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ObjectivePancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.DesignTwo unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33–ST2–CXCL3–CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.ResultsIL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33–ST2–MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3–CXCR2 signalling. Type III collagen was identified as the CXCL3–CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.ConclusionsOur work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.

The use of proton pump inhibitors (PPIs) may potentially predispose to the development of small intestinal bacterial overgrowth (SIBO), but this association is controversial due to conflicting results from studies conducted to date. The aim of this meta-analysis was to evaluate the association between the use of PPIs and the risk of SIBO. We systematically searched the online PubMed, Embase, and Cochrane Library databases and Web of Science for relevant articles published up to November 2016. Two researchers identified and extracted data independent of each other. The pooled analysis was performed using the generic inverse-variance random-effects model. Subgroup and sensitivity analysis were conducted to assess the stability and heterogeneity of the pooled results. The risk of publication bias was evaluated by assessing for funnel plot asymmetry and by Egger’s test and Begg’s test. A total of 19 articles met the eligibility criteria for the meta-analysis, reporting on 7055 subjects. The pooled odds ratio (OR) showed a statistically significant association between increased risk of SIBO and PPI use (OR 1.71, 95% confidence interval 1.20–2.43). Subgroup analyses demonstrated an association between SIBO and PPI use in studies that employed small bowel aspirates culture and glucose hydrogen breath tests (GHBT) as diagnostic tests for SIBO. Our meta-analysis suggests that the use of PPI moderately increases the risk of SIBO, thereby highlighting the need for appropriate prescribing of PPIs.

Lemmel syndrome is a rare cause of obstructive jaundice, induced by periampullary diverticulum(PAD). Endoscopic Ultrasonography(EUS) is helpful in detecting PAD and differentiating the obstruction cause in Lemmel syndrome by exposing the detail of ampulla structure and measuring the dilatation of common bile duct and pancreatic duct. Nineteen patients diagnosed Lemmel syndrome by EUS in our institute between January 1, 2019 to April 30, 2024 were enrolled. Their demographics, laboratory and imaging data were analyzed. The patients diagnosed with Lemmel syndrome were mostly elder male with the average age of 68.8 ± 2.4 years. We found Lemmel syndrome patients most present with a dilatation in middle and upper segments of common bile duct. Magnetic resonance cholangiopancreatography (MRCP), abdominal computed tomography (CT) and upper abdominal enhanced MR were all failed to diagnose Lemmel syndrome. Besides, a higher serum level of alkaline phosphatase was predominant in those complicating with cholecystitis or cholecystolithiasis than those without complications. Similar with non-invasive imaging examination, EUS was capable of confirming the diagnosis of Lemmel syndrome, evaluating PAD and pancreaticobiliary duct as well as periampullary structure. EUS could be a useful investigate method to distinguish Lemmel syndrome for patients with unexplained dilated common bile duct or jaundice.

Lemmel syndrome is a rare cause of obstructive jaundice, induced by periampullary diverticulum(PAD). Endoscopic Ultrasonography(EUS) is helpful in detecting PAD and differentiating the obstruction cause in Lemmel syndrome by exposing the detail of ampulla structure and measuring the dilatation of common bile duct and pancreatic duct. Nineteen patients diagnosed Lemmel syndrome by EUS in our institute between January 1, 2019 to April 30, 2024 were enrolled. Their demographics, laboratory and imaging data were analyzed. The patients diagnosed with Lemmel syndrome were mostly elder male with the average age of 68.8 ± 2.4 years. We found Lemmel syndrome patients most present with a dilatation in middle and upper segments of common bile duct. Magnetic resonance cholangiopancreatography (MRCP), abdominal computed tomography (CT) and upper abdominal enhanced MR were all failed to diagnose Lemmel syndrome. Besides, a higher serum level of alkaline phosphatase was predominant in those complicating with cholecystitis or cholecystolithiasis than those without complications. Similar with non-invasive imaging examination, EUS was capable of confirming the diagnosis of Lemmel syndrome, evaluating PAD and pancreaticobiliary duct as well as periampullary structure. EUS could be a useful investigate method to distinguish Lemmel syndrome for patients with unexplained dilated common bile duct or jaundice.

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2 + tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2 + pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2 + tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2 + breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers. Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels.

Inconsistent pathological diagnoses between pre- and post-endoscopic snare papillectomy (ESP) biopsies were frequently observed. We aimed to compare the differences in pathological upgrade and incomplete resection between endoscopic snare papillectomy for ampullary adenomas. The included patients were those referred to Sir Run Run Shaw Hospital and underwent ESP for an ampullary adenoma between 2012 and 2022. The endoscopic and clinicopathological features of ampullary adenomas were obtained using white light endoscopy, narrow-band imaging endoscopy, and endoscopic ultrasound (EUS). Adverse events, histological diagnosis, and follow-up data were also collected. Overall, 40 patients underwent ESP of ampullary adenomas and were included in the study. Seventeen patients had inconsistent pre- and post-ESP pathological diagnoses, as they were upgraded from either low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or from HGD to adenocarcinoma. Various characteristics varied between the pathological upgrade and non-upgrade groups, such as alanine transaminase (ALT), alkaline phosphatase levels (ALP), erosion and redness of papilla, a hybrid histological type, procedure time and extended lower bile duct width identified through EUS. Differences were observed between the complete and incomplete resection groups in terms of ALT, Gamma-glutamyl transferase (GGT) levels, tumor extension into the bile duct, and width of lower bile duct extension as determined by EUS. Pathological upgrading were relatively common after ESP for ampullary adenomas. Preoperative identification of specific clinical and endoscopic features can enhance diagnostic accuracy and inform treatment strategies.

