Gut microbiome changes associated with chronic pancreatitis and pancreatic cancer: A systematic review and Meta-analysis.

BACKGROUND: The study of changes in the microbiome in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) holds significant potential for developing noninvasive diagnostic tools as well as innovative interventions to alter the progression of diseases. This systematic review and meta-analysis aimed to analyze in detail the taxonomic and functional characteristics of the gut microbiome in patients with CP and PDAC. METHODS: Two researchers conducted a systematic search across public databases to gather all published research up to June 2023. Diversity and gut microbiota composition are the main outcomes we focus on. RESULTS: This meta-analysis included 14 studies, involving a total of 1511 individuals in the PDAC (n=285), CP (n=342), and control (n=649) groups. Our results show a significant difference in the composition of gut microbiota between PDAC/CP patients compared to healthy controls (HC), as evidenced by a slight decrease in α-diversity, including Shannon (SMD=-0.33; P=0.002 and SMD=-0.59; P<0.001, respectively) and a statistically significant ß-diversity (P<0.05). The pooled results showed that at the phylum level, the proportion of Firmicutes was lower in PDAC and CP patients than in HC patients. At the genus level, more than two studies demonstrated that 4 genera were significantly increased in PDAC patients compared to HC (e.g., Escherichia-Shigella and Veillonella). CP patients had an increase in 4 genera (e.g., Escherichia-Shigella and Klebsiella) and a decrease in 8 genera (e.g., Coprococcus and Bifidobacterium) compared to HC. Functional/metabolomics results from various studies also showed differences between PDAC/CP patients and HC. In addition, this study found no significant differences in gut microbiota between PDAC and CP patients. CONCLUSIONS: Current evidence suggests changes in gut microbiota is associated with PDAC/CP, commonly reflected by a reduction in beneficial species and an increase in the pathogenic species. Further studies are needed to confirm these findings and explore therapeutic possibilities.

A nomogram incorporating treatment data for predicting overall survival in gastroenteropancreatic neuroendocrine tumors: a population-based cohort study.

BACKGROUND: Over the last few decades, the annual global incidence of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) has steadily increased. Because of the complex and inconsistent treatment of GEP-NETs, the prognosis of patients with GEP-NETs is still difficult to assess. The study aimed to construct and validate the nomograms included treatment data for prediction overall survival (OS) in GEP-NETs patients. METHODS: GEP-NETs patients determined from the Surveillance, Epidemiology, and End Results (SEER)-13 registry database (1992-2018) and with additional treatment data from the SEER-18 registry database (1975-2016). In order to select independent prognostic factors that contribute significantly to patient survival and can be included in the nomogram, multivariate Cox regression analysis was performed using the minimum value of Akaike information criterion (AIC) and we analyzed the relationship of variables with OS by calculating hazard ratios (HRs) and 95% CIs. In addition, we also comprehensively compared the nomogram using to predict OS with the current 7th American Joint Committee on Cancer (AJCC) staging system. RESULTS: From 2004 to 2015, a total of 42 662 patients at diagnosis years with GEP-NETs were determined from the SEER database. The results indicated that the increasing incidence of GEP-NETs per year and the highest incidence is in patients aged 50-54. After removing cases lacking adequate clinicopathologic characteristics, the remaining eligible patients ( n =7564) were randomly divided into training (3782 patients) and testing sets (3782 patients). In the univariate analysis, sex, age, race, tumour location, SEER historic stage, pathology type, TNM, stage, surgery, radiation, chemotherapy, and CS tumour size were found to be significantly related to OS. Ultimately, the key factors for predicting OS were determined, involving sex, age, race, tumour location, SEER historic stage, M, N, grade, surgery, radiation, and chemotherapy. For internal validation, the C-index of the nomogram used to estimate OS in the training set was 0.816 (0.804-0.828). For external validation, the concordance index (C-index) of the nomogram used to predict OS was 0.822 (0.812-0.832). In the training and testing sets, our nomogram produced minimum AIC values and C-index of OS compared with AJCC stage. Decision curve analysis (DCA) indicated that the nomogram was better than the AJCC staging system because more clinical net benefits were obtained within a wider threshold probability range. CONCLUSION: A nomogram combined treatment data may be better discrimination in predicting overall survival than AJCC staging system. The authors highly recommend to use their nomogram to evaluate individual risks based on different clinical features of GEP-NETs, which can improve the diagnosis and treatment outcomes of GEP-NETs patients and improve their quality of life.

