Chemoresistant fibroblasts dictate neoadjuvant chemotherapeutic response of head and neck cancer via TGFα-EGFR paracrine signaling.

Conventional chemotherapy targets malignant cells without evaluating counter protection from the tumor microenvironment that often causes treatment failure. Herein, we establish chemoresistant fibroblasts (rCAFs) as regulators of neoadjuvant chemotherapeutic (NACT) response in head and neck squamous cell carcinoma (HNSCC). Clinically, high expression of CAF-related gene signature correlates with worse prognosis and chemotherapeutic response in multiple cancers, while the population of CAFs in the residual tumors of chemoresistant HNSCC patients remains unchanged after NACT treatment, compared to chemosensitive patients. Using a murine cancer model or patient-derived organoid, and primary CAFs isolated from chemo-sensitive (sCAFs) or -resistant patients, we show that rCAFs, but not sCAFs, are resistant to chemotherapy-induced apoptosis while reducing HNSCC cell chemosensitivity via paracrine signals. Combined multi-omics and biochemical analyses indicate an elevated PI3K/AKT/p65 driven cell survival and cytokine production in rCAFs, while rCAF-secreted TGFα promotes cancer cell chemoresistance by activating EGFR/Src/STAT3 survival signaling axis. Treatment with anti-EGFR cetuximab restores the chemosensitivity of tumors derived from co-injection of cancer cells and rCAFs in vivo, while the serum level of TGFα determines NACT response in HNSCC patients. Overall, our findings uncover a novel insight whereby the crosstalk between tumor cell and rCAF determines chemotherapeutic response and prognosis in cancer patients.

Identification of a distinct tumor endothelial cell-related gene expression signature associated with patient prognosis and immunotherapy response in multiple cancers.

BACKGROUND: Tumor endothelial cells (TECs) play a significant role in regulating the tumor microenvironment, drug response, and immune cell activities in various cancers. However, the association between TEC gene expression signature and patient prognosis or therapeutic response remains poorly understood. METHODS: We analyzed transcriptomics data of normal and tumor endothelial cells obtained from the GEO database to identify differentially expressed genes (DEGs) associated with TECs. We then compared these DEGs with those commonly found across five different tumor types from the TCGA database to determine their prognostic relevance. Using these genes, we constructed a prognostic risk model integrated with clinical features to develop a nomogram model, which we validated through biological experiments. RESULTS: We identified 12 TEC-related prognostic genes across multiple tumor types, of which five genes were sufficient to construct a prognostic risk model with an AUC of 0.682. The risk scores effectively predicted patient prognosis and immunotherapeutic response. Our newly developed nomogram model provided more accurate prognostic estimates of cancer patients than the TNM staging method (AUC = 0.735) and was validated using external patient cohorts. Finally, RT-PCR and immunohistochemical analyses indicated that the expression of these 5 TEC-related prognostic genes was up-regulated in both patient-derived tumors and cancer cell lines, while depletion of the hub genes reduced cancer cell growth, migration and invasion, and enhanced their sensitivity to gemcitabine or cytarabine. CONCLUSIONS: Our study discovered the first TEC-related gene expression signature that can be used to construct a prognostic risk model for guiding treatment options in multiple cancers.

Endoscopic ultrasonography is useful for predicting perforation in the endoscopic resection of gastric submucosal tumors originating from the muscularis propria: a retrospective case-control study.

