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Mengmeng Ji,1,* Xiao Ran,2,3,* Houjuan Zuo,1 Qin Zhang4 1Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Department of Critical-Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 3Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qin Zhang, Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave, Wuhan, 430030, People’s Republic of China, Tel +86-15717154768, Email qzhang8@tjh.tjmu.edu.cn Houjuan Zuo, Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave, Wuhan, 430030, People’s Republic of China, Tel +86-83663280, Email zuohoujuan@126.comAbstract: Fulminant myocarditis (FM) is characterized by rapid cardiac deterioration often instigated by an inflammatory cytokine storm. The kallikrein–kinin system (KKS) is a metabolic cascade known for releasing vasoactive kinins, such as bradykinin-related peptides, possessing diverse pharmacological activities that include inflammation, regulation of vascular permeability, endothelial barrier dysfunction, and blood pressure modulation. The type 1 and type 2 bradykinin receptors (B1R and B2R), integral components of the KKS system, mediate the primary biological effects of kinin peptides. This review aims to offer a comprehensive overview of the primary mechanisms of the KKS in FM, including an examination of the structural components, regulatory activation, and downstream signaling pathways of the KKS. Furthermore, it explores the involvement of the tissue kallikrein/B1R/inducible nitric oxide synthase (TK/B1R/iNOS) pathway in myocyte dysfunction, modulation of the immune response, and preservation of endothelial barrier integrity. The potential therapeutic advances targeting the inhibition of the KKS in managing FM will be discussed, providing valuable insights for the development of clinical treatment strategies. Keywords: fulminant myocarditis, Kallikrein–Kinin system, inducible nitric oxide synthase, nitric oxide, inflammatory

Fangqian Du,1,* Yuwei Xie,1,* Shengze Wu,1 Mengling Ji,2 Bingzi Dong,3 Chengzhan Zhu1 1Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan; 3Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chengzhan Zhu, Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China, Tel +86 0532-82919552, Fax +86 0532-82911885, Email zhuchengz@qduhospital.cn Bingzi Dong, Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China, Tel/Fax +86-82911383, Email dongbingzi@hotmail.comAbstract: Hepatobiliary and pancreatic diseases are becoming increasingly common worldwide and associated cancers are prone to recurrence and metastasis. For a more accurate treatment, new therapeutic strategies are urgently needed. The claudins (CLDN) family comprises a class of membrane proteins that are the main components of tight junctions, and are essential for forming intercellular barriers and maintaining cellular polarity. In mammals, the claudin family contains at least 27 transmembrane proteins and plays a major role in mediating cell adhesion and paracellular permeability. Multiple claudin proteins are altered in various cancers, including gastric cancer (GC), esophageal cancer (EC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), colorectal cancer (CRC) and breast cancer (BC). An increasing number of studies have shown that claudins are closely associated with the occurrence and development of hepatobiliary and pancreatic diseases. Interestingly, claudin proteins exhibit different effects on cancer progression in different tumor tissues, including tumor suppression and promotion. In addition, various claudin proteins are currently being studied as potential diagnostic and therapeutic targets, including claudin-3, claudin-4, claudin-18.2, etc. In this article, the functional phenotype, molecular mechanism, and targeted application of the claudin family in hepatobiliary and pancreatic diseases are reviewed, with an emphasis on claudin-1, claudin-4, claudin-7 and claudin-18.2, and the current situation and future prospects are proposed.Keywords: claudins, hepatocellular carcinoma, cholangiocarcinoma, pancreatic cancer, targeted therapy

