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Ying Chen,1 Mengxia Yan,1 Haoyan Chen,1 Yanan Sheng,2 Zhenhua Wang,3 Bin Wu1 1Clinical Research Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201112, People’s Republic of China; 2Medical Affairs, Takeda (China) International Trading Company, Beijing, 100006, People’s Republic of China; 3Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201112, People’s Republic of ChinaCorrespondence: Bin Wu, Tel/Fax +86-21-68383427, Email scilwsjtu-wb@yahoo.comPurpose: Understanding the quality of life and the factors that influence it for patients with short bowel syndrome (SBS) and their caregivers is of utmost importance in order to enhance their well-being. Therefore, This study aimed to provide a comprehensive understanding of the impact of SBS on patients and their caregivers, as well as its associated factors, by synthesizing the available evidence.Methods: A systematic review of the literature was done using PubMed, Embase databases, CNKI, and ISPOR conference papers. Included articles were manually searched to identify any other relevant studies. Quality was assessed using appropriate Joanna Briggs Institute critical appraisal tools.Results: This review included 16 studies, comprising 15 observational studies and 1 randomized controlled trial. The findings revealed that the QoL of patients with SBS was lower than that of the general population regarding physical functioning and psychological domain. Meanwhile, caregivers experienced challenges in maintaining their QoL. The QoL of SBS patients was found to be influenced by various factors such as treatment, age, sex, stoma, and small intestine length. Among them, the treatment is the most noteworthy factor that can be effectively improved through external interventions.Conclusion: While numerous studies have provided insights into the compromised QoL experienced by individuals with SBS and their caregivers, there remains a scarcity of large-sample quantitative investigations examining the determinants of QoL. The existing body of literature on caregivers is also notably deficient.Keywords: caregiver, malabsorption, quality of life, short bowel syndrome, stoma, age

Siyuan Zhou,1,2 Xiaojie Hu,1,2 Yunfei Wang,1,2 Wenting Fei,2 Yuqin Sheng,2 Huafa Que1,2 1Department of Traditional Chinese Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Longhua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Huafa Que, Department of Traditional Chinese Surgery, Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine, No. 725, Wanping South Road, Xuhui District, Shanghai, 200032, People’s Republic of China, Tel +86 18917763260, Email huafaque@126.comObjective: Diabetic foot ulcer (DFU) frequently leads to infections, with infected DFUs being a common cause of amputation. Infection by methicillin-resistant Staphylococcus aureus (MRSA) notably increases the necessity for amputation and surgical debridement in affected individuals. Consequently, determining the prevalence and trends of MRSA in patients with DFU is of critical importance. This study aimed to assess the global prevalence and to identify trends in the occurrence of MRSA in tissue or wound swab samples from DFU patients.Methods: We conducted a comprehensive literature search across PubMed, Embase, Scopus, and Ovid, spanning from the inception of these databases to July 2023, imposing no language restrictions. The inclusion criteria required that the studies report on 30 or more patients with DFU. Additionally, we categorized our analysis based on geographic region, publication date, and the economic status of the patient’s domicile. Our primary endpoint was to ascertain the prevalence of MRSA in DFUs. This systematic review has been registered at (https://www.crd.york.ac.uk/prospero/), with the identifier CRD 42023444360.Results: Our analysis encompassed 40 studies involving 12,924 patients across 20 countries. We found that the overall prevalence of MRSA in DFU was 17% (95% Confidence Interval [CI] 0.14– 0.20). Regional prevalence varied significantly: in South America, it was 61% (95% CI 0.46– 0.76), in North America 20% (95% CI 0.12– 0.27), in Europe 19% (95% CI 0.14– 0.25), in Africa 13% (95% CI 0.06– 0.20), and in other subgroups 11% (95% CI 0.08– 0.15). The prevalence of MRSA in DFUs also differed according to the economic status of the countries: 19% (95% CI 0.15– 0.23) in high-income countries, 24% (95% CI 0.1– 0.37) in upper-middle-income countries, 11% (95% CI 0.07– 0.15) in lower-middle-income countries, and 20% (95% CI 0.13– 0.27) in low-income countries. Notably, there has been a decline in MRSA prevalence, from 25% before 2010 to 9% thereafter.Conclusion: This meta-analysis reveals a decreasing yet still significant global prevalence of MRSA in DFUs. This trend has important implications for antimicrobial resistance and underscores the need for developing targeted programs focusing on infection prevention and exploring alternative therapeutic strategies.Keywords: diabetic foot ulcers, global prevalence, epidemiological trends, systematic review, meta-analysis

Yu-Yun Zhang,1 Wei Li,2 Yu Sheng,1 Qun Wang,3,&ast; Fang Zhao,4,&ast; Ying Wei4 1School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Endocrinology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 3Endocrinology and Metabolism Department, Peking University Third Hospital, Beijing, People’s Republic of China; 4Department of Endocrinology, China-Japan Friendship Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Sheng, School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 33 Badachu Road, Shijingshan District, Beijing, People’s Republic of China, Tel +86 138 1069 1298, Email shengyupumc2020@163.comPurpose: To address the prevalence of diabetes distress (DD) and its correlators in adults with type 2 diabetes.Patients and Methods: During 2021 and 2022, we conducted a cross-sectional study in three Class A tertiary comprehensive hospitals in China, and received 947 participants who completed a printed survey covering DD, demographic, diabetic, physiological, and psychosocial factors. We used Jonckheere-Terpstra, chi-square, and Fisher’s exact tests to assess intergroup differences between different levels of DD. We used ordinal logistic regression analysis to analyze correlators of DD further.Results: The prevalence of DD was 34.64%. In univariate analysis, those with lower satisfaction with financial status, longer durations of diabetes, more complications, higher glycemia, more severe insomnia, treatment by medications only, poorer lifestyle interventions, fewer self-care activities, more types and frequencies of insulin injections, and spending more money and time on treatment were susceptible to DD. Type D personality, negative illness perceptions, negative coping styles, and psychological effects of major life events were related to higher DD. Hope, self-efficacy, positive coping styles, and social support can reduce DD. In ordinal logistic regression analysis, hypoglycemic episode (β=− 1.118, p=0.019, “have hypoglycemic” as reference) and Brief Illness Perception Questionnaire (β=0.090, p< 0.001) were significant positive correlators for DD, while diet intervention (β=0.803, p=0.022, “have diet intervention” as reference), money spent on diabetes treatment (β

