC (Ca-Exo) MSCs, and their pro-angiogenic capacity was evaluated in human umbilical vein endothelial cells (HUVECs) and a subcutaneously implanted tumor model in nude mice. Quantitative proteomics analysis was used to compare the exosome-derived proteins between N-Exo, OLK-Exo, and Ca-Exo. RESULTS: Compared with that of the N-Exo and control, OLK-Exo and Ca-Exo treatment significantly promoted HUVEC migration, invasion, and tube-formation capability. In the nude mice model, immunofluorescence of CD31 showed that OLK-Exo and Ca-Exo substantially improved neovascularization around the grafts. Quantitative proteomics analysis revealed that matrix metalloproteinase 1 (MMP1) levels were significantly higher in the OLK-Exo and Ca-Exo groups than in the N-Exo groups. Silencing MMP1 expression reversed the functional promoting effect of OLK-Exo and Ca-Exo on HUVECs. CONCLUSION: Exosomes from OLK-MSCs and Ca-MSCs have a stronger pro-angiogenic ability through high MMP1 content. This new finding provides insight into the intervention with the secretion of MSC-derived exosomes, which may be an innovative strategy for carcinogenesis.

ncdDetect2: improved models of the site-specific mutation rate in cancer and driver detection with robust significance evaluation.

Motivation: Understanding the mutational processes that act during cancer development is a key topic of cancer biology. Nevertheless, much remains to be learned, as a complex interplay of processes with dependencies on a range of genomic features creates highly heterogeneous cancer genomes. Accurate driver detection relies on unbiased models of the mutation rate that also capture rate variation from uncharacterized sources. Results: Here, we analyse patterns of observed-to-expected mutation counts across 505 whole cancer genomes, and find that genomic features missing from our mutation-rate model likely operate on a megabase length scale. We extend our site-specific model of the mutation rate to include the additional variance from these sources, which leads to robust significance evaluation of candidate cancer drivers. We thus present ncdDetect v.2, with greatly improved cancer driver detection specificity. Finally, we show that ranking candidates by their posterior mean value of their effect sizes offers an equivalent and more computationally efficient alternative to ranking by their P-values. Availability and implementation: ncdDetect v.2 is implemented as an R-package and is freely available at http://github.com/TobiasMadsen/ncdDetect2. Supplementary information: Supplementary data are available at Bioinformatics online.

A Novel Angiotensin II-Induced Long Noncoding RNA Giver Regulates Oxidative Stress, Inflammation, and Proliferation in Vascular Smooth Muscle Cells.

RATIONALE: AngII (angiotensin II)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a major role in hypertension. Long noncoding RNAs have elicited much interest, but their molecular roles in AngII actions and hypertension are unclear. OBJECTIVE: To investigate the regulation and functions of a novel long noncoding RNA growth factor- and proinflammatory cytokine-induced vascular cell-expressed RNA ( Giver), in AngII-mediated VSMC dysfunction. METHODS AND RESULTS: RNA-sequencing and real-time quantitative polymerase chain reactions revealed that treatment of rat VSMC with AngII increased the expression of Giver and Nr4a3, an adjacent gene encoding a nuclear receptor. Similar changes were observed in rat and mouse aortas treated ex vivo with AngII. RNA-FISH (fluorescence in situ hybridization) and subcellular fractionation showed predominantly nuclear localization of Giver. AngII increased Giver expression via recruitment of Nr4a3 to Giver promoter. Microarray profiling and real-time quantitative polymerase chain reaction validation in VSMC showed that Giver knockdown attenuated the expression of genes involved in oxidative stress ( Nox1) and inflammation ( Il6, Ccl2, Tnf) but increased Nr4a3. Conversely, endogenous Giver overexpression showed opposite effects supporting its role in oxidative stress and inflammation. Chromatin immunoprecipitation assays showed Giver overexpression also increased Pol II (RNA polymerase II) enrichment and decreased repressive histone modification histone H3 trimethylation on lysine 27 at Nox1 and inflammatory gene promoters. Accordingly, Giver knockdown inhibited AngII-induced oxidative stress and proliferation in rat VSMC. RNA-pulldown combined with mass spectrometry showed Giver interacts with nuclear and chromatin remodeling proteins and corepressors, including NONO (non-pou domain-containing octamer-binding protein). Moreover, NONO knockdown elicited similar effects as Giver knockdown on the expression of key Giver-regulated genes. Notably, GIVER and NR4A3 were increased in AngII-treated human VSMC and in arteries from hypertensive patients but attenuated in hypertensive patients treated with ACE (angiotensin-converting enzyme) inhibitors or angiotensin receptor blockers. Furthermore, human GIVER also exhibits partial functional conservation with rat Giver. CONCLUSIONS: Giver and its regulator Nr4a3 are important players in AngII-mediated VSMC dysfunction and could be novel targets for antihypertensive therapy.