PURPOSE: Models for predicting perforation during endoscopic resection (ER) of gastric submucosal tumors (SMTs) originating from the muscularis propria (MP) are rare. Therefore, this study was conducted to determine important parameters in endoscopic ultrasonography (EUS) images to predict perforation and to build predictive models. METHODS: Consecutive patients with gastric SMTs originating from the MP who received ER from May 1, 2013 to January 15, 2021 were retrospectively reviewed. They were classified into case and control groups based on the presence of perforation. Logistic multivariate analysis was used to identify potential variables and build predictive models (models 1 and 2: with and without information on tumor pathology, respectively). RESULTS: In total, 199 EUS procedures (194 patients) were finally chosen, with 99 procedures in the case group and 100 in the control group. The ratio of the inner distance to the outer distance (I/O ratio) was significantly larger in the case group than in the control group (median ratio, 2.20 vs. 1.53; P<0.001). Multivariate analysis showed that age (odds ratio [OR], 1.036 in model 1; OR, 1.046 in model 2), the I/O ratio (OR, 2.731 in model 1; OR, 2.372 in model 2), and the pathology of the tumors (OR, 10.977 for gastrointestinal stromal tumors; OR, 15.051 for others in model 1) were risk factors for perforation. The two models to predict perforation had areas under the curve of 0.836 (model 1) and 0.755 (model 2). CONCLUSION: EUS was useful in predicting perforation in ER for gastric SMTs originating from the MP. Two predictive models were developed.

Clinical, endoscopic and pathological characteristics of primary gastrointestinal T-cell and NK/T-cell lymphomas.

BACKGROUND AND AIMS: Gastrointestinal T-cell and NK/T-cell lymphomas are relatively rare and may be difficult to diagnose. Therefore, we performed a retrospective study of the clinical, endoscopic and pathological characteristics of these lymphomas, to provide additional data on this issue. METHODS: From April 2013 to April 2021, consecutive patients diagnosed with primary gastrointestinal T-cell and NK/T-cell lymphomas were retrospectively reviewed. Their medical histories, laboratory, imaging, endoscopic, and pathology results were analyzed. RESULTS: Forty-two patients were finally chosen, among whom, 24 patients had ENKTCL, 9 patients had MEITL, 2 patients had ALCL, ALK-, 1 patient had ALCL, ALK+, and 6 patients had PTCL, NOS. The median age of all the patients was 48 years old, and 73.81% (31 patients) were male. The patients' symptoms were abdominal pain, diarrhea, gastrointestinal bleeding, weight loss, fever, and others. The endoscopic results of 26 patients could be traced, and 69.23% of the patients showed multiple lesions. Ulcerative and ulceroinfiltrative lesions were common. Among the pathologic findings, necrosis, ulceration, and crypt atrophy were commonly found while epitheliotropism was relatively less common. Twelve patients (28.57%) had a history of misdiagnosis. After a median follow-up time of 26.9 months, 26 patients (66.70%) died of the disease. The median overall survival time was 8 months. CONCLUSIONS: These lymphomas had nonspecific clinical manifestations, various endoscopic features, and were likely to be misdiagnosed as other diseases. The prognosis is still poor, and more in-depth research is needed to develop more precise treatments.

Efficacy and safety of midazolam combined with dezocine for sedation and analgesia in digestive endoscopy: A prospective open single-center study.

Objective: Digestive endoscopy is an important means of diagnosing and treating gastrointestinal diseases and a tool for screening and monitoring early gastrointestinal tumors. Digestive endoscopy can be performed using midazolam combined with dezocine for sedation and analgesia. This study explored the efficacy and safety of midazolam combined with dezocine. Methods: A total of 135 patients undergoing digestive endoscopy in the Department of Gastrointestinal Endoscopy of the Sixth Affiliated Hospital, Sun Yat-sen University, from June 2021 to September 2021, were enrolled and non-blindly and non-randomly divided into a sedation-endoscopy-group (SEG, n = 45), anesthesia-endoscopy-group (AEG, n = 44), and ordinary-endoscopy-group (OEG, n = 46). Vital signs, levels of sedation and analgesia, the degree of pain during colonoscopy, satisfaction, and the incidence of complications were compared among the three groups. Results: There were no statistically significant differences in vital signs (blood pressure, pulse, respiration, and blood oxygen saturation) among the three groups before endoscopy (p > 0.05). The AEG reported no pain during colonoscopy, and the pain score during colonoscopy for the SEG was lower than that for the OEG (1.11 ± 1.21 vs. 3.00 ± 1.16, p < 0.001). The scores for satisfaction were 8.84 ± 1.30 points in the SEG, 8.95 ± 1.10 points in the AEG, and 6.37 ± 0.90 points in the OEG; the differences were statistically significant (p < 0.001). The total incidence of complications in the AEG was 38.64% (17/44), which was significantly higher than that in the SEG [13.33% (6/45)] and OEG [13.04% (6/46)] (p < 0.001). In the SEG, the overall incidence of complications in women was significantly higher than that in men (p = 0.027). Conclusion: Digestive endoscopy using midazolam combined with dezocine for sedation makes patients more comfortable, more satisfied and more compliant than the ordinary endoscopy. Additionally, it is comparable to endoscopy under general anesthesia with propofol with regard to comfort, satisfaction, and patient compliance and comparable to the ordinary endoscopy with regard to safety. Considering the shortage of anesthesiologists, the application of midazolam combined with dezocine in digestive endoscopy is worthy of clinical popularization. This study has been registered in the Hospital Ethics Committee of the Sun Yat-sen University Sixth Affiliated Hospital (Ethical Number: 2021ZSLYEC-182).