Yunjian Sheng,1,&ast; Yu Zeng,1,&ast; Wenling Luo,1 Xuemei Zhang,1 Hang Wang,2 Jiahuan Jiao3 1Department of Infectious Diseases, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Department of Gastroenterology, Dazhou Hospital of Integrated Traditional and Western Medicine, Dazhou, Sichuan, People’s Republic of China; 3Department of Infectious Diseases, the People’s Hospital of Leshan, Leshan, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunjian Sheng, Department of Infectious Diseases, the Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Luzhou, Sichuan Province, People’s Republic of China, Email sheng200410@163.comBackground: Acute-on-chronic liver failure is a common clinical syndrome with high short-term mortality, and early assessment of its mortality risk is crucial, but the search for valid and accurate prognostic biomarkers is a challenging endeavor. The purpose of this study was to investigate the predictive value of the prothrombin time-international normalized ratio to albumin ratio (PTAR) for mortality in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF).Patients and methods: A total of 354 patients with HBV-ACLF were included in the retrospective study. Patients were divided into survival and non-survival groups based on 90-day follow-up. Cox regression analysis was used to explore the relationship between PTAR and 90-day mortality in patients with HBV-ACLF. The area under the receiver operating characteristic curve was used to evaluate the effectiveness of PTAR in predicting mortality.Results: PTAR was significantly higher in non-survivors than in survivors. The results of multivariate analysis showed that PTAR was a valid independent predictor of mortality in patients with HBV-ACLF. Its predictive ability for mortality was similar to that of the Child-Turcotte-Pugh score, the end-stage liver disease model (MELD) score, and the MELD-sodium score.Conclusion: PTAR may be a simple and effective tool for predicting the prognosis of patients with HBV-ACLF.Keywords: acute-on-chronic liver failure, hepatitis B virus, prothrombin time-international normalized ratio to albumin ratio, prognosis

Jihai Chen,1,2 Lijun Wei,2 Xiaoxia Zhu,2 Wenli Xu,2 Yuxin Zou,2 Xinyu Qi,2 Jia Fang,2 Xiaodong Wang,2 Xiaolan Shi,1 Yunlu Sheng,2 Guoxian Ding,2 Xiaojun Ouyang,1 Yu Duan2 1Department of Geriatric, Geriatric Hospital of Nanjing Medical University, Nanjing, 210024, People’s Republic of China; 2Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of ChinaCorrespondence: Yu Duan, Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China, Email duanyujsph@163.com Xiaojun Ouyang, Department of Geriatric, Geriatric Hospital of Nanjing Medical University, Luojia Road 30, Nanjing, 210024, People’s Republic of China, Email xiaojun_ouyang@aliyun.comBackground and Aims: Sarcopenia is a common disease in the elderly, and the thyroid hormone (TH) might participate in the pathogenesis of sarcopenia. However, the results of previous studies were not completely consistent. We performed this study to investigate the association between THs and sarcopenia in a Chinese elderly euthyroid population.Subjects and Methods: A total of 309 Chinese elderly euthyroid subjects with an average age of 85.19 ± 7.8 years were enrolled. Participants were divided into four groups (non-sarcopenia, possible sarcopenia, sarcopenia and serve sarcopenia) according to the consensus update of AWGS in 2019. Serum levels of TT3, FT3, TT4, FT4, TSH, rT3 and TBG were measured. Muscle mass was measured by multifrequency bioelectrical impedance analysis, hand grip (HG) was represented by spring-type dynamometer, and gait speed (GS) was determined by 6-metre walk test. The FRAIL scale was used to assess frailty.Results: Compared to the non-sarcopenia group, the sarcopenia group showed a significant increase in age and FRIAL score, while FT3 and TT3 levels decreased significantly. Partial correlation analysis (adjusted by age, gender and the scores of FRIAL scale) indicated that FT3, TT3 and TSH had significant positive correlations with HG, and there also was a significant positive correlation between TT3 and GS. In addition, after adjusting for age, gender, BMI, ALT, sCr, and score on the FRAIL scale, the multivariate linear regression analysis showed that TT3 was positively associated with muscle strength and negatively associated with sarcopenia risk.Conclusion: There is an association between the low TT3 level and sarcopenia. Therefore, maintaining higher T3 concentrations within the normal range appears to be beneficial for sarcopenia in the elderly. In addition, due to the fluctuation of FT3, TT3 is a more stable and practical indicator to evaluate the relationship between sarcopenia and thyroid hormone in the elderly euthyroid population.Graphical Abstract: Keywords: sarcopenia, thyroid hormone, elderly, muscle strength

