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Du-Jiang Yang,1,* Jun-Jie Xiong,1,* Xue-Ting Liu,2 Jiao Li,3 Kanagarathna Mudiyanselage Dhanushka Layanthi Siriwardena,4 Wei-Ming Hu11Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China; 2Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China; 3Department of Emergency, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China; 4West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, People’s Republic of China *These authors contributed equally to this work Aim: To assess whether total pancreatectomy (TP) is as feasible, safe, and efficacious as pancreaticoduodenectomy (PD).Materials and Methods: Major databases, including PubMed, EMBASE, Science Citation Index Expanded, Scopus and the Cochrane Library, were searched for studies comparing TP and PD between January 1943 and June 2018. The meta-analysis only included studies that were conducted after 2000. The primary outcomes were morbidity and mortality. Pooled odds ratios (ORs), weighted mean differences (WMDs) or hazard ratios (HRs) with 95 percent confidence intervals (CIs) were calculated using fixed effects or random effects models. The methodological quality of the included studies was evaluated by the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool.Results: In total, 45 studies were included in this systematic review, and 5 non-randomized comparative studies with 786 patients (TP: 270, PD: 516) were included in the meta-analysis. There were no differences in terms of mortality (OR: 1.44, 95% CI: 0.66–3.16; P=0.36), hospital stay (WMD: −0.60, 95% CI: −1.78–0.59; P=0.32) and rates of reoperation (OR: 1.12; 95% CI: 0.55–2.31; P=0.75) between the two groups. In addition, morbidity was not significantly different between the two groups (OR: 1.41, 95% CI: 1.01–1.97; P=0.05); however, the results showed that the TP group tended to have more complications than the PD group. Furthermore, the operation time (WMD: 29.56, 95% CI: 8.23–50.89; P=0.007) was longer in the TP group. Blood loss (WMD: 339.96, 95% CI: 117.74–562.18; P=0.003) and blood transfusion (OR: 4.86, 95% CI: 1.93–12.29; P=0.0008) were more common in the TP group than in the PD group. There were no differences in the long-term survival rates between the two groups.Conclusion: This systematic review and meta-analysis suggested that TP may not be as feasible and safe as PD. However, TP and PD may have the same efficacy.Keywords: total pancreatectomy, pancreaticoduodenectomy, morbidity, mortality, meta-analysis

Wen-Zhuo He,1,* Qiu-Xia Yang,2,* Jin-Ye Xie,3,* Peng-Fei Kong,1 Wan-Ming Hu,4 Lin Yang,1 Yuan-Zhong Yang,4 Qian-Kun Xie,1 Chang Jiang,1 Chen-Xi Yin,1 Gui-Fang Guo,1 Hui-Juan Qiu,1 Bei Zhang,1 Liang-Ping Xia1 1VIP Region, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People’s Republic of China; 2Department of Medical Imaging, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China; 3Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510060, People’s Republic of China; 4Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People’s Republic of China *These authors contributed equally to this work Background: Skeletal muscle depletion is a prognostic factor in patients with cancer. Here, we evaluated the association between the skeletal muscle index (SMI) and local and systemic responses in patients with colon cancer.Patients and methods: We analyzed the relationships of the SMI with neutrophil, lymphocyte, monocyte, and platelet counts; the neutrophil-to-lymphocyte ratio; albumin levels; and C-reactive protein levels in a cohort of 561 patients, and with the circulating levels of 39 cytokines in a cohort of 125 patients. We also studied the association between the SMI and tumor local inflammatory response and the effect of SMI on survival.Results: The median SMIs for male and female subjects were 44.1 and 34.2 cm2/m2, respectively. We observed positive correlations of the SMI with neutrophil (p=0.022), lymphocyte (p=0.001), and monocyte counts (p=0.003). A low SMI correlated significantly with an increased platelet count (p=0.017), decreased albumin level (p=0.006), neutrophil-to-lymphocyte ratio >3 (p=0.021), and an increased interferon γ-induced protein 10 level (IP-10, r = –0.276, p=0.002). The SMI did not correlate significantly with local inflammatory reactions or the C-reactive protein level. Finally, the SMI was a significant prognosticator in patients with stage III colon cancer (3-year disease-free survival rates: 35.1% for the low SMI arms versus 46.0% in the high SMI arms; HR =2.036; p=0.034).Conclusion: This study highlights the association of a low SMI with a high systematic inflammatory response and IP-10 levels. Furthermore, low SMI is a predictor of poor disease-free survival in patients with stage III colon cancer. Keywords: colon cancer, skeletal muscle, interferon γ-induced protein 10

Wen-Zhuo He,1,* Qian-Kun Xie,1,* Wan-Ming Hu,2–4,* Peng-fei Kong,1 Lin Yang,1 Yuan-Zhong Yang,2 Chang Jiang,1 Chen-Xi Yin,1 Hui-Juan Qiu,1 Hui-Zhong Zhang,2 Bei Zhang,1 Liang-Ping Xia1 1VIP Region, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China; 3Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People’s Republic of China; 4Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: The purpose of the present study was to examine the relationship among the number of negative lymph nodes (LNs), the local and systemic immune response, and survival in patients with colon cancer. Patients and methods: One thousand one hundred and fifty-seven patients with colon cancer who underwent surgery at Sun Yat-sen University Cancer Center between 2009 and 2014 were included. We examined negative LNs in relation to the local and systemic immune response, including percentage carcinoma, neutrophil and lymphocyte infiltration, Crohn’s-like reaction, neutrophil to lymphocyte ratio, platelets, and C-reactive protein (CRP). Disease-free survival and overall survival were also examined. We performed subgroup analysis based on the distribution of negative LNs. Results: An increased number of negative LNs was associated with greater neutrophil invasion (p=0.001), more lymphocyte invasion (p=0.001), and more Crohn’s-like reaction (p=0.001). No significant correlation was observed between negative LNs and the neutrophil to lymphocyte ratio. More than 12 negative LNs were associated with increased platelets and CRP levels. A higher number of negative LNs was independently associated with longer disease-free survival in stage I+II patients (p=0.004) and stage III patients (p=0.015), while negative LNs were also independent prognostic factors in stage IV patients (p=0.007). Conclusion: Our study suggests that negative LNs are indicators of the immune response and are associated with a better prognosis in patients with colon cancer. Keywords: colon cancer, negative lymph nodes, immune response, survival

Qian-Kun Xie,1,* Wen-Zhuo He,1,* Wan-Ming Hu,2–4 Lin Yang,1 Chang Jiang,1 Peng-Fei Kong,1 Yuan-Zhong Yang,2 Qiong Yang,1,5 Hui-Zhong Zhang,2 Bei Zhang,1 Liang-Ping Xia1 1VIP Region, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; 2Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, SunYat-sen University Cancer Center, Guangzhou, China; 3Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; 4Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; 5Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, China *These authors contributed equally to this work Background: Although tumor-infiltrating lymphocytes (TILs) have been understood for years as a favorable prognostic factor for colorectal cancers (CRCs) after complete surgical resection, its prognostic role in metastatic CRC (mCRC) remains poorly defined, and it is largely unknown how this prognostic benefit relates to the metastatic status and operation modality. Materials and methods: After reviewing 2215 consecutive cases of surgically resected CRC, 332 patients newly diagnosed with stage IV CRC and treated at the Sun Yat-Sen University Cancer Center between 2009 and 2014 were included. H&E-stained (HES) slides from surgical specimens were evaluated for the extent of TILs. The primary end point was overall survival (OS). Cox proportional hazards regression was conducted to determine the prognostic significance of TILs. All statistical tests were 2-sided. Results: HES slides from primary tumor samples were evaluable for 302 of the 332 included cases. Among the 302 patients, 105 patients (34.8%) were classified as high TIL, the remaining 197 (65.2%) were defined as low TIL. In the univariate analysis, TILs were significantly associated with better OS (P=0.015). Multivariable analysis confirmed that high TIL strongly predicted better survival (hazard ratio =0.62, 95% CI: 0.44–0.89, P=0.008), independent of other patients’ clinicopathological characteristics. Stratified analysis revealed a prognostic benefit of high TIL for patients in the subgroup with non-oligometastatic disease (P=0.002), ≥2 metastatic organs (P=0.006), and non-metastasectomy (P=0.005). By contrast, oligometastatic disease, 1 metastatic organ, or metastasectomy fully abrogated the prognostic effect of TIL. Conclusion: Our findings indicate that the level of TILs can be used to predict the outcome for patients with mCRC; however, the operation modality and the metastatic status of patients should also be taken into account. Keywords: colorectal cancer, stage IV, tumor-infiltrating lymphocytes, metastatic status, survival

