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Shao-Ting Wang,* Xiao-Yun He,* Juan Le, Ting Sun, Rui Peng Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rui Peng, Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China, Email pengruiwec@163.comBackground: Hypovitaminosis K has been linked to depression and suicide, but epidemiological research is scarce. This study aimed to explore the association among vitamin K with depression and suicidal attempts.Methods: This was a retrospective cross-sectional study involving 146 cases with a history of suicidal attempts and 149 subjects without a lifetime history of suicidal attempts. The levels of thyroid hormones, lipid profile, inflammatory cytokines, and vitamins were measured.Results: Subjects who had suicidal attempts presented with a significant decrease in FT4, TC, vitamin D, and vitamin K but increased CRP levels. In these variables, vitamin K has a better diagnostic value for suicidal attempts in depressed patients, with a sensitivity of 0.842 and a specificity of 0.715. Correlation analysis suggested that vitamin K was significantly and positively related to FT4, TC, LDL, and sdLDL. Multivariate analysis showed that serum vitamin K level predicts suicidal attempts in depressive patients (OR = 0.614, P = 0.004, 95% CI 0.153– 0.904). Moreover, a negative correlation between vitamin K and suicidal attempts was also noted for partial FT4, CRP, and vitamin D strata analysis.Conclusion: Our study suggests that low vitamin K levels were correlated with suicidal attempts in patients with depression, indicating that vitamin K deficiency might be a biological risk factor for depression.Keywords: vitamin K, suicidal attempts, depression

Abstract In situ profiling of subcellular proteomics in primary living systems, such as native tissues or clinic samples, is crucial for understanding life processes and diseases, yet challenging due to methodological obstacles. Here we report CAT-S, a bioorthogonal photocatalytic chemistry-enabled proximity labeling method, that expands proximity labeling to a wide range of primary living samples for in situ profiling of mitochondrial proteomes. Powered by our thioQM labeling warhead development and targeted bioorthogonal photocatalytic chemistry, CAT-S enables the labeling of mitochondrial proteins in living cells with high efficiency and specificity. We apply CAT-S to diverse cell cultures, dissociated mouse tissues as well as primary T cells from human blood, portraying the native-state mitochondrial proteomic characteristics, and unveiled hidden mitochondrial proteins (PTPN1, SLC35A4 uORF, and TRABD). Furthermore, CAT-S allows quantification of proteomic perturbations on dysfunctional tissues, exampled by diabetic mouse kidneys, revealing the alterations of lipid metabolism that may drive disease progression. Given the advantages of non-genetic operation, generality, and spatiotemporal resolution, CAT-S may open exciting avenues for subcellular proteomic investigations of primary samples that are otherwise inaccessible.

Baogen Zhang,1,&ast; Biqing Huang,2,&ast; Fan Yang,3,&ast; Jiandong Yang,1 Man Kong,1 Jing Wang,1 Yaoxian Xiang,1 Kangjie Wang,1 Ruchen Peng,4 Kun Yang,4 Chao An,5 Dong Yan1 1Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, People’s Republic of China; 2Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 3Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 4Department of Medical Imaging, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, People’s Republic of China; 5Department of Minimal Invasive Intervention, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative, Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong Yan, Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, People’s Republic of China, Tel/Fax +86-10-69543901, Email dongyan@mail.ccmu.edu.cn Chao An, Department of Minimal invasive intervention, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative, Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China, Tel/Fax +86-20-87343272, Email anchao-1983@163.comObjective: To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with transarterial chemoembolization (TACE) for the treatment of high-risk hepatocellular carcinoma (hHCC) patients.Methods: Between January 2014 and August 2022, a total of 1765 consecutive patients with hHCC who underwent initial intra-arterial therapies were reviewed and divided into a TACE group (n, 507) and a HAIC group (n, 426). The study used propensity score matching (PSM) to reduce selectivity bias. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan‒Meier curves with the Log rank test. The objective response rate (ORR), conversion surgery rate (CSR) adverse event (AE) comparison and subgroup analysis were performed between the two groups.Results: After PSM 1:1, 444 patients were divided into two groups. The patients with hHCC who received HAIC had higher median PFS (6.1 vs 3.3 months, P < 0.001) and OS (10.3 vs 8.2 months, P=0.303) than TACE. Higher ORR (24.8% vs 11.7%) and CSR (15.5% vs 8.9%) were found in the HAIC group than in the TACE group (both P < 0.05). The incidence of grade 3/4 AE was 23.9% and 8.1% in the TACE and HAIC groups, respectively. The subgroup analysis suggest that HAIC appeared to particularly benefit patients with tumor diameter of more than 10 centimeters (hazard ratio [HR], 0.6; 95% CI, 0.47– 0.77; p, 0.00) and PVTT Vp4 (HR, 0.56; 95% CI, 0.39– 0.8; P, 0.01) for PFS outperforming TACE.Conclusion: HAIC can provide better disease control for hHCC than cTACE, with a comparable long-term OS and safety.Keywords: hepatocellular carcinoma, transarterial chemoembolization, hepatic artery infusion chemotherapy, high risk

