Harnessing cytokines to optimize chimeric antigen receptor-T cell therapy for gastric cancer: Current advances and innovative strategies.

Enormous patients with gastric cancer (GC) are insensitive to chemotherapy and targeted therapy without the chance of radical surgery, so immunotherapy may supply a novel choice for them. Chimeric antigen receptor (CAR)-T cell therapy has the advantages of higher specificity, stronger lethality, and longer-lasting efficacy, and it has the potential for GC in the future. However, its application still faces numerous obstacles in terms of accuracy, efficacy, and safety. Cytokines can mediate the migration, proliferation, and survival of immune cells, regulate the duration and strength of immune responses, and are involved in the occurrence of severe side effects in CAR-T cell therapy. The expression levels of specific cytokines are associated with the genesis, invasion, metastasis, and prognosis of GC. Applications of cytokines and their receptors in CAR-T cell therapy have emerged, and various cytokines and their receptors have contributed to improving CAR-T cell anti-tumor capabilities. Large amounts of central cytokines in this therapy include chemokines, interleukins (ILs), transforming growth factor-ß (TGF-ß), and colony-stimulating factors (CSFs). Meanwhile, researchers have explored the combination therapy in treating GC, and several approaches applied to other malignancies can also be considered as references. Therefore, our review comprehensively outlines the biological functions and clinical significance of cytokines and summarizes current advances and innovative strategies for harnessing cytokines to optimize CAR-T cell therapy for GC.

POU5F1 promotes the proliferation, migration, and invasion of gastric cancer cells by reducing the ubiquitination level of TRAF6.

POU5F1 plays an important role in maintaining the cancer stem cell (CSC) -like properties of gastric cancer (GC) cells. The impact of POU5F1 on the proliferation and metastasis of GC was examined, along with the potential of ATRA as a specific therapeutic agent for GC. The dysregulation of POU5F1 expression in GC tissues was analyzed using public databases and bioinformatics techniques, and the disparity in POU5F1 expression between normal gastric tissues and GC tissues was further assessed through western blot, RT-qPCR, and immunohistochemistry. The present study aimed to investigate the impact of POU5F1 on the proliferation, migration, and invasion of GC cells through both in vivo and in vitro experiments. Additionally, the effects of ATRA on the proliferation, migration, and invasion of GC cells were examined using in vivo and in vitro approaches. Our findings revealed a significant upregulation of POU5F1 in GC tissues, which was found to be associated with a poorer prognosis in patients with GC. Moreover, POU5F1 was observed to enhance the proliferation, migration, and invasion of GC cells in vitro, as well as promote subcutaneous tumor growth and lung metastasis of GC cells in vivo. The overexpression of POU5F1 mechanistically triggers the process of Epithelial-mesenchymal transition (EMT) by down-regulating E-Cadherin and up-regulating N-Cadherin and VIM. POU5F1 hinders the ubiquitination of TRAF6 through negative regulation of TRIM59, thereby facilitating the activation of the NF-κB pathway. Furthermore, the administration of ATRA effectively impedes the proliferation, migration, and invasion of GC cells by suppressing the expression of POU5F1. The upregulation of POU5F1 elicits EMT, fosters the initiation of the NF-κB signaling pathway in GC cells, and stimulates the proliferation, invasion, and metastasis of GC cells. All-trans retinoic acid (ATRA) can impede these POU5F1-induced effects, thereby potentially serving as an adjunctive therapeutic approach for GC.

Personalized radiomics signature to screen for KIT-11 mutation genotypes among patients with gastrointestinal stromal tumors: a retrospective multicenter study.

