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Ya-Song Luan,1 Gao Zhan-ling,1 Li Mi,1 Liu Ying,2 Bai Lan,1 Li Tong1 1Department of Nursing Science, Shandong Traditional Chinese Medicine College, YanTai, People’s Republic of China; 2Department of Neurosurgery, YanTai Affiliated Hospital of Binzhou Medical College, YanTai, People’s Republic of ChinaCorrespondence: Ya-Song Luan, Department of Nursing Science, Shandong Traditional Chinese Medicine College, YanTai, People’s Republic of China, Email 1067880955@qq.comBackground: Few individuals have focused on the experience of students during social events, especially among college students with social anxiety disorder. This study aimed to explore the anxiety experience among college students with social anxiety disorder in social situations.Methods: This qualitative interpretive study was conducted on college students who were diagnosed with social anxiety disorder (SAD) and recruited from two colleges in Heilongjiang Province, China. A total of 7 participants were selected by purposive sampling with maximum variability. Data were collected through semistructured individual interviews, and data analysis was performed by using Colaizzi’s 7-step analysis method.Results: The findings from the analysis of the interviews were classified into 4 themes and several main categories, including distorted self-awareness (3 main categories), fear of negative reaction from others (2 main categories), adverse reaction of body and mind (4 main categories) and strong desire to seek treatment.Conclusion: In our study, we sought to understand the anxiety experience among college students with social anxiety disorder in social situations. The study results provide a reference for psychologists and clinical medical staff and establish a scientific basis for the prevention and intervention of social anxiety disorder.Keywords: social anxiety disorder, qualitative study, anxiety experience

Yue Zhang,1,* Shuanglin Han,1,* Li Lv,2 Xiaomei Wang,3 Yu Zhu,1 Li Ying1 1Department of Gastroenterology, The Second Hospital of Dalian Medical University, Dalian, Liaoning Province, 116027, People’s Republic of China; 2Department of Pathology, The Second Hospital of Dalian Medical University, Dalian, Liaoning Province, 116027, People’s Republic of China; 3Department of Nuclear Medicine, The Second Hospital of Dalian Medical University, Dalian, Liaoning Province, 116027, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Ying, Department of Gastroenterology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Shahekou Region, Dalian, Liaoning, 116023, People’s Republic of China, Tel +86-17709870657, Email yingli0209@163.comAbstract: HAC is a rare extrahepatic malignancy histologically resembling hepatocellular carcinoma which can occur in many organs. Especially for cases carrying HAC within the stomach or duodenum, we found that typically HAC only happened in either of them and there was no case exhibiting HAC in both sites. Here, we presented a case having HAC in both sites and to our knowledge, this is the first report presenting HAC in these two distinct organs simultaneously. Firstly, a 57-year-old male was tested for increased serum alpha-fetoprotein level. Following PET-CT images showed strengthened FDG uptake in the gastric antrum and proximal duodenum. Esophagogastroduodenoscopy also revealed an irregular lump at the gastric antrum and a deep ulceration at the duodenum bulb. Next, an immunohistochemistry panel confirmed the diagnosis of HAC. Finally, genetic tests were performed on this patient after the clinical diagnosis of HAC to reveal the molecular etiology.Keywords: HAC, case report, AFP, SALL4, endoscopy, NGS

Herein, high-performance printed all-polymer solar cells (all-PSCs) based on a bulk-heterojunction (BHJ) blend film are demonstrated using PTzBI as the donor and N2200 as the acceptor. A slot-die process is used to prepare the BHJ blend, which is a cost-effective, high-throughput approach to achieve large-area photovoltaic devices. The real-time crystallization of polymers in the film drying process is investigated by in situ grazing incidence wide-angle X-ray scattering characterization. Printing is found to significantly improve the crystallinity of the polymer blend in comparison with spin coating. Moreover, printing with 1,8-diiodooctane as the solvent additive enhances the polymer aggregation and crystallization during solvent evaporation, eventually leading to multi-length-scale phase separation, with PTzBI-rich domains in-between the N2200 crystalline fibers. This unique morphology achieved by printing fabrication results in an impressively high power conversion efficiency of 9.10%, which is the highest efficiency reported for printed all-PSCs. These findings provide important guidelines for controlling film drying dynamics for processing all-PSCs.

