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Zhuoran Li,1,* Yirui Zhai,1,* Fan Wu,2,* Dayong Cao,2,* Feng Ye,3,* Yan Song,4 Shulian Wang,1 Yueping Liu,1 Yongwen Song,1 Yuan Tang,1 Hao Jing,1 Hui Fang,1 Shunan Qi,1 Ningning Lu,1 Ye-Xiong Li,1 Jianxiong Wu,2 Bo Chen1 1State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China; 2Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China; 3Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China; 4Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Chen, State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China, Tel +86-10-87788280, Email chenboo@outlook.com Jianxiong Wu, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China, Tel +86-10-87781700, Email Dr_wujx@163.comPurpose: This study evaluated the clinical outcomes of patients with hepatocellular carcinoma (HCC) with hepatic vein tumor thrombus (HVTT) and/or inferior vena cava tumor thrombus (IVCTT) receiving radiotherapy (RT) combined with systemic therapies.Patients and Methods: Patients with HCC with HVTT and/or IVCTT who received RT were identified at our institution. The prescription doses were 30– 65 Gy for planning target volume and 40– 65 Gy for the gross tumor volume. Targeted therapy and immune checkpoint inhibitors were used concurrently if patients were at a high risk of or already had distant metastasis. After RT completion, follow-up was performed at 1, 3, 6, and 12 months, and 3 to 6 months thereafter. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity were recorded.Results: Thirty-four patients were retrospectively enrolled between January 2016 and September 2021. Most patients received concurrent targeted therapy (70.6%) and/or post-RT (79.4%). The in-field ORR and disease control rates were 79.4% and 97.1%, respectively. The OS rates were 77.6% at 1 year and 36.3% at 2 years (median OS, 15.8 months). The median PFS and median in-field PFS were 4.2 months and not reached, respectively. The PFS and in-field PFS rates were 24.6% and 79.2% at 1 year, 19.7% and 72.0% at 2 years, respectively. An alpha-fetoprotein level > 1000 ng/mL was a significant prognostic factor for worse OS (HR, 5.674; 95% CI, 1.588– 20.276; p=0.008); in-field complete/partial response was a significant prognostic factor for better OS (HR, 0.116; 95% CI, 0.027– 0.499; p=0.004). The most common site of first failure was the lungs (13/34 patients, 38.2%), followed by the liver (7/34 patients, 20.6%). No patients developed radiation-induced liver disease or pulmonary embolism during follow-up.Conclusion: Combining RT and systemic therapy was safe and effective in treating patients with HCC with HVTT and IVCTT.Keywords: liver cancer, immunotherapy, systemic therapy, radiation therapy

Han Chen,1,2 Jianhao Li,1,2 Dan Cao,1,2 Hong Tang1,2 1Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China; 2Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Hong Tang, Email tanghong6198@wchscu.cnBackground: The progression of hepatocellular carcinoma (HCC) is related to macrophage polarization (MP). Our aim was to identify genes associated with MP in HCC patients and develop a prognostic model based on these genes.Results: We successfully developed a prognostic model consisting of six MP-related genes (SCN4A, EBF3, ADGRB2, HOXD9, CLEC1B, and MSC) to calculate the risk score for each patient. Patients were then classified into high- and low-risk groups based on their median risk score. The performance of the MP-related prognostic model was evaluated using Kaplan-Meier and ROC curves, which yielded favorable results. Additionally, the nomogram demonstrated good clinical effectiveness and displayed consistent survival predictions with actual observations. Gene Set Enrichment Analysis (GSEA) revealed enrichment of pathways related to KRAS signaling downregulation, the G2M checkpoint, and E2F targets in the high-risk group. Conversely, pathways associated with fatty acid metabolism, xenobiotic metabolism, bile acid metabolism, and adipogenesis were enriched in the low-risk group. The risk score positively correlated with the number of invasion-related genes. Immune checkpoint expression differed significantly between the two groups. Patients in the high-risk group exhibited increased sensitivity to mitomycin C, cisplatin, gemcitabine, rapamycin, and paclitaxel, while those in the low-risk group showed heightened sensitivity to doxorubicin. These findings suggest that the high-risk group may have more invasive HCC with greater susceptibility to specific drugs. IHC staining revealed higher expression levels of SCN4A in HCC tissues. Furthermore, experiments conducted on HepG2 cells demonstrated that supernatants from cells with reduced SCN4A expression promoted M2 macrophage polarization marker, CD163 in THP-1 cells. Reduced SCN4A expression induced HCC-related genes, while increased SCN4A expression reduced their expression in HepG2 cells.Conclusion: The MP-related prognostic model comprising six MPRGs can effectively predict HCC prognosis, infer invasiveness, and guide drug therapy. SCN4A is identified as a suppressor gene in HCC.Keywords: hepatocellular carcinoma, macrophage polarization-related genes, tumor microenvironment, prognosis, SCN4A

Han Chen,1,2 Dan Cao,1,2 Ning Han,1,2 Mingming Zhang,1,2 Wei Jiang,1,2 Xin Wang,1,2 Qinmin Zeng,1,2 Hong Tang1,2 1Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Hong Tang, Email tanghong6198@wchscu.cnIntroduction: Hepatocellular carcinoma (HCC) is a solid tumor with a rich blood supply, and anti-angiogenesis has important clinical significance. Hepatitis B Virus-Encoded MicroRNA 3 (HBV-miR-3) has recently been reported to be involved in HCC development. In this study, we aim to elucidate the role of HBV-miR-3 in promoting HBV-related HCC angiogenesis through Factor Inhibiting Hypoxia-inducible factor 1 (FIH-1).Results: By analyzing HBV-related HCC tissue samples, we found that high expression of HBV-miR-3 was associated with poor overall survival and HBV-miR-3 expression was significantly correlated with VEGFR2 and FIH-1 expressions. In vitro, HBV-miR-3 agomir repressed FIH-1 expression and promoted HIF-1α/VEGFA signaling activation in HepG2 cells, resulting in increased HUVEC lumen formation in HepG2-HUVEC co-culture model. Conversely, HBV-miR-3 antagomir induced FIH-1 expression and inhibited HIF-1α/VEGFA signaling activation in HepG2.2.15 cells, resulting in decreased HUVEC lumen formation in HepG2.2.15-HUVEC co-culture model. The effect of HBV-miR-3 to HCC angiogenesis was also confirmed by a mouse tumor bearing model. We also confirmed that HBV-miR-3 repressed FIH-1 expression via targeting the 3’-UTR of FIH-1 mRNA by luciferase activity assay.Conclusion: HBV-miR-3 was related to HCC patients’ overall survival and it promoted angiogenesis by repressing FIH-1 expression. HBV-miR-3 may be a new marker for predicting prognosis and a novel target for anti-angiogenic treatment of HBV-related HCC. Keywords: HBV-miR-3, FIH-1, HBV-related HCC, angiogenesis

Angelo Oliva,1,2 Davide Cao,1,3 Alessandro Spirito,1 Johny Nicolas,1 Brunna Pileggi,1,4 Karim Kamaleldin,1 Birgit Vogel,1 Roxana Mehran1 1The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; 2Cardio Center, Humanitas Research Hospital IRCCS Rozzano, Milan, Italy; 3Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (MI), Italy; 4Department of Cardiopneumonology, Heart Institute of the University of Sao Paulo, Sao Paulo, BrazilCorrespondence: Roxana Mehran, Tel +1-212-659-9649, Email roxana.mehran@mountsinai.orgAbstract: Antiplatelet therapy is the cornerstone of antithrombotic prevention in patients with established atherosclerosis, since it has been proven to reduce coronary, cerebrovascular, and peripheral thrombotic events. However, the protective effect of antiplatelet agents is counterbalanced by an increase of bleeding events that impacts on patients’ mortality and morbidity. Over the last years, great efforts have been made toward personalized antithrombotic strategies according to the individual bleeding and ischemic risk profile, aiming to maximizing the net clinical benefit. The development of risk scores, consensus definitions, and the new promising artificial intelligence tools, as well as the assessment of platelet responsiveness using platelet function and genetic testing, are now part of an integrated approach to tailored antithrombotic management. Moreover, novel strategies are available including dual antiplatelet therapy intensity and length modulation in patients undergoing myocardial revascularization, the use of P2Y12 inhibitor monotherapy for long-term secondary prevention, the implementation of parenteral antiplatelet agents in high-ischemic risk clinical settings, and combination of antiplatelet agents with low-dose factor Xa inhibitors (dual pathway inhibition) in patients suffering from polyvascular disease. This review summarizes the currently available evidence and provides an overview of the principal risk-stratification tools and antiplatelet strategies to inform treatment decisions in patients with cardiovascular disease.Keywords: antiplatelet therapy, cardiovascular disease, P2Y12 inhibitor, aspirin

