Pancreatic cancer is characterized by nerve invasion and a high mortality rate， and its pathological process depends on the complex interaction network between tumor and the nervous system. Based on the concept of “pancreatic cancer neuroecology”， this article analyzes the mechanism of action of peripheral motor nerve， sensory nerve， and central nerve in tumorigenesis， pain regulation， and cachexia formation and emphasizes the synergistic regulatory role of immune cells， Schwann cells， and extracellular matrix in the microenvironment of perineural invasion. At the same time， this article further elaborates on the metabolic interaction and chemotaxis between neuraxis and tumor， the effect on promoting chemotherapy resistance， and the dynamic relationship between neuroplasticity and tumor adaptability. In clinical practice， this article summarizes the key value of perineural invasion in prognostic evaluation， preoperative evaluation， and the selection of surgical strategy. In addition， this article reviews the basic research advances in the biomarkers and potential targets associated with perineural invasion in pancreatic cancer and points out the limitations of current model and transformation research. In the future， systematically analyzing the nerve-tumor-immune network and targeting its key nodes may provide multi-dimensional strategies and new breakthroughs for the precise intervention of pancreatic cancer， the reversal of drug resistance， and the relief of symptoms.

Objective To explore the association of diabetes status with the development of tuberculosis (TB) among the community population in Shanghai, and to provide evidence for the formulation of tuberculosis prevention and control strategies. Methods This population-based cohort study was based on Shanghai Suburban Adult Cohort and Biobank (SSACB) in China. The baseline data were acquired by questionnaires, physical examinations and blood biochemistry tests. TB incidence was obtained by matching with TB management information system data. A Cox proportional risk model was established to assess the risk of tuberculosis. Results A total of 36 014 research subjects were included, with an average age of 56.3±11.3 years, of which 14 587 (40.5%) were male. Over 6 years of follow-up, 47 individuals progressed to tuberculosis (incidence rate: 19.8 per 100 000 person-year, 95% CI: 14.6 -26.4). An increased risk of TB was observed in participants with newly diagnosed diabetes compared with those without diabetes (adjusted hazard ratio [aHR], 2.73; 95% CI, 1.19 - 6.28). Conclusion The risk of tuberculosis in newly diagnosed diabetic patients is significantly increased, and strengthening tuberculosis screening for this population should be considered in practical work.

The Department of Thoracic Surgery of Shanghai Chest Hospital has performed esophageal function testing for over 30 years, being the only department of its kind in China with this capability. The pressure testing and 24-hour pH/impedance monitoring of the esophagus is of great help to assist in the diagnosis and treatment of benign and malignant esophageal diseases related to it. Thanks to the esophageal function test, in addition to the routine various endoscopic anti-reflux procedures, our hospital has taken the lead in China in recent years to carry out a series of clinical and research work for benign esophageal diseases, such as the development of magnetic ring, double nedoscopic combination and new anti-reflux endoscopic techniques. In recent years, we have carried out high-resolution esophageal manometry and 24-hour pH/impedance monitoring for patients with interstitial pneumonia and pulmonary fibrosis suspected to be caused by gastroesophageal acid reflux. We can better assess the correlation between gastroesophageal reflux and pulmonary fibrosis, and to provide the different clinical treatments and even surgical interventions. The Bravo capsule is used more often in the United States, and it has obvious advantages over traditional approach for acid measurement. We strongly call for the collaboration between industry and academic institutions in this field, and the development of our own related products with independent intellectual property rights.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Glutamate-ammonia ligase (GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

Humans ; Adolescent ; Fractures, Avulsion ; Fractures, Bone ; Fracture Fixation, Internal ; Ischium/surgery*

