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Background Hepatic lipid disorder impaired mitochondrial homeostasis and intracellular redox balance, triggering development of non-alcohol fatty liver disease (NAFLD), while effective therapeutic approach remains inadequate. Ginsenosides Rc has been reported to maintain glucose balance in adipose tissue, while its role in regulating lipid metabolism remain vacant. Thus, we investigated the function and mechanism of ginsenosides Rc in defending high fat diet (HFD)-induced NAFLD. Methods Mice primary hepatocytes (MPHs) challenged with oleic acid & palmitic acid were used to test the effects of ginsenosides Rc on intracellular lipid metabolism. RNAseq and molecular docking study were performed to explore potential targets of ginsenosides Rc in defending lipid deposition. Wild type and liver specific sirtuin 6 (SIRT6, 50721) deficient mice on HFD for 12 weeks were subjected to different dose of ginsenosides Rc to determine the function and detailed mechanism in vivo. Results We identified ginsenosides Rc as a novel SIRT6 activator via increasing its expression and deacetylase activity. Ginsenosides Rc defends OA&PA-induced lipid deposition in MPHs and protects mice against HFD-induced metabolic disorder in dosage dependent manner. Ginsenosides Rc (20mg/kg) injection improved glucose intolerance, insulin resistance, oxidative stress and inflammation response in HFD mice. Ginsenosides Rc treatment accelerates peroxisome proliferator activated receptor alpha (PPAR-α, 19013)-mediated fatty acid oxidation in vivo and in vitro. Hepatic specific SIRT6 deletion abolished ginsenoside Rc-derived protective effects against HFD-induced NAFLD. Conclusion Ginsenosides Rc protects mice against HFD-induced hepatosteatosis by improving PPAR-α-mediated fatty acid oxidation and antioxidant capacity in a SIRT6 dependent manner, and providing a promising strategy for NAFLD.

Long non-coding RNAs (LncRNAs) have crucial function in epithelial–mesenchymal transition (EMT) in pancreatic cancer. It is necessary to comprehensively analyze the potential role of EMT-related lncRNA in pancreatic cancer. In the present study, genomic data of pancreatic cancer from the TCGA database were downloaded and we found 368 EMT-related lncRNAs. According to the expression characteristics of prognostic-related lncRNAs, all samples could be divided into two clusters with different clinical outcomes and different tumor microenvironments. Moreover, an eleven EMT-related lncRNAs signature was established and verified. Patients with pancreatic cancer in the high-risk group had a shorter overall survival than those in the low-risk group and the signature could act as an independent prognostic factor. Further analysis suggested that the EMT-related lncRNAs might affect the prognosis of patients through immune mechanisms. All findings indicated that the signature and eleven lncRNAs might serve as potential prognostic biomarkers and therapeutic targets in the treatment of pancreatic cancer.

Background Esophageal cancer is the fifth most common cancer affecting men in China. The primary treatment options are surgery and traditional radio-chemotherapy; no effective targeted therapy exists yet. Self-assembled RNA nanocarriers are highly stable, easily functionally modified, and have weak off-tumor targeting effects. Thus, they are among the most preferred carriers for mediating the targeted delivery of anti-tumor drugs. miR-375 was found to be significantly down-regulated in esophageal squamous cell carcinoma (ESCC) tissues and its overexpression effectively inhibits the proliferation, migration, and invasion of ESCC cells. Moreover, epidermal growth factor receptor (EGFR) was overexpressed in ESCC cells, and accumulation of RNA nanoparticles in ESCC tumors was enhanced by EGFR-specific aptamer (EGFRapt) modification. Results Herein, a novel four-way junction RNA nanocarrier, 4WJ-EGFRapt-miR-375-PTX simultaneously loaded with miR-375, PTX and decorated with EGFRapt, was developed. In vitro analysis demonstrated that 4WJ-EGFRapt-miR-375-PTX possesses strong thermal and pH stabilities. EGFRapt decoration facilitated tumor cell endocytosis and promoted deep penetration into 3D-ESCC spheroids. Xenograft mouse model for ESCC confirmed that 4WJ-EGFRapt-miR-375-PTX was selectively distributed in tumor sites via EGFRapt-mediating active targeting and targeted co-delivery of miR-375 and PTX exhibited more effective therapeutic efficacy with low systemic toxicity. Conclusion This strategy may provide a practical approach for targeted therapy of ESCC. Graphical Abstract

Background Non-alcoholic fatty liver disease (NAFLD) has been entitled as metabolic-dysfunction associated fatty liver disease (MAFLD). Therefore anthropometric indicators of adiposity may provide a non-invasive predictive and diagnostic tool for this disease. This study intended to validate and compare the MAFLD predictive and diagnostic capability of eight anthropometric indicators. Methods The study involved a population-based retrospective cross-sectional design. The Fangchenggang area male health and examination survey (FAMHES) was used to collect data of eight anthropometric indicators, involving body mass index (BMI), waist-to-height ratio (WHtR), waist-hip ratio (WHR), body adiposity index (BAI), cardiometabolic index (CMI), lipid accumulation product (LAP), visceral adiposity index (VAI), and abdominal volume index (AVI). Receiver operating characteristics (ROC) curves and the respective areas under the curves (AUCs) were utilized to compare the diagnostic capacity of each indicator for MAFLD and to determine the optimal cutoff points. Binary logistic regression analysis was applied to identify the odds ratios (OR) with 95% confidence intervals (95% CI) for all anthropometric indicators and MAFLD. The Spearman rank correlation coefficients of anthropometric indicators, sex hormones, and MAFLD were also calculated. Results All selected anthropometric indicators were significantly associated with MAFLD (P Conclusion All anthropometric indicators were associated with MAFLD. WHtR was identified as the strongest predictor of MAFLD in young Chinese males, followed by LAP and AVI. The strongest association was found between LAP and sex hormones.

Immunotherapy involving immune checkpoint inhibitors (ICIs) for enhancing immune system activation is promising for tumor management. However, the patients’ responses to ICIs are different. Here, we applied a non-negative matrix factorization algorithm to establish a robust immune molecular classification system for colorectal cancer (CRC). We obtained data of 1503 CRC patients (training cohort: 488 from The Cancer Genome Atlas; validation cohort: 1015 from the Gene Expression Omnibus). In the training cohort, 42.8% of patients who exhibited significantly higher immunocyte infiltration and enrichment of immune response-associated signatures were subdivided into immune classes. Within the immune class, 53.1% of patients were associated with a worse overall prognosis and belonged to the immune-suppressed subclass, characterized by the activation of stroma-related signatures, genes, immune-suppressive cells, and signaling. The remaining immune class patients belonged to the immune-activated subclass, which was associated with a better prognosis and response to anti-PD-1 therapy. Immune-related subtypes were associated with different copy number alterations, tumor-infiltrating lymphocyte enrichment, PD-1/PD-L1 expression, mutation landscape, and cancer stemness. These results were validated in patients with microsatellite instable CRC. We described a novel immune-related class of CRC, which may be used for selecting candidate patients with CRC for immunotherapy and tailoring optimal immunotherapeutic treatment.

