Immune disguise: the mechanisms of Neu5Gc inducing autoimmune and transplant rejection.

Organ (stem cell) transplantation is the most effective treatment for advanced organ failure. Neu5Gc (N-hydroxyacetylneuraminic acid) is a pathogenic non-human sialic acid, which is very similar to the molecular structure of Neu5Ac (N-acetylneuraminic acid) in human body. Neu5Gc has the function of "immune disguise", which is the main obstacle to transplantation. Gene knockout such as cytidine monophosphate-N-acetylneuraminidase (CMAH) reduces donor antigenicity, making xenotransplantation from fiction to reality. Exploring the immune disguise event in this emerging field has become a hot topic in the research of transplantation immune tolerance mechanism.

Inguinal hernias in patients on continuous ambulatory peritoneal dialysis: is tension-free mesh repair feasible?

BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD), which often causes a common complication such as abdominal wall hernia, is a prevalent alternative therapy for end-stage renal failure patients. However, relevant studies are somewhat rare, and the peritoneal dialysis (PD) protocol during the perioperative period is still controversial. The aim of this study was to evaluate the effectiveness and perioperative management of tension-free mesh repair for inguinal hernias in CAPD patients. METHODS: Between January 2013 and December 2019, 18 CAPD patients with 20 inguinal hernias who underwent tension-free mesh repair were retrospectively analyzed. Data on demographics, perioperative features, the perioperative dialysis protocol and surgical complications were collected and assessed. RESULTS: All hernias were diagnosed after the start of CAPD, and the median duration from PD onset to hernia formation was 16 months (2-61 months). All patients underwent successful tension-free mesh repair, including 17 Lichtenstein and 3 anterior Kugel procedures. The median operation time was 62.5 min, and the median postoperative hospital stay was 3 days. Fifteen patients received low-exchange volumes and high-frequency exchanges from 1 to 3 days after surgery for 2 weeks with gradual resumption of the original CAPD regimen within 4 weeks. Complications included seroma (n = 2) and hematoma (n = 1). No wound or mesh infection or recurrence occurred during the follow-up period. CONCLUSIONS: Tension-free mesh repair is safe and feasible for inguinal hernias in CAPD patients, The Lichtenstein mesh repair should be the first choice, and anterior Kugel repair may be considered an effective procedure. Bridging hemodialysis seems unnecessary except for emergency surgery.

Correlation of postoperative splenic volume increase with prognosis of hepatocellular carcinoma after curative hepatectomy

Background: Previous studies have reported a close connection between the spleen and hepatic tumours. We investigated the prognostic value of postoperative splenic volume increase (PSVI) in patients with hepatocellular carcinoma after curative hepatectomy. Methods: This was a retrospective study of adult patients with hepatocellular carcinoma who underwent hepatectomy between January 2007 and May 2013. We categorized patients into 2 groups according to the cut-off value of the receiver operating characteristic curve: group A (PSVI < 19.0%) and group B (PSVI ≥ 19.0%). We compared the clinicopathological data, overall survival and disease-free survival between the 2 groups. We performed univariate and multivariate analyses to identify factors associated with disease-free and overall survival. Results: There were 275 patients in group A and 196 patients in group B. The 1-, 3- and 5-year overall survival rates were 98.9%, 74.9% and 63.6%, respectively, for patients in group A, and 97.4%, 65.3% and 49.8%, respectively, for patients in group B (p = 0.004). The corresponding disease-free survival rates were 69.5%, 48.0% and 40.3%, and 58.1%, 36.5%, and 29.8% (p = 0.01). On multivariate analysis, PSVI was an independent predictor of overall (p = 0.01) and disease-free (p = 0.03) survival. Conclusion: Postoperative splenic volume increase correlates with poor prognosis of patients with hepatocellular carcinoma after curative hepatectomy.

