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Tao Su,1,2,&ast; Ling Liu,3,&ast; Fan Meng,4,&ast; Hongzhen Wu,1,2 Tao Liu,1,2 Jun Deng,1,2 Xiang Peng,1,2 Min Zhi,1,2 Jiayin Yao1,2 1Department of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 2Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 3Department of Anesthesiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 4Digestive System Department, The First Affiliated Hospital of Gannan Medical University, Ganzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Zhi; Jiayin Yao, Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26th Yuancun the Second Road, Guangzhou, Guangdong Province, 510655, People’s Republic of China, Email zhimin@mail.sysu.edu.cn; yjyin@mail3.sysu.edu.cnBackground: Ustekinumab (UST) is recommended as the first-line treatment for patients with moderate to severe Crohn’s disease (CD). However, the efficacy of certain patients may be suboptimal and necessitate intensive treatment or modification of the treatment regimen. We sought to establish a nomogram model to predict the short-term effectiveness of UST in moderate to severe CD patients.Methods: We established a derivation cohort comprising patients diagnosed with CD and treated with UST at the Sixth Affiliated Hospital of Sun Yat-sen University from May 2020 to July 2023. The patient data, including demographic and clinical characteristics as well as treatment details, were systematically collected. The achievement of clinical remission (defined as Crohn’s Disease Activity Index, CDAI < 150, without corticosteroid usage) after induction therapy was the endpoint observed during follow-up. Potential predictors were identified through the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. Subsequently, a multivariate logistic regression analysis was conducted to construct a nomogram model. The predictive accuracy and discriminative power of the model were assessed by Receiver Operating Characteristics (ROC) curves and calibration curves. Decision curve analysis (DCA) was employed to assess the clinical application value of the model.Results: 162 patients were included in the derivation cohort. The predictor’s selection was according to the minimum criteria. Prognostic factors, including duration, body mass index (BMI), smoking, extraintestinal manifestations (EIMs), perianal lesions (P), history of Vedolizumab therapy, and albumin levels (ALB), were identified and included in the nomogram. The model showed good discrimination and calibration on internal validation based on the bootstrap method (C-index: 0.843, 95% confidence interval: 0.768– 0.903). Moreover, DCA demonstrated that the nomogram was clinically beneficial.Conclusion: We constructed a practical tool to assist clinicians in identifying moderate to severe CD patients who are expected to have a good clinical response to UST, promoting personalized treatment and the development of precision medicine.Keywords: Ustekinumab, Crohn’s disease, clinical remission, nomogram

Jing Sun,1,2,&ast; Wengang Li,3,&ast; Weiping He,3,&ast; Yanping Yang,4,&ast; Lewei Duan,5 Tingshi Su,6 Aimin Zhang,3 Tao Zhang,3 Xiaofang Zhao,7 Xiaoyun Chang,3 Xuezhang Duan1– 3 1 307 Clinical College of PLA, ANHUI Medical University, Beijing, People’s Republic of China; 2The Fifth Clinical College, ANHUI Medical University, Hefei, Anhui, People’s Republic of China; 3Department of Radiation Oncology, Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, People’s Republic of China; 4Department of Oncology, Kaifeng People’s Hospital, Kaifeng, Henan, People’s Republic of China; 5Laboratory of Epigenetics at Institutes of Biomedical Sciences, and Intelligent Medicine Institute, Fudan University, Shanghai, People’s Republic of China; 6Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of China; 7Graduate School of PLA Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuezhang Duan, 307 Clinical College of PLA, ANHUI Medical University, No. 8 East Street, Fengtai District, Beijing, People’s Republic of China, Email duanxuezhang2006@163.comPurpose: Radiofrequency ablation (RFA) is a micro-invasive treatment for early-stage HCC patients. Stereotactic body radiation therapy (SBRT) has also been proven an effective and safe treatment for HCC patients. This multi-center study is to compare the efficacy of computed tomography (CT)-guided RFA and CT-based SBRT in naïve HCC patients with tumor diameters ≤ 5 cm.Patients and Methods: This retrospective cohort study included 1001 treatment-naïve HCC patients from three hospitals or medical centers. The patients received RFA (n = 481) or SBRT (n = 520) treatment between December 2011 and May 2019. Furthermore, subgroup analyses of all patients were conducted based on Couinaud’s classification of liver segments.Results: After matching, the local control (LC) rates of the SBRT group were better than those of the RFA group (p=0.024&ast;), which mainly referred to the patients whose tumors were located in the S7/S8 (p=0.006&ast;). Among patients with tumors located in S1, nineteen patients (19/21) underwent SBRT. The 1-, 3- and 5-year LC rates were 100%, 87.8% and 87.8% in the SBRT group, and the 1-, 3- and 5-year OS rates were 100%, 69.8% and 69.8%, respectively. Moreover, the OS rates in S5/S6 group in RFA were higher than those in SBRT group.Conclusion: The LC rates were better in the SBRT group than in the RFA group for the patients with lesions localized in S7/S8, and SBRT could also be a therapeutic option for patients with lesions in S1. Moreover, patients with tumors located in S5/S6 were better candidates for RFA treatment than SBRT.Keywords: Stereotactic body radiation therapy, Computed tomography-guided radiofrequency, Naive hepatocellular carcinoma, Couinaud’s segmentation

Yujia Huang,1,2,&ast; Yinan Li,2,&ast; Tong Su,3 Hao Wang,2 Shuyu Xu,2 Jingzhou Xu,2 Siqi Zheng,4 Jing Du,2 Yajing Wang,2 Ruike Zhang,2 Yao Meng,2 Xin Guo,2 Lei Xiao,2 Yunxiang Tang3 1Psychology Department, The Second Naval Hospital of Southern Theater Command, Sanya, People’s Republic of China; 2Department of Medical Psychology, Faculty of Psychology, Naval Medical University, Shanghai, People’s Republic of China; 3Faculty of Psychology, Naval Medical University, Shanghai, People’s Republic of China; 4Department of Psychology, TongJi University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Xiao; Yunxiang Tang, Email xiaolei0237@163.com; tangyun7633@sina.comObjective: To investigate the effects of sleep quality, sleep deprivation, and napping on facial emotion recognition (FER) accuracy and speed.Methods: This research included a cross-sectional study (102 qualified participants) and a randomized controlled study (26 in the napping group and 24 in the control group). The stimuli for the FER task were obtained from the Chinese Facial Affective Picture System (CFAPS). Four facial expressions (fearful, disgusted, sad, and angry) were used. The Pittsburgh Sleep Quality Index (PSQI), Self-Rating Anxiety Scale, and Self-Rating Depression Scale were used to measure participants’ sleep quality and psychological conditions. In Study 1, FER ability was compared between good and poor sleepers. In Study 2, all participants were sleep-deprived for one night, and completed the FER task before and after sleep deprivation. After different interventions (ie, napping for one hour, or walking around for ten minutes), the participants completed the third FER task.Results: Study 1: Poor sleepers were able to recognize sad expressions more accurately compared with good sleepers. Study 2: 30-h sleep deprivation had no significant effect on the accuracy (ACC). Napping after sleep deprivation improved the FER ACC of upper-face expressions and marginally significantly improved the FER ACC of disgusted expressions.Conclusion: Better sleep quality was linked to lower FER accuracy, particularly in recognizing sad expressions, while no significant differences in recognition speed were observed. Additionally, 30 hours of sleep deprivation did not affect FER accuracy, but napping after sleep deprivation improved accuracy for upper-face and marginally for disgusted expressions.Keywords: facial emotion recognition, sleep quality, facial features, facial emotion, sleep deprivation, sleep loss