Xiaohui Zhang,1– 3 Da Zhen,4 Xuemei Li,1,2,5 Faling Yi,1,2,5 Zhanhao Zhang,1,2,5 Wei Yang,1,2,6 Xuguang Li,1,2,5 Yemeng Sheng,1,2,5 Xiaoli Liu,1,2,5 Tianbo Jin,1,2,5 Yongjun He1,2,5 1Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 2Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 3Department of Ultrasound, the Affiliated Hospital of Xizang Minzu University, Xianyang, People’s Republic of China; 4Department of Medical, Tibet Autonomous Region Maternity and Children’s Hospital, Lhasa, People’s Republic of China; 5School of Medicine, Xizang Minzu University, Xianyang, People’s Republic of China; 6Department of Emergency, the Affiliated Hospital of Xizang Minzu University, Xianyang, People’s Republic of ChinaCorrespondence: Tianbo Jin; Yongjun He, Xizang Minzu University, &num;6 East Wenhui Road, Xianyang, Shaanxi, 712082, People’s Republic of China, Email tianbo__jin@163.com; 545139647@qq.comBackground: Ventricular septal defect (VSD) is the most common congenital cardiac abnormality in children and the second most common in adults. This study aimed to explore the potentially causative genes in VSD patients in the Chinese Tibetan population, and to provide a theoretical basis for the genetic mechanism of VSD.Methods: Peripheral venous blood was collected from 20 VSD subjects, and whole-genome DNA was extracted. High-throughput sequencing was performed on qualified DNA samples using whole-exome sequencing (WES) technology. After filtering, detecting, and annotating qualified data, single nucleotide variations (SNVs) and insertion-deletion (InDel) markers were analyzed, and data processing software such as GATK, SIFT, Polyphen, and MutationTaster were used for comparative evaluation and prediction of pathogenic deleterious variants associated with VSD.Results: A total of 4793 variant loci, including 4168 SNVs, 557 InDels and 68 unknown loci and 2566 variant genes were obtained from 20 VSD subjects through bioinformatics analysis. According to the screening of the prediction software and database, the occurrence of VSD was predicted to be associated with five inherited pathogenic gene mutations, all of which were missense mutations, including NOTCH2 (c.1396C >A:p.Gln466Lys), ATIC (c.235C >T:p.Arg79Cys), MRI1 (c.629G >A:p.Arg210Gln), SLC6A13 (c.1138G >A:p.Gly380Arg), ATP13A2 (c.1363C >T:p.Arg455Trp).Conclusion: This study demonstrated that NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 gene variants were potentially associated with VSD in Chinese Tibetan population.Keywords: ventricular septal defect, genes, genetic variation, whole-exome sequencing

Background The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and hence, its resistance to immuno-oncology therapies (IOT), by generating extracellular adenosine (eAdo).Methods Using genetically engineered allograft models of PDAC in syngeneic mice with defined and different immune infiltration and response to IOT and autochthonous tumors in KPC mice we investigated the impact of the adenosine pathway on the PDAC tumor microenvironment (TME). Flow cytometry and imaging mass cytometry (IMC) were used to characterize the subpopulation frequency and spatial distribution of tumor-infiltrating immune cells. Mass spectrometry imaging (MSI) was used to visualize adenosine compartmentalization in the PDAC tumors. RNA sequencing was used to evaluate the influence of the adenosine pathway on the shaping of the immune milieu and correlate our findings to published data sets in human PDAC.Results We demonstrated high expression of adenosine pathway components in tumor-infiltrating immune cells (particularly myeloid populations) in the murine models. MSI demonstrated that extracellular adenosine distribution is heterogeneous in tumors, with high concentrations in peri-necrotic, hypoxic regions, associated with rich myeloid infiltration, demonstrated using IMC. Protumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking the in vivo formation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumor growth and reduced metastatic burden. Additionally, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Adoi remodeled the TME, by reducing the infiltration of M2 macrophages and regulatory T cells. RNA sequencing analysis showed that genes related to immune modulation, hypoxia and tumor stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC.Conclusions The formation of eAdo promotes the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the PDAC immune milieu and improve therapy response in patients with PDAC.

Yaru Sheng,1 Jiangjing Yuan,1 Jing Wang,1 Liya Wang,1 Yuhong Li,1 Yudong Wang1– 3 1Department of Gynecologic Oncology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai, People’s Republic of China; 3Shanghai Key Laboratory of Embryo Original Disease, Shanghai, People’s Republic of ChinaCorrespondence: Yudong Wang; Yuhong Li, Department of Gynecologic Oncology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 910 Hengshan Road, Shanghai, People’s Republic of China, Tel +86-21-64070434-18602 ; +86-21-64070434-25517, Email wangyudong@shsmu.edu.cn; 13022107898@163.comBackground: Ovarian mature cystic teratomas (MCTs) are the most common tumors in pregnant women. The premature rupture of membranes (PROM) is a typical complication of pregnancy; however, the relationship between MCT and PROM is unknown. Therefore, we aimed to determine whether MCT is associated with the occurrence of PROM during pregnancy.Methods: The data of patients with adnexal masses during pregnancy between January 2017 and August 2021 were retrospectively analyzed. Ovarian cystectomy was performed during cesarean delivery or after vaginal delivery. Univariate and multivariate logistic regression models were used for statistical analysis.Results: A total of 234 patients with histopathological results were included. Among these patients, 21 occurred PROM during pregnancy, of which 11 were diagnosed with MCT. Compared with other subtypes, MCT (p=0.025) showed a stronger correlation with PROM and was an independent risk factor for PROM (odds ratio [OR], 2.811; 95% confidence interval [CI], 1.096– 7.215; p=0.032). Furthermore, we found that MCT with a diameter > 5 cm (p=0.0037) was more likely to promote the development of PROM than those that with a diameter < 5 cm.Conclusion: MCT was an independent risk factor for PROM during pregnancy. Positive actions and preventative clinical treatments should be fully taken into consideration by clinicians for pregnant women with MCTs, especially those ≥ 5 cm in diameter, to reduce the clinical complications related to MCT-associated PROM.Keywords: benign ovarian tumor, mature cystic teratoma, premature rupture of membranes, pregnancy