Xiaoying Zhu,1,2 Fengqin Tian,2 Yulei Li,2 Qunfeng Lu,3 Qinqin Long,2 Xidai Long,1,2 Demin Cao2 1Medical College, Guangxi University, Nanning, Guangxi, People’s Republic of China; 2Clinical Pathological Diagnosis & Research Center, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China; 3School of Medical Laboratory Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of ChinaCorrespondence: Demin Cao; Xidai Long, Email caodm@ymun.edu.cn; sjtulongxd@ymun.edu.cnBackground: Recent research highlights the contribution of co-infections to elevated disease severity and mortality among COVID-19 patients. Given China’s decision to ease epidemic prevention policies in December 2022, a comprehensive exploration of the risks and characteristics of co-infections with respiratory pathogens becomes imperative.Methods: We conducted a retrospective analysis of 716 COVID-19 patients admitted to a primary hospital in China. The detection of twelve respiratory pathogens was conducted using qPCR, and the potential risk factors were analyzed through Cox regression analysis.Results: Within this cohort, 76.82% of cases exhibited co-infection involving eleven distinct pathogens. Among these, bacterial co-infections were observed in 74% of cases, with Streptococcus pneumoniae and Haemophilus influenzae emerging as the most prevalent bacterial co-infection agents. Additionally, 15% of cases presented with viral co-infections, predominantly involving influenza A virus and respiratory syncytial virus. Nevertheless, our investigation suggested that there might be some inappropriate antibiotic use in treatments. Furthermore, risk analysis unveiled dyspnea, hypoproteinemia, low lymphocyte counts, and co-infection with Mycoplasma pneumoniae as prominent risk factors for COVID-19 inpatients.Conclusion: Our findings underscore a significant occurrence of co-infections among COVID-19 patients during the epidemic, emphasizing the need for enhanced antibiotic stewardship. Effective management strategies should encompass respiratory status, nutritional aspects, and vigilance towards co-infections involving M. pneumoniae during COVID-19 treatment. This study underscores the significance of comprehensive management protocols to address the multifaceted challenges presented by co-infections in COVID-19 patients.Keywords: COVID-19, co-infection, respiratory pathogens, risk factors

In the experiments of neutron interaction with research samples, the incident neutron energy spectrum, distribution inside the irradiating sample volume, is affected by the unexpected neutron self-shielding effects. The nature of these effects is due to the formation and thickness of the irradiating sample, which significantly causes neutron self-absorption and multiple scattering inside the sample volume. The datasets presented in this article showed the thermal (Gth) and epithermal (Gepi) neutron self-shielding correction factors for the 186W(n,γ)187W neutron capture reaction rate in irradiating tungsten (W) foil samples with different thicknesses. The simulations were performed for three models of surface neutron source's geometries and relative orientations of the irradiating foil samples of isotropic cylinder surface neutron source with foil sample along to the center line, isotropic cylinder neutron source with foil sample flat to the center line, and isotropic spherical neutron source with foil sample placed at the center point. The range of sample thicknesses was from 10 µm to 2.5 mm. The uncertainties for each data point are also reported in the data table, making it more convenient for reuse in related experiments or evaluations.

Yujing Zhao,1– 4 Juan Wu,2– 4 Shuai Guan,5 Ting Xue,2– 4 Xiaolei Wei,1– 4 Dawei Cao,2– 4 Pengzhou Kong,6 Xinri Zhang2– 4 1Department of the First Clinical Medicine, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Department of NHC Key Laboratory of Pneumoconiosis, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 3Department of Shanxi Key Laboratory of Respiratory Diseases, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 5Department of Pediatric Infectious Diseases, The First People’s Hospital of Datong, Datong, Shanxi, People’s Republic of China; 6Department of Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of ChinaCorrespondence: Pengzhou Kong, Department of Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China, Email kongpengzhou@sxmu.edu.cn Xinri Zhang, Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Pneumoconiosis; Shanxi Key Laboratory of Respiratory Diseases, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China, Email ykdzxr61@163.comPurpose: Pulmonary artery hypertension (PAH) is a common complication of chronic obstructive pulmonary disease and obstructive sleep apnea/hypopnea syndrome worldwide. Pulmonary vascular alterations associated with PAH have multifactorial causes, in which endothelial cells play an important role. Autophagy is closely related to endothelial cell injury and the development of PAH. PIF1 is a multifunctional helicase crucial for cell survival. The present study investigated the effect of PIF1 on autophagy and apoptosis in human pulmonary artery endothelial cells (HPAECs) under chronic hypoxia stress.Methods: Chronic hypoxia Gene expression profiling chip-assays identified the PIF1 gene as differentially expressed, which was verified by RT-qPCR analysis. Electron microscopy, immunofluorescence, and Western blotting were used to analyze autophagy and the expression of LC3 and P62. Apoptosis was analyzed using flow cytometry.Results: Our study found that chronic hypoxia induces autophagy in HPAECs, and apoptosis was exacerbated by inhibiting autophagy. Levels of the DNA helicase PIF1 were increased in HPAECs after chronic hypoxia. PIF1 knockdown inhibited autophagy and promoted the apoptosis of HPAECs under chronic hypoxia stress.Conclusion: Based on these findings, we conclude that PIF1 inhibits the apoptosis of HPAECs by accelerating the autophagy pathway. Therefore, PIF1 plays a crucial role in HPAEC dysfunction in chronic hypoxia-induced PAH and may be a potential target for the treatment of PAH.Keywords: PIF1, autophagy, HPAEC, PAH, chronic hypoxia

Donghui Cao,1,&ast; Tongrong Su,2,&ast; Yanhua Wu,1 Zhifang Jia,1 Yingli Fu,1 Yuanlin Sun,2 Meishan Jin,3 Yueqi Wang,1 Jiaxin Yi,1 Yingnan Cui,2 Yuzheng Zhang,1 Haiyong Lv,1 Limei Qu,3 Jing Jiang,1 Xueyuan Cao2 1Division of Clinical Epidemiology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, People’s Republic of China; 3Division of Pathology, First Hospital of Jilin University, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xueyuan Cao, Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China, Email jd3d2ub@jlu.edu.cnPurpose: Gastric cancer (GC) remains a prevalent aggressive tumor with high morbidity and mortality globally. The identification of GC subtypes based on molecular features improved the prediction of prognosis and the selection of targeted therapies. PTEN is a characteristic tumor suppressor, while its association with different GC subtypes was unknown.Patients and Methods: The cohort consisted of 248 patients diagnosed with gastric cancer who were hospitalized and received radical gastrectomy. In addition, PTEN gene expression matrix of STAD was retrieved from TCGA. The mRNA and protein levels of PTEN and PD-L1 were detected using qRT-PCR and IHC staining. Multivariate logistic regression and Kaplan–Meier analysis were used to examine the relationship between PTEN expression and clinical characteristics.Results: In our study, PTEN was downregulated in gastric tumors both in mRNA and protein levels. Its inactivation was closely linked to higher histological grade (P = 0.005), neural invasion (P = 0.012), depth of invasion (P = 0.021), lymph metastasis (P = 0.026), and TNM stage (P = 0.001) of GC in the present study. Moreover, according to the molecular subtypes, high PTEN expression was related to high TPS score of PD-L1 positively (P = 0.010) but was not associated with MSI and EBV infection. Further, TCGA data validated that PTEN was indeed correlated with histological grade and invasion depth and positively related to PD-L1 expression (R = 0.29, adjusted P < 0.001).Conclusion: The above results suggested that PTEN expression was a useful marker in gastric carcinogenesis and progression and in the selection of immunotherapy-based treatments for GC patients.Keywords: gastric cancer, PTEN, molecular subtype, PD-L1, biomarker

