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Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reported. Envafolimab was well tolerated and no new safety signals were identified compared with other marketed products of the same class. Three patients reported Grade ≥ 3 envafolimab-related treatment-emergent adverse events (TEAE), including adrenal insufficiency, cerebral infarction, and immune-mediated enterocolitis. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve (AUC) and maximum serum concentration (C

We aimed to establish an artificial intelligence (AI) model to identify parathyroid glands during endoscopic approaches and compare it with senior and junior surgeons' visual estimation.A total of 1,700 images of parathyroid glands from 166 endoscopic thyroidectomy videos were labeled. Data from 20 additional full-length videos were used as an independent external cohort. The YOLO V3, Faster R-CNN, and Cascade algorithms were used for deep learning, and the optimal algorithm was selected for independent external cohort analysis. Finally, the identification rate, initial recognition time, and tracking periods of PTAIR (Artificial Intelligence model for Parathyroid gland Recognition), junior surgeons, and senior surgeons were compared.The Faster R-CNN algorithm showed the best balance after optimizing the hyperparameters of each algorithm and was updated as PTAIR. The precision, recall rate, and F1 score of the PTAIR were 88.7%, 92.3%, and 90.5%, respectively. In the independent external cohort, the parathyroid identification rates of PTAIR, senior surgeons, and junior surgeons were 96.9%, 87.5%, and 71.9%, respectively. In addition, PTAIR recognized parathyroid glands 3.83 s ahead of the senior surgeons (p = 0.008), with a tracking period 62.82 s longer than the senior surgeons (p = 0.006).PTAIR can achieve earlier identification and full-time tracing under a particular training strategy. The identification rate of PTAIR is higher than that of junior surgeons and similar to that of senior surgeons. Such systems may have utility in improving surgical outcomes and also in accelerating the education of junior surgeons.3 Laryngoscope, 132:2516-2523, 2022.

Background: Rhabdomyolysis (RM) associated acute kidney injury (AKI) is the most common systemic complication of RM. The present study aimed to assess the clinical characteristics and risk factors for intensive care unit (ICU) transfer for patients with RM-associated AKI.Methods: We included all patients who were age ≥ 18 years old with a diagnosis of RM from September 2012 to October 2018 and divided them into RM-associated AKI group and RM without AKI group. The primary outcome was transferring to ICU treatment. Regression analysis was performed to identify factors associated with ICU treatment and recovery of renal function.Results: Among the 149 patients with RM, 68 (45.6%) developed AKI. The percentage of patients with AKI who transferred to ICU was higher than patients without AKI (33.8% versus 12.3%, P < 0.002). Additionally, patients with AKI had higher percentage of undergoing dialysis (19.1% versus 2.5%, P < 0.01), all-cause mortality (13.2% versus 1.2%, P < 0.01), cost of hospitalization [10.8 1,000 yuan, IQR (5.5, 3.5) versus 5.9 1,000 yuan, IQR 5.9 (3.6, 9.9), P = 0.03], as well as longer length of hospital stay [8.0 (5.0, 14.0)] versus [6.0 (4.0, 11.0)], P = 0.02). Moreover, most patients with AKI achieved complete recovery (77.9%) at discharge. After adjusting for potential risk factors, RM-associated AKI remained an independent risk factor for ICU transfer (OR = 3.0, 95% CI, 1.11–8.3, P = 0.03). However, ICU transfer was not associated with recovery of renal function (OR = 0.88, 95% CI, 0.22–3.57, P = 0.856).Conclusion: RM leaded to AKI in most patients. RM-associated AKI could cause worse clinical outcome and predict ICU transfer for patients with RM.

Current chemopreventive strategies require 3–5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention. Prevention Relevance: This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.

Since microRNA-205 (miRNA-205) is a predictive biomarker for antiradiation of nasopharyngeal carcinoma (NPC), quantitative detection of miRNA-205 is important for developing personalized strategies for the treatment of NPC. In this investigation, based on the graphene oxide (GO) sensor and hybridization chain reaction (HCR) for fluorescence signal amplification, a highly sensitive and selective detection method for miRNA-205 was designed. A target-recycling mechanism is employed, where a single miRNA-205 target triggers the signal amplification of many DNA signal probes. The biosensor shows the ability to analyze miRNA-205 in solution, and it can detect miRNA-205 at concentrations as low as 311.96 pM. Furthermore, the method is specific in that it distinguishes between a target miRNA and a sequence with single-, double-, and three-base mismatches, as well as other miRNAs. Considering its simplicity and superior sensitivity, it was also verified in 1‰ serum with a detection limit of 111.65 pM. Importantly, the method successfully demonstrated that miRNA-205 could be imaged in living cells, which provided the possibility of localizing target molecules in live cell imaging applications. This method has great clinical application potential in the determination of miRNA-205, a biomarker for radiation-resistant NPC.

Summary Background Ocular changes are traditionally associated with only a few hepatobiliary diseases. These changes are non-specific and have a low detection rate, limiting their potential use as clinically independent diagnostic features. Therefore, we aimed to engineer deep learning models to establish associations between ocular features and major hepatobiliary diseases and to advance automated screening and identification of hepatobiliary diseases from ocular images. Methods We did a multicentre, prospective study to develop models using slit-lamp or retinal fundus images from participants in three hepatobiliary departments and two medical examination centres. Included participants were older than 18 years and had complete clinical information; participants diagnosed with acute hepatobiliary diseases were excluded. We trained seven slit-lamp models and seven fundus models (with or without hepatobiliary disease [screening model] or one specific disease type within six categories [identifying model]) using a development dataset, and we tested the models with an external test dataset. Additionally, we did a visual explanation and occlusion test. Model performances were evaluated using the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and F1* score. Findings Between Dec 16, 2018, and July 31, 2019, we collected data from 1252 participants (from the Department of Hepatobiliary Surgery of the Third Affiliated Hospital of Sun Yat-sen University, the Department of Infectious Diseases of the Affiliated Huadu Hospital of Southern Medical University, and the Nantian Medical Centre of Aikang Health Care [Guangzhou, China]) for the development dataset; between Aug 14, 2019, and Jan 31, 2020, we collected data from 537 participants (from the Department of Infectious Diseases of the Third Affiliated Hospital of Sun Yat-sen University and the Huanshidong Medical Centre of Aikang Health Care [Guangzhou, China]) for the test dataset. The AUROC for screening for hepatobiliary diseases of the slit-lamp model was 0·74 (95% CI 0·71–0·76), whereas that of the fundus model was 0·68 (0·65–0·71). For the identification of hepatobiliary diseases, the AUROCs were 0·93 (0·91–0·94; slit-lamp) and 0·84 (0·81–0·86; fundus) for liver cancer, 0·90 (0·88–0·91; slit-lamp) and 0·83 (0·81–0·86; fundus) for liver cirrhosis, and ranged 0·58–0·69 (0·55–0·71; slit-lamp) and 0·62–0·70 (0·58–0·73; fundus) for other hepatobiliary diseases, including chronic viral hepatitis, non-alcoholic fatty liver disease, cholelithiasis, and hepatic cyst. In addition to the conjunctiva and sclera, our deep learning model revealed that the structures of the iris and fundus also contributed to the classification. Interpretation Our study established qualitative associations between ocular features and major hepatobiliary diseases, providing a non-invasive, convenient, and complementary method for hepatobiliary disease screening and identification, which could be applied as an opportunistic screening tool. Funding Science and Technology Planning Projects of Guangdong Province; National Key RD Guangzhou Key Laboratory Project; National Natural Science Foundation of China.