Objectives Klotho, an anti-aging protein, has been identified to control tissue inflammatory responses. The objective of this research is to determine the linkage between soluble Klotho (S-Klotho) level and systemic immune-inflammation index (SII). Methods Eligible participants with complete information of S-Klotho level and SII were selected from the National Health and Nutrition Examination Surveys (NHANES). Subsequently, weighted multivariate linear regression and subgroup analysis were carried out to evaluate the association. Results Totally, 11,108 adults with complete data on S-Klotho level, SII and other important covariates were included in final analysis. Multivariate liner regression revealed that high level of S-Klotho was associated with low level of SII after multivariate adjustments (β=-0.08, 95%CI:-0.10- -0.05, P < 0.01). When classifying S-Klotho into tertiles, participants in S-Klotho tertile 3 (Q3) showed a decrease in SII level compared with those in the lowest tertile (Q1) (β=-45.44, 95%CI:-64.41- -26.47, P < 0.01 ). The negative associations remained significant regardless of age and gender, and varied depending on smoking status and BMI subgroups. Conclusion S-Klotho level was negatively related to SII after controlling for covariates. Further studies need to validate current findings and explore the fundamental mechanisms.

The Life’s Essential 8 (LE8) score was updated by the American Heart Association, which constituted cardiovascular health (CVH) and was significantly associated with overall and cardiovascular disease-specific mortality. The aim of this research was to evaluate the connection between LE8, the newly revised indicator of cardiovascular health, and the acceleration of biological age. Participants for this study were selected from the National Health and Nutrition Examination Survey. The LE8 scores, derived from measurements following the American Heart Association definitions, were categorized into three levels: low, moderate, and high, on a scale of 0 to 100. The PhenoAge algorithm was used to compute biological age, while the PhenoAge advancement was used to assess biological age acceleration. Linear and logistic regression analyses were used to examine the association between the LE8 score and biological age. A total of 17,153 individuals with an average age of 47.54 were included in the study. The average LE8 score was 68, and the average Phenotypic age was 44.61. Individuals with higher LE8 scores were found to have a younger Phenotypic age, as demonstrated by their lower PhenoAge scores. After controlling for potential confounding variables, a higher LE8 score was found to be associated with a decrease in PhenoAge advancement (β = − 1.22, P  < 0.01) and a lower likelihood of biological aging (OR = 0.65, P  <  0.01). Both health behavior and health factor scores were associated with biological aging (both P  < 0.01). Each type of LE8 score in the high group was positively associated with biological aging (both P  < 0.01). A significant inverse association between LE8 score and biological aging was observed in all subgroups (both P  < 0.01). The LE8 and its subscale scores showed a negative association with the likelihood of phenotypic aging. Maintaining ideal CVH levels could be advantageous in avoiding the potential acceleration of biological aging.

BackgroundOur aim was to validate the American Joint Committee on Cancer (AJCC) 8th edition stage system for gastric cancer in the Western world and to compare several modifications between the 7th and 8th edition systems.MethodsEligible patients having undergone surgical resection of gastric cancer during 2004–2011 from the Surveillance, Epidemiology, and End Results (SEER) database were included in the current study. Survival differences were assessed by Kaplan–Meier curve and log-rank tests. The discriminative power of the AJCC 8th and 7th editions was compared by Harrell’s concordance index (c-index).ResultsPatients with pN3a and pN3b presented distinct survival outcomes, especially for cases in which more than 15 lymph nodes were examined. The overall (OS) and cancer-specific survival (CSS) c-indices for the 8th edition were largely comparable with c-indices for the 7th edition throughout the cohort. Notably, the new edition improved the power of discrimination slightly in OS and CSS (c-indices: 0.717, 0.744) compared with the 7th edition (c-indices: 0.712, 0.739) for patients for whom 15 or more lymph nodes were examined. The analysis of stage migration in the new edition revealed nonhomogeneous survival outcomes in stages IIIB and IIIC.ConclusionThe AJCC 8th stage system for gastric cancer performs as well as the AJCC 7th edition in the United States (USA). Importantly, when more than 15 lymph nodes are examined, the discriminatory performance of the new edition is improved.

ObjectiveWe aimed to assess the associations between sleep duration and Visceral Adiposity Index (VAI).DesignCross-sectional study.SettingThe National Health and Nutrition Examination Survey (2007–2018).ParticipantsA total 11 252 eligible participants who have complete information for sleep duration and VAI.Outcome measureThe VAI index, which is sex-specific and takes into consideration factors such as waist circumference, body mass index, high-density lipoprotein cholesterol and triglycerides, was calculated in accordance with prior research. Multiple linear regressions and subgroup analyses were employed to evaluate the connection between the duration of sleep and the VAI.ResultsThe mean sleep duration and VAI of included participants were 7.05 hours/day and 2.03, respectively. After adjusting for the sociodemographic, lifestyle and other covariates, short sleep was significantly linked to increased VAI (β=0.15, 95% CI 0.01 to 0.28) in relation to middle sleep duration, whereas no significant association was found between long sleep duration and VAI. An L-shaped relationship was observed between sleep duration and VAI. When sleep duration was less than 7.5 hours/day, a negative association between sleep duration and VAI was obvious. However, when sleep duration was >7.5 hours/day, VAI was increased with a longer sleep duration, although it was not significant.ConclusionsAn L-shaped relationship was observed between sleep duration and VAI, with insufficient sleep, being independently linked to a higher VAI. This implies that sleep deprivation might be associated with visceral adipose distribution and disfunction.