Comparison of Fluid Resuscitation with Lactate Ringer's Versus Normal Saline in Acute Pancreatitis: An Updated Meta-Analysis.

BACKGROUND: Fluid resuscitation is one of the main therapies for acute pancreatitis (AP). There is still no consensus on the type of fluid resuscitation. This study investigated the differences between lactate Ringer's (LR) and normal saline (NS) in treating AP. METHODS: Two authors systematically searched Web of Science, Embase (via OVID), Cochrane Library, and PubMed to find all published research before July, 2023. The odds of moderately severe/severe AP and intensive care unit (ICU) admission are set as primary endpoints. RESULTS: This meta-analysis included 5 RCTs and 4 observational studies with 1424 AP patients in LR (n = 651) and NS (n = 773) groups. The results suggested that the odds of moderately severe/severe AP (OR 0.48; 95%Cl 0.34 to 0.67; P < 0.001) and ICU admission (OR 0.37; 95%Cl 0.16 to 0.87; P = 0.02) were lower in the LR group compared to NS group. In addition, the LR group had lower rates of local complications (OR 0.54; 95%Cl 0.32 to 0.92; P = 0.02), lower level of CRP, as well as a shorter hospital stay (WMD, - 1.09 days; 95%Cl - 1.72 to - 0.47 days; P < 0.001) than the NS group. Other outcomes, such as mortality, the rate of organ failure, SIRS, acute fluid collection, pancreatic necrosis, pseudocysts, and volume overload, did not differ significantly between two groups (P > 0.05). CONCLUSIONS: LR is preferred over NS as it decreases the odds of moderately severe/severe AP, the rate of ICU admission, local complication, and length of hospital stay. However, large-scale RCT are lacking to support these evidence.

Immune checkpoints signature-based risk stratification for prognosis of patients with gastric cancer.

Until now, few researches have comprehensive explored the role of immune checkpoints (ICIs) and tumor microenvironment (TME) in gastric cancer (GC) patients based on the genomic data. RNA-sequence data and clinical information were obtained from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) database, GSE84437 and GSE84433. Univariate Cox analysis identified 60 ICIs with prognostic values, and these genes were then subjected to NMF cluster analysis and the GC samples (n = 804) were classified into two distinct subtypes (Cluster 1: n = 583; Cluster 2: n = 221). The Kaplan-Meier curves for OS analysis indicated that C1 predicted a poorer prognosis. The C2 subtype illustrated a relatively better prognosis and characteristics of "hot tumors," including high immune score, overexpression of immune checkpoint molecules, and enriched tumor-infiltrated immune cells, indicating that the NMF clustering in GC was robust and stable. Regarding the patient's heterogeneity, an ICI-score was constructed to quantify the ICI patterns in individual patients. Moreover, the study found that the low ICI-score group contained mostly MSI-low events, and the high ICI-score group contained predominantly MSI-high events. In addition, the ICI-score groups had good responsiveness to CTLA4 and PD-1 based on The Cancer Immunome Atlas (TCIA) database. Our research firstly constructed ICIs signature, as well as identified some hub genes in GC patients.

Clinical and imaging features of lymphomatosis cerebri: analysis of 8 cases and systematic review of the literature.

Lymphomatosis cerebri (LC) is a rare type of primary central nervous system lymphoma with diffuse, nonenhancing infiltrative lesions and is often misdiagnosed. Our study aimed to investigate the clinical characteristics and prognosis of LC through analyzing patients from the literature and our own center, so as to improve early diagnosis and treatment. PubMed, Web of Science and our hospital databases were reviewed, and information on demographic, clinical, pathological, cerebrospinal fluid (CSF), neuroimaging and treatment options was extracted. Univariate survival analysis was conducted by generating survival curves and comparing them using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model to identify the prognostic predictors. A total of 81 patients (median age: 58 years; interquartile range, IQR: 50-66.5 years), 45 males and 36 females, were included. The most common symptoms were cognitive impairment (65.4%) and gait impairment (50.6%). Imaging studies indicated that all 81 patients had supratentorial structure involvement, and 93.8% (76/81) had bilateral hemisphere involvement. There were 53.3% (32/60) patients with CSF pleocytosis and 65% (39/60) patients with increased CSF protein levels. The median time of diagnosis was 4.8 months (IQR: 2.3-6.9 months). Compared with 4 (95% CI: 1.78-6.22) months for all 81 patients, the median OS was 20 (95% CI: 8.24-31.76) months for those who had chemotherapy plus radiotherapy. Multivariate Cox analysis revealed that chemoradiotherapy (HR: 0.12; 95% CI: 0.02-0.68) and higher CSF glucose level (HR: 0.01; 95% CI: 0.00-0.26) were inversely associated with death. The diagnosis of LC should be alerted when neuroimaging with bilateral hemispheric involvement and CSF abnormality with pleocytosis and increased protein. Once the diagnosis is confirmed, the combination of chemotherapy and radiotherapy can be considered if the patient's physical condition permits.Journal standard instruction requires an unstructured abstract. Kindly check and confirm.We have checked and confirmed that there is no problem.

