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Impaired autophagic flux induces aging-related ischemia vulnerability, which is the hallmark pathology in cardiac aging. Our previous work has confirmed that the accumulation of charged multivesicular body protein 2B (CHMP2B), a subunit of the ESCRT-III complex, in the heart can impair autophagy flux. However, whether CHMP2B accumulation contributes to aging-related intolerance to ischemia/reperfusion (I/R) injury and the regulatory mechanism for CHMP2B in aged heart remain elusive. The cardiac CHMP2B level was significantly higher in aged human myocardium than that in young myocardium. Increased CHMP2B were shown to inhibit autophagic flux leading to the deterioration of MI/R injury in aged mice hearts. Interestingly, a negative correlation was observed between SIRT6 and CHMP2B expression in human heart samples. Specific activation of SIRT6 suppressed CHMP2B accumulation and ameliorated autophagy flux in aged hearts. Using myocardial-specific SIRT6 heterozygous knockout mice and recovery experiments confirmed that SIRT6 regulated myocardial CHMP2B levels. Finally, activation of SIRT6 decreased acetylation of FoxO1 to promote its transcriptional function on Atrogin-1, a muscle-specific ubiquitin ligase, which subsequently enhanced the degradation of CHMP2B by Atrogin-1. This is a novel mechanism for SIRT6 against aging-related myocardial ischemia vulnerability, particularly by preventing excessive accumulation of autophagy key factors.

Siglec-15, a novel immune checkpoint, is an emerging target for next-generation cancer immunotherapy. However, the role of Siglec-15 in pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. We investigated the expression of Siglec-15 and its association with clinicopathological characteristics, programmed cell death-ligand 1 (PD-L1), immune cells, and DNA damage repair (DDR) molecules in a cohort of 291 patients with PDAC. Positive tumour cell expression of Siglec-15 and PD-L1 was observed in 18.6 and 30.3% of the samples, respectively. We also detected Siglec-15 positivity in macrophages in 3.4% of patients. Co-expression of Siglec-15 with PD-L1 was observed in 6.1% of the patients. A total of 33 PD-L1-negative samples (18.0%) were Siglec-15-positive. Siglec-15 was observed more frequently in moderate-to-well-differentiated tumours. Siglec-15 was associated with a low density of Tregs and CD45RO T cells, high BRCA1 expression, and improved survival. Both Siglec-15 and PD-L1 are independent factors of patient outcomes. The prognostic significance of Siglec-15 for survival was more discriminative in lymph node-negative, high BRCA1 expression, or low BRCA2 expression tumours than in lymph node-positive, low BRCA1 expression, or high BRCA2 expression tumours. In conclusion, we identified Siglec-15 as a promising predictor for prognosis combined with different DDR molecular statuses and complex tumour-infiltrating cells in PDAC. Targeting Siglec-15 may be a novel therapeutic option for patients who are unresponsive to anti-PD-1 therapy. Future studies are needed to validate the prognostic significance of Siglec-15 and to investigate its regulatory mechanisms in this disease.

Immunotherapy targeting programmed cell death-1 (PD-1) has considerably improved the prognosis of patients with advanced cancers; however, its efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC) is unfavourable. To address the issue of PDAC immunotherapy, we investigated the expression of two PD-1 ligands, PD-L1 and PD-L2, in PDAC, analysed their role in survival, and explored their correlation with clinicopathological features, immune infiltration, and DNA damage response molecules. Immunohistochemistry was performed on 291 surgically resected PDAC samples. In tumour cells (TCs) and immune cells (ICs), the positivity of PD-L1 expression was 30 and 20% and that of PD-L2 expression was 40 and 20%, respectively. Moreover, PD-L1 expression on TCs correlated with its expression on ICs (p 0.0001); a similar result was observed for PD-L2 (p 0.0001). Nonetheless, no correlation was observed between PD-L1 and PD-L2 expression. Positive PD-L1 expression on TCs was related to N1 stage (p = 0.011) and AJCC II stage (p = 0.002), whereas positive PD-L2 expression on TCs was associated with high FOXP3

Whether metformin reduces all-cause cardiovascular mortality and the incidence of cardiovascular events in patients with pre-existing cardiovascular diseases (CVD) remains inconclusive. Some randomised controlled trials (RCTs) and cohort studies have shown that metformin is associated with an increased risk of mortality and cardiovascular events.We conducted a pooling synthesis to assess the effects of metformin in all-cause cardiovascular mortality and incidence of cardiovascular events in patients with CVD. Studies published up to October 2021 in PubMed or Embase with a registration in PROSPERO (CRD42020189905) were collected. Both RCT and cohort studies were included. Hazard ratios (HR) with 95% CI were pooled across various trials using the random-effects model.This study enrolled 35 published studies (in 14 publications) for qualitative synthesis and identified 33 studies (published in 26 publications) for quantitative analysis. We analysed a total of 61,704 patients, among them 58,271 patients were used to calculate all-cause mortality while 12,814 patients were used to calculate cardiovascular mortality. Compared with non-metformin control, metformin usage is associated with a reduction in all-cause mortality (HR: 0.90; 95% CI 0.83, 0.98; p = 0.01), cardiovascular mortality (HR: 0.89; 95% CI 0.85, 0.94; p0.0001), incidence of coronary revascularisation (HR: 0.79; 95% CI 0.64, 0.98; p = 0.03), and heart failure (HR: 0.90; 95% CI 0.87, 0.94; p0.0001) in patients with pre-existing cardiovascular diseases.Metformin use is associated with a reduction in all-cause mortality, cardiovascular mortality, incidence of coronary revascularisation, and heart failure in patients with CVD; however, metformin usage was not associated with reduction in the incidence of myocardial infarction, angina, or stroke.

Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel noncovalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (Mpro) by employing a scalable high-throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro inhibitor with an inhibition constant (Ki) of 2.9 μM (95% CI 2.2, 4.0). Furthermore, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of Mpro forming stable hydrogen bond and hydrophobic interactions. We then used multiple μs-time scale molecular dynamics (MD) simulations and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro and offers a springboard for further therapeutic design.

Background Postpartum depression (PPD) is a serious postpartum mental health problem worldwide. To date, minimal is known about the alteration of topographical organization in the brain structural covariance network of patients with PPD. This study investigates the brain structural covariance networks of patients with PPD by using graph theoretical analysis. Methods High-resolution 3D T1 structural images were acquired from 21 drug-naive patients with PPD and 18 healthy postpartum women. Cortical thickness was extracted from 64 brain regions to construct the whole-brain structural covariance networks by calculating the Pearson correlation coefficients, and their topological properties (e.g., small-worldness, efficiency, and nodal centrality) were analyzed by using graph theory. Nonparametric permutation tests were further used for group comparisons of topological metrics. A node was set as a hub if its betweenness centrality (BC) was at least two standard deviations higher than the mean nodal centrality. Network-based statistic (NBS) was used to determine the connected subnetwork. Results The PPD and control groups showed small-worldness of group networks, but the small-world network was more evidently in the PPD group. Moreover, the PPD group showed increased network local efficiency and almost similar network global efficiency. However, the difference of the network metrics was not significant across the range of network densities. The hub nodes of the patients with PPD were right inferior parietal lobule (BC = 13.69) and right supramarginal gyrus (BC = 13.15), whereas those for the HCs were left cuneus (BC = 14.96), right caudal anterior-cingulate cortex (BC = 15.51), and right precuneus gyrus (BC = 15.74). NBS demonstrated two disrupted subnetworks that are present in PPD: the first subnetwork with decreased internodal connections is mainly involved in the cognitive-control network and visual network, and the second subnetwork with increased internodal connections is mainly involved in the default mode network, cognitive-control network and visual network. Conclusions This study demonstrates the alteration of topographical organization in the brain structural covariance network of patients with PPD, providing in sight on the notion that PPD could be characterized as a systems-level disorder.