Xiaohong Liu,1 Dedong Cao,1 Hui Liu,2 Dong Ke,3 Xiaokang Ke,4 Ximing Xu1 1Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 2Department of Hematology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 3Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 4Department of Pathology; Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of ChinaCorrespondence: Ximing Xu, Department of Oncology, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, 430060, People’s Republic of China, Tel +8627-88041911, Email doctorxu120@aliyun.comPurpose: This study aimed to analyze the clinical features and survival of primary small intestinal diffuse large B-cell lymphoma (PsI-DLBCL), and establish and independently validate a prognostic nomogram for individual risk prediction.Patients and methods: Data for 24 patients from the Renmin Hospital of Wuhan University were used as an independent validation cohort, data for 1144 patients with PsI-DLBCL from the SEER database were randomly assigned to training (N=817) and internal validation (N=327) sets. The survival nomogram was constructed with the most significant factors associated with OS using Univariate and multivariate analyses on the training set. Decision curve analysis (DCA) was conducted. Internal validation was SEER validation set. Our cancer center cohort was used as an external validation set to further verify the survival nomogram.Results: Five clinicopathological feature factors associated with OS of the training set yielded (age, marital status, Ann Arbor stage, surgery for primary site and chemotherapy), which were used to create a survival nomogram. Additionally, the calibration curves of the prognostic nomogram revealed good agreement between the predicted survival probabilities and the ground truth values. The stability of our survival nomogram was explained by internal and external validation data.Conclusion: Our nomogram proposes the clinical and therapeutic factors affecting OS for patients with PsI-DLBCL. It shows that chemotherapy and surgery are beneficial to patients in the choice of treatment options. These results suggest that a survival nomogram may be better at predicting OS for PsI-DLBCL patients.Keywords: large B-cell lymphoma, non-Hodgkin, small intestine, SEER, nomogram

Liang Wang,1,&ast; Longjiao Hu,2,&ast; Zhilian Peng,3 Honghong Cao,1 Danfeng Cao,4 Yiqin Long,4 Zhengyu Zou4 1Pharmacy Department, Traditional Chinese Medicine Hospital of Jiulongpo Distriction Chongqing, Chongqing, People’s Republic of China; 2Pharmacy Department, Chongqing Jiulongpo People’s Hospital, Chongqing, People’s Republic of China; 3Administrative Department, Traditional Chinese Medicine Hospital of Jiulongpo Distriction Chongqing, Chongqing, People’s Republic of China; 4Clinical Laboratory, Chongqing Jiulongpo People’s Hospital, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengyu Zou, Clinical Laboratory, Chongqing Jiulongpo People’s Hospital, Chongqing, People’s Republic of China, Email hulongjiao494@126.com Liang Wang, Pharmacy Department, Traditional Chinese Medicine Hospital of Jiulongpo Distriction Chongqing, Chongqing, People’s Republic of China, Email askliang621129@126.comBackground: Platycodon grandiflorus could significantly improve the pathological results of cutaneous scald injury, reduce the release of inflammatory factors and promote angiogenesis. This study investigated the wound healing effect of luteolin, an active component of P. grandiflorus, on induced cutaneous scald injury in Sprague-Dawley (SD) rats.Methods: The protein expression levels of TNF-α and IL-6 were detected by ELISA. QRT-PCR was adopted to detect the expression of TGF-β 1 and VEGF. Histopathological changes of scald wounds were analyzed by hematoxylin-eosin staining. Cell viability and migration ability were detected by CCK-8 assay and scratch assay.Results: Both in vivo and in vitro experiments showed that luteolin promoted wound healing of cutaneous scald injury. Gene Oncology (GO) functional analysis and rescue experiments showed that endothelial nitric oxide synthase 3 (NOS3) was the critical target of luteolin in treating cutaneous scald.Conclusion: This study demonstrated that luteolin is an effective component of P. grandiflorus and is effective in the treatment of cutaneous scald injury.Keywords: Platycodon grandiflorus, luteolin, scald injury, nitric oxide synthase, network pharmacology

Xue Lian,1,2 Dakui Cao,2 Xun Hu,3 Weiqiang Mo,2 Xiujuan Yao,4 Juanfen Mo,5 Haiqin Wang1,2 1Department of Respiratory Medicine, Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of China; 2Department of Respiratory Medicine, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, 314000, People’s Republic of China; 3Department of Thoracic Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, 314000, People’s Republic of China; 4Department of Pathology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, 314000, People’s Republic of China; 5The Key Laboratory, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, 314000, People’s Republic of ChinaCorrespondence: Haiqin Wang, Department of Respiratory Medicine, The Second Hospital of Jiaxing, 1518 Huanchen North Road, Jiaxing, Zhejiang, 314000, People’s Republic of China, Email w_haiqin@163.comBackground: Lung adenocarcinoma (LUAD) is a life-threatening disease worldwide with a high mortality rate. The early diagnosis of LUAD is crucial for improving subsequent treatment and prognosis. However, biomarkers for early detection remain a clinical challenge in LUAD. Here, we aimed to develop circular RNAs (circRNAs) in circulating plasma from LUAD patients as valuable diagnostic biomarkers in LUAD.Methods: CircRNA expression was determined by circRNA microarray in three pairs of LUAD tumour tissues and patient-matched normal lung tissues. Hsa_circ_101555 and hsa_circ_008068 were selected as potential biomarkers in LUAD tissues and plasma by RT–PCR, respectively. The diagnostic value was analysed by the area under the curve (AUC) and the receiver operating characteristic (ROC) test.Results: Our results showed that 6261 circRNAs were upregulated and 7238 circRNAs were downregulated in LUAD tumour tissues compared with patient-matched normal lung tissues. Hsa_circ_101555 and hsa_circ_008068 were filtered as biomarkers for early-stage LUAD. Q-PCR results showed that hsa_circ_101555 and hsa_circ_008068 were significantly upregulated in both LUAD cancer tissues and circulating plasma. Hsa_circ_101555 and hsa_circ_008068 were positively associated with tumour differentiation, tumour size and CEA (P< 0.05). The ROC analysis showed that hsa_circ_101555 and hsa_circ_008068 had a better diagnostic potential compared to the traditional biomarkers (CEA, SCC, CYFRA21-1) in the detection of early-stage LUAD.Conclusion: The circular RNAs hsa_circ_101555 and hsa_circ_008068 could serve as novel diagnostic biomarkers for early-stage LUAD.Keywords: circRNAs, lung adenocarcinoma, diagnostic biomarker, circ101555

Hui Han,1,&ast; Weidong Qin,1,&ast; Yue Zheng,2– 5 Dongming Cao,6 Haining Lu,7 Lu Zhang,8 Yi Cui,1 Yuanyuan Hu,1 Wei Li,9 Haipeng Guo,1 Dawei Wu,7 Chen Li,1 Hao Wang,1,2,10 Yuguo Chen2– 5 1Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 3Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 4Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 5The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 6Department of Critical Care Medicine, Liaocheng People’s Hospital Affiliated with Shandong First Medical University, Liaocheng, People’s Republic of China; 7Department of Critical Care Medicine, Qilu Hospital of Shandong University (Qingdao), Qingdao, People’s Republic of China; 8Department of Critical Care Medicine, The Second Hospital of Shandong University, Jinan, People’s Republic of China; 9Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 10Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao WangDepartment of Critical Care Medicine, Qilu Hospital of Shandong University, 107 Wenhua-xi Road, Jinan, 250012, People’s Republic of ChinaTel +86 18560081013Email wanghao34@126.comYuguo ChenDepartment of Emergency Medicine, Qilu Hospital of Shandong University, 107 Wenhua-xi Road, Jinan, 250012, People’s Republic of ChinaTel +86 0531-8216 6843Email chen919085@sdu.edu.cnBackground: Extensively drug-resistant Acinetobacter baumannii (XDR-AB) infections have become difficult to treat and are associated with a high mortality rate. Tigecycline is one of the most effective agents used to treat XDR-AB infections, but data from treating bloodstream infection (BSI) in standard dose do not look promising, because of its low plasma concentration. Secondary BSI with primary infection source may indicate tigecycline treatment with a higher dose. Currently, little is known about the application of high-dose tigecycline among patients with secondary BSI caused by XDR-AB. We aimed to investigate the outcomes for high-dose (HD) tigecycline treatment versus standard-dose (SD) treatment of these patients.Methods: An observational cohort study was conducted at four university affiliated hospitals in mainland China. Adult inpatients who were confirmed as having secondary BSI caused by XDR-AB and received definitive tigecycline treatment were consecutively included. Patients who were treated with 50 mg every 12 h were defined as the SD group, and a twice dose was defined as the HD group.Results: Of the enrolled patients, 63 received SD and 88 received HD tigecycline treatment. Patients in the two groups had similar with regard to baseline clinical conditions. The 30-day survival was affected by the source of the primary infection. Survival was significantly better in patients with non-pulmonary-infection-related BSI than in patients with pulmonary-infection-related BSI. Multivariate Cox regression confirmed that HD had a protective effect only observed in patients with non-pneumonia-related BSI.Conclusion: A tigecycline dose that is twice its standard dose is better for the treatment of XDR-AB infection only in BSI associated with non-pulmonary infection.Keywords: Acinetobacter baumannii, bloodstream infection, extensively drug-resistant, tigecycline, high-dose