Sijia Ge,1,* Hua Huang,2,* Wei Huang,1 Ran Ji,1 Jing Chen,1 Shuzhen Wu,1 Liyang Wang,1 Tianxin Huang,1 Yu Sheng,1 Haiou Yan,1 Cuihua Lu,1 Lin Ma3 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Jiangsu, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of Nantong University, Jiangsu, People’s Republic of China; 3Department of Gastroenterology, Affiliated Haian Hospital of Nantong University, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lin MaDepartment of Gastroenterology, Affiliated Haian Hospital of Nantong University, Nantong, 226600, Jiangsu, People’s Republic of China, Email 1908397778@qq.comCuihua LuDepartment of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People’s Republic of China, Email lch670608@sina.comBackground: As hepatocellular carcinoma (HCC) having the second-highest mortality rate globally, the early diagnosis and prognosis of HCC have always been the focus of various studies. Although PSME4 has been reported to be closely related to several malignancies, its role in HCC remains unclear.Materials and Methods: The TCGA-LIHC database and HCC tissues were used to explore the expression of PSME4 in HCC. Gene set enrichment analysis (GSEA) was used to forecast the biological behavior of HCC cells that PSME4 might be involved in regulation. In addition, CCK-8, colony formation and flow cytometry assays were used to explore the effect of PSME4 on HCC cells. Furthermore, the underlying PSME4-related signaling pathways in HCC were further confirmed using GSEA.Results: We found that the expression of PSME4 in HCC tissues was significantly higher than that in adjacent normal tissues, and patients with high PSME4 expression have a poor prognosis. CCK-8, colony formation and flow cytometry assays shown that knockdown of PSME4 inhibits HCC cell proliferation of HCC cells, promotes cell apoptosis and moves the cell cycle away from the S phase. Mechanistically, PSME4 may promote the development of HCC through mTOR signaling pathway.Conclusion: The high expression of PSME4 in HCC promotes the proliferation of HCC cells via the mTOR signalling pathway. Therefore, PSME4 is an emerging tumour marker for the early diagnosis and prognosis of HCC.Keywords: hepatocellular carcinoma, mTOR signaling, liver cancer prognosis, PSME4

Meiyan Luo,1– 3 Qian Zhang,1– 3 Yingchun Hu,4 Changfeng Sun,1– 3 Yunjian Sheng,1– 3 Cunliang Deng1– 3 1Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Louzhou, 646000, People’s Republic of China; 2Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Louzhou, 646000, People’s Republic of China; 3Infection and Immunity Laboratory,The Affiliated Hospital of Southwest Medical University, Louzhou, 646000, People’s Republic of China; 4Department of Emergency, The Affiliated Hospital of Southwest Medical University, Louzhou, 646000, People’s Republic of ChinaCorrespondence: Cunliang DengDepartment of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Louzhou, 646000, People’s Republic of ChinaEmail dengcunl64@vip.sina.comPurpose: This study aimed to screen differentially expressed proteins (DEPs) in plasma of patients with sepsis through data-independent acquisition (DIA) and enzyme-linked immunosorbent assays (ELISAs), and provide convenient and accurate serum markers for determining the condition of septic patients.Methods: A total of 53 septic patients and 16 normal controls who were admitted to the Affiliated Hospital of Southwest Medical University between January 2019 and December 2020 were enrolled in this study; 6 specimens from the normal group and 15 from the sepsis group were randomly selected for DIA-based quantitative proteomic analysis. The acquired data were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and a protein-protein interaction (PPI) network was constructed to screen potential markers. The selected proteins were further verified through ELISAs. The differences between control and sepsis groups and between survivors and non-survivors were analysed. Receiver operating characteristic (ROC) curves were drawn to explore their diagnostic value and prognostic efficacy.Results: A total of 149 DEPs were identified by bioinformatics methods. The analyses showed that these proteins are mainly involved in biological processes such as cell movement, stress response, cell proliferation, and immune response. Functional pathway analysis showed that they are mainly involved in leukocyte transendothelial migration, protein synthesis and processing, and various bacterial infections. LGALS3BP was selected as a potential plasma biomarker and further verified through an ELISA. Its level in septic patients was significantly higher than that in normal controls, and its level in non-survivors was also higher than that in survivors. The ROC curves suggested its great diagnostic efficacy and prognostic ability in sepsis.Conclusion: LGALS3BP levels were significantly different between the normal and sepsis groups; it has good diagnostic value in sepsis, and is related to patient prognosis; thus, it might be a biomarker for sepsis.Keywords: LGALS3BP, sepsis, plasma biomarker, DIA, ELISA

