Background: Cuproptosis is a novel pathway that differs from other forms of cell death and has been confirmed to be applicable for predicting tumor prognosis and clinical treatment response. However, the mechanism underlying the resistance of colorectal cancer (CRC) to cuproptosis at the molecular level has not been elucidated.
Methods: Using bioinformatics analysis, the expression of CCAAT/enhancer-binding protein beta (CEBPB) in CRC tissues and its enrichment in biological processes were detected. Quantitative reverse transcription polymerase chain reaction and western blotting (WB) were employed to test the expression of CEBPB in CRC cells. WB was utilized to assess the levels of proteins related to cuproptosis and the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. The MTT assay was used to test cell viability. Cell proliferation was assessed by a colony formation assay. Transwell assays were used to measure cell migration and invasion ability. DLAT-aggregate formation was determined by immunofluorescence.
Results: CEBPB was highly upregulated in CRC cells to enhance cell viability, proliferation, migration, and invasion. CEBPB was strongly implicated in copper ion homeostasis and the mTOR signaling pathway in CRC. In a CRC cuproptosis cell model, rescue experiments revealed that a PI3K/AKT/mTOR pathway inhibitor attenuated the promoting effect of CEBPB overexpression on the PI3K/AKT/mTOR pathway and rescued the sensitivity of CRC to cuproptosis.
Conclusion: This work demonstrated that CEBPB can activate the PI3K/AKT/mTOR signaling pathway, thereby decreasing the sensitivity of CRC to cuproptosis. These data suggested that targeting CEBPB or the PI3K/AKT/mTOR pathway may enhance the sensitivity of CRC patients to cuproptosis, providing a combined therapeutic strategy for cuproptosis-induced therapy.
Background: Several investigations suggested correlation between microscopic colitis (MC) and celiac disease (CD). This study aimed to examine this relationship using large-sized, population-based data with adequate control for confounding factors.
Methods: This study employed the National Inpatient Sample (NIS) database over 4 years (2016-2019). Patients with/without MC in the presence/absence of CD were identified through ICD-10 codes. Univariate and multi-variate analyses involving odds ratios (OR) and 95% confidence intervals (CI) were performed.
Results: Overall, 26,836,118 patients were analyzed. Of whom, 6,836 patients had MC (n = 179 with CD and n = 6,657 without CD). The mean hospital stay was not significantly different between both groups (5.42 ± 5.44 days vs. 4.95 ± 4.66 days, P = 0.202). The univariate analysis revealed a significant association between MC and CD (OR = 22.69, 95% [19.55, 26.33], P < 0.0001). In the multi-variate analysis, which adjusted for potential confounders including age, race, hospital region, hospital teaching status, ZIP income, smoking status, alcohol overuse, hypertension, diabetes mellitus, lipidemia-related disorders, non-steroidal anti-inflammatory drug use, and selected auto-immune diseases, the association remained significant (OR = 15.71, 95% CI [13.52, 18.25], P < 0.0001). Moreover, in patients with MC, the presence of CD emerged as a significant, independent variable of in-hospital mortality in univariate (OR = 2.87, 95% [1.14, 7.21], P = 0.025) and multi-variate (OR = 3.37, 95% CI [1.32, 8.60], P = 0.011) analyses.
Conclusion: This study establishes a probable link between MC and CD, backed by both univariate and multi-variate analyses, while also identifying CD as an independent risk factor for increased mortality among MC patients. These findings need to be validated in real-world clinical studies.
Background: Crohn's disease (CD) is a debilitating gastrointestinal disease with complex etiology. Although effective, recipients of anti-tumor necrosis factor (TNF) agents may experience primary or secondary nonresponse, necessitating alternative treatments. This study is intended to compare the short-term effectiveness of ustekinumab and vedolizumab in treating CD after failure of multiple lines of anti-TNF therapy using real-world data.
Methods: A retrospective study was conducted at a tertiary hospital in Dammam, Saudi Arabia, including adults (≥18 years old) with CD who did not respond to anti-TNF therapy. Primary endpoints were clinical improvement per the Harvey-Bradshaw Index (HBI) scores and remission at 12 weeks on an ordinal outcome scale. Secondary endpoints included clinical, biochemical, and endoscopic remission; clinical response; corticosteroid-free days; and cumulative steroid dose. Proportional odds and logistic regression Bayesian models were used to analyze outcomes, and the probability of treatment effectiveness was calculated from the posterior distribution.