Abstract Background Recruitment of participants is the greatest risk to completion of most clinical trials, with 20–40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier 1), followed by phone screening and medical records review (tier 2) prior to a final in-person visit to confirm eligibility and consent. Methods Two tiers of screening were established: an initial screen of general eligibility using a patient-facing web portal (tier 1), followed by a more detailed screen that included phone survey and medical record review (tier 2). If potential participants passed the tier 2 screen, they were referred directly to visit 1 at a study site, where final in-person screening and consent were performed. Rates of screening were tracked during the period of trial recruitment and sources of referrals were noted. Results The approach to screening and recruitment resulted in 6125 tier 1 screens, leading to 1121 referrals to tier 2. The tier 2 screening resulted in 224 medical record requests and identification of 86 qualifying participants for referral to sites. The study attained a viable recruitment rate of 6 enrolled per month prior to being disrupted by COVID 19. Conclusions A tiered approach to eligibility screening using a hybrid of web-based portals to self-identify and screen for general eligibility followed by a more detailed phone and medical record review allowed the study to use fewer sites and reduce cost. Despite the difficult and narrow population of patients suffering moderate chronic disability from stroke, this strategy produced a viable recruitment rate for this invasive study of intracranially injected neural stem cells. Trial registration ClinicalTrials.gov Identifier: NCT03629275

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT).

Yuhong Tang,1,&ast; Jun Cao,1,&ast; Rui Peng,1 Xingkang Mao,1 Bingbing Su,1 Hao Tang,1 Daoyuan Tu,1 Jie Zhou,1 Guoqing Jiang,1 Shengjie Jin,1 Qian Wang,1 Chen Zhang,2 Renjie Liu,1 Chi Zhang,1,3 Dousheng Bai1,3 1Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, People’s Republic of China; 2The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 3General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dousheng Bai; Chi Zhang, Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, 98 West Nantong Road, Yangzhou, 225000, People’s Republic of China, Email drbaidousheng@yzu.edu.cn; zc17212850@163.comIntroduction: Immune checkpoint therapy (ICIs) effectively improves the prognosis of advanced (stage III/IV) hepatocellular carcinoma (HCC) patients. However, its objective response rate (ORR) is below 20%, significantly limiting ICI use in advanced HCC patients. The level of tumour immune infiltration influences ICI response rate. Recent studies have found ubiquitinase to be an important factor that regulates tumour immune infiltration. Therefore, the aim of this study is to explore the key ubiquitination genes that regulate immune infiltration in advanced HCC and further validate them.Methods: A biotechnological process was performed as a means of classifying 90 advanced HCC patients into three immune subtypes and identifying associations with immune infiltration in the co-expressed modules. Ubiquitination-related genes were then screened with WGCNA. Gene enrichment analysis was performed for the target module and 30 hub genes were screened out by protein–protein interaction network (PPI). ssGSEA, single-gene sequencing and the MCP counter were used for exploring immune infiltration. TIDE score was applied for predicting drug efficacy and GSEA was used for exploring potential pathways. Finally, GRB2 expression in HCC tissue was validated by in vitro experiments.Results: GRB2 expression was found to have a significant correlation with the pathological stage and prognosis of HCC patients and a positive correlation with immune infiltration and tumour mutation burden (TMB). In addition, significant correlations with the efficacy of ICIs, sorafenib and transarterial chemoembolization (TACE) were identified. GRB2 was found to be most significantly associated with the JAK-STAT signalling pathway and cytosolic DNA sensing pathway. Finally, it was found that GRB2 expression is closely related to the prognosis, tumour size and TMN stage.Conclusion: A significant association was observed between the ubiquitinated gene GRB2 and the prognosis and immune infiltration of advanced HCC patients and it may potentially be used for predicting therapy efficacy in advanced HCC patients in the future.Keywords: ubiquitination, growth factor receptor-binding protein 2, liver cancer, tumour-infiltrating immune cells