Min Li,1 Tianqing Huang,2 Xiaolan Li,3 Zhiwei Shi,3 Yue Sheng,4 Mimi Hu,3 Kui Song3 1Department of Pharmacy, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People’s Republic of China; 3Department of Hematology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People’s Republic of China; 4Department of Pediatrics, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People’s Republic of ChinaCorrespondence: Kui SongDepartment of Hematology, The First Affiliated Hospital of Jishou University, Century Avenue, Jishou City, Hunan Province, 416000, People’s Republic of ChinaEmail js_hematology@163.comBackground: Checkpoint kinase 1 (CHK1) plays an important role in DNA damage response and cell cycle progression. Thus, targeting CHK1 is an efficient strategy for cancer therapy.Purpose: The present study aimed to investigate the potential therapeutic effects of GDC-0575, a CHK1-specific inhibitor, in colitis-associated cancer (CAC) and colitis.Methods: We established a DSS-induced acute colitis model and an azoxymethane/dextran sodium sulfate (DSS)-induced CAC model using mice and tested the effect of GDC-0575 on them. Flow cytometry and immunofluorescence were employed to investigate the infiltration of immune cells, and inflammatory cytokine expression in the colon of mice with CAC or colitis was investigated using ELISA and qPCR. We also investigated the correlation between CHK1 and CCL2/CCR2 in human colorectal cancer (CRC) tissues.Results: Administration of GDC-0575 significantly inhibited CHK1 expression in the colon and dramatically impaired the development of CAC and colitis in mice. Moreover, the inhibition of CHK1 expression resulted in efficient inhibition of infiltration by iNOS-positive macrophages, but had no significant effect on CD4 T cells, CD8 T cells, and myeloid-derived suppressor cells (MDSCs). Significant downregulation of TNF-α, IL-6, and IL-1β and dramatic upregulation of IL-10 were observed in the colons of both mice with CAC and colitis treated with GDC-0575. CCL2 expression was also downregulated by GDC-0575 in both mice with CAC and colitis; this was followed by the inhibition of CCR2+ macrophage infiltration in the colon. Furthermore, we report a positive correlation between CHK1 expression and CCL2/CCR2 expression in the malignant tissues of patients with CRC.Conclusion: Taken together, we infer that GDC-0575 impairs the development of CAC and colitis by regulating cytokine expression and inhibiting CCR2+ macrophage infiltration in mice colon.Keywords: colitis, colitis-associated cancer, CHK1, macrophage

Yuzheng Xue,1,* Yao Zhong,1,* Tielong Wu,1 Yingyue Sheng,1 Yuanyuan Dai,1 Lingling Xu,1 Chuanqing Bao2 1Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi 214041, Jiangsu, People’s Republic of China; 2Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi 214041, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuzheng XueDepartment of Gastroenterology, Affiliated Hospital of Jiangnan University, No. 585, Xingyuan North Road, Wuxi 214041, Jiangsu, People’s Republic of ChinaEmail xueyz001@163.comPurpose: The expression of microRNA-125b (miR-125b) is low in a variety of cancers, including gastric, lung, bladder, thyroid, and esophageal cancers. However, its specific mechanism in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study is aimed to explore the role of miR-125b in PDAC.Methods: PDAC tissues and adjacent tissues were collected for miR-125b analysis by qRT-PCR. Different PDAC cell lines were cultured for miR-125b detection by qRT-PCR, and CAPAN1 cells were selected for the downstream experiments. Cell proliferation was characterized by methyl thiazolyl tetrazolium (MTT) and 5-bromo-2-deoxyUridine (BrdU) staining. Flow cytometry was utilized for apoptosis and cell cycle changes. Cell invasion was determined by the Transwell assay and the dual-luciferase assay was utilized for validating the target gene. Western blotting was used to detect apoptosis related and PI3K/AKT signaling proteins.Results: miR-125b was significantly down-regulated in human PDAC tissues and cell lines (P < 0.05). miR-125b inhibited the growth and invasion of CAPAN1 cells, facilitated apoptosis, and blocked the cell cycle at the G0/G1 phase. Furthermore, miR-125 directly targeted NEDD9. The high expression of NEDD9 impaired the anti-proliferative and anti-apoptotic activity of miR-125b. miR-125b also inhibited apoptosis-related proteins and PI3K/AKT signaling pathways via NEDD9.Conclusion: miR-125b decreased cell growth and invasion, and facilitated apoptosis in CAPAN1 cells through PI3K/AKT inhibition via targeting NEDD9.Keywords: miR-125b, pancreatic ductal adenocarcinoma, apoptosis, NEDD9, PI3K/AKT

Gram-negative bacteria possess an asymmetric outer membrane (OM) composed primarily of lipopolysaccharides (LPSs) on the outer leaflet and phospholipids (PLs) on the inner leaflet. The loss of this asymmetry due to mutations in the LPS biosynthesis or transport pathways causes the externalization of PLs to the outer leaflet of the OM and leads to OM permeability defects. Here, we used metabolic labeling to detect a compromised OM in intact bacteria. Phosphatidylcholine synthase expression in Escherichia coli allowed for the incorporation of exogenous propargylcholine into phosphatidyl(propargyl)choline and exogenous 1-azidoethyl-choline (AECho) into phosphatidyl(azidoethyl)choline (AEPC), as confirmed by LC/MS analyses. A fluorescent copper-free click reagent poorly labeled AEPC in intact wild-type cells but readily labeled AEPC from lysed cells. Fluorescence microscopy and flow cytometry analyses confirmed the absence of significant AEPC labeling from intact wild-type E. coli strains and revealed significant AEPC labeling in an E. coli LPS transport mutant (lptD4213) and an LPS biosynthesis mutant (E. coli lpxC101). Our results suggest that metabolic PL labeling with AECho is a promising tool for detecting a compromised bacterial OM, revealing aberrant PL externalization, and identifying or characterizing novel cell-active inhibitors of LPS biosynthesis or transport.­

