The latest medical research on Gastroenterology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about gastroenterology gathered by our medical AI research bot.

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The Effect of Facility Volume on Survival Following Proctectomy for Rectal Cancer.

Gastrointestinal Surgery

Prior studies assessing colorectal cancer survival have reported better outcomes when operations are performed at high-volume centers. These studies have largely been cross-sectional, making it difficult to interpret their estimates. We aimed to assess the effect of facility volume on survival following proctectomy for rectal cancer.

Using data from the National Cancer Database, we included all patients with complete baseline information who underwent proctectomy for non-metastatic rectal cancer between 2004 and 2016. Facility volume was defined as the number of rectal cancer cases managed at the treating center in the calendar year prior to the patient's surgery. Overall survival estimates were obtained for facility volumes ranging from 10 to 100 cases/year. Follow-up began on the day of surgery and continued until loss to follow-up or death.

A total of 52,822 patients were eligible. Patients operated on at hospitals with volumes of 10, 30, and 50 cases/year had similar distributions of grade, clinical stage, and neoadjuvant therapies. 1-, 3-, and 5-year survival all improved with increasing facility volume. One-year survival was 94.0% (95% CI: 93.7, 94.3) for hospitals that performed 10 cases/year, 94.5% (95% CI: 94.2, 94.7) for 30 cases/year, and 94.8% (95% CI: 94.5, 95.0) for 50 cases/year. Five-year survival was 68.9% (95% CI: 68.0, 69.7) for hospitals that performed 10 cases/year, 70.8% (95% CI: 70.1, 71.5) for 30 cases/year, and 72.0% (95% CI: 71.2, 72.8) for 50 cases/year.

Treatment at a higher volume facility results in improved survival following proctectomy for rectal cancer, though the small benefits are less profound than previously reported.

The Role of Adjuvant Chemotherapy Following Right Hemicolectomy for Non-metastatic Mucinous and Nonmucinous Appendiceal Adenocarcinoma.

Gastrointestinal Surgery

Appendiceal adenocarcinoma (AA) represents a heterogenous group of neoplasms with distinct histologic features. The role and efficacy of adjuvant chemotherapy (AC) in non-metastatic disease remain controversial. The aim of this study was to ascertain the role of AC in non-metastatic AA in a national cohort of patients.

The National Cancer Database (NCDB) was queried to identify patients diagnosed with stage I-III mucinous and nonmucinous AA who underwent right hemicolectomy between 2006 and 2016. Kaplan-Meier and Cox regression analyses were used to evaluate the impact of AC on overall survival (OS) stratified by each pathologic stage.

A total of 1433 mucinous and 1954 nonmucinous AA were identified; 578 (40%) and 722 (40%) received AC respectively. In both AC groups, there was a higher proportion of T4 disease, lymph node metastasis, pathologic stage III, and poorly/undifferentiated grade (all P<0.05). On unadjusted analysis, there was no significant association between AC and OS for stage I-III mucinous AA. For nonmucinous AA, AC significantly improved OS only for stage II and III disease. On adjusted analysis, AC was independently associated with an improved OS for stage III nonmucinous AA (HR: 0.61, 95%CI 0.45-0.84, P=0.002), while for mucinous AA, AC was associated with worse outcomes for stage I/II disease (HR: 1.4, 95%CI 1.02-1.91, P=0.038) and had no significant association with OS for stage III disease.

This current analysis of a national cohort of patients suggests a beneficial role for AC in stage III nonmucinous AA and demonstrates no identifiable benefit for stage I-III mucinous AA.

Salidroside activates the AMP-activated protein kinase pathway to suppress non-alcoholic steatohepatitis.

Hepatology

Nonalcoholic steatohepatitis (NASH) is becoming a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC). Salidroside (p-hydroxyphenethyl-β-d-glucoside) has various biological and pharmacological activities, including anti-inflammatory, antioxidant and anticancer activities. However, the therapeutic effect and underlying molecular mechanism of salidroside in NASH remain to be further clarified.