Yue Lin,1,&ast; Zheyan Chen,2,&ast; Yinai Liu,3 Jiawen Wang,2 Wang Lv,1 Renyi Peng3 1Department of Emergency, The Third Affiliated Hospital of Shanghai University & Wenzhou No. 3 Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People’s Hospital, Wenzhou, People’s Republic of China; 2Department of Plastic Surgery, The Third Affiliated Hospital of Shanghai University & Wenzhou No. 3 Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People’s Hospital, Wenzhou, People’s Republic of China; 3Institute of Life Sciences, College of Life and Environmental Science, Wenzhou University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Renyi Peng, Tel +86 159-5771-6937, Email 20170032@wzu.edu.cnAbstract: Skin injuries caused by accidents and acute or chronic diseases place a heavy burden on patients and health care systems. Current treatments mainly depend on preventing infection, debridement, and hemostasis and on supplementing growth factors, but patients will still have scar tissue proliferation or difficulty healing and other problems after treatment. Conventional treatment usually focuses on a single factor or process of wound repair and often ignores the influence of the wound pathological microenvironment on the final healing effect. Therefore, it is of substantial research value to develop multifunctional therapeutic methods that can actively regulate the wound microenvironment and reduce the oxidative stress level at the wound site to promote the repair of skin wounds. In recent years, various bioactive nanomaterials have shown great potential in tissue repair and regeneration due to their properties, including their unique surface interface effect, small size effect, enzyme activity and quantum effect. This review summarizes the mechanisms underlying skin wound repair and the defects in traditional treatment methods. We focus on analyzing the advantages of different types of nanomaterials and comment on their toxicity and side effects when used for skin wound repair.Keywords: nanomedicine, nanomaterials, nano-formulations, skin injury, wound repair

Diabetic patients have larger infarcts, worse neurological deficits, and higher mortality rate after an ischemic stroke. Evidence shows that in diabetes, the hypothalamic–pituitary–adrenal (HPA) axis was dysregulated and levels of cortisol increased. Based on the role of the HPA axis in immunity, we hypothesized that diabetes-dysregulated stress response exacerbates stroke outcomes via regulation of inflammation. To test this hypothesis, we assessed the regulation of the HPA axis in diabetic mice before and after stroke and determined its relevance in the regulation of post-stroke injury and inflammation. Diabetes was induced in C57BL/6 mice by feeding a high-fat diet and intraperitoneal injection of streptozotocin (STZ), and then the mice were subjected to 30 min of middle cerebral artery occlusion (MCAO). Infarct volume and neurological scores were measured in the ischemic mice. The inflammatory cytokine and chemokine levels were also determined in the ischemic brain. To assess the effect of diabetes on the stroke-modulated HPA axis, we measured the expression of components in the HPA axis including corticotropin-releasing hormone (CRH) in the hypothalamus, proopiomelanocortin (POMC) in the pituitary, and plasma adrenocorticotropic hormone (ACTH) and corticosterone. Diabetic mice had larger infarcts and worse neurological scores after stroke. The exacerbated stroke outcomes in diabetic mice were accompanied by the upregulated expression of inflammatory factors (including IL-1β, TNF-α, IL-6, CCR2, and MCP-1) in the ischemic brain. We also confirmed increased levels of hypothalamic CRH, pituitary POMC, and plasma corticosterone in diabetic mice before and after stroke, suggesting the hyper-activated HPA axis in diabetic conditions. Finally, we confirmed that post-stroke treatment of metyrapone (an inhibitor of glucocorticoid synthesis) reduced IL-6 expression and the infarct size in the ischemic brain of diabetic mice. These results elucidate the mechanisms in which the HPA axis in diabetes exacerbates ischemic stroke. Maintaining an optimal level of the stress response by regulating the HPA axis may be an effective approach to improving stroke outcomes in patients with diabetes.