Background: Idiopathic ventricular arrhythmias (IVAs) arising from different portions of the communicating vein of the left ventricular summit (summit-CV) are not a rare phenomenon. Whereas its electrocardiographic (ECG) and electrophysiological characteristics are not fully investigated., Objective: This study aimed to identify distinct ECG and electrophysiological features of IVAs originating from different portions of summit-CV., Methods: Nineteen patients confirmed arising from summit-CV were included in this study., Results: The 19 patients were divided into proximal and distal portion groups based on their target sites in summit-CV. In the proximal portion group, 100% (11/11) VAs showed dominant negative (rs or QS) waves in lead I, while in the distal portion group, 87.5% (7/8) showed dominant positive waves (R, Rs or r) (p < 0.000). In lead V 1 , 100% (11/11) of the proximal portion group showed dominant positive waves (R or Rs), while 62.50% (5/8) of the distal portion group showed positive and negative bidirectional or negative waves (RS or rS) (p < 0.005). R I >4mV, S I <3.5mV, R V1 <13mV, S V1 >3.5mV, R I /S I >0.83, and R V1 /S V1 < 2.6 indicated a distal portion of summit-CV with the predictive value of 0.909, 1.000, 0.653, 0.972, 0.903, 0.966, respectively. A more positive wave in lead I and a more negative wave in lead V 1 indicated more distal origin in summit-CV. Target sites in proximal and distal summit-CV groups showed similar electrophysiological characteristics during mapping., Conclusions: There were significant differences in ECG characteristics of VAs at different portions of summit-CV, which could aid pre-procedure planning and facilitate radiofrequency catheter ablation (RFCA) procedures., (© 2024. The Author(s).)

Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.

The study aims to summarize the clinical characteristics of patients with ectopic gastric mucosa in the small intestine, comparing clinical presentation differences between domestic and foreign patients through literature review. The clinical characteristics of cases diagnosed with ectopic gastric mucosa in the small intestine at Peking Union Medical College Hospital from January 2000 to January 2024 were retrospectively analyzed. By searching databanks, such as PubMed, EMBASE, the Cochrane Library, Wanfang, VIP, CNKI, and etc (the inclusion period was from the establishment of the database to January 1, 2024). The literature review was conducted on ectopic gastric mucosa in the small intestine. A total of 10 cases were included, all male, age [ M ( Q 1 , Q 3 )] was 27 (13-69) years old. Gastrointestinal bleeding was the first manifestation in most cases, with severe cases leading to hemorrhagic shock. Abdominal CT indicated local intestinal wall thickening and luminal narrowing in 3 cases. Four cases lesions were located at the beginning of the jejunum and 6 lesions were located in the end segment of ileum. All cases underwent local lesion resection, with postoperative pathology confirming ectopic gastric mucosa. Symptoms disappeared postoperatively, with a follow-up period of 0.5-3.0 years. Literature review indicates that the main clinical manifestation of gastric mucosa ectopia in the small intestine in China is gastrointestinal bleeding, while foreign patients are often complicated with intestinal duplication and intussusception, with abdominal pain and vomiting as the primary and main symptoms. The occurrence rate of intestinal obstruction in female patients, both domestically and abroad, is higher than that in male patients. The occurrence rate of ileal lesions with intestinal obstruction and small intestinal duplication is higher than that of duodenal lesions in both domestic and foreign patients. Local small intestine resection is an effective treatment method with generally good prognosis. Ectopic small intestinal mucosa is relatively rare, with symptoms of gastrointestinal bleeding and intestinal obstruction being common presentations, which can serve as one of the differential diagnoses for unexplained gastrointestinal bleeding.

Objective: To investigate the occurrence of low back work-related musculoskeletal disorders (WMSDs) among workers in a container manufacturing factory, and to explore the influencing factors. Methods: In June 2022, 952 workers from a container factory were selected as the research objects by cluster random sampling. Through questionnaire survey, the incidence of low back WMSDs symptoms among workers in the past one year was collected, and the influencing factors of low back WMSDs were analyzed by logistic regression. Results: The incidence rate of low back WMSDs was 46.7% (445/952). The factors with higher exposure at work were frequent slight bending (77.0%, 733/952), frequent overtime (74.1%, 705/952), and the need to turn around while working (62.3%, 593/952). Multivariate logistic regression analysis showed that age over 40 years old, smoking, drinking, often bending over slightly, sitting for a long time, maintaining a large bending posture for a long time, often working overtime, limited operating space, and there was always a need to complete conflicting things in the container manufacturing factory workers were the risks of increasing the low back WMSDs ( OR =1.68, 1.96, 2.47, 1.49, 1.84, 2.11, 1.90, 1.82, 2.00, P <0.05). Standing at work, always friendly colleagues, and always supportive and helpful leaders were protective factors for low back WMSDs ( OR =0.60, 0.32, 0.40, P <0.05) . Conclusion: The incidence of low back WMSDs symptoms in container manufacturing workers is high, and work-related factors such as frequent slight bending, long time holding large bending posture and limited operating space are the focus of ergonomic intervention in container manufacturing enterprises.

Objective: To explore the evaluation effect of ultrasonography and Pirani score on tarsal deformity, treatment effect and pseudo-correction of congenital clubfoot in infants and young children, and the correlation between the two methods. Methods: This is a retrospective case series study. The clinical data of 26 children (40 feet) with congenital clubfoot who were evaluated by ultrasonography in the Third Affiliated Hospital of Zhengzhou University from January 2020 to January 2023 were retrospectively collected. There were 16 males and 10 females. The age at the first ultrasound examination was ( M (IQR)) 9.0 (18.0) days (range: 1 to 46 days). All patients were treated with Ponseti method by the same physician. The Pirani scores before and after treatment and at the last examination, and the talonavicular angle, calcaneocuboid angle and tibiocalcaneal angle measured by ultrasound were collected, and the treatment and follow-up were recorded. Paired sample t test, repeated measures analysis of variance or Kruskal-Wallis test were used for data comparison, and Spearman correlation analysis was used for correlation analysis. The receiver operating characteristic curve was used to calculate the efficacy of ultrasound in evaluating different Pirani scores. Results: The number of plaster fixation in 26 children was 4.0 (1.0) times (range: 2 to 8 times). The medial talonavicular angle and posterior tibiocalcaneal angle were significantly improved after treatment and at the last follow-up compared with those before treatment, and the differences were statistically significant (all P <0.01). There was no difference in lateral calcaneocuboid angle before and after treatment and at the last follow-up ( F =1.971, P >0.05). Pseudo-correction occurred in 2 cases (2 feet) during the treatment, with an incidence of 5%. Correlation analysis showed that there was a moderate positive correlation between talonavicular angle and Pirani midfoot score ( r =0.480, P <0.01). There was no correlation between calcaneocuboid angle and Pirani midfoot score ( r =0.114, P =0.105). There was a moderate negative correlation between tibial heel angle and Pirani hindfoot score ( r =-0.566, P <0.01). The cut-off point of Pirani midfoot score of 1.5 was 38.78°, the sensitivity was 0.90, the specificity was 0.56, and the area under the curve was 0.75. The cut-off value of angle was 27.51 °, the sensitivity was 0.16, the specificity was 0.92, and the area under the curve was 0.44.The cut-off points of Pirani midfoot score of 3.0 were 45.08°and 9.96°, the sensitivity was 0.94 and 0.91, the specificity was 0.37 and 0.42, and the area under the curve was 0.59 and 0.62, respectively. The cut-off values of Pirani hindfoot score of 2.0 and 3.0 were 167.46° and 160.15°, respectively. The sensitivity was 0.75 and 0.67, the specificity was 0.81 and 0.83, and the area under the curve was 0.78 and 0.71, respectively. Conclusion: Ultrasound can complement with Pirani score, visually and dynamically observe the morphology and position changes of talonavicular joint, calcaneocuboid joint and tibiotalocalcaneal joint, monitor the recovery and pseudo-correction of tarsal bones, and better evaluate the therapeutic effect.