Yanmei Wu,1 Yu Zhang,2 Hao Pi,1 Yuan Sheng1 1Department of Breast and Thyroid Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, People’s Republic of China; 2Medical Affairs, Pfizer Biopharmaceutical Group, Shanghai 200041, People’s Republic of ChinaCorrespondence: Yuan ShengDepartment of Breast and Thyroid Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, People’s Republic of ChinaEmail sheng528yuan@126.comAbstract: The clinical use of selective cyclin-dependent kinase (CDK) 4/6 inhibitors has significantly improved the prognosis of patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (ABC/mBC), which almost achieved the double progression-free survival (PFS) in combination with endocrine therapy (ET) compared with ET alone. To date, there are 3 CDK4/6 inhibitors (palbociclib, ribocilcib and abemaciclib) approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat patients with HR+/HER2-ABC/mBC in the first and later lines. The aim of this review is to summarize the current clinical use and ongoing clinical trials of CDK4/6 inhibitors, the published overall survival data, and the potential biomarkers and resistance to CDK4/6 inhibitors.Keywords: CDK4/6 inhibitor, breast cancer, mechanism, clinical efficacy, resistance

Jian Wang,1,* Yuchao Sheng,2,3,* Jun Ni,4 Jianyu Zhu,5 Zhigang Zhou,5 Tianwei Liu,5 Xiaoying Zhang,6 Qi Zhao2,3 1Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Epidemiology, School of Public Health, Fudan University, Shanghai, People’s Republic of China; 3The Key Laboratory of Public Health Safety of Ministry of Education, Shanghai, People’s Republic of China; 4Vaccination Clinics, Gangyan Community Health Service Center, Shanghai, People’s Republic of China; 5Vaccination Clinics, Tangqiao Community Health Service Center, Shanghai, People’s Republic of China; 6Vaccination Clinics, Huacao Community Health Service Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qi ZhaoDepartment of Epidemiology, School of Public Health, Fudan University, 130 Dongan Road, Xuhui District, Shanghai 200032, People’s Republic of ChinaTel/fax +86 21 5423 7335Email zhaoqi@shmu.edu.cnBackground: Parents play an important role in the management of their children’s illnesses, including in decisions concerning how and whether to use antibiotics. This study aims to assess the knowledge and attitude towards antibiotics usage among young parents from different areas in Shanghai and to identify contributing factors of antibiotics usage that are comprehensible for parents.Methods: A cross-sectional study was conducted at vaccination clinics of three community health centers from April to June 2017. Primary guardians who took children for vaccination under the national expanded immunization program were invited to participate.Results: Of the 1368 young parents interviewed, 78.4% of them have taken their children for medical treatment, and 68.9% of their children have taken antibiotics. Parents with education level of senior high school (OR=1.850, 95% CI: 1.214–2.818), or university/college, or above (OR=3.950, 95% CI: 2.604–5.991), and parents with high-income (OR=1.360, 95% CI: 1.013–1.827) have better comprehension of antibiotics. It is found that parents who deny the existence of antibiotic abuse in China (OR=1.857, 95% CI: 1.100–3.135), who have lower income (OR=1.536, 95% CI: 1.074–2.197) and who have antibiotics prescribed by doctors (OR=1.473, 95% CI: 1.048–2.070) are associated with those incorrect practices.Conclusion: Lack of knowledge and poor perception of antibiotics usage are found among young parents in Shanghai. Intervention should be conducted to publicize the rational use of antibiotics, reduce the rate of inappropriate behaviors and limit the sale of antibiotics.Keywords: antimicrobial resistance, KAP, China, urban area

Ageing is associated with increased vulnerability to environmental cold exposure. Previously, we identified the role of the cold-sensitive transient receptor potential (TRP) A1, M8 receptors as vascular cold sensors in mouse skin. We hypothesised that this dynamic cold-sensor system may become dysfunctional in ageing. We show that behavioural and vascular responses to skin local environmental cooling are impaired with even moderate ageing, with reduced TRPM8 gene/protein expression especially. Pharmacological blockade of the residual TRPA1/TRPM8 component substantially diminished the response in aged, compared with young mice. This implies the reliance of the already reduced cold-induced vascular response in ageing mice on remaining TRP receptor activity. Moreover, sympathetic-induced vasoconstriction was reduced with downregulation of the α2c adrenoceptor expression in ageing. The cold-induced vascular response is important for sensing cold and retaining body heat and health. These findings reveal that cold sensors, essential for this neurovascular pathway, decline as ageing onsets.

Siping Zhu,1,* Wei Lin,1,* Shu Chen,1,* Hanmei Qi,1 Siting Wang,2 Aisen Zhang,1 Jinmei Cai,1 Bing Lai,1 Yunlu Sheng,1 Guoxian Ding11Division of Geriatric Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Division of Intensive Care Unit, Nanjing Jiangning Hospital, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workBackground: Sarcopenia is typically defined as the loss of muscle mass, strength and low physical performance with aging. Ultrasound is a safe and easy method for evaluating muscle mass and quality by muscle thickness (MT) and pennation angle (PA), respectively. Although the positive correlations between MT and muscle mass and handgrip strength were observed, the relationship between MT, PA and physical performance remains unclear.Purpose: This study aimed to investigate the correlation of aforementioned ultrasound parameters with muscle mass, muscle strength and physical performance and explore the utility of ultrasound in predicting sarcopenia.Patients and methods: A total of 265 elderly Chinese community dwellers were included. MT of both forearm and lower leg as well as PA of gastrocnemius was assessed by ultrasound. Muscle mass was assessed by dual-energy X-ray absorptiometry. Muscle strength was measured by a Jamar hand dynamometer. Physical performance was assessed by the Short Physical Performance Battery (SPPB).Results: Anterior radial MT in men and regional MTs except posterior fibula in women were negatively correlated with the age. No significant correlation was observed between PA and the age in both genders. Posterior tibial MT and posterior fibula MT were positively correlated with the relative appendicular skeletal muscle mass in men and women, respectively. Anterior ulnar MT was positively correlated with grip strength in both genders. Moreover, gastrocnemius medialis PA showed a positive association with gait speed and SPPB in women but not in men.Conclusion: A combination of posterior fibula MT, anterior ulnar MT and gastrocnemius medialis PA measured by muscle ultrasound is helpful for the assessment of sarcopenia in Chinese elderly women. In addition, a combination of posterior tibial MT and anterior ulnar MT measured by muscle ultrasound is helpful for the assessment of sarcopenia in Chinese elderly men.Keywords: B-mode ultrasound, muscle thickness, pennation angle, muscle mass, muscle strength, physical performance