Background Primary cardiac schwannoma remains extremely rare and difficult to distinguish from other myocardial tumours. We report a case of cardiac schwannoma that occurred in the lateral wall of the right ventricle and grew in the myocardial walls. It is the third case of schwannoma that occurred in the free wall of the right ventricle. Moreover, we reviewed and summarised the literature for cases involving benign cardiac schwannomas. Case presentation We present a case of a 64-year-old woman who presented to our centre with syncope for 1–2 min. Echocardiogram and contrast-enhanced computed tomography subsequently revealed a 2.9 × 1.9 cm homogeneous mass originating from the anterior wall of the right ventricle. The patient underwent thoracotomy to resect the mass, which was pathologically verified as Schwann cell tumour. Conclusions This is a rare case added to the limited existing literature on cardiac schwannoma. Comprehensive analysis of various imaging examinations is helpful to determine the extent of the tumour. Complete surgical resection is recommended for similar cases involving cardiac schwannomas, especially when the patient has related symptoms. Patients generally have a good prognosis. The pathogenesis of cardiac schwannoma needs further research in order to prevent and manage this rare lesion.

Walking stability is an important factor that is related to working accidents at height. The understanding of the relationship between walking stability and walking conditions remains an unmet need. Therefore, this study aimed to investigate the effect of path height, width, and asymmetric conditions on the pressure and time information of the foot-ground interaction during walking. 12 subjects were required to walk at two height, three width, and asymmetric conditions. Plantar pressures during walking were measured with the F-scan insole sensors. The total pressures were normalized with body weight, and the temporal parameters were normalized with stance time. When the walking height increased, the plantar pressure at the “heel strike” phase did not change significantly, while that at “heel rise” and “toe off” phases significantly increased, and the “heel rise” occurred earlier, indicating a greater foot-ground interaction at the forefoot part of the sole. As the path width increased from 0.6 m to 1.2 m, the foot-ground interaction as well as the asymmetric effect approached to that of overground walking. The findings could help improve the risk assessment and footwear design.

Tuberculosis, caused by mycobacteria, continues to pose a substantial public health threat. Mycobacteria typically use cholesterol from the membranes of host macrophages as a carbon and energy source. Most genes that control cholesterol degradation are regulated by KstR, which is highly conserved in Mycobacterium tuberculosis and Mycobacterium smegmatis. Through bioinformatic analysis, we found a typical global nitrogen regulator (GlnR)-binding motif (CCGAC-AACAGT-GACAC) in the promoter region of kstR of M. smegmatis, and we determined its binding activity in vitro using electrophoretic mobility shift assays. Using RT-qPCR, we found that nine genes involved in side-chain or sterol-ring oxidation were upregulated in a ΔglnR M. smegmatis strain compared to the WT strain and glnR-complemented strains under nitrogen limitation. ATP assays in macrophages revealed that coordinated GlnR-KstR regulation significantly reduced the viability of M. smegmatis in macrophages. Thus, we found that various genes involved in cholesterol catabolism are regualted by GlnR via KstR in response to environmental nitrogen, and that they further affect the invasive ability of M. smegmatis. These findings revealed a novel regulatory mechanism of cholesterol catabolism, which may be useful in the development of new strategies for controlling tuberculosis. This article is protected by copyright. All rights reserved.

This work aimed to explore whether radiomic features on magnetic resonance diffusion weighted image (MR DWI) can be used to identify triple-negative breast cancer (TNBC) and other subtypes (non-TNBC).This retrospective study included 221 unilateral patients who underwent breast MR imaging prior to neoadjuvant chemotherapy. The subtypes of breast cancer include luminal A (n = 63), luminal B (n = 103), human epidermal growth factor receptor-2 (HER2) overexpressing (n = 30), and triple negative (n = 25). Radiomic features were extracted using Omini-Kinetic software on DWI. Student's t-test and Mann-Whitney U test were used to compare the features between TNBC and non-TNBC patients. Logistic regression analysis and receiver operating characteristic (ROC) curve were used to evaluate the diagnostic efficiency of radiomic features. The Fisher discriminant model was employed to distinguish TNBC and non-TNBC patients automatically. An additional validation dataset with 169 patients was utilized to validate the model.A total of 76 imaging features were extracted from each lesion on DWI images, and 12 radiomic features were statistically significant between TNBC and non-TNBC patients (P 0.05). The area of receiver operating characteristic curve (AUC) was 0.817 to apply logistic regression analysis. The accuracy of Fisher discriminant model in distinguishing TNBC and non-TNBC patients was 95.4%, and leave-one-out cross validation was achieved with an accuracy of 83.7%. The same classification analysis of the validation dataset showed an accuracy of 83.4% and an AUC of 0.804.Breast lesions exhibit differences in radiomic features from DWI, enabling good discrimination between TNBC and non-TNBC tumors.

Immune checkpoint modulation has been a vital therapeutic option in many malignancies, and targeting of novel immune checkpoints, including OX40/OX40L costimulatory signaling, is being assessed in clinical trials. However, little is known about the role of OX40 and OX40L in pancreatic ductal adenocarcinoma (PDAC). Thus, we investigated the clinical significance of OX-40 and OX40L and their associations with alternative immune checkpoints, immune infiltrates, clinicopathological features, and clinical outcomes. We performed multiplexed immunofluorescence staining for OX40, OX40L, CD8, and CD68 using tissue microarrays from 255 patients. Immunohistochemistry data for PD-L1, B7-H3, B7-H4, CD3, and Foxp3 were analyzed. And the RNA sequencing data of OX40/OX40L in The Cancer Genome Atlas and International Cancer Genome Consortium databases were also evaluated. The positive rates for OX40 on tumor cells (TCs) and immune cells (ICs) were 8.6% and 10.2%, respectively, and the positive rates for OX40L on TCs, ICs, and macrophages were 20%, 40.4%, and 12.9%, respectively. OX40 was associated with favorable clinicopathological features. OX40+ on ICs, OX40L+ on TCs, or OX40L+ on macrophages, rather than the total gene and protein levels of OX40/OX40L, were associated with improved survival. OX40+ on ICs and OX40L+ on macrophages were independent factors of clinical outcomes. Moreover, we could more accurately stratify patients through the combination of OX40 on ICs and OX40L on TCs, and patients with OX40+ ICs and OX40L+CK+ showed the best outcome. And we demonstrated that patients with OX40-ICs and low CD8+ T cells infiltration had unfavorable survival. Intriguingly, OX40+ ICs or OX40L+ macrophages demonstrated superior survival in patients with PD-L1 negativity than in those with PD-L1 positivity. Furthermore, OX40+ ICs were correlated with negative B7-H4 on TCs, high densities of CD3 T cells, and high densities of Foxp3 T cells; OX40+ TCs and OX40L+ TCs were associated with low densities of Foxp3 T cells. We identified OX40 and OX40L as promising predictors for prognosis in PDAC.

Although much is known about how adipose tissue affects the development of clear cell renal carcinoma (ccRCC), little information is available for the utility of sex-specific abdominal visceral fat composition as a predictor of clear cell renal carcinoma (ccRCC) T stage. We conducted CT-based sex-specific abdominal fat measurements in ccRCC patients to assess whether VFA distribution could predict the ccRCC T stage. In total, 253 patients (182 males and 71 females) from our hospital with pathologically confirmed ccRCC (178 low T-stage and 75 high T-stage) were retrospectively reviewed for the present study. Computed tomography (CT) scans were assessed using ImageJ to differentiate between the visceral and subcutaneous fat areas (VFA and SFA), after which the relative VFA (rVFA) and total fat area (TFA) were computed. The relationships between these fat area-related variables, patient age, sex, and BMI, and ccRCC T stage were then evaluated through univariate and multivariate logistic regression analysis to clarify the association between general or sex-specific abdominal visceral fat and T stage. Following adjustment for age, males with high T stage ccRCC exhibited an increased rVFA as compared to males with low T stage ccRCC, with the same relationship being observed among females. This association between rVFA and high T stage was confirmed through both univariate and multivariate models. As thus, sex-specific visceral fat composition is a reliable independent predictor that can identify both male and female patients with high T stage ccRCC.