Xiaofen Li,1 Limin Gao,2 Meng Qiu,1 Dan Cao1 1Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Dan Cao; Meng QiuDepartment of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaTel +86-28-85422589Fax +86-28-85423609Email caodan@wchscu.cn; qiumeng@wchscu.cnAbstract: Gallbladder cancer is a highly aggressive malignancy with an extremely poor prognosis. Germline BRCA1 mutation in gallbladder cancer is very rare. Herein, we present a case of a 73-year-old Asian patient diagnosed with lymph nodes and peritoneal metastases just two months after surgery for primary gallbladder cancer. The patient had a past history of early-stage breast cancer and received a left radical mastectomy 27 years ago. Next-generation sequencing (NGS) was performed as the patient refused to receive systemic chemotherapy. According to NGS result of germline BRCA1 mutation, the patient was administered first-line Olaparib and obtained a progression-free survival of about 6 months. Furthermore, we briefly summarized the current targeted treatment of gallbladder cancer. To the best of our knowledge, this is the first report of germline BRCA1 p. S451Lfs*20 mutation and first-line Olaparib treatment in a metastatic gallbladder cancer patient. As a highly heterogeneous and aggressive malignancy, we suggest making clinical decisions according to a precision medicine concept based on gene sequencing in advanced gallbladder cancer.Keywords: gallbladder cancer, BRCA1 mutation, Olaparib

Xiao Huo,1,* Hengzi Sun,2,3,* Dongyan Cao,3 Jiaxin Yang,3 Peng Peng,3 Linghua Kong,3 Fei Chen,3 Keng Shen,3 Shuhong Li2 1Center of Basic Medical Research, Peking University Third Hospital Institute of Medical Innovation and Research, Beijing, People’s Republic of China; 2Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuhong LiDepartment of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 GongTiNan Road, Beijing, People’s Republic of ChinaTel +86-10-8523 1831Email 1544563468@qq.comKeng ShenDepartment of Obstetrics and Gynecology, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of ChinaEmail shenkengpumc@163.comBackground: Colposcopy was referred in cases with severe abnormalities in co-testing. Although p16/Ki67 dual staining reduced the referral rate, its sensitivity and specificity need to be enhanced.Methods: The expressions of p16, Ki-67, SMAD3, YAP1, RELA were evaluated in the colposcopy referral population. The inclusion criteria included 30– 60 years and diagnosed with HPV16/18-positive, other HR-HPV-positive with ASCUS, LSIL, AGC (atypical glandular cell) in co-testing. Colposcopies, endocervical curettages of cervical biopsies were also collected. Cases were excluded if there were no biopsies, if the interval between a cervical screening test and biopsies was more than 6 months, or if insufficient tissue was available as a formalin-fixed paraffin-embedded block. The pathology was independently reviewed by two pathologists. Discrepant interpretations were adjudicated by a third pathologist.Results: In total, 1194 of 1273 cases who were referred to colposcopy were evaluated in the present study. The sensitivity and specificity of p16+ combined with Ki-67+ for predicting CIN2+ were 62.1% and 89.5%, respectively. p16+ combined with YAP1+ and/or RELA+ provided a sensitivity and specificity of 70.9% and 89.5%, respectively, while 72.8% and 86.4% were achieved by p16+ combined with YAP1+ and/or SMAD3+ and/or RELA+. In HPV16/18+ and LSIL subgroups, the sensitivity and specificity of p16+ combined with Ki-67+ for predicting CIN2+ were 67.7% and 87.6%, respectively, for the former group and 58.6%, 88.8%, respectively, for the latter group. p16+, YAP1+/RELA+ showed a better performance for predicting CIN2+ with a better sensitivity and considerable specificity in the other HPV+ combined with ASCUS group than were achieved by p16+ combined with Ki-67+. RELA+ and the combination of p16 and RELA/YAP1 also provided the Max AUC area.Conclusion: Our study shows that RELA and the combination of p16 and RELA/YAP1 achieved better sensitivity and specificity for detecting morphologically CIN2+ lesions.Keywords: cervical precancer, immunocytochemical strategy, morphological marker, colposcopy triage

Xiao Huo,1 Xiaoshuang Zhou,2,3 Peng Peng,2 Mei Yu,2 Ying Zhang,2 Jiaxin Yang,2 Dongyan Cao,2 Hengzi Sun,4 Keng Shen2 1Medical Research Center, Peking University Third Hospital, Beijing,, People’s Republic of China; 2Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Ultrasound, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Beijing, People’s Republic of China; 4Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Keng ShenDepartment of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel +86-10-69155200Email shenkengpumc@163.comCorrespondence: Hengzi SunDepartment of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 GongTiNan Road, Chaoyang District, Beijing, 100020, People’s Republic of ChinaTel +86 010 85231760Email Summerel1990@163.comBackground: Although the incidence of cervical cancer has decreased in recent decades with the development of human papillomavirus vaccines and cancer screening, cervical cancer remains one of the leading causes of cancer-related death worldwide. Identifying potential biomarkers for cervical cancer treatment and prognosis prediction is necessary.Methods: Samples with mRNA sequencing, copy number variant, single nucleotide polymorphism and clinical follow-up data were downloaded from The Cancer Genome Atlas database and randomly divided into a training dataset (N=146) and a test dataset (N=147). We selected and identified a prognostic gene set and mutated gene set and then integrated the two gene sets with the random survival forest algorithm and constructed a prognostic signature. External validation and immunohistochemical staining were also performed.Results: We obtained 1416 differentially expressed prognosis-related genes, 624 genes with copy number amplification, 1038 genes with copy number deletion, and 163 significantly mutated genes. A total of 75 candidate genes were obtained after overlapping the differentially expressed genes and the genes with genomic variations. Subsequently, we obtained six characteristic genes through the random survival forest algorithm. The results showed that high expression of SLC19A3, FURIN, SLC22A3, and DPAGT1 and low expression of CCL17 and DES were associated with a poor prognosis in cervical cancer patients. We constructed a six-gene signature that can separate cervical cancer patients according to their different overall survival rates, and it showed robust performance for predicting survival (training set: p ˂ 0.001, AUC = 0.82; testing set: p ˂ 0.01, AUC = 0.59).Conclusion: Our study identified a novel six-gene signature and nomogram for predicting the overall survival of cervical cancer patients, which may be beneficial for clinical decision-making for individualized treatment.Keywords: cervical cancer, bioinformatics, prognostic signature, Gene Expression Omnibus, overall survival