Rui Peng, Yan Li Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People’s Republic of ChinaCorrespondence: Yan LiDepartment of Clinical Laboratory, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, People’s Republic of ChinaTel +86 2788071553Email pengruiwec@163.comBackground: Elevated levels of tenascin-C are linked to increased risk and severity of major depressive disorder (MDD), while testosterone shows a protective effect. The present study explored associations between serum levels of tenascin-C and testosterone in Chinese men with MDD.Methods: Testosterone and tenascin-C levels were measured in sera of 412 men with MDD and 237 age- and sex-matched controls. Serum levels of thyroid hormone, lipids, and high-sensitivity C-reactive protein (hs-CRP) were also quantified. Potential associations were examined using covariance, subgroup analysis, and multivariate linear regression analyses.Results: Significantly higher concentrations of tenascin-C were detected in sera of subjects with MDD than in controls. Among subjects with MDD, testosterone concentrations inversely correlated with tenascin-C levels. This relationship was observed when patients were stratified by age at onset; duration or severity of depression; or concentration of thyroid hormones, low- or high-density lipoprotein, or hs-CRP. The negative association remained even when the statistical model was adjusted for age, smoking status, alcohol use, and body mass index. Linear regression with bootstrap resampling confirmed that high tenascin-C levels inversely correlated with testosterone levels.Conclusion: In men with MDD, high tenascin-C concentrations correlate with testosterone deficiency. The combination of elevated tenascin-C and testosterone deficiency may be associated with MDD progression.Keywords: tenascin-C, testosterone, major depressive disorder

Da Peng,1 Dongfeng Shan,2 Chengcheng Dai,1 Jie Li,3 Zifan Wang,1 Ziyi Huang,1 Rui Peng,1 Peng Zhao,4 Xuezhen Ma1 1Department of Oncology, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, Shandong, People’s Republic of China; 2The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 3Department of Oncology, Jiaozhou Central Hospital, Jiaozhou, People’s Republic of China; 4Biotherapy Center, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Xuezhen MaDepartment of Oncology, Affiliated Qingdao Central Hospital, Qingdao University, No. 127 Siliunan Road, Qingdao, Shandong, 266042, People’s Republic of ChinaTel +86-18660229289Fax +86-532-85953085Email qdlwyxpd@163.comPeng ZhaoBiotherapy Center, Affiliated Qingdao Central Hospital, Qingdao University, Qingdao, Shandong, People’s Republic of ChinaEmail zp8102@126.comPurpose: As a third-generation EGFR TKI has been taken orally, Osimertinib effectively inhibits mutant EGFR, including T790M EGFR resistance mutations. Here, we examined real-world efficacy and tolerability of Osimertinib among Chinese patients with advanced EGFR T790M-mutant NSCLC.Patients and Methods: A total of 106 advanced NSCLC patients who were taking Osimertinib following disease progression after EGFR-TKIs or other treatments were retrospectively recruited in this study. The PFS and OS after Osimertinib treatment were analyzed as the primary endpoints.Results: Osimertinib was used as a second line and ≥ 3rd line treatment in 22.6% and 77.4% of the patients, respectively. DCR and ORR were 93.4% and 57.5%, respectively. Median PFS was 12.4 12 (95% CI, 10.5– 13.5) months. The PFS was 11 (8.0, 14.0) and 12 (10.3,13.7) months (p = 0.373), in patients with and without CNS metastasis, respectively. PFS in 2nd and ≥ 3rd line treatment was 11 (9.0, 13.0) and 12.4 12 (8.9, 15.1) months (p = 0.799), respectively. In patients with EGFR exon 19 deletion and exon 21 L858 mutation, the median PFS was 11 (9.2, 12.8) and 12 (9.2, 14.8) months, respectively (p = 0.833). Median PFS in the monotherapy group and combined anti-angiogenesis group was 11 (9.9,12.1) and 14 (11.2,16.8) months, respectively. Median OS after Osimertinib initiation was 27 (19.6, 34.4) months: 15 (6.9, 23.1) and 27 (22, 32) months in patients with and without CNS metastasis (p=0.027), 27 (20.3,33.7) months and (undefined) as second line or ≥ 3rd line of treatment (p = 0.421), respectively. In patients with exon 19 deletion, the median OS was not reached, and in patients with exon 21 L858 mutations, the median OS was 23 (19.1,29.9) months (p=0.027). Median OS in the monotherapy group was 27 (21.7,32.3) months, and in combined anti-angiogenesis group was not reached (p=0.68).Conclusion: Osimertinib can effectively treat advanced NSCLC with T790M mutations independently of previous treatment lines.Keywords: osimertinib, EGFR-activating mutations, T790M EGFR mutation, tyrosine-kinase inhibitors, non-small cell lung cancer

