Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

OBJECTIVE To investigate the improvement effects of Runchang granules on the constipation in mice and its potential mechanism. METHODS The mice were randomly divided into normal control group， model group， Runchang granules low-dose and high-dose groups （5， 10 g/kg）， mosapride group （0.003 g/kg， positive control）， with 6 mice in each group. The latter 4 groups were given loperamide intragastrically （0.004 g/kg）， twice a day， for 3 consecutive days. Normal control group and model group were given purified water intragastrically， and administration groups were given relevant medicine intragastrically for 7 consecutive days. After the last medication， fecal moisture content and intestinal motility of mice were determined， while the structures of colon and ileum， and the secretion of colonic mucus were observed. Protein expressions of tyrosine kinase receptor （c-kit）， mucin 2 （MUC2） and stem cell factor （SCF） were determined in colon； meanwhile， the mRNA expression levels of inflammatory factors [tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， IL-1β， inducible nitric oxide synthase （iNOS）] as well as factors related to promoting intestinal motility [neuronal nitric oxide synthase （nNOS）， smooth muscle myosin light chain kinase （smMLCK）， 5-hydroxytryptamine 4 receptor （5-HT4R）， MUC2， SCF， c-kit] were determined. RESULTS Compared with model group， the fecal water content， intestinal propulsion rate， protein expression of c-kit in colon， relative expressions of MUC2 and SCF protein， and mRNA expressions of factors related to promoting intestinal motility （except for nNOS and SCF in Runchang granules low-dose group） were all increased significantly in Runchang granules low-dose and high-dose groups， and mosapride group （P＜0.05 or P＜0.01）. mRNA expression levels of inflammatory factors were decreased significantly（P＜0.05 or P＜0.01）. Both colon and ileum injuries improved， and the secretion of colon mucus was increased significantly in Runchang granules high-dose group （P＜0.01）. CONCLUSIONS Runchang granules have laxative effect and can improve constipation in mice， and its mechanism may be related to the promotion of the secretion of colon mucus and MUC2 expression， and the activation of SCF/c-kit signaling pathway.

Objective The main points of diagnosis and treatment of ureterocutaneous fistula after in situ bladder operation were discussed based on clinical data and literature.Methods This report presents the data of a patient who developed a ureterocutaneous fistula 10 years after an in situ bladder procedure at Yuechi County People's Hospital.Results A 77-year-old male underwent laparoscopic cystectomy with orthotopic ileal neobladder for bladder cancer.The case manifested as fluid leakage from the original surgical incision,initially misdiagnosed as abdominal wall sinus.After right nephrectomy due to non-functional kidney,the fistula healed.Conclusion Ureterocutaneous fistulas are commonly associated with kidney transplantation and postoperative complications of upper urinary tract such as calculi and xanthogranulomatous pyelonephritis.Fistulography can be conclusive for this condition.Prompt identification and repair of urinary tract injuries are crucial.

Objective:To investigate the clinical value of AB classification combined with Arima classification for predicting the invasion depth of superficial esophageal squamous cell carcinomas (SESCC).Methods:From July 2017 to December 2022, 76 cases of SESCC receiving endoscopic submucosal dissection and intra-epithelial papillary capillary loops (IPCL) AB classification as type B2 in Ningbo Medical Center Lihuili Hospital and Jiangsu Province Hospital of Chinese Medicine were included in the study. IPCL was reclassified according to Arima classification. The depth of infiltration determined by pathology was the gold standard. The sensitivity, the specificity, the positive predictive value and the negative predictive value of B2-Arima combined classification in predicting the invasion depth of SESCC were analyzed.Results:In the 76 cases of type B2 IPCL lesions, 31 cases (40.79%) were T1a-MM/T1b-SM1 SESCC. The sensitivity, the specificity, the positive predictive value, the negative predictive value and the diagnostic accuracy of type B2 IPCL to predict T1a-MM/T1b-SM1 SESCC were 70.45% (31/44), 79.64% (176/221), 40.79% (31/76), 93.12% (176/189), and 78.11% (207/265), respectively. After Arima classification, the above corresponding indicators of type B2-4ML and type B2-AVA-4M IPCL in predicting T1a-MM/T1b-SM1 SESCC were 61.36% (27/44), 88.24% (195/221), 50.94% (27/53), 91.98% (195/212), 83.77% (222/265) and 38.64% (17/44), 94.57% (209/221), 58.62% (17/29), 88.56% (209/236), 85.28% (226/265), respectively.Conclusion:B2 IPCL combined with Arima classification can improve the diagnostic accuracy of T1a-MM/T1b-SM1 ESSCC.