Zhen Yuan, Dongyan Cao, Ying Zhang, Keng Shen, Jiaxin Yang, Mei Yu, Huimei Zhou Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Dongyan Cao; Ying Zhang Email caodongyanpumch@sina.com; zhangyingpumch@163.comObjective: The aim of this study was to explore whether adjuvant chemotherapy could improve prognosis for cervical cancer patients with elevated pretreatment serum squamous-cell carcinoma antigen (SCC-Ag).Methods: Propensity-score matching and inverse probability of treatment weighting (IPTW) were used to ensure balanced groups for patients with (arm A) and without adjuvant chemotherapy (arm B). All patients were treated between January 2012 and December 2014 at a single center. Study outcomes were disease-free survival (DFS) and overall survival (OS).Results: In total, 81 patients were included in this study. By propensity-score matching, 35 patients were included in each group (arm A and arm B). Median follow-up was 60 months in arm A and 66 months in arm B. Overall, 85.7% of patients in arm A and 71.4% of those in arm B received adjuvant radiotherapy. DFS and OS curves were similar between arms A and B (P=0.971 and 0.633, respectively). With IPTW, arm A was not associated with prognosis in terms of DFS (HR 0.946, 95% CI 0.237– 3.784; P=0.938) or OS (HR 1.020, 95%CI 0.357– 2.913; P=0.970).Conclusion: For patients with elevated pretreatment SCC-Ag, adjuvant chemotherapy was not found to improve prognosis. Also, a considerable proportion of these patients had postoperative indications for adjuvant radiotherapy. For these cervical cancer patients with elevated pretreatment SCC-Ag, the choice of radical hysterectomy and adjuvant chemotherapy should be prudent.Keywords: adjuvant chemotherapy, cervical cancer, oncologic outcomes, serum squamous-cell carcinoma antigen

In this paper, four binary Ni-13.4 at.% Al/Ni-17.7 at.% Al diffusion couples were first prepared and subjected to homogenization at 1573 K for 10,800 s, from which a continuous concentration profile formed. The three diffusion couples were then cooled down for aging at respective temperatures, i.e., 1173, 1123, and 1073 K, for 14400 s. The effect of composition and aging temperature on the aging microstructure was studied in detail by means of different experimental techniques and statistical analysis. The volume fraction, grain size, and shape factor of γʹ precipitates in the three diffusion couples were plotted as a function of alloy composition and annealing temperatures. Together with the previously proposed evaluation function in which the phase fraction, grain size, and shape factor of γʹ precipitates were chosen as the evaluation indicators, the optimal alloy composition and aging temperature for binary Ni-Al alloys with the best mechanical properties were evaluated, and finally validated by the measured hardness values. The successful demonstration of alloy design in the present binary Ni-Al alloys indicated that the two-step diffusion couple, together with the evaluation function for mechanic properties, should be of generality for high-throughput screening of optimal alloy composition and heat treatment process in different alloys.

Jun Sha,1,2 Dandan Cao,1,2 Rui Cui,1,2 Lu Xia,1,2 Xin Hua,1,2 Yuan Lu,1,2 Shuhua Han1 1Department of Respiratory Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing City, Jiangsu Province, People’s Republic of China; 2Medicine Department of Southeast University, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Shuhua HanDepartment of Medical Microbiology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar (UOG), P.O. box 196, Gondar, EthiopiaTel +251-918-192721Email abty12@gmail.comIntroduction: Mannose, a major monosaccharide component of N-glycans, involves in the glycometabolism of human body. Recently, mannose has been shown to suppress tumor growth through enhancing chemosensitivity and reducing the activity of mannose phosphate isomerase (MPI). However, it is largely unknown whether mannose exerts effects on non-small cell lung cancer (NSCLC).Materials and Methods: First, a mannose IC50 assay was conducted to find a suitable concentration of mannose for cell experiments. Then, vitro studies including CCK-8 assay, scratch wound healing assay, and TUNEL assay were performed to evaluate the effects of mannose on A549 cells, and an animal model was established to evaluate the antitumoural effect of mannose on NSCLC in vivo. Finally, immunohistochemistry was done to detect the expression of MPI by Rabbit Anti-MPI.Results: In this study, a concentration of mannose, 15mM, was used to explore the suppressive effect of mannose on A549 cells. CCK-8 assay demonstrated that mannose significantly inhibited the proliferation of A549 cells and enhanced the anti-tumor efficacy of carboplatin. Wound healing assay showed that mannose inhibits the migration of A549 cells, and mannose-induced migration inhibition was more efficient in A549 cells treated with carboplatin. TUNEL assay demonstrated that mannose significantly enhanced the efficacy of carboplatin to promote apoptosis treated by mannose (15mM) or carboplatin. The results of animal experiments revealed that the size and weight of tumors derived from A549 cells treated with mannose were smaller than those derived from control cells, and co-treatment with mannose and carboplatin had most efficient inhibition on tumor growth. MPI expression detection showed that the expression level of MPI in the stage Tis (tumor in situ) was the highest, while the stage IV has the lowest.Discussion: Collectively, our findings suggest that mannose inhibited cell proliferation and migration, promoted cell apoptosis and enhanced the efficacy of carboplatin in lung adenocarcinoma. Preliminary results showed that mannose had less side effect on health. In the future, mannose may be a potential candidate drug for adjuvant therapy of lung adenocarcinoma.Keywords: mannose, NSCLC, cancer

Xingyuan Wang,1,2,* Zeyu Chen,1,2,* Shi Qiu,1,3,* Dehong Cao,1 Kun Jin,1,2 Jin Li,1,2 Bo Chen,1,2 Yin Huang,1,2 Yige Bao,1 Liangren Liu,1 Qiang Wei1 1Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2West China School of Medicine, Sichuan University, Chengdu, People’s Republic of China; 3Center of Biomedical Big Data, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liangren Liu; Qiang WeiDepartment of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan 610041, People’s Republic of ChinaEmail liuliangren@scu.edu.cn; weiqiang933@126.comObjective: To study the effect of cryptorchidism on clinical stage (CS) of testicular seminoma (TS).Patients and Methods: In the Surveillance Epidemiology and End Results (SEER) database (2006‐2016), people with TS were enrolled in our research. Multivariable logistic regression models were constructed to compare the impact of cryptorchidism on CS.Results: This research was based on the registry information of 12,991 TS patients. All patients with a median age of 36 (13– 107) years were pathologically diagnosed with orchiectomy or needle biopsy specimens. Patients with CS I, II, and III TS accounted for 70.68% (n = 9182), 8.30% (n = 1078), and 5.75% (n = 747) of all patients, respectively; still there were 15.27% (n = 1984) of patients whose CS could not be identified or was not available. Among all included patients, 43.45% (n = 5644) of them had normal testis, 2.93% (n = 272) had cryptorchidism, and the primary site of 54.46% (n = 7075) of patients’ testis was unavailable. According to our study, patients with cryptorchidism were more likely to suffer advanced CS [OR=1.14, 95% CI (1.01– 1.28), p=0.0407]. Furthermore, this effect became more remarkable after adjusting for other factors including age, region, marital status, race, year of diagnosis and laterality [OR=1.23, 95% CI (1.13– 1.32), p< 0.0001].Conclusion: According to this study, TS patients with cryptorchidism would be at a higher risk of suffering advanced cancer than patients with normal testis. It demonstrates that surgical correction for cryptorchidism should be timely, and specific management should be conducted on this kind of TS patients.Keywords: testicular seminoma, cryptorchidism, clinical stage

Zhen Yuan, Dongyan Cao, Mei Yu, Huimei Zhou, Ying Zhang, Jiaxin Yang, Keng Shen Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Dongyan CaoDepartment of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan Road, Dongcheng District, Beijing 100730, People’s Republic of ChinaEmail caodongyanpumch@sina.comObjective: Data on the treatment of patients with ovarian cancer (OC) and associated cerebral infarction (CI) are extremely limited. The objectives were to investigate the risk factors for prognosis in patients with OC and associated CI.Methods: We retrospectively reviewed the electronic medical records of patients with OC from January 2013 to November 2018 in Peking Union Medical Hospital.Results: In total, 2632 inpatients were diagnosed with malignant ovarian cancer in our institution, and 30 patients (1.1%) were diagnosed with OC-associated CI. The median age was 60 years (range, 37– 83). The standard treatment, according to National Comprehensive Cancer Network (NCCN) guidelines, was administered to 19 patients. The median follow-up time was 19.5 months (range, 1– 59 months). In total, 17 patients experienced tumor progression, and 16 of them died. In univariate analysis, overall survival was significantly associated with the D-dimer level (P=0.017), FIGO stage (P=0.014), complete cytoreduction (P< 0.000) and standard treatment (P< 0.000). In multivariate analysis, the standard treatment remained an independent protective factor for death (hazard ratio=0.061, 95% confidence interval=0.007– 0.537, P=0.012).Conclusion: Although the prognosis of patients with OC and associated CI was poor, those who underwent the standard treatment still benefited.Keywords: cerebral infarction, surgery, ovarian neoplasms, prognosis