In this study, we found that salidroside alleviated lipid accumulation and inflammatory response in primary hepatocytes after palmitic acid/oleic acid (PO) stimulation. In addition, salidroside effectively prevented high-fat/high-cholesterol (HFHC) diet induced NASH progression by regulating glucose metabolism dysregulation, insulin resistance, lipid accumulation, inflammation and fibrosis. Mechanistically, integrated RNA sequencing and bioinformatic analysis showed that salidroside promoted AMPK signaling pathway activation in vitro and in vivo, and this finding was further verified by determining the phosphorylation levels of AMPK. Furthermore, the protective effects of salidroside on lipid accumulation and inflammation in hepatocytes and livers induced by PO- or HFHC- stimulation were blocked by AMPK interruption.

Our studies demonstrate that salidroside protects against metabolic stress-induced NASH progression through activation of AMPK signaling, indicating that salidroside could be a potential new drug component for NASH therapy.

Hepatitis B Virus (HBV) Genotype: A Significant Risk Factor in Determining which Patients with Chronic HBV Infection should Undergo Surveillance for Hepatocellular Carcinoma: The Hepatitis B Alaska (HEP-B-AK) Study.

Hepatology

Information is limited regarding hepatitis B virus (HBV) genotype and the outcome of chronic HBV (CHB) infection. We examined HBV genotype on hepatocellular carcinoma (HCC) occurrence in Alaska Native (AN) persons with CHB where five HBV genotypes are found, A2, B6, C2, D and F1.

We calculated HCC incidence per 1000 person-years of follow-up to determine which groups by age, sex, and genotype met current American Association for the Study of Liver Diseases HCC surveillance criteria. We used Poisson regression to compare HCC risk by genotype, age, sex, and Alaska region. Incidence of HCC was calculated using the sex specific AASLD cutoff recommended for the Asian population of 50 years for women and 40 years for men. HCC screening was conducted semiannually using alpha-fetoprotein levels and abdominal ultrasound. Among 1185 AN persons, median follow up was 35.1 years; 667 (63%) were male. The HBV genotype distribution was: 49% D, 18% F, 13% A, 6% C, 3% B, 0.1% H, and 12% undetermined. Sixty-three cases of HCC occurred. HCC incidence for genotype F was 5.73 per 1000 person-years of follow-up, followed by 4.77 for C, 1.28 for A, 0.47 for D and 0.00 for B. The HCC risk was higher for genotypes F (Relative rate [RR] : 12.7, 95% confidence interval [CI]: 6.1-26.4) , C (RR: 10.6, 95% CI: 4.3-26.0) and A (RR: 2.9, 95% CI: 1.0-8.0) compared to genotypes B or D. Among males < 40 years of age and females < 50 years of age, genotype F had the highest incidence (4.79/1000 person-years).

HBV genotype was strongly associated with HCC HBV genotype should be considered in risk factor stratification.

ALDOB depletion promotes hepatocellular carcinogenesis through activating insulin receptor signaling and lipogenesis.

Hepatology

Insulin receptor (IR) transduces cell surface signal via phosphoinositide-3-kinase (PI3K)-AKT pathways, or translocates to nucleus and binds to the promoters to regulate genes associated with insulin actions including de novo lipogenesis (DNL). Chronic activation of IR signaling drives malignant transformation but the underlying mechanisms remain poorly defined. Down-regulation of fructose-1,6-bisphosphate aldolase B (ALDOB) in hepatocellular carcinoma (HCC) is correlated with poor prognosis. We aim to study whether and how ALDOB is involved in IR signaling in HCC.

Global or liver-specific ALDOB knockout (L-ALDOB-/-) mice were used in N-diethylnitrosamine (DEN)-induced HCC models, whereas restoration of ALDOB expression was achieved in L-ALDOB-/- mice by adeno-associated virus (AAV). 13C6-glucose was employed in metabolic flux analysis to track the de novo fatty acid synthesis from glucose, and non-targeted lipidomics and targeted fatty acid analysis using mass spectrometry were performed. We found that ALDOB physically interacts with IR and attenuates IR signaling through downregulating PI3K-AKT pathways and suppressing IR nuclear translocation. ALDOB depletion or disruption of IR/ALDOB interaction in ALDOB mutants promotes DNL and tumorigenesis, which is significantly attenuated with ALDOB restoration in L-ALDOB-/- mice. Notably, attenuated IR/ALDOB interaction in ALDOB-R46A mutant exhibits more significant tumorigenesis than releasing ALDOB/AKT interaction in ALDOB-R43A, while knockdown IR sufficiently diminishes tumor-promoting effects in both mutants. Furthermore, inhibiting p-AKT or fatty acid synthase significantly attenuates HCC in L-ALDOB-/- mice. Consistently, ALDOB down-regulation is correlated with upregulation of IR signaling and DNL in human HCC tumor tissues.