OBJECTIVES: Gastrointestinal stromal tumors (GISTs) carrying different KIT exon 11 (KIT-11) mutations exhibit varying prognoses and responses to Imatinib. Herein, we aimed to determine whether computed tomography (CT) radiomics can accurately stratify KIT-11 mutation genotypes to benefit Imatinib therapy and GISTs monitoring. METHODS: Overall, 1143 GISTs from 3 independent centers were separated into a training cohort (TC) or validation cohort (VC). In addition, the KIT-11 mutation genotype was classified into 4 categories: no KIT-11 mutation (K11-NM), point mutations or duplications (K11-PM/D), KIT-11 557/558 deletions (K11-557/558D), and KIT-11 deletion without codons 557/558 involvement (K11-D). Subsequently, radiomic signatures (RS) were generated based on the arterial phase of contrast CT, which were then developed as KIT-11 mutation predictors using 1408 quantitative image features and LASSO regression analysis, with further evaluation of its predictive capability. RESULTS: The TC AUCs for K11-NM, K11-PM/D, K11-557/558D, and K11-D ranged from 0.848 (95% CI 0.812-0.884), 0.759 (95% CI 0.722-0.797), 0.956 (95% CI 0.938-0.974), and 0.876 (95% CI 0.844-0.908), whereas the VC AUCs ranged from 0.723 (95% CI 0.660-0.786), 0.688 (95% CI 0.643-0.732), 0.870 (95% CI 0.824-0.918), and 0.830 (95% CI 0.780-0.878). Macro-weighted AUCs for the KIT-11 mutant genotype ranged from 0.838 (95% CI 0.820-0.855) in the TC to 0.758 (95% CI 0.758-0.784) in VC. TC had an overall accuracy of 0.694 (95%CI 0.660-0.729) for RS-based predictions of the KIT-11 mutant genotype, whereas VC had an accuracy of 0.637 (95%CI 0.595-0.679). CONCLUSIONS: CT radiomics signature exhibited good predictive performance in estimating the KIT-11 mutation genotype, especially in prediction of K11-557/558D genotype. RS-based classification of K11-NM, K11-557/558D, and K11-D patients may be an indication for choice of Imatinib therapy.

Development and validation of a preoperative nomogram for predicting the surgical difficulty of laparoscopic colectomy for right colon cancer: a retrospective analysis.

BACKGROUND: In laparoscopic right hemicolectomy for right colon cancer, complete mesocolic excision is a standard procedure that involves extended lymphadenectomy and blood vessel ligation. This study aimed to establish a nomogram to facilitate evaluation of the surgical difficulty of laparoscopic right hemicolectomy based on preoperative parameters. MATERIALS AND METHODS: The preoperative clinical and computed tomography-related parameters, operative details, and postoperative outcomes were analyzed. The difficulty of laparoscopic colectomy was defined using the scoring grade reported by Escal et al . with modifications. Multivariable logistic analysis was performed to identify parameters that increased the surgical difficulty. A preoperative nomogram to predict the surgical difficulty was established and validated. RESULTS: A total of 418 consecutive patients with right colon cancer who underwent laparoscopic radical resection at a single tertiary medical center between January 2016 and May 2022 were retrospectively enrolled. The patients were randomly assigned to a training data set ( n =300, 71.8%) and an internal validation data set ( n =118, 28.2%). Meanwhile, an external validation data set with 150 consecutive eligible patients from another tertiary medical center was collected. In the training data set, 222 patients (74.0%) comprised the non-difficulty group and 78 (26.0%) comprised the difficulty group. Multivariable analysis demonstrated that adipose thickness at the ileocolic vessel drainage area, adipose area at the ileocolic vessel drainage area, adipose density at the ileocolic vessel drainage area, presence of the right colonic artery, presence of type III Henle's trunk, intra-abdominal adipose area, plasma triglyceride concentration, and tumor diameter at least 5 cm were independent risk factors for surgical difficulty; these factors were included in the nomogram. The nomogram incorporating seven independent predictors showed a high C-index of 0.922 and considerable reliability, accuracy, and net clinical benefit. CONCLUSIONS: The study established and validated a reliable nomogram for predicting the surgical difficulty of laparoscopic colectomy for right colon cancer. The nomogram may assist surgeons in preoperatively evaluating risk and selecting appropriate patients.

Clinical Application of Indocyanine Green Fluorescence Technology in Laparoscopic Radical Gastrectomy.