Xin Guo,1,&ast; Ying Xu,1,&ast; Yao Meng,1,2,&ast; Hao Lian,1,&ast; Jingwen He,1 Ruike Zhang,1 Jingzhou Xu,1 Hao Wang,1 Shuyu Xu,1 Wenpeng Cai,1 Lei Xiao,1 Tong Su,3 Yunxiang Tang3 1Department of Medical Psychology, Faculty of Psychology, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Diving and Hyperbaric Medical Research, Naval Special Medical Center, Naval Medical University, Shanghai, People’s Republic of China; 3Faculty of Psychology, Naval Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunxiang Tang, Email tangyun7633@sina.comBackground: Napping deprivation in habitual nappers leads to cognitive impairment. The ameliorative effect of acute aerobic exercise has been demonstrated for this post-cognitive impairment. However, it is still unclear which intensity of aerobic exercise is the most effective and how long this improvement can be sustained.Methods: Fifty-eight healthy adults with a chronic napping habit were randomly assigned to four intervention groups after undergoing nap deprivation: a sedentary control group, a low-intensity exercise group (50– 59% maximum heart rate, HRmax), a moderate-intensity exercise group (60– 69% HRmax), and a high-intensity exercise group (70– 79% HRmax). Working memory (N-back task), vigilance (Psychomotor Vigilance Task, PVT), and response inhibitory capacity (Go/NoGo task) were measured.Results: Regression analyses showed a quadratic trend between exercise intensity and working memory reaction time and accuracy (F =3.297– 5.769, p < 0.05, R2 =10.7– 18.9%). The effects of exercise were optimal at low-intensity. There was a significant quadratic trend between exercise intensity and PVT lapse (F =4.314, p =0.042, R² =7.2%). The effect of exercise increased with higher intensity. Prolonged observation found that the effect of low-intensity exercise on working memory was maintained for 2 hours.Conclusion: The effect of low-intensity exercise might be underestimated. Low-intensity exercise significantly improved working memory performance, and the effects could be maintained throughout the afternoon. In contrast, the effects of high-intensity exercise were unlikely to be maintained and might even have negative effects. Future researchers can broaden the categories of participants to enhance the external validity and collect diverse physiological indicators to explore related physiological mechanisms.Keywords: exercise intensity, executive function, habitual nappers, nap deprivation, working memory

Hang Wang,1,&ast; Bobin Hu,1,&ast; Hengkai Liang,1 Rongming Wang,1 Lu Wei,1 Tumei Su,1 Qingmei Li,1 Qianbing Yin,1 Yanfei Feng,1 Minghua Su,1 Jianning Jiang1,2 1Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 2Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor(Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianning Jiang; Minghua Su, Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, People’s Republic of China, Tel +86-0771-5356531, Email gxjjianning@163.com; smh9292@163.comPurpose: Few studies have reported the integrated characteristics of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after long-term antiviral therapy. This study aimed to investigate the HBV integration features in HBV-HCC patients who had undergone long-term antiviral therapy, evaluate their impact on clinical indicators, and analyze the potential mechanisms involved.Patients and Methods: We utilized genome-wide association study (GWAS) to analyze liver cancer tissues and detect the presence of HBV integration. Seventeen patients with HBV integration were included in the integration (Int) group, while the remaining five patients were included in the non-integration (N-int) group. Clinical indicators were regularly monitored and compared between the two groups. The characteristics of HBV integration patterns were analyzed, and differences between the groups were explored at the chromosome and genomic levels.Results: After long-term antiviral therapy, although the frequency of HBV integration in HBV-HCC was reduced, residual HBV integration still accelerated the development of HCC. It affected the diagnosis, treatment, and prognosis of patients. HBV integration events led to changes in chromosome structure, which were closely related to HCC. Novel fusion genes were detected at a high frequency and had the potential to be specific detection sites for HBV-HCC.Conclusion: HBV integration events are synergistically involved in the human genome and HBV, which can lead to chromosome structural instability, gene rearrangement events closely related to HCC production, and the formation of new specific fusion genes.Keywords: hepatitis B virus, long-term antiviral therapy, hepatocellular carcinoma, integration, gene rearrangement

Ting Su, Wentong Wang, Xixi Xiong, Meihua Zhang, Yan Lu,&ast; Zhonglan Su&ast; Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Lu; Zhonglan Su, Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, People’s Republic of China, Email luyan6289@163.com; alice_su2595@126.comBackground: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, mimicking hemophagocytic lymphohistiocytosis (HLH) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL).Purpose: To establish the clinicopathological features and response to treatment of CHP and evaluate the prognosis of patients and guide therapy based on the current state of knowledge.Material and Methods: Clinical, laboratory, histopathological, and outcome data of 12 patients with CHP were retrospectively collected between 2009 and 2022.Results: All the patients presented with plaques or nodules, mostly located in the lower extremities (11/12). Fewer cases involved systemic symptoms (9/12) and laboratory abnormalities (6/12), and none were positive for serum Epstein-Barr virus (EBV)-DNA. Histopathological examination revealed mixed septal and lobular inflammatory infiltration of histiocytes and lymphocytes. Large or atypical lymphocytes were rarely present (2/12). In some patients, varying proportions of plasma cells, neutrophils, and eosinophils were observed. The extent of histocytophagy was mild (9/12), moderate (2/12), and severe (1/12). HLH was not observed in any of our cases, none of which were fatal.Conclusion: The uniqueness of our study lies in the presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders (CTD) and streptococcal infections. Our study reveals that EBV-negative CHP tends to a better prognosis than previously research, filling the gap in the much-needed details of CHP in the Chinese population. Moreover, CHP may present as a reactive process in combined primary diseases; further studies are required to validate these findings.Plain Language Summary: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, also may be present in hemophagocytic lymphohistiocytosis and subcutaneous panniculitis-like T-cell lymphoma.The presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders and streptococcal infections. In addition, EBV-negative CHP has a better prognosis than previously thought and provides knowledge of its prognosis in the Chinese population.With changes in the disease pedigree supported by the development of medical technology, CHP may present as a reactive process of a combined primary disease.Keywords: Cytophagic histiocytic panniculitis, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, retrospective study

Jing Wang, Changqin Xu, Hongwei Xu, Ruixia Wang, Tong Su, Shulei Zhao Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People’s Republic of ChinaCorrespondence: Shulei Zhao, Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Weiqi Road, Jinan, 250021, People’s Republic of China, Email wenzhu24@126.comPurpose: To explore the molecular mechanisms of intestinal injury and treatment by analyzing changes in cellular heterogeneity and composition in rat ileal tissue during injury and treatment processes.Methods: We constructed a rat model of SAP and evaluated treatment with an injected of monoacylglycerol lipase (MAGL) inhibitor (JZL184) solution using three experimental groups: healthy male Sprague-Dawley (SD) rats injected with vehicle (CON), male SD SAP model rats injected with vehicle (SAP), and male SAP rats injected with JZL184. We obtained and prepared a single-cell suspension of ileal tissue of each rat for single-cell transcriptome sequencing.Results: This project classified changes in cellular heterogeneity and composition in rat ileal tissue during SAP-induced intestinal injury and MAGL treatment. We found that the number of fibroblast clusters was decreased in the SAP group relative to the CON group, and increased after JZL184 treatment. Further analysis of differences in gene expression between cell clusters in each group reveals that fibroblasts had the greatest number of differentially expressed genes. Most notably, expression of genes involved in communication between cells was found to vary during SAP-induced intestinal injury and JZL184 treatment. Among these changes, the degree of difference in expression of genes involved in communication between fibroblasts and other cells was the highest, indicating that fibroblasts in rat ileal tissue affect intestinal injury and repair through cell-to-cell communication. In addition, our results reveal that differentially expressed RNA-binding proteins in fibroblasts may affect their functions in intestinal injury and treatment by affecting the expression of genes regulating communication between cells.Conclusion: These findings emphasize the importance of understanding the interactions between fibroblasts and other cells in the context of intestinal injury, providing valuable insights for further exploring molecular mechanisms and insight for discovering new treatment targets and strategies.Keywords: single-cell RNA sequencing, cell heterogeneity, fibroblasts, monoacylglycerol lipase, intestinal injury, RNA-binding protein, severe acute pancreatitis