Contexte: Des études antérieures faisaient état d'un lien étroit entre la rate et les tumeurs hépatiques. Nous avons étudié la valeur pronostique de l'augmentation postopératoire du volume de la rate (APVR) chez les patients ayant subi une hépatectomie curative en raison d'un carcinome hépatocellulaire. Méthodes: Il s'agit d'une étude rétrospective portant sur des adultes qui ont subi une hépatectomie entre janvier 2007 et mai 2013 pour cause de carcinome hépatocellulaire. Nous avons classé les patients en 2 groupes, selon un seuil sur la courbe ROC : le groupe A (APVR : < 19,0 %) et le groupe B (APVR : ≥ 19,0 %). Nous avons ensuite comparé les données clinicopathologiques, le taux de survie globale et le taux de survie sans récidive des 2 groupes, et avons effectué des analyses univariées et multivariées pour repérer les facteurs associés à la survie sans récidive et à la survie globale. Résultats: Le groupe A comptait 275 patients, tandis que le groupe B en comptait 196. Les taux de survie globale à 1 an, à 3 ans et à 5 ans étaient de 98,9 %, de 74,9 % et de 63,6 %, respectivement, dans le groupe A, et de 97,4 %, de 65,3 % et de 49,8 %, respectivement, dans le groupe B (p = 0,004). Les taux de survie sans récidive à 1 an, à 3 ans et à 5 ans étaient de 69,5 %, de 48,0 % et de 40,3 %, respectivement, dans le groupe A, et de 58,1 %, de 36,5 % et de 29,8 %, respectivement, dans le groupe B (p = 0,01). Selon l'analyse multivariée, l'APVR était un prédicteur indépendant de survie globale (p = 0,01) et de survie sans récidive (p = 0,03). Conclusion: L'augmentation postopératoire du volume de la rate est corrélée à un mauvais pronostic chez les patients ayant subi une hépatectomie curative en raison d'un carcinome hépatocellulaire.

Effects of different foods on blood glucose and lipid in type 2 diabetes mellitus in a rat model.

BACKGROUND: This study investigated the effects of duodenal-jejunal bypass (DJB) and new biliopancreatic diversion (NBPD) on blood glucose and lipid levels in type 2 diabetes mellitus (T2DM). An additional goal was to explore the potential mechanism or mechanisms underlying the therapeutic effects of surgery on T2DM. METHODS: Rats were fed a high-fat, high-glucose diet and then were intraperitoneally injected with streptozotocin, 35 mg/kg, to induce T2DM. Then, 33 T2DM rats were randomly assigned to one of three groups, a DJB group, an NBPD group, or a sham group. Fasting body weight, fasting glucose, and 2-h postprandial glucose were measured before and after surgery. Then, the rats were intragastrically administered lipid emulsion, peanut oil, glucose, starch, and Ansul, and blood glucose and lipid levels were measured. RESULTS: One week after surgery, 2-h postprandial glucose decreased from 24.41 ± 2.28 mmol/L before surgery to 19.87 ± 4.07 mmol/L after surgery in the DJB group, and from 25.88 ± 1.91 mmol/L before surgery to 20.34 ± 5.76 mmol/L after surgery in the NBPD group. After intragastric administration of lipid emulsion, free fatty acid levels increased from 534.60 ± 70.99 to 1082.83 ± 259.67 µEq/L in the DJB group and from 648.33 ± 139.26 to 1258.67 ± 204.18 µEq/L in the NBPD group. After surgery, free fatty acid levels in the DJB group and NBPD group were significantly lower than those in the sham group. CONCLUSIONS: Postprandial blood glucose and lipids decreased after DJB and NBPD, which may be ascribed to postoperative changes in digestion and absorption.

CT-based radiomics for predicting pathological grade in hepatocellular carcinoma.

Objective: To construct and validate radiomics models for hepatocellular carcinoma (HCC) grade predictions based on contrast-enhanced CT (CECT). Methods: Patients with pathologically confirmed HCC after surgery and underwent CECT at our institution between January 2016 and December 2020 were enrolled and randomly divided into training and validation datasets. With tumor segmentation and feature extraction, radiomic models were constructed using univariate analysis, followed by least absolute shrinkage and selection operator (LASSO) regression. In addition, combined models with clinical factors and radiomics scores (Radscore) were constructed using logistic regression. Finally, all models were evaluated using the receiver operating characteristic (ROC) curve with the area under the curve (AUC), calibration curve, and decision curve analysis (DCA). Results: In total 242 patients were enrolled in this study, of whom 170 and 72 formed the training and validation datasets, respectively. The arterial phase and portal venous phase (AP+VP) radiomics model were evaluated as the best for predicting HCC pathological grade among all the models built in our study (AUC = 0.981 in the training dataset; AUC = 0.842 in the validation dataset) and was used to build a nomogram. Furthermore, the calibration curve and DCA indicated that the AP+VP radiomics model had a satisfactory prediction efficiency. Conclusions: Low- and high-grade HCC can be distinguished with good diagnostic performance using a CECT-based radiomics model.