Background: This study aimed to observe the application and evaluate the feasibility and safety of indocyanine green (ICG) fluorescence technology in laparoscopic radical gastrectomy (LRG). Methods: Patients who underwent LRG & D2 lymphadenectomy at Qilu Hospital of Shandong University were included between January 2018 and August 2019. According to whether endoscopic injection of ICG was performed, patients were assigned to the ICG group (n=107) and the control group (n=88). The clinicopathologic features, retrieved lymph nodes, postoperative recovery, and follow-up data were compared between the two groups. Results: Baseline characteristics are comparable. The ICG group had a significantly larger number of lymph nodes retrieved (49.55 ± 12.72 vs. 44.44 ± 10.20, P<0.05), shorter total operation time (min) (198.22 ± 13.14 vs. 202.50 ± 9.91, P<0.05), shorter dissection time (min) (90.90 ± 5.34 vs. 93.74 ± 5.35, P<0.05) and less blood loss (ml) (27.51 ± 12.83 vs. 32.02 ± 17.99, P<0.05). The median follow-up time was 29.0 months (range 1.5-43.8 months), and there was no significant difference between the ICG group and the control group in 2-year OS (87.8% vs. 82.9%, P>0.05) or DFS (86.0% vs. 80.7%, P>0.05). Conclusions: ICG fluorescence technology in laparoscopic radical gastrectomy has advantages in LN dissection, operation time, and intraoperative blood loss. The 2-year OS and 2-year DFS rates between the two groups were comparable. In conclusion, ICG fluorescence technology is feasible and safe.

Objective follow-up after transection of uterine round ligament during laparoscopic repair of inguinal hernias in women: assessment of safety and long-term outcomes.

BACKGROUND: Whether to preserve the uterine round ligament during laparoscopic inguinal hernia repair in women is controversial. In this study, we aimed to compare outcomes of uterine round ligament preservation versus transection during such surgery and to explore the impact and long-term outcomes of transecting the round ligament. METHODS: The study cohort comprised 419 women who had undergone laparoscopic inguinal hernia repair in Beijing Chaoyang Hospital and Qilu Hospital from January 2013 to January 2020; 393 (93.8%) of whom were successfully followed up. Patient characteristics and technical details of the operative procedure were collected and analyzed retrospectively. Early and late postoperative follow-up data, complications, especially symptoms related to retroflexed uterus, and fertility outcomes, were collected by a single follow-up nurse who was blinded to the operative procedure. RESULTS: There were 218 women (239 sides) in the uterine round ligament preservation group and 175 (182 sides) in the transection group. The patients in the preservation group were younger (45.9 vs. 53.6 years, p = 0.000), and had lower American Society of Anesthesiologists scores (p = 0.000). The median follow-up times in the preservation and transection groups were 41.8 ± 24.2 and 42.7 ± 24.6 months, respectively (p = 0.692). Compared with the transection group, the preservation group had longer operative times for repair of both primary and recurrent hernias. Intraoperative bleeding, length of hospital stay, development of seromas, recurrence rate, incidence of postoperative pain at the first and third postoperative months, and time of last outpatient visit were similar in the two groups. There were more premenopausal patients in the preservation group; however, we found no evidence that transection of the round ligament affected subsequent pregnancy or childbirth. Moreover, we identified no differences in dyspareunia, dysmenorrhea, chronic pelvic pain, or uterine prolapse. CONCLUSION: Transection of the round ligament during laparoscopic inguinal hernia repair in women does not increase the incidence of dyspareunia, dysmenorrhea, chronic pelvic pain, or uterine prolapse, whereas it has the advantage of reducing the operation time.

Exploring Central Vascular Anatomy With Axial Computed Tomography During Surgery for Sigmoid Colon and Rectal Cancer: New Insights Into the Anatomical Relationship Between the Inferior Mesenteric Artery and the Duodenum.

Background: In some individuals, the inferior mesenteric artery (IMA) originates from the aorta above the lower edge of the duodenum. This anatomical feature has rarely been reported but may be important in guiding central vascular ligation and lymph node dissection in colorectal surgery. This retrospective study aimed to explore the anatomical relationship between the IMA and the duodenum and evaluate its potential impact on the efficacy of D3 lymph node dissection. Methods: A total of 439 patients undergoing laparoscopic colorectal surgery at the Department of General Surgery, Qilu Hospital of Shandong University, were retrospectively enrolled. Clinical data from axial computed tomography (CT) scans were collected and analysed. Results: In 27.69% of patients, the IMA originated at or above the lower edge of the duodenum (median distance: -8 mm). These patients were characterised by a shorter superior mesenteric artery to aortic bifurcation distance, a superiorly located IMA origin, and a greater distance between the IMA and both the left colic artery and the inferior mesenteric vein. The number of harvested lymph nodes was not significantly associated with the distance between the IMA and the duodenum (P = 0.858). Conclusions: Preoperative axial CT scans can provide a great deal of information regarding central vascular anatomy in the context of sigmoid colon and rectal cancer surgery. Nearly one-third of patients have the IMA originating at or above the duodenum. Whether this anatomical feature affects D3 lymph node dissection warrants further investigation.