Ulcerative colitis (UC) is a multifactorial inflammatory disease, and increasing evidence has demonstrated that the mechanism of UC pathogenesis is associated with excessive cellular apoptosis and reactive oxygen species (ROS) production. However, their function and molecular mechanisms related to UC remain unknown. In this study, Rab27A mRNA and protein were proven to be overexpressed in intestinal epithelial cells of UC patients and DSS‐induced colitis mice, compared with control (P

BackgroundIntracranial aneurysms (IAs) are common in the population and may cause death.ObjectiveTo develop a new fully automated detection and segmentation deep neural network based framework to assist neurologists in evaluating and contouring intracranial aneurysms from 2D+time digital subtraction angiography (DSA) sequences during diagnosis.MethodsThe network structure is based on a general U-shaped design for medical image segmentation and detection. The network includes a fully convolutional technique to detect aneurysms in high-resolution DSA frames. In addition, a bidirectional convolutional long short-term memory module is introduced at each level of the network to capture the change in contrast medium flow across the 2D DSA frames. The resulting network incorporates both spatial and temporal information from DSA sequences and can be trained end-to-end. Furthermore, deep supervision was implemented to help the network converge. The proposed network structure was trained with 2269 DSA sequences from 347 patients with IAs. After that, the system was evaluated on a blind test set with 947 DSA sequences from 146 patients.ResultsOf the 354 aneurysms, 316 (89.3%) were successfully detected, corresponding to a patient level sensitivity of 97.7% at an average false positive number of 3.77 per sequence. The system runs for less than one second per sequence with an average dice coefficient score of 0.533.ConclusionsThis deep neural network assists in successfully detecting and segmenting aneurysms from 2D DSA sequences, and can be used in clinical practice.

Non-textbook outcome (non-TO) represents a new prognostic evaluation index for surgical oncology. The present study aimed to develop new nomograms based on non-TO to predict the mortality and recurrence rate in patients with esophageal squamous cell cancer (ESCC) after minimally invasive esophagectomy (MIE).The study involved a retrospective analysis of 613 ESCC patients, from the prospectively maintained database from January 2011 to December 2018. All the included ESCC patients underwent MIE, and they were randomly (1:1) assigned to the training cohort (307 patients) and the validation cohort (306 patients). Kaplan-Meier survival analysis was used to analyze the differences recorded between overall survival (OS) and disease-free survival (DFS). In the case of the training cohort, the nomograms based on non-TO were developed using Cox regression, and the performance of these nomograms was calibrated and evaluated in the validation cohort.Significant differences were recorded for 5-year OS and DFS between non-TO and TO groups (p 0.05). Multivariate cox analysis revealed that non-TO, intraoperative bleeding, T stage, and N stage acted as independent risk factors that affected OS and DFS (p 0.05). The results for multivariate regression were used to build non-TO-based nomograms to predict OS and DFS of patients with ESCC, the t-AUC curve analysis showed that the nomograms predicting OS and DFS were more accurate as compared to TNM staging, during the follow-up period in the training cohort and validation cohort. Further, the nomogram score was used to divide ESCC patients into low-, middle-, and high-risk groups and significant differences were recorded for OS and DFS between these three groups (p 0.001).Non-TO was identified as an independent prognostic factor for ESCC patients. The nomograms based on non-TO could availably predict OS and DFS in ESCC patients after MIE.

Background: Colorectal cancer (CRC) is one of the high incidence tumors and is ranked second in cancer-related mortality. Even though great progress has been made, there are no effective therapeutic strategies for late stage and metastatic CRC patients. Acidity is one characteristic of the tumor microenvironment. However, how cancer cells respond to this acidic environment surrounding them remains largely unknown, especially in colorectal cancer. Methods: Proton sensor receptor expression was analyzed in GEO and TCGA datasets. The expression of GPR4 in CRC specimens was confirmed by western blotting and immunohistochemistry (IHC). The role of GPR4 in CRC progression was analyzed both in vitro and in vivo. Pharmacological intervention, immunofluorescence and gene set enrichment analyses were performed to reveal the underlying molecular mechanisms of GPR4. Findings: We found that GPR4 was upregulated in CRC samples. In addition, its high expression correlated with late stage tumors and poor overall survival in patients. Furthermore, loss-of-function assays proved that GPR4 promoted CRC carcinogenesis and metastatic ability. Mechanistically, GPR4 was activated by extracellular protons in the tumor microenvironment and enhanced RhoA activation and F-actin rearrangement, leading to LATS activity inhibition, YAP1 nuclear translocation and oncogene transcription. Conclusions: The expression of GPR4 is upregulated in colorectal cancer and is associated with shorter overall survival time in CRCpatients. These findings reveal the novel roles of GPR4 in CRC progression and suggest GPR4 might be a new therapeutic target for CRC treatment. Funding Statement: This work was supported by the grant from the National Natural Science Foundation of China (No.81702300 & No.81873555). Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: Study protocol that strictly in line with International Ethical Guidelines for Biomedical Research Involving Human Subjects was approved by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. Patients that had received no anti-tumor therapy and signed written informed consent were enrolled in this study.

Obesity is a major epigenetic cause for colorectal cancer (CRC). Leptin is implicated in obesity-associated CRC, but the underlying mechanism remains unclear. The current study identified over-expression of metallopanstimulin-1 (MPS-1) in CRC patients through microarray and histological analysis, especially in obese CRC patients. MPS-1 was correlated with advanced tumor stage, suggesting its association with CRC progression. In addition, MPS-1 over-expression was associated with poor overall survival (OS) in obese CRC patients, but not in their non-obese counterparts, suggesting its potential as a prognostic marker of obese CRC patients. MPS-1 expression was positively associated with circulating leptin levels in CRC patients, especially in obese cases. Functional experiments demonstrated that MPS-1 silencing inhibited tumor proliferation and colony formation, and induced apoptosis of CRC cells in vitro. Converse results were obtained from the experiments with MPS-1 over-expression. Mechanistically, MPS-1 executed its action through induction of c-Jun N-terminal kinase (JNK)/c-Jun pathway. Moreover, the promotion effect of MPS-1 on CRC progression was modulated by leptin. In vivo studies demonstrated that MPS-1 silencing suppressed tumor growth of CRC via inhibiting JNK/c-Jun signaling. Collectively, this study indicates that MPS-1 promotes leptin-induced CRC via activating JNK/c-Jun pathway. MPS-1 might represent a potent candidate for the treatment and prognostic prediction of obesity-associated CRC.