Global burden of adult non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) has been steadily increasing over the past decades and is expected to persist in the future.

Background: At present, there is a dearth of comprehensive data at the global, national, and regional levels regarding the adult non-alcoholic fatty liver disease (NAFLD) prevalence. This cross-sectional study aims at ascertaining the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH), utilizing body mass index (BMI) as a determining factor. Methods: Based on the NHANES database, sigmoidal fitting curves were generated to establish the relationship between BMI and the risk of NAFLD/NASH. Utilizing BMI data from the NCD Risk Factor Collaboration (NCD-RisC) database at both global and regional levels, the prevalence of NAFLD/NASH among adults was estimated from 1975 to 2016, encompassing global, regional, and national perspectives. Additionally, projections were made to forecast the prevalence of adult NAFLD/NASH from 2017 to 2030. Results: In 2016, the global prevalence of NAFLD was 41.12% for males and 37.32% for females, while the global prevalence of NASH was 15.79% for males and 16.48% for females. The prevalence of NAFLD/NASH increased with higher BMI in both genders. Over the period from 1975 to 2016, there has been a gradual increase in the global prevalence of NAFLD/NASH in adults, and this trend is expected to continue between 2017 and 2030. In males, the prevalence of adult NAFLD/NASH was found to be highest in High-income Western countries, while it was highest in Central Asia, Middle East, and North African countries after 1995. Conclusions: The prevalence of adult NAFLD/NASH has been observed to increase annually, with significant variations in burden across different countries and regions.

Cerebral 18F-FDG PET/CT Metabolism as Diagnostic Signature for Central Nervous System Toxicity After Immune Checkpoint Blockade Cancer Treatment.

Our aim was to investigate probable biomarkers specific to immune-related central nervous system toxicity (CNST) in cancer patients treated with immune checkpoint inhibitors (ICI) by analysis of 18F-FDG PET/CT images. Methods: Cancer patients receiving ICI treatment were enrolled in a multicenter observational study that analyzed regional metabolic changes before and during CNST onset from January 2020 to February 2022. In 1:1 propensity score-matched pairs, the regional SUVmean of each bilateral brain lobe of CNST patients (CNST+) was compared with that of patients who had central nervous system infections (CNSIs) and patients without CNST or CNSI (CNST-). In a validation cohort, patients were recruited from February 2022 to July 2023 and followed up for 24 wk after the start of ICI. Early changes in regional SUVmean at 5-6 wk after therapy initiation were evaluated for ability to predict later CNST onset. Results: Of 6,395 ICI-treated patients, 2,387 underwent prognostic 18F-FDG PET/CT and 125 of the scanned patients had CNST (median time from ICI treatment to onset, 9 wk; quartile range, 2-23 wk). Regional 18F-FDG PET/CT SUVmean changes were higher in CNST+ than in CNST- patients (117 patient pairs) but were lower than in CNSI patients (50 pairs). Differentiating analysis reached an area under the curve (AUC) of 0.83 (95% CI, 0.78-0.88) for CNST+ versus CNST- and of 0.80 (95% CI, 0.72-0.89) for CNST+ versus CNSI. Changes in SUVmean were also higher before CNST onset than for CNST- (60 pairs; AUC, 0.74; 95% CI, 0.66-0.83). In a validation cohort of 2,878 patients, preonset changes in SUVmean reached an AUC of 0.86 (95% CI, 0.79-0.94) in predicting later CNST incidence. Conclusion: Brain regional hypermetabolism could be detected during and before CNST clinical onset. CNST may be a distinct pathologic entity versus brain infections defined by 18F-FDG PET/CT brain scans. Regional SUV differences may be translated into early diagnostic tools based on moderate differentiating accuracy in our study.

Adropin deficiency worsens TNBS-induced colitis.