In order to understand the role of formaldehyde in living systems, real-time monitoring is required. Here the authors report a genetically encoded, reaction-based formaldehyde sensor (FAsor) that enables visualisation of formaldehyde in mammalian cells and tissues.

Mudi Yang,1,2 Jun Xie,2 Huan Zhang,2 Yingyong Chen,2 Shuo Xie,2 Rui Peng,2 Yu’e Jia,2 Yajing Chen,2 Lizi Wang1,2 1School of Nursing, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Admission Management Center of Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Lizi WangAdmission Management Center of Zhujiang Hospital, Southern Medical University, 253 Gongye Road M, Haizhu District, Guangzhou, Guangdong 510280, People’s Republic of ChinaTel/Fax +86 206 278 2038Email manbao99@126.comPurpose: Exploration of the reasons why people miss scheduled inpatient appointments from the perspectives of patients.Methods: Semi-structured interviews via telephone were conducted with patients who missed their inpatient appointments. Data were analyzed based on Colaizzi’s seven-step method.Results: Twenty-five patients and five dependents were enrolled. Three themes were identified: practical barriers, lack of knowledge about the disease, and negative emotional responses. Personal social obligations, state of illness, financial issues and long waiting times were the main practical barriers preventing patients from attending their inpatient appointment. Patients’ perceptions of feasible self-solving symptoms, readily believing people around them, and a blindly optimistic attitude towards disease contributed to their insufficient knowledge about the disease. Negative emotional responses (eg, sense of fear and lack of trust in physicians) had a detrimental effect on inpatient attendance.Conclusion: Three main factors contributed to non-attendance of inpatient appointments: practical barriers, lack of knowledge about disease, and negative emotional response. Our study provides new, valuable evidence on non-attendance of inpatient appointments in China. Our findings could offer meaningful insights into developing effective strategies to reduce non-attendance of inpatient appointments in other countries.Keywords: non-attendance, health-seeking behavior, medical appointment services, qualitative study, inpatient appointment

Rui Peng,1,* Yahui Wang,2,* Likai Mao,3 Fang Fang,4 Han Guan1 1Department of Urology, First Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China; 2Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shenshan Central Hospital, Shanwei, People’s Republic of China; 3Department of Urology, Second Affiliated Hospital of Bengbu Medical College, Bengbu, People’s Republic of China; 4Department of Immunology, School of Laboratory Medicine, Anhui Provincial Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Han GuanDepartment of Urology, First Affiliated Hospital of Bengbu Medical College, No. 87 Zhihuai Road, Longzhihu District, Bengbu, Anhui 233000, People’s Republic of ChinaTel +86 138 5522 8689Email gh668689@126.comIntroduction: Renal cell carcinoma (RCC) is one of the most common malignancies globally, among which clear cell carcinoma (ccRCC) accounts for 85– 90% of all pathological types. This study aims to screen out potential genes in metastatic ccRCC so as to provide novel insights for ccRCC treatment.Methods: GSE53757 and GSE84546 datasets in the Gene Expression Omnibus (GEO) were profiled to identify differentially expressed genes (DEGs) from ccRCC samples with or without metastasis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and the gene ontology (GO) analysis were performed to analyze pathway enrichment and functional annotation of DEGs. Protein–protein interaction (PPI) network was constructed, and survival analysis was conducted to evaluate the clinical values of the identified hub genes. In vitro loss-of-function assays were performed to explore the biological roles of these genes.Results: The bioinformatic analysis indicated that 312 DEGs were identified, including 148 upregulated genes and 164 downregulated ones. Using PPI and Cytoscape, 10 hub genes were selected (C3, CXCR4, CCl4, ACKR3, KIF20A, CCNB2, CDCA8, CCL28, S1PR5, and CCL20) from DEGs which might be closely related with ccRCC metastasis. In Kaplan–Meier analysis, three potential prognostic biomarkers (KIF20A, CCNB2 and CDCA8) were identified. Finally, cell proliferative and invasive assays further verified that KIF20A, CCNB2 and CDCA8 were associated with the proliferation and invasion of ccRCC cells.Conclusion: Our results demonstrated that metastatic ccRCC was partially attributed to the aberrant expression of KIF20A, CCNB2 and CDCA8, and more personalized therapeutic approaches should be explored targeting these hub genes.Keywords: clear cell renal cell carcinoma, hub genes, biomarkers, metastasis, differentially expressed gene