Chaoyong Shen,1,* Jiaoxue He,2,* Xiaoyan Le,2 Linmao Zheng,3 Dan Cao4 1Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of China; 2Department of Oncology, Wenjiang District People’s Hospital, Chengdu, Sichuan, People’s Republic of China; 3Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of China; 4Department of Abdominal Oncology, Cancer Center of West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dan CaoDepartment of Abdominal Oncology, Cancer Center of West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of ChinaTel +86-28-18980605963Fax +86-28-85422589Email caodan316@163.comAbstract: Glucagonoma, a rare neuroendocrine tumor of the pancreas, which is often misdiagnosed because of non-characteristic clinical manifestations. In addition, the treatment has not been well established for this disease so far. We here report a case of glucagonoma previous misdiagnosed as recurrent erythema. In this case, necrolytic migratory erythema was the main clinical manifestation, and he received surgical resection after admission although with liver metastasis. Postoperative pathological results showed that the heterogeneity of proliferative index in primary (Ki-67: 5∼10%) and metastatic (Ki-67: 25∼30%) tumors were obviously observed. One month postoperatively, abdominal CT and MRI showed multiple liver metastasis (type III) again. Interestingly, the skin rash was obviously improved after treatment with somatostatin combined with chemotherapy (octreotide, temozolomide and capecitabine). Subsequently, the patient received transarterial embolization (TAE). Up to now, no progression was noted for liver metastasis. Due to its rarity, clinical diagnosis is challenging; thus, further understanding of the disease by clinicians is helpful for early diagnosis and treatment, so as to improve the prognosis of patients.Keywords: glucagonoma, necrolytic migratory erythema, somatostatin, chemotherapy, TAE

Dandan Cao,1,2 Jun Sha,1,2 Rui Cui,1,2 Shuhua Han1 1Department of Pulmonary Medicine, Zhongda Hospital, School of Medicine, South-East University, Nanjing, Jiangsu, People’s Republic of China; 2Medicine Department of Southeast University, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Shuhua HanDepartment of Pulmonary Medicine, Zhongda Hospital, Ding Jia Qiao No. 87, Nanjing, Jiangsu 210009, People’s Republic of ChinaEmail hanshuhua0922@126.comAbstract: The concept of spread through air spaces (STAS) has been described as a new form of invasion in the lung in the 2015 WHO classification of Lung Tumors, namely invasion through alveolar spaces. STAS is a prognostic factor independent of growth pattern and tumor stage, and it is also an independent risk factor for unfavorable prognosis of stage I lung adenocarcinoma (ADC) and stage I lung squamous cell carcinoma (SCC). The pathological characteristics are different between ADC and SCC. STAS is not reported as routine, so setting a unified pathological reading standard, and hunting for STAS as a regular reading process is urgently advocated. We write this review to investigate the research progress of STAS and its effects on the prognosis of lung cancer.Keywords: lung cancer, STAS, pathological characteristics, prognosis

Zeyu Chen,1,2,* Shi Qiu,1,3,* Dehong Cao,1,* Jianbing Guo,1,2 Bo Chen,1,2 Yin Huang,1,2 Li Lai,1 Yige Bao,1 Qiang Dong,1 Liangren Liu,1 Qiang Wei11Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2West China School of Medicine, Sichuan University, Chengdu, People’s Republic of China; 3Center of Biomedical Big Data, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workObjective: To assess the clinical characteristics of testicular seminoma (TS).Patients and methods: A testicular cancer (TC) survey was conducted by the Department of Urology, West China Hospital, between 2008 and 2018. Tumors were classified according to the NCCN criteria such as age, tumor size, tumor marker levels, histopathology, clinical stage, initial treatment, follow-up, and clinical outcomes, were obtained from the database of our center.Results: Among 155 registered cases of TC with seminomatous element, 127 cases of pure TS were analyzed. All 127 patients with a median age of 37 years were pathologically diagnosed with orchiectomy specimens. Orchiectomy, chemotherapy, and radiotherapy were the main treatments for these patients. Patients with clinical stages I, II, and III testicular cancer of accounted for 81.1% (n=103), 15.7% (n=20), and 3.2% (n=4) of all patients, respectively. After a median follow-up time of 50 months, five patients presented with relapse during follow-up, and one among them died. Of the patients with stage I TS (T1N0M0S0 CS IA), three patients who only underwent orchiectomy relapsed. Among patients with stage II TS (T1N1M0S1 CS IIA), one patient relapsed after orchiectomy, post-surgery chemotherapy and radiotherapy. In four patients with stage III disease (T2N1M1aS1 CS IIIA), one relapsed after orchiectomy and chemotherapy, and died shortly after salvage chemotherapy and radiotherapy due to recurrence. The median overall survival time was 50 months. In all patients, the 2-year overall survival and progression-free survival probabilitis were 98.6% and 98.8%, respectively.Conclusion: The present study shows that patients with TS have good prognosis even at an advanced stage. Surveillance after orchiectomy was important for patients with CSI seminoma, and we recommend cisplatin-based chemotherapy as salvage therapy for patients with CSI seminoma. In addition, patients with a maximal tumor diameter >4 cm should undergo post-surgery chemotherapy.Keywords: testicular cancer, testicular seminoma, orchiectomy, post-orchiectomy therapy

Zicheng Hu,1–3 Songhua Fan,1–3 Meiling Liu,1–3 Jiaju Zhong,1–3 Du Cao,1–3 Peng Zheng,1–3 Ying Wang,1–3 Youdong Wei,1–3 Liang Fang,1–3 Peng Xie1–31Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, People’s Republic of China; 3Chongqing Key Laboratory of Neurobiology, Chongqing, People’s Republic of ChinaBackground: Post-stroke depression (PSD) is a frequent and serious complication of stroke. However, the underlying molecular basis of PSD remains largely unknown, and no empirical laboratory tests were available to diagnose this disorder.Materials and methods: A proton nuclear magnetic resonance (1H NMR)-based metabonomic approach was employed to profile plasma samples from 32 PSD, 35 stroke patients and 35 healthy comparison subjects (the training set) in order to identify metabolite biomarkers for PSD. Then, 10 PSD, 11 stroke patients and 11 healthy comparison subjects (test set) were used to validate the diagnostic performance of these biomarkers.Results: The multivariate statistical analysis demonstrated that PSD group was significantly distinguishable from non-PSD groups (non-depression stroke patients and healthy comparison group). Five plasma metabolites (phenylalanine, tyrosine, 1-methylhistidine, 3-methylhistidine and LDL CH3-(CH2)n-) were identified responsible for distinguishing PSD from non-PSD subjects. These metabolites were mainly involved in neurotransmitter metabolism and oxidative stress. The biomarker panel composing of these metabolites was capable of distinguishing test samples with a sensitivity of 100.0% and a specificity of 95.5%.Conclusion: Our findings suggest that plasma disturbances of neurotransmitter levels and oxidative stress were implicated in the onset of PSD; these disturbed metabolites biomarkers facilitate to the development of diagnostic tool for PSD.Keywords: post-stroke depression, stroke, metabonomics, diagnosis, NMR

Hengzi Sun, Keng Shen, Dongyan Cao Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Abstract: Cervical cancer is one of the most common gynecological malignancies. In recent years, the implementation of cervical cancer screening has resulted in the effective control of cervical cancer incidence. However, many deficiencies still exist in the current screening techniques and strategies. With advancements in cervical cancer screening research, immunochemical staining to determine cervical cytology has shown a broader application prospect in the early screening for cervical cancer, especially for triage in cervical cancer screening. Keywords: HSIL, dual staining, p16, Ki-67, triage strategy, colposcopy referral