Yi Sheng,1,* Wei Wang,2,* Bo Hong,2 Xingwang Jiang,1 Ruochuan Sun,1 Qiang Yan,1 Shangxin Zhang,1 Mingdian Lu,1 Shengyi Wang,1 Zhen Zhang,1 Wenchu Lin,2 Yongxiang Li1 1Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; 2High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, China *These authors contributed equally to this work Background: KIF20A is well known as one of the key proteins in mitosis. Recently, a number of studies illustrated that KIF20A might function as an oncogene in some carcinomas. However, its expression levels and clinical value remained unclear in gastric cancer (GC). Patients and methods: In this study, we investigated the expression of KIF20A in samples from GC patients and cell lines by quantitative real-time PCR and Western blot. The function of KIF20A in cell proliferation of GC cell lines was examined via cell viability and colony formation assays. Immunohistochemistry assay based on a tissue microarray consisting of 146 cases was performed to evaluate the prognostic value of KIF20A. The overall survival rate of 122 GC patients based on KIF20A expression was analyzed as well. Finally, using KIF20A inhibitor, genistein, and combining it with cisplatin or fluorouracil, the antitumor effects were studied. Results: Most GC samples (56.76%) showed higher KIF20A expression level compared to their corresponding normal specimens, which demonstrated the potential oncogenic role of KIF20A in GC. The functional studies elucidated the essential role of KIF20A in GC cell proliferation. Besides, tissue microarray result showed that the expression level of KIF20A was significantly related to the histological grades (P=0.036). Furthermore, we found the expression of KIF20A was related to poor overall survival rate, which is coincident with the results from Kaplan–Meier plotter database. In addition, we found that a KIF20A inhibitor, genistein, could enhance the antitumor activity of cisplatin and fluorouracil, which might be considered as a chemosensitive agent in GC. Conclusion: KIF20A can promote cell proliferation in GC, which might be used as an independent prognostic factor and a potential therapeutic target. Keywords: KIF20A, genistein, gastric cancer, prognosis

Abstract Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290 is a biased agonist in human cells expressing RXFP1 with long-term beneficial actions on markers of fibrosis in human cardiac fibroblasts (HCFs). ML290 did not directly compete with orthosteric relaxin binding and did not affect binding kinetics, but did increase binding to RXFP1. In HEK-RXFP1 cells, ML290 stimulated cAMP accumulation and p38MAPK phosphorylation but not cGMP accumulation or ERK1/2 phosphorylation although prior addition of ML290 increased p-ERK1/2 responses to relaxin. In human primary vascular endothelial and smooth muscle cells that endogenously express RXFP1, ML290 increased both cAMP and cGMP accumulation but not p-ERK1/2. In HCFs, ML290 increased cGMP accumulation but did not affect p-ERK1/2 and given chronically activated MMP-2 expression and inhibited TGF-β1-induced Smad2 and Smad3 phosphorylation. In vascular cells, ML290 was 10x more potent for cGMP accumulation and p-p38MAPK than for cAMP accumulation. ML290 caused strong coupling of RXFP1 to Gαs and GαoB but weak coupling to Gαi3. ML290 exhibited signalling bias at RXFP1 possessing a signalling profile indicative of vasodilator and anti-fibrotic properties.

Tao Han,1,* Zhaozhe Liu,1,* Hengyu Li,2,* Wanqing Xie,3,* Ranran Zhang,1 Li Zhu,2 Fang Guo,1 Yaling Han,4 Yuan Sheng,2 Xiaodong Xie11Department of Oncology, Cancer Center of People’s Liberation Army, General Hospital of Shenyang Military Region, Shenyang, People’s Republic of China; 2Department of Thyroid and Breast Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 3Liaoning University of Traditional Chinese Medicine, Shenyang, People’s Republic of China; 4Department of Cardiology, Institute of Cardiovascular Research of People’s Liberation Army, General Hospital of Shenyang Military Region, Shenyang, People’s Republic of China*These authors contributed equally to this workBackground: Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that is prone to recurrence and metastasis with worse prognosis. Epirubicin-based chemotherapy is of great importance for patients with TNBC, but resistance to epirubicin severely limits the application of this drug and this has emerged as a major problem in the treatment of TNBC. The ubiquitin protein D (UBD) molecule has often been considered a tumor oncogene, and has been shown to promote the recurrence and metastasis of malignant tumor cells. Since the role of UBD in epirubicin resistance and its prognostic value in TNBC have not been reported, the study reported here was designed to identify the epirubicin-resistance molecule and clarify the related biomarker for TNBC prognosis.Methods: UBD plasmid was transfected into MDA-MB-231 cells, and the cells were exposed to epirubicin to observe the ability of UBD in epirubicin resistance. UBD expression was also detected in 78 breast cancer tissues by immunohistochemistry. Statistical methods were used to study the relationship between UBD expression and epirubicin resistance in TNBC treatment. Kaplan–Meier survival analysis was used to determine the correlation between UBD expression and TNBC patients’ prognostic parameters.Results: UBD expression was found increased in breast cancer tissues. Forced UBD expression was found to have a relationship with TNBC epirubicin resistance in vitro. High expression of UBD was found in TNBC, compared with in non-TNBC, and this played a positive role in epirubicin resistance and indicated the poor prognosis of TNBC treatment.Conclusion: UBD may play an important role in epirubicin resistance in TNBC. UBD has the potential to be a novel biomarker in TNBC chemoresistance and may be a promising therapeutic target for TNBC patients.Keywords: prognosis, chemoresistance, biomarker