Guoming Zeng,1,2,* Libo Jin,3,4,* Qinsi Ying,5 Haojie Chen,3 Murinda Charmaine Thembinkosi,3 Chunguang Yang,6 Jinlong Zhao,6 Hao Ji,3 Sue Lin,3 Renyi Peng,3 Maolan Zhang,1,3 Da Sun3 1Chongqing University of Science and Technology, Chongqing 401331, People’s Republic of China; 2China Metallurgical Construction Engineering Group Co., Ltd., Chongqing 400044, People’s Republic of China; 3Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, People’s Republic of China; 4Biomedical Collaborative Innovation Center of Zhejiang Province & Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou, Zhejiang 325035, People’s Republic of China; 5Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325035, People’s Republic of China; 6Institute of Metal Research, Chinese Academy of Sciences, Shenyang, Liaoning 110016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Da SunInstitute of Life Sciences, Wenzhou University, Higher Educational Park, Wenzhou City 325035, Zhejiang Province, People’s Republic of ChinaEmail sunday@wzu.edu.cnMaolan ZhangChongqing University of Science and Technology, No. 19, Xijiao Branch Road, Jiulongpo District, Chongqing 400050, People’s Republic of ChinaEmail zml@cqu.edu.cnAbstract: Cancer immunotherapy is a promising approach that has recently gained its importance in treating cancer. Despite various approaches of immunotherapies being used to target cancer cells, they are either not effective against all types of cancer or for all patients. Although efforts are being made to improve the cancer immunotherapy in all possible ways, one important hindrance that lowers the immune response to kill cancer cells is the infiltration of Regulatory T (Treg) cells into the tumor cells, favoring tumor progression, on one hand, and inhibiting the activation of T cells to respond to cancer cells, on the other hand. Therefore, new anti-cancer drugs and vaccines fail to show promising results against cancer. This is due to the infiltration of Treg cells into the tumor region and suppression of anti-cancer activity. Thus, regardless of various types of immunotherapies being practiced, understanding the mechanisms of how Treg cells favor tumor progression and inhibition of anti-cancer activity is worthwhile. Therefore, the review highlights the importance of Tregs cells and how depletion of Treg cells can pave the way to an effective immunotherapy by activating the immune responses against cancer.Keywords: cancer immunotherapy, Treg cells, FoxP3, targeting Treg cells, anti-cancer