Wei Lin, Dongyan Cao, Keng Shen Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China Purpose: The purpose of this study was to evaluate the prognostic significance of preoperative serum carcinoembryonic antigen (CEA) in primary mucinous ovarian carcinoma (MOC).Patients and methods: We reviewed 57 patients with primary MOC, in whom preoperative serum CEA had been measured. All patients were treated at Peking Union Medical College Hospital between June 1996 and September 2016.Results: Preoperative serum CEA was elevated (>5.0 ng/mL) in 10 patients (17.5%), with a median serum CEA of 9.6 ng/mL (5.4–111.7 ng/mL). CEA was significantly associated with preoperative serum cancer antigen 125 (P=0.002), surgical debulking status (P=0.015), and tumor stage (P=0.001). Univariate analysis showed that patients with elevated CEA had significantly worse overall survival (OS) than patients with normal CEA (5-year OS: 50.8% vs 91.9%, respectively; P=0.013), but there was no significant difference in progression-free survival between the two groups (P=0.307). Multivariate analysis further demonstrated that advanced stage was an independent prognostic predictor for OS (P=0.002, HR: 15.925, 95% CI: 2.745–92.404).Conclusion: Elevated preoperative serum CEA was strongly correlated with advanced stage in primary MOC, which may indicate a poorer prognosis. Further investigation of the intrinsic relationship between CEA and primary MOC is now required. Keywords: epithelial ovarian cancer, mucinous carcinoma, tumor marker, carcinoembryonic antigen, prognosis

Yuyi Wang,1,* Li Tu,1,* Chi Du,2,* Xiaoxiao Xie,1 Yanyang Liu,1 Jiantao Wang,1 Zhixi Li,1 Ming Jiang,1 Dan Cao,1 Xi Yan,1 Feng Luo1 1Lung Cancer Center, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Oncology, The Second People’s Hospital of Neijiang, Neijiang, Sichuan, People’s Republic of China *These authors contributed equally to this work Background: Breast cancer is the leading cause of mortality from cancer in women worldwide, and cancer stem-like cell (CSC) is responsible for failure treatment of breast cancer. It plays an important role in resistant disease and metastasis. CD44/CD24 and ALDH are well-accepted protein markers of breast CSC, and it was reported that distinct subtypes of breast CSC were identified by the 2 markers. It is possible that there are various kinds of breast CSC which could be identified by different markers, and CSC markers utilized at present are not enough to fully understand breast CSC. Finding out more novel CSC markers is necessary. CXCR2 is involved in breast cancer metastasis, treatment resistance, and recurrence and has positive cross-talk with known breast CSC protein markers. It can be concluded that CXCR2 is related to breast CSC, and further study is in need.Results: In this study, we assessed expression of CXCR2 with immunohistochemistry in breast cancer tissues from 37 patients and discovered that level of CXCR2 was significantly lower in triple-negative breast cancer (TNBC) compared with non-TNBC. CXCR2 expression decreased in estrogen receptor-negative or HER2-negative breast cancer, but not progesterone receptor-negative counterparts. By immunofluorescence, we observed high coexpression rate of CXCR2 and CSC-related proteins, including NANOG and SOX2. To prove our speculation that CXCR2 was a novel CSC marker for TNBC, we used 4T1 cell, which is a TNBC cell line, to analyze CXCR2-positive subpopulations and observed that CXCR2-positive 4T1 cells showed characteristics of CSC, including resistance to cisplatinum, radiation, and hypoxia, low proportion (around 1%), much more tumor xenografts, tumor spherule formation, and higher levels of CSC-related mRNA compared with CXCR2-negative cells.Conclusion: CXCR2 is an acceptable and newly discovered CSC marker for only TNBC. Keywords: cancer stem-like cell, CXCR2, triple-negative breast cancer, marker

Hengzi Sun,1 Xiaoning Bi,1 Dongyan Cao,1 Jiaxin Yang,1 Ming Wu,1 Lingya Pan,1 Huifang Huang,1 Ge Chen,2 Keng Shen1 1Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Background: The aim of the study was to analyze the underlying causes and application of splenectomy in patients with epithelial ovarian cancer (EOC) and assess its effect on the surgical satisfaction and prognosis of these patients.Materials and methods: Clinical data of patients with ovarian epithelial cancer treated with cytoreductive surgery were collected from 2000 to 2015 at Peking Union Medical College Hospital.Results: A total of 2,882 patients underwent ovarian cancer cytoreductive surgery at Peking Union Medical College Hospital between 2000 and 2015, of whom 38 (1.3%) also underwent spleen resections. Of these 38 patients, one underwent splenectomy due to intraoperative trauma, whereas the remaining 37 patients underwent splenectomy due to splenic metastasis. Among these 37 patients, 27 underwent resection due to direct tumor spread in the spleen and 10 underwent resection due to hematogenous metastasis. For subsequent first-line chemotherapy, 22 patients were platinum sensitive and 15 were platinum resistant. Overall median survival and the postsplenectomy median survival time were 106 and 75 months, respectively. The overall median survival in secondary cytoreduction was 101 months compared with 20.3–56 months in literature reviews. Univariate analysis revealed that platinum resistance to first-line chemotherapy, suboptimal surgery, and hematogenous metastasis influenced survival. Chemosensitivity and residual disease were identified as independent risk factors by multivariate analysis. We also report a literature review concerning the efficacy and safety of splenectomy during cytoreductive surgery in EOC.Conclusion: Approximately 1.3% of patients with EOC underwent spleen resection during initial cytoreductive surgery and more often during recytoreductive surgery. Tumor involvement was the most common indication for splenectomy, and rare patients underwent splenectomy due to intraoperative trauma. Most patients achieved optimal surgery, and thus their overall survival and postsplenectomy survival rates were longer. The prognosis of patients was closely related to chemosensitivity and presence of residual tumors. Splenectomy should be attempted in all patients with splenic involvement in whom optimal cytoreductive surgery was achievable, no matter in primary or secondary cytoreduction. Keywords: optimal debulking surgery, chemosensitivity, postoperative complication, splenic involvement, metastasis, prognosis

Shuai Dong,1,2 Hongxi Shi,1 Xintong Zhang,1,2 Xi Chen,1 Donghui Cao,2 Chuanbin Mao,3,4 Xiang Gao,1 Li Wang1 1Key Laboratory of Molecular Epigenetics of Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, 2First Hospital of Jilin University, Changchun, Jilin, 3School of Materials Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, China; 4Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, Norman, OK, USA Background: Candida albicans is the most prevalent fungal pathogen of the human microbiota, causing infections ranging from superficial infections of the skin to life-threatening systemic infections. Due to the increasing occurrence of antibiotic-resistant C. albicans strains, new approaches to control this pathogen are needed. Photodynamic inactivation is an emerging alternative to treat infections based on the interactions between visible light and photosensitisers, in which pheophorbide a (PPA) is a chlorophyll-based photosensitizer that could induce cell death after light irradiation. Due to PPA’s phototoxicity and low efficiency, the main challenge is to implement photosensitizer cell targeting and attacking. Methods: In this study, PPA was conjugated with JM-phage by EDC/NHS crosslinking. UV-Vis spectra was used to determine the optimum conjugation percentages of PPA and JM-phage complex for photodynamic inactivation. After photodynamic inactivation, the efficacy of PPA-JM-phage was assessed by performing in vitro experiments, such as MTS assay, scanning electron microscopy, measurement of dysfunctional mitochondria, ROS accumulation, S cell arrest and apoptotic pathway.Results: A single-chain variable-fragment phage (JM) with high affinity to MP65 was screened from human single-fold single-chain variable-fragment libraries and designed as a binding target for C. albicans cells. Subsequently, PPa was integrated into JM phage to generate a combined nanoscale material, which was called PPA-JM-phage. After photodynamic inactivation, the growth of C. albicans was inhibited by PPA-JM-phage and apoptosis was observed. Scanning electron microscopy analysis revealed shrinking and rupturing of C. albicans. We also found that depolarization of mitochondrial membrane potential was decreased and intracellular reactive oxygen species levels were elevated significantly in C. albicans inhibited by PPA-JM-phage. Additionally, PPA-JM-phage also lead to S-phase arrest, and metacaspase activation resulting from mitochondrial dysfunction was also found to be involved in C. albicans apoptosis. Conclusion: PPa-JM-phage may induce C. albicans apoptosis through a caspase-dependent pathway and the results herein shed light on the potential application of phtototherapeutic nanostructures in fungal inactivation. Keywords: PPA, phage, photodynamic therapy, apoptosis, metacaspase