Background Cardiac MRI is an emerging modality for evaluating left ventricular (LV) diastolic dysfunction (LVDD), a pathological condition that is prevalent in aging populations. However, there is a lack of reports of MRI-derived LV diastolic properties in late diastole. Purpose To test the hypothesis that cine MRI-derived motion/deformation indices can be used to characterize age-related changes on LV relaxation patterns in late diastole. Study type Retrospective. Population In all, 412 participants (72.5 ± 4.6 years old, range 65-84) without a documented history of cardiovascular diseases. Field strength/sequence Balanced steady-state free precession(bSSFP) acquired at 1.5T. Assessment Participants were divided into younger (65-74 years old, n = 275) and older (75-84 years old, n = 137) groups. Status of diabetes mellitus (DM), hypertension (HTN), and lipid disorders were recorded for each participant. Cine MRI datasets were analyzed by using heart deformation analysis (HDA). LV motion/deformation indices (displacement, velocity, strain, and strain rate) were measured through 22 phases within a cardiac cycle. Statistical tests The prevalence of traditional cardiovascular risk conditions, LV ejection fraction (LVEF), peak LV regional displacement, velocity, and strain rates at early and late diastole were compared between two participant groups using chi-square tests or t-tests. Results Older participants had a significantly lower peak early radial displacement (0.797 ± 0.249 cm vs. 0.876 ± 0.286 cm), radial velocity (19.3 ± 6.3 mm/s vs. 17.5 ± 5.2 mm/s), and circumferential strain rate (64.6 ± 15.7%/s vs. 70.1 ± 17%/s) but a higher peak late circumferential strain rate (69.8 ± 16.3 %/s vs. 66 ± 15.8 %/s) than their younger counterparts. Data conclusion Cine MRI can be used to characterize age-related LV relaxation patterns in late diastole. Level of evidence 3. Technical efficacy stage 1.

The MG53 (also known as TRIM72) is a conserved, muscle-specific tripartite motif family protein that is abundantly expressed in cardiac or skeletal muscle and present in circulation. Recently, the MG53 had been hypothesized to serve a dual role in the heart: involving in repairing cell membranes that protect myocardial function while acting as an E3 ligase to trigger insulin resistance and cardiovascular complications. This review discusses the roles of MG53 in cardiac physiological function with emphasis on MG53 protective function in the heart and its negative impact on the myocardium due to the continuous elevation of MG53. Besides, this work reviewed the significance of MG53 as a potential therapeutic in human cardiovascular diseases. Despite the expression of MG53 being rare in the human, thus exogenous MG53 can potentially be a new treatment for human cardiovascular diseases. Notably, the specific mechanism of MG53 in cardiovascular diseases remains elusive.

Clear cell renal carcinoma (ccRCC) is the most common histological type of renal cancer and has the highest mortality. Several studies have been conducted on the relationship between adipose tissue and ccRCC prognosis, however, the results have been inconsistent to date. The current study aimed at establishing a link between abdominal fat composition and short-term prognosis in patients with ccRCC after T-stage stratification. We retrospectively analysed 250 patients with pathologically confirmed ccRCC (173 low T-stage and 77 high T-stage) in our hospital. The computed tomography (CT) images were evaluated using ImageJ. Then, subcutaneous and visceral fat areas (SFA and VFA), total fat areas (TFA) and the relative VFA (rVFA) were measured and computed. Meanwhile, biochemical indices of blood serum were analysed. The results showed that rVFA in low T-stage cohort who had a history of short-term postoperative complications were significantly lower than those who did not. No such association was observed in the high T-stage cohort. Further investigation revealed that the correlations between biochemical indexes and fat area-related variables varied across T-stage groups. As a result, rVFA is a reliable independent predictor of short-term prognosis in patients with low T-stage ccRCC but not in patients with high T-stage ccRCC.

BackgroundAlthough checkpoint blockade is a promising approach for the treatment of hepatocellular carcinoma (HCC), subsets of patients expected to show a response have not been established. As T cell-mediated tumor killing (TTK) is the fundamental principle of immune checkpoint inhibitor therapy, we established subtypes based on genes related to the sensitivity to TKK and evaluated their prognostic value for HCC immunotherapies.MethodsGenes regulating the sensitivity of tumor cells to T cell-mediated killing (referred to as GSTTKs) showing differential expression in HCC and correlations with prognosis were identified by high-throughput screening assays. Unsupervised clustering was applied to classify patients with HCC into subtypes based on the GSTTKs. The tumor microenvironment, metabolic properties, and genetic variation were compared among the subgroups. A scoring algorithm based on the prognostic GSTTKs, referred to as the TCscore, was developed, and its clinical and predictive value for the response to immunotherapy were evaluated.ResultsIn total, 18 out of 641 GSTTKs simultaneously showed differential expression in HCC and were correlated with prognosis. Based on the 18 GSTTKs, patients were clustered into two subgroups, which reflected distinct TTK patterns in HCC. Tumor-infiltrating immune cells, immune-related gene expression, glycolipid metabolism, somatic mutations, and signaling pathways differed between the two subgroups. The TCscore effectively distinguished between populations with different responses to chemotherapeutics or immunotherapy and overall survival.ConclusionsTTK patterns played a nonnegligible role in formation of TME diversity and metabolic complexity. Evaluating the TTK patterns of individual tumor will contribute to enhancing our cognition of TME characterization, reflects differences in the functionality of T cells in HCC and guiding more effective therapy strategies.

Background The interaction between tumor microenvironment (TME) and tumors offers various targets in mounting anti-tumor immunotherapies. However, the prognostic biomarkers in endometrial carcinoma (EC) are still limited. Here, we aimed to analyze the TME features and identify novel prognostic biomarkers for EC. Methods ESTIMATE, CIBERSORT, protein-protein interaction (PPI) network, univariate and multivariate Cox regression, and functional enrichment analysis were performed to identify immune- and survival-related hub genes as well as possible molecular mechanisms. The limma package and deconvolution algorithm were adopted to estimate the abundance of tumor-infiltrating immune cells (TICs) and their relationship with the target gene. In the validation section, tissue microarrays (TMAs) of EC and multiplex immunohistochemistry (m-IHC) were evaluated to validate the expression of TNFRSF4, and its correlation with immune markers, including CD4, CD8, and FOXP3. Besides, the receiver operating characteristic (ROC) curve was plotted to determine the diagnostic performance of TNFRSF4, CD4, CD8, and FOXP3 in EC. Results Two genes, TNFRSF4 and S1PR4, were screened out from 386 intersection differential expression genes (DEGs) shared by ImmuneScore and StromalScore in EC. Highlighted by TNFRSF4, we found that it was not only positively correlated with the TICs (mainly CD4+ T cells, CD8+ T cells, and Tregs) but significantly related to the prognosis in patients of EC, both verified by data from The Cancer Genome Altas (TCGA)-EC database and clinical samples. At the same time, the expression trend of TNFRSF4 was further confirmed by an integrated meta-analysis based on six microarrays from the Gene Expression Omnibus database (GEO). Conclusions Collectively, TNFRSF4, a previously unrecognized key player in EC, could serve as a potential biomarker for prognosis prediction and immunomodulation of EC.

Cisplatin is widely used in the treatment of solid tumors, but its application is greatly limited due to its nephrotoxicity; thus, there is still no effective medicine for the treatment of cisplatin-induced acute kidney injury (Cis-AKI). We previously identified that polydatin (PD) exerts nephroprotective effects by antioxidative stress in AKI models. Recent evidence suggests that oxidative stress-induced molecular events overlap with the process of ferroptosis and that there are common molecular targets, such as glutathione (GSH) depletion and lipid peroxidation. Nevertheless, whether the nephroprotective effect of PD is related to anti-ferroptosis remains unclear. In this study, the inhibitory effect of PD on ferroptosis was observed in both cisplatin-treated HK-2 cells (20 μM) in vitro and a Cis-AKI mouse model (20 mg/kg, intraperitoneally) in vivo, characterized by the reversion of excessive intracellular free iron accumulation and reactive oxygen species (ROS) generation, a decrease in malondialdehyde (MDA) content and GSH depletion, and an increase in glutathione peroxidase-4 (GPx4) activity. Remarkably, PD dose-dependently alleviated cell death induced by the system Xc− inhibitor erastin (10 μM), and the effect of the 40 μM dose of PD was more obvious than that of ferrostatin-1 (1 μM) and deferoxamine (DFO, 100 μM), classical ferroptosis inhibitors. Our results provide insight into nephroprotection with PD in Cis-AKI by inhibiting ferroptosis via maintenance of the system Xc−-GSH-GPx4 axis and iron metabolism.

