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Summary: Background: The tumour stroma microenvironment plays an important part in disease progression and its composition can influence treatment response and outcomes. Histological evaluation of tumour stroma is limited by access to tissue, spatial heterogeneity, and temporal evolution. We aimed to develop a radiological signature for non-invasive assessment of tumour stroma and treatment outcomes. Methods: In this multicentre, retrospective study, we analysed CT images and outcome data of 2209 patients with resected gastric cancer from five independent cohorts recruited from two centres (Nanfang Hospital of Southern Medical University [Guangzhou, China] and Sun Yat-sen University Cancer Center [Guangzhou, China]). Patients with histologically confirmed gastric cancer, at least 15 lymph nodes harvested, preoperative abdominal CT available, and complete clinicopathological and follow-up data were eligible for inclusion. Tumour tissue was collected for patients in the training cohort (321 patients), internal validation cohort one (246 patients), and external validation cohort one (128 patients). Four stroma classes were defined according to the protein expression of α-smooth muscle actin and periostin assessed by immunohistochemistry. The primary objective was to predict the histologically based stroma classes by using preoperative CT images. We trained a deep convolutional neural network model using the training cohort and tested the model in the internal and external validation cohort one. We evaluated the model's association with prognosis in the training cohort, two internal, and two external validation cohorts and compared outcomes of patients who received or did not receive adjuvant chemotherapy. Findings: The deep-learning model achieved a high diagnostic accuracy for assessing tumour stroma in both internal validation cohort one (area under the receiver operating characteristic curve [AUC] 0·96–0·98]) and external validation cohort one (AUC 0·89–0·94). The stromal imaging signature was significantly associated with disease-free survival and overall survival in all cohorts (p

Berberine (BBR), an isoquinoline alkaloid isolated from Rhizoma coptidis, is reported to possess antiviral activity. Our previous study has shown that BBR alleviates Coxsackievirus B3 (CVB3) replication in HeLa cells. However, the anti-CVB3 activity of BBR is still unclear in vivo. In this study, we explored the effect of BBR on CVB3-induced viral myocarditis in mice. These results demonstrated a beneficial effect of BBR on alleviating CVB3-induced myocarditis in vivo, which sheds new light on the utility of BBR as a therapeutic strategy against CVB3-induced viral myocarditis. This article is protected by copyright. All rights reserved.

Present study has aimed to understand the intervention and prevention of the mental health crisis of college students. For this purpose, this study has checked the effect of trust in wellbeing information on preventive behavior and mental wellbeing. The target population taken for this study is the students of colleges situated in Mainland in China. The data was collected from the 458 students of the college. Smart PLS has been employed on the data to get the results using partial least square structural equation modeling. For this purpose, the data were analyzed in two stages, i.e., measurement model stage and the structural model stage. Results of this study have revealed that trust in wellbeing information plays a significant and positive role in setting preventive behavior and the mental wellbeing of students. Further, it has also been revealed that preventive behavior also plays a significant and positive role in mental wellbeing. Additionally, preventive behavior has been found as an important mediating variable among the relationship of trust in wellbeing information and mental wellbeing. Moreover, family support is crucial by positively moderating the relationship between preventive behavior and mental wellbeing. Many practical implications have been found among which the foremost is that the education institutes must undertake those efforts that aim to ensure the fairness in the information spread regarding the mental wellbeing during seminars, workshops and administration should play a positive role responsible for strengthening the mental health of students by managing ideas, improving student education management, innovating management techniques and methods.

Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5′-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-to-mesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted β-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

Background Lymph node metastasis (LNM) is an important factor for both treatment and prognosis of early gastric cancer (EGC). Current methods are insufficient to evaluate LNM in EGC due to suboptimal accuracy. Herein, we aim to identify methylation signatures for LNM of EGC, facilitate precision diagnosis, and guide treatment modalities. Methods For marker discovery, genome-wide methylation sequencing was performed in a cohort (marker discovery) using 47 fresh frozen (FF) tissue samples. The identified signatures were subsequently characterized for model development using formalin-fixed paraffin-embedded (FFPE) samples by qPCR assay in a second cohort (model development cohort, n = 302, training set: n = 151, test set: n = 151). The performance of the established model was further validated using FFPE samples in a third cohorts (validation cohort, n = 130) and compared with image-based diagnostics, conventional clinicopathology-based model (conventional model), and current standard workups. Results Fifty LNM-specific methylation signatures were identified de novo and technically validated. A derived 3-marker methylation model for LNM diagnosis was established that achieved an AUC of 0.87 and 0.88, corresponding to the specificity of 80.9% and 85.7%, sensitivity of 80.6% and 78.1%, and accuracy of 80.8% and 83.8% in the test set of model development cohort and validation cohort, respectively. Notably, this methylation model outperformed computed tomography (CT)-based imaging with a superior AUC (0.88 vs. 0.57, p Conclusions A novel 3-marker methylation model was established and validated that shows diagnostic potential to identify LNM in EGC patients and thus reduce unnecessary gastrectomy in EGC.

Background The effect of comorbid hypertension and type 2 diabetes mellitus (T2DM) on coronary artery plaques examined by coronary computed tomography angiography (CCTA) is not fully understood. We aimed to comprehensively assess whether comorbid hypertension and T2DM influence coronary artery plaques using CCTA. Materials and methods A total of 1100 T2DM patients, namely, 277 normotensive [T2DM(HTN−)] and 823 hypertensive [T2DM(HTN +)] individuals, and 1048 normotensive patients without T2DM (control group) who had coronary plaques detected on CCTA were retrospectively enrolled. Plaque type, coronary stenosis, diseased vessels, the segment involvement score (SIS) and the segment stenosis score (SSS) based on CCTA data were evaluated and compared among the groups. Results Compared with patients in the control group, the patients in the T2DM(HTN−) and T2DM(HTN +) groups had more partially calcified plaques, noncalcified plaques, segments with obstructive stenosis, and diseased vessels, and a higher SIS and SSS (all P values 3 (OR = 2.233 and 3.769; both P values 5 (OR = 2.057 and 3.580; both P values 3 (OR = 1.647; P = 0.001) and an SSS > 5 (OR = 1.625; P = 0.001). Conclusion T2DM is related to the presence of partially calcified plaques, obstructive CAD, and more extensive coronary artery plaques. Comorbid hypertension and diabetes further increase the risk of partially calcified plaques, and more extensive coronary artery plaques.

A fibrotic stroma accumulates in advanced cancers, and invasive cancer cells migrate along collagen fibers that facilitate dissemination from the primary tumor. However, the ways in which tumor cells govern these processes remain unclear. Here, we report that the epithelial-mesenchymal transition-activating transcription factor ZEB1 increased type I collagen (Col1) secretion and enhanced tumor cell adherence to Col1. Mechanistically, ZEB1 increased the levels of α1β1 integrin (encoded by Itga1 and Itgb1) by inhibiting PP2A activity, which reduced nuclear accumulation of HDAC4 and, thereby, derepressed Itga1 gene transcription. In parallel, ZEB1 relieved the miRNA-148a-mediated silencing of Itga1. High levels of Itga1 enhanced tumor cell adherence to Col1 and were essential for Col1-induced tumor growth and metastasis. Furthermore, ZEB1 enhanced Col1 secretion by increasing the expression of a kinesin protein that facilitated transport and secretion of Col1-containing vesicles. Our findings elucidate a transcriptional mechanism by which lung adenocarcinoma cells coordinate a collagen deposition and adhesion process that facilitates tumor progression.

Background The association between body mass index (BMI) and the overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC) patients remains controversial and unclear, Method A total of 2010 patients from a high-volume center were enrolled in the study. The OS of PDAC patients was evaluated based on restricted cubic spline (RCS), propensity score (PS) and multivariable risk adjustment analyses. Result BMI was linearly related to the OS (total P = 0.004, nonlinear P = 0.124). BMI was analyzed as categorical data based on X-tile software-defined cutoffs and World Health Organization (WHO)-recommended cutoffs. Adjusted with confounding covariates, higher BMI manifested as a positive prognostic predictor. Furthermore, BMI was proven to be associated with the OS in the PS analysis. (UnderweightXtile vs. NormalXtileP = 0.003, OverweightXtile vs. NormalXtileP = 0.019; UnderweightWHO vs. NormalWHOP WHO vs. NormalWHOP = 0.024). It was also revealed that patients with higher BMI benefitted more from chemotherapy. (Adjusted hazard ratio (aHR): UnderweightXtile vs. NormalXtile vs. OverweightXtile: 0.565 vs. 0.474 vs. 0.409; UnderweightWHO vs. NormalWHO vs. OverweightWHO: 0.613 vs. 0.464 vs. 0.425). Conclusion Among PDAC patients, there was a positive association between BMI and the OS, especially in patients treated with chemotherapy.