Bo Yang,1– 3,* Lin-Lin Ji,1,2,* Hong-Liang Xu,1,* Xiao-Ping Li,3 Hong-Gang Zhou,4 Ting Xiao,4 Xiao-He Li,4 Zhou-Yong Gao,1,2 Jian-Zhong Li,5 Wei-Dong Zhang,3 Guang-Shun Wang,1 Ming-Jiang Li3 1Department of Thoracic Surgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, People’s Republic of China; 2State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, People’s Republic of China; 3Department of Thoracic Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, People’s Republic of China; 4State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key, Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People’s Republic of China; 5Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guang-Shun WangDepartment of Thoracic Surgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, People’s Republic of ChinaEmail wgs@bddhospital.comMing-Jiang LiDepartment of Thoracic Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, People’s Republic of ChinaEmail mingjiangli@nankai.edu.cnBackground: Zc3h12d is a negative regulator which plays a crucial role in immune modulation. However, the role of zc3h12d in lung adenocarcinoma (LUAD) remains unclear. We aim to explore the prognostic of zc3h12d and investigate the relationship between zc3h12d expression and immune infiltration in LUAD.Methods: TIMER site was used to analyze the expression of zc3h12d in LUAD. The zc3h12d protein levels in patient tissue samples were detected by immunohistochemistry staining assays. Meanwhile, based on UALCAN database and samples’ data from our cohort, we explored the relationship of clinicopathological features and zc3h12d expression to determine the clinical effect of zc3h12d in LUAD. Several databases including GEPIA, Kaplan–Meier plotter and our samples’ data were used to explore the prognostic value of zc3h12d in LUAD. Cox regression analysis was established to further evaluate the prognostic value of zc3h12d in LUAD. In addition, zc3h12d promoter methylation was analyzed by UALCAN database. Genetic alteration analysis was observed in the cBioPortal web. GO and KEGG analyses were conducted to elucidate the underlying mechanisms. Finally, the correlation between zc3h12d and tumor-infiltrating immune cells in LUAD was investigated by TIMER database. The B cells level was investigated by flow cytometry analysis of peripheral blood from our LUAD cohort.Results: Zc3h12d expression was significantly higher in LUAD, compared with adjacent normal tissues. The clinical data from the UALCAN database demonstrated that zc3h12d expression was closely related with cancer stage and nodal metastasis. However, patient sample detection revealed that zc3h12d expression was closely related to pathological N (p = 0.0431) and grade (p = 0.004). Moreover, low zc3h12d expression was associated with poorer overall survival in LUAD. We analyzed the methylation level of zc3h12d in LUAD and found that the methylation levels of zc3h12d promoter in LUAD were significantly reduced. In addition, zc3h12d genetic alterations, including deep deletion, could be found in LUAD. GO and KEGG pathway analysis results indicated that zc3h12d has a certain value in immune infiltration. We investigated the expression of zc3h12d in tumor-immune interactions. It was found that zc3h12d might be associated with the immune infiltration and markers of infiltrating immune cells of LUAD. The results of patient sample detection confirmed that B cells level was significantly lower in the patients with low zc3h12d expression than those in the patients with high zc3h12d expression.Conclusion: zc3h12d might be considered as a potential biomarker for determining prognosis and immune-related therapeutic target in LUAD.Keywords: zc3h12d, lung adenocarcinoma, hypomethylation, tumor microenvironment, prognosis

Purpose: To investigate the influence of a combination of abiraterone and prednisone on serum chromogranin A (CgA) and neuron-specific enolase (NSE) in patients with metastatic castrationresistant prostate cancer (mCRPC) without previous chemotherapy, so as to provide reference data for drug therapy of prostate cancer. Methods: A total of 103 mCRPC patients without chemotherapy from January 2013 to March 2017 were included in this retrospective study. Seventy-one (71) patients received prednisone combined with abiraterone (study group), while 32 patients accepted prednisone (control group). The CgA, NSE and prostate-specific antigen (PSA) in the two groups were monitored, while PSA progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS) were determined during follow-up. Results: PSA-PFS, rPFS and OS in the study group were significantly higher than those in the control group (p < 0.05). The increased proportion of CgA or NSE in the study group was significantly lower than that in the control group at 6 months of treatment (p < 0.05). The occurrences of NED before treatment and 6 months after treatment were both independent predictors of PSA and radiographic progression in the study group (p < 0.05). Conclusion: The combination of prednisone and abiraterone is helpful for prognosis in mCRPC patients that are not on chemotherapy. The occurrence of NED predicts mostly poor prognosis of mCRPC patients on a combination of abiraterone and prednisone

PURPOSE: TUBB8 is a gene that is frequently analysed in the genetic diagnosis of female infertility; 102 variants of this gene have been identified. However, the evaluation of its pathogenicity and the resulting phenotypes vary. Here, we aimed to identify novel TUBB8 variants as well as to summarize the reported variants and phenotypes in order for them to be included in genetic counselling analyses. METHODS: We performed whole exome sequencing to screen for candidate variants in 100 infertile female subjects and 100 controls who were able to conceive naturally. All variants were confirmed by Sanger sequencing. The effects of the variants in oocytes/arrested embryos were assessed by morphological observations, polar body biopsies, and chromosome analysis. A molecular modelling analysis was used to evaluate the possible effects of variants on protein secondary structure. RESULTS: We identified 29 TUBB8 variants, of which 20 were novel and five were maternally inherited. We identified three of a total of six recurrent variants that were specific for complete cleavage failure. Moreover, we obtained evidence that TUBB8 variants with large polar bodies had chromosome segregation errors. CONCLUSIONS: Our study expands the spectrum of TUBB8 variants, particularly for embryonic arrest. Together with the extant knowledge of TUBB8 variants, this study provides a foundation for the genetic counselling of female infertility. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02219-9.

The function of Casein kinase 2 beta (CSNK2B) in human malignancies has drawn increasing attention in recent years. However, its role in colorectal cancer (CRC) remains unclear. In the present study, we aimed to explore the expression and biological functions of CSNK2B in CRC. Public gene expression microarray data from online database and immunohistochemistry analysis demonstrated that CSNK2B was highly expressed in CRC tissues than in normal tissues. In vitro and in vivo cellular functional experiments showed that increased CSNK2B expression promoted CRC cell viability and tumorigenesis of CRC. Further western blots and rescue experiments confirmed that CSNK2B promoted CRC cell proliferation mainly by activating the mTOR signaling pathway. These findings identified CSNK2B as a novel oncogene contributing to the development of CRC.

To investigate the potential benefits of acarbose therapy on cardiovascular events (CVD) in Type 2 diabetes (T2DM) in an urban community over 10-year follow-up. The study population of Beijing Community Diabetes Study (BCDS) were type 2 diabetes (T2DM) living in 21 communities in Beijing. All patients received comprehensive intervention in accordance with the Chinese guidelines for the prevention and treatment of diabetes. Professors in endocrinology from top tier hospitals regularly visited the communities for consultations, which was a feature of this study. A total of 1797 T2DM in BCDS study had complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose continuous therapy. After 10-year follow-up, the risks of CVD outcomes were assessed according to whether patients had received acarbose therapy or not. All patients were followed-up to assess the long-term effects of the multifactorial interventions. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. From the beginning of 8th year follow-up, the joint target control rate in patients with acarbose therapy was significantly higher than that of acarbose therapy free. During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events. The incidences of myocardial infarction (from the 4th year of follow-up) and all-cause death (from the 2nd year of follow-up) in patients who received acarbose therapy were significantly lower than that of acarbose therapy free respectively. In Cox multivariate analyses, there were significant differences in incidences of myocardial infarction and all-cause death between afore two groups during the 10-year follow-up, and the adjusted HRs were 0.50 and 0.52, respectively. After multifactorial interventions, T2DM with acarbose therapy revealed significant reductions of myocardial infarction and all-cause death. The long-term effects of with acarbose therapy on improving joint target control might be one of the main reasons of myocardial infarction and all-cause death reduction.Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090.