Since microRNA-205 (miR-205) is predictive biomarkers for radiation-resistant of nasopharyngeal carcinoma, monitoring of the dynamic variation of miR-205 is of great interest for developing a personalized strategy for the treatment of NPC. Herein, a method for detection of miR-205 was designed based on graphene oxide (GO) and fluorescent probe. The method was successfully used to sensitively and selectively assay miR-205 in aqueous solution, and a low limit of detection of 1.18 nM was obtained in the range 0–300 nM and R2 = 0.990. In addition, the designed platform is specific in that it can distinguish the target miRNA from non-target miRNAs, and even the sequences with single base, double base and three base mismatches. Considering the simplicity and superior sensitivity, it has great potential for clinical application in determining biomarker of radiation-resistant nasopharyngeal carcinoma.

Background Injectable hyaluronic acid fillers have been widely applied in the clinical treatment of facial wrinkles. However, further information and clinical evidence concerning dermal changes and hyaluronic acid filler longevity after injection and diffusion pattern are limited. Methods The authors evaluated the longevity and diffusion pattern of two hyaluronic acid fillers generated by different cross-linking technologies used in the treatment of nasolabial folds using high-frequency ultrasound. Forty-one subjects were treated with Restylane 2 and the remaining 41 were treated with Dermalax DEEP. Wrinkle severity rating scale score and high-frequency ultrasound evaluation of nasolabial folds were performed before and after the injection of hyaluronic acid filler. The ultrasound images were acquired and analyzed to determine dermal thickness and the shape and distribution of hyaluronic acid filler. Results At 2 and 24 weeks from baseline, increased dermal thickness induced by hyaluronic acid filler treatment was not significantly different between groups. At 48 weeks after injection, increased dermal thicknesses of the Restylane 2 group (0.14 ± 0.12 mm) were much lower than those of the Dermalax DEEP group (0.20 ± 0.13 mm). Ultrasound examination revealed that hyaluronic acid materials form well-demarcated and hypoechogenic areas. Restylane 2 tended to form a more diffuse pattern, with multiple smaller bubbles, whereas Dermalax DEEP developed into a more localized configuration, with larger clumps. Conclusions This study is the first long-term assessment of nasolabial fold correction that reveals the performance of different hyaluronic acid materials in vivo and validates high-frequency ultrasound as a simple and rapid modality. Hyaluronic acid fillers generated by different cross-linking technologies display differential diffusion patterns in skin tissues. Clinical question/level of evidence Therapeutic, II.

Adeno-associated virus (AAV) receptor (AAVR) is an essential receptor for the entry of multiple AAV serotypes with divergent rules; however, the mechanism remains unclear. Here, we determine the structures of the AAV1-AAVR and AAV5-AAVR complexes, revealing the molecular details by which PKD1 recognizes AAV5 and PKD2 is solely engaged with AAV1. PKD2 lies on the plateau region of the AAV1 capsid. However, the AAV5-AAVR interface is strikingly different, in which PKD1 is bound at the opposite side of the spike of the AAV5 capsid than the PKD2-interacting region of AAV1. Residues in strands F/G and the CD loop of PKD1 interact directly with AAV5, whereas residues in strands B/C/E and the BC loop of PKD2 make contact with AAV1. These findings further the understanding of the distinct mechanisms by which AAVR recognizes various AAV serotypes and provide an example of a single receptor engaging multiple viral serotypes with divergent rules., Multiple adeno-associated viruses (AAV) use the same receptor (AAVR), but the binding mode is not clear. Here, the authors determine the structures of the AAV1-AAVR and AAV5-AAVR complexes, identify residues necessary for virus entry and compare the receptor interfaces of different AAV capsids.

Fibroblast growth factor 21 is an evolutionarily conserved factor that plays multiple important roles in metabolic homeostasis. During the past two decades, extensive investigations have improved our understanding of its delicate metabolic roles and identified its pharmacological potential to mitigate metabolic disorders. However, most clinical trials have failed to obtain the desired results, which raises issues regarding its clinical value. Fibroblast growth factor 21 is dynamically regulated by nutrients derived from food intake and hepatic/adipose release, which in turn act on the central nervous system, liver, and adipose tissues to influence food preference, hepatic glucose, and adipose fatty acid output. Based on this information, we propose that fibroblast growth factor 21 should not be considered merely an anti-hyperglycemia or anti-obesity factor, but rather a means of balancing of nutrient fluctuations to maintain an appropriate energy supply. Hence, the specific functions of fibroblast growth factor 21 in glycometabolism and lipometabolism depend on specific metabolic states, indicating that its pharmacological effects require further consideration.

This systematic review aims to verify the efficacy of acarbose monotherapy in treating obese or overweight patients without diabetes. In the study, we conducted a systematic search of the Pub-Med, EMBASE, Cochrane and Science Citation Index Expanded databases in search of clinical trials on acarbose treatment, overweight and obesity. The crucial inclusion criteria were as follows: (1) patients were diagnosed as overweight or obese (BMI ≥ 25 kg/m2); (2) randomized controlled trials (RCTs); (3) patients had undergone acarbose monotherapy or placebo control; (4) acarbose treatment had been carried out for at least 3 months. Exclusion criteria were as follows: (1) patients diagnosed with diabetes mellitus (DM); (2) patients had received a weight loss medication or surgery in the past 3 months; (3) papers not published in English; (4) repeated research results of the same experiment or repeated published documents. A total of 7 studies involving 132 in the acarbose group and 137 in placebo group, 269 subjects in total, were included in this meta-analysis. From the selected seven papers, we extracted the following clinical parameters: systolic blood pressure (SBP), diastolic blood pressure (DBP), body weight (BW), body mass index (BMI), triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), high density cholesterol (HDL) and fasting plasma glucose (FPG). An important finding of our research is that TG was the only significantly reduced parameter in the acarbose group. Weight mean difference (WMD) was − 0.21 (95% CI − 0.33, − 0.09) mmol/l between acarbose (P = 0.0006) and placebo patients. Reduction of BMI was also greater for acarbose than placebo subjects, although the discrepancy was not statistically significant (P = 0.56). Moreover, no hypoglycemia occurred in either the acarbose group or placebo group. A few subjects experienced gastrointestinal reactions, but these were mild and improved over time. Acarbose has no obvious influence on other metabolic indexes. Acarbose monotherapy is beneficial in reducing TG levels in obese or overweight patients and will not result in hypoglycemia during medication. The side effects of acarbose are mild.