PURPOSE: To assess baseline ocular biometric risk factors for progression from primary angle closure suspect (PACS) to primary angle closure (PAC) or acute angle closure (AAC). DESIGN: Prospective observational study. PARTICIPANTS: 643 mainland Chinese aged 50 to 70 years with untreated PACS. METHODS: Participants received baseline clinical examinations including gonioscopy, anterior segment OCT (AS-OCT) imaging (Visante OCT, Carl Zeiss Meditec, Dublin, CA), and A-scan ultrasound biometry as part of the Zhongshan Angle Closure Prevention (ZAP) Trial. PACS was defined as inability to visualize pigmented trabecular meshwork in two or more quadrants based on static gonioscopy. PAC was defined as development of elevated intraocular pressure (IOP) > 24 mmHg or peripheral anterior synechiae (PAS). Progression was defined as development of PAC or an acute angle closure (AAC) attack. Multivariable logistic regression models were developed to assess biometric risk factors for progression. MAIN OUTCOME MEASURES: Progression from PACS to PAC or AAC over 6 years. RESULTS: 643 untreated eyes (609 non-progressors, 34 progressors) of 643 ZAP participants were included in the primary analysis. In a multivariable model with continuous parameters, narrower horizontal angle opening distance 500 μm from the scleral spur (AOD500; OR=1.10 per 0.01 mm decrease, p=0.03), flatter horizontal iris curvature (IC; OR=1.96 per 0.1 mm decrease, p=0.01), and older age (OR=1.11 per year increase, p=0.01) at baseline were significantly associated with progression (AUC=0.73). Smaller cumulative gonioscopy score was not associated with progression (OR=1.03 per 1 modified Shaffer grade decrease; p=0.85) when replacing horizontal AOD500 in the multivariable model. In a separate multivariable model with categorical parameters, participants in the lowest quartile of horizontal AOD500 (OR=3.10, p=0.002) and IC (OR=2.48, p=0.014) measurements and aged 59 years and older (OR=2.68, p=0.01) at baseline had higher odds of progression (AUC=0.72). CONCLUSIONS: Ocular biometric measurements can help risk stratify patients with early angle closure for more severe disease. AS-OCT measurements of biometric parameters describing the angle and iris are predictive of progression from PACS to PAC or AAC, whereas gonioscopy grades are not.

Objective Deep neck infection (DNI) associated with descending necrotizing mediastinitis (DNM) is a highly lethal condition. This retrospective review was performed to share our experience performing multidisciplinary management of DNI associated with DNM during a 7-year period. Methods We reviewed 16 patients who had been surgically treated for DNM at Peking Union Medical College Hospital from April 2010 to July 2017. The clinical outcomes were analysed to determine the most appropriate therapeutic strategy. Results Five women and 11 men were included in this study. Their mean age was 54.9 ± 14.3 years. DNM-associated infections most commonly occurred secondary to odontogenic infections (n = 10). Thirteen patients required tracheotomy because of tracheal compression. All patients underwent unilateral or bilateral cervicotomy. Six patients with DNM localized in the upper mediastinal space underwent transcervical mediastinal drainage, while 10 patients with DNM extending to the lower mediastinum were treated by cervicotomy and video-assisted thoracoscopic surgery. Three patients died of multiple organ failure. Conclusion Multidisciplinary treatment can achieve favourable outcomes in >80% of patients with DNM. Early diagnosis, proper airway management, and adequate surgical drainage are crucial for reducing mortality in patients with DNM, and minimally invasive procedures also play an important role.

Aim: To identify the circRNAs expression pattern and roles in bisphenol A (BPA) induced germ cell apoptosis. Materials & methods: We performed circRNA/miRNA/mRNA-Seq in 120 μM BPA treated and nontreated GC-2 cells. Bioinformatic analysis, qPCR, apoptosis assays, luciferase report were done in the function analysis. Results: A large number of apoptosis related circRNAs/miRNAs/mRNAs were differentially expressed with competing endogenous RNA network constructed. Interestingly, most investigated upregulated circRNAs, including circDcbld2, circMapk1, circMpp6 and circTbc1d20 showed protective effects in antagonizing BPA toxicity, with the effects individually and synergistically observed. CircMapk1 may take its role by sponging miR-214-3p. Conclusion: circRNAs can play protective roles via sponging miRNAs in toxicity. Some circRNAs may serve as novel targets for BPA toxicity intervention or as biomarkers.

Background Platelets play a crucial role in cancer progression and metastasis. The aim of the present study was to assess the relationship between platelet indices and non-small cell lung cancer (NSCLC) with brain metastases. Methods Between January 2015 and December 2017, 232 NSCLC patients with brain metastases and 244 NSCLC patients without metastases were retrospectively analyzed. Patients' clinicopathological characteristics data were collected. Results Platelet count was increased and mean platelet volume (MPV) was reduced in NSCLC patients with brain metastases compared with NSCLC patients without metastases. In addition, the prevalence of NSCLC decreased as MPV quartiles increased. After adjusting for other risk factors, the ORs (95% CIs) for NSCLC brain metastases according to MPV quartiles were 1.757 (1.024-3.015), 2.097 (1.209-3.635), 1.517 (0.874-2.635), and 1.000, respectively. Conclusions MPV is reduced in NSCLC patients with brain metastases compared with NSCLC patients without metastases. Moreover, MPV is found to be independently associated with the presence of NSCLC brain metastases.

Insulin resistance and autonomic imbalance are important pathological processes in metabolic syndrome-induced cardiac remodeling. Recent studies determined that disruption of mitochondrial cristae shape is associated with myocardial ischemia; however, the change in cristae shape in metabolic syndrome-induced cardiac remodeling remains unclear. This study determined the effect of pyridostigmine (PYR), which reversibly inhibits cholinesterase to improve autonomic imbalance, on high-fat diet (HFD)-induced cardiac insulin resistance and explored the potential effect on the shape of mitochondrial cristae. Feeding of a HFD for 22 weeks led to an irregular and even lysed cristae structure in cardiac mitochondria, which contributed to decreased mitochondrial content and ATP production and increased oxygen species production, ultimately impairing insulin signaling and lipid metabolism. Interestingly, PYR enhanced vagal activity by increasing acetylcholine production and exerted mito-protective effects by activating the LKB1/AMPK/ACC signal pathway. Specifically, PYR upregulated OPA1 and Mfn1/2 expression, promoted the formation of the mitofilin/CHCHD3/Sam50 complex, and decreased p-Drp1 and Fis1 expression, resulting in tight and parallel cristae and increasing cardiac mitochondrial complex subunit expression and ATP generation as well as decreasing release of cytochrome C from mitochondria and oxidative damage. Furthermore, PYR improved glucose and insulin tolerance and insulin-stimulated Akt phosphorylation, decreased lipid toxicity, and ultimately ameliorated HFD-induced cardiac remodeling and dysfunction. In conclusion, PYR prevented cardiac and insulin insensitivity and remodeling by stimulating vagal activity to regulate mitochondrial cristae shape and function in HFD-induced metabolic syndrome in mice. These results provide novel insights for the development of a therapeutic strategy for obesity-induced cardiac dysfunction that targets mitochondrial cristae.

BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor type in the gastrointestinal system. Presently, various classification systems to prognosticate GISTs have been proposed. AIM To evaluate the application value of four different risk stratification systems for GISTs. METHODS Patients who were diagnosed with GISTs and underwent surgical resection at four hospitals from 1998 to 2015 were identified from a database. Risk of recurrence was stratified by the modified National Institute of Health (NIH) criteria, the Armed Forces Institute of Pathology (AFIP) criteria, the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic nomogram, and the contour maps. Receiver operating characteristic (ROC) curves were established to compare the four abovementioned risk stratification systems based on the area under the curve (AUC). RESULTS A total of 1303 patients were included in the study. The mean age of the patients was 55.77 ± 13.70 yr; 52.3% of the patients were male. The mean follow-up period was 64.91 ± 35.79 mo. Approximately 67.0% the tumors were located in the stomach, and 59.5% were smaller than 5 cm; 67.3% of the patients had a mitotic count ≤ 5/50 high-power fields (HPFs). Thirty-four tumors ruptured before and during surgery. Univariate analysis demonstrated that tumor size > 5 cm (P < 0.05), mitotic count > 5/50 HPFs (P < 0.05), non-gastric location (P < 0.05), and tumor rupture (P < 0.05) were significantly associated with increased recurrence rates. According to the ROC curve, the AFIP criteria showed the largest AUC (0.754). CONCLUSION According to our data, the AFIP criteria were associated with a larger AUC than the NIH modified criteria, the MSKCC nomogram, and the contour maps, which might indicate that the AFIP criteria have better accuracy to support therapeutic decision-making for patients with GISTs.

This study aimed to develop and validate a prognostic nomogram for recurrence-free survival (RFS) after surgery in the absence of adjuvant therapy to guide the selection for adjuvant imatinib therapy based on Residual Neural Network (ResNet).The ResNet model was developed based on contrast-enhanced computed tomography (CE-CT) in a training cohort consisted of 80 patients pathologically diagnosed gastrointestinal sromal tumors (GISTs) and validated in internal and external validation cohort respectively. Independent clinicopathologic factors were integrated with the ResNet model to construct the individualized nomogram. The performance of the nomogram was evaluated in regard to discrimination, calibration, and clinical usefulness.The ResNet model was significantly associated with RFS. Integrable predictors in the individualized ResNet nomogram included the tumor site, size, and mitotic count. Compared with modified NIH, AFIP, and clinicopathologic nomogram, both ResNet nomogram and ResNet model showed a better discrimination capability with AUCs of 0·947(95%CI, 0·910–0·984) for 3-year-RFS, 0·918(0·852–0·984) for 5-year-RFS, and AUCs of 0·912 (0·851–0·973) for 3-year-RFS, 0·887(0·816–0·960) for 5-year-RFS, respectively. Calibration curve shows the good calibration of the nomogram in terms of the agreement between the estimated and the observed 3- and 5- year outcomes. Decision curve analysis showed that the ResNet nomogram had a higher overall net benefit.In conclusion, we presented a deep learning-based prognostic nomogram to predict RFS after resection of localized primary GISTs with excellent performance and could be a potential tool to select patients for adjuvant imatinib therapy. Keywords: Gastrointestinal Stromal Tumors, Deep Learning, Residual Neural Network, Recurrence-free Survival, Imatinib

Previous studies have indicated that outdoor light at night (LAN) is associated with a higher prevalence of overweight or obesity in adults. However, the association of LAN levels with overweight or obesity in children is still unknown. This study utilized data from the Seven Northeastern Cities study, which included 47,990 school-aged children and adolescents (ages 6-18 years). Outdoor LAN levels were measured using satellite imaging data. Weight and height were used to calculate age-sex-specific body mass index (BMI) Z-scores based on the World Health Organization (WHO) growth standards. Overweight status and obesity were defined using the Chinese standard. Information regarding socioeconomic status, sleep-related characteristics, and obesogenic factors were obtained using a questionnaire. A generalized linear mixed model examined the associations of outdoor LAN levels (in quartiles) with the outcomes of interest. Compared to children in the lowest quartile of outdoor LAN levels, children exposed to higher outdoor LAN levels had larger BMI Z-scores and higher odds of being overweight (including obesity) or obese, with the largest estimates in the third quartile [BMI Z-score: β = 0.26, 95% CI: 0.18-0.33; overweight (including obesity): OR = 1.40, 95% CI: 1.25-1.56; obesity: OR = 1.46, 95% CI: 1.29-1.65]. There was a significant sex difference (P

Background and Objectives: The adjuvant treatment of stem cell therapy for acute myocardial infarction (AMI) has been studied in multiple clinical trials, but many questions remain to be addressed, such as efficacy, safety, identification of the optimal cell type, tractable route of delivery, transplant dosage, and transplant timing. The current meta-analysis aimed to explore the issues of mesenchymal stem cells (MSCs) transplantation in patients with AMI based on published randomized controlled trials (RCTs) and guide the design of subsequent clinical trials of MSCs therapy for AMI. Methods: The Cochrane Library, PubMed, EMBASE databases were searched for relevant clinical trials from January 1, 2000, to January 23, 2021. Results from RCTs involving MSCs transplantation for the treatment of AMI were identified. According to the Cochrane systematic review method, the literature quality, including studies, was evaluated and valid data was extracted. Rev- Man 5.3 and Stata 15.1 software were used for Meta-analysis. Results: After literature search and detailed evaluation, 9 randomized controlled trials enrolling 460 patients were included in the quantitative analysis. Pooled analyses indicated that MSCs therapy was associated with a significantly greater improvement in overall left ventricular ejection fraction (LVEF), and the effect was maintained for up to 24 months. No significant difference in favor of MSCs treatment in left ventricular (LV) volume and in the risk of rehospitalization as a result of heart failure (HF) was noted, compared with the controls. For transplantation dose, the LVEF of patients accepting a MSCs dose of 107-108 cells was significantly increased by 2.62% (95% CI 1.54 to 3.70; P < 0.00001; I2 =0%), but this increase was insignificant in the subgroup that accepted a MSCs dose of < 107 cells (1.65% in LVEF, 95% CI, 0.03 to 3.27; P =0.05; I2 =75%) or >108 cells (4.65% in LVEF, 95% CI, -4.55 to 13.48; P =0.32; I2 =95%), compared with the controls. For transplantation timing, a significant improvement of LVEF of 3.18% was achieved in the group of patients accepting a MSCs infusion within 2 to 14 days after percutaneous coronary intervention (PCI) (95% CI, 2.89 to 3.47; P Conclusion: Results from our systematic review suggest that MSCs therapy for patients with AMI appears to be safe and might induce a significant increase in LVEF with a limited impact on LV volume and rehospitalization caused by HF. The effect was maintained for up to 24 months. MSCs dose of 107-108 cells was more likely to achieve better clinical endpoints than 108 cells. The optimal time window for cell transplantation might be within 2-14 days after PCI. This meta-analysis was registered with PROSPERO, number CRD 42021241104.

IMPORTANCE: Subretinal injection for gene augmentation in retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium, potentially damaging photoreceptors and/or retinal pigment epithelium cells. OBJECTIVE: To use adaptive optics scanning light ophthalmoscopy (AOSLO) to assess the short-term integrity of the cone mosaic following subretinal injections of adeno-associated virus vector designed to deliver a functional version of the CHM gene (AAV2-hCHM) in patients with choroideremia. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal case series study enrolled adult patients with choroideremia from February 2015 to January 2016 in the US. To be included in the study, study participants must have received uniocular subfoveal injections of low-dose (5 × 10(10) vector genome per eye) or high-dose (1 × 10(11) vector genome per eye) AAV2-hCHM. Analysis began February 2015. MAIN OUTCOMES AND MEASURES: The macular regions of both eyes were imaged before and 1 month after injection using a custom-built multimodal AOSLO. Postinjection cone inner segment mosaics were compared with preinjection mosaics at multiple regions of interest. Colocalized spectral-domain optical coherence tomography and dark-adapted cone sensitivity was also acquired at each time point. RESULTS: Nine study participants ranged in age from 26 to 50 years at the time of enrollment, and all were White men. Postinjection AOSLO images showed preservation of the cone mosaic in all 9 AAV2-hCHM–injected eyes. Mosaics appeared intact and contiguous 1 month postinjection, with the exception of foveal disruption in 1 patient. Optical coherence tomography showed foveal cone outer segment shortening postinjection. Cone-mediated sensitivities were unchanged in 8 of 9 injected and 9 of 9 uninjected eyes. One participant showed acute loss of foveal optical coherence tomography cone outer segment–related signals along with cone sensitivity loss that colocalized with disruption of the mosaic on AOSLO. CONCLUSIONS AND RELEVANCE: Integrity of the cone mosaic is maintained following subretinal delivery of AAV2-hCHM, providing strong evidence in support of the safety of the injections. Minor foveal thinning observed following surgery corresponds with short-term cone outer segment shortening rather than cone cell loss. Foveal cone loss in 1 participant raises the possibility of individual vulnerability to the subretinal injection.