Longzheng Xia,1,* Shiming Tan,1,* Yujuan Zhou,1 Jingguan Lin,1 Heran Wang,1 Linda Oyang,1 Yutong Tian,1 Lu Liu,1 Min Su,1 Hui Wang,1 Deliang Cao,1,2 Qianjin Liao1 1Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, Hunan, China; 2Department of Medical Microbiology, Immunology, and Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, USA *These authors contributed equally to this work Abstract: Cancer is a group of cells that malignantly grow and proliferate uncontrollably. At present, treatment modes for cancer mainly comprise surgery, chemotherapy, radiotherapy, molecularly targeted therapy, gene therapy, and immunotherapy. However, the curative effects of these treatments have been limited thus far by specific characteristics of tumors. Abnormal activation of signaling pathways is involved in tumor pathogenesis and plays critical roles in growth, progression, and relapse of cancers. Targeted therapies against effectors in oncogenic signaling have improved the outcomes of cancer patients. NFκB is an important signaling pathway involved in pathogenesis and treatment of cancers. Excessive activation of the NFκB-signaling pathway has been documented in various tumor tissues, and studies on this signaling pathway for targeted cancer therapy have become a hot topic. In this review, we update current understanding of the NFκB-signaling pathway in cancer. Keywords: nuclear factor kappa-B, p65, signaling pathway, cancer, inflammation

Yanyang Liu,1,* Li Tu,1,* Li Wang,1,* Jianlin Long,1 Jiantao Wang,1 Yuyi Wang,1 Feng Luo,1 Dan Cao2 1Department of Medical Oncology, Lung Cancer Center, 2Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China *These authors contributed equally to this work Background: Although anti-angiogenic therapy is widely applied clinically, its efficacy has been less than expected. Screening for regulatory factors and sensitive indicators to define the effectiveness of these drugs is required. Through a retrospective study of clinical data, we found that patients with a higher peripheral monocyte-to-lymphocyte ratio (MLR) obtained less benefit from recombinant human endostatin (rhES, Endostar®), an anti-angiogenic drug, in lung cancer. Because MLR is positively correlated with macrophage count in tumors, this result suggests that macrophages may influence the effectiveness of rhES therapy in lung cancer.Methods: Clinical data from 72 lung cancer patients treated with rhES were collected. Animal study, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, Western blot analysis, and transwell migration assays were carried on Lewis lung carcinoma (LLC) cells, bone marrow-derived macrophages, macrophage cell line RAW264.7, and ANA-1 cells.Results: Clinical data showed that compared with the baseline MLR before rhES treatment, patients with progressive disease had higher MLRs than those of patients with partial response. Experimental results showed that more macrophages were recruited in the LLC tumors after rhES treatment and the majority of them displayed an M2-like phenotype. rhES aggravated hypoxia and the inflammatory response in the tumor microenvironment. Hypoxia promoted the expression of CCL2 by endothelial and fibroblast cells, which could induce macrophages recruitment, and increased levels of inflammatory cytokines (interleukin-4 [IL-4], IL-6, and IL-10) skewed macrophage polarization toward the M2-like phenotype. Hypoxia or inflammation cytokine-treated macrophages enhanced the progression of LLC in vitro and in vivo.Conclusion: We found rhES could aggravate hypoxia and the inflammatory response in the tumor microenvironment. These changes were favorable for macrophage accumulation, and skewed their polarization toward the M2-like phenotype which could help LLC to escape from the anti-angiogenic therapy. Thus, these data indicate the accumulation of macrophages in the tumor microenvironment may adversely affect the efficacy of rhES on lung cancer. Keywords: macrophage, anti-angiogenic therapy, recombinant human endostatin, lung cancer, tumor microenvironment

Dong Cao,1 Qiong Ding,1 Wubin Yu,1 Ming Gao,1 Yilian Wang2 1Department of General Surgery, The People’s Hospital of Putuo, Zhoushan, 2Department of Cardiology, The Second People’s Hospital of Lianyungang, Xinpu, People’s Republic of China Abstract: The clinical significance and biological functions of long noncoding RNA SPRY4 intronic transcript 1 (SPRY4-IT1) in colorectal cancer (CRC) remain largely unclear. Herein, we are the first to report that the SPRY4-IT1 was significantly upregulated in CRC tissues, serum, and cells. Higher SPRY4-IT1 expression was markedly associated with advanced Tumor Node Metastasis (TNM) stage in a cohort of 84 CRC patients. Multivariate analyses indicated that SPRY4-IT1 expression could be useful as an independent predictor for overall survival. Further in vitro experiments revealed that knockdown of SPRY4-IT1 inhibited the proliferation, migration, and invasion of CRC cells and induced cell cycle arrestment. Moreover, we confirmed that the expression of epithelial–mesenchymal transition-related genes was modulated through alteration of SPRY4-IT1 expression. These results suggest that SPRY4-IT1, as an oncogenic regulator, may serve as a candidate prognostic marker and potential target for CRC therapies. Keywords: long noncoding RNA, SPRY4-IT1, colorectal cancer, survival

Shouqin Tian,1 Duanwen Cao,2 Haijuan Zou,1 Feng Bai,1 Zhongjuan Wang,1 Shirong Pan,1,3 Min Feng11School of Pharmaceutical Sciences, Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, 2Department of Pharmaceutical Sciences, Nanfang Hospital, Southern Medical University, 3Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, People’s Republic of ChinaAbstract: Upregulation of vascular endothelial growth factor (VEGF) expression can inhibit intimal thickening after vascular injury. However, the lack of efficient gene delivery systems leads to insufficient VEGF expression, which prevents its application in gene therapy. In the present study, to improve the delivery of the plasmid vector with the VEGF gene (pVEGF165) to the injured vessel wall, we explored the potentially important difference between endothelial cell-targeted and nontargeted polymeric carriers. The αvβ3 integrin is overexpressed on activated endothelial cells but not on normal quiescent vessels. In this study, CDG2-cRGD, synthesized by conjugating an αvβ3 integrin-binding cyclic arginylglycylaspartic acid (cRGD) peptide with the Generation 2 polycation polyamidoamine (PAMAMG2)-g-cyclodextrin (termed as CDG2), was developed as a targetable carrier. It was observed that the specific integrin–ligand interactions greatly enhanced cellular internalization of CDG2-cRGD in human umbilical vein endothelial cells (HUVECs), which are notoriously difficult to transfect. Consequently, HUVECs were found to show remarkably high levels of VEGF165 expression induced by the CDG2-cRGD polyplex. Interestingly, VEGF165 overexpression in vivo was more complex than that in vitro, and in vivo assays demonstrated that the stimulus response to balloon injury in arteries could obviously upregulate VEGF165 expression in the saline-treated group, although it was not enough to prevent intimal thickening. In gene-transfected groups, intravascular delivery of pVEGF165 with the CDG2-cRGD polyplex into rabbits after vascular injury resulted in a significant inhibition of intimal thickening at 4 weeks, whereas the low therapeutic efficacy in the nontargeted CDG2-treated group was only comparable to that in the saline-treated group. It is becoming clear that the conflicting results of VEGF165 gene therapy in two gene-transfected groups are reflective of the pivotal role of the cRGD-conjugated carriers in achieving the beneficial therapeutic effects of vascular gene therapy.Keywords: pVEGF165, αvβ3 integrin binding, intimal thickening, vascular gene therapy

We presented a risk assessment model to distinguish between type 1 diabetes (T1D) affected and unaffected siblings using only three single nucleotide polymorphism (SNP) genotypes. In addition we calculated the heritability from genome-wide identity-by-descent (IBD) sharing between full siblings. We analyzed 1,253 pairs of affected individuals and their unaffected siblings (750 pairs from a discovery set and 503 pairs from a validation set) from the T1D Genetics Consortium (T1DGC), applying a logistic regression to analyze the area under the receiver operator characteristic (ROC) curve (AUC). To calculate the heritability of T1D we used the Haseman-Elston regression analysis of the squared difference between the phenotypes of the pairs of siblings on the estimate of their genome-wide IBD proportion. The model with only 3 SNPs achieving an AUC of 0.75 in both datasets outperformed the model using the presence of the high-risk DR3/4 HLA genotype, namely AUC of 0.60. The heritability on the liability scale of T1D was approximately from 0.53 to 0.92, close to the results obtained from twin studies, ranging from 0.4 to 0.88.