The sensibility of the new blood lipid indicator--atherogenic index of plasma (AIP) in menopausal women with coronary artery disease.

BACKGROUND: Dyslipidemia is a key driver of coronary artery disease (CAD) development. This study aimed to determine whether the atherogenic index of plasma (AIP), a novel comprehensive lipid index, is an independent and reliable predictor of CAD risk in postmenopausal women. METHODS: A cohort of consecutive 4644 postmenopausal women (aged 50 or above) undergoing coronary angiography (CAG) in Anzhen Hospital (Beijing, China) from January-December 2014 was included in the analysis. Of them, 3039 women were CAD patients, and 1605 were non-CAD subjects. RESULTS: Relative to control subjects, TG levels in CAD patients were higher and HDL-C levels were lower. In CAD patients, non-traditional lipid profile values (TC/HDL-C, AI, and AIP) were significantly elevated relative to controls. AIP was positively correlated with TC (r = 0.157), TG (r = 0.835), LDL-C (r = 0.058), non-HDL-C (r = 0.337), TC/HDL-C (r = 0.683), LDL-C/HDL-C (r = 0.437), LCI (r = 0.662), and AI (r = 0.684), and negatively correlated with HDL-C (r = - 0.682) (all P < 0.001), but was independent of age (r = - 0.022; P = 0.130) and BMI (r = 0.020, P = 0.168). Aunivariate logistic regression analysis revealed AIP to be the measured lipid parameter most closely related to CAD, and its unadjusted odds ratio was 1.824 (95% CI: 1.467-2.267, P < 0.001). After adjusting for several CAD risk factors (age, BMI, smoking, drinking, EH, DM, hyperlipidemia, and family history of CVD, AIP was still found to represent a significant CAD risk factor (OR 1.553, 95% CI: 1.234-1.955, P < 0. 001). CONCLUSION: AIP may be a powerful independent predictor of CAD risk in Chinese Han postmenopausal women, and may be superior to the traditional lipid indices.

Could remnant-like particle cholesterol become a risk factor in diabetic menopausal women with coronary artery disease? A cross-sectional study of single academic center in China.

BACKGROUND AND AIMS: It has been confirmed that remnant-like particle cholesterol (RLP-C) mediates the progression of coronary artery disease (CAD). Currently there is limited information on RLP-C in menopausal women. With the special status of diabetes mellitus (DM) combined with the special body changes of the menopausal women, the RLP-C is particularly important when studying the changes that occurred in response to CAD and its associated risk factors. This study discussed whether RLP-C could be an independent risk factor for menopausal women with CAD and DM. METHODS: The cohort consisted of 4753 menopausal women who had undergone coronary angiography. Subjects were separated into CAD and non-CAD groups, and univariate and multivariate logistic regression analysis of CAD risk factors were performed. All patients with a history of DM were divided into DM subgroups. Then, the univariate and multivariate logistic regression analysis of the risk factors of CAD and the comparison among age groups in the DM subgroup were performed. After age stratification of the DM group, the Kruskal-Wallis test was used to analyze the differences of various lipid indexes among age groups. RESULTS: The multivariate logistic regression showed that RLP-C was an independent risk factor for CAD in menopausal women (OR 1.232, 95%CI 1.070-1.419). In the DM subgroup, it was also found that RLP-C was an independent risk factor for CAD (OR 1.366, 95%CI 1.043-1.791). Kruskal-Wallis test analysis found that RLP-C had no significant difference among three groups (P > 0.05). CONCLUSIONS: RLP-C was proved to be an independent risk factor for menopausal women with CAD and DM.

Obesity is associated with worse long-term outcomes in hypertrophic cardiomyopathy patients with acute myocardial infarction.