This study aims to establish and validate a radiomics nomogram based on contrast-enhanced spectral mammography (CESM) for prediction of axillary lymph node (ALN) metastasis in breast cancer. This retrospective study included 394 patients with breast cancer who underwent CESM examination in two hospitals. The least absolute shrinkage and selection operator (LASSO) logistic regression was established for feature selection and utilized to construct radiomics signature. The nomogram model included the radiomics signature and independent clinical factors. The receiver operating characteristic (ROC) curves were used to confirm the performance of the nomogram in training and validation sets. The nomogram model, which includes the radiomics signature and the CESM-reported lymph node status, has areas under the ROC curves of 0.774 (95% confidence interval (CI) 0.689–0.858), 0.767 (95% CI 0.583–0.857), and 0.79 (95% CI 0.63–0.94) in the training, internal validation, and external validation sets, respectively. We identified the cutoff score in the radiomics nomogram as − 1.49, which corresponded to a total point of 49 that could diagnose ALN metastasis with a sensitivity of > 95%. The CESM-based radiomics nomogram is a noninvasive predictive tool that shows good application prospects in the preoperative prediction of ALN metastasis in breast cancer. • The CESM-based radiomics nomogram shows good performance in predicting ALN metastasis in breast cancer. • The application of radiomics nomogram in this study provides a new approach for establishing a prediction model with multiple characteristics. • The nomogram has good application prospects in assisting clinical decision makers.

Ovarian cancer (OC) is the most lethal gynaecological malignancy, characterized by high recurrence and mortality. However, the mechanisms of its pathogenesis remain largely unknown, hindering the investigation of the functional roles. This study sought to identify key hub genes that may serve as biomarkers correlated with prognosis. Here, we conduct an integrated analysis using the weighted gene co‐expression network analysis (WGCNA) to explore the clinically significant gene sets and identify candidate hub genes associated with OC clinical phenotypes. The gene expression profiles were obtained from the MERAV database. Validations of candidate hub genes were performed with RNASeqV2 data and the corresponding clinical information available from The Cancer Genome Atlas (TCGA) database. In addition, we examined the candidate genes in ovarian cancer cells. Totally, 19 modules were identified and 26 hub genes were extracted from the most significant module (R 2 = .53) in clinical stages. Through the validation of TCGA data, we found that five hub genes (COL1A1, DCN, LUM, POSTN and THBS2) predicted poor prognosis. Receiver operating characteristic (ROC) curves demonstrated that these five genes exhibited diagnostic efficiency for early‐stage and advanced‐stage cancer. The protein expression of these five genes in tumour tissues was significantly higher than that in normal tissues. Besides, the expression of COL1A1 was associated with the TAX resistance of tumours and could be affected by the autophagy level in OC cell line. In conclusion, our findings identified five genes could serve as biomarkers related to the prognosis of OC and may be helpful for revealing pathogenic mechanism and developing further research.

OBJECTIVES To investigate the coronary venous system (CVS) and its spatial relationship with coronary arteries by using 256-slice computed tomography (CT). METHODS One hundred one patients underwent coronary CT angiography by using a 256-slice CT. In each patient, the CVS and its spatial relationship with coronary arteries were analyzed. We measured the diameters and angulations of the coronary sinus (CS), great cardiac vein, anterior interventricular vein (AIV), left marginal vein, posterior vein of the left ventricle (PVLV), and posterior interventricular vein (PIV), and the distances, respectively, from the CS ostium and from the crossing point to the ostium of corresponding tributaries. RESULTS The following 5 pairs of veins and arteries had a higher frequency of intersecting compared with others: the CS/great cardiac vein and the left circumflex coronary artery (97.1%), the AIV and the diagonal or ramus branch (92.1%), the PIV and the posterior branch of left ventricle artery (88.1%), the left marginal vein and the circumflex or circumflex marginal (73.9%), and the PVLV and the circumflex or circumflex marginal (31.6%). The other 2 pairs had a higher frequency of running parallel to each other: the AIV and the left anterior descending artery (76.2%) and the PIV and the posterior descending artery (54.4%). Most tributaries were lateral to their corresponding arteries at the crossing point except for the AIV. For the PVLV and PIV, the distances from the crossing point to the ostium of corresponding veins when the veins were lateral to the arteries were smaller than those when the veins were medial to the arteries (P < 0.05). CONCLUSIONS The CVS and its anatomical relationship with the coronary arterial system can be examined with details by using a 256-slice CT, which has important clinical implications.

Frontometaphyseal dysplasia 2 (FMD2) is a rare disease caused by MAP3K7 gene mutation. We report a 7-year-old sporadic patient with FMD2 due to a de novo splicing variant in MAP3K7. He has the common characteristics of FMD2 but also has some characteristics that have never been reported, which increases the clinical phenotype of FMD2. Moreover, no systematic description of the imaging characteristics of FMD2 in computed tomography (CT) is available. In the present work, we found some different features of FMD2, reviewed previous literature, and summarized the general imaging manifestations of FMD2. This case emphasizes the important clinical value of CT and VR in the diagnosis of FMD2. We can clearly find the characteristics of FMD2 by CT examination, indicating its great significance for the prompt diagnosis and treatment of FMD2 patients.La displasia frontometafisaria 2 (DFM2) es una enfermedad rara causada por una mutación en el gen MAP3K7. En este artículo, se informa sobre un paciente de 7 años con DFM2 causada por una variante nueva de corte y empalme en MAP3K7. El paciente presenta las características frecuentes de la DFM2, pero algunas nunca antes informadas. No se dispone de una descripción sistemática de las características de las imágenes tomográficas de la DFM2. Describimos ciertas diferencias en las características de la DFM2, la bibliografía publicada y las manifestaciones imagenológicas generales de la DFM2. Este caso resalta la importancia del valor clínico de la tomografía computada (TC) y la renderización de volúmenes (VR) en el diagnóstico de la DFM2. Las características de la DFM2 pueden observarse claramente en los estudios tomográficos, lo que señala la gran importancia de la TC para el diagnóstico y el tratamiento precoces de los pacientes con DFM2.

Pregnancy leads to long-lasting changes in human brain structure; however, little is known regarding alterations in the topological organization of functional networks. In this study, we investigated the effect of pregnancy on human brain function networks. Resting-state fMRI data was collected from eighteen primiparous mothers and twenty-four nulliparous control women of similar age, education level and body mass index (BMI). The functional brain network and topological properties were calculated by using GRETNA toolbox. The demographic data differences between two groups were computed by the independent two sample t-test. We tested group differences in network metrics' area under curve (AUC) using non-parametric permutation test of 1,000 permutations and corrected for false discovery rate (FDR). Differences in regional networks between groups were evaluated using non-parametric permutation tests by network-based statistical analysis (NBS). Compared with the nulliparous control women, a hub node changed from left inferior temporal gyrus to right precentral gyrus in primiparous mothers, while primiparous mothers showed enhanced network global efficiency (p = 0.247), enhanced local efficiency (p = 0.410), larger clustering coefficient (p = 0.410), but shorter characteristic path length (p = 0.247), smaller normalized clustering coefficient (p = 0.111), and shorter normalized characteristic path length (p = 0.705). Although both groups of functional networks have small-world property (σ 1), the σ values of primiparous mothers were decreased significantly. NBS evaluation showed the majority of altered connected sub-network in the primiparous mothers occurred in the bilateral frontal lobe gyrus (p 0.05). Altered functional network metrics and an abnormal sub-network were found in primiparous mothers, suggested that pregnancy may lead to changes in the brain functional network.