Xulin Liao,1,2 Chu Qi Li,1 Qian Min Ge,1 Li Ying Tang,3 Ting Su,4 Qiu Yu Li,1 Yi Cong Pan,1 Hui Ye Shu,1 Li Juan Zhang,1 Yi Shao1 1Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong SAR, People’s Republic of China; 3Department of Ophthalmology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, 361004, People’s Republic of China; 4Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USACorrespondence: Yi Shao, Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, No. 17, Yong Wai Zheng Street, Dong Hu District, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel/Fax +86 791-88692520, Email freebee99@163.comPurpose: The purpose of this study was to use the percent amplitude of fluctuation (PerAF) to study the changes in brain activity and nerve function of herpes zoster keratitis (HZK) patients.Methods: We recruited 20 HZK patients and 20 healthy controls (HCs). Each of these groups included ten males and ten females and were matched in weight and age. All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI). The percent amplitude of fluctuation (PerAF) method was used for analysis and detected differences between the two groups in the neurological function of brain areas. We also applied the receiver operating characteristic (ROC) curve to analyze the two groups and did a correlation analysis between the PerAF value, anxiety and depression score, and visual acuity.Results: The PerAF signal at the right putamen and right precentral gyrus was significantly higher in patients than in HCs. However, the PerAF value of the left inferior temporal was lower in patients than in HCs. In addition, the HZK patients’ anxiety and depression score (HADS) and visual acuity (V.A.) Log MAR negatively correlated with the PerAF value at the left inferior temporal gyrus.Conclusion: HZK patients had some changes in brain regions, and the changes were also related to their mood and visual acuity. These findings might contribute to other studies on the potential pathological mechanism, disease development, prognosis, and brain function in HZK patients.Keywords: herpes zoster keratitis, resting-state functional magnetic resonance imaging, brain activity patterns, brain region, the percent amplitude of fluctuation

Hua-Man Wu,1,2,&ast; Zhi-Jun Wang,1,&ast; Chao-Hong Cheng,1 Tong Su,1 Jing Wang,1 Ye-Zhou Li,3 Qiao-Jun Wang,4 Fei Han,4 Rui Chen1,4 1Department of Respiratory, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Zigong First People’s Hospital, Zigong, Sichuan, People’s Republic of China; 3School of Medicine, the University of Manchester, Manchester, UK; 4Department of Sleeping Center, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui Chen, Department of Respiratory/Department of Sleeping Center, the Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, People’s Republic of China, Tel +86(0512)67784857, Email chenruigood@126.comPurpose: Obstructive sleep apnea hypopnea syndrome (OSAHS) can lead to cognitive impairment, though few studies have so far examined hypercapnia as its causal mechanism, due to the invasive nature of conventional arterial CO2 measurement. The study aims to investigate the effects of daytime hypercapnia on working memory in young and middle-aged patients with OSAHS.Patients and Methods: This prospective study screened 218 patients and eventually recruited 131 patients (aged 25– 60 years) with polysomnography (PSG)-diagnosed OSAHS. Using a cut-off of 45mmHg daytime transcutaneous partial pressure of carbon dioxide (PtcCO2), 86 patients were assigned into the normocapnic group and 45 patients into the hypercapnic group. Working memory was evaluated using the Digit Span Backward Test (DSB) and the Cambridge Neuropsychological Test Automated Battery.Results: Compared with the normocapnic group, the hypercapnic group performed worse in verbal, visual, and spatial working memory tasks. PtcCO2≥ 45mmHg was an independent predictor for lower DSB scores (OR=4.057), lower accuracy in the immediate Pattern Recognition Memory (OR=2.600), delayed Pattern Recognition Memory (OR=2.766) and Spatial Recognition Memory (OR=2.722) tasks, lower Spatial Span scores (OR=4.795), and more between errors in the Spatial Working Memory task (OR=2.734 and 2.558, respectively). Notably, PSG indicators of hypoxia and sleep fragmentation did not predict task performance.Conclusion: Hypercapnia may be plays an important role in working memory impairment in patients with OSAHS, perhaps more so than hypoxia and sleep fragmentation. Routine CO2 monitoring in these patients could prove of utility in clinical practices.Keywords: hypercapnia, obstructive, sleep apnea, working memory

Qingqing Li,1,&ast; Tong Su,2,&ast; Xu Zhang,3,&ast; Yanfeng Pan,1,&ast; Shengli Ma,4 Lu Zhang,4 Xianqiang Zhang,1 Xiaojuan Gao1 1Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 2Department of Medical, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou city, People’s Republic of China; 4Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanfeng Pan, Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Jinshui District, Zhengzhou city, 450000, People’s Republic of China, Tel +8613938448759, Email panfirstfeng@163.comPurpose: To observe the efficacy and safety of anlotinib as a first-line treatment for patients with advanced hepatocellular carcinoma (aHCC) in a real-word environment, explore the optimal treatment regimen for patients with aHCC using anlotinib as a first-line treatment.Patients and Methods: Data from 62 patients with aHCC who received anlotinib single-drug first-line therapy between February 2019 and November 2021. Patients received anlotinib monotherapy, which may be interrupted or discontinued or changed in the event of unacceptable or severe adverse events (AEs) or failure to inhibit tumor progression. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate(ORR), disease control rate (DCR), overall survival (OS), and safety.Results: Among the 62 patients, in the best overall response assessment, there were 12 with complete response (CR; 19.4%), 17 with partial response (PR; 27.4%), 25 with stable disease (SD; 40.3%), and 8 with progressive disease (PD; 14.5%). The ORR and DCR were 46.8% and 87.1%, respectively. Among the 11 patients who received tyrosine kinase inhibitors (TKIs) combined with programmed death 1 (PD-1) inhibitors after disease progression, three (27.3%) had CR, one (9.1%) had PR, three (27.3%) had SD, and four (36.4%) had PD. Therefore, the ORR and DCR were 36.4% and 63.6%, respectively. The median PFS for anlotinib monotherapy was 7.37 months (95% confidence interval [CI]: 5.88– 8.86) and the median OS did not reach. AEs occurred in 95.2% of patients during anlotinib monotherapy, with the most common being thrombocytopenia (51.6%). The incidence of grade ≥ 3 AEs was 38.7%.Conclusion: Anlotinib is effective and well-tolerated as a first-line treatment for patients with aHCC. Treatment with TKIs and PD-1 inhibitors after disease progression has also shown preliminary efficacy and safety; therefore, sequential therapy with anlotinib-TKIs and PD-1 inhibitors may be an effective treatment for patients with aHCC.Keywords: hepatocellular carcinoma, anlotinib, sequential therapy, real world

Jing Du, Yajing Wang, Shuyu Xu, Yujia Huang, Ruike Zhang, Lei Xiao, Jingzhou Xu, Hao Wang, Tong Su, Yunxiang Tang Department of Medical Psychology, Naval Medical University, Shanghai, People’s Republic of ChinaCorrespondence: Tong Su; Yunxiang Tang, Department of Psychology, Naval Medical University, Shanghai, People’s Republic of China, Email sutong-2006@163.com; tangyun7633@sina.comPurpose: Previous epidemiological and psychological studies have assessed the effects of napping on individual performance and health. However, these studies did not distinguish between spontaneous and passive napping due to sleep disorders. Therefore, this study aimed to explore the potential motivation for napping among Chinese college students and to assess the relationship between different nap motivations and sleep.Patients and Methods: This cross-sectional study was conducted at a university in Shanghai in March 2021 using convenience sampling. A total of 564 Chinese college students with self-reported napping habits participated in this study. Exploratory factor analysis (EFA) was employed to analyze 34 self-rated motivations for napping to derive a potential structural model of napping motivation. Correlation and multiple linear regression analyses were performed to determine the influence of nap motivation on sleep behavior.Results: Chinese college students mainly take naps to reduce fatigue, usually in the form of frequent and long naps (6.25 ± 1.24 days; 64.62 ± 23.70 min). A structural model of nap motivation named the I-DREAM model was proposed, consisting of six factors: restorative, induced, mindful, appetitive, dysregulative, and exercise naps. There were also sex differences in nap motivation, as women preferred restorative naps and appetitive naps, while men preferred exercise naps (p < 0.01, p < 0.05). Furthermore, there was a significant correlation between nap motivation on nap duration, frequency and nighttime sleep quality (R2= 2.70– 18.9%).Conclusion: The proposed I-DREAM model implies that there are population differences in napping motivation. Different motivations also have different relationships with napping patterns and nighttime sleep. In understanding the relationship between naps and health status, nap motivation may be an extremely important influencing factor.Keywords: nap, sleep quality, Chinese college student, exploratory factor analysis