Non-closure of the Free Peritoneal Flap During Laparoscopic Hernia Repair of Lower Abdominal Marginal Hernia: A Retrospective Analysis.

Background: During lower abdominal marginal hernia repair, the peritoneal flap is routinely freed to facilitate mesh placement and closed to conclude the procedure. This procedure is generally called trans-abdominal partial extra-peritoneal (TAPE). However, the necessity of closing the free peritoneal flap is still controversial. This study aimed to investigate the safety and feasibility of leaving the free peritoneal flap in-situ. Methods: A retrospective review was conducted on 68 patients (16 male, 52 female) who underwent laparoscopic hernia repair between June 2014 and March 2021. Patients were diagnosed as the lower abdominal hernia and all required freeing the peritoneal flap during the operation. Patients were divided into 2 groups: one group was TAPE group with the closed free peritoneal flap, another group left the free peritoneal flap unclosed. Analyses were performed to compare both intraoperative parameters and postoperative complications. Results: There were no significant differences in demographic, comorbidity, hernia characteristics and ASA classification. The intra-operative bleeding volume, visceral injury, hospital stay, urinary retention, visual analog scale (VAS) score, dysuria, intestinal obstruction, surgical site infection, mesh infection, recurrence rate and hospital stay were similar among the two groups. Mean operative time of the flap closing procedure was higher than for patients with the free peritoneal flap left in-situ (p = 0.002). Comparisons of postoperative complications showed flap closure resulted in a higher incidence of seroma formation (p = 0.005). Conclusion: Providing a barrier-coated mesh is used during laparoscopic lower abdominal marginal hernia repair, it is safe to leave the free peritoneal flap in-situ and this approach may prevent the occurrence of seromas.

Enhanced Production of Pterostilbene in Escherichia coli Through Directed Evolution and Host Strain Engineering.

Pterostilbene is a derivative of resveratrol with a higher bioavailability and biological activity, which shows antioxidant, anti-inflammatory, antitumor, and antiaging activities. Here, directed evolution and host strain engineering were used to improve the production of pterostilbene in Escherichia coli. First, the heterologous biosynthetic pathway enzymes of pterostilbene, including tyrosine ammonia lyase, p-coumarate: CoA ligase, stilbene synthase, and resveratrol O-methyltransferase, were successively directly evolved through error-prone polymerase chain reaction (PCR). Four mutant enzymes with higher activities of in vivo and in vitro were obtained. The directed evolution of the pathway enzymes increased the pterostilbene production by 13.7-fold. Then, a biosensor-guided genome shuffling strategy was used to improve the availability of the precursor L-tyrosine of the host strain E. coli TYR-30 used for the production of pterostilbene. A shuffled E. coli strain with higher L-tyrosine production was obtained. The shuffled strain harboring the evolved pathway produced 80.04 ± 5.58 mg/l pterostilbene, which is about 2.3-fold the highest titer reported in literatures.

Central GLP-1 contributes to improved cognitive function and brain glucose uptake after duodenum-jejunum bypass on obese and diabetic rats.

The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and Glp-1r KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.NEW & NOTEWORTHY The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.

Sleeve Gastrectomy Ameliorates Diabetes-Related Spleen Damage by Improving Oxidative Stress Status in Diabetic Obese Rats.