Background Mesenchymal stem cells (MSCs) have shown great potential in the treatment of cardiovascular diseases, with fat being a more accessible source of MSCs. This study investigated the effect of human adipose-derived mesenchymal stem cells (hMSCs-Ad) exosomes on T lymphocytes and its role in atherosclerosis (AS). Methods The exosomes were preliminarily isolated hMSCs-Ad and co-cultured with human H9 T lymphocytes. The effects of hMSCs-Ad exosomes on the proliferation and apoptosis of H9 were examined by performing functional experiments. The serum lipid level and inflammatory factor level in tail vein of mice were measured by biochemical analyzer and enzyme linked immunosorbent assay (ELISA) respectively. Results The hMSCs-Ad-derived exosomes up-regulate the expression of micro (mi)R-125b-1-3p in H9 and AS arterial tissues. miR-125b-1-3p shared a targeted binding site with B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B gene (BCL11B). miR-125b-1-3p negatively regulated the expression of BCL11B in H9, and that knocking down BCL11B in H9 promoted its apoptosis. Injection of hMSCs-Ad-derived exosomes via the tail vein effectively reduced blood lipid and inflammatory factors, and that relieved the symptoms of AS in AS model mice. Conclusions miR-125b-1-3p was expressed in hMSCs-Ad exosomes and can promote T lymphocyte apoptosis and alleviate AS by down-regulating BCL11B expression. It provides potential molecular targets for the clinical treatment of AS.

To introduce sub-adventitial divestment technique (SDT), a procedure to remove the tumor while preserving the artery during curative pancreatectomy. Peri-operative safety profile was also evaluated. In a single center consecutive series of pancreatectomy for pancreatic cancer, the outcome of patients who had pancreatectomy with SDT was compared to standard pancreatic surgery. From June 2014 to June 2016, 72 patients had pancreatectomy with SDT and 235 had standard surgery. Tumor stage was T4 in all 72 (100%) tumors removed using SDT compared to four (2%) with standard pancreatectomy (p

BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has adversely affected diagnosis and treatment of noncommunicable diseases. Its effects on delivery of diagnostic care for cardiovascular disease, which remains the leading cause of death worldwide, have not been quantified. OBJECTIVES The study sought to assess COVID-19`s impact on global cardiovascular diagnostic procedural volumes and safety practices. METHODS The International Atomic Energy Agency conducted a worldwide survey assessing alterations in cardiovascular procedure volumes and safety practices resulting from COVID-19. Noninvasive and invasive cardiac testing volumes were obtained from participating sites for March and April 2020 and compared with those from March 2019. Availability of personal protective equipment and pandemic-related testing practice changes were ascertained. RESULTS Surveys were submitted from 909 inpatient and outpatient centers performing cardiac diagnostic procedures, in 108 countries. Procedure volumes decreased 42% from March 2019 to March 2020, and 64% from March 2019 to April 2020. Transthoradc echocardiography decreased by 59%, transesophageat echocardiography 76%, and stress tests 78%, which varied between stress modalities. Coronary angiography (invasive or computed tomography) decreased 55% (p < 0.001 for each procedure). hi multivariable regression, significantly greater reduction in procedures occurred for centers in countries with lower gross domestic product. Location in a low-income and lower-middle-income country was associated with an additional 22% reduction in cardiac procedures and less availability of personal protective equipment and teteheatth. CONCLUSIONS COVID-19 was associated with a significant and abrupt reduction in cardiovascular diagnostic testing across the globe, especially affecting the world's economically challenged. Further study of cardiovascular outcomes and COVID-19-related changes in care delivery is warranted. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Pancreatic cancer (PAAD) is a common malignancy with a poor survival rate. The identification of novel biomarkers could improve clinical outcomes for patients with PAAD. Here we evaluated the expression and clinical significance of PPP1CB in PAAD. PPP1CB expression was higher in PAAD tissue than in matched paracancerous tissue (P, Graphical abstract

Tetraspanin CD63 has been widely implicated in tumour progression of human malignancies. However, its role in the tumorigenesis and metastasis of hepatocellular carcinoma (HCC) remains unclear yet. In the present study, we aimed to investigate the specific function and underlying mechanisms of CD63 in HCC progression. CD63 expression in HCC tissues was detected using immunohistochemistry and quantitative real‐time PCR analyses; effects of CD63 on HCC cell proliferation and migration were investigated by CCK‐8 assay, colony formation assay, transwell assay and a xenograft model of nude mice. RNA‐sequencing, bioinformatics analysis, dual‐luciferase reporter assay and Western blot analysis were performed to explore the underlying molecular mechanisms. Results of our experiments showed that CD63 expression was frequently reduced in HCC tissues compared with adjacent normal tissues, and decreased CD63 expression was significantly associated with larger tumour size, distant site metastasis and higher tumour stages of HCC. Overexpression of CD63 inhibited HCC cell proliferation and migration, whereas knockdown of CD63 promoted these phenotypes. IL‐6, IL‐27 and STAT3 activity was regulated by CD63, and blockade of STAT3 activation impaired the promotive effects of CD63 knockdown on HCC cell growth and migration. Our findings identified a novel CD63‐IL‐6/IL‐27‐STAT3 axis in the development of HCC and provided a potential target for the diagnosis and treatment of this disease.

ObjectiveImpaired hepatic fatty acids oxidation results in lipid accumulation and redox imbalance, promoting the development of fatty liver diseases and insulin resistance. However, the underlying pathogenic mechanism is poorly understood. Krüppel-like factor 16 (KLF16) is a transcription factor that abounds in liver. We explored whether and by what mechanisms KLF16 affects hepatic lipid catabolism to improve hepatosteatosis and insulin resistance.DesignKLF16 expression was determined in patients with non-alcoholic fatty liver disease (NAFLD) and mice models. The role of KLF16 in the regulation of lipid metabolism was investigated using hepatocyte-specific KLF16-deficient mice fed a high-fat diet (HFD) or using an adenovirus/adeno-associated virus to alter KLF16 expression in mouse primary hepatocytes (MPHs) and in vivo livers. RNA-seq, luciferase reporter gene assay and ChIP analysis served to explore the molecular mechanisms involved.ResultsKLF16 expression was decreased in patients with NAFLD, mice models and oleic acid and palmitic acid (OA and PA) cochallenged hepatocytes. Hepatic KLF16 knockout impaired fatty acid oxidation, aggravated mitochondrial stress, ROS burden, advancing hepatic steatosis and insulin resistance. Conversely, KLF16 overexpression reduced lipid deposition and improved insulin resistance via directly binding the promoter of peroxisome proliferator-activated receptor α (PPARα) to accelerate fatty acids oxidation and attenuate mitochondrial stress, oxidative stress in db/db and HFD mice. PPARα deficiency diminished the KLF16-evoked protective effects against lipid deposition in MPHs. Hepatic-specific PPARα overexpression effectively rescued KLF16 deficiency-induced hepatic steatosis, altered redox balance and insulin resistance.ConclusionsThese findings prove that a direct KLF16–PPARα pathway closely links hepatic lipid homeostasis and redox balance, whose dysfunction promotes insulin resistance and hepatic steatosis.

BackgroundFat mass and obesity-associated (FTO) gene is an obesity susceptibility gene and its relationship with the nonalcoholic fatty liver disease (NAFLD) remains unclear. This study aims to investigate the relationships of FTO gene variations with NAFLD risk in a Chinese male population.MethodsA 1:2 matched case–control study was performed on 275 cases of NAFLD and 550 controls matched for age. Nine of the FTO gene single nucleotide polymorphisms (SNPs) were genotyped.ResultsLogistic regression analysis found that FTO rs1477196 was significantly associated with the susceptibility to NAFLD in recessive genetic models [unadjusted odds ratio (OR) = 2.52, 95% confidence interval (CI): 1.22–5.19, P = 0.012] and the relativity weakened after further adjustment for body mass index (BMI), uric acid, metabolic syndrome, smoking, and drinking (adjusted OR = 2.18, 95% CI: 0.96–4.99, P = 0.06). In the obese group, the AA + AG genotypes of rs1121980 and rs9940128 were associated with a decreased risk of NAFLD, when compared with the GG genotype, respectively (rs1121980: adjusted OR = 0.62, 95% CI = 0.39–0.99, P = 0.044; rs9940128: adjusted OR = 0.61, 95% CI = 0.38–0.97, P = 0.038). Furthermore, rs1477196 was associated with the severity of NAFLD (OR = 2.95, 95% CI = 1.09–7.94, P = 0.034).ConclusionsOur results demonstrated that the FTO gene was related to the presence and severity of NAFLD in a Chinese male population, and the relationships of the tested SNPs with NAFLD are most probably mediated by BMI.