The aim of this study was to describe the effects of adropin deficiency on the distribution, phenotype and pathological phenotype of macrophages in colonic and mesenteric tissues of AdrKO (Enho-/-) mice, so as to explore the mechanism of adropin deficiency in spontaneous and experimental colitis. In this study, RNA-seq and metabonomics were used to screen the regulatory mechanism of adropin on the phenotypic transformation of macrophages. We found that adropin levels in active UC patients were significantly lower than those in normal subjects and remission UC patients, and at the same time, a large number of proinflammatory M1-type macrophages were infiltrated in the mesenteric tissue of colonic tissues from UC and CD patients. At the same time, spontaneous colitis occurred in Enho-/- (adropin-deficient)C57BL/6 mice, and there was an imbalance of M2 â†’ M1 polarization of macrophages in colon and mesentery of Enho-/- mice. In vivo, it has showed that adropin deficiency could exacerbate the pathological phenotype of colitis induced by TNBS. In vitro, adropin was used to intervene RAW264.7 macrophages, and then combined analysis of RNA-seq and metabolomics demonstrated that adropin regulated lipid metabolism of macrophages through PPARγ, thus promoting the repolarization of macrophages from M1 to M2. Adropin deficiency led to an imbalance in the phenotypic distribution of macrophages infiltrating the colon and mesenteric tissues, namely, an increase in M1 type, which led to the occurrence and development of colitis.

Adropin attenuates pancreatitis­associated lung injury through PPARγ phosphorylation­related macrophage polarization.

Acute pancreatitis (AP)­associated lung injury (ALI) is a critical complication of AP. Adropin is a regulatory protein of immune metabolism. The present study aimed to explore the immunomodulatory effects of adropin on AP­ALI. For this purpose, serum samples of patients with AP were collected and the expression levels of serum adropin were detected using ELISA. Animal models of AP and adropin knockout (Adro­KO) were constructed, and adropin expression in serum and lung tissues was investigated. The levels of fibrosis and apoptosis were evaluated using hematoxylin and eosin staining, Masson's staining and immunohistochemistry of in lung tissue. M1/M2 type macrophages in the lungs were detected using immunofluorescence staining, western blot analysis and reverse transcription­quantitative PCR. As shown by the results, adropin expression was decreased in AP. In the Adro­KO + L­arginine (L­Arg) group, macrophage infiltration, fibrosis and apoptosis were increased. The expression of peroxisome proliferator­ activated receptor γ (PPARγ) was downregulated, and the macrophages exhibited a trend towards M1 polarization in the Adro­KO + L­Arg group. Adropin exogenous supplement attenuated the levels of fibrosis and apoptosis in the model of AP. Adropin exogenous supplement also increased PPARγ expression by the regulation of the phosphorylation levels, which was associated with M2 macrophage polarization. On the whole, the findings of the present study suggest that adropin promotes the M2 polarization of lung macrophages and reduces the severity of AP­ALI by regulating the function of PPARγ through the regulation of its phosphorylation level.

METTL3 enhances pancreatic ductal adenocarcinoma progression and gemcitabine resistance through modifying DDX23 mRNA N6 adenosine methylation.

The aim of the present study was to clarify the mechanism of how METTL3 regulated pancreatic ductal adenocarcinoma (PDAC) progression by m6A modification of its downstream target mRNA and signaling pathway. Immunoblotting and qRT-PCR assays was employed to determine the expression levels of METTL3. In situ fluorescence hybridization was conducted to localize the cellular distribution of METTL3 and DEAD-box helicase 23 (DDX23). CCK8, colony formation, EDU incorporation, TUNEL, wound healing and Transwell assays were carried out accordingly to study the viability, proliferation, apoptosis, and mobility of cells under different treatments in vitro. Xenograft and animal lung metastasis experiments were also conducted to study the functional role of METTL3 or DDX23 on tumor growth and lung metastasis in vivo. MeRIP-qPCR and bioinformatical analyses were used to obtain the potential direct targets of METTL3. It was shown that m6A methyltransferase METTL3 was upregulated in PDAC tissues with gemcitabine resistance, and its knockdown sensitized pancreatic cancer cells to chemotherapy. Furthermore, silencing METTL3 remarkably reduced pancreatic cancer cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, validation experiments confirmed that DDX23 mRNA was a direct target of METTL3 in YTHDF1-dependent manner. Additionally, DDX23 silence resulted in the suppression of pancreatic cancer cell malignancy and PIAK/Akt signaling inactivation. Strikingly, rescuse experiments demonstrated the inhibitive effects of METTL3 silence on cell phenotypes and gemcitabine resistance were partially reversed by forcibly expressed DDX23. In summary, METTL3 promotes PDAC progression and gemcitabine resistance by modifying DDX23 mRNA m6A methylation and enhancing PI3K/Akt signaling activation. Our findings establish a potential tumor promotive and chemo-resistant role for METTL3/DDX23 axis in PDAC.