MiR-195-5p suppresses the proliferation, migration, and invasion of gallbladder cancer cells by targeting FOSL1 and regulating the Wnt/ß-catenin pathway.

Background: MicroRNA-messenger RNA (miRNA-mRNA) regulatory networks are essential factors that regulate tumor development and metastasis in various cancers including gallbladder carcinoma (GBC). Here, we identified the miR-195-5p/Fos-like antigen-1 (FOSL1) axis in GBC by bioinformatics analysis and aimed to investigate its role and regulatory mechanism in the development and progression of GBC. Methods: Bioinformatics analysis was used to construct a miRNA-mRNA regulatory network. Real-time quantitative polymerase chain reaction (qRT-PCR), western blot, and dual luciferase reporter assays confirmed that miR-195-5p targets FOSL1 in GBC. Cell Counting Kit-8 (CCK-8), wound healing, transwell, flow cytometry assays, western blotting, and immunofluorescence were used to detect the biological effects of the miR-195-5p/FOSL1 regulatory axis and the Wnt/ß-catenin signaling pathway on the proliferation, migration, invasion, and cell cycle of GBC cells. A nude mouse tumorigenesis model was constructed to verify the role of miR-195-5p in vivo. Results: Bioinformatics analysis and qRT-PCR confirmed that the miR-195-5p/FOSL1 regulatory axis was closely related to GBC cells. Overexpression of miR-195-5p inhibited the proliferation, migration, and invasion of GBC cells, and the cells were blocked in the G0/G1 phase. Dual luciferase reporter gene assays and western blot analysis showed that FOSL1 is targeted by miR-195-5p. The recovery experiment showed that miR-195-5p can inhibit cell proliferation, migration, invasion, and increase of cells in the G0/G1 phase, and the overexpression of FOSL1 could restore this effect by regulating the Wnt/ß-catenin signaling pathway. Finally, we confirmed that miR-195-5p inhibited the growth of transplanted tumors in vivo. Conclusions: The overexpression of miR-195-5p inhibits the proliferation and metastasis of GBC cells by directly targeting FOSL1 and regulating the Wnt/ß-catenin signaling pathway.

Negative correlations between bile reflux gastritis and Helicobacter pylori infection.

OBJECTIVE: There are a few articles to study the relationship between bile reflux gastritis (BRG) and H. pylori infection, and the results are debatable. This study set out to determine the relationship between BRG and Helicobacter pylori (H. pylori) infection. METHODS: In this retrospective study, patients from January, 1st 2013 to January, 1st, 2021 were divided into two groups based on whether they had BRG. The control group was got by 1:1 propensity-score matching (PSM) based on age and sex. Then, the relationship between BRG and H. pylori in patients was analyzed via Chi-squared test and Phi (φ) detection. RESULTS: 26449 patients were included in this study, and there were 1918 patients in each group after age and sex matching. patients with HP were responsible for 35% (9345/26449) and patients with BRG were 7% (1918/26449). Further relationship exploration, there is a negative, but weak, the relationship between BRG and HP infection (X2 = 45.62, p < .001, Phi (φ)= -0.109). CONCLUSION: Patients with bile reflux may have less likely to get HP infection. HP eradication is an important thing for the prevention of gastric cancer and this study serves as a foundation and may provide directions for future research.