Peptide transporter 1 (PepT1), highly expressed on the apical membrane of enterocytes, is involved in energy balance and mediates intestinal absorption of peptidomimetic drugs. In this study, we investigated whether and how diabetes affected the function and expression of intestinal PepT1. Diabetes was induced in rats by combination of high-fat diet and low dose streptozocin injection. Pharmacokinetics study demonstrated that diabetes significantly decreased plasma exposures of cephalexin and acyclovir following oral administration of cephalexin and valacyclovir, respectively. Single-pass intestinal perfusion analysis showed that diabetes remarkably decreased cephalexin absorption, which was associated with decreased expression of intestinal PepT1 protein. We assessed the levels of bile acids in intestine of diabetic rats, and found that diabetic rats exhibited significantly higher levels of chenodeoxycholic acid (CDCA), cholic acid (CA) and glycocholic acid (GCA), and lower levels of lithocholic acid (LCA) and hyodeoxycholic acid (HDCA) than control rats; intestinal deoxycholic acid (DCA) levels were unaltered. In Caco-2 cells, the 6 bile acids remarkably decreased expression of PepT1 protein with CDCA causing the strongest inhibition, whereas TNF-α, LPS and insulin little affected expression of PepT1 protein; short-chain fatty acids induced rather than decreased expression of PepT1 protein. Farnesoid X receptor (FXR) inhibitor glycine-β-muricholic acid or FXR knockdown reversed the downregulation of PepT1 expression by CDCA and GW4064 (another FXR agonist). In diabetic rats, the expression of intestinal FXR protein was markedly increased. Oral administration of CDCA (90, 180 mg·kg(−1)·d(−1), for 3 weeks) dose-dependently decreased the expression and function of intestinal PepT1 in rats. In conclusion, diabetes impairs the expression and function of intestinal PepT1 partly via CDCA-mediated FXR activation.

The purpose of this study was to identify independent prognostic factors for breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes, and discuss the role of postmastectomy radiotherapy(PMRT) in these patients.Between January 2005 and December 2015, the data on 840 eligible patients with breast cancer were retrospectively reviewed. Of these patients, 368 women received PMRT and 472 did not. The endpoints were locoregional recurrence (LRR) and distant metastasis (DM).With a median follow-up of 62.0 months, multivariate analysis identified the following independent risk factors for increased LRR: tumor size ≥ 4 cm (HR: 2.994, 95% CI: 1.190-7.535, P = 0.020), ER- and PR-negative tumor (HR: 2.540, 95% CI: 1.165-5.537, P = 0.019), preoperative high neutrophil-to-lymphocyte ratio (NLR) (HR: 4.716, 95% CI: 1.776-12.528, P = 0.002)and low neutrophil-to-monocyte ratio (NMR) (HR: 0.231, 95% CI: 0.084-0.633, P = 0.004). And independent risk factors for increased DM: ER- and PR-negative tumor (HR: 2.540, 95% CI: 1.880-5.625, P = 0.000), high NLR (HR: 2.693, 95% CI: 1.426-5.084, P = 0.002) and low NMR (HR: 0.460, 95% CI: 0.257-0.824, P = 0.009). The high-risk patients (≥ 2 risk factors) had worse LRRFS and DFS than low-risk patients (0-1 risk factor) (all, P 0.05). In the subgroup analysis, both low- and high-risk patients received PMRT had better LRRFS and DFS than those who without PMRT (all, P 0.05), and the high-risk patients received PMRT had similar 5-year rates of LRRFS and DFS than low-risk patients who without PMRT (94.5 vs. 94.3%, P = 0.402; 83.4 vs.87.4%, P = 0.877, respectively).Tumor size, ER/PR status, preoperative NLR and NMR were independent predictors of risk of recurrence. PMRT could improve locoregional control even in low-risk subgroup of breast cancer patients with T1-2 tumors and 1-3 positive lymph nodes significantly.

A series of new 3-(1H-benzimidazol-2-yl)quinolin-2(1H)-one derivatives (5a1−5d6) were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that some compounds exhibited moderate to high inhibitory activity against HepG2, SK-OV-3, NCI-H460 and BEL-7404 tumor cell lines, and most compounds exhibited much lower cytotoxicity against the HL-7702 normal cell line compared to 5-FU and cisplatin. In vivo antitumor assay results demonstrated that 5a3 exhibited effective inhibition on tumor growth in the NCI-H460 xenograft mouse model and that 5d3 displayed excellent antiproliferative activity in the BEL-7402 xenograft model. These results suggested that both 5a3 and 5d3 could be used as anticancer drug candidates. Mechanistic studies suggested that compounds 5a3 and 5d3 exerted their antitumor activity by up-regulation of Bax, intracellular Ca2+ release, ROS generation, downregulation of Bcl-2, activation of caspase-9 and caspase-3 and subsequent cleavage of PARP, inhibition of CDK activity and activation of the p53 protein.

Background Alternate-day fasting (ADF) is a novel diet therapy that may achieve reduction in body weight and improvement of dyslipidaemia, but the impact of this diet on patients with non-alcoholic fatty liver disease (NAFLD) remains unknown. The aim of this study was to evaluate the effects of ADF on the body weight and lipid profile of individuals with NAFLD. Methods NAFLD patients (n = 271) were randomised to the ADF group, time-restricted feeding (TRF) group, or the control group and subjected to the respective diet for 12 weeks. Anthropometric measurements (body weight, fat mass/fat-free mass) were performed, and plasma lipids were analysed enzymatically. Results Within 4 weeks, the body weight decreased significantly (P P Conclusions ADF appears to be an effective diet therapy for individuals with NAFLD that can achieve weight loss and improvement of dyslipidaemia within a relatively short period of time (4 to 12 weeks). Potential preventive effects of ADF on cardiovascular disease need to be confirmed by future investigations. Trial registration ChiCTR1900024411, this trial was retrospectively registered on July 10, 2019.

Previous preclinical evidence has suggested that the elevation of epoxyeicosatrienoic acids (EETs) derived from the cytochrome P450 (CYP) epoxygenases-dependent metabolism of arachidonic acid has important anti-inflammatory effects. However, the levels of EETs and their synthetic and metabolic enzymes in human ulcerative colitis has not been evaluated.To evaluate EETs and the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), tissue biopsies were collected from 16 pairs of ulcerative colitis patients' tissues and matched with adjacent non-inflamed tissues. EETs were extracted from tissue homogenates and analyzed by liquid chromatography coupled with tandem mass spectrometry.The concentration of EETs was higher in ulcerative colitis tissues compared with matched adjacent non-inflamed tissues (1.91 ± 0.98 ng/mg vs. 0.96 ± 0.77 ng/mg, mean ± SD, P 0.01). As shown by immunohistochemistry, sEH was present in the cytoplasm and intestinal mucosa and showed a decline in ulcerative colitis tissues compared with matched adjacent non-inflamed tissues. Western blot analyses showed reduced sEH expression in ulcerative colitis tissues compared with matched adjacent non-inflamed tissues, whereas CYP2J2 increased in ulcerative colitis tissues (P 0.05). However, there was no statistically significant difference observed in CYP2C8 and CYP2C9 protein expression between them (P 0.05).Our data suggest that the increase in EET levels may be part of a protective mechanism in ulcerative colitis. Furthermore, the concentration of EETs could be a key factor for drug therapy for ulcerative colitis.