Magnetic fluctuations is the leading candidate for pairing in cuprate, iron-based, and heavy fermion superconductors. This view is challenged by the recent discovery of nodeless superconductivity in CeCu2Si2, and calls for a detailed understanding of the corresponding magnetic fluctuations. Here, we mapped out the magnetic excitations in superconducting (S-type) CeCu2Si2 using inelastic neutron scattering, finding a strongly asymmetric dispersion for E ≲ 1.5 meV, which at higher energies evolves into broad columnar magnetic excitations that extend to E ≳ 5 meV. While low-energy magnetic excitations exhibit marked three-dimensional characteristics, the high-energy magnetic excitations in CeCu2Si2 are almost two-dimensional, reminiscent of paramagnons found in cuprate and iron-based superconductors. By comparing our experimental findings with calculations in the random-phase approximation,we find that the magnetic excitations in CeCu2Si2 arise from quasiparticles associated with its heavy electron band, which are also responsible for superconductivity. Our results provide a basis for understanding magnetism and superconductivity in CeCu2Si2, and demonstrate the utility of neutron scattering in probing band renormalization in heavy fermion metals.

AbstractThe Third Pole (TP) is experiencing rapid warming and is currently in its warmest period in the past 2,000 years. This paper reviews the latest development in multidisciplinary TP research associated with this warming. The rapid warming facilitates intense and broad glacier melt over most of the TP, although some glaciers in the northwest are advancing. By heating the atmosphere and reducing snow/ice albedo, aerosols also contribute to the glaciers melting. Glacier melt is accompanied by lake expansion and intensification of the water cycle over the TP. Precipitation has increased over the eastern and northwestern TP. Meanwhile, the TP is greening and most regions are experiencing advancing phenological trends, although over the southwest there is a spring phenological delay mainly in response to the recent decline in spring precipitation. Atmospheric and terrestrial thermal and dynamical processes over the TP affect the Asian monsoon at different scales. Recent evidence indicates substantial roles that mesoscale convective systems play in the TP’s precipitation as well as an association between soil moisture anomalies in the TP and the Indian monsoon. Moreover, an increase in geohazard events has been associated with recent environmental changes, some of which have had catastrophic consequences caused by glacial lake outbursts and landslides. Active debris flows are growing in both frequency of occurrences and spatial scale. Meanwhile, new types of disasters, such as the twin ice avalanches in Ali in 2016, are now appearing in the region. Adaptation and mitigation measures should be taken to help societies’ preparation for future environmental challenges. Some key issues for future TP studies are also discussed.

Semiconductive transition metal dichalcogenides (TMDs) have been considered as next generation semiconductors, but to date most device investigations are still based on microscale exfoliation with a low yield. Wafer scale growth of TMDs has been reported but effective doping approaches remain challenging due to their atomically thick nature. This work reports the synthesis of wafer-scale continuous few-layer PtSe2 films with effective doping in a controllable manner. Chemical component analyses confirm that both n-doping and p-doping can be effectively modulated through a controlled selenization process. The electrical properties of PtSe2 films have been systematically studied by fabricating top-gated field effect transistors (FETs). The device current on/off ratio is optimized in two-layer PtSe2 FETs, and four-terminal configuration displays a reasonably high effective field effect mobility (14 and 15 cm2 V−1 s−1 for p-type and n-type FETs, respectively) with a nearly symmetric p-type and n-type performance. Temperature dependent measurement reveals that the variable range hopping is dominant at low temperatures. To further establish feasible application based on controllable doping of PtSe2, a logic inverter and vertically stacked p–n junction arrays are demonstrated. These results validate that PtSe2 is a promising candidate among the family of TMDs for future functional electronic applications.

Cultural resources are often overlooked in climate change and resiliency planning, despite them being integral to community identity and the restoration of a sense of normalcy after significant weather events. This vulnerability assessment demonstrates how cultural resources can be included in planning efforts, and how they can be prioritized based on specific criteria. To complete this assessment, a working group with local land managers and cultural resource professionals was formed, and members employed a sophisticated Geo Tool, ACUNE (Adaptation of Coastal Urban and Natural Ecosystems) for climate adaptation, to predict how cultural resources throughout Collier County, Florida, would be impacted in two specific climate scenarios. The working group selected ten significant sites in the county and used ACUNE to prioritize action at these sites, using a matrix of hazard exposure, sensitivity, adaptive capacity, and the environmental, social, and economic consequences of the loss of these sites. Based on the results of our case study vulnerability assessment of cultural resources in Collier County, the next decade (2020 to 2030) has the potential to increase the number of sites at risk of storm flooding from 267 to 318, alerting managers that immediate action is needed for the sites of greatest value. The analysis of 10 case study sites is presented to demonstrate an approach for land managers and other cultural resource professionals to prioritize action at their own sites. [ABSTRACT FROM AUTHOR]