Microvesicles from bone marrow-derived mesenchymal stem cells promote Helicobacter pylori-associated gastric cancer progression by transferring thrombospondin-2.

BACKGROUND: Our previous study found that bone marrow-derived mesenchymal stem cells (BMSCs) promote Helicobacter pylori (H pylori)-associated gastric cancer (GC) progression by secreting thrombospondin-2 (THBS2). Extracellular vesicles (EVs) are important carriers for intercellular communication, and EVs secreted by BMSCs have been shown to be closely related to tumor development. The aim of this study was to investigate whether BMSC-derived microvesicles (MVs, a main type of EV) play a role in H. pylori-associated GC by transferring THBS2. METHODS: BMSCs and THBS2-deficient BMSCs were treated with or without the supernatant of H. pylori for 12 h at a multiplicity of infection of 50, and their EVs were collected. Then, the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on the GC cell line MGC-803 were assessed by in vitro proliferation, migration, and invasion assays. In addition, a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model were constructed to evaluate the effects of BMSC-derived MVs and THBS2-deficient BMSC-derived MVs on GC development and metastasis in vivo. RESULTS: BMSC-derived MVs could be readily internalized by MGC-803 cells. BMSC-derived MVs after H. pylori treatment significantly promoted their proliferation, migration and invasion in vitro (all P < 0.05) and promoted tumor development and metastasis in a subcutaneous xenograft tumor model, a nude mouse intraperitoneal metastasis model, and a tail vein injection metastasis model in vivo (all P < 0.05). The protein expression of THBS2 was significantly upregulated after H. pylori treatment in BMSC-derived MVs (P < 0.05). Depletion of the THBS2 gene reduces the tumor-promoting ability of BMSC-MVs in an H. pylori infection microenvironment both in vitro and in vivo. CONCLUSION: Overall, these findings indicate that MVs derived from BMSCs can promote H. pylori-associated GC development and metastasis by delivering the THBS2 protein. Video Abstract.

L-Fucose promotes enteric nervous system regeneration in type 1 diabetic mice by inhibiting SMAD2 signaling pathway in enteric neural precursor cells.

BACKGROUND: Diabetes can lead to extensive damage to the enteric nervous system (ENS), causing gastrointestinal motility disorders. However, there is currently a lack of effective treatments for diabetes-induced ENS damage. Enteric neural precursor cells (ENPCs) closely regulate the structural and functional integrity of the ENS. L-Fucose, is a dietary sugar that has been showed to effectively ameliorate central nervous system injuries, but its potential for ameliorating ENS damage and the involvement of ENPCs in this process remains uncertain. METHODS: Genetically engineered mice were generated for lineage tracing of ENPCs in vivo. Using diabetic mice in vivo and high glucose-treated primary ENPCs in vitro, the effects of L-Fucose on the injured ENS and ENPCs was evaluated by assessing gastrointestinal motility, ENS structure, and the differentiation of ENPCs. The key signaling pathways in regulating neurogenesis and neural precursor cells properties, transforming growth factor-ß (TGF-ß) and its downstream signaling pathways were further examined to clarify the potential mechanism of L-Fucose on the injured ENS and ENPCs. RESULTS: L-Fucose improved gastrointestinal motility in diabetic mice, including increased defecation frequency (p < 0.05), reduced total gastrointestinal transmission time (p < 0.001) and bead expulsion time (p < 0.05), as well as enhanced spontaneous contractility and electric field stimulation-induced contraction response in isolated colonic muscle strips (p < 0.001). The decrease in the number of neurons and glial cells in the ENS of diabetic mice were reversed by L-Fucose treatment. More importantly, L-Fucose treatment significantly promoted the proportion of ENPCs differentiated into neurons and glial cells both in vitro and in vivo, accompanied by inhibiting SMAD2 phosphorylation. CONCLUSIONS: L-Fucose could promote neurogenesis and gliogenesis derived from ENPCs by inhibiting the SMAD2 signaling, thus facilitating ENS regeneration and gastrointestinal motility recovery in type 1 diabetic mice. Video Abstract.