The prognostic role of marital status on colorectal signet ring cell carcinoma (SRCC) has not been studied. In this study, the correlation of marital status with prognosis of colorectal SRCC was analyzed. Eligible subjects were extracted from the Surveillance, Epidemiology, and End Results (SEER) dataset from 2004 to 2015, followed by comparison of cancer-specific survival (CSS) and overall survival (OS) between married and unmarried group. 3152 patients were identified including 1777 married patients (56.38%). Married populations tended to be more patients aged P < 0.05).Moreover, 5-year CSS (30.04% vs. 28.19%, P = 0.0013) and OS rates (26.68% vs. 22.94%, P P = 0.016) and OS (HR: 0.898; 95%CI: 0.827–0.975; P = 0.011).In addition, CSS as well as OS were superior in married populations than unmarried ones in most subgroups. Marital status was an independent prognostic factor for survival in patients with colorectal SRCC. Additionally, married patients obtained better survival advantages.

INTRODUCTION: Treatments for young patients with gastric cancer (GC) remain poorly defined, and their effects on survival are uncertain. We aimed to investigate the receipt of chemotherapy by age category (18–49, 50–64, and 65–85 years) and explore whether age differences in chemotherapy matched survival gains in patients with GC. METHODS: Patients who were histologically diagnosed with GC were included from a Chinese multi-institutional database and the Surveillance, Epidemiology, and End Results database. There were 5,122 and 31,363 patients aged 18–85 years treated between 2000 and 2014, respectively. Overall survival and stage-specific likelihood of receiving chemotherapy were evaluated. RESULTS: Of the 5,122 and 31,363 patients in China and Surveillance, Epidemiology, and End Result data sets, 3,489 (68.1%) and 18,115 (57.8%) were men, respectively. Younger (18–49 years) and middle-aged (50–64 years) patients were more likely to receive chemotherapy compared with older patients (65–85 years) (64.9%, 56.7%, and 45.4% in the 3 groups from the China data set). Among patients treated with surgery alone, a significantly better prognosis was found in younger and middle-aged patients than their older counterparts; however, no significant differences were found in overall survival among age subgroups in patients who received both surgery and chemotherapy, especially in the China data set. The survival benefit from chemotherapy was superior among older patients (all P < 0.0001) compared with that among younger and middle-aged patients in stage II and III disease. DISCUSSION: Potential overuse of chemotherapy was found in younger and middle-aged patients with GC, but the addition of chemotherapy did not bring about matched survival improvement, especially in the China data set.

The antimetabolite 5-fluorouracil (5-FU) is a widely used chemotherapy regimen for the treatment of gastric cancer (GC). However, resistance to 5-FU remains a major drawback in the clinical use. The treatments of anti-tumor chemo-agents recruit tumor associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that YAP1 is overexpressed in resistant GC tissues compared to sensitive GC tissues. Further, IL-3 secreted by YAP1-overexpressed GC could skew macrophage polarization to M2-like phenotype and inducing GLUT3-depended glycolysis program. Meanwhile, polarized M2 macrophages enhance 5-FU resistance in tumor cells by secreting CCL8 and activating phosphorylation of JAK1/STAT3 signaling pathway.

Objective: Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a critical role in atherosclerosis, vascular restenosis, and hypertension. Choline exerts cardioprotective effects; however, little is known about its effects on VSMC phenotypic switching and vascular remodeling. Here, we investigated whether choline modulates VSMC phenotypic changes and explored the underlying mechanisms. Approach and Results: In cultured VSMCs, choline promoted Nrf2 (nuclear factor erythroid 2–related factor 2) nuclear translocation, inducing the expression of HO-1 (heme oxygenase-1) and NQO-1 (NAD[P]H quinone oxidoreductase-1). Consequently, choline ameliorated Ang II (angiotensin II)–induced increases in NOX (NAD[P]H oxidase) expression and the mitochondrial reactive oxygen species level, thereby attenuating Ang II–induced VSMC phenotypic switching, proliferation, and migration, presumably via M3AChRs (type 3 muscarinic acetylcholine receptors). Downregulation of M3AChR or Nrf2 diminished choline-mediated upregulation of Nrf2, HO-1, and NQO-1 expression, as well as inhibition of VSMC phenotypic transformation, suggesting that M3AChR and Nrf2 activation are responsible for the protective effects of choline. Moreover, activation of the Nrf2 pathway by sulforaphane suppressed Ang II–induced VSMC phenotypic switching and proliferation, indicating that Nrf2 is a key regulator of VSMC phenotypic switching and vascular homeostasis. In a rat model of abdominal aortic constriction in vivo, choline attenuated VSMC phenotypic transformation and vascular remodeling in a manner related to activation of the Nrf2 pathway. Conclusions: These results reveal that choline impedes VSMC phenotypic switching, proliferation, migration, and vascular remodeling by activating M3AChR and Nrf2-antioxidant signaling and suggest a novel role for Nrf2 in VSMC phenotypic modulation.

Summary Currently, COVID‐19 has been reported in nearly all countries globally. To date, little is known about the viral shedding duration, clinical course, and treatment efficacy of COVID‐19 near Hubei Province, China. This multicentre, retrospective study was performed in 12 hospitals in Henan and Shaanxi Provinces from January 20 to February 8, 2020. Clinical outcomes were followed up until March 26, 2020. The viral shedding duration, full clinical course, and treatment efficacy were analysed in different subgroups of patients. A total of 149 COVID‐19 patients were enrolled. The median age was 42 years, and 61.1% (91) were males. Of them, 133 (89.3%) had fever, 131 of 144 (91%) had pneumonia, 27 (18.1%) required intensive care unit (ICU) management, 3 (2%) were pregnant, and 3 (2%) died. Two premature newborns were negative for SARS‐CoV‐2. In total, the median SARS‐CoV‐2 shedding period and clinical course were 12 (IQR: 9‐17; mean: 13.4, 95% CI: 12.5, 14.2) and 20 (IQR: 16‐24; mean: 21.2, 95% CI: 20.1, 22.3) days, respectively; and ICU patients had longer median viral shedding periods (21 [17‐24] vs 11 [9‐15]) and clinical courses (30 [22‐33] vs 19 [15.8‐22]) than non‐ICU patients (both p0.05) in real‐life settings. In conclusion, the viral shedding duration and clinical course in Henan and Shaanxi Provinces were shorter than those in Hubei Province, and current antiviral therapies were ineffective for shortening viral shedding duration and clinical course in real‐world settings. These findings expand our knowledge of the SARS‐CoV‐2 infection and may be helpful for management of the epidemic outbreak of COVID‐19 worldwide. Further studies concerning effective antiviral agents and vaccines are urgently needed.

This study aimed to investigate the effect of splenectomy on dexmedetomidine-activated cholinergic anti-inflammatory pathway-mediated alleviation of LPS-induced AKI. A mouse model of septic kidney injury was established in C57BL/6 mice. A total of 30 C57BL/6 mice were randomly divided into the control group, LPS group, dexmedetomidine + LPS group, splenectomy group, splenectomy + LPS group, and splenectomy + dexmedetomidine + LPS group. The pathological effects in kidney tissues in each group were analyzed by HE staining. Apoptosis in each group was examined by the TUNEL method. Cr and Cys-C levels in each group were measured by ELISA. The expression levels of IL-6, NF-κB p65, Caspase-3, the antiapoptotic protein Bcl-2, the proapoptotic protein Bax, and α7nAChR in each group were measured by qRT-PCR and Western blotting. Dexmedetomidine alone reduced apoptosis in kidney tissue; however, apoptosis was increased after splenectomy in mice treated with dexmedetomidine. Splenectomy reduced the production of proinflammatory cytokines in circulation and had a protective effect on the kidney. Splenectomy inhibited dexmedetomidine-mediated activation of the α7nAChR pathway. Dexmedetomidine effectively alleviated LPS-induced kidney injury, and splenectomy inhibited the anti-inflammatory, antiapoptotic, and renoprotective effects of dexmedetomidine. The kidney-spleen axis is mediated by the α7nAChR-NF-κB signaling pathway and is involved in the development of AKI.