Results: The study included 101 patients (ustekinumab, n = 71 and vedolizumab, n = 30) with a median age of 32 years (IQR: 26.0-38.0); 54.4% were male. At 12 weeks, the HBI endpoint showed an adjusted odds ratio (aOR) = 0.60 (95% confidence interval [CI]: 0.25-1.31), favoring ustekinumab, with a 75% probability of treatment effectiveness over vedolizumab. The clinical ordinal scale had an aOR = 0.61 (95% CI: 0.26-1.35) with a 73% probability of effectiveness for ustekinumab. Ustekinumab was also associated with favorable outcomes in secondary endpoints, reaching up to a 90% probability of effectiveness.
Conclusion: In CD patients with anti-TNF failure, ustekinumab was more effective than vedolizumab in the short term. These real-world insights contribute to understanding CD management but require validation in larger prospective studies and randomized controlled trials.
Background: A recent name change of nonalcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) to metabolic dysfunction-associated steatotic liver disease was primarily driven by potential stigma associated with the terminology. This stigma can be different between patients and healthcare providers and differ according to geographic regions of the world. Our aim was to better understand stigma and disease burden among patients with NAFLD enrolled in the global survey from Saudi Arabia (SA).
Methods: Members of the Global NASH Council created a 68-item survey about patients' experience with NAFLD, covering history of stigmatization and discrimination due to the disease, various aspects of the disease burden [(Liver Disease Burden (LDB), 35 items, 7 domains], and perception of various diagnostic terms for NAFLD. Patients whose country of residence was SA were asked to complete the survey.
Results: The survey was completed by 804 patients with NAFLD from SA. Of all enrolled patients, 17% ever disclosed having NAFLD/nonalcoholic steatohepatitis (NASH) to family/friends. The most commonly used term for the disease was "fatty liver" (96% used it at least sometimes, 79% frequently or always). There were 3.7% who reported experiencing stigma or discrimination (at least sometimes) due to obesity/overweight versus only 2.7% due to NAFLD. Female patients reported a history of stigmatization or discrimination more frequently than males: 5.9% versus 3.0% due to obesity ( P = 0.06) and 5.4% versus 1.8% due to NAFLD ( P = 0.01). There were 43% of patients who reported ever missing or avoiding a visit to a primary care provider due to NAFLD (48% male vs 28% female, P < 0.0001). The greatest social-emotional burden among patients with NAFLD (by LDB) was being or being identified as a person with liver disease (10% agree, 4% male vs 26% female) and feeling like they could not do anything about their liver disease (6.4% agree, 3% male vs 16% female). Regarding how patients perceived diagnostic terms, there were no substantial differences between "fatty liver disease", "NAFLD", "NASH", and "MAFLD".
Conclusion: Stigmatization in terms of disease burden, disease-related stigma, and perception of various diagnostic terms are rarely observed in patients with NAFLD in SA. In comparison to male patients, female patients with NAFLD reported more commonly a history of stigmatization and discrimination and a significantly greater disease burden. The findings will help inform policymakers to develop programs to increase awareness and provide education about stigma related to NAFLD.
Background: Globally, viral hepatitis is decreasing, but nonalcoholic fatty liver disease (NAFLD), now metabolic dysfunction-associated steatotic liver disease (MASLD), is increasing. We assessed the burden and trends of MASLD and viral hepatitis in Saudi Arabia.
Methods: Prevalence, death, and disability data due to MASLD, hepatitis C virus (HCV), and hepatitis B virus (HBV) were obtained from 2019 Global Burden of Disease (GBD) database for Saudi Arabia. Time trends were assessed by annual percent change (APC) from joinpoint regression.