Our study uncovers a mechanism by which loss of ALDOB activates IR signaling primarily through releasing IR/ALDOB interaction to promote DNL and HCC, highlighting a potential therapeutic strategy in HCC.

Survival Outcomes for Malignant Peritoneal Mesothelioma at Academic Versus Community Hospitals.

Gastrointestinal Surgery

Malignant peritoneal mesothelioma is a rare disease with poor outcomes. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is the cornerstone of therapy. We aim to compare outcomes of malignant peritoneal mesothelioma treated at academic versus community hospitals.

This was a retrospective cohort study using the National Cancer Database to identify patients with malignant peritoneal mesothelioma from 2004 to 2016. Patients were divided according to treating facility type: academic or community. Outcomes were assessed using log-rank tests, Cox proportional-hazard modeling, and Kaplan-Meier survival statistics.

In total, 2682 patients with malignant peritoneal mesothelioma were identified. A total of 1272 (47.4%) were treated at an academic facility and 1410 (52.6%) were treated at a community facility. Five hundred forty-six (42.9%) of patients at academic facilities underwent debulking or radical surgery compared to 286 (20.2%) at community facilities. Three hundred sixty-six (28.8%) of patients at academic facilities received chemotherapy on the same day as surgery compared to 147 (10.4%) of patients at community facilities. Unadjusted 5-year survival was 29.7% (95% CI 26.7-32.7) for academic centers compared to 18.3% (95% CI 16.0-20.7) for community centers. In multivariable analysis, community facility was an independent predictor of increased risk of death (HR: 1.19, 95% CI 1.08-1.32, p = 0.001).

We demonstrate better survival outcomes for malignant peritoneal mesothelioma treated at academic compared to community facilities. Patients at academic centers underwent surgery and received chemotherapy on the same day as surgery more frequently than those at community centers, suggesting that malignant peritoneal mesothelioma patients may be better served at experienced academic centers.

Modelling PNPLA3-Associated Non-Alcoholic Fatty Liver Disease Using Human Induced Pluripotent Stem Cells.

Hepatology

NAFLD is a growing public health burden. However, the pathogenesis of NAFLD has not yet been fully elucidated and the importance of genetic factors has only recently been appreciated. Genomic studies have revealed a strong association between NAFLD progression and the I148M variant in PNPLA3. Nonetheless, very little is known about the mechanisms by which this gene and its variants can influence disease development. In order to investigate these mechanisms, we have developed an in vitro model that takes advantage of the unique properties of human induced pluripotent stem cells (hiPSC) and the CRISPR/CAS9 gene editing technology.

We used isogenic human induced pluripotent stem cell (hiPSC) lines with either a knock-out (PNPLA3KO ) of the PNPLA3 gene or with the I148M variant (PNPLA3I148M ) to model PNPLA3-associated NAFLD. The resulting hiPSCs were differentiated into hepatocytes, treated with either unsaturated or saturated free fatty acids to induce NAFLD-like phenotypes, and characterized by various functional, transcriptomic, and lipidomic assays. PNPLA3KO hepatocytes showed higher lipid accumulation as well as an altered pattern of response to lipid-induced stress. Interestingly, loss of PNPLA3 also caused a reduction in xenobiotic metabolism and predisposed PNPLA3KO cells to be more susceptible to ethanol- and methotrexate-induced toxicity. The PNPLA3I148M cells exhibited an intermediate phenotype between the wild type and PNPLA3KO cells.

Together, these results indicate that the I148M variant induces a loss of function predisposing to steatosis and increased susceptibility to hepatotoxins.