PURPOSE: Oxidative stress and inflammation are important pathogenic mediators in diabetes-related organ damage. Accumulating evidence suggests that immunodeficiency in diabetes is associated with diabetes-induced spleen damage. Sleeve gastrectomy (SG) has been proved to improve diabetes and its multiple associated complications. However, the ameliorative role of SG against spleen damage in diabetes has not been investigated. MATERIALS AND METHODS: Animal model of diabetic obese rats induced by high-fat diet (HFD) combined with streptozotocin (STZ) was treated with sham operation, caloric restriction, and SG. Metabolic parameters were measured, and the morphological and histopathological changes, status of oxidative stress, and levels of inflammatory factors were evaluated. RESULTS: SG reduced body weight and improved glucose tolerance and insulin sensitivity in diabetic obese rats. SG significantly reversed splenic atrophy and alleviated abnormalities of white and red pulp. Additionally, SG also reversed the increased splenocyte apoptosis (P < 0.001). Meanwhile, indicators of oxidative stress including reactive oxygen species (ROS), nitric oxide (NO), malondialdehyde (MDA), and protein carbonylation were reduced, and the activity and expression of antioxidant enzymes including SOD and CAT were improved after SG. The mRNA expression of inflammatory factors in SG groups such as TNF-α (P < 0.001), IL-6 (P < 0.001), MCP-1 (P < 0.01), and ICAM-1 (P < 0.001) was also significantly reduced. CONCLUSION: SG ameliorates diabetes-related splenic injury by restoring the balance between oxidative stress process and antioxidant defense systems as well as reducing inflammation in the spleen. These findings indicate that SG is an appropriate therapeutic strategy for diabetes-related spleen damage.

Sleeve gastrectomy ameliorates endothelial function and prevents lung cancer by normalizing endothelin-1 axis in obese and diabetic rats.

BACKGROUND: Previous evidence has implied that obesity is an independent risk factor for developing cancer. Being closely related to obesity, type 2 diabetes mellitus provides a suitable environment for the formation and metastasis of tumors through multiple pathways. Although bariatric surgeries are effective in preventing and lowering the risk of various types of cancer, the underlying mechanisms of this effect are not clearly elucidated. AIM: To uncover the role and effect of sleeve gastrectomy (SG) in preventing lung cancer in obese and diabetic rats. METHODS: SG was performed on obese and diabetic Wistar rats, and the postoperative transcriptional and translational alterations of the endothelin-1 (ET-1) axis in the lungs were compared to sham-operated obese and diabetic rats and age-matched healthy controls to assess the improvements in endothelial function and risk of developing lung cancer at the postoperative 4th, 8th, and 12th weeks. The risk was also evaluated using nuclear phosphorylation of H2A histone family member X as a marker of DNA damage (double-strand break). RESULTS: Compared to obese and diabetic sham-operated rats, SG brought a significant reduction to body weight, food intake, and fasting blood glucose while improving oral glucose tolerance and insulin sensitivity. In addition, ameliorated levels of gene and protein expression in the ET-1 axis as well as reduced DNA damage indicated improved endothelial function and a lower risk of developing lung cancer after the surgery. CONCLUSION: Apart from eliminating metabolic disorders, SG improves endothelial function and plays a protective role in preventing lung cancer via normalized ET-1 axis and reduced DNA damage.

Sleeve Gastrectomy Attenuates Diabetic Nephropathy by Upregulating Nephrin Expressions in Diabetic Obese Rats.

PURPOSE: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and sleeve gastrectomy (SG) is considered to be an effective strategy to improve pre-existing DN. However, the mechanism remains unknown. MATERIALS AND METHODS: Animal model of DN was induced by high-fat diet (HFD) and streptozotocin (STZ). SG or sham surgery was performed and rats were sacrificed at 4, 8, and 12 weeks after surgery. The basic parameters (blood glucose, body weight, kidney weight), indicators of renal function including serum creatinine (Scr), blood urea nitrogen (BUN), urine microalbumin, urine creatinine (Ucr), microalbumin creatinine ratio (UACR), ultrastructural changes of glomerulus, and the expression of nephrin gene and protein in glomerular podocytes were compared among groups. RESULTS: Blood glucose and body weight of SG rats were significantly lower than those of the sham-operated rats, and renal function of SG groups were also significantly improved within the postoperative period of 12 weeks. The results of periodic acid-Schiff staining (PAS) and transmission electron microscopy (TEM) showed that glomerular hypertrophy and accumulation of extracellular matrix proteins were significantly alleviated after SG, and the thickness of basement membrane and the fusion or effacement of foot processes were also significantly improved. The mRNA and protein expression of nephrin in SG groups was significantly higher than that in the sham group. CONCLUSION: These results suggest that SG attenuates DN by upregulating the expression of nephrin and improving the ultrastructure of glomerular filtration membrane. This study indicates that SG can be used as an available therapeutic intervention for DN.

Correlation between laparoscopic transection of an indirect inguinal hernial sac and postoperative seroma formation: a prospective randomized controlled study.