Tiannan Chen, Yuesen Lin, Chengshuo Cui, Fangfang Zhang, Tingting Su, Kaiyu Guo, Jialin Hu Department of Burn and Wound Repair, Yueqing City People’s Hospital; Wenzhou Medical College Affiliated Yueqing Hospital, Wenzhou City, Zhejiang, 325600, People’s Republic of ChinaCorrespondence: Jialin Hu, Department of Burn and Wound Repair, Yueqing City People’s Hospital; Wenzhou Medical College Affiliated Yueqing Hospital, No. 338, Qingyuan Road, Chengnan Street, Yueqing City, Wenzhou City, Zhejiang, 325600, People’s Republic of China, Tel +86 15868777770, Fax +86 577-62061788, Email hujialin_ys@163.comObjective: To explore the clinical effect of wound edge microgranular skin grafting in the treatment of various small wounds.Methods: From September 2018 to September 2021, Yueqing people’s Hospital of Wenzhou City, Zhejiang Province collected and recorded the data of 12 patients with chronic wounds and third degree burns. The method of skin grafting with particles at the edge of the wound was used to graft skin on the wound. Scar evaluation scale was used to evaluate the wound. The patients were followed up for 12 months. The preoperative and postoperative data, scar index and patient satisfaction after healing were recorded and statistically analyzed.Results: All patients in this group were followed up for 3– 12 months, and the results showed that SCAR Scale score decreased gradually over time, with patient satisfaction ranging from 80% to 96%. The patient gradually healed, scar hyperplasia gradually improved, functional activities gradually returned to normal, clinical effect is satisfactory.Conclusion: Microparticle skin grafting at the edge of wound avoids skin grafting at different skin donor sites. It has the characteristics of simple anesthesia, small trauma and convenient operation. This method can be considered when treating patients with chronic wounds and burns who need skin grafting.Keywords: wound-edge microgranular skin grafting, chronic wounds, burns, curative effect analysis

Jin Wu,1– 3,&ast; Tianyi Zhang,1– 3,&ast; Haofeng Xiong,1– 4 Liujun Zeng,1– 3 Zijia Wang,1– 3 Ying Peng,1– 3 Weijun Chen,1– 3 Xin Hu,1– 3 Tong Su1– 3 1Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, People’s Republic of China; 2Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, People’s Republic of China; 3Institute of Oral Cancer and Precancerous Lesions, Central South University, Changsha, Hunan, 410008, People’s Republic of China; 4Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, 410008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tong Su; Xin HuCenter Department of Oral and Maxillofacial Surgery, of Stomatology, Xiangya Hospital of Central South University, No. 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of ChinaEmail sutong@csu.edu.cn; huxin_666@qq.comObjective: Oral squamous cell carcinoma (OSCC) is the most frequent oral malignancy with a poor prognosis, in which tumor-infiltrating immune cells may play a critical role. Therefore, our study aims to screen potential immune cells and immune-related genes for predicting OSCC prognosis.Methods: A total of 310 OSCC patients with full transcriptional data and clinical characteristics were extracted from the TCGA database. Then, we obtained their abundance of tumor-infiltrating immune cells on TIMER 2.0 and analyzed them using xCell method. Univariate and multivariate Cox regressions were applied successively to identify the immune cells associated with overall survival of OSCC patients. Furthermore, we screened the prognostic genes that related to the identified immune cells and validated their expressions by immunohistochemistry.Results: CD4+ central memory T (TCM) cell was recognized as the sole independent immune cell correlated with OSCC prognosis (p = 0.0085). A novel nomogram based on CD4+ TCM cell abundance was established for predicting the prognosis of OSCC patients, with calibration plots showing good performance for 1-, 3-, 5-year overall survival. Thirty-four related prognostic genes were screened according to the differential abundance of CD4+ TCM cell infiltration. In immunohistochemistry analysis, DEFB1 showed a significant positive relationship with the density of CD4+ TCM cells (p = 0.0075).Conclusion: CD4+ central memory T cell was proposed as an independent prognostic biomarker for OSCC patients. DEFB1 might positively regulate the abundance of tumor-infiltrating CD4+ TCM cells, thus improving OSCC prognosis. Our findings may provide a new insight into better prognosis prediction and precise medicine for OSCC.Keywords: oral squamous cell carcinoma, CD4+ central memory T cell, DEFB1, prognosis biomarker

Yue Chen,1,&ast; Yan-Chang Yang,2,&ast; Li-Ying Tang,3,&ast; Qian-Min Ge,4 Wen-Qing Shi,1,4 Ting Su,3,5 Hui-Ye Shu,1,4 Yi-Cong Pan,1,4 Rong-Bin Liang,4 Qiu-Yu Li,4 Yi Shao4 1Department of Dermatology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangzhou, 518033, People’s Republic of China; 2Department of Anesthesiology, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 3Department of Ophthalmology, Zhongshan Hospital of Xiamen University, Xiamen, Fujian Province, 361102, People’s Republic of China; 4Department of Geriatric Medicine and Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 5Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, 02114, USA&ast;These authors contributed equally to this workCorrespondence: Yi ShaoDepartment of Geriatric Medicine and Ophthalmology, The First Affiliated Hospital of Nanchang University, No. 17, YongWaiZheng Street, DongHu District, Nanchang, Jiangxi, 330006, People’s Republic of ChinaTel/Fax +86 791-88692520Email freebee99@163.comObjective: Gastric adenocarcinoma originates from the glands in the superficial layer or mucosa of the stomach. It is prone to metastases, of which ocular metastasis (OM) is rare, but once it occurs the disease is considered more serious. The aim of this study was to investigate the risk factors for OM in gastric adenocarcinoma.Methods: Patients with gastric adenocarcinoma were recruited to this study between June 2003 and July 2019. Demographic data and serological indicators (SI) were compared between patients with and without OM, and binary logistic regression was used to explore whether the relevant SI may be risk factors for OM of gastric adenocarcinoma. Receiver operating characteristic (ROC) curves were used to analyze different SIs for OM in gastric cancer patients.Results: Chi-square tests showed significant between-groups difference in gender composition (P < 0.05), but not in age or histological grade (P > 0.05). t-test results showed that low-density lipoprotein (LDL) and carbohydrate antigen-724 (CA724) were significantly higher in patients with than without OM (P < 0.05). Binary logistic regression analysis showed that LDL was an independent risk factor for OM (P < 0.001). ROC curve analysis showed that the areas under the curves (AUC) for LDL and CA724 were 0.903 and 0.913 respectively, with higher AUC for combined LDL and CA724 (0.934; P < 0.001).Conclusion: LDL and CA724 have value as predictors for OM in patients with gastric adenocarcinoma, with higher predictive value when these factors are combined.Keywords: gastric adenocarcinoma, serological indicators, ocular metastases, risk factors, ROC curve

Zhenyu Ji,1 Jinyuan Luo,1 Ting Su,2 Changzheng Chen,1 Yu Su1 1Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China; 2Eye Institute of Xiamen University, Xiamen University, Xiamen, Fujian, 361102, People’s Republic of ChinaCorrespondence: Yu SuDepartment of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of ChinaTel/Fax +86-2788041911Email sy_daisy1206@163.comIntroduction: Diabetic retinopathy (DR) is one of the major leading causes for vision loss globally. Current study illustrates the role of miR-7a in DR.Material and Methods: Retinal pericytes (RPs) and Endothelial cells (ECs) were isolated from mouse model of DR. qRT-PCR was done for expression of miR-7a and target gene mRNA, Western blot for protein expression. Identification of miR-7a target gene was done by TargetScan and Luciferase assay. Cell viability and invasion was done by MTT and Transwell chamber assay.Results: The expression of miR-7a was down-regulated whereas level of IRS-2 was unregulated in isolated RPs and ECs. Luciferase assay suggested correlation between miR-7a and IRS-2, over-expression of miR-7a using a mimic resulted in suppression in viability and invasion capacity of RPs and ECs and inhibited the protein levels of PI3K/Akt cascade and IRS-2, and however the inhibitor reversed them respectively. Transfection of siRNA targeting IRS-2 caused alteration in miR-7a mediated changes in ECs suggesting that miR-7a may decrease angiogenesis in DR by inhibiting the levels of IRS-2.Conclusion: miR-7a suppresses PI3K/Akt cascade via targeting IRS-2, thus decreasing the viability and invasion capacity of RPs and ECs, suggesting an interesting treatment target for DR.Keywords: miR-7a, diabetic retinopathy; DR, IRS-2, PI3K/Akt, endothelial cells; ECs, retinal pericytes; RPs