IL-1β-induced Elevation of SLC7A11 Promotes Hepatocellular Carcinoma Metastasis through Upregulating PD-L1 and CSF1.

Hepatology

Due to paucity of effective treatment options, metastasis is still a major cause for hepatocellular carcinoma (HCC)-associated mortality. Molecular mechanism of inflammation-induced HCC metastasis is largely unknown. Here, we characterized the function of solute carrier family 7 member 11 (SLC7A11) in inflammation-related HCC metastasis and probed therapy strategies for this subpopulation patients.

Elevated expression of SLC7A11 was positively correlated with poor tumor differentiation, and higher tumor-nodule-metastasis (TNM) stage, and indicated poor prognosis in human HCC. SLC7A11 increased HIF1α expression through reducing α-ketoglutarate (αKG) level via exporting glutamate. SLC7A11 upregulated programmed death-1-ligand 1 (PD-L1) and colony stimulating factor-1 (CSF1) expression through αKG-HIF1α cascade. SLC7A11 overexpression in HCC cells promoted intratumoral tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) infiltration through CSF1/CSF1R axis, whereas knockdown of CSF1 attenuated SLC7A11-mediated intratumoral TAMs and MDSCs infiltration and HCC metastasis. Depletion of either TAMs or MDSCs decreased SLC7A11-mediated HCC metastasis. Furthermore, combination of CSF1R inhibitor BZL945 and anti-PD-L1 antibody blocked SLC7A11-induced HCC metastasis. In addition, interleukin 1β (IL-1β) upregulated SLC7A11 expression through the IL-1R1/ERK/SP1 pathway. SLC7A11 knockdown impaired IL-1β-promoted HCC metastasis. Anakinra, an IL-1R1 antagonist, reversed IL-1β-promoted HCC metastasis. In human HCC tissues, SLC7A11 expression was positively associated with HIF1α, PD-L1, and CSF1 expression, and intratumoral TAMs and MDSCs infiltration.

IL-1β-induced SLC7A11 overexpression upregulated PD-L1 and CSF1 through αKG/HIF1α axis, which promoted TAMs and MDSCs infiltration. Interruption of this oncogenic loop may provide a promising therapy strategy for the inhibition of SLC7A11-mediated HCC metastasis.

miR-511-3p promotes hepatic sinusoidal obstruction syndrome by activating Hedgehog pathway via targeting Ptch1.

Am J Physiol

As a major complication of hematopoietic stem cell transplantation, the incidence of hepatic sinusoidal obstruction syndrome (HSOS) is as high as 70%. Previous evidence has demonstrated that miR-511-3p was involved in HSOS, but the mechanism remains unclear. This study aims to examine the mechanism underlying miR-511-3p regulating HSOS.

Monocrotaline (MCT) was used to create an HSOS rat model and to treat liver sinusoidal endothelial cells (LSECs). H&E and Masson staining were used to detect pathological changes in liver tissue. The expression of miR-511-3p and Hedgehog pathway-related proteins were assessed by qRT-PCR and Western blotting. The effect of miR-511-3p in regulating HSOS was investigated by MTT, ELISA assay and flow cytometry. Finally, the interaction between miR-511-3p and Ptch1 was determined by luciferase reporter assay.

The rats showed a typical HSOS phenotype, including LSEC damage, liver injury and fibrosis after MCT administration. miR-511-3p was upregulated in hepatic tissue of rat HSOS model and MCT-induced LSECs. miR-511-3p directly targeted patched1 (Ptch1) and suppressed Ptch1 expression while activated the Hedgehog signaling pathway. Depletion of miR-511-3p showed a protective effect against MCT-induced HSOS, as evidenced by decreased HSOS pathogenesis factors, MMP-2, MMP-9, TNF-α and IL-1β, and decreased LSEC apoptosis rates. Nevertheless, knockdown of Ptch1 reversed the protective effect of miR-511-3p depletion against MCT-induced LSEC injury and apoptosis.

miR-511-3p aggravates HSOS by activating the Hedgehog signaling pathway through targeting Ptch1, and miR-511-3p may develop as the potential therapy for the treatment of HSOS.