Results: From 2012 through 2019, MASLD prevalence in children and adults increased from 28.02% ( n = 8.34 million) to 33.11% ( n = 11.83 million); APC +2.43% (95% confidence interval: 2.33% to 2.54%). HBV prevalence decreased from 1.83% ( n = 0.54 million) to 1.53% ( n = 0.55 million); APC -1.74% (-2.66% to -0.81%). HCV prevalence stabilized from 0.72% ( n = 0.21 million) to 0.73% ( n = 0.26 million): APC +0.32% (-0.13% to 0.78%). Among adults (>20 years), MASLD prevalence increased from 40.64% to 43.95% (APC = +1.15%, 1.12% to 1.18%), HBV prevalence decreased from 2.67% to 2.05% (APC = -2.96%, -3.90% to -2.01%), and HCV leveled from 0.88% to 0.86% (APC = -0.30%, -0.75% to 0.16%). MASLD liver mortality rate from liver cancer and cirrhosis increased: APC of +1.15% (0.82% to 1.48%) from 1.31 to 1.43 (per 100,000). HBV and HCV liver mortality increased at slower rates (APC = +0.78%, 0.38% to 1.19%): 2.07 to 2.20 (per 100,000) and (APC = +0.55%, 0.09% to 0.89%): 6.32 to 6.61 (per 100,000), respectively.
Conclusions: MASLD burden is increasing, while HBV and HCV burden is decreasing/remaining stable. Early prevention and diagnosis health policies for MASLD are needed.
Background: To delineate the levels of serum Hepatitis B virus (HBV) RNA in patients with HBV-related hepatocellular carcinoma (HCC) and study comparisons with those of individuals afflicted with cirrhosis.
Methods: Adult patients diagnosed with HBV-related cirrhosis or HCC (initial diagnosis) were enrolled in the cross-sectional study. Serum HBV DNA level was quantified through a real-time polymerase chain reaction assay with a lower limit of quantification (LLQ) of 20 IU/ml. Additionally, serum HBV RNA was quantified employing RNA real-time fluorescence thermostatic amplification detection technology with LLQ of 100 copies/ml. Propensity score matching (PSM) was conducted to ensure balance in between-group confounders.
Results: A total of 187 patients (47 with HCC and 140 with cirrhosis) were recruited, among whom 140 (74.9%) had undergone antiviral therapy prior to their inclusion, with varying durations. Serum HBV RNA was detectable in 89.4% of HCC patients at the time of carcinoma diagnosis. After PSM, individuals with HCC exhibited significantly elevated levels of serum HBV DNA and HBV RNA compared to those with cirrhosis (median lgHBV RNA 3.1 vs 2.0 copies/ml, P = 0.001). Subgroup analysis, including 38 patients who exhibited ultrasensitive HBV DNA negativity, revealed similar results (median lgHBV RNA 3.0 vs 0.0 copies/ml, P < 0.001).
Conclusions: Serum HBV RNA levels were significantly higher in HBV-related HCC patients compared to cirrhotic patients. The presence of serum HBV RNA positivity or elevated levels was associated with the onset of HCC.
Abstract: Bile acids serve as endogenous ligands for nuclear and cell membrane receptors and play a crucial role in bile acid and lipid metabolism. These detergent-like compounds promote bile flow and aid in the absorption of dietary fats and fat-soluble vitamins in the intestine. Synthesized in the liver as end products of cholesterol catabolism, bile acids exhibit a chemical structure comprising a nucleus and a side chain featuring a carboxyl group, with diverse steric arrangements and potential polar substituents. Critical interactions occur between bile acid species and various nuclear and cell membrane receptors, including the farnesoid X receptor and G-protein-coupled bile acid receptor 1. This research aimed to review the literature on bile acids and their roles in treating different diseases. Currently, numerous investigations are concentrating on specific bile acid species that target nuclear receptors in the gastrointestinal system, aiming to improve the treatment of conditions such as nonalcoholic fatty liver disease. Given the global attention this topic has garnered from research groups, it is considered relatively new, thus anticipating some gaps or incomplete data. Bile acid species have a significant therapeutic promise, especially in their ability to activate or inhibit nuclear receptors, such as farnesoid X receptor. This research provides to offer essential information for scientists and medical practitioners interested in discovering new studies that underscore the importance of bile acids in ameliorating and impeding the progression of disorders. Furthermore, it opens avenues for previously overlooked bile acid-based therapies.
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