Background/Aims: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion. Methods: The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed. Results: ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice. Conclusion: ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers.

Odontogenic ameloblast-associated protein (ODAM), an acidic matricellular protein, has been implicated in several epithelial neoplasms. However, its biological functions and molecular mechanisms in cancer progression, particular colorectal carcinoma (CRC), remain unknown. Here we demonstrated that ODAM was significantly down-regulated in CRC tissues compared with their normal counterparts. Then, we established that ODAM expression level was closely correlated with CRC development and patient prognosis. The abnormal expression of ODAM dramatically affected CRC cell growth in vitro and in vivo. We further revealed that the inhibitory effects of ODAM on CRC cell growth were associated with PTEN elevation and PI3K/AKT signaling inactivation. Furthermore, we determined that silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing CRC cells. Our study suggests matricellular protein ODAM may serve as a novel prognostic marker and act as a CRC growth suppressor.

Huntington's disease is a chronic progressive neurodegeneration which is caused by CAG repeat sequences expanding in the huntingtin gene. There is currently no disease-modifying treatment for the disease, and its progression can only be slowed down before the onset of symptoms. A novel fluorescent platform which contains an RNA probe and graphene oxide for detection of the biomarker of Huntington's disease, CAG repeat sequences, was constructed in this investigation. In addition, RNase H was employed in the fluorescent system to enhance the sensitivity of the detection capability. The fluorescent signal was increased through the cyclic amplified reaction, which results from RNase H, specifically digestion of the RNA strand in the complement of the RNA-DNA duplex. The designed measurement method can detect CAG repeat sequences with a detection limit of 108 pM (R2 = 0.968) under which we optimized assay conditions. Furthermore, the detection limit is approximately 18 times lower than the traditional DNA and graphene oxide detection method without assistance of RNase H. Additionally, the probing platform also shows stronger ability to discriminate between the fluorescence of the target sequence and that of other non-target sequences. The results of our studies demonstrate that the RNase H amplified RNA probe and graphene oxide system exhibited excellent sensitivity and selectivity to the target of CAG repeats sequences.

To observe the relationship between the analgesic effect of balance acupuncture and functional changes in brain in patients with migraine without aura.A total of 40 cases of migraine without aura were equally randomized into a headache-acupoint group and a sham-acupoint group. When acupuncture given, a filiform needle was inserted into the headache-acupoint (the midpoint of the depression region anterior to the juncture of the first and second metatarsal bones on the dorsum of the foot) or the sham point (the midpoint of the depression region anterior to the juncture site between the 3After acupuncture, the analgesic effect of headache-acupoint was better than that of the sham-acupoint in both intervention stage and the follow-up stage (Balance acupuncture stimulation of headache acupoint has an analgesic effect in migraine patients without aura, which may be related to its effect in regulating resting state brain function of the limbic-system-dominated multiple brain regions.

Cell-mediated immunity may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), kynurenine metabolite—quinolinic acid (QA), and neopterin as markers of interferon-gamma-induced cellular immune activation with lung cancer risk in 5,364 cases and 5,364 individually matched control subjects from 20 prospective cohorts included the international Lung Cancer Cohort Consortium (LC3). Tryptophan, kynurenine, QA, and neopterin were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with different levels of these metabolites and KTR were calculated using conditional logistic regression with adjustment for matched smoking variables and circulating cotinine. Overall, the highest quintiles of circulating kynurenine, KTR, QA and neopterin were associated with a 20–30% higher risk of lung cancer, and tryptophan with a 15% lower risk compared with the lowest quintile (all P(trend)

Automatic detection of left ventricle myocardium is essential to subsequent cardiac image registration and tissue segmentation. However, it is considered challenging mainly because of the complex and varying shape of the myocardium and surrounding tissues across slices and phases. In this study, a hybrid model is proposed to detect myocardium in cardiac magnetic resonance (MR) images combining region proposal and deep feature classification and regression. The model firstly generates candidate regions using new structural similarity-enhanced supervoxel over-segmentation plus hierarchical clustering. Then it adopts a deep stacked sparse autoencoder (SSAE) network to learn the discriminative deep feature to represent the regions. Finally, the features are fed to train a novel nonlinear within-class neighborhood preserved soft margin support vector (C-SVC) classifier and multiple-output support vector ( &epsilon, SVR) regressor for refining the location of myocardium. To improve the stability and generalization, the model also takes hard negative sample mining strategy to fine-tune the SSAE and the classifier. The proposed model with impacts of different components were extensively evaluated and compared to related methods on public cardiac data set. Experimental results verified the effectiveness of proposed integrated components, and demonstrated that it was robust in myocardium localization and outperformed the state-of-the-art methods in terms of typical metrics. This study would be beneficial in some cardiac image processing such as region-of-interest cropping and left ventricle volume measurement.

Rab3D belongs to Rab protein family. Previous reports showed that the expression of Rab3D was dysregulated in various types of cancer. Rab3D belongsRab3D belongs. However, little is known about the role of Rab3D in carcinogenesis and progression of colorectal cancer (CRC). Here, we first evaluated the expression of Rab3D in 32 fresh CRC and matched normal tissues and found Rab3D was dramatically increased in CRC tissues compared to normal tissues (p

// Zheng-Shi Wang 1, * , Ming Zhong 1, * , Yu-Hai Bian 1 , Yi-Fei Mu 1 , Shao-Lan Qin 1 , Min-Hao Yu 1 , Jun Qin 1 1 Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China * These authors have contributed equally to this work Correspondence to: Jun Qin, email: dr.qinjun@gmail.com Min-Hao Yu, email: fishmeangood@163.com Keywords: microRNA-187, CD276, colorectal cancer, growth, invasion Received: October 14, 2015 Accepted: May 11, 2016 Published: June 14, 2016 ABSTRACT Aberrantly expressed microRNAs contribute to the initiation and progression of human cancers. However, the underlying functions of microRNA-187 (miR-187) in colorectal cancer (CRC) remain largely unexplored. Here, we demonstrated that miR-187 was significantly down-regulated in CRC tissues and cell lines compared to their normal counterparts. By Kaplan-Meier analysis, we revealed that decreased miR-187 expression was closely associated with shorter overall survival and relapse-free survival of patients with CRC. By gain- and loss-of-function studies, we showed that miR-187 remarkably suppressed CRC cell proliferation, migration, invasion, and promoted cell apoptosis. Furthermore, bioinformatics analysis and luciferase reporter assay identified that CD276 was the direct functional target of miR-187 in CRC. Genetic silencing of CD276 recapitulated similar phenotype as observed in over-expression of miR-187, and restoration of CD276 completely rescued the inhibitory effect of miR-187 in CRC cells. Taken together, our study implied the essential roles of miR-187 in suppressing CRC progression, and a novel link between miR-187 and CD276 in CRC.