Objectives: In patients with acute pancreatitis (AP), minimally invasive treatment and the step-up approach have been widely used to deal with infected pancreatic necrosis (IPN) in the last decade. It is unclear whether IPN has become a less important determinant of mortality relative to organ failure (OF). We aimed to statistically aggregate recent evidence from published studies to determine the relative importance of IPN and OF as determinants of mortality in patients with AP (PROSPERO: CRD42020176989)., Methods: Relevant studies were sourced from MEDLINE and EMBASE databases. Relative risk (RR) or weighted mean difference (WMD) was analyzed as outcomes. A two-sided P value of less than 0.05 was regarded as statistical significance., Results: Forty-three studies comprising 11 601 patients with AP were included. The mortality was 28% for OF patients and 24% for those with IPN. Patients with OF without IPN had a significantly higher risk of mortality compared to those with IPN but without OF (RR 3.72, P < 0.0001). However, patients with both OF and IPN faced the highest risk of mortality. Additionally, IPN increased length of stay in hospital for OF patients (WMD 28.75, P = 0.032)., Conclusion: Though IPN remains a significant concern, which leads to increased morbidity and longer hospital stay, it is a less critical mortality determinant compared to OF in AP., (© 2023 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Invasion and metastasis are the main causes of unfavourable prognosis in patients diagnosed with bladder cancer. The efficacy of immunotherapy in bladder cancer remains suboptimal due to the presence of an immunosuppressive microenvironment. The novel protein family with sequence similarity 171B (FAM171B) has been identified, but its precise role and mechanism in bladder cancer remain unclear., Methods: In this study, we conducted an analysis to investigate the associations between FAM171B expression and the prognosis and clinicopathological stage of bladder cancer. To this end, we utilized RNA sequencing data from the TCGA and GEO databases, as well as tumor tissue specimens obtained from our clinical centre. RNA sequencing analysis allowed us to examine the biological function of FAM171B at the transcriptional level in bladder cancer cells. Additionally, we used immunoprecipitation and mass spectrometry to identify the protein that interacts with FAM171B in bladder cancer cells. The effects of FAM171B on modulating tumor-associated macrophages (TAMs) and vimentin-mediated tumor progression, as well as the underlying mechanisms, were clarified by phalloidin staining, immunofluorescence staining, ELISA, RNA immunoprecipitation, flow cytometry and a bladder cancer graft model., Results: FAM171B expression exhibits strong positive correlation with poor survival outcomes and advanced clinicopathological stages in patients with bladder cancer. FAM171B significantly promoted bladder cancer growth and metastasis, accompanied by TAM accumulation in the microenvironment, in vivo and in vitro. Through studies of the molecular mechanism, we found that FAM171B contributes to tumor progression by stabilizing vimentin in the cytoplasm. Additionally, our research revealed that FAM171B enhances the splicing of CCL2 mRNA by interacting with heterogeneous nuclear ribonucleoprotein U (HNRNPU), ultimately leading to increased recruitment and M2 polarization of TAMs., Conclusions: In this study, we identified FAM171B as a potent factor that promotes the progression of bladder cancer. These findings establish a solid theoretical foundation for considering FAM171B as a potential diagnostic and therapeutic biomarker for bladder cancer., (© 2023. The Author(s).)

Aim: Epstein-Barr virus-associated intrahepatic cholangiocarcinoma (EBVaICC) has a distinct genomic profile and increased CD3 + and CD8 + T cells infiltration. However, the efficacy of immunotherapy in EBVaICC remains largely unknown. This study aimed to assess the efficacy of programmed cell death protein 1 (PD-1) antibody therapy in EBVaICC., Methods: Patients with metastatic biliary tract cancer (BTC) diagnosed at Sun Yat-sen University Cancer Center from January 2016 to December 2021 were identified. In situ hybridisation was performed to detect EBV. Overall survival (OS) and progression-free survival (PFS) were measured., Results: A total of 698 patients with metastatic BTC were identified, of whom 39 (5.6%) had EBVaICC. Among the 136 patients who were not administered PD-1 antibody, the OS was similar between patients with EBVaICC and EBV-negative ICC (median OS 12.5 versus 9.5 months, respectively; P = 0.692). For the 205 patients who were administered PD-1 antibody, patients with EBVaICC had significantly longer OS than patients with EBV-negative ICC (median OS 24.9 versus 11.9 months, respectively; P = 0.004). Seventeen patients with EBVaICC were administered PD-1 antibody. Eight patients (47%) achieved a partial response, and 17 patients achieved disease control. The median PFS was 17.5 months., Conclusions: This study identified a clinically actionable subset of patients with EBVaICC with a promising response to the PD-1 antibody., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

5-lipoxygenase (encoded by ALOX5) plays an important role in immune regulation. Zileuton is currently the only approved ALOX5 inhibitor. However, the mechanisms of ALOX5 and Zileuton in progression of pancreatic cancer remain unclear. Therefore, we investigated the effects of Zileuton on tumor-associated macrophage M2 polarization and pancreatic cancer invasion and metastasis, both in vivo and in vitro. In bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analyses, we found a significant association between elevated levels of ALOX5 and poor survival, adverse stages, M2 macrophage infiltration, and the activation of JAK/STAT pathways in macrophages. In clinical samples, immunofluorescence, quantitative real-time PCR and immunohistochemical results verified the high expression of ALOX5 in pancreatic cancer, primarily in macrophages. We constructed PANC-1 human pancreatic cancer cells and macrophages overexpressing ALOX5 using lentivirus. In PANC-1 pancreatic cancer cells, low-dose Zileuton inhibited PANC-1 cell invasion and migration by blocking ALOX5. In macrophages, ALOX5 induced the M2-like phenotype through the JAK/STAT pathway and promoted the chemotaxis of macrophages towards PANC-1 cells, while Zileuton can inhibit these effects. We constructed the nude mouse model of in situ transplantation tumor of pancreatic cancer. After treatment with Zileuton, the mice showed increased survival rates and reduced liver metastasis. These findings indicate that ALOX5 regulates tumor-associated macrophage M2 polarization via the JAK/STAT pathway and promotes invasion and metastasis in pancreatic cancer. Zileuton can inhibit these effects by inhibiting ALOX5. These results provide a theoretical basis for the potential use of Zileuton in the treatment of pancreatic cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Chronic hypercortisolism leads to a phenotype resembling metabolic syndrome. We aimed to investigate the association between gut microbiota and metabolic abnormalities in endogenous hypercortisolism (Cushing's syndrome)., Methods: A total of 23 patients with Cushing's syndrome (18 female and 5 men, aged 47.24 ± 12.99 years) and 30 age-, sex-and BMI-matched healthy controls (18 female and 12 men, aged 45.03 ± 6.69 years) were consecutively recruited. Differences in gut microbiota and plasma short-chain fatty acid (SCFAs) concentrations between the Cushing's syndrome patients and controls were analyzed by 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS)., Results: Compared to the controls, the Simpson and Pielou indices of α diversity were dramatically decreased in Cushing's syndrome ( P < 0.05). The gut microbiota community structure differed significantly between Cushing's syndrome patients and controls. Compared to controls, the bacterial communities of the Cushing's syndrome patients were enriched in Proteobacteria and Escherichia-Shigella , and depleted in Firmicutes , including Agathobacter , Blautia , Anaerostipes , Eubacterium&#95;eligens&#95;group , and Lachnospira . Spearman analysis demonstrated that HbA1c, SBP, DBP, and cortisol levels were significantly positively correlated with Proteobacteria and Escherichia-Shigella , whereas negatively correlated with Agathobacter, Blautia, Anaerostipes, Eubacterium&#95;hallii&#95;group, and Lachnospira , etc. Cushing's syndrome patients also had a lower propionic acid concentration (0.151±0.054 vs. 0.205±0.032 µg/mL, P =0.039) than controls. Furthermore, the level of propionic acid was negatively correlated with systolic pressure and cortisol levels ( P <0.05)., Conclusion: Gut microbiota dysbiosis and decreased propionic acid levels were observed in patients with Cushing's, suggesting that the gut microbiota may be a potential therapeutic intervention target to improve hypercortisolism-related metabolic abnormalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Hu, Deng, Wan, Wang and Jin.)