Jianpeng Li,1– 3,* Jinlong Cao,1– 3,* Pan Li,1– 3 Ran Deng,1– 3 Zhiqiang Yao,1– 3 Lijun Ying,1– 3 Junqiang Tian1– 3 1Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, People’s Republic of China; 2Key Laboratory of Gansu Province for Urological Diseases, The Second Hospital of Lanzhou University, Lanzhou, People’s Republic of China; 3Clinical Center of Gansu Province for Nephron-Urology, The Second Hospital of Lanzhou University, Lanzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junqiang TianDepartment of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730030, People’s Republic of ChinaEmail ery_tianjq@lzu.edu.cnBackground: Clear cell renal cell carcinoma (ccRCC) is a commonly occurring tumor. Through a deeper understanding of the immune regulatory mechanisms in the tumor microenvironment, immunotherapy may serve as a potential treatment for cancer patients. This study aimed at identifying the survival-related immune cells and hub genes, which could be potential targets for immunotherapy in ccRCC.Methods: The gene expression profiles and clinical data of ccRCC patients were extracted from UCSC Xena and Gene Expression Omnibus (GEO) databases. Kaplan–Meier (KM) survival and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were utilized to select the survival-related tumor-infiltrating immune cells. Multivariate Cox regression was utilized to develop a signature based on the tumor-infiltrating immune cells (TIICs). Based on the signature, the risk score was calculated, following which the samples were divided into high-risk and low-risk groups. Differentially expressed genes (DEGs) between the two risk groups were identified. Functional enrichment analysis was performed and cytoHubba plug-in of Cytoscape was used to identify the hub genes. Multiple datasets were utilized to validate these hub genes, including the Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and the Human Protein Atlas (HPA), and the GEO datasets. Finally, a correlation analysis was performed to evaluate the relationship between the hub genes and TIICs.Results: Four immune survival-related cells, including T cell CD4 memory-activated, T cell regulatory (Tregs), eosinophils, and mast cell resting were identified. Nine immune-specific hub genes were identified, which included APOE, CASR, CTLA4, CXCL8, EGF, F2, KNG1, MMP9, and IL6. Furthermore, these hub genes were significantly correlated with clinical traits and closely associated with some TIICs.Conclusion: A total of four survival-related immune cell types and nine hub genes were found to be closely associated with ccRCC. These findings may have implications for the development of novel potential immunotherapeutic targets for ccRCC.Keywords: ccRCC, tumor-infiltrating immune cells, hub genes, TCGA, tumor microenvironment

Abstract Network analysis methods can potentially quantify cancer aberrations in gene networks without introducing fitted parameters or variable selection. A new network curvature-based method is introduced to provide an integrated measure of variability within cancer gene networks. The method is applied to high-grade serous ovarian cancers (HGSOCs) to predict response to immune checkpoint inhibitors (ICIs) and to rank key genes associated with prognosis. Copy number alterations (CNAs) from targeted and whole-exome sequencing data were extracted for HGSOC patients (n = 45) treated with ICIs. CNAs at a gene level were represented on a protein–protein interaction network to define patient-specific networks with a fixed topology. A version of Ollivier–Ricci curvature was used to identify genes that play a potentially key role in response to immunotherapy and further to stratify patients at high risk of mortality. Overall survival (OS) was defined as the time from the start of ICI treatment to either death or last follow-up. Kaplan–Meier analysis with log-rank test was performed to assess OS between the high and low curvature classified groups. The network curvature analysis stratified patients at high risk of mortality with p = 0.00047 in Kaplan–Meier analysis in HGSOC patients receiving ICI. Genes with high curvature were in accordance with CNAs relevant to ovarian cancer. Network curvature using CNAs has the potential to be a novel predictor for OS in HGSOC patients treated with immunotherapy.