Background and purposeAcidification of the tumor microenvironment from abnormal metabolism along with angiogenesis to meet metabolic demands are both hallmarks of malignant brain tumors; however, the interdependency of tumor acidity and vascularity has not been explored. Therefore, our aim was to investigate the association between pH-sensitive amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) and relative cerebral blood volume (CBV) measurements obtained from dynamic susceptibility contrast (DSC) perfusion MRI in patients with gliomas.Materials and methodsIn this retrospective study, 90 patients with histologically confirmed gliomas were scanned between 2015 and 2018 (median age, 50.3 years; male/female ratio = 59:31). pH-weighting was obtained using chemical exchange saturation transfer echo-planar imaging estimation of the magnetization transfer ratio asymmetry at 3 ppm, and CBV was estimated using DSC-MR imaging. The voxelwise correlation and patient-wise median value correlation between the magnetization transfer ratio asymmetry at 3 ppm and CBV within T2-hyperintense lesions and contrast-enhancing lesions were evaluated using the Pearson correlation analysis.ResultsGeneral colocalization of elevated perfusion and high acidity was observed in tumors, with local intratumor heterogeneity. For patient-wise analysis, median CBV and magnetization transfer ratio asymmetry at 3 ppm within T2-hyperintense lesions were significantly correlated (R = 0.3180, P = .002), but not in areas of contrast enhancement (P = .52). The positive correlation in T2-hyperintense lesions remained within high-grade gliomas (R = 0.4128, P = .001) and in isocitrate dehydrogenase wild-type gliomas (R = 0.4300, P = .002), but not in World Health Organization II or in isocitrate dehydrogenase mutant tumors. Both magnetization transfer ratio asymmetry at 3 ppm and the voxelwise correlation between magnetization transfer ratio asymmetry and CBV were higher in high-grade gliomas compared with low-grade gliomas in T2-hyperintense tumors (magnetization transfer ratio asymmetry, P = .02; Pearson correlation, P = .01). The same trend held when comparing isocitrate dehydrogenase wild-type gliomas and isocitrate dehydrogenase mutant gliomas (magnetization transfer ratio asymmetry, P = .04; Pearson correlation, P = .01).ConclusionsA positive linear correlation between CBV and acidity in areas of T2-hyperintense, nonenhancing tumor, but not enhancing tumor, was observed across patients. Local heterogeneity was observed within individual tumors.

Time-resolved cathodoluminescence using 30 keV ultrafast electron pulses has been used to perform direct measurements of the minority hole lifetime τ h as a function of 3.7 MeV α -particle fluence in high-quality free-standing n-type GaN substrates. The lifetime damage factor K calculated from these measurements was found to monotonically decrease from 6.9 × 10−2 to 6.4 × 10−4 cm2 s−1 ion−1 with increasing α -fluence from 108 to 1012 cm−2, implying a reduction in trap cross section and/or an aggregation of α -induced traps. The small, ∼ 200–300 nm, hole diffusion length estimated from the minority hole lifetime for the highest α -fluence necessitates the deployment of α -voltaic device strategies and architectures that emphasize depletion and drift over diffusion for effective charge collection and optimal power conversion efficiency. [ABSTRACT FROM AUTHOR]

Abstract Colorectal cancer (CRC) remains a leading cause of cancer mortality. Here, we define the colonic epithelial expression of cathelicidin (LL‐37) in CRC. Cathelicidin exerts pleotropic effects including anti‐microbial and immunoregulatory functions. Genetic knockout of cathelicidin led to increased size and number of colorectal tumours in the azoxymethane‐induced murine model of CRC. We aimed to translate this to human disease. The expression of LL‐37 in a large (n = 650) fully characterised cohort of treatment‐naïve primary human colorectal tumours and 50 matched normal mucosa samples with associated clinical and pathological data (patient age, gender, tumour site, tumour stage [UICC], presence or absence of extra‐mural vascular invasion, tumour differentiation, mismatch repair protein status, and survival to 18 years) was assessed by immunohistochemistry. The biological consequences of LL‐37 expression on the epithelial barrier and immune cell phenotype were assessed using targeted quantitative PCR gene expression of epithelial permeability (CLDN2, CLDN4, OCLN, CDH1, and TJP1) and cytokine (IL‐1β, IL‐18, IL‐33, IL‐10, IL‐22, and IL‐27) genes in a human colon organoid model, and CD3+, CD4+, and CD8+ lymphocyte phenotyping by immunohistochemistry, respectively. Our data reveal that loss of cathelicidin is associated with human CRC progression, with a switch in expression intensity an early feature of CRC. LL‐37 expression intensity is associated with CD8+ T cell infiltrate, influenced by tumour characteristics including mismatch repair protein status. There was no effect on epithelial barrier gene expression. These data offer novel insights into the contribution of LL‐37 to the pathogenesis of CRC and as a therapeutic molecule.