The Global Burden of Disease Attributable to Diet High in Red Meat in 204 Countries and Territories, 1999-2019: An updated Analysis of the Global Burden of Disease Study.

SCOPE: The study aims to estimates of the deaths and disability-adjusted life year rates (DALYs) of a diet high in red meat from 1999 to 2019. METHODS AND RESULTS: The deaths and disability-adjusted life year rates (DALYs) attributable to diet high in red meat were analyzed by sex, age, and geographical location and by Socio-demographic Index (SDI) from 1999 to 2019. RESULTS: Globally, deaths and DALYs attributable to diets high in red meat have steadily increased between 1999 and 2019. The global deaths attributable to diet high in red meat have increased from 319,338 (95% UI 190,418 to 441,406) in 1999 to 411,066 (95% UI 250,993 to 573,864) in 2019 for females, and have increased from 335,711 (95% UI 183,491 to 472,091) in 1999 to 484,608 (95% UI 282,347 to 686,919) in 2019 for males. The global DALYs attributable to diet high in red meat have increased from 7,763,803 (95% UI 5,023,428 to 10,370,477) in 1999 to 10,164,451 (95% UI 6,816,205 to 13,348,860) in 2019 for females, and have increased from 9,564,377 (95% UI 5,528,491 to 13,231,311) in 1999 to 13,696,622 (95% UI 8,669,245 to 18,725,223) in 2019 for males. CONCLUSION: Globally, since 1999, deaths and DALYs caused by diets high in red meat have steadily increased.

Epidemiologic trends and survival of early-onset gastroenteropancreatic neuroendocrine neoplasms.

Background: The epidemiologic trends and survival related to early-onset gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have not been well explored. Methods: Trends in the incidence and incidence-based mortality of early-onset GEP-NENs between 1975 and 2018 were obtained from the Surveillance, Epidemiology, and End Results database, and were stratified by age, sex, race, tumor site, stage, and grade. Associated population data were used to determine overall survival (OS) and independent prognostic factors for patients with early-onset GEP-NENs. Results: A total of 17299 patients diagnosed with early-onset GEP-NENs were included in this study. Results revealed an increase in the incidence (5.95% per year, 95% confidence interval (CI), 5.75-6.14%) and incidence-based mortality (4.24% per year, 95% CI, 3.92-4.56%) for early-onset GEP-NENs from 1975 to 2018, with higher rates of increase than those of later-onset GEP-NENs (incidence: 4.45% per year, 95% CI, 4.38-4.53; incidence-based mortality: 4.13% per year, 95% CI, 3.89-4.37; respectively). Increases in incidence were observed across all age, races, tumor sites, grades, and stages, except for patients with unknown stage. Compared to those with later-onset GEP-NENs, a higher proportion of female gender (54.5% vs. 49.0%, p <0.001), well-differentiated tumor (31.1% vs. 28.0%, p <0.05), and localized disease (55.2% vs. 46.7%, p <0.05) were observed in the cohort of patients with early-onset GEP-NENs. Moreover, early-onset GEP-NENs exhibited a superior overall survival in comparison to later-onset GEP-NENs, irrespective of tumor site, grade, or stage (p <0.0001). Multivariable survival analysis identified that race, marital status, stage, grade, chemotherapy, and primary site were significantly correlated with OS in individuals with early-onset GEP-NENs. Conclusions: The incidence and incidence-based mortality rates of early-onset GEP-NENs have steadily increased over time, with higher rates of increase than those of later-onset GEP-NENs. The clinical characteristics and survival were different between early-onset and later-onset GEP-NENs groups. Race, marital status, stage, grade, chemotherapy, and primary site were independent prognostic factors for early-onset GEP-NENs. Further investigations are warranted to better understand the characteristics of this disease subgroup.

Trends in the incidence of cirrhosis in global from 1990 to 2019: A joinpoint and age-period-cohort analysis.