BACKGROUND: Hypertrophic cardiomyopathy is associated with poor prognosis. In our previous study, it has been reported that patients with acute myocardial infarction and hypertrophic cardiomyopathy exhibited worse long-term outcomes than those with acute myocardial infarction without hypertrophic cardiomyopathy and those with hypertrophic cardiomyopathy without acute myocardial infarction. In this article, we aimed to assess the impact of body mass index on the long-term outcomes of hypertrophic cardiomyopathy patients with acute myocardial infarction. METHODS: Seventy-eight consecutive patients with hypertrophic cardiomyopathy and acute myocardial infarction were included. Obesity was defined as body mass index ⩾28 kg/m2 adapted to Chinese. The long-term endpoints were major adverse cardiac events and secondary endpoints, which included re-hospitalization, recurrent angina, thrombosis, bleeding, heart failure, and arrhythmias. RESULTS: There were no differences in observed in-hospital mortality or 5-year mortality between the two groups of hypertrophic cardiomyopathy and acute myocardial infarction patients divided by body mass index. However, significantly increased incidence of re-percutaneous coronary intervention and stroke was observed in the obese group (re-percutaneous coronary intervention: 0.0% vs. 21.4%, p = 0.007; stroke: 5.6% vs. 28.6%, p = 0.042). The 5-year outcomes of major adverse cardiac events were inferior in the obese group (log-rank p = 0.020). CONCLUSION: Acute myocardial infarction and hypertrophic cardiomyopathy patients who were obese exhibited worse long-term outcomes than those without obesity.

Tumor Necrosis Factor-alpha (TNF-α) Enhances miR-155-Mediated Endothelial Senescence by Targeting Sirtuin1 (SIRT1).

BACKGROUND Sirtuin1 (SIRT1) participates in a wide variety of cellular processes, but the molecular mechanism remains largely unknown. miR-155 is an element of the inflammatory signaling pathway in atherosclerosis. Therefore, we tested the hypothesis that TNF-alpha stimulates miR-155 to target SIRT1 and thereby regulates endothelial senescence, and we also explored the function of miR-155 as a regulator of cardiovascular diseases. MATERIAL AND METHODS TNF-alpha was used to stimulate human umbilical vein endothelial cells (HUVECs), after which protein and gene expression were assessed via Western blotting and RT-qPCR. miR-155 targeting of SIRT1 was confirmed via luciferase reporter assays, while MTT and senescence-associated ß-galactosidase (SA-ß-gal) assays were used for quantifying cellular proliferation and senescence. RESULTS We found that miR-155 was upregulated in response to TNF-alpha treatment, in addition to inducing marked changes in SIRT1/FoxO-1/p21 pathway protein level. When we overexpressed miR-155 mimics, SIRT1 was markedly reduced, whereas miR-155 inhibition had the opposite effect in TNF-alpha-treated cells. We additionally confirmed that miR-155 was able to directly bind to SIRT1 3'-UTR, and that inhibition of miR-155 reduced the ability of TNF-alpha to induce senescence in HUVECs, thereby leading to their enhanced proliferation. Simvastatin was associated with suppression of miR-155 expression in HUVECs following TNF-alpha treatment, and with a corresponding reduction in TNF-alpha-induced senescence, whereas miR-155 overexpression had the opposite effect. CONCLUSIONS Our findings suggest that TNF-alpha upregulates miR-155, which then targets SIRT1, suppressing its expression and driving HUVEC apoptosis. Simvastatin disrupted this senescence mechanism via the miR-155/SIRT1/FoxO-1/p21 pathway signaling. Hence, miR-155 is a possible therapeutic approach to endothelial senescence in the development of cardiovascular diseases.

A site specific model and analysis of the neutral somatic mutation rate in whole-genome cancer data.

BACKGROUND: Detailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation rate differs between cancer types, between patients and along the genome depending on the genetic and epigenetic context. Therefore, methods that predict the number of different types of mutations in regions or specific genomic elements must consider local genomic explanatory variables. A major drawback of most methods is the need to average the explanatory variables across the entire region or genomic element. This procedure is particularly problematic if the explanatory variable varies dramatically in the element under consideration. RESULTS: To take into account the fine scale of the explanatory variables, we model the probabilities of different types of mutations for each position in the genome by multinomial logistic regression. We analyse 505 cancer genomes from 14 different cancer types and compare the performance in predicting mutation rate for both regional based models and site-specific models. We show that for 1000 randomly selected genomic positions, the site-specific model predicts the mutation rate much better than regional based models. We use a forward selection procedure to identify the most important explanatory variables. The procedure identifies site-specific conservation (phyloP), replication timing, and expression level as the best predictors for the mutation rate. Finally, our model confirms and quantifies certain well-known mutational signatures. CONCLUSION: We find that our site-specific multinomial regression model outperforms the regional based models. The possibility of including genomic variables on different scales and patient specific variables makes it a versatile framework for studying different mutational mechanisms. Our model can serve as the neutral null model for the mutational process; regions that deviate from the null model are candidates for elements that drive cancer development.