Real-Time Artificial Intelligence-Based Histologic Classifications of Colorectal Polyps Using Narrow-Band Imaging.

Background and Aims: With the development of artificial intelligence (AI), we have become capable of applying real-time computer-aided detection (CAD) in clinical practice. Our aim is to develop an AI-based CAD-N and optimize its diagnostic performance with narrow-band imaging (NBI) images. Methods: We developed the CAD-N model with ResNeSt using NBI images for real-time assessment of the histopathology of colorectal polyps (type 1, hyperplastic or inflammatory polyps; type 2, adenomatous polyps, intramucosal cancer, or superficial submucosal invasive cancer; type 3, deep submucosal invasive cancer; and type 4, normal mucosa). We also collected 116 consecutive polyp videos to validate the accuracy of the CAD-N. Results: A total of 10,573 images (7,032 images from 650 polyps and 3,541 normal mucous membrane images) from 478 patients were finally chosen for analysis. The sensitivity, specificity, PPV, NPV, and accuracy for each type of the CAD-N in the test set were 89.86%, 97.88%, 93.13%, 96.79%, and 95.93% for type 1; 93.91%, 95.49%, 91.80%, 96.69%, and 94.94% for type 2; 90.21%, 99.29%, 90.21%, 99.29%, and 98.68% for type 3; and 94.86%, 97.28%, 94.73%, 97.35%, and 96.45% for type 4, respectively. The overall accuracy was 93%. We also built models for polyps ≤5 mm, and the sensitivity, specificity, PPV, NPV, and accuracy for them were 96.81%, 94.08%, 95%, 95.97%, and 95.59%, respectively. Video validation results showed that the sensitivity, specificity, and accuracy of the CAD-N were 84.62%, 86.27%, and 85.34%, respectively. Conclusions: We have developed real-time AI-based histologic classifications of colorectal polyps using NBI images with good accuracy, which may help in clinical management and documentation of optical histology results.

Mitofusin-2 Restrains Hepatic Stellate Cells' Proliferation via PI3K/Akt Signaling Pathway and Inhibits Liver Fibrosis in Rats.

The mitochondrial GTPase mitofusin-2 (MFN2) gene can suppress the cell cycle and regulate cell proliferation in a number of cell types. However, its function in hepatic fibrosis remains largely unexplored. We attempted to understand the mechanism of MFN2 in hepatic stellate cell (HSC) proliferation and the development of hepatic fibrosis. Rat HSC-T6 HSC were cultured and transfected by adenovirus- (Ad-) Mfn2 or its negative control (NC) vector (Ad-green fluorescent protein (GFP)); a rat liver cirrhosis model was established via subcutaneous injection with carbon tetrachloride (CCl4). Seventy-two rats were randomly divided into four groups: CCl4, Mfn2, GFP, and NC. Ad-Mfn2 or Ad-GFP was transfected into the circulation via intravenous injection at day 1, 14, 28, 42, or 56 after the first injection of CCl4 in the Mfn2/GFP groups. Biomarkers related to HSC proliferation and the development of hepatic fibrosis were detected using western blotting, hematoxylin-eosin and Masson staining, and immunohistochemistry. In vitro, Mfn2 interfered specifically with platelet-derived growth factor- (PDGF-) induced signaling pathway (phosphatidylinositol 3-kinase- (PI3K-) AKT), inhibiting HSC-T6 cell activation and proliferation. During the process of hepatic fibrosis in vivo, extracellular collagen deposition and the expression of fibrosis-related proteins increased progressively, while Mfn2 expression decreased gradually. Upregulating Mfn2 expression at the early stage of fibrosis impeded the process, triggered the downregulation of type I collagen, and antagonized the formation of factors associated with liver fibrosis. Mfn2 suppresses HSC proliferation and activation and exhibits antifibrotic potential in early-stage hepatic fibrosis. Therefore, it may represent a significant therapeutic target for eradicating hepatic fibrosis.