Use of Human Tissue Stem Cell-Derived Organoid Cultures to Model Enterohepatic Circulation.

Am J Physiol

The use of human tissue stem cell-derived organoids has advanced our knowledge of human physiologic and pathophysiological processes that are unabl...

NR4A1 modulates inflammation-associated intestinal fibrosis and dampens fibrogenic signaling in myofibroblasts.

Am J Physiol

Intestinal fibrosis is a common complication of the inflammatory bowel diseases(IBD), contributing to tissue stiffening and luminal narrowing. NR4A1 was previously reported to regulate mesenchymal cell function and dampen fibrogenic signaling. NR4A1 gene variants are associated with IBD risk, and it has been shown to regulate intestinal inflammation. Here, we tested the hypothesis that NR4A1 acts as a negative regulator of intestinal fibrosis through regulating myofibroblast function.

Using the SAMP1/YitFc mouse, we tested whether two pharmacological agents known to enhance NR4A1 signaling: cytosporone B(Csn-B) or 6-mercaptopurine(6-MP); could reduce fibrosis. We also employed the dextran sulphate sodium(DSS) model of colitis and assessed the magnitude of colonic fibrosis in Nr4a1-/- and their wild-type littermates(Nr4a1+/+). Lastly, intestinal myofibroblasts isolated from Nr4a1-/- and Nr4a1+/+ mice or primary human intestinal myofibroblasts were stimulated with transforming growth factor-beta-1(TGF-β1), in the presence or absence of Csn-B or 6-MP, and proliferation and ECM gene expression assessed.

Csn-B or 6-MP treatment significantly reduced ileal thickness, collagen and overall ECM content in SAMP1/YitFc mice. This was associated with a reduction in proliferative markers within the mesenchymal compartment. Nr4a1-/- mice exposed to DSS exhibited increased colonic thickening and ECM content. Nr4a1-/- myofibroblasts displayed enhanced TGF-β1-induced proliferation. Furthermore, Csn-B or 6-MP treatment was anti-proliferative in Nr4a1+/+, but not Nr4a1-/- cells. Lastly, activating NR4A1 in human myofibroblasts reduced TGF-β1-induced collagen deposition and fibrosis-related gene expression.

Our data suggest that NR4A1 can attenuate fibrotic processes in intestinal myofibroblasts and could provide a valuable clinical target to treat inflammation-associated intestinal fibrosis.

Improved outcomes for patients undergoing colectomy for acute severe inflammatory colitis by adopting a multi-disciplinary care bundle.

Gastrointestinal Surgery

Severe inflammatory colitis as a consequence of inflammatory bowel disease (IBD) may not be amenable to medical management, and surgery is often required. The optimal timing of surgery and perioperative therapeutic care requires a formal link between surgical department and gastroenterology which is often lacking. In this study, we assess the impact of adopting a multidisciplinary care bundle on complication rates of subtotal colectomy in IBD patients.

This is a single-centre retrospective observational study. Patients were identified through clinical discharge ICD10 codes. Clinical notes of patients who underwent subtotal colectomies from 1 January 2006 to 31 December 2019 were analysed. Socio-demographics, diagnosis, and medical and surgical management data were collected. A multimodule bundle, including weekly MDT discussions, was started in our unit on 1 April 2014. Multivariable logistic regression analysis was performed on these data.

A total of 296 patients were identified with 113 patients of these (38.2%) experiencing a complication post operation. The overall complication rate improved over time (p = 0.023). Those patients treated after the initiation of the MDT bundle had reduced complication rates (44.6% versus 33.7%, p = 0.045). On multivariate analysis, increasing age (1.023 OR; 95% CI 1.004, 1.041) and procedure performed before MDT bundle (3.1 OR; 95% CI 1.689, 5.723) were independent predictors for post-operative complications.

Closer links between gastroenterology and colorectal specialties have improved patient outcomes in our unit. Whilst IBD MDTs have previously been shown to improve outcomes for patients managed medically, we demonstrate that this interaction, implemented as a multidisciplinary care bundle, also improves surgical outcomes.