Objective:To investigate the clinical, endoscopic and pathological features, and treatment and prognosis of gastric adenocarcinoma of fundic gland type of chief cell predominant type (GA-FG-CCP).Methods:Data of 40 GA-FG-CCP patients with 41 lesions diagnosed by histopathology at Ningbo Medical Center Lihuili Hospital and Shanghai East Hospital from January 2018 to May 2023 were collected. Their clinical and endoscopic features, pathological features, immunohistochemical results, endoscopic treatment, and prognosis were analyzed.Results:Among the 40 GA-FG-CCP patients, there were 15 males and 25 females, and the mean age was 60.03 years. Most of them had no obvious clinical symptoms or family history of tumor. Except one case, others had no helicobacter pylori infection. The endoscopic features of white light observation were: ① the main location was the upper part of the gastric body (63.41%, 26/41); ② faded or whitish mucosal surface (56.10%, 23/41); ③ dilated vessels with branch architecture (78.05%, 32/41); ④ no background mucosal atrophy (100.00%, 41/41). The features of magnifying endoscopy with narrow band imaging (ME-NBI) were: ① no obvious demarcation line (85.37%, 35/41); ② enlargement of the crypt opening (87.80%, 36/41); ③ widening of the intervening part (92.68%, 38/41); ④ lack of irregular microvascular pattern (95.12%, 39/41). All patients were confirmed gastric adenocarcinoma of the fundic gland by biopsy. The glands showed a low degree of dysplasia, similar to the differentiation of chief cell predominant pattern, also with scattered parietal cells, forming irregular and anastomosing cords. In the 40 patients, 20 did not receive endoscopic therapy. Twelve out of 21 lesions in 20 cases treated with endoscopic resection infiltrated into the submucosa (20-520 μm), 9 cases were intramucosal carcinoma. There was no lymphatic or venous infiltration, and horizontal and vertical margins were negative. Immunohistochemical staining results showed that the tumor was postive for pepsinogen-Ⅰ and MUC 6, with scattered postive for H +-K +-ATPase, but negative for MUC5AC, MUC2 and CD10, and the Ki-67 labeling index was low. No patients had recurrence or metastasis during mean follow-up of 15.85 months. Conclusion:GA-FG-CCP is rare and very well differentiated. Its clinical symptoms are not obvious, but there is endoscopic characteristics. The detection rate of GA-FG-CCP can be improved by white light and ME-NBI, and the diagnosis can be confirmed by pathology and immunohistochemical staining.

OX40 is a costimulatory receptor that is expressed primarily on activated CD4⁺, CD8⁺, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice ; Animals ; Receptors, Tumor Necrosis Factor/physiology* ; Receptors, OX40 ; Membrane Glycoproteins ; Ligands ; Antibodies, Monoclonal/pharmacology* ; Antineoplastic Agents/pharmacology*

Objective:To investigate the differences in understanding and diagnosis of polycystic ovary syn-drome(PCOS)among obstetricians and gynecologists with different clinical experiences,in order to promote com-munication and improve medical quality.Methods:This was a multi-center cross-sectional survey.Information on participants'basic information and their knowledge of PCOS comorbidities and treatment management was col-lected online.Physicians were divided into two groups according to their experience:experienced(>200 consulta-tions/year)and inexperienced(≤200 consultations/year).The differences in the diagnosis and treatment of PCOS among different groups were compared.Logistic regression analysis was used to explore other factors that might influence the diagnosis and treatment of PCOS.Results:1689 questionnaires were finally included,among which 95 were experienced and 1594 were inexperienced.①In the comparison of basic conditions,the proportion of experienced persons in tertiary hospitals and reproductive endocrinology specialties was higher than that of in-experienced persons(P<0.05);The percentage of experienced persons who predicted patients with comorbid insulin resistance(proportion>30%)and predicted comorbid overweight/obesity(proportion 30%-50%)was higher than that of less experienced persons(P<0.05).②There was no significant difference in the evaluation of PCOS and its complications among different groups(P>0.05).Logistic regression suggested that different expe-riencers did not significantly affect the assessment of androgens,OGTT and lipid testing(P>0.05).③There was no statistical significance in the choice of treatment for those with no fertility need(P>0.05).For those with fertili-ty needs,metformin and letrozole were more actively selected by experienced group than inexperience(P<0.05).In terms of weight loss,experienced participants were more active in using metformin(P<0.05)and were more likely to choose1.0 or1.5 g/d(P<0.05)than those with inexperience.Conclusions:There was no signifi-cant difference in PCOS assessment among participants with different experience,but in treatment,experienced participants were better able to take into account the multi-system abnormalities brought by PCOS,and at the same time,they give more comprehensive and accurate treatment opinions on patients with or without fertility needs.