The identification of mosaicism is important in establishing a disease diagnosis, assessing recurrence risk, and genetic counseling. Next-generation sequencing (NGS) with deep sequence coverage enhances sensitivity and allows for accurate quantification of the level of mosaicism. NGS identifies low-level mosaicism that would be undetectable by conventional Sanger sequencing. A customized DNA probe library was used for capturing targeted genes, followed by deep NGS analysis. The mean coverage depth per base was approximately 800×. The NGS sequence data were analyzed for single-nucleotide variants and copy number variations. Mosaic mutations in 10 cases/families were detected and confirmed by NGS analysis. Mosaicism was identified for autosomal dominant (JAG1, COL3A1), autosomal recessive (PYGM), and X-linked (PHKA2, PDHA1, OTC, and SLC6A8) disorders. The mosaicism was identified either in one or more tissues from the probands or in a parent of an affected child. When analyzing data from patients with unusual testing results or inheritance patterns, it is important to further evaluate the possibility of mosaicism. Deep NGS analysis not only provides insights into the spectrum of mosaic mutations but also underlines the importance of the detection of mosaicism as an integral part of clinical molecular diagnosis and genetic counseling.

Phytochemical investigation of the 70% EtOH extract of the rhizome of Anemone amurensis led to the isolation of two new oleanane-type triterpenoid saponins 1 and 2. Their structures were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR data, and HR–ESI–MS. Compounds 1 and 2 were tested for cytotoxicities against two human cancer cell lines (A549 and Hep-G2). Compound 2 showed potent cytotoxicity with IC50 values of 38.53 and 66.17 μM, respectively, while compound 1 with IC50 > 100 μM.

Aberrant expression of the miR-129 family has been found in several types of cancer, yet its expression and potential biologic role in breast cancer remain largely unknown. In the present study, we found that miR-129-2 was consistently downregulated in the breast cancer specimens and cell lines. Overexpression of miR-129-2-3p markedly suppressed breast cancer cell proliferation and induced its apoptosis. In addition, a luciferase reporter assay revealed that miR-129-2-3p suppressed BCL2L2 expression. Furthermore, BCL2L2 was able to reverse miR-129-2-3p-mediated cell apoptosis, indicating that BCL2L2 plays a crucial role in mediating the tumor-suppressive role of miR-129-2-3p. Moreover, bisulfite DNA sequencing PCR (BSP) analysis identified that promoter hypermethylation was responsible for the downregulation of miR-129-2 in breast cancer. Collectively, our findings indicate that miR-129-2 is downregulated in breast cancer cells by promoter hypermethylation. Moreover, downregulation of miR-129-2 results in BCL2L2 overexpression and disease progression in breast cancer patients.

Objective To investigate the relationship between inflammatory factors, oxidative stress and type 1 deiodinase (DIO-1) concentration in patients with chronic renal failure (CRF) with or without euthyroid sick syndrome (ESS). Methods This study recruited patients with CRF and divided them into two groups: group 1 had low free triiodothyronine (FT3) levels; and group 2 had normal FT3 levels. Group 3 consisted of healthy volunteers. Serum levels of interleukin (IL)-6, IL-1β, tumour necrosis factor (TNF)-α, 8-isoprostane and DIO-1 were measured using enzyme-linked immunosorbent assays. Multiple regression analysis was used to analyse correlations between parameters. Results Sixty patients were enrolled into each group and the groups were comparable in terms of vital signs, white blood cell count, free thyroxine and thyroid stimulating hormone concentrations. The serum DIO-1 concentration was significantly higher in group 2 than in groups 1 and 3. Multivariate regression analysis revealed that the DIO-1 concentration was inversely correlated with the TNF-α concentration. Conclusions Patients with CRF without ESS showed higher concentrations of DIO-1 than patients with ESS. The DIO-1 concentration was inversely correlated with the TNF-α concentration, which might indicate that the inflammatory response was milder in the patients with CRF without ESS than in those with ESS.

Transforming growth factor β-stimulated clone 22 domain 1 (TSC22) has been identified as a cancer suppressor gene in various kinds of cancers. The purpose of this study was to explore the expression of TSC22 in colorectal cancer (CRC) tissues and cell lines. 24 matched CRC and normal tissue samples by qPCR along with 18 pairs of them by Western blot demonstrated TSC22 level was decreased in CRC compared with normal tissue. The protein expression of TSC22 was examined in 310 CRC specimens. Results showed low expression of TSC22 was significantly correlated with tumor size (P = 0.048) and tumor infiltration (P = 0.016). Kaplan-Meier method suggested low expression of TSC22 was inversely associated with OS for 276 samples (P

Chicken seasoning is a widely consumed palatable seasoning made with chicken meat. Quality, and especially sensory quality, may determine the consumer choice of food. The same bag of chicken seasoning will be stored by the consumers over a long period of time when it is in use, so it is particularly important to be able to assess its sensory quality. However, the sensory quality defects of chicken seasoning during storage remain unknown. This study evaluated flavor changes in chicken seasoning during storage using sensory evaluation and gas chromatography-mass spectrometry (GC-MS).The sensory evaluation indicated a perceptible change in rancidity during storage. The GC-MS results showed increases in the content of aldehydes, heterocyclic compounds, ketones, and sulfur compounds associated with lipid oxidation. A random forest model was constructed to predict the storage time based on the data for volatile compounds related to lipid oxidation. The low average predicted error indicated a good correlation between lipid oxidation and storage time.These results suggest that lipid oxidation is the main factor behind sensory quality defects in chicken seasoning during storage. This can be used as the basis for further evaluation of sensory quality and the shelf life of chicken seasoning. © 2018 Society of Chemical Industry.

Epithelial cell transforming sequence 2 (ECT2) is a well-studied guanine nucleotide exchange factor for the Rho family GTPase, which has been demonstrated as an oncogene in many types of human cancers. However, little is known about the prognostic value of ECT2 in colorectal cancer (CRC). In current study, we investigated the expression pattern and underlying clinical significance of ECT2 in CRC. ECT2 expression was detected in 345 CRC specimens by immunohistochemistry, and its correlation with clinicopathologic parameters and prognosis of CRC patients were analyzed. Data from Oncomine database and real-time PCR demonstrated that ECT2 expression was elevated in CRC compared with normal tissues. Among the clinical parameters analyzed, high expression level of ECT2 significantly associated with tumor size (P=0.020), serum CEA levels (P = 0.000) and TNM stage (P=0.027). Kaplan-Meier survival analysis showed that patients with high ECT2 expression had a remarkably shorter overall survival. Cox regression analysis revealed that ECT2 expression level was a significant and independent prognostic factor for overall survival rate of CRC patients. These data suggested that ECT2 is an unfavorable biomarker of prognosis in CRC and that ECT2 may be a potential therapeutic candidate for CRC treatment.