Poor prognosis of esophageal cancer is associated with limited clinical treatment efficacy and lack of targeted therapies. With advances in nanomedicine, nanoparticle drug delivery systems play increasingly important roles in tumor treatment by enabling the simultaneous delivery of multiple therapeutic agents. We here propose a novel nanovector for targeted combination gene therapy and chemotherapy in esophageal cancer. A novel lipid nanovector (EYLN) was designed to carry the chemotherapy drug doxorubicin (Dox) and small interfering RNA against the lipid anabolic metabolism gene LPCAT1, which we previously showed to be significantly overexpressed in esophageal cancer tissues, and its interference inhibited the proliferation, invasion, and metastasis of esophageal cancer cells. This vector, EYLN-Dox/siLPCAT1, was further coated with leukocyte membranes to obtain mEYLNs-Dox/siLPCAT1. The particle size of the coated nanovector was approximately 136 nm, and the surface zeta potential was -21.18 mV. Compared with EYLNs-Dox/siLPCAT1, mEYLNs-Dox/siLPCAT1 were more easily internalized by esophageal cancer cells due to the LFA-1 highly expressed leukocyte membrane coating and showed significant inhibition of the proliferation, migration, and metastasis of esophageal cancer cells, along with their LPCAT1 expression, through more effective delivery of the drugs. Moreover, the nanovectors showed improved blood circulation time, tissue distribution, tumor targeting, and tumor suppression in a mouse model. Thus, combining chemo and gene therapy with this new nanodelivery system achieved greater therapeutic efficacy, providing a new strategy for the treatment of esophageal cancer.

STUDY QUESTION Whether the testis-specific extracellular vesicle (EV) long noncoding RNAs (lncRNAs) in seminal plasma could be utilized to predict the presence of testicular spermatozoa in nonobstructive azoospermia (NOA) patients? SUMMARY ANSWER Our findings indicate that the panel based on seminal plasma EV lncRNAs was a sensitive and specific method in predicting the presence of testicular spermatozoa and may improve clinical decision-making of NOA. WHAT IS KNOWN ALREADY The adoption of sperm retrieval techniques, especially microdissection testicular sperm extraction (mTESE), in combination with ICSI has revolutionized treatment for NOA. However, there are no precise and noninvasive methods for predicting whether there are testicular spermatozoa in NOA patients before mTESE. STUDY DESIGN, SIZE, DURATION RNA sequencing was performed on seminal plasma EVs from 6 normozoospermic men who underwent IVF due to female factor and 5 idiopathic NOA patients who failed to obtain testicular spermatozoa by mTESE and were diagnosed as having Sertoli cell-only syndrome by postoperative pathology. A biomarker panel of lncRNAs was constructed and verified in 96 NOA patients who underwent mTESE. Decision-making process was established based on the panel in seminal plasma EVs from 45 normozoospermia samples, 43 oligozoospermia samples, 62 cryptozoospermia samples, 96 NOA samples. PARTICIPANTS/MATERIALS, SETTING, METHODS RNA sequencing was done to examine altered profiles of EV lncRNAs in seminal plasma. Furthermore, a panel consisting of EV lncRNAs was established and evaluated in training set and validation sets. MAIN RESULTS AND THE ROLE OF CHANCE A panel consisting of nine differentially expressed testis-specific lncRNAs, including LOC100505685, SPATA42, CCDC37-DT, GABRG3-AS1, LOC440934, LOC101929088 (XR_927561.2), LOC101929088 (XR_001745218.1), LINC00343 and LINC00301, was established in the training set and the AUC was 0.986. Furthermore, the AUC in the validation set was 0.960. Importantly, the panel had a unique advantage when compared with models based on serum hormones from the same group of NOA cases (AUC, 0.970 vs 0.723; 0.959 vs 0.687, respectively). According to the panel of lncRNAs, a decision-making process was established, that is when the score of an NOA case exceeds 0.532, sperm retrieval surgery may be recommended. LIMITATIONS, REASONS FOR CAUTION In the future, the sample size needs to be further expanded. Meanwhile, the regulatory functions and mechanism of lncRNAs in spermatogenesis also need to be elucidated. WIDER IMPLICATIONS OF THE FINDINGS When the score of our panel is below 0.532, subjecting the NOA patients to ineffective surgical interventions may not be recommended due to poor sperm retrieval rate. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China (81871110, 81971314 and 81971759); the Guangdong Special Support Plan-Science and Technology Innovation Youth Top Talents Project (2016TQ03R444); the Science and Technology Planning Project of Guangdong Province (2016B030230001 and 201707010394); the Key Scientific and Technological Program of Guangzhou City (201604020189); the Pearl River S&T Nova Program of Guangzhou (201806010089); the Transformation of Scientific and Technological Achievements Project of Sun Yat-sen University (80000-18843235) and the Youth Teacher Training Project of Sun Yat-sen University (17ykpy68 and 18ykpy09). There are no competing interests related to this study. TRIAL REGISTRATION NUMBER N/A.

Patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) cancers are prone to response to programmed cell death-1 (PD-1) checkpoint inhibitors. Therefore, we explored the efficacy and safety of a PD-1 checkpoint inhibitor camrelizumab in advanced or metastatic solid tumour with dMMR/MSI-H. Patients with dMMR/MSI-H advanced or metastatic solid tumours who had received at least one line of prior systemic chemotherapy were recruited. Camrelizumab was given intravenously 200 mg every 2-week treatment cycle. The primary endpoint was objective response rate according to Response Evaluation Criteria in Solid Tumours v1.1. Twelve patients were enrolled. As data cutoff, eight patients (66.7%, 95% CI 34.9–90.1) achieved objective response. Disease control rate reached 100% (95% CI 73.5–100). Progression-free survival rate at 12 months was 83.3% (95% CI 48.2–95.6), and overall survival rate at 12 months was 90% (95% CI 47.3–98.5). The most common treatment-related adverse events were reactive cutaneous capillary endothelial proliferation (100%), increased alanine aminotransferase (41.7%), and increased aspartate aminotransferase (41.7%). Camrelizumab provided durable objective response and disease control in pre-treated patients with dMMR/MSI-H advanced or metastatic solid tumour, being a promising treatment option for these patients.

Background. Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. Methods. CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. Results. Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF compared with the corresponding tumor tissue samples (3.56 ± 0.75 vs. 2.22 ± 0.32, P = 0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.1% ± 6.0% vs. 73.8% ± 6.0%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3 histone, family 3A (H3F3A) which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. Conclusion. Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

This paper explores the diagnostic value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for the prognosis of glioma, and judges the relevant factors affecting the prognosis of glioma. This paper used a Cox proportional hazards model to retrospectively analyze clinical data of 81 patients with complete neuroglioma from the same neurosurgery medical team from January 2012 to November 2018, including DCE-MRI data. To determine the prognostic factors, P < 0.05 was used as the statistical standard, and the survival curve of statistically significant factors was drawn by Kaplan-Meier method. The Cox proportional hazard model analysis showed the preoperative Karnofsky Performance Status Scale (KPS) score, age, tumor pathologic grade, postoperative radiotherapy, temozolomide use, and Ki-67 expression had an impact on the prognosis of patients with neuroglioma. Multivariate analysis and DCE-MRI data showed that age, tumor grade, preoperative KPS score, postoperative radiotherapy, and Ki-67 expression were prognostic factors for patients with glioma. The older the age, the higher the pathologic grade, the higher the Ki-67 expression level, and the lower the KPS score before surgery, the worse the prognosis. Postoperative radiotherapy and appropriate temozolomide chemotherapy will help improve the prognosis of patients with neuroglioma.