Importance It is not clear whether laparoscopic and open distal gastrectomy produce similar outcomes among patients with locally advanced gastric cancer. Data from a multicenter, randomized clinical trial (Chinese Laparoscopic Gastrointestinal Surgical Study [CLASS]-01) showed that laparoscopic distal gastrectomy did not result in inferior disease-free survival at 3 years compared with open distal gastrectomy. Objective To report 5-year overall survival data from the CLASS-01 trial of laparoscopic vs open distal gastrectomy among patients with locally advanced gastric cancer. Design, setting, and patients This was a noninferiority, open-label, randomized clinical trial conducted at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3, or T4a gastric cancer without bulky nodes or distant metastases were enrolled from September 12, 2012, to December 3, 2014. Final follow-up was on December 31, 2019. Interventions Participants were randomized in a 1:1 ratio after stratification by site, age, cancer stage, and histologic features to undergo either laparoscopic distal gastrectomy (n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy. Main outcomes and measures The 5-year overall survival rates were updated to compare laparoscopic distal gastrectomy with open distal gastrectomy. All analyses were performed on an intention-to-treat basis. In addition, per-protocol and as-treated analyses were performed for overall survival. Results Data from 1039 patients (726 men [69.9%]; mean [SD] age, 56.2 [10.7] years) who received curative therapy were analyzed. At 5 years, the overall survival rates were 72.6% in the laparoscopic distal gastrectomy group and 76.3% in the open distal gastrectomy group (log-rank P = .19; hazard ratio, 1.17; 95% CI, 0.93-1.48; P = .19). After comparison for competing risk events, gastric cancer-related deaths (hazard ratio, 1.14; 95% CI, 0.87-1.49; P = .34) and deaths from other causes (hazard ratio, 1.23; 95% CI, 0.74-2.05; P = .42) did not differ significantly between groups. Overall rates of survival did not differ significantly between groups with each tumor stage. Conclusions and relevance This study found that laparoscopic distal gastrectomy with D2 lymphadenectomy performed by experienced surgeons in high-volume specialized institutions resulted in similar 5-year overall survival compared with open distal gastrectomy among patients with locally advanced gastric cancer. Trial registration ClinicalTrials.gov Identifier: NCT01609309.

The long-term outcomes of laparoscopic gastrectomy (LG) versus open gastrectomy (OG) for gastric cancer (GC) remain obscure, especially for advanced cancer and disease affecting the upper stomach and in older patients. This study aimed to comprehensively assess the long-term efficacy of LG for GC using a large prospective database. Totally, 1877 consecutive patients (1186 receiving LG and 691 OG) operated in 2004–2016 were analyzed, with a median follow-up of 63 months. Association of LG versus OG with disease-specific survival (DSS) and disease-free survival (DFS) overall and in various subgroups were investigated using multivariable Cox regression. Propensity score matching (PSM) was performed for sensitivity analysis. Before PSM, overall, there was no significant association of LG versus OG with survival after multivariable adjustment; however, in subgroup analyses, LG was associated with superior DSS in patients aged ≥ 70 years and those with upper GC. No significant associations regarding DFS were observed overall or in stratifications. PSM analyses revealed that LG was associated with better DSS also in patients aged ≥ 70 years (hazard ratio (HR) = 0.33, 95% confidence interval (CI) = 0.15–0.72) and in those with upper GC (HR = 0.51, 95% CI = 0.29–0.91), and with better DFS in those with upper GC (HR = 0.60, 95% CI = 0.37–0.99). Multivariable analysis showed that age, hepatitis B, performance status, tumor histology, stage, and vascular invasion were significantly associated with post-LG survival. LG-specific nomograms were then constructed with concordance indexes of 0.814 (DSS) and 0.809 (DFS) and excellent calibration. In this large institutional analysis, while LG for GC was associated with DSS and DFS similar to those for OG overall, non-inferior LG-associated survival especially DSS was observed in some subgroups rarely investigated in prospective or randomized settings. There could still be biases even after PSM due to confounders not accounted for in this observational study. However, these findings offer novel hypotheses for further validation.

Rationale: This study is to validate the clinicopathologic significance and potential prognostic value of SLP2 in gastric cancer (GC), to investigate the biological function and regulation mechanism of SLP2, and to explore potential therapeutic strategies for GC. Methods: The expression of SLP2 in GC tissues from two cohorts was examined by IHC. The biological function and regulation mechanism of SLP2 and PHB was validated via loss-of-function or gain-of-function experiments. In vitro proliferation detection was used to evaluate the therapeutic effects of Sorafenib. Results: We validated that SLP2 was significantly elevated in GC tissues and its elevation was associated with poor prognosis of patients. Loss of SLP2 drastically suppressed the proliferation of GC cells and inhibited the tumor growth, while SLP2 overexpression promoted the progression of GC. Mechanistically, SLP2 competed against E3 ubiquitin ligase SKP2 to bind with PHB and stabilized its expression. Loss of SLP2 significantly suppressed phosphorylation of Raf1, MEK1/2, ERK1/2 and ELK1. Furthermore, phosphorylated ELK1 could in turn activate transcription of SLP2. Finally, we demonstrated that a Raf1 inhibitor, Sorafenib, was sufficient to inhibit the proliferation of GC cells. Conclusion: Our findings demonstrated a positive feedback loop of SLP2 which leads to acceleration of tumor progression and poor survival of GC patients. This finding also provided evidence for the reason of SLP2 elevation. Moreover, we found that sorafenib might be a potential therapeutic drug for GC and disrupting the interaction between SLP2 and PHB might also serve as a potential therapeutic target in GC.

To develop and validate a radiomics signature for the prediction of gastric cancer (GC) survival and chemotherapeutic benefits. In this multicenter retrospective analysis, we analyzed the radiomics features of portal venous-phase computed tomography in 1591 consecutive patients. A radiomics signature was generated by using the Lasso-Cox regression model in 228 patients and validated in internal and external validation cohorts. Radiomics nomograms integrating the radiomics signature were constructed, demonstrating the incremental value of the radiomics signature to the traditional staging system for individualized survival estimation. The performance of the nomograms was assessed with respect to calibration, discrimination, and clinical usefulness. The radiomics signature consisted of 19 selected features and was significantly associated with DFS (disease-free survival) and OS (overall survival). Multivariate analysis demonstrated that the radiomics signature was an independent prognostic factor. Incorporating the radiomics signature into the radiomics-based nomograms resulted in better performance for the estimation of DFS and OS than the clinicopathological nomograms and TNM staging system, with improved accuracy of the classification of survival outcomes. Further analysis showed that stage II and III patients with higher radiomics scores exhibited a favorable response to chemotherapy. In conclusion, the newly developed radiomics signature is a powerful predictor of DFS and OS, and it may predict which patients with stage II and III GC benefit from chemotherapy.

Typical halogenated persistent organic pollutants (Hal-POPs), including polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs), polychlorinated biphenyls (PCBs), and dichlorodiphenyltrichloroethane (DDT), are a group of ubiquitous organic pollutants with an endocrine disrupting effect. This study evaluated the accumulation and congener profiles of Hal-POPs in the bodies of men who live/work in areas of South China where electronic wastes are collected and managed, especially in their semen samples. The results show that the detection frequency and serum concentrations of Hal-POP congeners within the high-exposure group (HEG) were higher than those of the low-exposure group (LEG). Furthermore, an identical trend was observed for the seminal plasma concentrations of Hal-POPs. The distribution characteristics, such as their mean, median, and discrete values, of PBDE congeners in serum and semen samples from the same subjects were consistent with each other. However, the distribution characteristics of PCB congeners in serum samples were different from those in semen samples. BDE153 was one of the most abundant congeners found in the serum and semen samples; hence, it can be identified as an indicator PBDE congener. Further research is needed to explore the mechanism of Hal-POPs distribution in human semen and serum samples. Keywords: Halogenated persistent organic pollutants (Hal-POPs), Polybrominated diphenyl ethers (PBDEs), Polychlorinated biphenyls (PCBs), Semen, Congener profiles

Androgen receptor (AR) is a crucial driver of prostate cancer (PC). AR-relevant resistance remains a major challenge in castration-resistant prostate cancer (CRPC). Bromodomain and extra-terminal domain (BET) family are critical AR coregulators. Here, we developed several diphenylamine derivatives and identified compound 7d that disrupted the functions of AR and BET family in prostate cancer and exhibited favorable metabolic stability in vitro and high drug exposure in vivo. We showed 7d not only bound to AR, suppressed transactivation of wild-type AR (wt-AR) and the mutant that mediates Enzalutamide resistance, but also reduced c-Myc protein expression through BET inhibition. In addition, 7d inhibited the proliferation of AR-positive PC cells with favorable selectivity and suppressed AR-V7-expressing VCaP and 22Rv1 xenografts growth in vivo. Collectively, these results indicate the potential of lead compound 7d as an orally available AR and BET inhibitor to treat CRPC and overcome antiandrogen resistance.