OBJECTIVE The use of bone marrow cells (BMCs) to regenerate the myocardium and vessels is a new treatment for ischemic heart diseases (IHD) that has been receiving attention. In this study, a meta-analysis was used to analyze the efficacy of combining coronary artery bypass graft (CABG) surgery with BMC transplantation in the treatment of IHD. METHODS AND RESULTS MEDLINE, EMBASE, Cochrane, CNKI, WAN-FANG, and WEI-PU databases were searched. The main inclusion criteria were as follows: (a) studies that analyzed patients diagnosed with chronic IHD. (b) Studies that had randomized-controlled trials. (c) Studies that included research comparing the efficacy of CABG and CABG combined with bone BMC transplantation in the treatment of IHD. (d) Studies with specific enumeration data at the end of the follow-up with a follow-up time of at least 3 months. Nine randomized trials were included. There were 158 patients in the group that received the treatment of CABG surgery as well as stem cell transplantation, referred to as the 'cell transplantation group.' A total of 147 patients were in the group that only received the treatment of CABG surgery, referred to as the 'CABG group'. Our data show that not only did stem cell transplantation significantly improve left ventricular ejection fraction (odds ratio=11.7, 95% confidence interval: 4.04-19.36; P=0.003) but it also significantly reduced the left ventricular end-diastolic volume and left ventricular end-systolic volume (P

Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin.

Two new triterpenoid saponins were isolated from the 70% ethanol extract of the rhizome of Anemone amurensis, they are oleanolic acid 28-O-β-d-glucopyranosyl-(1 → 3)-α-l-rhamnopyranosyl-(1 → 4)-β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranosyl ester (1) and 23,27-dihydroxy oleanolic acid 3-O-α-l-arabinopyranoside (2). The structures of 1 and 2 were elucidated on the basis of chemical and spectral analysis, including 1D and 2D NMR data and HR-ESI-MS. Compounds 1 and 2 were tested for cytotoxicities against three human cancer cell lines (A549, Hep-G2, and MCF-7). Compound 1 showed potent cytotoxicity with IC50 values of 34.76, 41.17, and 28.92 μM, respectively, while compound 2 with IC50>100 μM.

To observe the influence of electroacupuncture stimulation (EA) of "Neiguan" (PC 6)/"Lieque" (LU 7) on ST segment of electrocardiogram (ECG) and the expression of myocardiac chloride channel (CLC)-2 and calcium (CaThirty ASIC 3Outcomes of HE staining showed that the ischemic injury (sarcoplasm swelling and necrosis, etc.) of the left ventrical myocardial tissue after mo-deling was relatively milder in the EA-PC 6 group, not in the EA-non-acupoint group. The SOD activity was significantly lower in the model group than in the control group (EA of "Neiguan" (PC 6) can effectively suppress the increase of expression of CLC-2 and CLCA proteins in the left ventricle myocardium, which may contribute to its effect in relieving myocardial injury in mice.

Loss of TGF-β tumour suppressive response is a hallmark of human cancers. As a central player in TGF-β signal transduction, SMAD4 (also known as DPC4) is frequently mutated or deleted in gastrointestinal and pancreatic cancer. However, such genetic alterations are rare in most cancer types and the underlying mechanism for TGF-β resistance is not understood. Here we describe a mechanism of TGF-β resistance in ALK-positive tumours, including lymphoma, lung cancer and neuroblastoma. We demonstrate that, in ALK-positive tumours, ALK directly phosphorylates SMAD4 at Tyr 95. Phosphorylated SMAD4 is unable to bind to DNA and fails to elicit TGF-β gene responses and tumour suppressing responses. Chemical or genetic interference of the oncogenic ALK restores TGF-β responses in ALK-positive tumour cells. These findings reveal that SMAD4 is tyrosine-phosphorylated by an oncogenic tyrosine kinase during tumorigenesis. This suggests a mechanism by which SMAD4 is inactivated in cancers and provides guidance for targeted therapies in ALK-positive cancers.

Laparoscopic surgery is widespread and safe for the management of patients with colorectal cancer (CRC). Although the use of standard surgical techniques can prevent perioperative wound infections, surgical site infections (SSIs) remain an unresolved complication in laparoscopic-assisted colectomy. The present study investigated the ability of plastic wound protectors applied to the extraction incision during the externalized portion of the procedure to reduce the rate of infection in laparoscopic-assisted colectomy. We completed a retrospective review of the medical records of patients who underwent nonemergent laparoscopic-assisted between January 2015 and June 2016. Outcomes for patients with and without the use of a wound protector were compared. A total of 109 patients were included in this study. There was 1 patient in the wound protector group (n = 57) and 7 in the nonwound protector group (n = 52) who developed a wound infection at the colon extraction site (P = .02). Furthermore, the average postoperative hospital stay in the wound protector group was shorter compared to the nonwound protector group (7.47 ± 0.24 vs 8.73 ± 0.54 days, P = .03). In conclusion, this study indicates that the use of a plastic wound protector during laparoscope-assisted colectomy does reduce postoperative wound infection rates, and the wound protectors are beneficial for specimen extraction and digestive tract reconstruction.

Context • Subclinical hypothyroidism (SCH) in pregnancy can be associated with increased complications in pregnant women and neurocognitive deficits in fetuses. Two recently published meta-analyses investigated the effects of levothyroxine (LT4) supplementation on pregnancy outcomes but did not report adverse complications and neonatal outcomes. Objectives • The study intended to assess the effects of LT4 supplementation in the treatment of pregnant women with thyroid dysfunction. Design • The research team performed a meta-analysis of randomized controlled trials (RCTs) published in PubMed, Embase, Web of Science, Chinese BioMedical Literature Service System, and China National Knowledge Infrastructure databases. Participants • Participants were infertile women who had SCH or were TPO antibody positive and who participated in the RCTs examined in the study. Intervention • The participants in the RCTs in the intervention groups received LT4 supplementation and the control groups received a placebo or no treatment. Outcome Measures • The main outcome measures included maternal outcomes-delivery rate, miscarriage rate, fertilization rate, clinical pregnancy rate, preeclampsia, gestational diabetes, and gestational hypertension-and neonatal outcomes-preterm delivery, lower birth weight, intrauterine growth restriction, neonatal death, and congenital malformations. Results were expressed as risk ratios with 95% confidence intervals. Results • A total of 14 RCTs involving 1918 patients were included in the meta-analysis. Compared with control treatments, LT4 supplementation significantly increased the delivery, clinical pregnancy, and fertilization rates. Moreover, LT4 significantly reduced the miscarriage rate, gestational diabetes, and gestational hypertension, but not preeclampsia. For the neonatal outcomes, the study found that the LT4 group had fewer preterm deliveries, birth weights2500 g, deaths, and congenital malformations.LT4 supplementation showed beneficial effects in pregnancy outcomes among patients with thyroid dysfunction. Thus, LT4 should be recommended to improve clinical pregnancy outcomes in women with thyroid dysfunction.

Background & Aims Stearoyl-CoA desaturase (SCD) synthesizes monounsaturated fatty acids (MUFAs) and has been associated with the development of metabolic syndrome, tumorigenesis, and stem cell characteristics. We investigated whether and how SCD promotes liver fibrosis and tumor development in mice. Methods Rodent primary hepatic stellate cells (HSCs), mouse liver tumor-initiating stem cell-like cells (TICs), and human hepatocellular carcinoma (HCC) cell lines were exposed to Wnt signaling inhibitors and changes in gene expression patterns were analyzed. We assessed the functions of SCD by pharmacologic and conditional genetic manipulation in mice with hepatotoxic or cholestatic induction of liver fibrosis, orthotopic transplants of TICs, or liver tumors induced by administration of diethyl nitrosamine. We performed bioinformatic analyses of SCD expression in HCC vs nontumor liver samples collected from patients, and correlated levels with HCC stage and patient mortality. We performed nano-bead pull-down assays, liquid chromatography–mass spectrometry, computational modeling, and ribonucleoprotein immunoprecipitation analyses to identify MUFA-interacting proteins. We examined the effects of SCD inhibition on Wnt signaling, including the expression and stability of low-density lipoprotein–receptor–related proteins 5 and 6 (LRP5 and LRP6), by immunoblot and quantitative polymerase chain reaction analyses. Results SCD was overexpressed in activated HSC and HCC cells from patients; levels of SCD messenger RNA (mRNA) correlated with HCC stage and patient survival time. In rodent HSCs and TICs, the Wnt effector β-catenin increased sterol regulatory element binding protein 1–dependent transcription of Scd , and β-catenin in return was stabilized by MUFAs generated by SCD. This loop required MUFA inhibition of binding of Ras–related nuclear protein 1 (Ran1) to transportin 1 and reduced nuclear import of elav-like protein 1 (HuR), increasing cytosolic levels of HuR and HuR–mediated stabilization of mRNAs encoding LRP5 and LRP6. Genetic disruption of Scd and pharmacologic inhibitors of SCD reduced HSC activation and TIC self-renewal and attenuated liver fibrosis and tumorigenesis in mice. Conditional disruption of Scd2 in activated HSCs prevented growth of tumors from TICs and reduced the formation of diethyl nitrosamine–induced liver tumors in mice. Conclusions In rodent HSCs and TICs, we found SCD expression to be regulated by Wnt-β-catenin signaling, and MUFAs produced by SCD provided a forward loop to amplify Wnt signaling via stabilization of Lrp5 and Lrp6 mRNAs, contributing to liver fibrosis and tumor growth. SCD expressed by HSCs promoted liver tumor development in mice. Components of the identified loop linking HSCs and TICs might be therapeutic targets for liver fibrosis and tumors.

A series of group-10 metal complexes 1–14 of oxoisoaporphine derivatives were designed and synthesized. 1–14 were more selectively cytotoxic to Hep-G2 cells comparing with normal liver cells. In vitro cytotoxicity results showed that complexes 1–6, 7, 8, 10 and 11, especially 3, were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S phase arrest. In addition, 1–6 also caused mitochondrial dysfunction. Notably, 3 with 6-amino substituted ligand La exhibited less side effects than 6 with 8-amino substituted ligand Lb and cisplatin, but similar tumor growth inhibition efficacy in BEL-7402 xenograft model. Complex 3 has the potential to be developed as an effective anticancer agent.

BackgroundObesity is highly prevalent worldwide. More and more studies have been conducted on the relationship between H. pylori infection and obesity or overweight. But the relationship between them is controversial in the literatures and there is no comprehensive evidence for the correlation.AimTo evaluate the prevalence of H. pylori infection in Chinese adult subjects who received routine physical examinations and the relationship between H. pylori and obesity.MethodsLiteratures on H. pylori infection and obesity in Chinese population were searched in online databases. Relevant data were extracted independently by two researchers and meta-analysis was performed by using Review manager 5.3 software.Results22 articles were selected with a total sample size of 178033. The pooled prevalence of H. pylori was 42% (95%CI: 37% to 47%) and mean difference of BMI between subjects with and without H. pylori infection was 0.94 (95%CI: -0.04 to 1.91). 9 eligible studies with 27111 subjects were used to calculated pooled OR value because they contained obesity groups. The OR value showed that H. pylori-positive subjects tended to be obese at a risk of 1.20 (95% CI: 1.13 to 1.28).ConclusionIn China, obesity has association with H. pylori infection. H. pylori infection may be one of the risk factors for obesity.

This paper presents a new scheme to improve the performance of finger-vein identification systems. Firstly, a vein pattern extraction method to extract the finger-vein shape and orientation features is proposed. Secondly, to accommodate the potential local and global variations at the same time, a region-based matching scheme is investigated by employing the Scale Invariant Feature Transform (SIFT) matching method. Finally, the finger-vein shape, orientation and SIFT features are combined to further enhance the performance. The experimental results on databases of 426 and 170 fingers demonstrate the consistent superiority of the proposed approach.

The objective of this study was to investigate the effects of rat umbilical cord mesenchymal stem cells (UCMSCs) from Wharton's jelly on dibutyltin dichloride (DBTC)-induced chronic pancreatitis (CP) and subsequent pancreatic fibrosis in rats.A rat model of CP induced by DBTC was used. Male Sprague-Dawley rats were randomly divided into 4 groups: the control, DBTC, DBTC + UCMSCs, and control + UCMSC groups. Umbilical cord mesenchymal stem cells were administered intravenously on day 5 after the administration of DBTC. On days 14 and 28, the rats were evaluated morphologically and biochemically. The expression levels of inflammatory cytokines and chemokines in the pancreatic tissues of different groups were evaluated using quantitative real-time polymerase chain reaction. The activation of pancreatic stellate cells was estimated by immunochemistry and Western blot analysis of α-smooth muscle actin.Umbilical cord mesenchymal stem cells were detected in inflamed pancreatic tissues. Umbilical cord mesenchymal stem cell treatment improved the histological scores and alleviated the fibrosis of pancreas samples, The expression of cytokines in the DBTC + UCMSC group was significantly lower than that in the DBTC group. Also, pancreatic stellate cell activation was inhibited by UCMSC treatment.Xenogeneic transplantation of UCMSCs is a novel approach for the treatment of CP and subsequent fibrosis. Umbilical cord mesenchymal stem cells may be a promising therapeutic intervention for human CP in the future.

Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1–3 have been synthesized and fully characterized. 1–3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1–3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80–3 and SK-OV-3/DDP cells, with IC50 value of 0.23−4.31 μM. Interestingly, 0.5 μM 1–3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins. In addition, 1–3 induced HepG2 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by p53 activation, ROS production, Bax up-regulation and Bcl-2 down-regulation, mitochondrial dysfunction, cytochrome c release, caspase activation and PARP cleavage. Furthermore, 3 inhibited tumor growth in HepG2 xenograft model, and displayed more safety profile in vivo than cisplatin.