Ruixin Jia,1,* Lesheng Teng,2,* Lingyu Gao,1 Ting Su,1 Lu Fu,3 Zhidong Qiu,1 Ye Bi1,4 1College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of China; 2School of Life Science, Jilin University, Changchun, Jilin, People’s Republic of China; 3College of Life Science, Jilin Agricultural University, Changchun, Jilin, People’s Republic of China; 4Practice Training Center, Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ye BiPractice Training Center, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, People’s Republic of ChinaTel/Fax +86-431-86763979Email biye88@outlook.comZhidong QiuCollege of Pharmacy, Changchun University of Chinese Medicine, 1035 Boshuo Road, Changchun, Jilin, People’s Republic of ChinaTel/Fax +86-431-86763979Email qzdcczy@163.comAbstract: Nanomedicines afford unique advantages in therapeutic intervention against tumors. However, conventional nanomedicines have failed to achieve the desired effect against cancers because of the presence of complicated physiological fluids and the tumor microenvironment. Stimuli-responsive drug-delivery systems have emerged as potential tools for advanced treatment of cancers. Versatile nano-carriers co-triggered by multiple stimuli in different levels of organisms (eg, extracorporeal, tumor tissue, cell, subcellular organelles) have aroused widespread interest because they can overcome sequential physiological and pathological barriers to deliver diverse therapeutic “payloads” to the desired targets. Furthermore, multiple stimuli-responsive drug-delivery systems (MSR-DDSs) offer a good platform for co-delivery of agents and reversing multidrug resistance. This review affords a comprehensive overview on the “landscape” of MSR-DDSs against tumors, highlights the design strategies of MSR-DDSs in recent years, discusses the putative advantage of oncotherapy or the obstacles that so far have hindered the clinical translation of MSR-DDSs.Keywords: multi-stimuli responsive nanoparticles, drug delivery, tumor microenvironment, oncotherapy

Yan Zhao,1 Huan Wang,2 Yang Yang,2 Wendan Jia,1 Tong Su,1 Yuxin Che,2 Yixin Feng,1 Xuemei Yuan,1 Xuelian Wang2 1Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang 110122, People’s Republic of China; 2Department of Microbiology and Parasitology, College of Basic Medical Sciences, China Medical University, Shenyang 110122, People’s Republic of ChinaCorrespondence: Xuelian Wang Email xlwang18@cmu.edu.cnBackground: Previously, we demonstrated the therapeutic efficacy of a human papillomavirus (HPV) vaccine, including HPV16 E7 peptide and CpG oligodeoxynucleotides (CpG ODN), against small TC-1 grafted tumors. Here, we developed an HPV16 E7 peptide and CpG ODN vaccine delivered using liposomes modified with DC-targeting mannose, Lip E7/CpG, and determined its anti-tumor effects and influence on systemic immune responses and the tumor microenvironment (TME) in a mouse large TC-1 grafted tumor model.Methods: L-alpha-phosphatidyl choline (SPC), cholesterol (CHOL), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol-2000)] (DSPE-PEG-2000), 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) and Mannose-PEG-DSPE, loaded with HPV16 E7 peptide and CpG ODN, were used to construct the Lip E7/CpG vaccine. The anti-tumor effects and potential mechanism of Lip E7/CpG were assessed by assays of tumor growth inhibition, immune cells, in vivo cytotoxic T lymphocyte (CTL) responses and cytokines, chemokines, CD31, Ki67 and p53 expression in the TME. In addition, toxicity of Lip E7/CpG to major organs was evaluated.Results: Lip E7/CpG had a diameter of 122.21± 8.37 nm and remained stable at 4°C for 7 days. Co-delivery of HPV16 E7 peptide and CpG ODN by liposomes exerted potent anti-tumor effects in large (tumor volume ≥ 200mm3) TC-1 grafted tumor-bearing mice with inhibition rates of 80% and 78% relative to the control and Free E7/CpG groups, respectively. Vaccination significantly increased numbers of CD4+ and CD8+ T cells, and IFN-γ-producing cells in spleens and tumors and enhanced HPV-specific CTL responses, while reducing numbers of inhibitory cells including myeloid-derived suppressor cells and macrophages. Expression of cytokines and chemokines was altered and formation of tumor blood vessels was reduced in the Lip E7/CpG group, indicating possible modulation of the immunosuppressive TME to promote anti-tumor responses. Lip E7/CpG did not cause morphological changes in major organs.Conclusion: Lip E7/CpG induced anti-tumor effects by enhancing cellular immunity and improving tumor-associated immunosuppression. Mannose-modified liposomes are the promising vaccine delivery strategy for cancer immunotherapy.Keywords: immunotherapy, human papillomavirus, peptide vaccine, CpG ODN adjuvant, liposome, tumor microenvironment

Xiaolin Li,1,2 Ting Su,3 Hua Xiao,1 Peichun Gao,4 Chongxiang Xiong,1 Jinghua Liu,3 Hequn Zou1 1Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China; 2Department of Endocrinology, Hunan University of Medicine, Huaihua 418000, Hunan, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of China; 4School of Public Health, Southern Medical University, Guangzhou 510080, People’s Republic of ChinaCorrespondence: Jinghua LiuGuangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of ChinaTel +86 20 61648392Fax +86 20 61648231Email liujhua@smu.edu.cnHequn ZouDepartment of Nephrology, The Third Affiliated Hospital, Southern Medical University, 183 Zhongshan Dadao, Tianhe District, Guangzhou 510630, People’s Republic of ChinaTel +86 20 62784393Fax +86 20 62784399Email hequnzou@hotmail.comPurpose: To explore the association between the anti-inflammatory and renal protective roles of high-density lipoprotein cholesterol (HDL-c) and its different levels in type 2 diabetes mellitus (T2D), hypertension (HTN), and chronic kidney disease (CKD) and to lay a theoretical basis for precise, maximum-benefit HDL-c-raising therapy for patients with these diseases.Patients and Methods: A total of 2127 participants (195 with T2D, 618 with HTN, 162 with CKD, and 1152 controls) were selected and divided into four groups according to their baseline HDL-c level, namely, low HDL-c (L-HDL-c, ≤ 1.03 mmol/L), medium HDL-c (M-HDL-c, 1.04– 1.55 mmol/L), high HDL-c (H-HDL-c, 1.56– 2.05 mmol/L) and extremely high HDL-c (E-HDL-c, ≥ 2.06 mmol/L). Serum and morning urine samples were collected to analyze the correlation between high-sensitivity C-reactive protein (HsCRP), interleukin-6 (IL-6), urine n-acetyl-β-d-glucosidase (U-NAG), retinol binding protein (RBP), and cystatin c (Cys-C) levels with the HDL-c levels.Results: The HDL-c levels of patients with T2D, HTN and CKD were universally lower than those in the control group in both sexes (p< 0.05), while male patients also manifested a lower level of HDL-c than female patients. However, although they had lower values of the renal impairment index, female patients were found to have anomalously higher amounts of proinflammatory cytokines. In addition, the correlations between HsCRP and RBP levels and HDL-c levels were most significant in patients with HTN (p< 0.05), whereas in patients with T2D and CKD, such relevance was less significant.Conclusion: Existence of substantial differences in HDL-c levels between different types of disease and sex highlighted that a higher HDL level does not always predict a better clinical outcome of patients. Moreover, we found that both HsCRP and RBP correlated negatively with HDL-c in HTN patients, indicating that monitoring HsCRP and RBP may serve as indicators for therapeutic efficacy of HDL-c-raising medications in HTN patients.Keywords: high-density lipoprotein cholesterol, anti-inflammation, renal protection, sex difference, functional heterogeneity