Two anti-thymocyte globulin (ATG) forms are used in graft-versus-host disease (GVHD) prophylaxis during haploidentical hematopoietic stem cell transplantations (haplo-HSCTs): ATG-thymoglobulin (ATG-T) and ATG-fresenious (ATG-F). However, comparable dosages for haplo-HSCT remain unclear. We compared and evaluated the effects of ATG-T (7.5 mg/kg) or ATG-F (20 mg/kg) dosages in a relatively homogenous population in haplotype HSCT settings. Patients administered ATG-T 7.5 mg/kg (n = 81) or ATG-F 20 mg/kg (n = 35) as part of GVHD prophylaxis during haplo-HSCT were enrolled. Incidence and severity of GVHD, Epstein–Barr virus (EBV) infection, and immune cell recovery were compared using the Mann-Whitney U rank test and chi-square test. Cumulative incidences of GVHD, EBV infection and its subgroups, and relapse mortality were computed; overall survival (OS) was analyzed using the Kaplan-Meier method, with the log-rank test used for univariate comparison. Risk factors for OS were analyzed by the Cox proportional hazards model. Incidence and cumulative incidence of all grades of acute GVHD and subgroups were comparable in both groups (all p > 0.05); however, cumulative incidence of any grade and limited chronic GVHD was significantly higher in the ATG-T group (p = 0.002, p = 0.007, respectively). Cumulative incidences of EBV infections, EBV-DNAemia, and EBV-related diseases were similar; relapse mortality and OS rates were comparable between both groups (all p > 0.05). ATG-T dosage (7.5 mg/kg) appeared comparable to ATG-F dosage (20 mg/kg) for haplo-HSCT. Currently approved ATG-T and ATG-F doses appear efficient to balance the risk–benefit ratio of GVHD, OS, relapse mortality, and EBV infection in haplo-HSCT.

Gliomas are the most common primary brain tumors. Because of their high degree of malignancy, patient survival rates are unsatisfactory. Therefore, exploring glioma biomarkers will play a key role in early diagnosis, guiding treatment, and monitoring the prognosis of gliomas. We found two lncRNAs, six miRNAs, and nine mRNAs that were differentially expressed by analyzing genomic data of glioma patients. The diagnostic value of mRNA expression levels in gliomas was determined by receiver operating characteristic (ROC) curve analysis. Among the nine mRNAs, the area under the ROC curve values of only CEP55 and SHCBP1 were >0.7, specifically 0.834 and 0.816, respectively. Additionally, CEP55 and SHCBP1 were highly expressed in glioma specimens and showed increased expression according to the glioma grade, and outcomes of high expression patients were poor. CEP55 was enriched in the cell cycle, DNA replication, mismatch repair, and P53 signaling pathway. SHCBP1 was enriched in the cell cycle, DNA replication, ECM receptor interaction, and P53 signaling pathway. Age, grade, IDH status, chromosome 19/20 cogain, and SHCBP1 were independent factors for prognosis. Our findings suggest the PART1-hsa-miR-429-SHCBP1 regulatory network plays an important role in gliomas.

USP32, a member of the ubiquitin-specific proteases family, has been implicated in the development of breast cancer and small lung cancer. However, its biological functions and clinical significance in gastric cancer (GC) remain unclear. In the present study, we reported that knockdown or depletion of USP32 significantly inhibited GC cell proliferation and migration in vitro and in vivo, indicating that USP32 functions as an oncogene in GC. Importantly, results from immunohistochemical staining in a tissue microarray revealed that USP32 was upregulated in GC tissues compared with paracancerous tissues. Further analyses showed that high expression of USP32 was closely related with high T-staging and poor outcomes of GC patients. Mechanistically, USP32 silencing caused a decrease in the expression of SMAD2, which resulted in the inhibitory effects of GC cells on growth, motility, and chemoresistance to cisplatin. Therefore, our findings strongly suggest the involvement of USP32 in GC progression and provide a potential target for future therapy of GC.

BackgroundRecurrence of liver metastasis after pancreatectomy is often a predictor of poor prognosis. Comprehensive genomic analysis may contribute to a better understanding of the molecular mechanisms of postoperative liver metastasis and provide new therapeutic targets.MethodsA total of 67 patients from The Cancer Genome Atlas (TCGA) were included in this study. We analyzed differentially expressed genes (DEGs) by R package “DESeq2.” Weighted gene co-expression network analysis (WGCNA) was applied to investigate the key modules and hub genes. Immunohistochemistry was used to analyze tumor cell proliferation index and CD4+ T cells infiltration.ResultsFunctional analysis of DEGs between the liver metastatic and recurrence-free groups was mainly concentrated in the immune response. The liver metastasis group had lower immune and stroma scores and a higher TP53 mutation rate. WGCNA showed that the genes in key modules related to disease-free survival (DFS) and overall survival (OS) were mainly enriched in the cell proliferation process and tumor immune response. Immunohistochemical analysis showed that the pancreatic cancer cells of patients with early postoperative liver metastasis had higher proliferative activity, while the infiltration of CD4+ T cells in tumor specimens was less.ConclusionOur study suggested that increased immune cell infiltration (especially CD4+ T cells) and tumor cell proliferation may play an opposite role in liver metastasis recurrence after pancreatic cancer.

BackgroundLimited available evidence implicated that the anthropometric indicators of adiposity may contribute to the predictive and diagnosis capability of non-alcoholic fatty liver disease (NAFLD) in a facile, low-cost and noninvasive way while NAFLD had been entitled as metabolic-dysfunction associated fatty liver disease (MAFLD) in 2020. This study aimed to validate and compare the predictive and diagnostic capability of eight anthropometric indicators in MAFLD individuals and determined an optimal diagnostic predictor for MAFLD, which may beneficial for resource scarce regions.MethodsThe retrospective cross-sectional population-based study conducted from Fangchenggang Area Male Health and Examination Survey (FAMHES) involved 2428 participants whose comprehensive questionnaire, detailed data, anthropometric parameters and biochemical measurements were collected. Eight anthropometric indicators including body mass index (BMI), waist-to-height ratio (WHtR), waist-hip ratio (WHR), body adiposity index (BAI), cardiometabolic index (CMI), lipid accumulation product (LAP), visceral adiposity index (VAI) and Abdominal volume index(AVI) were enrolled into analyzed. Receiver operating characteristic (ROC) curve analysis and the area under the ROC curves (AUCs) were used to compare the diagnostic ability of each indicator for MAFLD and optimal cut-off points fully determined. Binary logistic regression analysis was used to explore associations of all anthropometric indicators and MAFLD by determined the odds ratios (ORs) and 95% confidence interval (CI).ResultsAll selected anthropometric indicators were substantially associated with MAFLD (p ) and their diagnostic value of MAFLD by AUCs fully above 0.79. WHtR [OR 22.181(95%CI, 16.216–30.340)] had the strongest association with MAFLD, regardless of potential confounders. LAP had the largest AUC [0.868(95%CI 0.853–0.883)], intimately followed by WHtR [0.863(95%CI 0.848–0.879)]. AVI with OR 19.275(95%CI 14.266–26.041) and AUC 0.859 (95% CI 0.843–0.874) ranked second and third respectively among all indicators. The cut-off points of WHtR, LAP and AVI were 0.49, 24.29, and 13.61, separately.ConclusionAll eight anthropometric indicators illustrated the superior diagnostic value of MAFLD. Comparatively, WHtR might stressed as the most powerful diagnostic predictor for MAFLD, follow by LAP and AVI which presented highly potential as well.