ObjectiveTo explore the possible mechanism of Osteoking （OK） on postmenopausal osteoporosis （PMOP）. MethodForty adult female mice were randomly divided into a sham operation （Sham） group， osteoporosis model （OVX） group， estradiol intervention （E₂） group， and OK group， with 10 mice in each group. The modeling was completed by conventional back double incision ovariectomy， and the corresponding drugs were given one week later. After 12 weeks， the body mass and uterine index of mice were measured， and the pathological changes of bone tissue and the number of osteoclasts （OCs） were determined by hematoxylin-eosin （HE） and tartrate-resistant acid phosphatase （TRAP） staining， respectively. Bone mineral density （BMD）， trabecular number （Tb.N）， trabecular separation （Tb.Sp）， and bone volume fraction （BV/TV） were measured by microcomputed tomography （Micro-CT）. The maximum load of the femur was detected by a three-point bending test. The contents of tumor necrosis factor-α （TNF-α） and bone resorption marker C-terminal telopeptide of type Ⅰ collagen （CTX-1） were measured by enzyme linked immunosorbent assay （ELISA）. The protein expression levels of nuclear factor-kappa B p65 （NF-κB p65）， phosphorylated nuclear factor-kappa B p65 （p-NF-κB p65）， nuclear factor kappa B inhibitor alpha （IκBα）， phosphorylated nuclear factor kappa B alpha （p-IκBα）， nuclear factor of activated T cells 1 （NFATc1）， and proto-oncogene （c-Fos） were detected by Western blot. The mRNA expressions of OCs-related specific genes matrix metalloproteinase-9 （MMP-9）， NFATc1， TRAP， cathepsin K （CTSK）， and c-Fos were detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultCompared with the Sham group， the uterine index decreased significantly in the OVX group， and the body mass （BMI） increased significantly. The structure of bone trabeculae was completely damaged， and the number of OCs increased. BMD， Tb.N， BV/TV， and maximum load decreased， while Tb.Sp was up-regulated. The levels of TNF-α and CTX-1 in serum were up-regulated. The protein expressions of c-Fos， p-NF-κB p65/NF-κB p65， NFATc1， and p-IκBα/IκBα were increased. The mRNA expressions of NFATc1， c-Fos， CTSK， TRAP， and MMP-9 were up-regulated （P<0.05， P<0.01）. Compared with the OVX group， the body mass of the OK and E₂ groups decreased， and the uterine index increased. The bone trabeculae increased， and the number of OCs decreased. BMD， Tb.N， BV/TV， and maximum load increased， while Tb.Sp decreased. The levels of TNF-α and CTX-1 in serum were decreased. The protein expressions of c-Fos， p-NF-κB p65/NF-κB p65， NFATc1， and p-IκBα/IκBα were decreased， and the mRNA expressions of NFATc1， c-Fos， CTSK， TRAP， and MMP-9 were decreased （P<0.05， P<0.01）. ConclusionOK can inhibit the NF-κB/NFATc1 signaling pathway and reduce bone mass loss by reducing the level of inflammatory injury factors in PMOP mice， which is one of the mechanisms for treating PMOP.

Objective To compare the effect of serratus anterior plane block(SAPB)and thoracic para-vertebral block(TPVB)on acute and chronic pain and plasma tumor necrosis factor-α(TNF-α)level after breast cancer modified radical operation.Methods A total of 99 patients with elective breast cancer modified radical operation,aged 35-70 years,American Society of Anesthesiologists physical status(ASA):grade Ⅰ-11,Body Mass Index(BMI):18-25 kg/m2,were randomly divided into three groups:the simple patient-con-trolled intravenous analgesia(PCIA)group(C group),PCIA combined with TPVB group(TC group)and PCI A combined witj SAPB group(SC group).TPVB and SAPB were performed before induction in the TC group and the SC group,and the relevant situation of regional blocking operation was recorded.The Visual Analogue Scales(VAS)scores in rest and activity at 2,4,8,12,24,48 h after operation,effective pressing times of analgesic pump and remedial analgesia situation after operation were recorded.The TNF-α levels be-fore anesthesia and at postoperative 12,48 h,in postoperative 3,6 months were measured by enzyme linked immunosorbent assay(ELISA).Results Compared with the TC group,the block operation time in the SC group was shorter(P＜0.05).Compared with the C group,the VAS scores in the state of rest and activity at postoperative 2,4,8,12,24 h in the TC group and SC group were significantly decreased(P＜0.05),and the dosage of remifentanil during operation,incidence rates of postoperative nausea and vomiting,effective press-ing times of analgesic pump and rate of remedial analgesia were all decreased(P＜0.05).There was no statis-tical difference in the incidence rate of post-mastectomy pain syndrome(PMPS)among the three groups(P＞0.05).Compared with the C group,the levels of plasma TNF-α in the TC group and SC group were decreased at postoperative 12,48 h,in postoperative 3,6 months,moreover the VAS score in the patients with PMPS was lower(P＜0.05).Compared with the patients without PMPS occurrence,the levels of plasma TNF-α in postoperative 3,6 months in the patients with PMPS were significantly up-regulated(P＜0.05).Conclusion By blocking the afference of pain signals caused by peripheral injury and reducing plasma TNF-α level,SAPB or TPVB may relieve the acute and chronic pain degree in the patients with breast cancer modified radi-cal operation.