Objective: Congenital lipid adrenal hyperplasia (LCAH) is the most serious type of congenital adrenal hyperplasia and is caused by steroid-based acute regulatory (STAR) protein mutations. Herein, we report compound heterozygous mutations c.558C>A (p.S186 R) and c.772C>T (p.Q258*) in a newborn 46 XY patient diagnosed with classic LCAH and explore their clinical and functional characteristics. Methods: Peripheral blood samples were collected from LCAH patient and their families. The pathogenic variant identified by whole-exome sequencing was further confirmed by Sanger sequencing and pedigree verification. The functional consequence and ability to convert cholesterol into progesterone of the identified STAR Q258* and S186 R mutations were analyzed by cell transfection and in vitro assays. Results: The proband was presented with severe glucocorticoid and mineralocorticoid deficiency, high adrenocorticotropic hormone, and enlarged adrenals. Heterozygous mutations p. S186 R and p. Q258* in the STAR gene were identified in the patient, and her parents were carriers, which is consistent with an autosomal recessive disorder. The STAR p. Q258* mutation has been reported and generates a truncated protein. The p. S186 R mutation is a novel variant that disrupts STAR. The residual STAR activities of p. S186R, p. Q258*, and p. S186R/p.Q258* were 13.9%, 7.3%, and 11.2%, respectively, of the wild-type, proving the main negative effects of the mutant proteins. Conclusion: Our findings reveal the molecular mechanisms underlying LCAH pathogenesis, further expanding the genotype and clinical spectrum of LCAH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Dai, Guang, Hu and Jin.)

Objective: To investigate the characteristics of gut microbiota in type 2 diabetes mellitus (T2DM) patients with hypertriglyceridemia (HTG). Methods: Eighty-one patients first diagnosed with T2DM were enrolled in the Third Xiangya Hospital of Central South University from January 2018 to December 2020, including 58 patients [46 males and 12 females, aged (43±13) years] with HTG [HTG group, triglyceride (TG)≥1.7 mmol/L]. There were 23 cases without HTG (NTG group), including 20 males and 3 females, aged (46±13) years. According to the severity of HTG, the patients of HTG group were divided into severe HTG group (STG group, TG ≥5.6 mmol/L) and mild HTG group (MTG group, 1.7 mmol/L≤TG<5.6 mmol/L). Thirty healthy controls were matched accordingly, including 21 males and 9 females, aged (45±6) years. Clinical laboratory indicators and feces of the subjects were collected and 16S rRNA sequencing was performed to compare the differences in intestinal flora among the groups. Results: The Shannon and Simpson indexes in HTG group were lower than those in NTG group and healthy control group (5.02±0.91 vs 5.45±0.55 and 5.60±0.63, P =0.003; 0.90±0.06 vs 0.93±0.04, 0.94±0.04, P =0.002). Compared with healthy control group and NTG group, the abundance of intestinal P&#95;Proteobacteria , g&#95;Escherichia&#95;Shigella , s&#95;Escherichia&#95;Coli and g&#95;Clostridium&#95;sensu&#95;stricto&#95;1 increased in HTG group, while the abundance of p&#95;Firmicutes , g&#95;Faecalibacterium and Faecalibacterium&#95;prausnitzii decreased. The abundance of g&#95;Clostridium&#95;sensu&#95;stricto&#95;1 in the STG group was higher than that of NTG and MTG groups, while the abundance of g&#95;Faecalibacterium decreased. Spearman correlation analysis suggested that g&#95;Clostridium&#95;sensu&#95;stricto&#95;1 was positively correlated with glycosylated hemoglobin ( r =0.22, P =0.044), fasting blood glucose ( r =0.36, P =0.001), TG ( r =0.27, P =0.015) and total cholesterol ( r =0.44, P <0.001). Logistic regression analysis indicated that g&#95;Faecalibacterium was a protective factor for T2DM with HTG( OR =0.90, 95% CI :0.83-0.97, P =0.006). Conclusions: The intestinal flora of T2DM patients with HTG was dysregulated, which was manifested as decreased diversity, increased abundance of P&#95;Proteobacteria and decreased abundance of p&#95;Firmicutes . g&#95;Faecalibacterium is a protective factor for T2DM with HTG.

Background: The severity of acute pancreatitis in pregnancy (APIP) is correlated with higher risks of maternal and fetal death., Aim: To develop a nomogram that could predict moderately severe and severe acute pancreatitis in pregnancy (MSIP)., Methods: Patients with APIP admitted to West China Hospital between January 2012 and December 2018 were included in this study. They were divided into mild acute pancreatitis in pregnancy (MAIP) and MSIP. Characteristic parameters and laboratory results were collected. The training set and test set were randomly divided at a ratio of 7:3. Least absolute shrinkage and selection operator regression was used to select potential prognostic factors. A nomogram was developed by logistic regression. A random forest model was used to validate the stability of the prediction factors. Receiver operating characteristic curves and calibration curves were used to evaluate the model's predictive performance., Results: A total of 190 patients were included in this study. A total of 134 patients (70.5%) and 56 patients (29.5%) were classified as having MAIP and MSIP, respectively. Four independent predictors (lactate dehydrogenase, triglyceride, cholesterol, and albumin levels) were identified for MSIP. A nomogram prediction model based on these factors was established. The model had areas under the curve of 0.865 and 0.853 in the training and validation sets, respectively. The calibration curves showed that the nomogram has a good consistency., Conclusion: A nomogram including lactate dehydrogenase, triglyceride, cholesterol, and albumin levels as independent predictors was built with good performance for MSIP prediction., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: This study aimed to compare the curative efficacy of hemivertebra resection via the posterior approach assisted with unilateral and bilateral internal fixation in the treatment of congenital scoliosis (CS)., Methods: In this study, 29 children (15 males and 14 females), who underwent hemivertebra resection via the posterior approach and received internal fixation from November 2005 to September 2018, were analyzed retrospectively. The age of these patients ranged from 0.9 to 15 years, with an average of 3.8 years. The follow-up duration ranged from 2 to 12.3 years, with an average of 5.7 years. The patients in group A received unilateral internal fixation, and those in group B received bilateral internal fixation. The operation duration, bleeding volume, and complications during the operation, as well as the Cobb angles of scoliosis and kyphosis before and after the operation and at the last follow-up, were compared between the two groups., Results: In group A, the operation duration was 207.4 ± 54.5 min, and the bleeding volume was 215.3 ± 75.4 ml; in group B, the operation duration was 249.5 ± 51.0 min, and the bleeding volume was 291.3 ± 115.6 ml ( P < 0.05). The Cobb angles of segmental scoliosis, segmental kyphosis, cephalic compensatory curve, and caudal compensatory curve were significantly improved in the two groups after operation and at the last follow-up ( P < 0.05). The post-operative correction rate of the scoliosis Cobb angle was 67.2% in group A and 79.5% in group B; and the difference was statistically significant ( P < 0.05). At the last follow-up, the correction rate of the scoliosis Cobb angle was 72.7% in group A and 76.2% in group B ( P > 0.05). After the operation and at the last follow-up, the correction rates of kyphosis were 83.1 and 79.6% in group A and 71.8 and 65.5% in group B ( P > 0.05)., Conclusion: Hemivertebra resection via posterior approach with unilateral internal fixation can also achieve the effect of bilateral internal fixation in the treatment of CS. It is able to preserve a certain degree of contralateral spinal growth potential and is a feasible method., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Liu, Hu, Liu, Xia, Niu, Li and Zhao.)