Tongrong Su,1 Liang He,1 Tianyu Zhou,1 Menghui Wu,1 Yaohua Guo,1 Quan Wang,1 Jing Jiang,2 Xueyuan Cao1 1Department of Gastric and Colorectal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin Province, People’s Republic of China; 2Division of Clinical Research, The First Hospital of Jilin University, Changchun 130021, Jilin Province, People’s Republic of ChinaCorrespondence: Xueyuan CaoDepartment of Gastric and Colorectal Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, Jilin Province, People’s Republic of ChinaTel/Fax +86-431-81875602Email caoxy@aliyun.comJing JiangDivision of Clinical Research, The First Hospital of Jilin University, 71 Xinmin Street, Changchun 130021, Jilin Province, People’s Republic of ChinaTel/Fax +86-431-81875408Email jiangjing19702000@jlu.edu.cnBackground: Adult intussusception is less common than paediatric intussusception. The aim of this study was to explore the clinical presentation, aetiology, diagnosis and treatment of adult intussusception.Methods: Adults (> 18 years) with intussusception treated by surgical or conservative measures were included from January 2005 to January 2018, and the manifestation, types, diagnosis and treatment of adult intussusception in our centre were reviewed.Results: A total of 150 patients with adult intussusception were included in this study. The clinical manifestations included 111 cases (74%) of abdominal pain, 38 cases (25.3%) of bloody stool, 37 cases (24.7%) of bowel obstructions, 33 cases (22%) of abdominal distension, 29 cases (19.3%) of nausea and vomiting, 19 cases (12.7%) of an abdominal mass, and 12 cases (8.0%) of diarrhoea. The types of intussusception were classified into 36 cases (24%) of enteric intussusception, 87 cases (58%) of intestine-colon intussusception and 27 cases (18%) of colonic intussusception. Surgical intervention was applied in 139 cases (92.7%), including 115 patients who underwent open surgery, and laparoscopy-assisted surgery was performed in 24 patients. The main pathogenesis of intussusception was malignant tumors in 51 cases (36.7%) and benign tumors and polyps in 49 cases (35.3%).Conclusion: Malignant and benign tumors are the main causes of adult intussusception. Abdominal CT is the preferred evaluation method for the preoperative diagnosis of this condition. The choice of surgical procedure depends on the location and type of intussusception.Keywords: adult intussusception, pathogenesis, surgical, treatment

Shou-Long Hu,1,2,* Li-Ying Tang,3,* Jian-Wen Fang,2,* Ting Su,3 Qian-Min Ge,2 Qi Lin,2 Biao Li,2 Wen-Qing Shi,2 Qiu-Yu Li,2 Rong-Bin Liang,2 Yi Shao2 1National Center for Children’s Health, MOE Key Laboratory of Major Diseases in Children, Department of Ophthalmology, Beijing Children’s Hospital, Capital Medical University, Beijing 100045, People’s Republic of China; 2Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute, Nanchang 330006, Jiangxi, People’s Republic of China; 3Department of Ophthalmology, Xiang’an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Eye Institute of Xiamen University; Xiamen University School of Medicine, Xiamen 361102, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Shao Email freebee99@163.comPurpose: To investigate differences in the functional connectivity (FC) of the primary visual cortex between patients with corneal ulcer (CU) and healthy controls (HCs) using resting-state functional magnetic resonance imaging.Patients and Methods: A total of 30 patients with CU and 30 HCs were closely matched in terms of sex, age, and level of education. Two-sample t-test, receiver operating characteristic curve, and Pearson’s correlation coefficient analyses were used to determine the differences in FC between the two groups, the mean FC value of patients with CU and HCs, and the correlation between FC signal values and clinical manifestations in different brain regions of patients.Results: The CU group showed significantly elevated FC in the left and right middle frontal gyri and lower FC with the right cuneus compared with the HC group. In addition, the FC of the right cingulate and left superior frontal gyri also increased in the CU group. The receiver operating characteristic curve revealed high diagnostic value in those brain regions.Conclusion: CU involves aberrant FC of the primary visual cortex in different brain areas, including visual-related and cognitive-related regions. This finding may unveil the underlying neural mechanisms of impaired visual function in CU.Keywords: corneal ulcer, functional magnetic resonance imaging, resting state, spontaneous brain activity, primary visual cortex

Yi Zhong,1,* Tao Su,1,* Qiuxiao Shi,1 Yanru Feng,1 Ze Tao,1 Qiuxia Huang,1 Lan Li,1 Liqiang Hu,1 Shengfu Li,1 Hong Tan,2 Shan Liu,3 Hao Yang1 1Key Lab of Transplant Engineering and Immunology, MOH, West China-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of General Surgery, Chengdu Integrated TCM & Western Medicine Hospital (Chengdu First People’s Hospital), Chengdu 610041, People’s Republic of China; 3Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shan LiuDepartment of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, No. 32, West Second Section First Ring Road, Chengdu, Sichuan 610072, People’s Republic of ChinaTel +86 28 6138 2518Email shanliusyy@163.comHao YangKey Lab of Transplant Engineering and Immunology, MOH, West China Hospital, No. 1, Keyuan 4th Road, Hi-tech Zone, Chengdu 610041, People’s Republic of ChinaTel +86 28 85164031Email yanghao@scu.edu.cnBackground: Nanoparticles exhibit great promise for improving the solubility and tissue-specific distribution of chemotherapeutic agents; however, the passive and highly variable enhanced permeability and retention (EPR) effects observed in tumors frequently leads to insufficient delivery of nanodrugs into tumors. The tumor-penetrating peptide iRGD can actively enhance tumor-selective delivery of nanoparticles into tumors by binding to integrin and interacting with tissue-penetrating receptor neuropilin-1.Materials and methods: To improve colorectal cancer treatment, in this study, we prepared a paclitaxel (PTX)-loaded PLGA nanoparticle (PLGA-PTX) and evaluated its tumor-targeting and antitumor activity by co-administration with iRGD.Results: Compared to free PTX, encapsulated PTX retained preferential cytotoxicity toward various colorectal cancer cells while effectively sparing healthy cells. PLGA-PTX treatment resulted in cell cycle arrest at the G2/M phase and apoptosis, leading to inhibition of cancer cell migration and invasion. PLGA-PTX combined with iRGD displayed little enhancement of cytotoxicity in vitro. Despite this, iRGD receptors integrin and neuropilin-1 were found to be primarily overexpressed on abundant tumor vessels in mice bearing colorectal tumors. Consequently, co-administration of nanoparticles with iRGD promoted the selective delivery of nanoparticles into tumor tissues in vivo. Additionally, the combined regimen enhanced the antitumor effects compared to those of each individual reagent.Conclusion: Our findings suggest that PLGA nanoparticles combined with the iRGD peptide provide a promising drug delivery strategy for facilitating active drug accumulation into tumors, given that iRGD receptors are overexpressed on tumor vessels. This co-administration system lacking covalent conjugation provides a more convenient means to combine various therapeutic agents with iRGD to achieve personalized nanotherapy.Keywords: tumor penetrating peptide, nanoparticle, iRGD, paclitaxel, tumor vasculature, colorectal cancer

Feiyin Zhu,1,2,* Liying Tang,3,4,5,6,* Peiwen Zhu,1 Qi Lin,1 Qing Yuan,1 Wenqing Shi,1 Biao Li,1 Lei Ye,1 Youlan Min,1 Ting Su,3–6 Yi Shao11Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute, Nanchang, Jiangxi 330006, People’s Republic of China; 2Department of Clinical Medicine, Queen Mary College of Nanchang University, Nanchang, Jiangxi 330031, People’s Republic of China; 3Department of Ophthalmology, Xiang’an Hospital of Xiamen University, Xiamen, Fujian 361102, People’s Republic of China; 4Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian 361102, People’s Republic of China; 5Eye Institute of Xiamen University, Xiamen, Fujian 361102, People’s Republic of China; 6School of Medicine, Xiamen University, Xiamen, Fujian 361102, People’s Republic of China*These authors have contributed equally to this workPurpose: To investigate alternations in spontaneous brain activities reflected by functional connectivity density (FCD) in patients with corneal ulcer (CU) using resting-state functional connectivity (rsFC).Methods: We recruited 24 patients with CU (12 males, 12 females), and 24 healthy controls (HCs; 12 males, 12 females) matched for age, gender and education status. Functional magnetic resonance imaging examinations were performed on all subjects in a resting state and the following parameters determined: rsFC, long-range FCD (longFCD) and short-range FCD (IFCD). Receiver operating characteristic (ROC) curves were then used to differentiate patients with CU from HCs.Results: Compared with HCs, CU patients showed significantly reduced rsFC values in the right cerebellum posterior lobe gyrus, right middle frontal gyrus/inferior frontal gyrus/superior frontal gyrus and left inferior parietal lobule/precuneus. Significantly reduced longFCD values were found in the right hippocampus/inferior temporal gyrus and the left inferior temporal gyrus. Moreover, compared with HCs, IFCD values were significantly reduced in the left inferior temporal gyrus/middle temporal gyrus, left limbic lobe/medial frontal gyrus, and left precuneus/limbic lobe, but were significantly increased in the right insula/superior temporal gyrus, left superior temporal gyrus/inferior frontal gyrus/insula, right superior temporal gyrus/postcentral gyrus, and left precentral gyrus.Conclusions: Patients with CU exhibited alterations in spontaneous brain activities in several brain areas. These novel findings may help to reveal the neuropathological mechanisms underlying CU.This study provides a direction for further exploration of underlying neural mechanisms of CU and facilitate the clinical diagnosis and treatment of CU.Keywords: functional connectivity density, corneal ulcer, spontaneous brain activities