Lingwen Ying,1,&ast; Yong Zhang,2,&ast; Jun Yin,1,&ast; Yufei Wang,1 Wei Lu,1 Wei Zhu,1 Yuqian Bao,1 Jian Zhou1 1Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Clinical Center for Diabetes; Shanghai Diabetes Institute; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, 200233, People’s Republic of China; 2Department of Immunology and Microbiology, Shanghai Jiao Tong University, School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian ZhouDepartment of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, People’s Republic of ChinaTel +86-21-64369181Fax +86-21-64368031Email zhoujian@sjtu.edu.cnPurpose: We aimed to explore the immunological characteristics and cytokine profile of the initial stage of type 1 diabetes.Patients and Methods: In total, 123 age- and sex-matched subjects with newly diagnosed classic type 1 diabetes mellitus (T1ADM), fulminant type 1 diabetes mellitus (FT1DM), and normal glucose tolerance (NGT) were enrolled. Serum cytokine levels were measured using Milliplex MAP multifactor detection.Results: There was a significant increase in the levels of transforming growth factor β (TGFβ 1) and TGFβ 2 and decrease in programmed death-1 (PD-1), PD ligand 1 (PD-L1), pro-inflammatory cytokines, and anti-inflammatory cytokines in type 1 diabetes patients compared with the NGT subjects (all P < 0.05). There was no significant difference in C-reactive protein (CRP) and blood routine indicators between the two groups. Type 1 diabetes was further divided into T1ADM and FT1DM subgroups. FT1DM patients had much higher CRP levels than T1ADM patients (4.90 [0.95– 26.05] mg/L vs 0.39 [0.20– 0.74] mg/L, P < 0.01). Blood routine results showed that the number of leukocytes was significantly increased in FT1DM compared with that in T1ADM (9.2 [5.1– 18.8] × 109 cells/L vs 5.4 [4.5– 6.7] × 109 cells/L, P < 0.01). In FT1DM patients, neutrophil% was increased, and lymphocyte% was declined significantly, compared with that in T1ADM patients (neutrophil%: 80.2 [59.2– 85.2]% vs 59.5 [54.8– 64.0]%; lymphocyte%: 18.3 [10.1– 32.3]% vs 32.6 [26.8– 35.9]%; both P < 0.01). However, there was no difference between FT1DM and T1ADM in cytokine profile except for the decrease in CTLA-4 in T1ADM (P < 0.05).Conclusion: Compared with T1ADM, CRP and leukocytes’ levels were increased significantly in FT1DM, with an increase in neutrophil% and decline in lymphocyte%, suggesting that FT1DM may have more abrupt onset and occur as a more serious subtype of type 1 diabetes mellitus.Keywords: cytokine profile, fulminant type 1 diabetes mellitus, immune response, multifactor detection, type 1 diabetes mellitus

Abstract Tetrathiomolybdate (TM) is a novel, copper-depleting compound associated with promising survival in a phase II study of patients with high-risk and triple-negative breast cancer. We sought to elucidate the mechanism of TM by exploring its effects on collagen processing and immune function in the tumor microenvironment (TME). Using an exploratory cohort, we identified markers of collagen processing (LOXL2, PRO-C3, C6M, and C1M) that differed between those with breast cancer versus controls. We measured these collagen biomarkers in TM-treated patients on the phase II study and detected evidence of decreased collagen cross-linking and increased degradation over formation in those without disease compared to those who experienced disease progression. Preclinical studies revealed decreased collagen deposition, lower levels of myeloid-derived suppressor cells, and higher CD4+ T-cell infiltration in TM-treated mice compared with controls. This study reveals novel mechanisms of TM targeting the TME and immune response with potential applications across cancer types.