Objective: Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein, which plays a role in pre-mRNA splicing and in the regulation of alternative splicing events. However, little was known about the correlation between PTBP1 and glioma and its prognostic significance in glioma patients. Our aim was to investigate the expression, functional role, and prognostic value of PTBP1 in glioma., Methods: We explored the expression of PTBP1 protein using immunohistochemistry in 150 adult malignant glioma tissues and 20 normal brain tissues and evaluated its association with clinicopathological parameters by chi-square test. Kaplan-Meier method was used to evaluate the prognostic effect of PTBP1 in glioma. Univariate/multivariate Cox analyses were used to identify independent prognostic factors. Transcriptional regulation network was constructed based on differentially expressed genes (DEGs) of PTBP1 from TCGA/CGGA database. GO and KEGG enrichment analyses were used to explore the function and pathways of DEGs., Results: Out of the 150 malignant glioma tissues (60 LGG and 90 GBMs) and 20 normal brain tissues in our cohort, PTBP1 protein was high expressed in glioma tissues (79/150, 52.7%), but no expression was detected in normal brain tissues (0/20, 0%). The expression of PTBP1 was significantly higher in GBMs ( P < 0.001). More than half of GBMs (62/90, 68.9%) were PTBP1 high expression. Chi-square test showed that the expression of PTBP1 was correlated with patient age, WHO grade, Ki-67 index, and IDH status. High expression of PTBP1 was significantly associated with poor prognosis in glioma, and it was an independent risk factor in glioma patients. Furthermore, we shed light on the underlying mechanism of PTBP1 by constructing a miR-218-TCF3-PTBP1 transcriptional network in glioma., Conclusion: PTBP1 was high expressed in glioma, and it significantly correlated with poor prognosis, suggesting a potential therapeutic target for glioma, particularly for GBM., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Pan Liu et al.)

A new phenylpropanoid, ligulaveitnoid A ( 1 ), along with four known compounds, ( E )-2,3-dihydroconiferyl p -coumarate ( 2 ), dihydroconiferyl ferulate ( 3 ), 4-hydroxy-3-methoxybenzaldehyde ( 4 ) and ( E )- p -coumaric acid ( 5 ) were isolated from rhizomes and roots of L. veitchiana . All the structures of compounds were identified by the interpretation of their spectroscopic data and comparison with those reported in the literature. The anti-inflammatory activity of the isolates was examined for their inhibitory effects on LPS-induced NO production in macrophage RAW264.7 cells. Among them, compound 2 showed strong inhibitory activities towards the LPS-induced NO production in macrophage RAW264.7 cells with IC 50 value of 8.0  μ M.

Background: Rearranged during transfection (RET) is a targetable oncogene. RET fusions have been reported in patients with metastatic colorectal cancer (mCRC). However, RET mutations in mCRC are less studied. Here, we aimed to characterize the clinical, pathological, and molecular landscape of RET-mutated mCRC., Methods: Five hundred and eighty-two patients were included in this study. Next-generation sequencing was performed to detect RET mutations and calculate tumor mutation burden (TMB). We compared the clinical, pathological, and molecular characteristics of mCRC cases with tumors that harbored somatic RET mutations (N = 16, 2.7%) or had wild-type RET (N = 566, 97.3%)., Results: Males comprised the absolute majority of cases with RET mutations (15/16 [93.8%]) compared to their fraction among cases with wild-type RET (339/566 [59.9%]). Furthermore, all patients with RET mutations were younger than 60 years (16/16 [100%]), whereas such patients were less predominant in the group with wild-type RET (379/566 [67.0%]). Individuals with tumors positive for RET mutations more frequently exhibited mucinous histology (5/16 [31.2%] vs. 55/566 [9.7%]), exhibited a lower incidence of liver metastasis (4/16 [25.0%] vs. 335/566 [59.2%]), and higher incidence of peritoneal metastasis (9/16 [56.2%] vs.161/566 [28.4%]), expressed wild-type TP53 (8/16 [50.0%] vs.120/566 [21.2%]), and showed an increased frequency of MSI-high (6/16 [37.5%] vs. 18/566 [3.2%]). In those with microsatellite-stable mCRC, patients with RET mutations had a higher median TMB than patients with wild-type RET (9.4 vs. 6.7 mutations/Mb, respectively, p = 0.001). The median progression-free survival was similar in individuals with mutated and wild-type RET on the oxaliplatin-based regimen (7.1 vs. 8.7 months, p = 0.516)., Conclusions: Our study suggests that cases with RET mutations represent a separate mCRC subtype. Further studies are needed to evaluate the efficacy of RET inhibitors in mCRC patients with RET mutations., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Deep vein thrombosis (DVT) may cause pulmonary embolus, leading to late deaths. The systemic inflammatory and hypercoagulable state of moderate and severe acute pancreatitis (non-mild acute pancreatitis, NMAP) patients may contribute to the development of venous thromboembolism. Accurate prediction of DVT is conducive to clinical decisions., Aim: To develop and validate a potential new prediction nomogram model for the occurrence of DVT in NMAP., Methods: NMAP patient admission between 2013.1.1 and 2018.12.31 at the West China Hospital of Sichuan University was collected. A total of 220 patients formed the training set for nomogram development, and a validation set was constructed using bootstrapping with 100 resamplings. Univariate and multivariate logistic regression analyses were used to estimate independent risk factors associated with DVT. The independent risk factors were included in the nomogram. The accuracy and utility of the nomogram were evaluated by calibration curve and decision curve analysis, respectively., Results: A total of 220 NMAP patients over 60 years old were enrolled for this analysis. DVT was detected in 80 (36.4%) patients. The final nomogram included age, sex, surgery times, D-dimer, neutrophils, any organ failure, blood culture, and classification. This model achieved good concordance indexes of 0.827 (95%CI: 0.769-0.885) and 0.803 (95%CI: 0.743-0.860) in the training and validation sets, respectively., Conclusion: We developed and validated a prediction nomogram model for DVT in older patients with NMAP. This may help guide doctors in making sound decisions regarding the administration of DVT prophylaxis., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Gliomas are the most prevalent primary malignant central nervous system tumors among all tumors occurring in the brain and spinal cord. The poor outcome of glioma requires the discovery of novel biomarkers with potential therapeutic value. Somatostatin receptor subtype 2 (SSTR2) represents a diagnostic biomarker and potential therapeutic target in many cancers, such as meningioma and neuroendocrine tumors (NETs). However, the relationship of SSTR2 and glioma was unclear. Therefore, this study aimed to investigate the expression of SSTR2 and assess its prognostic and potential therapeutic value in a large cohort of patients with WHO grade I to IV glioma from a single Chinese center. Immunohistochemical analysis revealed that SSTR2 was highly expressed in 23.84% (72 of 302) of glioma (I-IV grade) samples. Among all glioma subtypes, high SSTR2 expression was detected mainly in oligodendroglioma, anaplastic oligodendroglioma, and astrocytoma, whereas SSTR2 was expressed at a low level, or not at all, in glioblastoma. Western blotting also confirmed the low expression of SSTR2 in glioblastoma cell lines. Statistical analysis showed that SSTR2 protein expression correlated significantly with WHO grade, the location of the tumor, epilepsy syndrome, mitosis (PHH3), proliferation index (Ki-67), IDH and 1p/19q-codeleted status. Kaplan-Meier analysis indicated that SSTR2 high expression was a good prognostic factor in glioma. In summary, this study demonstrated that SSTR2 might be a valuable prognostic factor and therapeutic target in certain glioma subtypes., Competing Interests: None., (AJTR Copyright © 2021.)