To develop and evaluate a radiomics nomogram for differentiating the malignant risk of gastrointestinal stromal tumours (GISTs). A total of 222 patients (primary cohort: n = 130, our centre; external validation cohort: n = 92, two other centres) with pathologically diagnosed GISTs were enrolled. A Relief algorithm was used to select the feature subset with the best distinguishing characteristics and to establish a radiomics model with a support vector machine (SVM) classifier for malignant risk differentiation. Determinant clinical characteristics and subjective CT features were assessed to separately construct a corresponding model. The models showing statistical significance in a multivariable logistic regression analysis were used to develop a nomogram. The diagnostic performance of these models was evaluated using ROC curves. Further calibration of the nomogram was evaluated by calibration curves. The generated radiomics model had an AUC value of 0.867 (95% CI 0.803–0.932) in the primary cohort and 0.847 (95% CI 0.765–0.930) in the external cohort. In the entire cohort, the AUCs for the radiomics model, subjective CT findings model, clinical index model and radiomics nomogram were 0.858 (95% CI 0.807–0.908), 0.774 (95% CI 0.713–0.835), 0.759 (95% CI 0.697–0.821) and 0.867 (95% CI 0.818–0.915), respectively. The nomogram showed good calibration. This radiomics nomogram predicted the malignant potential of GISTs with excellent accuracy and may be used as an effective tool to guide preoperative clinical decision-making. • CT-based radiomics model can differentiate low- and high-malignant-potential GISTs with satisfactory accuracy compared with subjective CT findings and clinical indexes. • Radiomics nomogram integrated with the radiomics signature, subjective CT findings and clinical indexes can achieve individualised risk prediction with improved diagnostic performance. • This study might provide significant and valuable background information for further studies such as response evaluation of neoadjuvant imatinib and recurrence risk prediction.

Introduction: Locked-in syndrome (LIS) results from a brainstem lesion in the pons. Ischemic stroke is the most common etiology of LIS. People with LIS have poor mobility with serious complications due to immobilization. Benefits of exercise after stroke have been widely reported. However, little is known about what and how much exercise should be prescribed for these patients. Objectives: To explore and evaluate the effect of exercise on the physical recovery of people with LIS after stroke. Methods: We searched the following databases (last searched August 2017): EMBASE, MEDLINE, PubMed, CINAHL, AMED, PEDro, Cochrane Central Register of Controlled Trials, REHABDATA, Google Scholar, WANFANG, CNKI, and CQVIP. Handsearching of relevant journals and reference lists was also performed. The Oxford Centre for Evidence-Based Medicine was used to assess the evidence level of the included studies. Results: We identified 5 papers from 207 papers involving 35 cases; 26 cases had various degrees of improvement in physical performance after exercise; 9 cases had no change. Five types of exercises and prescriptions were adopted. Study designs and interventions were heterogeneous. All studies contained mixed rehabilitation interventions. A total of 8 different outcome measurement tools have been reported in the studies. Conclusion: Studies indicate a positive trend of effect of exercise for physical recovery of people with LIS after stroke including the improvement of muscle strength, tone, walking ability, and activity in daily living. Mixed physical exercises were used. The effects were not significant. No adverse event has been reported. The quality of the existing evidence is relatively low since the papers were either case series or case studies. Further studies are needed on exercise types and dosages for better prescriptions for people with LIS after stroke. This may help to extend their lives with better control of the complications and to improve their quality of life.

Unhealthy substance use is associated with increased rates of STDs, including HIV. Within three high-risk New York City (NYC) sexual health clinics between 2008 and 2012 (n = 146,657), 17% of patients screened positive for a current SUD but only 5.3% ever received prior treatment. The goal of Project Renew was to expand the reach of substance use early intervention services within and across sexual health clinics citywide and decrease substance use, poor mental health, and risky sexual behavior. To accomplish this goal, Screening, Brief Intervention, and Referral to Treatment (SBIRT), an evidence-based substance use early intervention model, was implemented in all eight NYC sexual health clinics February 2012-January 2015. Clinic patients were screened for substance misuse using the AUDIT/DAST-10, and those who screened positive were eligible for on-site brief intervention. Overall, 130,597 substance misuse screenings were conducted (66,989, or 51%, positive), and 17,474 on-site brief interventions and 1238 referrals were provided (not unique to individual patients). A 10% sample of 14,709 unique patients who screened positive were interviewed using a federal data collection tool at baseline and six months later to assess changes in substance use, sexual risk behaviors, mental health, and health status (n = 1328). At six-month follow-up, patients reported reduced substance use, less sexual activity, improved overall health, and fewer days of depression and anxiety compared to measures at baseline (p 0.05). Based on positive results, Project Renew SBIRT services have been sustained, ensuring essential care which may help prevent acquisition of HIV/STDs among a large population of high-risk New Yorkers.

Docetaxel (DTX) solution is among the most widely-used parenteral formulations used in advanced breast cancer therapy. However, severe side effects have been observed due to the use of ethanol and polysorbate 80. Herein, a novel DTX-based prodrug, docetaxel-linoleic acid conjugate (DTX-LA) was successfully synthesized. The high lipid solubility of DTX and DTX-LA resulted in a tendency for them to become entrapped in the oil core of the emulsions. As anticipated, nano-sized, sterically stabilized oil-in-water lipid emulsions (LMs) of DTX-LA LMs and DTX LMs were successfully constructed. Unlike DTX solution, LMs exhibited high colloidal stability and sustained-release behavior, having a narrow size distribution that was ∼220 nm in diameter. Compared with DTX LMs, DTX-LA LMs had a greater drug-loading capacity. Although the cytotoxicity of DTX-LA LMs was reduced in comparison with DTX solution, the pharmacokinetic study demonstrated increased bioavailability (p 0.001) and half-life (p 0.01). Finally, DTX-LA LMs displayed significant antitumor efficacy with reduced side effects in a 4T1 breast cancer xenograft model. Thus, the novel lipid emulsion-based docetaxel prodrug delivery system may be a promising strategy for improving intravenous administration for breast cancer treatment.

Laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer has been widely applied; however, its oncologic efficacy has yet been well established. The study aimed to compare the long-term oncologic outcomes of LADG versus open distal gastrectomy (ODG) on gastric cancer. The clinicopathologic data of gastric cancer patients who underwent distal gastrectomy with curative intent from October 2004 through September 2014 were included and analyzed in a retrospective cohort. The last follow-up was September 2016. 769 eligible patients (LADG 414 vs. ODG 355) were included in the study. No significant difference was observed between the groups in 5-year DFS (LADG 61.2% vs. ODG 59.1%; p = 0.384) and OS rates (LADG 65.8% vs. ODG 66.3%; p = 0.750). During surgery, though LADG group had longer operating time, the blood loss was less than ODG group. LADG group had faster postoperative recovery course including shorter time to oral intake, ambulation, and discharge time. Postoperative complication rate within 30 days showed no significant difference between the groups (LADG 15.7% vs. ODG 13.0%; p = 0.281). Age over 65 years old, blood loss > 200 ml, postoperative complication, and advanced T and N stage were identified as independent risk factors for DFS and OS. LADG could yield similar oncologic outcomes compared with ODG in treating distal gastric cancer. However, the findings need to be further confirmed through ongoing prospective randomized controlled trials.