Acute kidney injury (AKI) may develop in patients with coronavirus disease 2019 (COVID‐19) and is associated with in‐hospital death. We investigated the incidence of AKI in 223 hospitalized COVID‐19 patients and analyzed the influence factors of AKI. The incidence of cytokine storm syndrome and its correlation with other clinicopathologic variables were also investigated. We retrospectively enrolled adult patients with virologically confirmed COVID‐19 who were hospitalized at three hospitals in Wuhan and Guizhou, China between February 13, 2020, and April 8, 2020. We included 124 patients with moderate COVID‐19 and 99 with severe COVID‐19. AKI was present in 35 (15.7%) patients. The incidence of AKI was 30.3% for severe COVID‐19 and 4.0% for moderate COVID‐19 (p

Despite the discovery that the human immunodeficiency virus 1 (HIV-1) is the pathogen of acquired immunodeficiency syndrome (AIDS) in 1983, there is still no effective anti-HIV-1 vaccine. The major obstacle to the development of HIV-1 vaccine is the extreme diversity of viral genome sequences. Nonetheless, a number of broadly neutralizing antibodies (bNAbs) against HIV-1 have been made and identified in this area. Novel strategies based on using these bNAbs as an efficacious preventive and/or therapeutic intervention have been applied in clinical. In this review, we summarize the recent development of bNAbs and its application in HIV-1 acquisition prevention as well as discuss the innovative approaches being used to try to convey protection within individuals at risk and being treated for HIV-1 infection.

Introduction: Metastatic (m) colorectal cancer (CRC) can be divided into specific subgroups under the ‘one gene, one drug’ paradigm of precision medicine. Progress of targeted therapy in mCRC patie...

Objective:To explore parents’ knowledge, attitudes and behaviours regarding sugar-sweetened beverages (SSBs, e.g. soft drinks, juice drinks, sports drinks) and other beverages provided by parents at youth sports events.Design:Qualitative analysis of focus group discussions.Setting:Ada County, Idaho, USA.Method:A total of 3 focus groups were conducted with 24 parents of 6- to 11-year-old children participating in one community recreational soccer league. Parents were asked how they selected beverages for their children at soccer practices and games, and shared ideas for improving healthy beverage consumption in this setting. Two coders performed an inductive content analysis of the focus group transcripts, and an external reviewer established the trustworthiness of the data.Results:Parents expressed uncertainty about which beverages other than water were best for children’s health and performance. Beverage choices were affected by factors such as cost, convenience, the weather, the level of competition and children’s ages. Parents also noted the influence of coaches, other parents, their children’s preferences, their beverage habits at home and the media. Parents desired evidence-based guidance on optimal beverages for youth athletes and recommended specific interventions to reduce consumption of SSBs in the context of youth sport events.Conclusion:Results indicate the need for developmentally appropriate expert recommendations for healthy beverage consumption in recreational youth sport, and reinforce findings from existing research which suggest that parents desire support to ensure healthy beverages are offered at youth sports events.

Targeted therapy and immunotherapy have changed the treatment modes for advanced non-small cell lung cancer (NSCLC), moving from second-line to first-line treatment and significantly extending patients' survival. Surgery and chemoradiotherapy remain the main treatment options for patients with locally advanced lung cancer, but recurrence and metastasis still occur in some patients. The survival rates of conventional perioperative chemotherapy among NSCLC patients have increased by only 5%. Therefore, more studies have begun to explore targeted and immune neoadjuvant/adjuvant therapies in early-stage and locally advanced NSCLC, and the relevant clinical research data have shown good efficacy and safety profiles. This article summarizes several clinical studies of critical importance.

Background Cancer neoantigens are expressed only in cancer cells and presented on the tumor cell surface in complex with major histocompatibility complex (MHC) class I proteins for recognition by cytotoxic T cells. Accurate and rapid identification of neoantigens play a pivotal role in cancer immunotherapy. Although several in silico tools for neoantigen prediction have been presented, limitations of these tools exist. Results We developed pTuneos, a computational pipeline for prioritizing tumor neoantigens from next-generation sequencing data. We tested the performance of pTuneos on the melanoma cancer vaccine cohort data and tumor-infiltrating lymphocyte (TIL)-recognized neopeptide data. pTuneos is able to predict the MHC presentation and T cell recognition ability of the candidate neoantigens, and the actual immunogenicity of single-nucleotide variant (SNV)-based neopeptides considering their natural processing and presentation, surpassing the existing tools with a comprehensive and quantitative benchmark of their neoantigen prioritization performance and running time. pTuneos was further tested on The Cancer Genome Atlas (TCGA) cohort data as well as the melanoma and non-small cell lung cancer (NSCLC) cohort data undergoing checkpoint blockade immunotherapy. The overall neoantigen immunogenicity score proposed by pTuneos is demonstrated to be a powerful and pan-cancer marker for survival prediction compared to traditional well-established biomarkers. Conclusions In summary, pTuneos provides the state-of-the-art one-stop and user-friendly solution for prioritizing SNV-based candidate neoepitopes, which could help to advance research on next-generation cancer immunotherapies and personalized cancer vaccines. pTuneos is available at https://github.com/bm2-lab/pTuneos, with a Docker version for quick deployment at https://cloud.docker.com/u/bm2lab/repository/docker/bm2lab/ptuneos.

Background Budd-Chiari syndrome (BCS) is a rare disorder that has relatively high prevalence in the Huang-Huai area of China. Effective treatment of BCS accompanied with inferior vena cava thrombosis is challenging. Objective This study retrospectively analyzed the clinical effectiveness and safety of traditional open operations versus preopening and staged percutaneous transluminal angioplasty (PTA) of the inferior vena cava in treating BCS accompanied with inferior vena cava thrombosis. Methods Data from patients hospitalized and treated for BCS accompanied with inferior vena cava thrombosis between January 1997 and December 2017 were retrospectively analyzed. Thirty-two patients received traditional open operation (open group). Fifty-six patients received preopening and staged PTA of the inferior vena cava (PTA group). Baseline and clinical data were compared between groups. The patients were followed for up to 60 months. Postoperative recurrence rates and restenosis degree were recorded. Results Eighty-eight patients were included (47 males and 41 females), aged 41.82 ± 10.12 years (range 29–65). In the open group, no pulmonary arterial embolism was found during and after the operation, and the technique success rate was 100%. One patient died of intrathoracic bleeding. In the PTA group, 2 patients had shifting of thrombus in the inferior vena cava that blocked the blood flow restored by the preopening, one resulted in treatment failure, while the other had blood flow restored by dilation with a 12-mm balloon; the success rate was 55/56 (98.21%). The median follow-up time was 32 months (range 3–60). Two patients in the open group developed restenosis 2 years after operation (recurrence rate: 6.25%), and were successfully treated by balloon PTA. Seven patients in the PTA group had severe restenosis 18–42 months after operation (recurrence rate: 12.96%). No thrombosis was found in these 7 patients, and normal blood flow was restored in the inferior vena cava after balloon PTA. Conclusions Preopening and staged PTA of the inferior vena cava is a safe and simple method for the treatment of BCS accompanied with inferior vena cava thrombosis, with satisfactory treatment effectiveness that could be applied in clinical practice.

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Weaning is a critical period for the growth and development of mammals, in which various physiological and biochemical indicators of the body have undergone great changes. The development, differentiation, and maturation of the nervous system are regulated by many proteins. Changes in related proteins affect the physiological functions of the nervous system. However, the regulation of selfrenewal and differentiation of the nervous system at this stage is still poorly understood. The mechanism of differentiation and regulation of the major proteins in the nervous system during this special period of weaning remains to be investigated. Therefore, this paper aims to summarize the alteration of the nervous system during weaning and provide the basis for subsequent research.