As the sixth most lethal cancers worldwide, hepatocellular carcinoma (HCC) has been treated with doxorubicin (Dox) for decades. However, chemotherapy resistance, especially for Dox is an even more prominent problem due to its high cardiotoxicity. To find a regimen to reduce Dox resistance, and identify the mechanisms behind it, we tried to identify combination of drugs that can overcome drug resistance by screening tyrosine kinase inhibitor(s) with Dox with various HCC cell lines in vitro and in vivo . We report here that combination of Crizo and Dox has a synergistic effect on inducing HCC cell death. Accordingly, Crizo plus Dox increases Dox accumulation in nucleus 3-16 times compared to Dox only; HCC cell death enhanced at least 50% in vitro and tumor weights reduced ranging from 35 to 65%. Combining these two drugs reduces multiple drug resistance 1 (MDR1) protein as a result of activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), which phosphorylates eIF2α, leading to protein translational repression. Additionally, PERK stimulation activates C-Jun terminal kinase (JNK), resulting in accumulation of unfused autophagosome to enhance autophagic cell death via Poly-ADP-ribosyltransferase (PARP-1) cleavage. When the activity of PERK or JNK is blocked, unfused autophagosome is diminished, cleaved PARP-1 is reduced, and cell death is abated. Therefore, Crizo plus Dox sensitize HCC drug resistance by engaging PERK-p- eIF2α-MDR1, and kill HCC cells by engaging PERK-JNK- autophagic cell death pathways. These newly discovered mechanisms of Crizo plus Dox not only provide a potential treatment for HCC but also point to an approach to overcome MDR1 related drug resistance in other cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shao, Shi, Gao, Gao, Li, Li, Cui, Hu, Chen, Wu, Zhang, Xu, Sy and Li.)

Overactivation of the PI3-K/Akt/mTOR signaling pathway and inhibition of autophagy in the brain are involved in Alzheimer's disease. The present paper's goal was to explore the potential mechanisms of geniposide to protect against Alzheimer's disease. We treated the human neuroblastoma SH-SY5Y cell line with Aβ 1-42 as an Alzheimer's disease in vitro model to explore the potential mechanisms of geniposide to protect against Alzheimer's disease. Further, SH-SY5Y cells damaged by Aβ 1-42 were treated with geniposide. Akt/mTOR-related proteins and autophagy-associated proteins were measured to reveal the molecular mechanisms by which geniposide protects against Aβ 1-42 -induced toxicity. Results showed that Akt and mTOR's geniposide inhibited phosphorylation induced by Aβ 1-42 , enhanced expression of the LC3II/LC3I ratio, and Atg7 and Beclin1 expression and inhibited expression of p62 induced by Aβ 1-42 . Our results lead us to hypothesize that inhibition of the Akt/mTOR signaling pathway and autophagy enhancement are fundamental molecular mechanisms for geniposide to protect against Aβ toxicity., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Published by IMR Press.)

An efficient [4 + 1] annulation between α-bromooximes and sulfur ylides via in situ generation of nitrosoalkenes under mild basic reaction conditions has been developed, providing an expeditious and scalable approach to synthesize biologically interesting isoxazoline derivatives with good to excellent yields.

Background: Microbiota profiles differ between patients with pancreatic cancer and healthy people, and understanding these differences may help in early detection of pancreatic cancer. Saliva sampling is an easy and cost-effective way to determine microbiota profiles compared to fecal and tissue sample collection., Aim: To investigate the saliva microbiome distribution in patients with pancreatic adenocarcinoma (PDAC) and the role of oral microbiota profiles in detection and risk prediction of pancreatic cancer., Methods: We conducted a prospective study of patients with pancreatic cancer ( n = 41) and healthy individuals ( n = 69). Bacterial taxa were identified by 16S ribosomal ribonucleic acid gene sequencing, and a linear discriminant analysis effect size algorithm was used to identify differences in taxa. Operational taxonomic unit values of all selected taxa were converted into a normalized Z-score, and logistic regressions were used to calculate risk prediction of pancreatic cancer., Results: Compared with the healthy control group, carriage of Streptococcus and Leptotrichina (z-score) was associated with a higher risk of PDAC [odds ratio (OR) = 5.344, 95% confidence interval (CI): 1.282-22.282, P = 0.021 and OR = 6.886, 95%CI: 1.423-33.337, P = 0.016, respectively]. Veillonella and Neisseria (z-score) were considered a protective microbe that decreased the risk of PDAC (OR = 0.187, 95%CI: 0.055-0.631, P = 0.007 and OR = 0.309, 95%CI: 0.100-0.952, P = 0.041, respectively). Among the patients with PDAC, patients reporting bloating have a higher abundance of Porphyromonas ( P = 0.039), Fusobacterium ( P = 0.024), and Alloprevotella ( P = 0.041); while patients reporting jaundice had a higher amount of Prevotella ( P = 0.008); patients reporting dark brown urine had a higher amount of Veillonella ( P = 0.035). Patients reporting diarrhea had a lower amount of Neisseria and Campylobacter ( P = 0.024 and P = 0.034), and patients reporting vomiting had decreased Alloprevotella ( P = 0.036)., Conclusion: Saliva microbiome was able to distinguish patients with pancreatic cancer and healthy individuals. Leptotrichia may be specific for patients living in Sichuan Province, southwest China. Symptomatic patients had different bacteria profiles than asymptomatic patients. Combined symptom and microbiome evaluation may help in the early detection of pancreatic cancer., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest were disclosed., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To explore the feasibility of Ponseti method in treatment of secondary clubfoot in young children with Tethered Cord Syndrome(TCS). Methods: The clinical data of 53 young children with clubfeet treated with Ponseti method from March 2014 to March 2017 at Department of Pediatric Orthopedics, the Third Affiliated Hospital of Zhengzhou University were analyzed retrospectively. These patients were divided into TCS group and Idiopathic group according to the etiology. There were 19 patients (33 feet) in TCS group,with an mean age of 2.8 months(range:0.2 to 24.0 months), including 13 males and 6 females, 5 patients with unilateral clubfeet and 14 patients with bilateral clubfeet. There were 34 patients (45 feet) in idiopathic group, with an mean age of 3.1 months(range: 0.1 to 21.0 months), including 18 males and 16 females, 23 patients with unilateral clubfeet and 11 patients with bilateral clubfeet. All the children received casts correction according to Ponseti method, and were followed up at 3 weeks, 3 months, 6 months and every 6 months after the Achilles tendon tenotomy or the last cast correction. Complications were recorded and therapeutic effect was evaluated of these children by Dimeglio Scoring System and the International Clubfoot Study Group (ICFSG) at the last follow-up. Independent t test, Mann-Witney U test or χ(2) test were used to compare the indicators of the two groups. Results: The number of plaster fixation in TCS group was (6.1±2.0) times, and that of idiopathic group was (4.8±1.0) times( t= 3.482, P< 0.01).In TCS group, 22 feet treated with Achilles tendon transection and that of idiopathic group was 40 feet(χ(2)=0.279, P= 0.598). There were 18 cases recurrence in TCS group and 8 cases in Idiopathic group ( t= 11.149, P< 0.01). In TCS group, 16 cases (27 feet) completed the initial correction, the success rate was 60.6% (27/33), 3 cases (6 feet) could not correct the deformity after 9 to 10 times of plaster fixation, and then underwent soft tissue release.In idiopathic group, 34 cases (45 feet) achieved initial correction after Ponseti treatment(χ(2)=6.488, P= 0.011).At the last follow up, there were 5 cases (9 feet) in TCS group and 2 cases (2 feet) in idiopathic group underwent soft tissue release(χ(2)=6.110, P= 0.013). The classification grade of ICFSG score of the two groups without soft tissue release were (2.1±0.6) and (1.8±0.7), the difference was not statistically significant ( t= 1.765, P= 0.082). All the children had no skin ulceration, bedsores, skin allergy and other complications. Conclusion: Ponseti method is effective in the treatment of clubfoot secondary to TCS, and the functional recovery is similar to that of children with idiopathic clubfoot.