Jianqin Yan,1,* Hai Zhang,1,* Furong Cheng,1 Yanmei He,1 Ting Su,1 Xuequan Zhang,2 Man Zhang,2 Yutong Zhu,3 Congrui Li,3 Jun Cao,1 Bin He1 1National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China; 2College of Chemical Engineering, Sichuan University, Chengdu 610065, China; 3College of Chemistry, Sichuan University, Chengdu 610065, China *These authors contributed equally to this work Background: Stability, enhanced drug-loading efficiency (DLE), and specific accumulation of therapeutics at tumor sites remain major challenges for successful cancer therapy.Purpose: This study describes a newly developed intelligent nanosystem that integrates stealthy, active targeting, stimulus-responsiveness, and π-π interaction properties in a single carrier, based on the multifunctional star-shaped biodegradable polyester.Patients and methods: This highly stable, smart nanocarrier with spherical structures and a low critical micelle concentration (CMC) can provide spacious harbor and strong π–π interaction and hydrophobic interactions for hydrophobic doxorubicin (DOX). Its structure and morphology were characterized by proton nuclear magnetic resonance (1H-NMR) spectra, Fourier transform infrared (FTIR) spectra, Gel permeation chromatography (GPC), dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Antitumor effciency of polymeric micelles using CCK-8 assay, and the intracellular-activated delivery system was tracked by confocal laser scanning microscopy (CLSM) and flow cytometry.Results: The synthesized copolymer can be self-assembled into nanoparticles with size of 50 nm and critical micellar concentration of 2.10 µg/mL. The drug-loading content of nanoparticles can be enhanced to 17.35%. Additionally, the stimulus-responsive evaluation and drug release study showed that the nanocarrier can rapidly respond to the intracellular reductive environment and dissociate for drug release. An in vitro study demonstrated that the nanocarrier can ferry doxorubicin selectively into tumor tissue, rapidly enter cancer cells, and controllably release its payload in response to an intracellular reductive environment, resulting in excellent antitumor activity in vitro.Conclusion: This study provides a facile and versatile approach for the design of multifunctional star-shaped biodegradable polyester nanovehicles for effective cancer treatment. Keywords: intelligent, star-shaped, biodegradable multifunctional polyester, stimuli-responsiveness, intracellular drug delivery, active targeting, cancer therapy

Missing-mass spectroscopy with the 3H(e, e′K+) reaction was carried out at Jefferson Lab’s (JLab) Hall A in Oct–Nov, 2018. The differential cross section for the 3H(γ∗, K+)Λnn was deduced at ω = Ee − Ee′ = 2.102 GeV and at the forward K+-scattering angle (0° ≤ θγ∗K ≤ 5°) in the laboratory frame. Given typical predicted energies and decay widths, which are (BΛ, Γ) = (−0.25, 0.8) and (−0.55, 4.7) MeV, the cross sections were found to be 11.2 ± 4.8(stat.)+4.1−2.1(sys.) and 18.1 ± 6.8(stat.)+4.2−2.9(sys.) nb/sr, respectively. The obtained result would impose a constraint for interaction models particularly between Λ and neutron by comparing to theoretical calculations.

We performed an experiment using tritium and hydrogen cryogenic gas targets at Thomas Jefferson National Accelerator Facility (JLab) in 2018 (E12-17-003)[1, 2]. In this article, we discuss the Λ/Σ0 hyperon electroproduction from hydrogen target. Elementary Λ/Σ0 hyperon production processes are important not only for an absolute mass scale calibration in our experiment, but also for the study of the electroproduction mechanisms themselves. In this article, we reported the results of the differential cross section for the p(e, e’K+)Λ/Σ0 reaction at Q2 ∼ 0.5 (GeV/c)2.

Abstract. An nnΛ is a neutral baryon system with no charge. The study of the pure Λ-neutron system such as nnΛ gives us information on the Λn interaction. The nnΛ search experiment (E12-17-003) was performed at JLab Hall A in 2018. In this article, the Λn FSI was investigated by a shape analysis of the 3H(e, e′K+)X missing mass spectrum, and a preliminary result for the Λn FSI study is given.

You-Lan Min,1,* Ting Su,2,* Yong-Qiang Shu,3 Wen-Feng Liu,1 Ling-Long Chen,3 Wen-Qing Shi,1 Nan Jiang,2 Pei-Wen Zhu,1 Qing Yuan,1 Xiao-Wei Xu,1 Lei Ye,1 Yi Shao1 1Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute, Nanchang 330006 Jiangxi, China; 2Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen 361102, Fujian, China; 3Department of Radiology, The First Affiliated Hospital of Nanchang University, Nanchang 330006 Jiangxi, China *These authors contributed equally to this work Objective: Previous studies have demonstrated that strabismus or amblyopia can result in markedly brain function and anatomical alterations. However, the differences in spontaneous brain activities of strabismus with amblyopia (SA) patients still remain unclear. This current study intended to use the amplitude of low-frequency fluctuation (ALFF) technique to investigate the intrinsic brain activity changes in SA subjects. Patients and methods: A total of 16 patients with SA (6 males and 10 females) and 16 healthy controls (HCs; 6 males and 10 females) similarly matched in age, gender, and education status were recruited and examined with the resting-state functional MRI. The spontaneous brain activity changes were investigated using the ALFF technique. The receiver operating characteristic curve was performed to classify the mean ALFF signal values of the SA patients from HCs. The correlations between the ALFF values of distinct brain regions and the clinical manifestations in SA patients were evaluated in terms of the Pearson’s correlation analysis. Results: Compared with HCs, SA patients had significantly decreased ALFF in the left cerebellum posterior lobe, left middle frontal gyrus, and bilateral thalamus. In contrast, SA patients showed increased ALFF values in the right superior frontal gyrus, right precuneus, left cuneus, and bilateral precentral gyrus. Nonetheless, there was no linear correlation between the mean ALFF values in brain regions and clinical features. Conclusion: Diverse brain regions including vision-related and motion-related areas exhibited aberrant intrinsic brain activity patterns, which imply the neuropathologic mechanisms of oculomotor disorder and vision deficit in the SA patients. Keywords: strabismus, amblyopia, functional MRI, ALFF, spontaneous brain activity

Yi Zhang,1,2,* Hui Guo,1,* Brian Chi-Yan Cheng,1 Tao Su,1 Xiu-Qiong Fu,1 Ting Li,1 Pei-Li Zhu,1 Kai-Wing Tse,1 Si-Yuan Pan,3 Zhi-Ling Yu1,3,4 1Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong; 2Department of Pharmacology, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, People’s Republic of China; 4Consun Chinese Medicines Research Centre for Renal Diseases, Hong Kong Baptist University, Hong Kong, People’s Republic of China *These authors contributed equally to this work Background: Dingchuan tang (asthma-relieving decoction), a formula of nine herbs, has been used for treating respiratory inflammatory diseases for >400 years in the People’s Republic of China. However, the mechanisms underlying the anti-inflammatory action of dingchuan tang is not fully understood. This study aims to investigate the effects of Dingchuan tang essential oil (DCEO) on inflammatory mediators and the underlying mechanism of action.Materials and methods: DCEO was extracted by steam distillation. Lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were used as the cell model. Production of nitric oxide (NO) was determined by the Griess test. Protein secretion and mRNA levels of inflammatory mediators were measured by the enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Protein levels were examined by Western blot. Nuclear localization of nuclear factor-kappa B (NF-κB) was detected using immunofluorescence analyses.Results: DCEO significantly reduced LPS-triggered production of NO and prostaglandin E2 (PGE2) and decreased protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). LPS induced upregulation of protein and mRNA levels of cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]), and chemokines (monocyte chemoattractant protein-1 [MCP-1], chemokine [C-C motif] ligand 5 [CCL-5], and macrophage inflammatory protein [MIP]-1α) were suppressed by DCEO treatment. Phosphorylation and nuclear protein levels of transcription factors (activator protein-1 [AP-1], NF-κB, interferon regulatory factor 3 [IRF3]) were decreased by DCEO. Protein levels of phosphorylated IκB-α, IκB kinase α/β (IKKα/β), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), TGF β-activated kinase 1 (TAK1), TANK-binding kinase 1 (TBK1), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), and c-Jun N-terminal kinase (JNK) were lowered by DCEO. Moreover, degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) and IRAK4 induced by LPS was inhibited by DCEO treatment.Conclusion: Suppression of the interleukin-1 receptor-associated kinase (IRAK)/NF-κB, IRAK/AP-1 and TBK1/IRF3 pathways was associated with the inhibitory effects of DCEO on inflammatory mediators in LPS-stimulated RAW264.7 macrophages. This study provides a pharmacological justification for the use of dingchuan tang in managing inflammatory disorders. Keywords: traditional Chinese medicine, respiratory diseases, anti-inflammation, molecular pathways