Yu Liu,1,2,* Wenju Chang,1– 3,* Wentao Tang,1– 3,* Ye Wei,1– 3 Tianyu Liu,1,2 Yijiao Chen,1,2 Meiling Ji,1– 3 Fei Liang,4 Li Ren,1– 3 Jianmin Xu1– 3 1Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, People’s Republic of China; 4Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianmin XuDepartment of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of ChinaTel +86 13501984869Email xujmin@aliyun.comBackground: Rectal gastrointestinal stromal tumors (GISTs) are rare digestive tumors. The treatment methods of rectal GISTs are diverse, while no standardized treatment was recommended. The aim of this study was to report the treatment mode of rectal GISTs in our center.Methods: Patients with pathologically confirmed rectal GISTs who received neoadjuvant therapy and surgical resection were retrospectively collected. Perioperative complications and long-term prognosis were evaluated.Results: From January 2010 to December 2019, 36 patients were pathologically diagnosed with primary rectal GISTs. After excluding patients who were treated with surgery or imatinib alone, 21 patients received neoadjuvant therapy and surgery was enrolled. During neoadjuvant treatment, tumors shrank significantly (6.53cm to 4.68cm, p< 0.001) without toxicities over grade 2. The total postoperative complication rate was 42.9% (all grade). R0 resection was achieved in 76.2% patients. Transanal resection had advantages on anus preservation and postoperative recovery. No patients died during the follow-up period, 4 patients relapsed and the relapse-free survival was 81.0%.Conclusion: The combination of neoadjuvant therapy and surgical resection was a safe and effective treatment for rectal gastrointestinal stromal tumors.Keywords: rectal gastrointestinal stromal tumors, GISTs, neoadjuvant therapy, surgical resection

Weiguang Qiang,1 Hongbing Shi,1 Jun Wu,1 Mei Ji,1 Changping Wu1,2 1Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, People’s Republic of China; 2Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, People’s Republic of ChinaCorrespondence: Changping Wu; Weiguang QiangDepartment of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, People’s Republic of ChinaEmail wcpjjt@163.com; qwgwutongyu@163.comPurpose: Liver metastases in patients with gastric cancer often indicate poor prognosis. Once liver metastases are extensive, it is difficult to achieve disease control by using systemic chemotherapy alone. The purpose of this study was to evaluate the effect and safety of hepatic arterial infusion (HAI) combined with systemic chemotherapy on extensive liver metastases from gastric cancer.Patients and Methods: Between 2012 and 2019, 21 patients with extensive liver metastases from gastric cancer (LMGC) were enrolled in our study. Liver metastases were identified as unresectable and a major factor affecting prognosis mainly based on size and number of intrahepatic lesions. All patients received systemic chemotherapy with S-1 and HAI oxaliplatin plus floxuridine (FUDR).Results: Liver metastases in 16 patients (76.2%) were evaluated as H3. The overall response rate was 76.2% (9.5% complete response). Intrahepatic and extrahepatic median progression-free survival times were 9.5 and 5.2 months, respectively. Median survival time (MST) was 12.3 months. All patients did not have the toxicity of grade 4. Grade 3 toxic effects included bone marrow suppression (14.3%) and diarrhea (9.5%). The other treatment-related toxicities were mild and reversible.Conclusion: HAI combined with systemic chemotherapy for extensive LMGC seems to be safe and effective, which achieves a high-local response and may contribute to long survival time for patients.Keywords: gastric cancer, liver metastases, hepatic arterial infusion, systemic chemotherapy