Weaning is a stressful event associated with gastrointestinal disorders and increased disease susceptibility. Many studies have reported the changes that happened in the gut of various mammals such as pigs and rats after weaning. These findings suggest that the development of intestinal tract mainly is affected at the time of weaning through interfering in the differentiation and proliferation of intestinal stem cells. Weaning stress stimulates the rapid differentiation and proliferation of intestinal stem cells in order to adjust to changes caused by weaning, which are mainly manifested as deeper crypt depth and decreased intestine villus height. However, the accelerated cellular process may lead to an increase in the proportion of immature intestinal epithelial cells and goblet cells, which affect intestinal permeability and reduce the gut-barrier function against toxins and pathogens. This review briefly describes the effects coforticotrophin-releasing factor (CRF), epidermal growth factor (EGF) and polyamines on the differentiation and proliferation of intestinal stem cells after weaning and discusses its possible underlying regulatory mechanisms. Firstly, weaning stress activates CRF to binds its receptors, which induces proinflammatory responses and promote rapid differentiation and proliferation of intestinal stem cells to a larger fraction of immature intestinal epithelial cells and goblet cells. Secondly, the lack of EGF after weaning inhibits the expression of goblet cell maturation factors and makes it difficult for goblet cells and intestinal epithelial cells to mature. Finally, diet and endogenous synthesis lead to excessive polyamines in the intestine, which promote the proliferation of intestinal stem cells by regulating the expression of human antigen R (HuR) and other related genes at the time of weaning.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, and its incidence is increasing annually. It is critical to reveal and delineate the molecular mechanism promoting PDAC development and progression. Mammalian STE20-like kinase 1 (MST1) is a proapoptotic cytoplasmic kinase and also one of the core components of the Hippo pathway. Here, we showed that MST1 expression was decreased in PDAC, and restored expression of MST1 promoted PDAC cell death and suppressed the proliferation, migration, invasion, and cell spheroid formation of PDAC via caspase-1–induced pyroptosis. Further studies demonstrated that pyroptosis induced by MST1 was independent of the Hippo pathway, but mediated by reactive oxygen species (ROS). And ROS scavenger N-acetyl-cysteine attenuated the activation of caspase-1 induced by MST1 and the effect of MST1 in PDAC cell death, proliferation, migration, and invasion. Collectively, our study demonstrated that MST1 suppressed the progression of PDAC cells at least partly through ROS-induced pyroptosis. Implications: In this study, we identified a new mechanism of MST1 in inhibiting PDAC development and progression and revealed that MST1 would be a potential prognostic and therapeutic target for PDAC.

Angiogenesis is central to a wide range of physiological and pathological processes including wound healing, macular degeneration, and cancer. Excessive or inappropriate vascular supply of tumors is one of the main targets for cancer therapy. Recently, critical and selective transcriptional factors such as yes-associated protein (YAP) that control the expression of angiogenesis factors have gained increasing attention in antiangiogenic therapy. In this study, we have identified and characterized a novel inhibitor of YAP, gambogic acid (GA), which exerted striking antiangiogenic effects both in vitro and in vivo. We demonstrated that GA remarkably inhibited a variety of vascular endothelial growth factor-induced angiogenesis processes including proliferation, migration, sprouting, and tube formation of endothelial cells in vitro. In addition, GA resulted in decreased neo-vessel formation in Matrigel plugs of mice and chick chorioallantoic membrane. More importantly, we showed that GA limited tumor growth via preventing tumor angiogenesis and vascular maturation. Further mechanistic studies illustrated that GA directly targeted YAP/STAT3 signaling axis, which is critical for the transcriptional regulation of a series of angiogenic factors. Taken together, these preclinical findings suggest that GA significantly repressed tumor angiogenesis and may serve as a promising drug candidate against cancer.

Study Design Retrospective analysis of clinical records. Objective To determine the efficacy of transpedicular wedge resection osteotomy (TWRO) of the apical vertebrae to treat severe and rigid thoracic kyphoscoliosis in 26 adults. Summary of Background Data Although posterior vertebral column resection has traditionally been used to correct severe and rigid kyphoscoliosis, TWRO may achieve the same correction with a shorter operative time and lower rate of complications. Methods Between May 2011 and December 2014, 29 adults underwent a TWRO of the apical vertebrae for severe and rigid thoracic kyphoscoliosis, and 26 adults completed the 24-month follow-up. Radiologic measurements, including coronal plane major curve, kyphotic curve, coronal offset, and sagittal offset, were measured and compared. The following patient-reported health-related quality of life outcomes, including Oswestry Disability Index score, visual analog scale score for back pain, and SRS-22 questionnaire, were used to evaluate the clinical outcomes. Results For the 26 patients followed over 24 months, the mean coronal plane major curve improved from 107.6° to 37.5° immediately after surgery and to 40.0° at 24 months postoperatively. The mean kyphotic curve improved from 90.6° to 30.5° immediately after surgery and to 33.3° at 24 months postoperatively. The mean coronal offset and sagittal offset were also improved. Improved self-reported quality of life scores were achieved postoperatively and at 24 months postoperatively, including all domains of the SRS-22 questionnaire. Bony fusion was achieved at 6 or 12 months in all patients. Unilateral leg paresis occurred in one case and recovered after three months, with a neurologic complication rate of 3.8%. Conclusions TWRO of the apical vertebrae as a treatment for severe and rigid thoracic kyphoscoliosis in adult patients provided excellent clinical outcomes. However, the procedure remains technically demanding and exhausting, with a potential risk for complications. Level of Evidence Level IV.

Central pancreatectomy (CP) has been applied for treating benign and low-grade malignant tumors in pancreatic neck, but studies regarding CP for pancreatic ductal adenocarcinoma (PDAC) are quite limited. We aimed to investigate the role of central pancreatectomy in the treatment of PDAC in the neck of the pancreas. Patients who underwent CP at our hospital between 2009 and 2016 were identified. Patients treated by distal pancreatectomy (DP) were matched according to the tumor size, location, and staging. The surgical and survival outcomes were compared between the CP and DP groups. Nine patients had CP. Five (56%) had postoperative complications and three (33%) had clinically significant (grade B + C) fistula. No significant difference was found between the CP and DP groups for the rate of overall morbidity, pancreatic fistula, reoperation, and readmission. Tumor size was smaller in the CP group compared to the DP group. The mortality of both groups was zero. The median postoperative survival was similar between the two groups (20.4 months for CP vs 19.4 months for DP, P = 0.842). CP is safe for patients with small PDAC at the neck of the pancreas. Considering the good preservation of pancreatic endocrine and exocrine functions, CP could be considered as an alternative procedure for single small PDAC in pancreatic neck.

Genetic variants can predict other "linked" diseases because alterations in one or more genes in vivo may affect relevant phenotype properties. Our study systematically explored the pan-cancer common gene and cancer type-specific genes based on GWAS loci and TCGA data of multiple cancers. It was found that there were 17 SNPs were significantly associated with the expression of 18 genes. Associations between the 18 cis-regulatory genes and the pathologic stage of each cancer showed that MYL2 and PTGFR in HNSC, 4 genes (F8, SATB2, G6PD and UGT1A6) in KIRP, 3 genes (CHMP4C, MAP3K1 and MECP2) in LUAD were all strongly associated with cancer stage levels. Additionally, the survival association analysis showed that SATB2 was correlated with HNSC survival, and MPP1 was strongly associated with the survival of SARC. This study will shed light on the biological pathways involved in cancer-genetic associations, and has the potential to be applied to the predictions of the risk of cancers developing in healthy individuals.