The value of parotid sialography in the diagnosis and staging of Sjogren's syndrome.

Background/purpose: 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) primary Sjögren's syndrome (SS) diagnostic criteria did not incorporate radiographic examination while staging SS according to salivary gland imaging and serological autoantibody tests was not discussed. The aim is to study the value of parotid sialography for diagnosing SS, and to initially explore the method of staging SS based on the results of imaging and serological autoantibody tests. Materials and methods: 287 patients' clinical records were included. The sensitivity and specificity of parotid sialography in the diagnosis of SS were investigated. SS patients were categorized into early stage (autoantibody positive, imaging does not support SS), active stage (autoantibody positive, imaging supports SS), and quiescent stage (autoantibody negative, imaging supports SS), clinical characteristics of different stages were compared. Results: The sensitivity of parotid sialography for the diagnosis of SS was 82.6%, the specificity was 71.5%. 10-minute USFR of the patients in the active stage (0.18 ± 0.38 ml/10min) was significantly lower than that of early stage (0.34 ± 0.47 ml/10min) and quiescent stage (0.54 ± 0.52 ml/10min), P = 0.010, and the rate of confirmed SS was significantly higher in the active stage (82.9%) than that in the early stage (44.4%) and the quiescent stages (14.8%), P < 0.001. Conclusion: Parotid sialography remains valuable in the diagnosis of SS. Performing imaging and serological autoantibody tests before lip gland biopsy may reduce invasive examinations for patients without significantly increasing the rate of missed diagnosis. According to imaging and serological autoantibody tests, SS can be categorized into early, active, and quiescent stages.

Obesity is associated with long-term outcome of catheter ablation of atrial fibrillation in patients with dilated cardiomyopathy.

BACKGROUND: Patients with atrial fibrillation (AF) and dilated cardiomyopathy (DCM) often exhibit cardiac dysfunction and a poor prognosis. However, the specific reasons are unclear. This study aimed to describe the impact of obesity in patients with AF and DCM. METHODS: Seventy-four consecutive patients with AF and DCM were enrolled and classified by body mass index. We measured primary endpoints, including cardiac death, recurrent AF, recurrent atrial tachyarrhythmia and stroke, as well as secondary endpoints. RESULTS: In multivariate analysis, compared to the normal-weight group, the overweight and obese groups had greater incidences of recurrent AF (0.0 vs 30.3 vs 40.0%, respectively, log-rank p = 0.048) and rehospitalisation (9.1 vs 36.4 vs 45.0%, respectively, log-rank p = 0.035). Compared to the normal-weight group, five-year outcomes for primary endpoints were inferior in the overweight and obese groups (18.2 vs 30.3 vs 50.0%, respectively, log-rank p = 0.042). Overweight patients exhibited more benefit in recovery of left ventricular ejection fraction after ablation (from 39.1 to 50.0%, p = 0.005) than the normal-weight group (from 43.1 to 52.3%, p = 0.199) and obese group (from 44.9 to 51.2%, p = 0.216). CONCLUSION: Patients with AF and DCM with overweight or obesity exhibited worse long-term outcomes in recurrent AF than normal-weight patients. However, overweight patients showed the most benefit in cardiac function after ablation.

Differences in the response of normal oral mucosa, oral leukoplakia, oral squamous cell carcinoma-derived mesenchymal stem cells, and epithelial cells to photodynamic therapy.