BACKGROUND: Seroma is the most common early minor complication of inguinal hernia repair. Seromas generally resolve spontaneously within a few weeks, but can sometimes cause other complications. The optimal ways to repair inguinal hernia and handle the hernial sac are still debatable. Large scale, prospective, randomized, controlled studies focusing on the correlation between transection of the hernial sac and seroma formation are scarce. METHODS: A total of 159 adult male patients with primary indirect inguinal hernia who underwent laparoscopic transabdominal preperitoneal repair were recruited. The patients were randomized to undergo either complete dissection or transection of the hernial sacs. Patients were followed up at postoperative 7 days, 1 and 3 months, looking specifically for seroma. Seroma was diagnosed via physical examination, and a prestructured form was used to evaluate patient recovery and define the type of seroma present at each follow-up visit. RESULTS: There were 83 patients in the completely dissected group and 76 in the transected group. The overall incidence of postoperative seroma was 12.6% (n = 20). The χ2 test demonstrated that significantly more patients developed seroma in the transected group than in the completely dissected group (18.4% vs. 7.2%, p = 0.034); there were also significant differences between the two groups in the incidences of seroma at postoperative 7 days (18.4% vs. 6.0%, p = 0.016) and 1 month (14.5% vs. 4.8%, p = 0.037). Seroma formation was correlated with age, body mass index, use of anticoagulants, hernia type, hernia size, sac size, and operative time. There were no significant differences between the two groups in the degree of postoperative pain and time taken for the resumption of outdoor activities. CONCLUSIONS: When using the laparoscopic transabdominal preperitoneal technique for indirect inguinal hernia repair, the risk of postoperative seroma formation is greater after transection compared with complete dissection of the hernial sac.

Transcriptome sequencing identifies key pathways and genes involved in gastric adenocarcinoma.

The present study aimed to investigate the key pathways and genes associated with gastric adenocarcinoma via transcriptome sequencing. Five pairs of gastric adenocarcinoma tissue and normal tumor­adjacent tissue were harvested. After sequencing, raw data were processed and differentially expressed genes (DEGs) between tumor and control groups were screened, followed by functional enrichment analysis and gene clustering analysis. The effect of DEGs on patient prognosis was analyzed on the basis of the survival data from gastric adenocarcinoma patients in The Cancer Genome Atlas database. Several genes were validated through reverse transcription­quantitative polymerase chain reaction. In total, 1,477 upregulated and 282 downregulated DEGs were screened in tumor groups. These genes were segregated into four clusters. Genes in cluster 1 were significantly involved in metabolism of xenobiotics by cytochrome P450, genes in cluster 2 were majorly involved in apoptosis, tight junction formation, and platelet activation, genes in cluster 3 were primarily enriched in the p53 signaling pathway and genes in cluster 4 were significantly enriched in the insulin resistance pathway. Furthermore, 15 DEGs significantly influenced prognosis, including F2R, CTHRC1, and RASGRP3. The expression levels of CYP2B6, MAPK13, CTHRC, RASGRP3 and PYGM were consistent with our analysis results. In conclusion, pathways for metabolism of xenobiotics via cytochrome P450, apoptosis, tight junction formation, platelet activation, and insulin resistance may serve important roles in the progression of gastric adenocarcinoma. Notably, CTHRC1 and RASGRP3 may serve as key prognostic markers.

The modified laparoscopic keyhole parastomal hernia repair with in situ re-ostomy has low recurrence rate.

PURPOSE: This study aimed to present a modified laparoscopic keyhole parastomal hernia repair technique with in situ re-ostomy and show its safety and feasibility at a mid-term follow-up. METHODS: The technique begins with adhesiolysis during laparoscopy. An annular incision is made between the skin and stomal mucosa. Then, after all adhesions of the stomal bowel and its mesentery are separated from the hernial sac, the stomal bowel is delivered through the keyhole mesh. The mesh is then stitched to the stomal bowel and placed intraperitoneally. The hernial ring is narrowed, and the mesh is further stitched to the hernial ring and stomal tube. After the mesh is fixed, the redundant stomal bowel is shortened, and a new in situ stoma is matured in the conventional way. RESULTS: Altogether, 65 consecutive patients underwent successful hernia repair via a modified laparoscopic keyhole with in situ re-ostomy. Two of the patients had recurrent parastomal hernias. No mortalities occurred during the perioperative period. Morbidities included two cases of seroma and three of ileus, all of which were cured with conservative treatment. In addition, one case of intestinal perforation was rescued by intestinal resection and enteroenterostomy. Median follow-up was 29 months (range 3-60 months). No complications of mesh-related infection or patch erosion were noted during the follow-up. CONCLUSIONS: Modified laparoscopic keyhole parastomal hernia repair with in situ re-ostomy is a safe procedure with a low recurrence rate at the mid-term follow-up.