Microbial spectrum and drug resistance of pathogens cultured from gallbladder bile specimens of patients with cholelithiasis: A single-center retrospective study.

BACKGROUND: Bacterial infection is an important cause of cholelithiasis or gallstones and interferes with its treatment. There is no consensus on bile microbial culture profiles in previous studies, and identified microbial spectrum and drug resistance is helpful for targeted preventive and therapeutic drugs in the perioperative period. AIM: To analyze the bile microbial spectrum of patients with cholelithiasis and the drug susceptibility patterns in order to establish an empirical antibiotic treatment for cholelithiasis-associated infection. METHODS: A retrospective single-center study was conducted on patients diagnosed with cholelithiasis between May 2013 and December 2018. RESULTS: This study included 185 patients, of whom 163 (88.1%) were diagnosed with gallstones and 22 (11.9%) were diagnosed with gallstones and common bile duct stones (CBDSs). Bile culture in 38 cases (20.5%) was positive. The presence of CBDSs (OR = 5.4, 95%CI: 1.3-21.9, P = 0.03) and longer operation time (> 80 min) (OR = 4.3, 95%CI: 1.4-13.1, P = 0.01) were identified as independent risk factors for positive bile culture. Gram-negative bacteria were detected in 28 positive bile specimens, and Escherichia coli (E. coli) (19/28) and Klebsiella pneumoniae (5/28) were the most frequently identified species. Gram-positive bacteria were present in 10 specimens. The resistance rate to cephalosporin in E. coli was above 42% and varied across generations. All the isolated E. coli strains were sensitive to carbapenems, with the exception of one imipenem-resistant strain. K. pneumoniae showed a similar resistance spectrum to E. coli. Enterococcus spp. was largely sensitive to glycopeptides and penicillin, except for a few strains of E. faecium. CONCLUSION: The presence of common bile duct stones and longer operation time were identified as independent risk factors for positive bile culture in patients with cholelithiasis. The most commonly detected bacterium was E. coli. The combination of ß-lactam antibiotics and ß-lactamase inhibitors prescribed perioperatively appears to be effective against bile pathogens and is recommended. Additionally, regular monitoring of emerging resistance patterns is required in the future.

Dynamic Nomogram for Predicting Lateral Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma.

OBJECTIVE: To establish a dynamic nomogram based on preoperative clinical data for prediction of lateral lymph node metastasis (LLNM) of papillary thyroid carcinoma. STUDY DESIGN: Retrospective study. SETTING: The Sixth Affiliated Hospital of Sun Yat-Sen University. METHODS: The data of 477 patients from 2 centers formed the training group and validation group and were retrospectively reviewed. Preoperative clinical factors influencing LLNM were identified by univariable and multivariable analysis and were to construct a predictive dynamic nomogram for LLNM. Receiver operating characteristic analysis and calibration curves were used to evaluate the predictive power of the nomogram. RESULTS: The following were identified as independent risk factors for LLNM: male sex (odds ratio [OR] = 4.6, P = .04), tumor size ≥10.5 mm (OR = 7.9, P = .008), thyroid nodules (OR = 6.1, P = .013), irregular tumor shape (OR = 24.6, P = .001), rich lymph node vascularity (OR = 9.7, P = .004), and lymph node location. The dynamic nomogram constructed with these factors is available at https://zxh1119.shinyapps.io/DynNomapp/. The nomogram showed good performance, with an area under the curve of 0.956 (95% CI, 0.925-0.986), a sensitivity of 0.87, and a specificity of 0.91, if high-risk patients were defined as those with a predicted probability ≥0.3 or total score ≥200. The nomogram performed well in the external validation cohort (area under the curve, 0.915; 95% CI, 0.862-0.967). CONCLUSIONS: The dynamic nomogram for preoperative prediction of LLNM in papillary thyroid carcinoma can help surgeons identify high-risk patients and develop individualized treatment plans.