Yun Du,1,2 Wentong Zhang,3 Feng Lei,4 Xia Yu,1 Zhuming Li,1 Xiaodong Liu,1 Yanan Ni,1 Li Deng,4 Mingfang Ji1 1Cancer Research Institute of Zhongshan City, Zhongshan City People’s Hospital, Zhongshan 528400, People’s Republic of China; 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Stockholm, Sweden; 3Department of Chinese Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 4Department of Radiotherapy, Zhongshan City People’s Hospital, Zhongshan, People’s Republic of ChinaCorrespondence: Mingfang JiCancer Research Institute of Zhongshan City, Zhongshan City People’s Hospital, No. 2. Sunwen Road East, Zhongshan 528400, Guangdong, People’s Republic of ChinaTel +86 135 3206 2222Fax +86 076488822698Email jmftbh@sina.comPurpose: NPC is a malignant and invasive tumor with the incidence rate of 19/100,000 per year in Zhongshan City, a prefecture city in southern China. Long-term survival analysis on intensity-modulated radiotherapy (IMRT)-based treatment in local prefecture-level hospitals have not been investigated. We aimed to evaluate the 5-year clinical outcomes and prognostic factors of NPC treated with IMRT in Zhongshan City People’s Hospital (ZSPH), a prefecture-level hospital in South China.Patients and Methods: The number of 149 newly diagnosed non-metastatic NPC cases treated with IMRT were included from Zhongshan City People’s Hospital between January 2010 and December 2011. The survival outcomes, treatment toxicities and prognostic factors were analyzed by Kaplan-Meier method and Cox proportional hazards model.Results: With a median follow-up period of 65 months for the cohort, the 5-year local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS) and distant metastasis-free survival (DMFS) and overall survival (OS) were 86.80%, 94.80%, 86.10% and 80.50%, respectively. The 5-year OS rates were 100%, 95.2%, 87% and 67.2% for stage I, II, II and IVa-b, respectively (P=0.004). The 5-year LRFS rates were 97.2%, 96.0%, 90.4% and 72.0% for T1, T2, T3 and T4, respectively (P=0.001); the 5-year DMFS rates were 100% for T1, 96.8% for T2, 81.9% for T3 and 74.6% for T4 (P=0.022). A multivariate analysis revealed tumor stage as an independent prognostic factor for LRFS, DMFS and OS. No patients died from acute toxicities. Late toxicities were observed for 130 (87.2%) patients, and most late toxicities were graded I/II.Conclusion: NPC treatment effect in a prefecture-level hospital in South China was comparable to international results and toxicities were tolerable. Tumour stage was an independent prognostic factor for survival outcome. More NPC survival data from local and remote places are needed.Keywords: nasopharyngeal carcinoma, intensity-modulated, radiotherapy, prognosis, long-term survival results

Chun-ming Ma, Qin Liu, Ming-li Li, Mei-jing Ji, Jian-dong Zhang, Bo-hua Zhang, Fu-Zai Yin Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, People’s Republic of ChinaCorrespondence: Fu-Zai YinDepartment of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, People’s Republic of ChinaTel +86-335-5908368Fax +86-335-3032042Email yinfuzai62@163.comObjective: The aim of the study was to explore the relationship between type 2 diabetes (T2DM) and postoperative pneumonia, and the effects of T2DM and postoperative pneumonia on the mortality in inpatients with surgery.Methods: A retrospective study was conducted on 43,174 inpatients with surgery in The First Hospital of Qinhuangdao. These patients were divided into four groups according to T2DM and postoperative pneumonia, Group A subjects without T2DM and postoperative pneumonia, Group B subjects with T2DM only, Group C subjects with postoperative pneumonia only and Group D subjects with T2DM and postoperative pneumonia. In-hospital mortality was collected.Results: The incidences of postoperative pneumonia were higher in patients with T2DM than patients without T2DM (T2DM 3.2% vs Non-diabetes 1.7%, χ2=36.219, P