Tumor angiogenesis is a complex process that is unamenable to intravital whole‐process monitoring, especially on microscopic assessment of tumor microvessel and quantifying microvascular hemodynamics before and after the nanotherapeutics, which hinder the understanding of nanotheranostics outcomes in tumor treatment. Herein, a new photoacoustic (PA) imaging‐optical coherence tomography angiography (OCTA)‐laser speckle (LS) multimodal imaging strategy is first proposed, which is not only able to precisely macro guide the thermo‐chemotherapy of tumor by monitoring blood oxygen saturation (SaO2) and hemoglobin content (HbT), but also capable of long‐term microscopic investigating the microvessel morphology (microvascular density) and hemodynamics changes (relative blood flow) before and after the nanotherapeutics in vivo. Moreover, to realize the tumor thermo‐chemotherapy treatment based on this novel multimodal imaging strategy, a 2D 5‐fluorouracil silicon nanosheets (5‐Fu‐Si NSs) therapeutic agent is designed. Furthermore, 2D high‐resolution tumor microvascular images in different stage display that tendency of the thermo‐chemotherapy effect is closely associated with tumor angiogenesis. Taken together, the investigations establish the fundamental base in theory and technology for further tailoring the novel specific diagnosis and treatment strategy in tumor. More importantly, this technique will be beneficial to evaluate the tumor microvascular response to nanotherapeutics at microscale., A promising biocompatible nanotheranostics agent based on chemotherapeutic drug 5‐fluorouracil and 2D silicon nanosheets is developed for synergistic thermo‐chemotherapy strategy. The tumor tissue functional parameters, including SaO2, HbT, micro microvascular morphology, and hemodynamics, are dynamically monitored by multimodal PA/ OCTA/ LS imaging strategy to accurately evaluate overall therapeutic effects. This novel strategy exhibited prominent therapeutic efficiency on malignant glioma U87‐MG.

Postpartum depression (PPD) is a common mood disorder with increasing incidence year by year. However, the dynamic changes in local neural activity of patients with PPD remain unclear. In this study, we utilized the dynamic amplitude of low-frequency fluctuation (dALFF) method to investigate the abnormal temporal variability of local neural activity and its potential correlation with clinical severity in PPD.Twenty-four patients with PPD and nineteen healthy primiparous mothers controls (HCs) matched for age, education level and body mass index were examined by resting-state functional magnetic resonance imaging (rs-fMRI). A sliding-window method was used to assess the dALFF, and a k-means clustering method was used to identify dALFF states. Two-sample t-test was used to compare the differences of dALFF variability and state metrics between PPD and HCs. Pearson correlation analysis was used to analyze the relationship between dALFF variability, states metrics and clinical severity.(1) Patients with PPD had lower variance of dALFF than HCs in the cognitive control network, cerebellar network and sensorimotor network. (2) Four dALFF states were identified, and patients with PPD spent more time on state 2 than the other three states. The number of transitions between the four dALFF states increased in the patients compared with that in HCs. (3) Multiple dALFF states were found to be correlated with the severity of depression. The variance of dALFF in the right middle frontal gyrus was negatively correlated with the Edinburgh postnatal depression scale score.This study provides new insights into the brain dysfunction of PPD from the perspective of dynamic local brain activity, highlighting the important role of dALFF variability in understanding the neurophysiological mechanisms of PPD.

Data availability statement: The trajectories of Mpro simulations and models of the metastable states can be downloaded from 10.5281/zenodo.4782284. β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensable role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand–protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV Mpro. Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor. There was no funding for this work

Ectopic spleen is a rare clinical malformation in which the spleen is relocated from its normal anatomical position to other parts of the abdomen. We report a rare case of abdominopelvic ectopic spleen caused by splenic ligament deficiency. A patient experienced intermittent pain in the left upper abdomen that was progressively aggravated. This was confirmed by comprehensive imaging examinations and postoperative pathology. We also performed a review of the literature on the current state of the field. Our data may help to improve the diagnosis and treatment of ectopic spleen.

Background Metformin is a first-line drug in type 2 diabetes mellitus (T2DM) treatment, yet whether metformin may increase all-cause or cardiovascular mortality of T2DM patients remains inconclusive. Methods We searched PubMed and Embase for data extracted from inception to July 14, 2020, with a registration in PROSPERO (CRD42020177283). This study included randomized controlled trials (RCT) assessing the cardiovascular effects of metformin for T2DM. This study is followed by PRISMA and Cochrane guideline. Risk ratio (RR) with 95% CI was pooled across trials by a random-effects model. Primary outcomes include all-cause mortality and cardiovascular mortality. Results We identified 29 studies that randomly assigned patients with 371 all-cause and 227 cardiovascular death events. Compared with untreated T2DM patients, metformin-treated patients was not associated with lower risk of all-cause mortality (RR: 0.98; 95%CI: 0.69–1.38; P = 0.90), cardiovascular mortality (RR: 1.13; 95% CI: 0.60, 2.15; P = 0.70), macrovascular events (RR: 0.87; 95%CI: 0.70–1.07; P = 0.19), heart failure (RR: 1.02; 95% CI:0.61–1.71; P = 0.95), and microvascular events (RR: 0.78; 95% CI:0.54–1.13; P = 0.19). Combination of metformin with another hypoglycemic drug was associated with higher risk of all-cause mortality (RR: 1.49; 95% CI: 1.02, 2.16) and cardiovascular mortality (RR: 2.21; 95% CI: 1.22, 4.00) compared with hypoglycemic drug regimens with no metformin. Conclusion The combination of metformin treatment may impose higher risk in all-cause and cardiovascular mortality. This finding, at least in part, shows no evidence for benefits of metformin in combination in terms of all-cause/cardiovascular mortality and cardiovascular events for T2DM. However, the conclusion shall be explained cautiously considering the limitations from UK Prospective Diabetes Study (UKPDS).

Background Postpartum depression (PPD) is a serious postpartum mental health problem worldwide. However, the cortical structural alterations in patients with PPD remain unclear. This study investigated the cortical structural alterations of PPD patients through multidimensional structural patterns and their potential correlations with clinical severity. Methods High-resolution 3D T1 structural images were acquired from 21 drug-naive patients with PPD and 18 healthy postpartum women matched for age, educational level, and body mass index. The severity of PPD was assessed by using the Hamilton Depression Scale (HAMD) and Edinburgh Postnatal Depression Scale (EPDS) scores. Cortical morphological parameters including cortical thickness, surface area, and mean curvature were calculated using the surface-based morphometric (SBM) method. General linear model (GLM) analyses were performed to evaluate the relationship of cortical morphological parameters with clinical scales. Results In the present study, PPD patients showed a thinner cortical thickness in the right inferior parietal lobule compared with the healthy controls. Increased surface area was observed in the left superior frontal gyrus, caudal middle frontal gyrus, middle temporal gyrus, insula, and right supramarginal cortex in PPD patients. Likewise, PPD patients exhibited a higher mean curvature in the left superior and right inferior parietal lobule. Furthermore, increased cortical surface area in the left insula had a positive correlation with EPDS scores, and higher mean curvature in the left superior parietal lobule was negatively correlated with EPDS scores. Limitations First, SBM cannot reflect the changes of subcortical structures that are considered to play a role in the development of PPD. Second, the sample size of this study is small. These positive results should be interpreted with caution. Third, this cross-sectional study does not involve a comparison of structural MRI before and after pregnancy. Conclusions The complex cortical structural alterations of patients with PPD mainly involved the prefrontal and parietal regions. The morphometric alterations in these specific regions may provide promising markers for assessing the severity of PPD.

Background: Castleman Disease (CD) of the kidney is extremely rare. In this study, we have presented a case of CD of the left kidney and comprehensively described the findings of computed tomography urography. Case Presentation: The case involved unusual imaging characteristics of the focal central cystic area. Conclusion: The small and regular cyst-like structures and the hyperdense mass relative to the renal parenchyma in plain scans might help distinguish the CD of the kidney from other hypervascular tumors.