We aimed to evaluate whether radiomic feature-based fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging signatures allow prediction of gastric cancer (GC) survival and chemotherapy benefits. Methods: A total of 214 GC patients (training (n = 132) or validation (n = 82) cohort) were subjected to radiomic feature extraction (80 features). Radiomic features of patients in the training cohort were subjected to a LASSO cox analysis to predict disease-free survival (DFS) and overall survival (OS) and were validated in the validation cohort. A radiomics nomogram with the radiomic signature incorporated was constructed to demonstrate the incremental value of the radiomic signature to the TNM staging system for individualized survival estimation, which was then assessed with respect to calibration, discrimination, and clinical usefulness. The performance was assessed with concordance index (C-index) and integrated Brier scores. Results: Significant differences were found between the high- and low-radiomic score (Rad-score) patients in 5-year DFS and OS in training and validation cohorts. Multivariate analysis revealed that the Rad-score was an independent prognostic factor. Incorporating the Rad-score into the radiomics-based nomogram resulted in better performance (C-index: DFS, 0.800; OS, 0.786; in the training cohort) than TNM staging system and clinicopathologic nomogram. Further analysis revealed that patients with higher Rad-scores were prone to benefit from chemotherapy. Conclusion: The newly developed radiomic signature was a powerful predictor of OS and DFS. Moreover, the radiomic signature could predict which patients could benefit from chemotherapy.

In this study, the co-infection of Torque teno sus virus (TTSuV) and porcine circovirus type 3 (PCV3) was reported. One hundred and ten of 132 (83.3%) PCV3-positive samples were co-infected with Torque teno sus virus 1 (TTSuV1). Ninety-four of 132 (71.2%) PCV3-positive samples were co-infected with Torque teno sus virus 2 (TTSuV2). Sixty-six of 132 (50.0%) of PCV3-positive samples were co-infected with both TTSuV1 and TTSuV2. There were no clinical signs of infection in pigs that were both PCV3-positive and PCV2-negative, in either multiparous sows or live-born infants. The high co-infection rate provides valuable information for the further study of the pathological correlation between PCV3 and TTSuVs.

Background The effect of corticosteroids on influenza A(H1N1)pdm09 viral pneumonia patients remains controversial and the impact of dosage has never been studied. Methods Using data of hospitalized adolescent and adult patients with influenza A(H1N1)pdm09 viral pneumonia, prospectively collected from 407 hospitals in mainland China, the effects of low-to-moderate dose (25-150 mg·day−1) and high-dose (> 150 mg·day−1) corticosteroids on 30-day mortality, 60-day mortality, and nosocomial infection were assessed with multivariate Cox regression and propensity score-matched case-control analysis. Results In total, 2141 patients (median age: 34 y; morality rate: 15.9%) were included. Among them, 1160 (54.2%) had PaO2/FiO2 < 300 mmHg on admission, and 1055 (49.3%) received corticosteroids therapy. Corticosteroids, without consideration of dose, did not influence either 30-day or 60-day mortality. Further analysis revealed that, as compared with the no-corticosteroid group, low-to-moderate dose corticosteroids was related to reduced 30-day mortality (adjusted hazard ratio [aHR] 0.64 [95%CI 0.43-0.96, p=0.033]). In the subgroup analysis among patients with PaO2/FiO2 < 300 mmHg, low-to-moderate dose corticosteroid treatment significantly reduced both 30-day (aHR 0.49 [95%CI 0.32-0.77]) and 60-day mortality (aHR 0.51 [95%CI 0.33-0.78]), while high-dose corticosteroid therapy yielded no difference. For patients with PaO2/FiO2 ≥ 300 mmHg, corticosteroids (irrespective of dose) showed no benefit, and even increased 60-day mortality (aHR 3.02 [95%CI 1.06-8.58]). Results were similar in the propensity model analysis. Conclusions Low-to-moderate dose corticosteroids might reduce mortality of influenza A(H1N1)pdm09 viral pneumonia patients with PaO2/FiO2 < 300 mmHg. Mild patients with PaO2/FiO2 ≥ 300 mmHg could not benefit from corticosteroids therapy. This article is protected by copyright. All rights reserved.

Although CircRNA_100269 is a biomarker used to predict cancer recurrence, its expression and function in gastric cancer (GC) remain unknown. In this study, the expression of circRNA_100269 and its potential downstream miRNA targets were investigated. The molecular function and regulatory mechanism of circRNA_100269 in GC cell lines were also elucidated. The expression levels of circRNA_100269 and its linear isomer LPHN2 mRNA were found to be downregulated (p

// Huan Zhang 1, * , Li Liu 2, * , Shuang Fu 1, * , Yan-Song Liu 3 , Changsong Wang 3 , Tiemin Liu 1, 4 , Zhi-Ping Liu 5 , Rui-Tao Wang 1, 6 and Kai-Jiang Yu 3, 6 1 Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, China 2 Department of Histology and Embryology, Harbin Medical University, Harbin, Heilongjiang, 150081, China 3 Department of Intensive Care Unit, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, China 4 Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA 5 Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA 6 Heilongjiang Academy of Medical Science, Harbin, Heilongjiang, 150081, China * These authors have contributed equally to this work Correspondence to: Rui-Tao Wang, email: ruitaowang@126.com Kai-Jiang Yu, email: kaijiang_yu@yeah.net Keywords: laryngeal cancer, platelet distribution width, prognosis, survival Received: March 29, 2017 Accepted: May 01, 2017 Published: May 30, 2017 ABSTRACT Background: Activated platelets promote cancer progression and metastasis. However, the prognostic value of platelet indices in laryngeal cancer remains poorly understood. The purpose of this study was to investigate the predictive significance of platelet indices in laryngeal cancer. Results: Of the 241 patients, high platelet distribution width (PDW) levels were observed in 116 (48.1 %) patients. In the Kaplan-Meier analysis, increased PDW was significantly associated with a poorer overall survival (p < 0.001). In the multivariate Cox model, PDW was an independent prognostic index for overall survival (HR=4.381, 95% CI=2.313-8.298, P < 0.001). Method: The retrospective study included 241 consecutive patients with laryngeal cancer between January 2009 and December 2009. The relationships between PDW and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of PDW. Conclusions: Elevated PDW might be a novel prognostic marker in laryngeal cancer.

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are the primary toxicants released by electronic waste (e-waste) recycling, but their adverse effects on people working in e-waste recycling or living near e-waste sites have not been studied well. In the present study, the serum concentrations of PBDEs, PCBs, and hydroxylated PCBs, the circulating levels of thyroid hormones (THs), and the mRNA levels of seven TH-regulated genes in peripheral blood leukocytes of e-waste recycling workers were analyzed. The associations of the hormone levels and gene expression with the exposure to these contaminants were examined using multiple linear regression models. There were nearly no associations of the TH levels with PCBs and hydroxylated PCBs, whereas elevated hormone (T4 and T3) levels were associated with certain lower-brominated BDEs. While not statistically significant, we did observe a negative association between highly brominated PBDE congeners and thyroid-stimulating hormone (TSH) levels in the e-waste workers. The TH-regulated gene expression was more significantly associated with the organohalogen compounds (OHCs) than the TH levels in these workers. The TH-regulated gene expression was significantly associated with certain PCB and hydroxylated PCB congeners. However, the expression of most target genes was suppressed by PBDEs (mostly highly brominated congeners). This is the first evidence of alterations in TH-regulated gene expression in humans exposed to OHCs. Our findings indicated that OHCs may interfere with TH signaling and/or exert TH-like effects, leading to alterations in related gene expression in humans. Further research is needed to investigate the mechanisms of action and associated biological consequences of the gene expression disruption by OHCs. Keywords: Thyroid hormone, Polybrominated diphenyl ethers, Polychlorinated biphenyls, Gene expression, Serum, E-waste