Cirrhosis remains a major public health concern globally; the burden of cirrhosis should be further clarified worldwide and helped us to understand the current situation of cirrhosis. In the present study, we estimate DALYs and mortality rates attributable to several major cirrhosis risk factors and use joinpoint and age-period-cohort methods to determine the trends of cirrhosis incidence and deaths in the global population in the 1990-2019 period. Globally, from 1990 to 2019, the incidence of cirrhosis, deaths due to cirrhosis, and cirrhosis DALY cases increased from 1274 (103 , 95% uncertainty interval [UI]: 1027.2-1548.5) to 2051.6 (103 , 95% UI: 1661.4-2478.1), 1013 (103 , 95% UI: 948.9-1073.9) to 1472 (103 , 95% UI: 1374.6-1578.7), and 34727.7 (103 , 95% UI: 32383.0-37132.8) to 46189.4 (103 , 95% UI: 43027.1-49551.3), respectively. Hepatitis virus was the most important cirrhosis mortality risk factor. Globally, hepatitis virus infection (HBV+HCV) accounted for more than 45% of the incidence of cirrhosis cases and about 50% of cirrhosis deaths. Importantly, from 1990 to 2019, the proportion of cirrhosis incidence due to HBV decreased from 24.3% to 19.8%, whereas that due to alcohol use increased from 18.7% to 21.3%. Additionally, the proportion of NAFLD-induced cirrhosis incidence increased from 5.5% to 6.6% over the same period. Our findings on the global disease burden of cirrhosis provide a valuable resource for developing targeted prevention strategies.

The impact of surgery and survival prediction in patients with gastroenteropancreatic neuroendocrine tumors: a population-based cohort study.

OBJECTIVE: This study aimed at assessing the impact of surgical treatments in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: A propensity score-matched analysis based on data in the Surveillance, Epidemiology, and End Results database was used to assess the efficacy of surgical treatment in patients with GEP-NETs. RESULTS: A total of 7515 patients diagnosed with GEP-NETs from 2004 to 2015 were evaluated from the Surveillance, Epidemiology, and End Results database. There were 1483 patients in the surgery group and 6032 patients in the nonsurgery group. Compared with patients in the surgery group, patients in the nonsurgery group were inclined to receive chemotherapy (50.8 vs. 16.7%) and radiation (12.9 vs. 3.7%) as treatment options. Multivariate Cox regression analysis revealed higher rates of overall survival (OS) outcomes for GEP-NETs patients who had been subjected to surgery (hazard ratio=0.483, 95% CI=0.439-0.533, P <0.001). Then, to reduce the impact of bias, a 1 : 1 propensity score-matched analysis was performed for the two groups of patients. A total of 1760 patients were assessed and each subgroup included 880 patients. In the matched population, the patients exhibited the ability to significantly benefit from surgery (hazard ratio=0.455, 95% CI=0.439-0.533, P <0.001). The OS outcomes for radiation or chemotherapy patients who had been treated with surgery were better than those of patients who had not been treated with surgery ( P <0.001). In addition, it was found that the OS of patients was not significant after rectum and small intestine surgery, whereas there was a significant difference in OS after colon, pancreas, and stomach surgery on the patients. Patients who had been subjected to surgery in the rectum and small intestines exhibited better therapeutic benefits. CONCLUSION: Patients with GEP-NETs who are treated with surgery have better OS outcomes. Therefore, surgery is recommended for specified selected patients with metastatic GEP-NETs.

Epigenetic and Tumor Microenvironment for Prognosis of Patients with Gastric Cancer.

BACKGROUND: Epigenetics studies heritable or inheritable mechanisms that regulate gene expression rather than altering the DNA sequence. However, no research has investigated the link between TME-related genes (TRGs) and epigenetic-related genes (ERGs) in GC. METHODS: A complete review of genomic data was performed to investigate the relationship between the epigenesis tumor microenvironment (TME) and machine learning algorithms in GC. RESULTS: Firstly, TME-related differential expression of genes (DEGs) performed non-negative matrix factorization (NMF) clustering analysis and determined two clusters (C1 and C2). Then, Kaplan-Meier curves for overall survival (OS) and progression-free survival (PFS) rates suggested that cluster C1 predicted a poorer prognosis. The Cox-LASSO regression analysis identified eight hub genes (SRMS, MET, OLFML2B, KIF24, CLDN9, RNF43, NETO2, and PRSS21) to build the TRG prognostic model and nine hub genes (TMPO, SLC25A15, SCRG1, ISL1, SOD3, GAD1, LOXL4, AKR1C2, and MAGEA3) to build the ERG prognostic model. Additionally, the signature's area under curve (AUC) values, survival rates, C-index scores, and mean squared error (RMS) curves were evaluated against those of previously published signatures, which revealed that the signature identified in this study performed comparably. Meanwhile, based on the IMvigor210 cohort, a statistically significant difference in OS between immunotherapy and risk scores was observed. It was followed by LASSO regression analysis which identified 17 key DEGs and a support vector machine (SVM) model identified 40 significant DEGs, and based on the Venn diagram, eight co-expression genes (ENPP6, VMP1, LY6E, SHISA6, TMEM158, SYT4, IL11, and KLK8) were discovered. CONCLUSION: The study identified some hub genes that could be useful in predicting prognosis and management in GC.