Accumulating evidence has indicated that inflammation is required for the initiation and progression of hepatocellular carcinoma (HCC). The annexin family protein, which has a highly similar structure, has been demonstrated to participate in pro- or anti-inflammatory regulation in the developing of tumours. However, the potential effects of ANXA3 in the immune microenvironment of HCC remain unknown. In present study, we found that increased ANXA3 expression is associated with a higher infiltrated neutrophil-lymphocyte ratio (iNLR) in HCC. Moreover, HCC patients with a high iNLR and high ANXA3 expression confer the highest risk of death. ANXA3 can be detected in both cell lysates and culture supernatants. However, the secretory ANXA3 did not directly regulate the iNLR. Further study demonstrated that ANXA3 upregulated the iNLR by inducing chemokine CXCL8 and CCL25 release from HCC cells. We further confirmed that ANXA3 promotes tumourigenesis and detected the same associations between ANXA3 and the iNLR or chemokines in vivo. Our findings indicate that ANXA3 regulates the chemokine to remodel the iNLR and promotes tumourigenicity in HCC. These results further expanded our understanding of ANXA3 in the microenvironment of HCC and might provide novel targets for the investigation of molecular treatments for HCC patients., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited endocrine tumor syndrome caused by inactivating variants of the MEN1 gene. The aim of this study is to explore the clinical and genetic characteristics of four MEN1 patients. We isolated genomic deoxyribonucleic acid from lymphocytes, parathyroid, and thymic tumoral tissue specimens from the MEN1 patients. All exons of the MEN1 and CDNK1B genes and adjacent exon-intron sequences were amplified by polymerase chain reaction and subsequently sequenced. Further, the splice alterations were studied by sequencing the amplified RT-PCR products for MEN1 cDNA. We identified four heterozygous MEN1 germline variants: c.564delC, c.1268G>A, IVS5+5delG, and c.1546&#95;1547insC. Both c.564delC and IVS5+5delG were novel variants. The impact of the MEN1 splice variant, IVS5+5delG, was evaluated using bioinformatics and in vitro analyses. The analyses indicated that this variant resulted in skipping of the neighboring exon and was disease-causing. Two novel somatic variants, c.249&#95;252delGTCT and c.313&#95;314insC, were found. Additionally, loss of heterozygosity (LOH) for the MEN1 locus (IVS5+5delG and c.564delC) was found in tumor tissue samples from the MEN1 patients, consistent with Knudson's two-hit mechanism. We identified four MEN1 germline variants and two novel somatic variants. Early recognition of the phenotype coupled with variant screening of the MEN1 gene is the key to diagnosing and treating MEN1 effectively at an early stage., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue with an extended half-life of approximately 1 week has being come into clinic trial to treat parkingson's disease but little is known about its effect to prevent against Alzheimer's disease (AD). The goal of the present study was to explore the potential mechanisms of semaglutide to protect against AD., Methods: We treated SH-SY5Y cell line with Aβ 25-35 as an AD model. Further, SH-SY5Y cells damaged by Aβ 25-35 were treated by semaglutide. Autophagy-related proteins and apoptosis-related proteins were measured to explore molecular mechanisms for semaglutide to protect against Aβ 25-35 ., Results: Semaglutide enhanced autophagy by increasing the expression of LC3II, Atg7, Beclin-1 and P62 which were inhibited by Aβ 25-35 . Further we showed that semaglutide inhibited apoptosis by inhibiting the expression of Bax induced by Aβ 25-35 and increasing the expression of Bcl2 inhibited by Aβ 25-35 ., Conclusion: Our results provide a clue for the hypothesis that autophagy enhancement and apoptosis inhibition may be involved in the effect of semaglutide to protect against Aβ 25-35 ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Patients with schizophrenia are at a higher risk for suicide compared with the general population. Dopamine beta-hydroxylase (DβH) plays a key role in the conversion of dopamine to norepinephrine, which is related to suicidal behavior and cognitive regulation., Objective: To examine whether there is the effect of DβH 5'-insertion/deletion (Ins/Del) polymorphism on cognitive performance in suicide attempters with chronic schizophrenia., Methods: This polymorphism was detected in 114 suicide attempters and 617 non-suicide attempters with chronic schizophrenia. Cognitive performance was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)., Results: The allelic and genotypic frequencies of this polymorphism between two groups did not differ after controlling for covariates (both, p > .05). There were no differences in RBANS scores between two groups after adjusting for covariates (all, p > .05). However, based on the genotype grouping in suicide attempters and non-attempters, the attention score significantly differed after adjusting for covariates (both, p < .05). Further analysis indicated that this polymorphism was associated with attention score in suicide attempters (p < .05), but not in non-suicide attempters (p > .05)., Conclusions: DβH 5'-Ins/Del polymorphism was not a risk locus of suicide attempters, but it was implicated in attention regulation in suicide attempters with chronic schizophrenia., (© 2020 John Wiley & Sons Ltd.)

Background: A profound understanding of the molecular landscape of glioblastoma multiforme (GBM) will make it possible to develop better and more intelligent therapies directed toward specific molecular targets and may one day yield better prognostic capabilities. Immune checkpoint molecules have inspired the emergence of immune checkpoint-targeting therapeutic strategies. However, the prognostic significance of the immune checkpoint molecule T cell immunoglobulin mucin-3 (Tim-3) on tumor-infiltrating immune cells (TIICs) and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has not yet been fully elucidated. We aimed to develop an MGMT promoter methylation status-associated immune prognostic signature for GBM., Patients and Methods: A total of 84 patients with newly diagnosed GBM were included in this study. MGMT promoter methylation status was retrospectively analyzed, and the expression level of Tim-3 was investigated using immunohistochemistry (IHC). The correlation between Tim-3 expression combined with MGMT promoter methylation status and prognosis was explored., Results: Tim-3 expression varied in GBM patients. Mesenchymal expression of Tim-3 in GBM tissues was present 73.81% (62/84) of patients, and these were subdivided into groups based on low 15.48% (13/84), moderate 7.14% (6/84), or strong expression 51.19% (43/84). Forty-eight patients had tumors that tested positive for MGMT promoter methylation, while the remaining 36 patients tested negative., Conclusions: We profiled the immune status of MGMT promoter methylation in GBM and established a local immune signature for GBM that could independently identify patients with a favorable prognosis, indicating a relationship between prognosis and GBM immune signature. MGMT promoter methylation with lower Tim-3 expression was significantly associated with better survival., (Copyright © 2020 Zhang, Sai, Wang, Ye, Liang, Zhou, Chen, Hu and Liu.)