Global burden of common cancers attributable to metabolic risks from 1990 to 2019.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is usually accompanied by metabolic syndrome, which is associated with increased risk of cancer. To inform a tailored cancer screen in patients at higher risks, we estimated the global burden of cancer attributable to metabolic risks. METHODS: Data of common metabolism-related neoplasms (MRNs) were derived from the Global Burden of Disease (GBD) 2019 database. Age-standardized, disability-adjusted life year (DALY) rates and death rates of patients with MRNs were extracted from the GBD 2019 database and stratified by metabolic risk, sex, age, and level of socio-demographic index (SDI). The annual percentage changes of age-standardized DALYs and death rates were calculated. FINDINGS: Metabolic risks, consisting of high body mass index and fasting plasma glucose, contributed substantially to the burden of neoplasms, including colorectal cancer (CRC), tracheal, bronchus, and lung cancer (TBLC), etc. Globally, in 2019, there was an estimated age-standardized DALY rate (ASDR) of 234 (95% confidence interval [CI] 124-376) per 100,000 person years for neoplasms attributable to metabolic risks. ASDRs of MRNs were higher for CRC, TBLC, men, patients aged ≥50 years, and patients with high or high-middle SDI. CONCLUSIONS: The findings of this study further underpin the correlation between NAFLD and intrahepatic and extrahepatic cancers and highlight the possibility of tailored cancer screening for the NAFLD population at higher risks. FUNDING: This work was supported by the National Natural Science Foundation of China and Natural Science Foundation of Fujian Province of China.

Multi-omics Analysis Reveals the Crucial Mediators of DJB in the Treatment of Type 2 Diabetes.

PURPOSE: Duodenal-jejunal bypass (DJB) has a definite hypoglycemic effect; however, the intrinsic mechanisms remain unclear. The purpose of this study was to determine whether DJB may cause changes in the gut microbiota and metabolite of portal venous blood and to explore the effects of DJB on blood glucose metabolism. METHODS: T2DM was induced in rats with a high-fat diet and a low dose of streptozotocin, which were randomly divided into two groups: Sham operation and DJB. RESULTS: DJB significantly improved several diabetic parameters. 16S rRNA analyses showed that the compositions of the gut microbiota were significantly different between the two groups. The results of metabolomics showed that DJB could significantly regulate the metabolites, among which diaminopimelic acid and isovaleric acid had a significant down-regulation in the DJB group. Transcriptomic analysis showed that DJB can regulate the expression of hepatic genes related to abnormal glucose metabolism, such as Ltc4s, Alox15, Ggt1, Gpat3, and Cyp2c24. Correlation analyses showed that diaminopimelic acid was positively associated with Allobaculum, Serratia, and Turicibacter. There was a significant correlation between diaminopimelic acid and Gpat3, and its Spearman correlation coefficient was the highest among metabolite-DEG pairs (ρ=0.97). DISCUSSIONS: These results suggest an important cue of the relation between the diaminopimelic acid, Gpat3, and gut microbiome in the mechanism by which DJB can improve glucose metabolism.

Two-point Fixation for Biological Mesh in Laparoscopic Inguinal Hernia Repair.