Objective: To examine the causal relationships between obesity, peripheral blood lipid indicators and non-small cell lung cancer (NSCLC) using Mendelian randomization (MR) method, so as to provide the basis for developing NSCLC prevention and control strategies. Methods: Genetic variation data of three obesity evaluation indicators, including body mass index (BMI), body fat ratio (BFR) and waist-to-hip ratio (WHR), and seven peripheral blood lipid indicators, including triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and lipoprotein a [LP (a)] were collected through genome-wide association studies (GWAS) and related public databases. Potential causal relationships between obesity, peripheral blood lipid indicators and NSCLC were analyzed using inverse-variance weighted (IVW) method and multivariable MR analysis upon a random effect model. Heterogeneity and horizontal pleiotropy of instrumental variables were evaluated using Cochran's Q test and MR-Egger regression. Results: There was statistically association between BMI with NSCLC (OR=1.256, 95%CI: 1.087-1.451); there were no statistically associations between BFR, WHR, seven peripheral blood lipid indicators and NSCLC (all P>0.005). There was heterogeneity in the association between BMI, BFR, WHR, TG, HDL-C and NSCLC (all P<0.05); no horizontal pleiotropy of instrumental variables was found (all P>0.05). There was no statistically association between BMI and NSCLC after adjusting BFR (OR=1.367, 95%CI: 0.878-2.128); there was still statistically association between BMI and NSCLC after adjusting WHR and peripheral blood lipid indicators (both P<0.05). Conclusions The increase of BMI is associated with the increased risk of NSCLC incidence. BFR may be a potential influencing factor for the association between BMI and NSCLC.

Objective To investigate the renal protective effect and mechanism of sodium acetate(Ace)on hyperuricemic nephropathy(HN)in mice.Methods Uric acid nephropathy mice model was prepared by intraperitoneal injection of potassium oxonate combined with adenine gavage.Mice were divided into blank control group(0.9％NaCl+0.5％carboxymethyl cellulose sodium),Ace group(200 mmol·L-1 Ace+0.5％carboxymethyl cellulose sodium),model group(0.9％NaCl+350 mg·kg-1 potassium oxonate+70 mg·kg-1 adenine),and experimental group(based on model group with additional 200 mmol·L-1 Ace).Serum and urine uric acid(UA)and serum creatinine(SCr)levels were observed in each group.Real-time fluorescence quantitative reverse transcription-polymerase chain reaction(qRT-PCR)was used to detect the expression levels of kidney injury molecule-1(Kim-1)and anti-aging gene Klotho,renal fibrosis markers Collagen Ⅰ and Fibronectin,intestinal inflammation-related factors interleukin-1 β(IL-1 β),and mRNA expression levels of tight junction proteins Zo-1.Results The serum UA levels of blank control group,Ace group,model group,and experimental group mice were(259.52±24.40),(227.71±35.91),(604.06±73.55),and(496.24±30.16)μmol·L-1,respectively;SCr levels were(16.85±0.40),(16.18±0.94),(22.38±1.56),and(19.78±1.43)μmol·L-1;Kim-1 mRNA relative expression levels were 1.04±0.25,1.17±0.28,13.00±2.87,and 4.24±3.92;Klotho mRNA relative expression levels were 1.04±0.15,1.02±0.18,0.43±0.12,and 0.69±0.12;Collagen Ⅰ mRNA relative expression levels were 1.05±0.15,1.02±0.18,3.19±1.09,and 1.61±0.55;Fibronectin mRNA relative expression levels were 1.07±0.18,1.02±0.25,7.86±2.40,and 3.34±2.10;intestinal IL-1β mRNA relative expression levels were 1.00±0.01,1.01±0.03,2.55±0.63,and 1.21±0.28;intestinal Zo-1 mRNA relative expression levels were 1.00±0.07,1.07±0.09,0.54±0.20,and 0.92±0.17.The above indicators in blank control group compared with model group,and experimental group compared with model group,all showed statistically significant differences(P＜0.05,P＜0.01,P＜0.001).Conclusion Sodium acetate can effectively reduce UA levels in HN mice,significantly improve renal injury and fibrosis,and its mechanism may be related to the improvement of intestinal inflammatory response and up-regulation of intestinal Zo-1/Occuludin pathway to reduce intestinal mucosal permeability.