Jing Xing,*,1,2 Xiquan Zhang,*,3 Zhe Wang,4 Huanqing Zhang,3 Peng Chen,1,2 Gaoxin Zhou,5 Chunlong Sun,6 Ning Gu,1,2 Min Ji1,21School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, People’s Republic of China; 2School of Biological Science and Medical Engineering and Collaborative Innovation Center of Suzhou Nano Science and Technology, Southeast University, Suzhou 215123, People’s Republic of China; 3Nanjing Institute of Pharmaceutical Research and Development, Chia-Tai Tianqing Pharmaceutical Group Co. Ltd, Nanjing 210023, People’s Republic of China; 4Emergency Department, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 5School of Biomedical Engineering, Shenzhen University, Shenzhen 518071, People’s Republic of China; 6College of Biological and Environmental Engineering, Binzhou University, Binzhou 256603, People’s Republic of China*These authors contributed equally to this workBackground: SN38 (7-ethyl-10-hydroxy camptothecin), as a potent metabolite of irinotecan, is highly efficacious in cancer treatment. However, the clinical utility of SN38 has been greatly limited due to its undesirable properties, such as poor solubility and low stability.Materials and methods: In order to overcome these weaknesses, moeixitecan, a lipophilic SN38 prodrug containing a SN-38, a trolox, a succinic acid linker, and a hexadecanol chain, was loaded into liposomal nanoparticles by ethanol injection method.Results: Experiments showed that the moeixitecan-loaded liposomal nanoparticles (MLP) with a diameter of 105.10±1.49 nm have a satisfactory drug loading rate (90.54±0.41%), high solubility and stability, and showed sustained release of SN38. Notably, MLP exhibited better antitumor activity against human colon adenocarcinoma cells than irinotecan, a FDA-approved drug for the treatment of advanced colorectal cancer. Furthermore, xenograft model results showed that MLP outperformed irinotecan in terms of pharmacokinetics, in vivo therapeutic efficacy and safety. Finally, we used molecular dynamic simulations to explore the association between the structure of MLP and the physical and functional properties of MLP, moeixitecan molecules in MLP folded themselves inside the hydrocarbon chain of the lipid bilayer, which led an increased acyl chain order of the lipid bilayer, and therefore enhanced the lactone ring stability protecting it from hydrolysis.Conclusion: Our MLP constructing strategy by liposome engineering technology may serve a promising universal approach for the effective and safe delivery of lipophilic prodrug.Keywords: SN38, lipophilic prodrug, liposomes, molecular dynamic simulations, cancer therapy

Jun Ye,1–3 Yanfang Yang,1,2 Wujun Dong,1,2 Yue Gao,1,2 Yingying Meng,1,2 Hongliang Wang,1,2 Lin Li,1,2 Jing Jin,1 Ming Ji,1 Xuejun Xia,1,2 Xiaoguang Chen,1 Yiqun Jin,3 Yuling Liu1,21State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People’s Republic of China; 2Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, People’s Republic of China; 3Research and Development Department, Beijing Wehand-bio Pharmaceutical Co. Ltd, Beijing, 102600, People’s Republic of ChinaBackground: Tumor-associated macrophages (TAMs) are critical in tumor progression and metastasis. Selective targeting of TAMs holds great potential to ameliorate the immunosuppressive tumor microenvironment and enhance the efficacy of antitumor therapy. Various liposomes have been developed to target TAMs via cell-specific surface receptors either to deplete or re-educate TAMs. Since immuno-stimulation often initiates with the interaction of nanocarriers with the innate immunity cells such as macrophages, the intrinsic impact of drug-free liposomes on macrophage activation and polarization via cell interaction is one of the most critical issues in nanomedicine for promoting effective immunotherapy.Methods: In this study, conventional bare liposomes, PEGylated liposomes, and mannosylated liposomes were developed and the cytotoxicity, cellular internalization, immunostimulatory activity, targeting efficiency, antitumor efficacy, and mechanism were evaluated in vitro and in vivo.Results: All liposomes displayed an ideal particle size, good biocompatibility, and controlled release behavior. Mannosylated liposomes exhibited superior in vitro cellular internalization and tumor spheroid penetration with the aid of the mannose receptor-mediated TAMs-targeting effects. In particular, mannosylated liposomes promoted the polarization of both M0 and M2 to the M1 phenotype by enhancing the expression ratio of CD86/CD206 in vitro. Of note, mannosylated liposomes could inhibit G422 glioma tumor growth, which may be attributed to the polarization of TAMs, as evidenced by the reduction in expression level of the TAMs surface marker.Conclusion: These results indicate the potential value of mannosylated liposomes in the design of a rational delivery system to enhance the antitumor immune efficacy of immunomodulators by inducing a shift from the M2 to the M1 phenotype.Keywords: liposomes, cancer immunotherapy, tumor-associated macrophages, mannose receptor, drug delivery