Alcohol-associated liver disease (ALD) is the most common chronic liver disease and carries a significant healthcare burden. ALD has no long-term treatment options aside from abstinence, and the mechanisms that contribute to its pathogenesis are not fully understood. This study aimed to investigate the role of formyl peptide receptor 2 (FPR2), a receptor for immunomodulatory signals, in the pathogenesis of ALD. WT and Fpr2−/− mice were exposed to chronic–binge ethanol administration and subsequently assessed for liver injury, inflammation, and markers of regeneration. The differentiation capacity of liver macrophages and the oxidative burst activity of neutrophils were also examined. Compared to WT, Fpr2−/− mice developed more severe liver injury and inflammation and had compromised liver regeneration in response to ethanol administration. Fpr2−/− mice had fewer hepatic monocyte-derived restorative macrophages, and neutrophils isolated from Fpr2−/− mice had diminished oxidative burst capacity. Fpr2−/− MoMF differentiation was restored when co-cultured with WT neutrophils. Loss of FPR2 led to exacerbated liver damage via multiple mechanisms, including abnormal immune responses, indicating the crucial role of FPR2 in ALD pathogenesis.

Shengkai Gong,1 Liang Ying,2 Yu’ning Fan,1 Zhentao Sun1 1Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, People’s Republic of China; 2Department of Anesthesiology, The Second Affiliated Hospital of Zhejiang University Medical College, Hangzhou, Zhejiang 310009, People’s Republic of ChinaCorrespondence: Zhentao SunDepartment of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan 450052, People’s Republic of ChinaEmail sunzhentaozzu@126.comPurpose: Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases and remains the primary cause of cancer-related deaths worldwide. Fentanyl is a commonly utilized anesthetic during the process of tumor resection, and exhibits inhibitory effects on the progression of numerous cancer types, including pancreatic cancer, colorectal cancer and gastric cancer. However, the effects of fentanyl on the cell viability and invasion of NSCLC has not been investigated. Current study aimed to investigate the effects and the mechanisms underlying the effects of fentanyl on NSCLC.Methods: The expression of μ-opioid receptor (MOR) was proved by flow cytometry. The expression of microRNA-331-3p (miR-331-3p) and histone deacetylase 5 (HDAC5) in NSCLC tissues and cell lines are evaluated by reverse transcription-quantitative PCR (RT-qPCR) and Western blot, respectively. Cell viability and invasion are measured by cell counting kit-8 (CCK-8) assay and transwell assay, respectively. The interaction between miR-331-3p and 3ʹ-untranslated region (UTR) of HDAC5 is predicted by TargetScan 7.1 (http://www.targetscan.org/vert_71/), validated by dual luciferase assay, RT-qPCR and Western blot.Results: There was lower miR-331-3p expression and higher HDAC5 expression in NSCLC cell lines A549 and CALU-1 compared with BEAS-2B, which was reversed by fentanyl administration. miR-331-3p targeted 3ʹ-UTR of HDAC5 in NSCLC cell lines A549 and CALU-1. miR-331-3p inhibitor partially abrogated the inhibitory effects of fentanyl on NSCLC cell viability and invasion by targeting HDAC5. In addition, there was higher HDAC5 expression and lower miR-331-3p expression in tumor tissues which were isolated from patients with NSCLC compared to the adjacent normal tissues, and miR-331-3p was negatively correlated with HDAC5 in NSCLC tumor tissues.Conclusion: Fentanyl inhibits the viability and invasion of NSCLC cells by induction of miR-331-3p and reduction of HDAC5.Keywords: non-small cell lung cancer; NSCLC, fentanyl, cell invasion, cell viability, miR-331-3p, HDAC5

Alcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested whether human beta defensin-2 (hBD-2), a small anti-microbial peptide, attenuates experimental chronic ALD. Male C57Bl/6J mice were fed an ethanol (EtOH)-containing diet for 6 weeks with daily administration of hBD-2 (1.2 mg/kg) by oral gavage during the final week. Two independent cohorts of mice with distinct baseline gut microbiota were used. Oral hBD-2 administration attenuated liver injury in both cohorts as determined by decreased plasma ALT activity. Notably, the degree of hBD-2-mediated reduction of EtOH-associated liver steatosis, hepatocellular death, and inflammation was different between cohorts, suggesting microbiota-specific mechanisms underlying the beneficial effects of hBD-2. Indeed, we observed differential mechanisms of hBD-2 between cohorts, which included an induction of hepatic and small intestinal IL-17A and IL-22, as well as an increase in T regulatory cell abundance in the gut and mesenteric lymph nodes. Lastly, hBD-2 modulated the gut microbiota composition in EtOH-fed mice in both cohorts, with significant decreases in multiple genera including Barnesiella, Parabacteroides, Akkermansia, and Alistipes, as well as altered abundance of several bacteria within the family Ruminococcaceae. Collectively, our results demonstrated a protective effect of hBD-2 in experimental ALD associated with immunomodulation and microbiota alteration. These data suggest that while the beneficial effects of hBD-2 on liver injury are uniform, the specific mechanisms of action are associated with baseline microbiota.

Nina Lu,1 Chin Loon Neoh,2 Zhengying Ruan,3 Lei Zhao,4 Limei Ying,1 Xiaochang Zhang,1 Sai Chen,1 Linglong Xu1 1Department of Hematology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang 318000, People’s Republic of China; 2Department of Hematology, Royal Marsden Hospital, London SW3 6JJ, UK; 3Department of Pathology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang 318000, People’s Republic of China; 4Department of Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang 318000, People’s Republic of ChinaCorrespondence: Linglong Xu Email daniongniong@163.comAbstract: Essential thrombocythaemia (ET) and Waldenström macroglobulinaemia (WM) are two distinct disorders. Studies have reported several cases of myeloproliferative neoplasms (MPNs) with concomitant plasma cell dyscrasia. However, there were no reported cases of ET with concomitant WM to date. Here, we present a 55-year-old Chinese man with thrombocytosis and raised immunoglobulin level. Further investigations led to a diagnosis of ET and coexistent WM. Next-generation sequencing (NGS) of his bone marrow identified 3 mutated genes: JAK2 V617F, MYD88 L265P, and ATM F1036L. After being treated with pegylated interferon and low-dose aspirin, his platelet count normalized and immunoglobulin M (IgM) level reduced. To the best of our knowledge, this is the first reported case of dual pathology ET with WM.Keywords: myeloproliferative neoplasm, Waldenström macroglobulinaemia, Janus kinase 2, myeloid differentiation factor 88

Ethanol (EtOH)-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury. ω-6 PUFAs exert pro-inflammatory activity, while ω-3 PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators [e.g., resolvin D1 (RvD1)]. We tested the hypothesis that a decrease in the ω-6:ω-3 PUFA ratio would attenuate EtOH-mediated alterations in the gut-liver axis. ω-3 FA desaturase-1 (fat-1) mice, which endogenously increase ω-3 PUFA levels, were protected against EtOH-mediated downregulation of intestinal tight junction proteins in organoid cultures and in vivo. EtOH- and lipopolysaccharide-induced expression of INF-γ, Il-6, and Cxcl1 was attenuated in fat-1 and WT RvD1-treated mice. RNA-seq of ileum tissue revealed upregulation of several genes involved in cell proliferation, stem cell renewal, and antimicrobial defense (including Alpi and Leap2) in fat-1 versus WT mice fed EtOH. fat-1 mice were also resistant to EtOH-mediated downregulation of genes important for xenobiotic/bile acid detoxification. Further, gut microbiome and plasma metabolomics revealed several changes in fat-1versus WT mice that may contribute to a reduced inflammatory response. Finally, these data correlated with a significant reduction in liver injury. Our study suggests that ω-3 PUFA enrichment or treatment with resolvins can attenuate the disruption in intestinal homeostasis caused by EtOH consumption and systemic inflammation with a concomitant reduction in liver injury.