OBJECTIVE: The objective of this study is to investigate the variances in transcriptome gene expression of normal oral mucosa-derived mesenchymal stem cell (OM-MSC), oral leukoplakia-derived MSC (OLK-MSC) and oral squamous cell carcinoma-derived MSC(OSCC-MSC). as Additionally, the study aims to compare the in vitro proliferation, migration, invasion ability, and response to photodynamic therapy (PDT) of these three MSC, HOK, DOK, leuk1, and Cal27 cell lines. METHODS: HOK, DOK, leuk1, Cal27 cells were cultured in vitro. 3 MSC cells were obtained from OM, OLK, OSCC tissue (n = 3) and identified through flow cytometry. They were also cultured in vitro for osteogenic and lipogenic-induced differentiation. Based on the Illumina HiSeq high-throughput sequencing platform, OM-MSC, OLK-MSC, OSCC-MSC (n = 3) were subjected to transcriptome sequencing, functional annotation, and enrichment analysis of differentially expressed genes and related genes. CCK8 assay, wound healing assay, and transwell assay were performed to compare the proliferation, migration, and invasion of the seven types of cells. The 7 cells were incubated with 0, 0.125 mM, 0.25 mM, 0.5 mM, 1 mM, and 2 mM of the photosensitizer (5-aminolevulinic acid, 5-ALA) in vitro. Subsequently, they were irradiated with a 150 mM, 635 nm laser for 1 min, and the cell activity was detected using the CCK8 assay after 24 h. The mitochondrial changes in the 7 cells before and after the treatment of PDT were detected using the JC-10 probe, and the changes in ATP content were measured before and after the PDT treatment. RESULTS: OM-MSC, OLK-MSC, and OSCC-MSC expressed positive MSC surface markers. After osteogenic and lipogenic-induced differentiation culture, stained calcium nodules and lipid droplets were visible, meeting the identification criteria of MSC. Pathway enrichment analysis revealed that the differentially expressed genes (DEGs) of OSCC-MSC compared to OLK-MSC were primarily associated with the PI3K-Akt signaling pathway and tumor-related pathways. OSCC-MSC exhibited stronger migratory and invasive abilities compared to Cal27. The IC50 values required for OM, OLK, and OSCC-derived MSC were lower than those required for epithelial cells treated with PDT, which were 1.396 mM, 0.9063 mM, and 2.924 mM, respectively. Cell membrane and mitochondrial disruption were observed in seven types of cells after 24 h of PDT treatment. However, HOK, DOK, leuk1, and Cal27 cells had an ATP content increased. CONCLUSIONS: OLK, OSCC epithelial cells require higher concentrations of 5-ALA for PDT treatment than MSC of the same tissue origin. The concentration of 5-ALA required increases with increasing cell malignancy. Differences in the response of epithelial cells and MSC to PDT treatment may have varying impacts on OLK recurrence and malignancy.

Efficacy and safety of total glucosides of paeony in the treatment of recurrent aphthous ulcers: a systematic review and meta-analysis.

Background: Recurrent aphthous ulcer (RAU) had high prevalence and lacked widely recognized treatment. Total glucosides of paeony (TGP) was used in the treatment of RAU in recent years. This study was to summarize the efficacy and safety of TGP in the treatment of RAU. Methods: We searched eight commonly used databases for relevant studies that published before 1 November 2023. Primary outcome was visual analogue scale (VAS). Secondary outcomes included overall response rate, significant response rate, ulcer healing time, interval, number of ulcers, and serum inflammatory factors. We conducted the meta-analysis, assessed risk of bias and the confidence of the evidence, by using Stata 15.0, Review Manager 5.4, and Gradepro. Results: Nine randomized controlled trials (RCTs) encompassing 883 patients with RAU were included in the final analysis. The VAS in the TGP group was lower than that in the control group (MD = -1.18, 95% CI = -1.58 to -0.78, p < 0.001, moderate-certainty evidence), subgroup analysis suggested longer (>8 weeks) medication and observation led to a more significant reduction in pain (p = 0.02). Moreover, TGP had higher overall response rate (RR = 1.18, 95% CI = 1.04 to 1.33, p = 0.008, very low-certainty evidence) and significant response rate (RR = 1.72, 95% CI = 1.38 to 2.14, p < 0.001, very low-certainty evidence), accelerated ulcer healing (MD = -1.79, 95% CI = -2.67 to -0.91, p < 0.001, low-certainty evidence), and extended intervals (MD = 23.60, 95% CI = 14.17 to 33.03, p < 0.001, very low-certainty evidence). The efficacy of TGP in reducing the number of ulcers showed no significant difference compared to the control group (MD = -1.66, 95% CI = -3.60 to 0.28, p = 0.09, low-certainty evidence). Moreover, TGP treatment was associated with a higher incidence of abdominal symptoms (RR = 3.27, 95% CI = 1.62 to 6.60, p < 0.001). Conclusion: TGP appears to hold promise as a widely-used clinical therapeutic option for treating RAU. Nevertheless, further rigorous studies of high quality are required to validate its effectiveness. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=471154, Identifier CRD42023471154.