Yu Liang,1,2 Kai-hua Chen,1 Jie Yang,1 Jing Zhang,1 Ru-rong Peng,1 Song Qu,1 Ling Li,1 Xiao-dong Zhu1– 4 1Affiliated Wuming Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of China; 3Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, People’s Republic of China; 4Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaCorrespondence: Xiao-dong ZhuAffiliated Wuming Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaEmail zhuxdonggxmu@126.comPurpose: To explore acute toxicities and prognosis of elderly NPC patients after IMRT; to identify predictors regarding age, chemotherapy, comorbidities, nutrition status, and psychological condition; and to establish a nomogram for the prediction of prognosis.Patients and Methods: Elderly NPC patients were divided into three groups (age of 60– 65, age of 66– 70, and age over 70) and were retrospectively analyzed. The acute toxicities, prognosis, and potential predictors were analyzed. Then, a nomogram for PFS was established, and the performance of nomogram was compared with the performance of TNM system.Results: A total of 214 elderly patients (214/1981, 10.8%) were involved. Patients of Stage III and IV accounted for 73.4%. The 3-year, 5-year PFS and OS were 77.9%, 66.3%, 79.3% and 66.8%, respectively. Elder patients had a worse prognosis (P=0.002). The main cause of death remained in recurrence and metastasis; few died from comorbidities, and some died from nutrition status and psychological condition. Age (HR=1.10, 95% CI=1.05– 1.15, P< 0.001), ALB level (HR=0.93, 95% CI=0.88– 0.99, P=0.019), and T stage (HR=1.85, 95% CI=1.10– 3.13, P=0.022) were critical for PFS, but chemotherapy or comorbidities were not. Acute toxicities were mainly at or under grade II. N stage (OR=2.50, 95% CI=1.28– 4.88, P=0.007) and chemotherapy (OR=6.01, 95% CI=3.11– 11.63, P< 0.001) were risk factors for hematological toxicity; while age (OR=0.59, 95% CI=0.37– 0.92, P=0.020) and chemotherapy (OR=225.14, 95% CI=61.91– 818.64, P< 0.001) influenced emesis; ALB (OR=1.11, 95% CI=1.04– 1.19, P=0.002) affected mucositis. Comorbidities were not influential in acute toxicities. The nomogram for PFS (C-index=0.682, 95% CI=0.617– 0.747) performed better than the TNM system (C-index=0.604, 95% CI=0.532– 0.674, P< 0.001).Conclusion: Elderly NPC patients sustained poor prognosis. The easily applied nomogram is hopeful to benefit the clinical decision-making.Keywords: cancer, geriatric, survival, outcome, side effect, model

Introduction: The number of thrombectomy passes during endovascular therapy (EVT) for large vessel occlusion (LVO) in acute ischemic stroke (AIS) has been associated with probability of favorable functional outcome, with worse outcomes correlating with greater pass number. While first‐pass recanalization is a strong predictor of functional outcomes, the optimal or maximum recommended number of passes at which patients continue to benefit from EVT remains controversial. Moreover, among patients requiring more attempts, it is unclear if a certain subset of patients continue to benefit despite multiple passes. In this study, we determine predictors of functional outcome among patients requiring a high pass number to achieve successful vessel recanalization. Methods: From our prospectively maintained multi‐institutional registry across 4 comprehensive stroke centers, we identified patients with LVO AIS who underwent EVT requiring ≥ 3 passes to achieve successful reperfusion, defined as ≥ TICI 2b. Patient demographics, co‐morbidities, and severity of stroke based on NIHSS and ASPECTS were included within the analysis. Favorable outcome was defined as 90‐day post‐stroke modified Rankin Scale (mRS) 0–2. The primary outcomes were predictors of favorable outcome, which was assessed by multivariable logistic regression adjusted for age, baseline mRS, NIHSS, admission systolic and diastolic blood pressure, administration of tPA, number of passes during thrombectomy, history of hypertension, hyperlipidemia, atrial fibrillation, coronary artery disease, congestive heart failure, carotid stenosis, and diabetes. Results: Among 116 patients, median age was 70 (IQR 59–80), 48% were female, median NIHSS was 16.5 (IQR 13–22), and median number of passes was 3 (IQR 3–4, range 3–8). Patients with favorable outcome were younger (mean age 63±18.1 vs 70±14.5, favorable vs. non‐favorable, p = 0.041), and had lower NIHSS on presentation (mean 13.9±6.0 vs 18.3±7.4, favorable vs. non‐favorable p = 0.003). Patients with favorable outcome also had lower initial systolic blood pressure (149.6±32.8 vs 163.0±30.0 mmHg, favorable vs. non‐favorable, p = 0.047). In multivariable logistic regression adjusted for demographics and clinical characteristics, lower NIHSS was significantly associated with likelihood of good outcome (OR 0.88, 95% CI 0.81‐0.97, p = 0.009). Conclusions: Patients presenting with lower NIHSS are more likely to benefit from continued EVT attempts. These findings suggest that this population benefits from continued attempts at revascularization.