Synthesis and Peroxide Activation Mechanism of Bimetallic MOF for Water Contaminant Degradation: A Review.

Metal-organic framework (MOF) materials possess a large specific surface area, high porosity, and atomically dispersed metal active sites, which confer excellent catalytic performance as peroxide (peroxodisulfate (PDS), peroxomonosulfate (PMS), and hydrogen peroxide (H2O2)) activation catalysts. However, the limited electron transfer characteristics and chemical stability of traditional monometallic MOFs restrict their catalytic performance and large-scale application in advanced oxidation reactions. Furthermore, the single-metal active site and uniform charge density distribution of monometallic MOFs result in a fixed activation reaction path of peroxide in the Fenton-like reaction process. To address these limitations, bimetallic MOFs have been developed to improve catalytic activity, stability, and reaction controllability in peroxide activation reactions. Compared with monometallic MOFs, bimetallic MOFs enhance the active site of the material, promote internal electron transfer, and even alter the activation path through the synergistic effect of bimetals. In this review, we systematically summarize the preparation methods of bimetallic MOFs and the mechanism of activating different peroxide systems. Moreover, we discuss the reaction factors that affect the process of peroxide activation. This report aims to expand the understanding of bimetallic MOF synthesis and their catalytic mechanisms in advanced oxidation processes.

Bone mesenchymal stem cells promote gastric cancer progression through TGF-ß1/Smad2 positive feedback loop.

AIMS: Bone marrow-derived mesenchymal stem cells (BMSCs) have been proven to be recruited into the tumor microenvironment and contribute to gastric cancer (GC) progression, but the underlying mechanism is still unclear. The purpose of this study is to explore the exact role and potential mechanism of BMSCs in the progression of GC. MATERIALS AND METHODS: Bioinformatics analyzed were used to clarify the correlation between TGF-ß1 and prognosis of gastric cancer. Cell co-culture were used to explore the interaction between gastric cancer cells (GCs) and BMSCs. Quantitative real time-PCR and Western blot assay were used to detect gene and protein expression, respectively. The biological characteristics of GCs and BMSCs were detected by immunofluorescence, Transwell migration, Elisa and invasion assay. Xenograft models in nude mice were constructed to evaluate GC development in vivo. KEY FINDINGS: TGF-ß1 was overexpressed in GC cells and tissues, and is positively related to the poor prognosis of patients. TGF-ß1 from GCs activated the Smad2 pathway in BMSCs, promoting their differentiation into carcinoma-associated fibroblasts (CAFs) and TGF-ß1 expression. Concomitantly, TGF-ß1 secreted by CAFs activate Smad2 signaling in GC cells, thus inducing their epithelial-mesenchymal transition (EMT) and TGF-ß1 secretion. BMSCs can dramatically promote the proliferation, migration, and invasion of GCs while blocking TGF-ß1/Smad2 positive feedback loop can reverse these effects. SIGNIFICANCE: The TGF-ß1/Smad2 positive feedback loop between GCs and BMSCs, promotes the CAFs differentiation of BMSCs and the EMT of GCs, resulting in the progression of GC.

Nomograms for Predicting Survival Outcomes in Patients with Neuroendocrine Neoplasms of the Gallbladder Undergoing Primary Tumor Resection: A Population-Based Study.

BACKGROUND: Neuroendocrine neoplasms of the gallbladder (GB-NENs) are a rare group of histologically heterogeneous tumors, and surgical resection of the primary tumor is the mainstream treatment at the moment. The current study aimed to establish and validate novel nomograms for patients with GB-NENs undergoing primary tumor resection to predict the 6-, 12-, and 18-month overall survival (OS) and cancer-specific survival (CSS). METHODS: Clinicopathological information of patients with GB-NENs undergoing primary tumor resection between 2004 and 2018 was derived from the Surveillance, Epidemiology, and End Results (SEER) database. Candidate prognostic factors were selected by Cox regression analyses, and the nomograms were constructed. Finally, concordance index (C-index), calibration plot, area under the curve from the receiver operating characteristic curve (AUC), and decision curve analysis (DCA) were utilized to assess the effective performance of the nomograms. RESULTS: A total of 221 patients with GB-NENs undergoing resection were enrolled in this retrospective study. Using the Cox regression analyses, age, pathological classification, tumor size, and SEER stage were identified as the independent prognostic factors of patients with GB-NENs undergoing resection, and nomograms were constructed. The C-indexes of OS and CSS in training dataset were 0.802 (95% CI: 0.757-0.848) and 0.846 (95% CI: 0.798-0.895), while those of internal validation dataset were 0.862 (95% CI: 0.802-0.922) and 0.879 (95% CI: 0.824-0.934), respectively. CONCLUSIONS: Taken together, the nomograms are accurate enough to predict the prognostic factors of GB-NEN patients undergoing resection, allowing for treatment decision-making and clinical monitoring for future clinical work.