Deactivation of the NLRP3 inflammasome in infiltrating macrophages by duodenal-jejunal bypass surgery mediates improvement of beta cell function in type 2 diabetes.

OBJECTIVE: Bariatric surgery could improve pancreatic beta cell function, thereby leading to the remission of the type 2 diabetes mellitus (T2DM). However, the specific mechanism underlying this phenomenon is yet to be revealed. The aim of this study is to test the hypothesis that Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in infiltrating macrophages plays an important role in the modulation of beta cell function after duodenal-jejunal bypass (DJB) surgery. METHODS: DJB and sham surgery were performed in diabetic Sprague-Dawley (SD) rats induced by high-fat diet (HFD) and streptozotocin (STZ). Body weight, food intake, and glucose tolerance test (GTT) were measured at indicated time points. Apoptosis of the beta cells was measured by Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) assay. We also assessed the macrophage content and NLRP3 expression in the rat model. Furthermore, macrophage reconstitution was performed after DJB surgery. Beta cell function and NLRP3 inflammasome pathway were re-evaluated in wild-type macrophage reconstitution group and NLRP3-knockdown macrophage reconstitution group. RESULTS: DJB surgery group rats displayed rapid and sustained improvement in glucose tolerance. Decreased apoptosis and improved secretion function of the beta cells were observed in DJB surgery group. NLRP3 inflammasome pathway in infiltrating macrophages was also suppressed after DJB surgery. Moreover, diabetic remission acquired by DJB sustained in NLRP3-knockdown macrophage reconstitution group, while extinguished in group reconstituted with wild-type macrophage. CONCLUSIONS: NLRP3 inflammasome deactivation in infiltrating macrophages is involved in marked beta cell function improvement after DJB surgery.

Duodenal-jejunal bypass surgery on type 2 diabetic rats reduces the expression of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in the thoracic aorta.

BACKGROUND: Bariatric surgery offers a productive resolution of type 2 diabetes mellitus (T2DM). The development of T2DM vasculopathy is due to chronic inflammation, which increases matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) expression. This study sought to examine MMP-9 and TIMP-1 expression in the thoracic aorta after duodenal-jejunal bypass (DJB) surgery on a T2DM rat model induced by a high-fat diet and low dose streptozotocin (STZ). METHODS: Twenty-one T2DM Wistar rats induced by high-fat diet and low dose STZ were randomly divided into DJB and sham duodenal-jejunal bypass (S-DJB) groups. Ten Wistar rats were fed a normal diet as a control. Recovery of gastrointestinal function post-operation and resumption of a normal diet completed the experiment. Body weight, blood glucose, blood lipid levels, and MMP-9 and TIMP-1 expression levels in aortic endothelial cells were measured throughout. RESULTS: DJB rats showed significant weight loss 2 weeks post-operation compared with S-DJB rats. After surgery, DJB rats showed significant improvement and steady glycemic control with improved insulin sensitivity and glucose tolerance. They also exhibited improved lipid metabolism with a decrease in fasting free fatty acids (FFAs) and triglycerides (all P < 0.05). Immunohistochemistry showed decreased MMP-9 and TIMP-1 expression 12 weeks after surgery (P < 0.01). CONCLUSIONS: DJB surgery on an induced T2DM rat model improves blood glucose levels and lipids, following a high-fat diet and low dose STZ treatment. In addition, DJB decreased MMP-9 and TIMP-1 expression in vascular endothelial cells, which may play an important role in delaying the development of T2DM vascular disease.

Differential role for p120-catenin in regulation of TLR4 signaling in macrophages.

Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-кB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow-derived macrophages. We observed that p120 inhibited MyD88-dependent NF-κB activation and release of TNF-α and IL-6, but enhanced TIR domain-containing adapter-inducing IFN-ß-dependent IFN regulatory factor 3 activation and release of IFN-ß upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4-TIR domain-containing adapter-inducing IFN-ß signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS-induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin.