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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

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.

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.

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.

Chronic alcohol consumption leads to disturbances in intestinal function which can be exacerbated by inflammation and modulated by different factors, e.g., polyunsaturated fatty acids (PUFAs). The mechanisms underlying these alterations are not well understood. In this study, RNA-seq analysis was performed on ileum tissue from WT and fat-1 transgenic mice (which have elevated endogenous n-3 PUFAs). Mice were chronically fed ethanol (EtOH) and challenged with a single lipopolysaccharide (LPS) dose to induce acute systemic inflammation. Both WT and fat-1 mice exhibited significant ileum transcriptome changes following EtOH + LPS treatment. Compared to WT, fat-1 mice had upregulated expression of genes associated with cell cycle and xenobiotic metabolism, while the expression of pro-inflammatory cytokines and pro-fibrotic genes was decreased. In response to EtOH + LPS, fat-1 mice had an increased expression of genes related to antibacterial B cells (APRIL and IgA), as well as an elevation in markers of pro-restorative macrophages and γδ T cells that was not observed in WT mice. Our study significantly expands the knowledge of regulatory mechanisms underlying intestinal alterations due to EtOH consumption and inflammation and identifies the beneficial transcriptional effects of n-3 PUFAs, which may serve as a viable nutritional intervention for intestinal damage resulting from excessive alcohol consumption.

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.