BACKGROUND Inferior vena cava (IVC) filters have proven valuable for the prevention of pulmonary embolism. However, retrieval of IVC filters can be challenging and complicated techniques are needed. The aim of this study was to retrospectively review the outcomes after retrieval of retrievable IVC filters which required complicated retrieval techniques. MATERIAL AND METHODS This study was a single-center retrospective observational study. All patients who underwent complicated IVC filter retrieval from September 2012 to May 2016 were included. Patient demographics and filter retrieval procedure were documented. Clinical outcomes and procedure-related complications were evaluated. Villalta score and VEINES-QOL/Sym were recorded to assess post-thrombotic syndrome. RESULTS A total of 79 consecutive patients, 37 males and 42 were female, with a mean age of 46.5 years (age range: 22-65 years) were included in this study. IVC filters, with mean indwell time of 108 days (range: 74-157 days), were refractory to standard treatment and underwent complicated IVC filter retrieval. There were 6 serious procedure-related complications: 4 popliteal puncture area hematoma complications and 2 hematuria complications. With a mean follow‑up of 20.5 months (range: 18-24 months), no pulmonary embolisms occurred, and 2 patients experienced recurrent deep venous thrombosis. Twenty-seven patients developed post-thrombotic syndrome within the first 2 years after IVC retrieval. CONCLUSIONS Complicated methods can be used to safely remove IVC filters, alleviate filter-related morbidity, and reduce risk for post-thrombotic syndrome. The application of these techniques was safe and effective for patients with refractory IVC filters.

Human phosphatidylinositol-4-phosphate adaptor protein-2 (FAPP2) is well-known to function as a cytoplasmic lipid transfer protein during vesicle maturation. However, the expression and role of FAPP2 in tumor remain elusive. In this study, data from immunohistochemical assays displayed that FAPP2 was remarkably upregulated (57.8%) in 90 cases of colon cancer samples in contrast to their corresponding adjacent tissues. Disruption of FAPP2 by CRISPR/Cas9 technique in colon cancer cells led to an attenuated effect on cell growth analyzed by CCK8 and colony formation assays. Meanwhile, the tumorigenicity of FAPP2 downregulated cells also decreased in nude mice model. Accordantly, CCK8 assays also indicated that FAPP2 overexpression could promote colon cancer cell growth. In addition, dual luciferase reporter assays and western blot analyses revealed that Wnt/β-catenin signaling was involved in the FAPP2-regulated tumor cell growth. These findings suggest that FAPP2 could act as an oncogene in the regulation of tumor growth and may provide a new therapeutic target for human colon cancer.

Obesity increases the risk of developing cardiovascular disease and other metabolic diseases. We intended to compare three different anthropometric indicators of obesity, in predicting the incidence of cardiovascular events in Chinese type 2 diabetes. Beijing Community Diabetes Study was a prospective multi-center study conducted in Beijing community health centers. Type 2 diabetes patients from fourteen community health centers were enrolled at baseline. The primary endpoint was cardiovascular events. The upper quartile of neck circumference (NC) was set as greater NC. A total of 3299 diabetes patients were enrolled. In which, 941 (28.52%) had cardiovascular disease at baseline. Logistic analysis showed that central obesity (waist circumference (WC) above 90 cm in men and 85 cm in women) and greater NC were all related to baseline cardiovascular disease (adjusted OR = 1.49, and 1.55). After 10-year follow-up, 340 (10.31%) had cardiovascular events. Compared with patients without cardiovascular events, those having cardiovascular events had higher BMI, larger WC and NC. Cox regression analysis showed that greater WC and NC were all associated with the occurrence of cardiovascular events (adjusted HR = 1.41, and 1.38). A higher NC and WC might increase the risk of cardiovascular events by about 40% in type 2 diabetes patients in Beijing communities.

The prognosis of pancreatic cancer is poor because patients are usually asymptomatic in the early stage and the early diagnostic rate is low. Therefore, in this study, we aimed to identify potential prognosis-related genes in pancreatic cancer to improve diagnosis and the outcome of patients. The mRNA expression profile data from The Cancer Genome Atlas database and GSE79668, GSE62452, and GSE28735 datasets from Gene Expression Omnibus were downloaded. The prognosis-relevant genes and clinical factors were analyzed using Cox regression analysis and the optimal gene sets were screened using the Cox proportional model. Next, the Kaplan-Meier survival analysis was used to evaluate the relationship between risk grouping and patient prognosis. Finally, an optimal gene-based prognosis prediction model was constructed and validated using a test dataset to discriminate the model accuracy and reliability. The results showed that 325 expression variable genes were identified, and 48 prognosis-relevant genes and three clinical factors, including lymph node stage (pathologic N), new tumor, and targeted molecular therapy were preliminarily obtained. In addition, a gene set containing 16 optimal genes was identified and included FABP6, MAL, KIF19, and REG4, which were significantly associated with the prognosis of pancreatic cancer. Moreover, a prognosis prediction model was constructed and validated to be relatively accurate and reliable. In conclusion, a gene set consisting of 16 prognosis-related genes was identified and a prognosis prediction model was constructed, which is expected to be applicable in the clinical diagnosis and treatment guidance of pancreatic cancer in the future.

Lower extremity deep venous thrombosis (LEDVT) is a venous reflux disorder caused by abnormal coagulation of blood. LEDVT can obstruct the lumen and LEDVT is the third vascular disease after cerebrovascular diseases and coronary artery diseases. miRNAs are associated with thrombosis, and miR-185 was reported to affect the proliferation and apoptosis of vascular endothelial cells by regulating receptor of advanced glycation end products (RAGE). However, no study has reported the effect of miR-185 on LEDVT. Here, we studied the effects of miR-185 on the PI3K/AKT and MAPK signaling pathways in the LEDVT cells. The results showed that miR-185 promotes cell proliferation through activating the PI3K/AKT and MAPK signaling pathways and then inhibits tissue factor and fibrin expression to reduce thrombosis. In short, our study provides new ideas and a theoretical basis for research on the prevention, diagnosis, and treatment of LEDVT.

A fever clinic within a hospital plays a vital role in pandemic control because it serves as an outpost for pandemic discovery, monitoring and handling. As the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan was gradually brought under control, the fever clinic in the West Campus of Wuhan Union Hospital introduced a new model for construction and management of temporary mobile isolation wards. A traditional battlefield hospital model was combined with pandemic control regulations, to build a complex of mobile isolation wards that used adaptive design and construction for medical operational, medical waste management and water drainage systems. The mobile isolation wards allowed for the sharing of medical resources with the fever clinic. This increased the capacity and efficiency of receiving, screening, triaging and isolation and observation of patients with fever. The innovative mobile isolation wards also controlled new sudden outbreaks of COVID-19. We document the adaptive design and construction model of the novel complex of mobile isolation wards and explain its characteristics, functions and use.

To assess the diagnostic value of shear wave elastography (SWE) for evaluating the histological spermatogenic function of azoospermic males, 91 patients with azoospermia who underwent standardised greyscale ultrasound and SWE examinations followed by testicular biopsy were retrospectively recruited. Spermatogenic function was classified by biopsy as normal testicular spermatogenesis (n = 61), hypospermatogenesis (n = 18), spermatogenesis arrest (n = 6) and Sertoli cell-only syndrome (n = 6). Significant differences in testicular size and SWE values were observed between these 4 groups (p < .01). The mean SWE value had good discrimination power (AUC = 0.79) with a cut-off value of 1.55 KPa, a sensitivity of 0.58, specificity of 0.85, positive predictive value (PPV) of 0.36 and negative predictive value (NPV) of 0.93. Testicular volume had an AUC of 0.75. With a cut-off value of 8.41 ml, the testicular volume had a sensitivity of 0.58, specificity of 0.92, PPV of 0.54 and NPV of 0.93. The mean SWE value and testicular volume efficiently discriminated patients with normal spermatogenesis and hypospermatogenesis from patients with Sertoli cell-only syndrome and spermatogenesis arrest.