// Bin Li 1 , Xunbo Jin 1 , Huilin Meng 1 , Bo Hu 1 , Tao Zhang 1 , Jiang Yu 1 , Shaoan Chen 1 , Xudong Guo 1 , Weiguo Wang 2 , Wei Jiang 3 and Jin Wang 4, 5 1 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China 2 Department of Urology, Jining No.1 People’s Hospital, Jining 272011, Shandong, China 3 Department of Urology, Dongying People’s Hospital, Dongying 257091, Shandong, China 4 Department of Urology, Shandong Provincial Qianfoshan Hospital Affiliated to Shandong University, Jinan 250014, Shandong, China 5 School of Basic Medical Sciences, Shandong University, Jinan 250012, Shandong, China Correspondence to: Jin Wang, email: wjinsdu@163.com Keywords: prostate cancer, morin, paclitaxel-resistance, microRNA (miR)-155, GATA binding protein 3 (GATA3) Received: February 28, 2017 Accepted: April 21, 2017 Published: May 24, 2017 ABSTRACT Paclitaxel is a first-line microtubule-stabilizing drug in treating prostate cancer. However, most patients develop resistance and experience relapse. Morin (3,5,7,20,40-pentahydroxyflavone) is an anti-tumor flavonoid in a numerous types of cancer cells including breast, ovarian and lung cancers. We therefore researched the effects of morin as an adjuvant to paclitaxel in in treating DU145 and PC-3 cells in vitro and DU145 derived prostate cancers in nude mice models. The chemosensitivities of these cells to the treatments of morin and paclitaxel were tested through viability assays utilizing cell counting kit 8 (CCK-8) and apoptosis assays through flow cytometry analyses. MicroRNA (miRNA) microarray was employed to determine the changes in miRNA profile of morin treated DU145 cells. The results from microarrays were further certified by quantitative real-time reverse transcription-PCR (qRT-PCR). The underlying targets of miR-155 were verified using luciferase assays followed by Western blot assays. In the results, morin was capable of repressing the cell viabilities in the paclitaxel-treated cells. MiR-155might be an effective target that can be down-regulated in morin-treated cells. We also discovered that GATA binding protein 3 (GATA3) was directly repressed by miR-155, and the treatment of morin reversed the expression of GATA3. In conclusion, morin might be a potential adjuvant of paclitaxel in treating prostate cancer through regulating miR-155/GATA3 axis.

Purpose: Elevated levels of neutrophils have been associated with poor survival in various cancers, but direct evidence supporting a role for neutrophils in the immunopathogenesis of human cancers is lacking. Experimental Design: A total of 573 patients with gastric cancer were enrolled in this study. Immunohistochemistry and real-time PCR were performed to analyze the distribution and clinical relevance of neutrophils in different microanatomic regions. The regulation and function of neutrophils were assessed both in vitro and in vivo. Results: Increased neutrophil counts in the peripheral blood were associated with poor prognosis in gastric cancer patients. In gastric cancer tissues, neutrophils were enriched predominantly in the invasive margin, and neutrophil levels were a powerful predictor of poor survival in patients with gastric cancer. IL17+ neutrophils constitute a large portion of IL17-producing cells in human gastric cancer. Proinflammatory IL17 is a critical mediator of the recruitment of neutrophils into the invasive margin by CXC chemokines. Moreover, neutrophils at the invasive margin were a major source of matrix metalloproteinase-9, a secreted protein that stimulates proangiogenic activity in gastric cancer cells. Accordingly, high levels of infiltrated neutrophils at the invasive margin were positively correlated with angiogenesis progression in patients with gastric cancer. Conclusions: These data provide direct evidence supporting the pivotal role of neutrophils in gastric cancer progression and reveal a novel immune escape mechanism involving fine-tuned collaborative action between cancer cells and immune cells in the distinct tumor microenvironment. Clin Cancer Res; 23(6); 1575–85. ©2016 AACR.

Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload‐induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β‐myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4 pathway and suppression of the interaction of Orai1/STIM1.

// Xin Zhang 1, * , Ming-Ming Cui 1, * , Shuang Fu 1 , Lu-Lu Li 2 , Yan-Song Liu 3 , Zhi-Ping Liu 4 , Tiemin Liu 5 , Rui-Tao Wang 1 , Kai-Jiang Yu 3 1 Department of Internal Medicine, The Third Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, China 2 Department of Geriatrics, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, 150086, China 3 Department of Intensive Care Unit, The Third Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, 150081, China 4 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA 5 Division of Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, 75390, USA * These authors have contributed equally to this work Correspondence to: Rui-Tao Wang, email: ruitaowang@126.com Kai-Jiang Yu, email: kaijiang_yu@yeah.net Keywords: gastric cancer, platelet distribution width, prognosis, survival Received: September 27, 2016 Accepted: January 17, 2017 Published: February 21, 2017 ABSTRACT Background: Activated platelets promote tumor cell growth, aberrant angiogenesis, and invasion. However, the value of platelet indices for predicting survival in gastric cancer remains unknown. The goal of this study was to investigate the predictive significance of platelet indices in gastric cancer. Result: Reduced platelet distribution width (PDW) was significantly correlated with age, carcinoembryonic antigen, tumor stage, nodule stage, and tumor-nodule-metastases stage. Moreover, decreased PDW correlated with a shorter overall survival in gastric cancer. Multivariate analysis identified PDW as an independent prognostic factor for overall survival (hazard ratio: 0.493, 95% confidence interval: 0.319-0.761, p = 0.001). Method: A total of 294 patients with gastric cancer were retrospectively analyzed between January 2009 and December 2009. The association between platelet indices and overall survival were evaluated. The prognostic analysis was carried out with Cox regression model. Conclusion: PDW is easily available with routine blood counts. Our data revealed that reduced PDW is unfavorable prognostic factor in gastric cancer. Further studies are warranted.

Alternative splicing is emerging as an oncogenic mechanism. In prostate cancer, generation of constitutively active forms of androgen receptor (AR) variants including AR-V7 plays an important role in progression of castration-resistant prostate cancer (CRPC). AR-V7 is generated by alternative splicing that results in inclusion of cryptic exon CE3 and translation of truncated AR protein that lacks the ligand binding domain. Whether AR-V7 can be a driver for CRPC remains controversial as the oncogenic mechanism of AR-V7 activation remains elusive. Here, we found that KDM4B promotes AR-V7 and identified a novel regulatory mechanism. KDM4B is phosphorylated by protein kinase A under conditions that promote castration-resistance, eliciting its binding to the splicing factor SF3B3. KDM4B binds RNA specifically near the 5′-CE3, upregulates the chromatin accessibility, and couples the spliceosome to the chromatin. Our data suggest that KDM4B can function as a signal responsive trans-acting splicing factor and scaffold that recruits and stabilizes the spliceosome near the alternative exon, thus promoting its inclusion. Genome-wide profiling of KDM4B-regulated genes also identified additional alternative splicing events implicated in tumorigenesis. Our study defines KDM4B-regulated alternative splicing as a pivotal mechanism for generating AR-V7 and a contributing factor for CRPC, providing insight for mechanistic targeting of CRPC.

Diabetic patients are more susceptible to myocardial ischemia damage than nondiabetic patients, with worse clinical outcomes and greater mortality. The mechanism may be related to glucose metabolism, mitochondrial homeostasis, and oxidative stress. Pyridostigmine may improve vagal activity to protect cardiac function in cardiovascular diseases. Researchers have not determined whether pyridostigmine regulates glucose metabolism and mitochondrial homeostasis to reduce myocardial vulnerability to injury in diabetic mice. In the present study, autonomic imbalance, myocardial damage, mitochondrial dysfunction, and oxidative stress were exacerbated in isoproterenol-stimulated diabetic mice, revealing the myocardial vulnerability of diabetic mice to injury compared with mice with diabetes or exposed to isoproterenol alone. Compared with normal mice, the expression of glucose transporters (GLUT)1/4 phosphofructokinase (PFK) FB3, and pyruvate kinase isoform (PKM) was decreased in diabetic mice, but increased in isoproterenol-stimulated normal mice. Following exposure to isoproterenol, the expression of (GLUT)1/4 phosphofructokinase (PFK) FB3, and PKM decreased in diabetic mice compared with normal mice. The downregulation of SIRT3/AMPK and IRS-1/Akt in isoproterenol-stimulated diabetic mice was exacerbated compared with that in diabetic mice or isoproterenol-stimulated normal mice. Pyridostigmine improved vagus activity, increased GLUT1/4, PFKFB3, and PKM expression, and ameliorated mitochondrial dysfunction and oxidative stress to reduce myocardial damage in isoproterenol-stimulated diabetic mice. Based on these results, it was found that pyridostigmine may reduce myocardial vulnerability to injury via the SIRT3/AMPK and IRS-1/Akt pathways in diabetic mice with isoproterenol-induced myocardial damage. This study may provide a potential therapeutic target for myocardial damage in diabetic patients.