OBJECTIVE: To evaluate the clinical outcomes and safety of two-point fixation for biological mesh in laparoscopic totally extraperitoneal (TEP) inguinal hernia repair. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: The first Affiliated Hospital of Fujian Medical University Hospital, Fuzhou, China, from January to December 2019. METHODOLOGY: A total of 38 patients with a primary inguinal hernia who underwent laparoscopic TEP repair with a small intestine submucosal matrix biological mesh were included. A novel two-point fixation method was performed at the level of 2 cm above the upper margin of the hernia ring. The mesh was fixed at 3 cm medial and lateral to the inferior epigastric artery. The recurrence rate, surgical site infection rate, postoperative chronic pain, hematoma/seroma, and chronic pain were evaluated. RESULTS: There was no conversion to open procedure. The surgical time was 60.0 (range 35-72) min, and the time of mesh fixation was 4.00 (range 2.5-6.0) minutes. All patients were discharged on the first postoperative day and had similar pain scores (VAS score = 1). Hematoma/seroma was detected in only three (7.9%) patients. No infection or recurrence was observed. CONCLUSION: The two-point fixation for biological mesh is reliable and easy to perform. Further study with a larger sample size may be needed to validate it. KEY WORDS: Inguinal hernia, Laparoscopy, Biological mesh, Surgical mesh, Herniorrhaphy, Two-point fixation.

N6-methyladenosine-mediated SH3BP5-AS1 upregulation promotes GEM chemoresistance in pancreatic cancer by activating the Wnt signaling pathway.

BACKGROUND: Pancreatic cancer (PC) is highly malignant. Chemotherapy is the main treatment strategy, especially for patients with advanced PC. However, chemoresistance has always been a frequently encountered bottleneck. Hence, there is an urgent need to enhance the sensitivity of PC to gemcitabine (GEM). RESULTS: We demonstrated that SH3BP5-AS1 was significantly upregulated in GEM-resistant PC and predicted a poorer prognosis. SH3BP5-AS1 stability was regulated by ALKBH5/IGF2BP1-mediated m6A modification. Loss of SH3BP5-AS1 reduced PC cell migration and invasion and enhanced the sensitivity of PC to GEM, as confirmed by gain- and loss-of-function assays in vitro and in vivo. Bioinformatics analysis revealed that SH3BP5-AS1 acted as a ceRNA against miR-139-5p and directly targeted CTBP1, affecting the biological behavior of PC cells. The mechanistic studies revealed that the upregulation of SH3BP5-AS1 increased CTBP1 expression by directly activating the Wnt signaling pathway, promoting GEM resistance. CONCLUSIONS: This study revealed that SH3BP5-AS1 activated Wnt signaling pathway by sponging miR-139-5p, upregulating CTBP1 expression, and contributing to the sensitivity of PC cells to GEM. SH3BP5-AS1 might be a potential target for PC therapy.

Effect of modified transanal Soave assisted by laparoscopy in the treatment of Hirschsprung's disease in children and its influencing factors.

OBJECTIVE: To investigate the effect of modified transanal Soave assisted by laparoscopy in children with Hirschsprung's disease (HD). METHODS: The clinical data of 120 children with Hirschsprung's disease admitted to Fujian Children's Hospital from January 2018 to November 2021 were retrospectively analyzed. Based on the surgical methods, 58 children treated with modified transanal Soave were regarded as the modified group and 62 children treated with modified transanal Soave assisted by laparoscopy were divided into the laparoscopic group. The operative indexes, anal function, quality of life and perianal pressure 6 months after surgery, complications within 1 month after surgery, and recovery within 6 months after surgery of the two groups were compared. The risk factors influencing the postoperative recovery of hirschsprung's disease in children were analyzed by univariate and logistic regression analysis. RESULTS: The operation time, intraoperative blood loss, length of hospital stay and gastrointestinal recovery time in the laparoscopic group were lower than those in modified group (P < 0.05). The excellent and good rate of postoperative anal function in laparoscopic group was 87.10%, which was higher than that in modified group (68.97%) (P < 0.05). The proportion of patients with good quality of life in laparoscopic group (90.32%) was higher than that in modified group (74.14%) (P < 0.05). The anal resting pressure and systolic pressure in laparoscopic group were lower than those in modified group (all P < 0.05). The total complication rate of laparoscopic group (6.45%) was lower than that of modified group (22.41%) (P < 0.05). After 6 months, 64 cases (53.33%) were cured and 56 cases (46.67%) were not. After univariate analysis, there were statistically significant differences in enteritis, abdominal distension, and anastomotic stenosis between cured children and uncured children (all P < 0.05). There was no significant difference in other factors (P > 0.05). Logistic regression analysis showed that enteritis, abdominal distension and anastomotic stenosis were the risk factors affecting the recovery of hirschsprung's disease in children (all P < 0.05). CONCLUSIONS: Modified transanal Soave assisted by laparoscopy can improve anal function and quality of life, relieve anal pressure, and have a low complication rate. Enteritis, abdominal distension, and anastomotic stenosis are the factors affecting the recovery of Hirschsprung's disease in children.

METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification.

Spermine synthase (SMS) is an enzyme participating in polyamine synthesis; however, its function and role in pancreatic cancer remains elusive. Here we report that SMS is upregulated in pancreatic cancer and predicts a worse overall survival and significantly promotes the proliferation and migration of pancreatic cancer cells. Excessive SMS reduces the accumulation of spermidine by converting spermidine into spermine, which activates the phosphorylation of serine/threonine kinase (AKT) and epithelial-mesenchymal transition (EMT) signaling pathway, thereby inhibiting pancreatic cancer cell proliferation and invasion. Moreover, SMS was identified as the direct target of both methyltransferase like 3 (METTL3) and insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly bind to the m6A modification sites of SMS and inhibit mRNA degradation. Knockdown of METTL3 or IGF2BP3 significantly reduced the SMS protein expression and inhibited the migration of pancreatic cancer. We propose a novel regulatory mechanism in which the METTL3-IGF2BP3 axis mediates the mRNA degradation of SMS in an m6A-dependent manner to regulate spermine/spermidine conversion, which regulates AKT phosphorylation and EMT activation, thereby inducing tumor progression and migration in pancreatic cancer.

Prognostic value of neutrophil-to-lymphocyte ratio in colorectal cancer liver metastasis: A meta-analysis of results from multivariate analysis.

We aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in colorectal cancer liver metastasis (CRLM). A comprehensive search was conducted across PubMed, MedLine, and the Cochrane Library databases for articles published from January 1, 2000 to April 30, 2022 that investigated the long-term prognostic value of NLR in CRLM; only studies with multivariate analyses were enrolled. Hazard ratio (HR) with 95% confidence interval (CI) was used to determine the effect size. A total of 2,522 patients in 12 studies were selected; the meta-analysis demonstrated that elevated NLR correlated with poor overall survival (OS) and disease-free survival (DFS) (HR, 1.95, 95%CI, 1.698-2.223, P < 0.01; HR, 1.80, 95%CI, 1.363-2.363, P < 0.01; respectively). The 5-year OS and disease-free survival rates were higher in the patients with normal NLR than in patients with high NLR (47% vs. 27%, P < 0.01; 37% vs. 6%, P < 0.01, respectively). Further analysis of clinicopathological parameters indicated no significant difference between the patients with and without elevated NLR. Begg's and Egger's tests for publication bias revealed no significant publication bias (P = 0.891 and P = 0.926, respectively). Multivariate analysis revealed that NLR had an excellent prognostic ability in CRLM, which can be used in deciding the treatment and predicting the clinical outcomes. Further multicenter randomized controlled trials are required to verify this conclusion.

N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer.

BACKGROUND: Alternative splicing (AS) of genes has been found to affect gene stability, and its abnormal regulation can lead to tumorigenesis. CELF2 is a vital splicing factor to participate in mRNA alternative splicing. Its downregulation has been confirmed to promote the occurrence and development of pancreatic cancer (PC). However, the regulatory role and mechanisms in PC has not been elucidated. RESULTS: CELF2 was downregulated in PC tissues, which affected tumor TNM stage and tumor size, and low expression of CELF2 indicated a poor prognosis of PC. In vivo and in vitro experiments showed that abnormal expression of CELF2 affected the stemness, apoptosis, and proliferation of PC cells. Furthmore, we also found that CELF2 was targeted by ALKBH5 for m6A modification, leading to CELF2 degradation by YTHDF2. Bioinformatic analysis of AS model based on the TCGA database indicated that CELF2 could target CD44 to form different spliceosomes, thereby affecting the biological behavior of PC cells. The conversion of CD44s to CD44V is the key to tumorigenesis. Transcriptomic analysis was conducted to reveal the mechanism of CELF2-mediated CD44 AS in PC. We found that CELF2-mediated splicing of CD44 led to changes in the level of endoplasmic reticulum stress, further regulating the endoplasmic reticulum-associated degradation (ERAD) signaling pathway, thereby affecting apoptosis and cell stemness. In addition, ERAD signaling pathway inhibitor, EerI, could effectively reverse the effect of CD44 on tumors. CONCLUSIONS: This study indicates that N6-methyladenosine-mediated CELF2 promotes AS of CD44, affecting the ERAD pathway and regulating the biological behavior of PC cells. CELF2 is expected to be a new target for targeted-drug development.

