Early Liver Transplant for Alcohol-associated Liver Disease Has Excellent Survival but Higher Rates of Harmful Alcohol Use.

BACKGROUND & AIMS: Early liver transplantation (LT) for alcohol-associated liver disease (ALD) has increased worldwide. Short-term outcomes have been favorable, but data on longer-term outcomes are lacking. METHODS: Single-center retrospective study of primary LT recipients between 2010 and 2020, with follow-up through July 1, 2022. Survival analysis was performed using log rank, Cox models, and Kaplan-Meier method. Cox models were created to identify variables associated with mortality; logistic regression to identify variables associated with post-LT alcohol use. RESULTS: Of 708 patients who underwent LT, 110 (15.5%) had ALD and abstinence <6 months prior to LT (ELT), 234 (33.1%) had ALD and alcohol abstinence >6 months (SLT), and 364 (51.4%) had non-ALD diagnoses. Median follow-up was 4.6 years (interquartile range, 2.6-7.3 years). ELT recipients were younger (P = .001) with median abstinence pre-LT of 61.5 days. On adjusted Cox model, post-LT survival was similar in ELT and SLT (hazard ratio [HR], 1.31; P = .30) and superior to non-ALD (HR, 1.68; P = .04). Alcohol use (40.9% vs 21.8%; P < .001) and harmful alcohol use (31.2% vs 16.0%; P = .002) were more common in ELT recipients. Harmful alcohol use was associated with post-LT mortality on univariate (HR, 1.69; P = .03), but not multivariable regression (HR, 1.54; P = .10). Recurrence of decompensated ALD trended toward more common in ELT (9.1% vs 4.4%; P = .09). Greater than 6 months pre-LT abstinence was associated with a decreased risk of harmful alcohol use (odds ratio, 0.42; P = .001), but not in a multivariable model (odds ratio, 0.71; P = .33). CONCLUSIONS: Patients who undergo ELT for ALD have similar or better survival than other diagnoses in the first 10 years after LT despite a higher incidence of post-LT alcohol use.

Dietary macro and micronutrients associated with MASLD: Analysis of a national US cohort database.

INTRODUCTION AND OBJECTIVES: Our objective was to measure and compare the intake of macro and micronutrients in a cohort of individuals with Metabolic Syndrome Associated Steatotic Liver Disease (MASLD) compared with matched controls to identify areas of further research in this area; we identified nutrition-associated associations with MASLD in the United States general population. MATERIALS AND METHODS: We used the 2017 - 2018 NHANES dataset. Elastography Controlled Attenuation Parameter (CAP score>280) in the absence of other liver disease was defined as MASLD in adults (>18). Advanced fibrosis was defined by transient elastography >10 kPa. Controls were adults without liver disease. RESULTS: 1648 MASLD cases (11.4 % advanced fibrosis) and 2527 controls were identified. MASLD cases were older (P<0.001), more likely males (P = 0.01), less likely to have a college education (P = 0.04) and more likely married (P = 0.002). MASLD cases were more likely to be of Mexican American or Hispanic ethnicity (P = 0.002), have higher BMI, and have higher prevalence of diabetes, hyperlipidemia and hypertension (P<0.001 for all). MASLD cases had higher hs-CRP (P = 0.02) and ferritin (P = 0.02). MASLD cases had lower total (P = 0.004) and added vitamin E in their diet (P = 0.002), lower vitamin K intake (P = 0.005), and higher selenium intake (P = 0.03). Caloric intake (P = 0.04), carbohydrate intake (P = 0.02), cholesterol intake (P = 0.03) and saturated fatty acid intake (P = 0.05) were higher in MASLD. Individuals with MASLD were more likely to be on a diet (P<0.001), sedentary (P = 0.008) and less likely to participate in moderate or vigorous recreational activities (P<0.001). CONCLUSIONS: The deficiencies of micronutrients and excess of macronutrients point to oxidative stress, pro-inflammatory state, and lipotoxicity as pathways linking the US diet to MASLD. MASLD patients are more often on special diets, which may reflect prior provider counseling on diet changes to improve health.

Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development.

The surface receptor FcγRIIIA (CD16a) is encoded by the FCGR3A gene and is acquired by human NK cells during maturation. NK cells bind the Fc portion of IgG via CD16a and execute Ab-dependent cell-mediated cytotoxicity, which is critical for the effectiveness of several antitumor mAb therapies. The role of epigenetic regulatory mechanisms controlling transcriptional and posttranscriptional CD16 expression in NK cells is unknown. In this study, we compared specific patterns of DNA methylation and expression of FCGR3A with FCGR3B, which differ in cell type-specific expression despite displaying nearly identical genomic sequences. We identified a sequence within the FCGR3A promoter that selectively exhibits reduced methylation in CD16a+ NK cells versus CD16a- NK cells and neutrophils. This region contained the transcriptional start site of the most highly expressed CD16a isoform in NK cells. Luciferase assays revealed remarkable cell-type specificity and methylation-dependent activity of FCGR3A- versus FCGR3B-derived sequences. Genomic differences between FCGR3A and FCGR3B are enriched at CpG dinucleotides, and mutation of variant CpGs reversed cell-type specificity. We further identified miR-218 as a posttranscriptional negative regulator of CD16a in NK cells. Forced overexpression of miR-218 in NK cells knocked down CD16a mRNA and protein expression. Moreover, miR-218 was highly expressed in CD16a- NK cells compared with CD16a+ NK cells. Taken together, we propose a system of FCGR3A regulation in human NK cells in which CpG dinucleotide sequences and concurrent DNA methylation confer developmental and cell type-specific transcriptional regulation, whereas miR-218 provides an additional layer of posttranscriptional regulation during the maturation process.

Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data.

BACKGROUND: Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment. AIM: To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets. METHODS: We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information's Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis. RESULTS: Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms. CONCLUSION: This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.

Probing predilection to Crohn's disease and Crohn's disease flares: A crowd-sourced bioinformatics approach.

Background: Crohn's Disease (CD) is an inflammatory disease of the gastrointestinal tract that affects millions of patients. While great strides have been made in treatment, namely in biologic therapy such as anti-TNF drugs, CD remains a significant health burden. Method: We conducted two meta-analyses using our STARGEO platform to tag samples from Gene Expression Omnibus. One analysis compares inactive colonic biopsies from CD patients to colonic biopsies from healthy patients as a control and the other compares colonic biopsies from active CD lesions to inactive lesions. Separate tags were created to tag colonic samples from inflamed biopsies (total of 65 samples) and quiescent tissue in CD patients (total of 39 samples), and healthy tissue from non-CD patients (total of 30 samples). Results from the two meta-analyses were analyzed using Ingenuity Pathway Analysis. Results: For the inactive CD vs healthy tissue analysis, we noted FXR/RXR and LXR/RXR activation, superpathway of citrulline metabolism, and atherosclerosis signaling as top canonical pathways. The top upstream regulators include genes implicated in innate immunity, such as TLR3 and HNRNPA2B1, and sterol regulation through SREBF2. In addition, the sterol regulator SREBF2, lipid metabolism was the top disease network identified in IPA (Fig. 1). Top upregulated genes hold implications in innate immunity (DUOX2, REG1A/1B/3A) and cellular transport and absorption (ABCG5, NPC1L1, FOLH1, and SLC6A14). Top downregulated genes largely held roles in cell adhesion and integrity, including claudin 8, PAQR5, and PRKACB.For the active vs inactive CD analysis, we found immune cell adhesion and diapedesis, hepatic fibrosis/hepatic stellate cell activation, LPS/IL-1 inhibition of RXR function, and atherosclerosis as top canonical pathways. Top upstream regulators included inflammatory mediators LPS, TNF, IL1B, and TGFB1. Top upregulated genes function in the immune response such as IL6, CXCL1, CXCR2, MMP1/7/12, and PTGS2. Downregulated genes dealt with cellular metabolism and transport such as CPO, RBP2, G6PC, PCK1, GSTA1, and MEP1B. Conclusion: Our results build off established and recently described research in the field of CD. We demonstrate the use of our user-friendly platform, STARGEO, in investigating disease and finding therapeutic avenues.

Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia.

Acute myelogenous leukemia (AML) is a heterogeneous disease and often relapses after standard chemotherapy. Recently, the neddylation (NEDD8) and the mammalian target of rapamycin (mTOR) signaling pathways have emerged as promising pharmaceutical targets for AML therapy. However, the interaction of these two pathways remains unclear. Here we evaluated the effects of pevonedistat, an inhibitor of the NEDD8 activating enzyme (NAE), and sapanisertib (TAK-228), an inhibitor of mTORC1 and mTORC2 as single agents or in combination on AML cell lines. We found that inhibition of neddylation with pevonedistat partially inhibited mTOR signaling transduction and vice versa, inhibition of mTOR signaling with sapanisertib partially inhibited neddylation in AML cell lines. Pevonedistat alone was able to induce cytotoxicity in most AML cell lines as well as in primary AML, whereas sapanisertib alone decreased cell metabolic activity, reduced cell size and arrested cells in G0 phase with only minimal induction of cell death. In addition, pevonedistat was able to induce cell differentiation, arrest cells in G2/M cell cycle phases, and induce DNA re-replication and damage. However, co-treatment with sapanisertib suppressed pevonedistat induced apoptosis, differentiation, S/G2/M arrest, and DNA damage. Taken together, our data demonstrate that pevonedistat and sapanisertib exhibit distinct anti-tumor effects on AML cells, i.e. cytotoxic and cytostatic effects, respectively; however, sapanisertib can attenuate pevonedistat-induced cellular responses in AML cells. Understanding mTOR and neddylation pathway interaction could provide therapeutic strategies for treatment of AML and other malignancies.

Amiloidose cutânea atípica (nodular primitiva) e doença de Rendu-Osler-Weber / Primary localized cutaneous amyloidosis and hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber's disease)

Os autores relatam um caso de amiloidose cutânea, localizada em uma paciente de 58 anos, associada a telangiectasia hemorrágica hereditária. Esta forma de amiloidose é rara, e apresenta as características histopatológicas e prognósticas diferentes das variantes liquenóide e maculosa. O aspecto peculiar deste caso é associaçäo das doenças, fato do nosso conhecimento näo foi referido na literatura