Wenshuo Wang,1,* Huan Liu,1,* Yuntao Lu,1,* Xiaole Wang,2,* Bohan Zhang,3 Shuo Cong,1 Yun Zhao,1 Minbiao Ji,3 Hongyue Tao,4 Lai Wei1,5 1Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, China; 2Department of Radiology, Second People’s Hospital of Nantong City, Nantong 226002, Jiangsu, China; 3State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai 200433, China; 4Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200040, China; 5Department of Cardiac Surgery, Shanghai Public Health Clincal Center, Shanghai 201508, China *These authors contributed equally to this work Background: Hydrogen sulfide (H2S) has shown promising therapeutic benefits in reversing a variety of pathophysiological processes in cardiovascular system, including myocardial ischemia–reperfusion (IR) injury. However, the achievement of controlled and sustained release of H2S has been a technical bottleneck that limits the clinical application of the gas molecule.Methods: The current study describes the development of mesoporous iron oxide nanoparticles (MIONs) which were loaded with diallyl trisulfide (DATS), a H2S donor compound, and calibrated by stimulated Raman scattering/transient absorption.Results: The synthesized MIONs were characterized with excellent mesoporosity and a narrow size distribution, which enabled them to slow down the release of H2S to a suitable rate and prolong the plateau period. The controlled-release feature of DATS-MIONs resulted in little adverse effect both in vitro and in vivo, and their protective effect on the heart tissue that underwent IR injury was observed in the mouse model of myocardial ischemia. The rapid biodegradation of DATS-MIONs was induced by Kupffer cells, which were specialized macrophages located in the liver and caused limited hepatic metabolic burden.Conclusion: The sustained-release pattern and excellent biocompatibility make DATS-MIONs a promising H2S donor for research and medical purposes. Keywords: steady release, porous structure, biocompatibility, biodegeneration

Jie Xing,1 Li Min,1 Hao Zhang,2 Peng Li,1 Wei Li,1 Fujin Lv,1 Yongjun Wang,1 Zheng Zhang,1 Hengcun Li,1 Qingdong Guo,1 Siyi Wang,1 Yu Zhao,1 Junmin Wang,3 Xiaoyan Shi,4 Anxin Wang,5 Shengtao Zhu,1 Ming Ji,1 Yongdong Wu,1 Shutian Zhang1 On behalf of the NCECS Study Group 1Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, People’s Republic of China; 2Department of Gastroenterology, Jizhong Energy Fengfeng Group Hospital, Handan, Hebei 056200, People’s Republic of China; 3Department of Gastroenterology, Handan Central Hospital, Handan, Hebei 056001, People’s Republic of China; 4Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, People’s Republic of China; 5Department of Epidemiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100029, People’s Republic of China Background: Endoscopy is the main approach used for esophageal squamous cell carcinoma (ESCC) screening, especially in high-risk areas. However, little consensus has been achieved in recent ESCC screening programs, and endoscopists have selected patients only by age and family history. Patients and methods: To generate a proper strategy for selecting an eligible population for endoscopic screening based on demographic factors, lifestyle, and eating habits, a total of 7,830 residents in an area with a high risk of ESCC were recruited for this study. All participants underwent endoscopic examinations that were conducted by experienced endoscopists. Risk factors for ESCC and other lesions were selected by univariate and multivariate logistic regressions. A nomogram for the prediction of ESCC and premalignant lesions was constructed, which included information on age, sex, occupation, labor intensity, income, and mining exposure. Receiver operating characteristic (ROC) curve analysis was performed to present the predictive accuracy of the nomograms. Results: The area under the curve (95% CI) was 0.749 (0.711–0.788) for this nomogram. By applying this nomogram, we could exclude 60% (4704/7830) of patients before endoscopy screening and detect all ESCC cases as well as most esophageal lesions in the remaining population. Conclusion: In conclusion, we provided a ready-to-use preclinical tool with the potential to select eligible people with high risk of ESCC for endoscopy screening. Keywords: nomogram, endoscopy screening, ESCC, population-based study