The side effects of cancer drugs limit their utility. Here, the authors developed a method in which an inactive (prodrug) version of the cancer drug doxorubicin enters tumour cells and then gets activated inside the cells upon a trigger facilitated by enzyme-instructed supramolecular self-assembly.

Abstract The protein-protein interaction between the human CMG2 receptor and the Bacillus anthracis protective antigen (PA) is essential for the transport of anthrax lethal and edema toxins into human cells. We used a genetically encoded high throughput screening platform to screen a SICLOPPS library of 3.2 million cyclic hexapeptides for inhibitors of this protein-protein interaction. Unusually, the top 3 hits all contained stop codons in the randomized region of the library, resulting in linear rather than cyclic peptides. These peptides disrupted the targeted interaction in vitro; two act by binding to CMG2 while one binds PA. The efficacy of the most potent CMG2-binding inhibitor was improved through the incorporation of non-natural phenylalanine analogues. Cell based assays demonstrated that the optimized inhibitor protects macrophages from the toxicity of lethal factor.

Mapping protein-protein interaction using crosslinking and mass spectroscopy strategies is hampered by a high rate of false-positive results. Here, the authors develop a genetically encoded photo-affinity probe for accurate identification of protein interaction partners and crosslinking sites.

The interactions between electrons and antiferromagnetic magnons (AFMMs) are important for a large class of correlated materials. For example, they are the most plausible pairing glues in high-temperature superconductors, such as cuprates and iron-based superconductors. However, unlike electron-phonon interactions (EPIs), clear-cut observations regarding how electron-AFMM interactions (EAIs) affect the band structure are still lacking. Consequently, critical information on the EAIs, such as its strength and doping dependence, remains elusive. Here we directly observe that EAIs induce a kink structure in the band dispersion of Ba1-xKxMn2As2, and subsequently unveil several key characteristics of EAIs. We found that the coupling constant of EAIs can be as large as 5.4, and it shows strong doping dependence and temperature dependence, all in stark contrast to the behaviors of EPIs. The colossal renormalization of electron bands by EAIs enhances the density of states at Fermi energy, which is likely driving the emergent ferromagnetic state in Ba1-xKxMn2As2 through a Stoner-like mechanism with mixed itinerant-local character. Our results expand the current knowledge of EAIs, which may facilitate the further understanding of many correlated materials where EAIs play a critical role.

Identification of the tyrosine phosphorylation (pY)-dependent interactome of immune co-receptors is crucial for understanding signal pathways involved in immunotherapy. However, identifying the motif-specific interactome for each pY commonly found on these multi-phosphorylated membrane proteins remains challenging. Here, we describe a photoaffinity-based chemical proteomic approach to dissect the motif-specific cytoplasmic interactomes of the critical immune co-receptor CD28. Various full-length CD28 cytoplasmic tails (CD28cyto) with defined pY and selectively replaced photo-methionine were synthesized and applied to explore three pY-motif-dependent CD28cyto interactomes. We identified a stand-alone interaction of phospholipase PLCG1 with the Y191 motif with enhanced affinity for the sequence neighboring the transmembrane domain. Importantly, taking advantage of native top-down mass spectrometry with a 193-nm laser, we discovered the direct association of a previously undefined pY218 motif with the kinase PKCθ through its C2 domain. This synthetic CD28cyto-based photoaffinity proteomic approach is generically applicable to the study of other immune co-receptors with multiple pY sites on their linear cytoplasmic tail.

The ability to control magnetic vortex is critical for their potential applications in spintronic devices. Traditional methods including magnetic field, spin-polarized current etc. have been used to flip the core and/or reverse circulation of vortex. However, it is challenging for deterministic electric-field control of the single magnetic vortex textures with time-reversal broken symmetry and no planar magnetic anisotropy. Here it is reported that a deterministic reversal of single magnetic vortex circulation can be driven back and forth by a space-varying strain in multiferroic heterostructures, which is controlled by using a bi-axial pulsed electric field. Phase-field simulation reveals the mechanism of the emerging magnetoelastic energy with the space variation and visualizes the reversal pathway of the vortex. This deterministic electric-field control of the single magnetic vortex textures demonstrates a new approach to integrate the low-dimensional spin texture into the magnetoelectric thin film devices with low energy consumption.