Cardiovascular-Specific Mortality among Gastrointestinal Stromal Tumor Patients: A Population-Based Analysis.

Background: The overall risk of cardiovascular mortality (CVM) in cancer survivors has increased with time. The trend of CVM in patients with gastrointestinal stromal tumors (GISTs) remains unclear. This study is aimed at assessing the risks and independent predictors of CVM in GIST patients. Methods: Data of the GIST patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2019). The standardized mortality ratio (SMR) was used to evaluate the risk of CVM, and a multivariate competing risk model was utilized to identify the predictors for CVM. Results: A total of 12,058 patients with GIST were included in this study, of whom 477 (4.0%) patients died of cardiovascular disease (CVD). The SMR for CVM among GIST patients was significantly higher than in the general population (SMR, 3.23, 95% CI: 2.97-3.52), and all categories of CVD were associated with a significantly elevated SMR. The cumulative mortality of CVD was the lowest among all causes of death, while the CVM was the second most common cause of death in patients ≥ 80 years when stratified by age at diagnosis. Furthermore, male sex, older age at diagnosis, White race, unmarried, earlier year of diagnosis, and not receiving chemotherapy were the poor prognostic factors for CVM. Conclusions: The CVM risk in GIST patients was significantly higher relative to the general US population. Timely screening and cardioprotective interventions should be implemented to prevent the occurrence of CVM in patients with GIST.

BMSCs Promote Differentiation of Enteric Neural Precursor Cells to Maintain Neuronal Homeostasis in Mice With Enteric Nerve Injury.

BACKGROUND & AIMS: Our previous study showed that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) promoted functional enteric nerve regeneration in denervated mice but not through direct transdifferentiation. Homeostasis of the adult enteric nervous system (ENS) is maintained by enteric neural precursor cells (ENPCs). Whether ENPCs are a source of regenerated nerves in denervated mice remains unknown. METHODS: Genetically engineered mice were used as recipients, and ENPCs were traced during enteric nerve regeneration. The mice were treated with benzalkonium chloride to establish a denervation model and then transplanted with BMSCs 3 days later. After 28 days, the gastric motility and ENS regeneration were analyzed. The interaction between BMSCs and ENPCs in vitro was further assessed. RESULTS: Twenty-eight days after transplantation, gastric motility recovery (gastric emptying capacity, P < .01; gastric contractility, P < .01) and ENS regeneration (neurons, P < .01; glial cells, P < .001) were promoted in BMSCs transplantation groups compared with non-transplanted groups in denervated mice. More importantly, we found that ENPCs could differentiate into enteric neurons and glial cells in denervated mice after BMSCs transplantation, and the proportion of Nestin+/Ngfr+ cells differentiated into neurons was significantly higher than that of Nestin+ cells. A small number of BMSCs located in the myenteric plexus differentiated into glial cells. In vitro, glial cell-derived neurotrophic factor (GDNF) from BMSCs promotes the migration, proliferation, and differentiation of ENPCs. CONCLUSIONS: In the case of enteric nerve injury, ENPCs can differentiate into enteric neurons and glial cells to promote ENS repair and gastric motility recovery after BMSCs transplantation. BMSCs expressing GDNF enhance the migration, proliferation, and differentiation of ENPCs.

Risk of adenoma recurrence after polypectomy in patients younger than 50 years vs. 50 years old and over with diminutive or small adenomas.