A quantitative analysis of contrast-enhanced spectral mammography (CESM) enhancement was conducted for the early prediction of the pathological response after neoadjuvant chemotherapy (NAC). Retrospective analysis of the data of 111 patients was conducted, and all of them underwent NAC in our hospital and surgical resection after the end of all cycles from January 2018 to May 2019. They were divided into pathological complete response (PCR) and non-PCR groups. We determined whether a statistical difference in the percentage of CESM grey value reduction (ΔCGV) was present in the PCR and non-PCR groups and whether a statistical difference was observed in the diagnostic efficiency of craniocaudal (CC) and mediolateral oblique (MLO) view subtraction images. Independent sample t-test was used to compare different groups, the receiver operating characteristic (ROC) curve was used to compare the diagnostic efficacy of CC and MLO for pathological response after NAC, and the Delong test was used to compare the area under the ROC curve (AUC). Statistical significance was considered at P

Background: Carotid body tumors (CBTs) are relatively uncommon neoplasms that rarely have malignant potential. However, malignant CBTs (MCBTs) are still associated with a poor prognosis and the treatment is still challenging clinically. Therefore, we evaluated the necessity of intraoperative level IIA lymph node dissection in patients with CBT. Methods: The clinical characteristics, intraoperative details, and pathological diagnosis of 126 CBT patients who had undergone surgery were retrospectively reviewed. The patients were divided into 2 groups according to whether level IIA lymph node dissection was performed. The prognosis was analyzed using Kaplan-Meier curves and Cox model multivariate survival analysis. Results: Among the 126 patients, 7 patients (10.3%) in the selective lymph node dissection (SLND) group (68 patients) were diagnosed with MCBTs with evidence of lymph node metastasis. Two patients (3.4%) in the lymph node nondissection (LNND) group (58 patients) were diagnosed with MCBTs later after the second operation because they could not be diagnosed as malignant initially because of the lack of lymph node pathology results although the pathology of the primary lesion showed features of malignancy. The SLND group had a significantly higher relapse-free survival rate than the LNND group (94.1% vs. 79.3%, p = 0.021). Patients with a confirmed diagnosis had a better prognosis than those with insufficient evidence of a malignancy due to the lack of lymph node information. Twenty-nine patients in the SLND group and 26 patients in the LNND group had postoperative nerve injuries, with no significant difference between the groups (p = 0.879). Conclusion: Intraoperative dissection of level IIA lymph nodes around the tumor in CBT patients can help improve the diagnosis and prognosis of MCBTs without causing additional cranial nerve injury.

The factors that determine the anatomical variations of the coronary venous system (CVS) are poorly understood. The objective of this study was to evaluate the anatomical variations of the CVS in patients with coronary artery calcification. 196 patients underwent non-contrast CT and coronary CT angiography using 256-slice CT. All subjects were divided into four groups based on their coronary artery calcium score (CACS): 50 patients with CACS = 0 Agatston unit (AU), 52 patients with CACS = 1–100 AU, 44 patients with CACS = 101–400 AU, and 50 patients with CACS > 400 AU. The presence of the following cardiac veins was evaluated: the coronary sinus (CS), great cardiac vein (GCV), posterior interventricular vein (PIV), posterior vein of the left ventricle (PVLV), left marginal vein (LMV), anterior interventricular vein (AIV), and small cardiac vein (SCV). Vessel diameters were also measured. We found that the CS, GCV, PIV, and AIV were visualized in all patients, whereas the PVLV and LMV were identified in a certain proportion of patients: 98% and 96% in the CACS = 0 AU group, 100% and 78.8% in the CACS = 1–100 AU group, 93.2% and 77.3% in the CACS = 101–400 AU group, and 98% and 78% in the CACS > 400 AU group, respectively. The LMV was less often identified in the last three groups than in the first group (p < 0.05). The frequency of having either one PVLV or LMV was higher in the last three groups than in the first group (p < 0.05). No significant differences in vessel diameters were observed between the groups. It was concluded that patients with coronary artery calcification were less likely to have the LMV, which might hamper the left ventricular lead implantation in cardiac resynchronization therapy.

Several serum parameters can be used to assess ulcerative colitis (UC) disease activity. However, the value of these parameters for predicting UC severity has not been studied in depth. Therefore, we sought to investigate the value of serum total bilirubin (TB) as a predictor of UC severity.This cross-sectional study included 448 UC patients and 308 healthy participants. Data regarding the serum levels of TB, hemoglobin (Hb), albumin (Alb), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were collected. UC severity was evaluated according to the Truelove and Witts criteria. Wilcoxon rank sum tests were used to compare data between groups, while Spearman correlation analyses between TB and the levels of Hb, Alb, ESR and CRP were performed. Logistic regression analyses were used to determine the odds ratios (ORs) for severe UC in UC patients.UC patients had lower Hb, Alb, and TB levels than healthy participants (Serum TB level is an effective predictor of the severity of UC.

Background The torsion of normal adnexa is rare during pregnancy, especially in the third trimester. Nonspecific symptoms and signs as well as the limitations of ultrasound (US) make the diagnosis difficult, resulting in the loss of adnexa and fetal compromise. The magnetic resonance imaging (MRI) features of the torsion of normal adnexa are not classically described during pregnancy and only reported in a few cases. We find some different MRI features of the torsion of normal adnexa in late pregnancy and its diagnosis and treatment values are discussed in our report. Case presentation A 27-year-old woman at 31 + 5 weeks’ gestation presented to the emergency department with a three-day history of the left lower abdominal pain. US discovered a mass of 87 × 61 mm in the left abdomen, but did not show whether the mass originated from the left ovary or the uterus. MRI showed the left ovary was increased in size to 82 × 42 × 85 mm with peripheral follicles. On fat-suppressed T2-weighted images, the signal intensity of the lesion was significantly decreased compared with the right ovary. The adjacent fallopian tube was found to be thickened. The radiologists diagnosed ovary infarction secondary to adnexal torsion. With the provisional diagnosis of adnexal torsion, the patient was taken to surgery. The left adnexal torsion was found during surgery. There was extensive hemorrhage and necrosis, so a left salpingo-oophorectomy was performed. The histopathology confirmed an extensively hemorrhagic fallopian tube and ovary with partial necrosis. Conclusion We believe MRI is helpful where US is indeterminate in diagnosis of the torsion of normal adnexa in advanced pregnancy. We found that aside from hyperintensity on fat-saturated T1-weighted images, the low signal intensity on T2-weighted images can also reflect adnexal hemorrhage in conjunction with the torsion of normal adnexa.

Necroptosis is crucially involved in severe cardiac pathological conditions. However, whether necroptosis contributes to age‐related intolerance to ischemia/reperfusion (I/R) injury remains elusive. In addition, metformin as a potential anti‐aging related injury drug, how it interacts with myocardial necroptosis is not yet clear. Male C57BL/6 mice at 3–4‐ (young) and 22–24 months of age (aged) and RIPK3‐deficient (Ripk3−/−) mice were used to investigate aging‐related I/R injury in vivo. Metformin (125 μg/kg, i.p.), necrostatin‐1 (3.5 mg/kg), and adenovirus vector encoding p62‐shRNAs (Ad‐sh‐p62) were used to treat aging mice. I/R‐induced myocardial necroptosis was exaggerated in aged mice, which correlated with autophagy defects characterized by p62 accumulation in aged hearts or aged human myocardium. Functionally, blocking autophagic flux promoted H/R‐evoked cardiomyocyte necroptosis in vitro. We further revealed that p62 forms a complex with RIP1‐RIP3 (necrosome) and promotes the binding of RIP1 and RIP3. In mice, necrostatin‐1 treatment (a RIP1 inhibitor), RIP3 deficiency, and cardiac p62 knockdown in vivo demonstrated that p62‐RIP1‐RIP3‐dependent myocardial necroptosis contributes to aging‐related myocardial vulnerability to I/R injury. Notably, metformin treatment disrupted p62‐RIP1‐RIP3 complexes and effectively repressed I/R‐induced necroptosis in aged hearts, ultimately reducing mortality in this model. These findings highlight previously unknown mechanisms of aging‐related myocardial ischemic vulnerability: p62‐necrosome‐dependent necroptosis. Metformin acts as a cardioprotective agent that inhibits this unfavorable chain mechanism of aging‐related I/R susceptibility., Metformin treatment restores autophagy flux in aged hearts and decreases p62 interaction with necrosomes in I/R‐injured myocardium, ultimately reducing mortality in this model. We conclude that p62 accumulation provides a direct link between aging and the onset of necroptosis enhancement in a pathophysiological context.