Aims: The objective of this study is to explore the association between documented diabetes, fasting plasma glucose (FPG), and the clinical outcomes of Coronavirus disease 2019 (COVID-19)., Methods: This retrospective study included 255 patients with COVID-19. Of these, 214 were admitted to isolation wards and 41were admitted to intensive care units (ICUs). Demographic, clinical, treatment, and laboratory data were collected and compared between ICU and non-ICU patients. Multivariable logistic regression models were used to explore the risk factors associated with poor clinical outcomes (ICU admission or death)., Results: There were significant changes in several clinical parameters in ICU patients (leukopenia, lymphopenia, elevated D-dimer, as well as higher levels of FPG, cardiac troponin, serum ferritin, IL-6, and high-sensitivity C-reactive protein)compared with non-ICU patients. The prevalence of known diabetes was substantially higher in ICU than non-ICU patients (31.7% vs. 17.8%, P = 0.0408). Multivariable regression analysis showed that a history of diabetes [odds ratio (OR), 0.099; 95% confidence interval (CI), 0.016-0.627; P = 0.014], high FPG at admission (OR, 1.587; 95% CI, 1.299-1.939, P < 0.001), high IL-6 (OR, 1.01; 95% CI, 1.002-1.018, P = 0.013), and D-dimer higher than 1 mg/L at admission (OR, 4.341; 95% CI, 1.139-16.547, P = 0.032) were independent predictors of poor outcomes. Cox proportional hazards analysis showed that compared with FPG < 7 mmol/L, FPG levels of 7.0-11.1 mmol/L and ≥ 11.1 mmol/L were associated with an increased hazard ratio (HR) for poor outcome (HR, 5.538 [95% CI, 2.269-13.51] and HR, 11.55 [95% CI, 4.45-29.99], respectively)., Conclusion: Hyperglycemia and a history of diabetes on admission predicted poor clinical outcomes in COVID-19., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: It is unknown whether or not the body composition is correlated with the prognosis and inflammatory response in patients with nasopharyngeal cancer (NPC)., Materials and Methods: This cohort included 1767 patients with NPC. Visceral, subcutaneous and intra muscular adipose tissues (VAT, SAT and IMAT), and skeletal muscle index were quantified with computed tomography. We used the optimal stratification to select cut points for VAT, SAT and IMAT. We defined sarcopenia according to a widely used cut-point. The primary endpoint was overall survival (OS). The association between body composition and inflammatory response was also examined., Results: Low VAT, SAT, IMAT and sarcopenia were observed in 260 (14.7%), 451 (25.5%), 773 (43.7%) and 683 (38.7%) patients, respectively. Low VAT (P < 0.001, hazard ratio [HR], 1.884; 95% confidence interval [CI], 1.436-2.473,) and SAT (P = 0.022, HR, 1.334, 95%CI, 1.043-1.706) were both associated worse survival. IMAT and sarcopenia were not with prognostic value. In multivariate analysis, we found the prognostic value of the VAT (HR: 1.544, 95% CI: 1.128-2.114; P = 0.007) was independent of T stage, N stage, disease stage, lactic dehydrogenase, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), the systemic immune-inflammation index (SII), EBV-DNA and body mass index. We observed higher NLR (P = 0.028) and PLR (P < 0.001) in patients with low SAT. Both low VAT (P = 0.009) and SAT (P = 0.005) were associated with decreased stromal lymphocyte infiltrating intensity., Conclusions: Among body composition parameters, VAT was an independent prognostic factor, especially in patients with locally advanced NPC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: This study aimed to develop a predictive model based on the risk of locoregional recurrence (LRR) in epidermal growth factor receptor ( EGFR )-mutant stage III-pN2 lung adenocarcinoma after complete resection. Methods: A total of 11,020 patients with lung surgery were screened to determine completely resected EGFR -mutant stage III-pN2 lung adenocarcinoma. Patients were excluded if they received preoperative therapy or postoperative radiation therapy (PORT). The time from surgery to LRR was recorded. Clinicopathological variables with statistical significance predicting LRR in the multivariate Cox regression were incorporated into the competing risk nomogram. Patients were then sub-grouped based on different recurrence risk as a result of the nomogram. Results: Two hundred and eighty-eight patients were enrolled, including 191 (66.3%) with unforeseen N2 (IIIA1-2), 75 (26.0%) with minimal/single station N2 (IIIA3), and 22 (7.6%) with bulky and/or multilevel N2 (IIIA4). The 2-year overall cumulative incidence of LRR was 27.2% (confidence interval [CI], 16.3%-38.0%). IIIA4 disease (hazard ratio, 2.65; CI, 1.15-6.07; P =0.022) and extranodal extension (hazard ratio, 3.33; CI, 1.76-6.30; P <0.001) were independent risk factors for LRR and were incorporated into the nomogram. Based on the nomogram, patients who did not have any risk factor (low-risk) had a significantly lower predicted 2-year incidence of LRR than those with any of the risk factors (high-risk; 4.6% vs 21.9%, P <0.001). Conclusions: Pre-treatment bulky/multilevel N2 and pathological extranodal extension are risk factors for locoregional recurrence in EGFR -mutant stage III-pN2 lung adenocarcinoma. Intensive adjuvant therapies and active follow-up should be considered in patients with any of the risk factors., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: To investigate the predictive values of plasma Epstein-Barr Virus (EBV)- deoxyribonucleic acid (DNA) copy number on disease progression and survival in stage I-III pulmonary lymphoepithelioma-like carcinoma (LELC). Patients and Methods: Patients with pathologically confirmed, initially diagnosed or locally recurrent stage I-III pulmonary LELC, who received locally radical treatment and had plasma EBV-DNA results, were retrospectively reviewed. Risk factors of progression-free survival (PFS) and overall survival (OS) were assessed, including the predictive value of pre- and post-treatment EBV-DNA levels. The EBV-DNA change during follow-up was analyzed to determine its association with tumor progression and survival. Results: A total of 102 patients were included in analysis. Eighty-eight patients had initially-diagnosed and 14 had locally recurrent disease. There were 33 patients treated with radical surgery, 55 with definite radiotherapy and 14 with both. EBV-DNA was tested pre-treatment ( N = 66), post-treatment ( N = 93) and/or during follow-up ( N = 58). Forty-one patients had complete EBV-DNA results of all three time points. The overall 2-year PFS and OS were 66.3 and 96.0%, respectively. Pre-treatment EBV-DNA copy number > 10,000 copies/mL was a risk factor of PFS (2-year PFS, > 10,000 vs. ≤ 10,000 copies/mL, 37.2 vs. 75.1%, p = 0.007). Positive post-treatment EBV-DNA also indicated a worse PFS in univariable (2-year PFS, > 0 vs. 0 copy/mL, 25.6 vs. 76.8%, p < 0.001) and multivariable analysis (HR = 3.44, 95% CI, 1.52-7.78; p = 0.003). In the follow-up set, an increasing EBV-DNA exceeding 1,000 copies/mL strongly predicted disease progression within 3 months, with a specificity of 97.5% (95% CI: 86.8-99.6%) and was associated with impaired OS (2-year OS, > 1,000 vs. ≤ 1,000 copies/mL, 72.9 vs. 100%, p < 0.001). Conclusions: Regular testing of EBV-DNA is suggested for pulmonary LELC to predict disease progression. If EBV-DNA copy number was increasing and beyond 1,000 copies/mL during follow-up, intensive radiologic evaluations are recommended., (Copyright © 2020 Li, Qiu, Hu, Guo, Wu, Zhu, Hu, Ai, Chen, Guo, Hu, Liu, Zeng and Liu.)

Objective: To study the expression of IL13RA2 in gliomas and to analyze its correlation with clinicopathological/molecular features, immune cell infiltration and prognostic significance., Methods: mRNA expression data for IL13RA2 were downloaded and analyzed from two open access datasets (TCGA & CGGA). IL13RA2 protein expression was examined by immunohistochemistry. The association between IL13RA2 and important clinicopathological/molecular markers was examined using χ 2 and Spearman correlation tests. The TIMER tool was used to evaluate the correlation of IL13RA2 with multiple intra-tumoral immune cell types in glioma. Kaplan-Meier test and multivariate Cox analyses were applied to evaluate the prognosis., Results: Out of the 297 glioma tissues and 20 normal brain tissues in our cohort, IL13RA2 protein was highly expressed in 115 glioma tissues (115/297, 38.7%), but no expression was detected in normal brain tissues (0/20, 0%). The expression of IL13RA2 was significantly higher in GBMs (P<0.001). More than half of GBMs (68/132, 51.5%) were high expression of IL13RA2 protein, especially GBM patients with IDH wild-type and TERT promoter mutated (60/78, 76.9%). Moreover, 11/13 (84.6%) diffuse midline gliomas and 31/51 (64.7%) IDH wild-type LGGs also highly expressed IL13RA2 in our cohorts. Chi-square test showed that the expression of IL13RA2 was correlated with patient age, WHO grade, Ki67 index, IDH status, TERT promoter status and immune cell infiltration. Additionally, IL13RA2 was strongly associated with patients' OS and served as a negative prognostic marker in infiltrating gliomas., Conclusion: IL13RA2 was high expression in some glioma subtypes, and significantly correlated with poor prognosis. Based on its role in CAR-T therapy, it might act as an extremely important and specific therapeutic target for human malignant gliomas, especially in IDH wild-type LGG, "IDH wild-type and TERT promoter mutated" GBM and H3K27M-mutated diffuse midline glioma, and improve the clinical outcomes of these patients., Competing Interests: None., (AJTR Copyright © 2020.)