Yihao Mao,1,* Qingyang Feng,1,2,* Peng Zheng,1,* Liangliang Yang,1,* Tianyu Liu,1 Yuqiu Xu,1 Dexiang Zhu,1,2 Wenju Chang,1,2 Meiling Ji,1,2 Li Ren,1,2 Ye Wei,1,2 Guodong He,1,2 Jianmin Xu1,2 1Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200030, China; 2Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai 200030, China *These authors contributed equally to this work Purpose: Tumor purity is defined as the proportion of cancer cells in the tumor tissue. The impact of tumor purity on colon cancer (CC) prognosis, genetic profile, and microenvironment has not been thoroughly accessed.Materials and methods: Clinical and transcriptomic data from three public datasets, GSE17536/17537, GSE39582, and TCGA, were retrospectively collected (n=1,248). Tumor purity of each sample was inferred by a computational method based on transcriptomic data. Survival-related analyses were performed on microarray dataset containing GSE17536/17537 and GSE39582 (n=794), whereas TCGA dataset was utilized for subsequent genomic analysis (n=454).Results: Right-sided CC patients showed a significantly lower tumor purity. Low purity CC conferred worse survival, and tumor purity was identified as an independent prognostic factor. Moreover, high tumor purity CC patients benefited more from adjuvant chemotherapy. Subsequent genomic analysis found that the mutation burden was negatively associated with tumor purity, with only APC and KRAS significantly more mutated in high purity CC. However, no somatic copy number alteration event was correlated with tumor purity. Furthermore, immune-related pathways and immunotherapy-associated markers (programmed cell death protein 1 [PD-1], programmed death-ligand 1 [PD-L1], cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], Lymphocyte-activation gene 3 [LAG-3] and T-cell immunoglobulin and mucin-domain containing-3 [TIM-3]) were highly enriched in low purity samples. Notably, the relative proportion of M2 macrophages and neutrophils, which indicated worse survival in CC, was negatively associated with tumor purity.Conclusion: Tumor purity exhibited potential value for CC prognostic stratification as well as adjuvant chemotherapy benefit prediction. The relative worse survival in low purity CC may attribute to higher mutation frequency in key pathways and purity-related microenvironmental changing. Keywords: adjuvant chemotherapy, colon cancer, prognosis, tumor microenvironment, tumor purity

Peng Zheng,* Li Ren,* Qingyang Feng,* Dexiang Zhu,* Wenju Chang, Guodong He, Meiling Ji, Mi Jian, Qi Lin, Tuo Yi, Ye Wei, Jianmin Xu Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: To investigate differences in clinical characteristics and mutational patterns between synchronous and metachronous colorectal liver metastases (CLMs). Patients and methods: From June 2008 to December 2014, patients with RAS wild-type CLMs treated at Zhongshan Hospital, Fudan University were included. DNA extracted from formalin-fixed paraffin-embedded tissue of primary tumors was sequenced with next-generation sequencing for single-nucleotide polymorphism of 96 genes according to custom panel. Mutations were compared between synchronous and metachronous liver metastases and correlated with clinical characteristics. Results: A total of 161 patients were included: 93 patients with synchronous CLM and 68 patients with metachronous CLM. Patients with metachronous CLM were obviously elder. For pathology of primary tumors, synchronous CLMs were larger in size, poorly differentiated, and more frequently local advanced and lymph node positive. For evaluation of liver metastases, synchronous CLM had more and larger metastatic lesions. The median number of mutations in synchronous CLMs was significantly higher than in metachronous group (22 vs. 18, p

We describe the behaviour of 23 dynamical ocean-atmosphere models, in the context of comparison with observations in a common framework. Fields of tropical sea surface temperature (SST), surface wind stress and upper ocean vertically averaged temperature (VAT) are assessed with regard to annual mean, seasonal cycle, and interannual variability characteristics. Of the participating models, 21 are coupled GCMs, of which 13 use no form of flux adjustment in the tropics. The models vary widely in design, components and purpose: nevertheless several common features are apparent. In most models without flux adjustment, the annual mean equatorial SST in the central Pacific is too cool and the Atlantic zonal SST gradient has the wrong sign. Annual mean wind stress is often too weak in the central Pacific and in the Atlantic, but too strong in the west Pacific. Few models have an upper ocean VAT seasonal cycle like that observed in the equatorial Pacific. Interannual variability is commonly too weak in the models: in particular, wind stress variability is low in the equatorial Pacific. Most models have difficulty in reproducing the observed Pacific 'horseshoe' pattern of negative SST correlations with internnual Nino3 SST anomalies, or the observed Indian-Pacific lag correlations. The results for the fields examined indicate that several substantial model improvements are needed, particularly with regard to surface wind stress.