Background To establish pharmacokinetic parameters and a radiomics model based on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for predicting sentinel lymph node (SLN) metastasis in patients with breast cancer. Methods A total of 164 breast cancer patients confirmed by pathology were prospectively enrolled from December 2017 to May 2018, and underwent DCE-MRI before surgery. Pharmacokinetic parameters and radiomics features were derived from DCE-MRI data. Least absolute shrinkage and selection operator (LASSO) regression method was used to select features, which were then utilized to construct three classification models, namely, the pharmacokinetic parameters model, the radiomics model, and the combined model. These models were built through the logistic regression method by using 10-fold cross validation strategy and were evaluated on the basis of the receiver operating characteristics (ROC) curve. An independent validation dataset was used to confirm the discriminatory power of the models. Results Seven radiomics features were selected by LASSO logistic regression. The radiomics model, the pharmacokinetic parameters model, and the combined model yielded area under the curve (AUC) values of 0.81 (95% confidence interval [CI]: 0.72 to 0.89), 0.77 (95% CI: 0.68 to 0.86), and 0.80 (95% CI: 0.72 to 0.89), respectively, for the training cohort and 0.74 (95% CI: 0.59 to 0.89), 0.74 (95% CI: 0.59 to 0.90), and 0.76 (95% CI: 0.61 to 0.91), respectively, for the validation cohort. The combined model showed the best performance for the preoperative evaluation of SLN metastasis in breast cancer. Conclusions The model incorporating radiomics features and pharmacokinetic parameters can be conveniently used for the individualized preoperative prediction of SLN metastasis in patients with breast cancer.

The aim of the present study was to establish T1 variation (T1v) thresholds for duplicated measurements of regional T1 values in left ventricle (LV) using magnetic resonance imaging (MRI). Eighteen healthy volunteers were recruited to undergo two consecutive cardiac MRI scans using modified Look-Locker Inversion recovery (MOLLI) with two spatial resolutions on different days to repeat T1 measurements on LV. The absolute differences (d) and standard deviations (SDs) of regional T1 values were acquired with the two scans and two readers. T1v threshold (mean difference + 2SD), intra-class correlation coefficient (ICC) and coefficient of variation (CoV) were calculated. T1 mapping using the MOLLI sequence (with multiple spatial resolutions) was successfully performed in all 18 volunteers twice. On a per-slice basis, ICCs for intra-observer, inter-observer, inter-resolution and inter-study T1v were 0.988, 0.899, 0.763 and 0.6. CoVs were 0.72, 2.39, 3.90 and 4.28%. T1v thresholds were 22, 66, 118 and 120 ms. On a per-segment basis, ICCs for intra-observer, inter-observer, inter-resolution and inter-study T1v were 0.974, 0.859, 0.711 and 0.594. CoVs were 1.09, 3.36, 4.69 and 5.01%. T1v thresholds were 33, 94, 140 and 144 ms. Those thresholds may be useful for discriminating disease-initiated T1v from random errors of T1 measurements.

Background Cigarette smoking has been established as a major risk factor for chronic kidney disease (CKD) development in people with diabetes. Conflicting evidence exists among representative community-based studies as to whether smoking is an independent risk factor for CKD. The aim of this meta-analysis was to assess the effects of tobacco smoking on the development of CKD in adult general populations. Methods A literature search was conducted using MEDLINE and Embase from their inception through 31 May 2016 for prospective cohort studies that reported relative risks of CKD with smoking status in the general population. Summary relative risks (SRRs) and 95% confidence intervals (CIs) were calculated using a random effects model. Results A total of 15 prospective cohort studies, including 65 064 incident CKD cases, were included. Compared with never-smokers, the SRRs of incident CKD were 1.27 (95% CI 1.19-1.35) for ever-smokers, 1.34 (95% CI 1.23-1.47) for current smokers and 1.15 (95% CI 1.08-1.23) for former smokers. The SRRs for end-stage renal disease development were 1.51 (95% CI 1.24-1.84) for ever-smokers, 1.44 (95% CI 1.00-2.09) for former smokers and 1.91 (95% CI 1.39-2.64) for current smokers. Considerable heterogeneity was observed among these studies. After combining an additional three prospective cohort studies, which involved 5747 incident proteinuria cases, a null smoking-proteinuria association in the general population was observed. Conclusions Our meta-analysis suggests evidence for cigarette smoking as an independent risk factor for incident CKD. Future studies are required to investigate whether smoking cessation can decrease incident CKD in the general adult population.

The present study was carried out to investigate the expression pattern, clinical significance and biological functions of microRNA-30d (miR-30d) in esophageal carcinogenesis. Quantitative real-time PCR was performed to detect the expression levels of miR-30d in esophageal squamous cell carcinoma (ESCC) tissues and cell lines. Then, associations between miR-30d expression and various clinicopathological features of patients with ESCC were statistically evaluated. In addition, the effects of miR-30d on the migration and invasion of two human ESCC cell lines transfected with miRNA or co-transfected with miRNA mimics and the expression vector of its target gene were determined. The results revealed that the expression levels of miR-30d were markedly decreased in ESCC tissues and cell lines, comparing with the corresponding normal controls. Notably, reduced expression of miR-30d occurred more frequently in ESCC patients with positive lymph node metastasis, moderate-poor differentiation and advanced tumor-node-metastasis stage than those with negative features. Functionally, enforced expression of miR-30d was found to inhibit cell invasion and migration of the ESCC cell lines. Luciferase reporter assay identified enhancer of zeste homolog 2 (EZH2) as a direct target gene of miR-30d. The expression level of EZH2 mRNA was negatively correlated with the expression of miR-30d in the ESCC tissues. Moreover, the inhibitory effect of miR-30d on ESCC cell motility was reversed by EZH2 overexpression. Collectively, these findings provide convincing evidence that decreased expression of miR-30d may be implicated in esophageal carcinogenesis and progression. We also confirmed miR-30d as a tumor-suppressor which may inhibit cancer cell motility by targeting EZH2, a potential therapeutic target for ESCC.

Myocardial ischemia-reperfusion (IR) injury during acute myocardial infarction or open-heart surgery would promote oxidative stress, leading to the accumulation of reactive aldehydes that cause cardiac damage. It has been well demonstrated that aldehyde dehydrogenase (ALDH)-2 is an important cardioprotective enzyme for its central role in the detoxification of reactive aldehydes. ALDH2 activation by small molecule activators is a promising approach for cardioprotection for myocardial IR injury.

INTRODUCTION The Bispectral Index (BIS) provides an objective measure of the level of sedation and general anesthesia. We performed this meta-analysis and trial sequential analysis (TSA) of randomized clinical trials to clarify whether BIS monitoring is helpful in enhancing intraprocedual safety, shortening procedure duration or promoting recovery during sedation for endoscopic procedures. EVIDENCE ACQUISITION PubMed, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials [CENTRAL]) databases, reference lists of articles as well as relevant articles from "Google Scholar" were searched until May 31st, 2018. Randomized controlled trials (RCTs) comparing BIS with clinical signs for titration of sedation depth during endoscopy were screened and identified if they reported one of the following outcome measures: intraprocedual safety (hemodynamic stability and cardiorespiratory complications such as hypoxia, hypertension/hypotension, and bradycardia/tachycardia), procedure duration, recovery time and patient/endoscopist's satisfaction. EVIDENCE SYNTHESIS Twelve studies with 13 RCTs recruiting 1372 patients were identified with great inter-trial heterogeneity. Meta-analysis found that BIS monitoring of sedation depth was associated with lower incidences of intraprocedural hypoxia (P=0.009) compared with clinical signs which was not confirmed by TSA. Meta-analysis and TSA found that the endoscopic procedure duration (P=0.143), recovery time (P=0.083), satisfaction scores from both the cases (P=0.085) and endoscopists (P=0.125) and the incidences of hypertension/ hypotension (P=0.639) or heart rates (P=0.201) were similar between BIS and control group. CONCLUSIONS More high-quality large-sampled RCTs are needed to confirm whether BIS monitoring for endoscopy sedation helps reduce intraprocedural hypoxia. BIS monitoring fails to shorten procedure duration, promote recovery or boost satisfaction among patients and endoscopists.