Background and aims: Current studies have shown that polyp recurrence occurs after colonic adenomas polypectomy (AP), but the difference in recurrence risk between patients in patients older than 50 years and younger than 50 years has not been clearly studied. Methods: 490 patients after AP were enrolled in the study. The patients were classified according to age (<50 years old or ≥50 years old), and then further categorized according to the baseline adenoma characteristics: Group 1: 1-2 non-advanced adenomas (NAAs) 1-5 mm in size; Group 2: ≥3 NAAs, 1-5 mm; Group 3: 1-2 NAAs, 6-9 mm; Group 4: ≥3 NAAs, 6-9 mm; and Group 5: advanced adenomas. Results: During a mean follow-up interval of 2.52 years (2.51 years for ≥50 years old and 2.55 years for patients <50 years old), NAA recurrence was detected in 147 patients (30.0%). Overall, the hazard ratio (HR) for NAA recurrence after AP was higher in patients ≥50 years old than that in patients <50 years old (HR, 1.774, P = 0.003). For patients <50 years old, HRs (Group 2-5 vs. G1, respectively) for NAA recurrence were 0.744 (P = 0.773), 3.885 (P = 0.007), 5.337 (P = 0.003), and 3.334 (P = 0.015). For patients ≥50 years old, HRs (Group 2-5 vs. G1, respectively) for NAA recurrence were 1.033 (P = 0.965), 1.250 (P = 0.405), 2.252 (P = 0.015), and 1.887 (P = 0.009). For G1, the risk of NAA recurrence was significantly higher in patients ≥50 years old (HR, 2.932, P = 0.011) than that in patients <50 years old; for G2-G5, the risk was similar in the two age groups (P > 0.05). Conclusions: For patients <50 years old with less than 3 NAAs that are 1-5 mm in size, the recurrence rate of NAA is less than that of patients ≥50 years old with the same index colonoscopy findings. When the adenomas are ≥5 mm, or their number exceeds 3, they have similar recurrence risk as that for patients ≥50 years old.

Siglec-15 as a New Perspective Therapy Target in Human Giant Cell Tumor of Bone.

The main features of a giant cell tumor of bone (GCTB) are frequent recurrence and aggressive osteolysis, which leads to a poor prognosis in patients. Although the treatment methods for a GCTB, such as scraping and resection, effectively inhibit the disease, the tendency toward malignant transformation remains. Therefore, it is important to identify new treatment methods for a GCTB. In this study, we first found high Siglec-15 expression in GCTB tissues, which was significantly associated with Campanacci staging and tumor recurrence. In Spearman's analysis, Siglec-15 expression was significantly correlated with Ki-67 levels in tumor tissues. In vitro, the mRNA and protein levels of Siglec-15 were high in GCTB stromal cells (Hs737. T), and Siglec-15 knockdown inhibited the biological characteristics of GCTB stromal cells. The RNA sequencing results enabled a prediction of the downstream genes by using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and MCODE analyses, and the findings showed that CXCL8 was significantly regulated by Siglec-15 and might be a promising downstream target gene of Siglec-15. Therefore, Siglec-15 may be a potential immunotherapy target for a GCTB.

Efficacy and Safety of the Ketogenic Diet for Mitochondrial Disease With Epilepsy: A Prospective, Open-labeled, Controlled Study.

Background: The ketogenic diet (KD) is increasingly used to treat drug-resistant epilepsy because of its favorable effect on seizure reduction. Patients with mitochondrial diseases tend to experience seizures. Therefore, this study aimed to test the efficacy of the KD on participants with mitochondrial diseases in a controlled trial. Methods: Participants from fourteen clinical centers who were diagnosed with mitochondrial disease were semi-randomized to either the intervention (KD) or control group. The KD group followed a 3-month KD intervention, while the control group received a 1-month normal diet initially and then a 3-month KD intervention. The primary outcome measure was seizure reduction. Biomarker changes, cognitive impairments, and side effects were also recorded, if available. Result: A total of 33 participants were assigned to the KD (n = 22) and control groups (n = 11). In the KD group, 31.8% (7/22) of participants achieved ≥50% seizure reduction after 1 month of diet intervention, which increased to 40.9% (9/22) at 3 months. In the control group, only 18.2% (2/11) of the participants had ≥50% seizure reduction during the normal diet period. After the control group was transferred to the KD, 63.6% (7/11) of participants had >50% seizure reduction, and this rate increased to 72.7% (8/11) at 3 months. The KD also showed high efficacy in participants with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) or pathogenic variants in mitochondrial DNA (mtDNA) (90% and 93.3% response rates, respectively). The most frequent side effects reported at the 3-month review were vomiting, cold, hyperlipidemia, and bloating. Conclusion: The KD is a safe and effective therapy for seizure control in mitochondrial diseases, especially MELAS and pathogenic variants of mtDNA. KD intervention can be considered in the management of these patients.