ABSTRACT OBJECTIVE To investigate the effects and mechanism of ginsenoside Rh2 on the proliferation and apoptosis in human glioma U87 and U251 cells. METHODS Using human glioma U87 and U251 cells as subjects， the proliferation and apoptosis， as well as the expression of histone deacetylase 1（HDAC1） protein and apoptosis-related proteins [B cell lymphoma-2（Bcl-2）， Bcl-2-associated X protein （Bax） and cleaved caspase-3] were detected after being treated with different concentrations of ginsenoside Rh2. RESULTS The concentrations of 10，20，30，40，50，60，70，80 μmol/L ginsenoside Rh2 could generally significantly increase the proliferation inhibition rate of U87 and U251 cells （P＜0.05 or P＜0.01）， and the half inhibitory concentrations of this component after 48 hours of action were 51.34 and 55.84 μmol/L， respectively；30，50 μmol/L ginsenoside Rh2 could increase the total apoptotic rate of both types of cells， reduced the protein expressions of HDAC1 and Bcl-2， and increased the protein expressions of Bax and cleaved caspase-3 significantly （P＜0.05 or P＜0.01）. CONCLUSIONS Ginsenoside Rh2 has a significant inhibitory effect on the proliferation of glioma cells and promotes the apoptosis of cells， which may be through reducing the expression of HDAC1 protein and activating the Bcl-2 family protein-mediated apoptosis pathway.

OBJECTIVE：To study the effects of costunolide （COS）on the cell cycle distribution and apoptosis of human breast cancer SK-BR- 3 cells and its mechanism. METHODS ：Human breast cancer SK-BR- 3 cells were divided into blank control group，and COS groups of 10，20，30，40，50 μmol/L. MTT assay was used to detect the effects of COS on cell proliferation. SK-BR-3 cells were divided into blank control group ，COS low ，medium and high concentration groups （10，20，30 μmol/L）. After cultured for 24 h，flow cytometry was used to detect the distribution of cell cycle. Hoechst 33258 fluorescence staining was used to detect cell apoptosis. Western blot assay was used to detect the expression of p 53，caspase-3，Bcl-2，Bax，p21，CDK2 and cyclinE. RESULTS ：Compared with blank control group ，COS could significantly inhibit the proliferation of SK-BR- 3 cells（P＜ 0.05 or P＜0.01），and in a dose and time-dependent manner. Low ，medium and high concentrations of COS could induce cell apoptosis and arrest cell at G 1/S phase （P＜0.05 or P＜0.01），could significantly up-regulate the protein expression of p 53， caspase-3，Bax and p 21（P＜0.05 or P＜0.01），and could significantly down-regulate the protein expression of Bcl- 2，CDK2 and cyclinE（P＜0.01）. CONCLUSIONS ：COS can inhibit the proliferation of human breast cancer SK-BR- 3 cells and induce cell apoptosis and cell cycle arrest. The mechanism may be related to the regulation of p 53/Bax/Bcl-2/caspase-3 apoptosis signal pathway.

BACKGROUND: As one of the most common endocrinal disorders for women at childbearing age, the diagnostic criteria of polycystic ovary syndrome (PCOS) have been defined differently among different international health organizations. Phenotypic heterogeneity of PCOS also brings about difficulties for its diagnosis and management assessment. Therefore, more efficient biomarkers representing the progression of PCOS are expected to be integrated into the monitoring of management process using metabolomic approaches. METHODS: In this prospective randomized controlled trial, 117 PCOS patients were enrolled from December 2016 to September 2017. Classical diagnostic parameters, blood glucose, and metabolome were measured in these patients before and at 2 months and 3 months of different medical interventions. The receiver operating characteristic (ROC) curves were built based on multivariate statistical analysis using data at baseline and 3 months' management, and combinational biomarkers with appreciable sensitivity and specificity were selected, which then validated with data collected at 2 months. RESULTS: A set of metabolites including glutamic acid, aspartic acid, 1-methylnicotinamide, acetylcarnitine, glycerophosphocholine, and oleamide were filtered out with high performance in representing the improvement through 3-month management of PCOS with high sensitivity and specificity in ROC analysis and validation with other two groups showed an appreciable area under the curve over 0.96. CONCLUSIONS: The six metabolites were representative of the remission of PCOS through medical intervention, making them a set of potential biomarkers for assessing the outcome of PCOS management. TRIAL REGISTRATION ClinicalTrials.gov, NCT03264638.
Biomarkers ; Female ; Humans ; Metabolomics ; Polycystic Ovary Syndrome/diagnosis* ; Prospective Studies ; ROC Curve