Reappraisal of the T Category for Solitary Intrahepatic Cholangiocarcinoma by Tumor Size in 611 Early-Stage (T1-2N0M0) Patients After Hepatectomy: a Surveillance, Epidemiology, and End Results (SEER) Analysis.

BACKGROUND: The association between tumor size and survival in patients with intrahepatic cholangiocarcinoma (ICC) after hepatectomy is controversial, and the T category in the American Joint Committee on Cancer (AJCC) stage for ICC is a topic of debate. METHODS: Data from 611 T1-2N0M0 ICC patients classified by the AJCC 8th edition who underwent hepatectomy were extracted from the Surveillance, Epidemiology, and End Results (SEER) database during 1988-2015. Cancer-specific survival was evaluated using Kaplan-Meier analysis. The optimal cutoff value of solitary tumor size was used an adjusted p value approach to discriminating patient survival. RESULTS: In the AJCC 8th staging system, using a 5-cm cut-off value of tumor size for solitary ICC without vascular invasion (S/VI-) was not associated with survival in T1 category (p = 0.201), and multifocal ICC with vascular invasion had a worse survival than solitary ICC with vascular invasion (S/VI+) in T2 category (p = 0.014). Tumor size was a prognostic factor for both S/VI- and S/VI+, the optimal cutoff value of tumor size was obtained 8 cm for S/VI- and 3 cm for S/VI+. S/VI- ≤ 8 cm had a similar survival to S/VI+ ≤ 3 cm (p = 0.126), S/VI- > 8 cm had a similar survival to S/VI+ > 3 cm (p = 0.655), and multifocal ICC had a similar survival with S/VI- > 8 cm (p = 0.159) and S/VI+ > 3 cm (p = 0.196). When the cohort was divided into two groups-new T1 (S/VI- ≤ 8 cm and S/VI+ ≤ 3 cm) and new T2 (S/VI- > 8 cm, S/VI+ > 3 cm and multifocal ICC)-significant survival difference was observed (p < 0.0001). CONCLUSIONS: The discriminatory power of the AJCC 8th edition for solitary ICC could be further enhanced by subdividing tumors according to size and vascular invasion (8 cm for S/VI- and 3 cm for S/VI+).

Hypoglycemic mechanism of intestinal bypass surgery in type 2 diabetic rats.

To investigate the effect of duodenal-jejunal bypass (DJB) surgery on postoperative blood glucose in type 2 diabetic rats, and further explore possible mechanisms for the effect of surgical treatment of type 2 diabetes. Forty rats with type 2 diabetes were randomly assigned to 4 groups (n = 10 rats per group), which subsequently underwent DJB, new biliopancreatic diversion (NBPD) or duodenal-jejunal exclusion (DJE) surgery or a sham operation (SHAM). Fasting glucose, 2-h postprandial glucose and blood lipids were measured, and the mRNA in liver and intestinal tissue for bile acid receptor (FXR), as well as the FXR protein expression in the liver tissues were determined. Postprandial blood glucose and fasting TG and FFA in the DJB and NBPD groups were significantly lower than those in the SHAM group and preoperative (p < 0.05) at 8 weeks postoperation. Liver FXR protein was expressed at significantly higher in the DJB and NBPD groups than in the other two (p < 0.05), and the intestinal FXR mRNA in the DJE group were highest. DJB up-regulates the expression of bile acid receptors in the liver and down-regulates those receptors in the intestinal tract via biliopancreatic diversion. This process reduces TG levels, and subsequently any lipotoxicity to islet cells to produce a hypoglycemic effect.