IMPORTANCE: Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention. OBJECTIVE: To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin. DESIGN, SETTING, AND PARTICIPANTS: This cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018. EXPOSURES: Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure. MAIN OUTCOMES AND MEASURES: All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score–matched cohort. RESULTS: Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score–matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score–matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality (adjusted HR, 0.72 [95% CI, 0.55–0.95]; ARR, 1.28% [95% CI, 0.26–2.31]) and hazard of readmission, with mortality as a competing risk at both 30 days (ARR, 2.09% [95% CI, 0.35–3.82]; sub-HR, 0.84 [95% CI, 0.72–0.98]) and 90 days (ARR, 2.78% [95% CI, 0.62–4.95]; sub-HR, 0.86 [95% CI, 0.77–0.97]). Preoperative inflammation was reduced in those with metformin prescriptions compared with those without (mean neutrophil to leukocyte ratio, 4.5 [95% CI, 4.3–4.6] vs 5.0 [95% CI, 4.8–5.3]; P < .001). E-value analysis suggested robustness to unmeasured confounding. CONCLUSIONS AND RELEVANCE: This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.

Statistics released by the World Health Organization in 2018 show that the total death of people is 56.9 million worldwide in 2016. The first one is cardiovascular diseases, including ischemic heart disease and stroke, which accounted for 17.65 million people (31%) [1] . Treadmill Exercise Test is suitable for measuring the changes in Electrocardiography (ECG) initial, middle, and after exercise [2] . They are using it to distinguish chest pain without apparent causes, judging the severity of coronary artery disease, and screening personnel with coronary artery disease risk factors. The most important contribution of this study is to use the Hilbert Huang Transform (HHT) [3] , a non-invasive method, to decompose the original ECG signals of inspectors through the Empirical Mode Decomposition (EMD) [4] , [5] , [6] , [7] , not the commonly used of 12-lead ECG detection method. There is a total of 49 participants in 24 pseudo-positive persons; 4 were re-judged into positive, reducing 83.3% pseudo-positive persons who need to do the follow-up testing, significantly reducing the consumption of medical and time.

The objective of the present study was to investigate the in vitro and in vivo anticancer and apoptotic effects of 3-β-erythrodiol, a plant-derived triterpene against MKN-45 human gastric cancer cells. In addition, effects on cellular morphology, cell cycle phase distribution, DNA fragmentation, and ROS generation were also elucidated in the current research work. Cytotoxic activity of 3-β-erythrodiol was demonstrated by MTT cell viability and LDH assay. Cellular morphological study was carried out using phase contrast, fluorescence and scanning electron microscopy. Cell cycle analysis was evaluated by flow cytometry and gel electrophoresis was used to evaluate DNA fragmentation pattern. The results of the present study revealed that 3-β-erythrodiol induced dose-dependent as well as time-dependent anticancer effects in MKN-45 gastric cancer cells. Cellular morphological changes in MKN-45 cells as indicated by fluorescence and scanning electron microscopy were induced by 3-β-erythrodiol. This triterpene induced both early and late apoptotic features in these cancer cells. 3-β-Erythrodiol treatment led to sub-G1 cell cycle arrest with a corresponding decrease in S-phase cells and an increase in G2/M phase cells. DNA fragments were evident in gel electrophoresis experiment following 3-β-erythrodiol treatment. It was observed that 0.50 and 1.0 µg/g 3-β-erythrodiol injection reduced the tumor weight from 1.4 g in PBS-treated group (control) to 0.61 and 0.22 g, respectively. Similarly, 0.50 and 1.0 µg/g 3-β-erythrodiol injection reduced the tumor volume from 1.5 cm3 in PBS-treated group (control) to 0.91 and 0.31 cm3, respectively. The present investigation indicates that 3-β-erythrodiol exerts anti-proliferative effects in human gastric cancer by inducing early and late apoptosis, cell cycle arrest, and ROS generation. It also decreased the tumor volume and tumor weight in male Balb/c nude mice.

A novel and highly selective electrochemical sensing platform (ZnCl2-CF/GCE) based on combination of kiwi skin and zinc chloride nanoparticles was developed for the simultaneous detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA). The constructed electrode shows a high surface area and micro-mesoporous structure. And the electrochemical behaviors of the electrode were further explored by cyclic voltammetry (CV), impedance analysis (EIS), and differential pulse voltammetry (DPV). Under the optimal conditions, the ZnCl2-CF provides a high sensitivity and selective signaling in the co-existence system of AA, DA, and UA with linear response ranges of 0.05–200 μM, 2–2000 μM, and 1–2500 μM, respectively. The detection limits (S/N = 3) were calculated to be 0.02 μM, 0.16 μM, and 0.11 μM, respectively. In addition, the method has been successfully applied to determine AA, DA, and UA in real samples, which provides potential applications in further sensing study.

Background Cardiovascular disease (CVD) is a risk factor for cognitive impairment in the elderly. Manifestations of subclinical CVDs can be found in patients with cognitive impairment. The aim of the present study was to test the hypothesis that patients with mild cognitive impairment (MCI) have different magnetic resonance imaging (MRI)-derived regional myocardial motion indices compared with healthy controls. Methods Eleven MCI patients (age, 65.5 years ±5.9; range, 55–81 years old) and 11 sex−/age-matched healthy volunteers were enrolled. All of the participants underwent a head MRI and cardiac MRI. Global cortical atrophy (GCA) was graded on the head MRI. The left ventricular ejection fraction (LVEF) and regional strain, strain rate, displacement and velocity were measured on cine images. The GCA scores, global cardiac function and regional myocardial motion indices were compared between MCI patients and healthy controls using the t-test. Results MCI patients had a higher GCA score than healthy controls (p = 0.048). However, there was no significant difference in LVEF between MCI patients and controls. Compared to healthy controls, MCI patients had a lower peak radial strain (29.1% ± 24.1% vs. 46.4% ± 43.4%, p

Cognitive dysfunction is an important complicated disease in obesity. Exercise ameliorates obesity and the related cognitive dysfunction. However, the underlying mechanism is still unclear. In this study, we investigated whether aerobic interval training (AIT) could attenuate high-fat-diet- (HFD-) associated cognitive dysfunction and the possible mechanism of SIRT3-MnSOD pathway. C57BL/6 wild-type (WT) mice and SIRT3 knockout (KO) mice were randomized into control (Con) or HFD group with or without AIT training for 6 weeks. The spatial learning and memory ability were impaired in HFD group compared to the control group. The levels of mitochondrial protein acetylation were increased in the hippocampus of HFD group. The acetylation level of antioxidative MnSOD was increased as well. As a result, the ROS and MDA levels were significantly increased, which leads to the neuron apoptosis in the hippocampus. SIRT3 deficiency further aggravated HFD-induced cognitive dysfunction and susceptibility to oxidative stress injury. However, AIT upregulated neuron SIRT3 expression and decreased the acetylation of MnSOD. The hippocampus neuron oxidative stress and apoptosis were both decreased compared to untrained HFD group, which finally improved cognitive function of HFD mice. Collectively, AIT attenuates HFD-associated cognitive dysfunction through SIRT3 upregulation and improvement of antioxidative MnSOD activity.