Zhihong Chai,1,* Yufei Yang,2,3,* ZhongYi Gu,4,* Xianli Cai,1 Wenwei Ye,1 Lin Kong,1 Xiaoxiao Qiu,1 Lingxiao Ying,1 Ziliang Wang,2,3 Linyou Wang1 1Department of Gynecology and Department of Radiology, Taizhou Municipal Hospital Affiliated to Taizhou University School of Medicine, Taizhou 318000, People’s Republic of China; 2Department of Obstetrics and Gynecology, Xihua Hospital Affiliated to Shanghai Jiaotong University School Medicine, Shanghai 200092, People’s Republic of China; 3Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 4Department of Nephrology, Children’s Hospital of Fudan University, Shanghai 201102, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ziliang WangDepartment of Obstetrics and Gynecology, Xihua Hospital Affiliated to Shanghai Jiaotong University School Medicine, 1665 Kongjiang Road, Shanghai 200092, People’s Republic of ChinaEmail huf_zlwang@126.comLinyou WangDepartment of Radiology, Taizhou Municipal Hospital, 381 East Zhongshan Road, Taizhou 318000, People’s Republic of ChinaEmail wanglinyou2007@163.comPurpose: Capsid protein L2 is the minor capsid protein of human papillomavirus 16 (HPV16). Although L2-based vaccines were developed, the therapeutic effect of recombinant viral capsid protein L2 (rVL2) was still to be illustrated.Methods: We used glucose uptake and lactate production assay to verify the inhibitory effect of rVL2 on the glucose metabolism in cervical cancer cells. Secondly, we performed gene-chip assay, RT-PCR, and Western blot to determine the role of ITGB7/C/EBPβ signaling pathway in rVL2-mediated glucose metabolism in vitro. Finally, we used an animal model to verify the function of rVL2 in cervical cancer.Results: We found that rVL2 reduced glucose uptake and lactate production levels in cervical cancer cells, which caused the inhibition of cell proliferation. rVL2 decreased the expression levels of key metabolic enzymes, including GLUT1, LDHA, and ALDOA, to affect cell metabolism in cervical cancer cells by inhibiting ITGB7/C/EBPβ signaling pathway in vitro and in vivo.Conclusion: These results demonstrated the vital role of rVL2 in the glycolysis-induced cell growth and proliferation via suppressing ITGB7/C/EBPβ signaling axis.Keywords: recombinant viral capsid protein L2, rVL2, C/EBPβ, glucose metabolism, cervical cancer

Linglong Xu, Xiaoxiao Ding, Limei Ying, Xiaochang Zhang, Nina Lu Department of Hematology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, People’s Republic of ChinaCorrespondence: Linglong XuDepartment of Hematology, Taizhou Central Hospital (Taizhou University Hospital), 999 Donghai Road, Taizhou, Zhejiang 318000, People’s Republic of ChinaTel +86 576 8852 6258Email daniongniong@163.comAbstract: MYD88 mutation has been reported in various lymphomas, specifically in lymphoplasmacytic lymphoma. Yet, the mutation has not been reported in primary follicular lymphoma. Here, we present a 62-year-old male with follicular lymphoma who had an MYD88 L265P somatic mutation and monoclonal IgM gammopathy. He received four cycles of R-CHOP immunochemotherapy. Interim PET/CT evaluation indicated a state of stable disease (SD). Neither did serum IgM remarkably drop. He was then given a bortezomib-contained regimen which significantly reduced the level of serum IgM. To the best of our knowledge, this is the first report of follicular lymphoma with monoclonal IgM and MYD88 L265P mutation. The present case indicated bortezomib may benefit these patients.Keywords: follicular lymphoma, monoclonal gammopathy, immunochemotherapy, MYD88 mutation