The electromagnetic form factors of the proton and neutron encode information on the spatial structure of their charge and magnetization distributions. While measurements of the proton are relatively straightforward, the lack of a free neutron target makes measurements of the neutron's electromagnetic structure more challenging and more sensitive to experimental or model-dependent uncertainties. Various experiments have attempted to extract the neutron form factors from scattering from the neutron in deuterium, with different techniques providing different, and sometimes large, systematic uncertainties. We present results from a novel measurement of the neutron magnetic form factor using quasielastic scattering from the mirror nuclei ^{3}H and ^{3}He, where the nuclear effects are larger than for deuterium but expected to largely cancel in the cross-section ratios. We extracted values of the neutron magnetic form factor for low-to-modest momentum transfer, 0.6

Zhao Y, Wang H, Yang Y, et al. Int J Nanomedicine. 2020:15:9571–9586 The authors have advised Figure 4F on page 9579 is incorrect. Due to an error at the time of figure assembly the representative image from free E7/CpG group twice instead the image of Lip E7/CpG. The correct Figure 4 is shown below. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Chong Li, Yan Zhang, Tingting Su, Lianlian Feng, Yingying Long, Zhangbao ChenKey Laboratory on Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, ChinaAbstract: We investigated flexible liposomes as a potential oral drug delivery system. However, enhanced membrane fluidity and structural deformability may necessitate liposomal surface modification when facing the harsh environment of the gastrointestinal tract. In the present study, silica-coated flexible liposomes loaded with curcumin (CUR-SLs) having poor water solubility as a model drug were prepared by a thin-film method with homogenization, followed by the formation of a silica shell by the sol-gel process. We systematically investigated the physical properties, drug release behavior, pharmacodynamics, and bioavailability of CUR-SLs. CUR-SLs had a mean diameter of 157 nm and a polydispersity index of 0.14, while the apparent entrapment efficiency was 90.62%. Compared with curcumin-loaded flexible liposomes (CUR-FLs) without silica-coatings, CUR-SLs had significantly higher stability against artificial gastric fluid and showed more sustained drug release in artificial intestinal fluid as determined by in vitro release assays. The bioavailability of CUR-SLs and CUR-FLs was 7.76- and 2.35-fold higher, respectively, than that of curcumin suspensions. Silica coating markedly improved the stability of flexible liposomes, and CUR-SLs exhibited a 3.31-fold increase in bioavailability compared with CUR-FLs, indicating that silica-coated flexible liposomes may be employed as a potential carrier to deliver drugs with poor water solubility via the oral route with improved bioavailability.Keywords: silica, flexible liposome, oral bioavailability, curcumin

Ta-Chen Su1, Pao-Ling Torng2, Jiann-Shing Jeng3, Ming-Fong Chen1, Chiau-Suong Liau1,41Division of Cardiology, Department of Internal Medicine, 2Department of Obstetrics and Gynecology, 3Department of Neurology, National Taiwan University Hospital, National Taiwan University College of Medicine, 4Cardiovascular Center, Taipei Buddist Tzu-Chi Hospital, Hsin-Dian, Taipei, TaiwanBackground: Vegetarianism is associated with a lower risk of cardiovascular disease. However, studies of arterial function in vegetarians are limited.Methods: This study investigated arterial function in vegetarianism by comparing 49 healthy postmenopausal vegetarians with 41 age-matched omnivores. The arterial function of the common carotid artery was assessed by carotid duplex, while the pulse dynamics method was used to measure brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR). Fasting blood levels of glucose, lipids, lipoprotein (a), high-sensitivity C-reactive protein, homocysteine, and vitamin B12 were also measured.Results: Vegetarians had significantly lower serum cholesterol, high-density and low-density lipoprotein, and glucose compared with omnivores. They also had lower vitamin B12 but higher homocysteine levels. Serum levels of lipoprotein (a) and high-sensitivity C-reactive protein were no different between the two groups. There were no significant differences in carotid beta stiffness index, BAC, and BAD between the two groups even after adjustment for associated covariates. However, BAR was significantly lower in vegetarians than in omnivores. Multiple linear regression analysis revealed that age and pulse pressure were two important determinants of carotid beta stiffness index and BAD. Vegetarianism is not associated with better arterial elasticity.Conclusion: Apparently healthy postmenopausal vegetarians are not significantly better in terms of carotid beta stiffness index, BAC, and BAD, but have significantly decreased BAR than omnivores. Prevention of vitamin B12 deficiency might be beneficial for cardiovascular health in vegetarians.Keywords: postmenopausal women, vegetarians, carotid stiffness, brachial arterial distensibility

The E12-14-012 experiment, performed in Jefferson Lab Hall A, has measured the (e,e′p) cross section in parallel kinematics using a natural titanium target. In this paper, we report the analysis of the dataset obtained in different kinematics for our solid natural titanium target. Data were obtained in a range of missing momentum and missing energy between 15?pm?250 MeV/c and 12?Em?80 MeV, respectively, and using an electron beam energy of 2.2 GeV. We measured the reduced cross section with ∼7% accuracy as a function of both missing momentum and missing energy. Our Monte Carlo simulation, including both a model spectral function and the effects of final-state interactions, satisfactorily reproduces the data.

The E12-14-012 experiment, performed in Jefferson Lab Hall A, has measured the (e,e′p) cross section in parallel kinematics using a natural argon target. Here, we report the full results of the analysis of the data set corresponding to beam energy 2.222 GeV, and spanning the missing momentum and missing energy range 1 pm 300 MeV/c and 12 Em 80 MeV. The reduced cross section, determined as a function of pm and Em with ≈4% accuracy, has been fitted using the results of Monte Carlo simulations involving a model spectral function and including the effects of final state interactions. The overall agreement between data and simulations turns out to be quite satisfactory (χ2/d.o.f.=1.9). The resulting spectral function will provide valuable new information, needed for the interpretation of neutrino interactions in liquid argon detectors.

A mass spectroscopy experiment with a pair of nearly identical high-resolution spectrometers and a tritium target was performed in Hall A at Jefferson Lab. Utilizing the (e,e′K+) reaction, enhancements, which may correspond to a possible Λnn resonance and a pair of ςNN states, were observed with an energy resolution of about 1.21 MeV (σ), although greater statistics are needed to make definitive identifications. An experimentally measured Λnn state may provide a unique constraint in determining the Λn interaction, for which no scattering data exist. In addition, although bound A=3 and 4 ς hypernuclei have been predicted, only an A=4 ς hypernucleus (Heς4) was found, utilizing the (K-,π-) reaction on a He4 target. The possible bound ςNN state is likely a ς0nn state, although this has to be confirmed by future experiments.

The small binding energy of the hypertriton leads to predictions of the non-existence of bound hypernuclei for isotriplet three-body systems such as nnΛ. However, invariant mass spectroscopy at GSI has reported events that may be interpreted as the bound nnΛ state. The nnΛ state was sought by missing-mass spectroscopy via the (e, e′K+) reaction at Jefferson Lab's experimental Hall A. The present experiment has higher sensitivity to the nnΛ-state investigation in terms of better precision by a factor of about three. The analysis shown in this article focuses on the derivation of the reaction cross-section for the 3H(γ∗, K+)X reaction. Events that were detected in an acceptance, where a Monte Carlo simulation could reproduce the data well (δ p/p| < 4), were analyzed to minimize the systematic uncertainty. No significant structures were observed with the acceptance cuts, and the upper limits of the production cross-section of the nnΛ state were obtained to be 21 and 31 nb sr-1 at the $90\%$ confidence level when theoretical predictions of (-BΛ, Γ) = (0.25, 0.8) MeV and (0.55, 4.7) MeV, respectively, were assumed. The cross-section result provides valuable information for examining the existence of nnΛ.