Miracle-dz/UniFAR-FTUs huggingface dataset:
Hepatitis C virus drug resistance–associated substitutions: State of the art summary

Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon‐free, all‐oral combinations of direct‐acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct‐acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors’ trials as a tool to inform the HCV drug development field. (Hepatology 2015;62:1623–1632)
Gallstone and Severe Hypertriglyceride-Induced Pancreatitis in Pregnancy

Importance Patients with biliary disease or underlying dyslipidemias are at risk for pancreatitis in pregnancy. Appropriate treatment can decrease the risk of recurrence and perinatal complications. Prevention of severe lipid elevations can prevent the development of pancreatitis in pregnancy. Objective To review the pathophysiology, diagnosis and treatment of gallstone and severe hypertriglyceride-induced pancreatitis in pregnancy. Evidence Acquisition We performed a literature search regarding pancreatitis, gallstones, hyperlipidemia, and the treatment of both severe hypertriglyceride-induced pancreatitis and gallstone pancreatitis in pregnancy. Results In the setting of acute pancreatitis, removal of the offending agent, either gallstones or serum lipids, can lead to improved status and decrease recurrence risk. Conclusions and Relevance Patients with acute pancreatitis should be treated with analgesia and fluid resuscitation and maintain a nothing-per-os status. In cases of gallstone pancreatitis, removal of the offending stone through endoscopic retrograde cholangiopancreatography or cholecystectomy can decrease recurrence risk. Severe hypertriglyceride-induced pancreatitis includes similar management. Lipopheresis may be considered in refractory cases. Patients with severe hypercholesterolemia should maintain a low-fat diet and can continue lipid-lowering agents outside the statin class of medications. Preventing severe dyslipidemia in gestation can decrease the risk of pancreatitis and improve maternal and neonatal outcomes. Target Audience Obstetricians and gynecologists, family physicians Learning Objectives After completing this activity, the learner will be better able to diagnose and begin initial treatment of pancreatitis in pregnancy, explain the physiology of pancreatitis and the association with gallstones and hyperlipidemia, screen patients for familial hyperlipidemia syndromes, and discuss the various forms of familial dyslipidemias, potential pregnancy complications, and methods for prevention and treatment of complications.
YAP promotes proliferation, chemoresistance, and angiogenesis in human cholangiocarcinoma through TEAD transcription factors

The Yes‐associated protein (YAP)/Hippo pathway has been implicated in tissue development, regeneration, and tumorigenesis. However, its role in cholangiocarcinoma (CC) is not established. We show that YAP activation is a common feature in CC patient biopsies and human CC cell lines. Using microarray expression profiling of CC cells with overexpressed or down‐regulated YAP, we show that YAP regulates genes involved in proliferation, apoptosis, and angiogenesis. YAP activity promotes CC growth in vitro and in vivo by functionally interacting with TEAD transcription factors (TEADs). YAP activity together with TEADs prevents apoptosis induced by cytotoxic drugs, whereas YAP knockdown sensitizes CC cells to drug‐induced apoptosis. We further show that the proangiogenic microfibrillar‐associated protein 5 (MFAP5) is a direct transcriptional target of YAP/TEAD in CC cells and that secreted MFAP5 promotes tube formation of human microvascular endothelial cells. High YAP activity in human CC xenografts and clinical samples correlates with increased MFAP5 expression and CD31+ vasculature. Conclusions: These findings establish YAP as a key regulator of proliferation and antiapoptotic mechanisms in CC and provide first evidence that YAP promotes angiogenesis by regulating the expression of secreted proangiogenic proteins. (Hepatology 2015;62:1497–1510)
Stimulation of nuclear receptor peroxisome proliferator–activated receptor‐γ limits NF‐κB‐dependent inflammation in mouse cystic fibrosis biliary epithelium

Cystic fibrosis–associated liver disease is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing biliary chloride and bicarbonate secretion, up‐regulation of toll‐like receptor 4/nuclear factor kappa light‐chain‐enhancer of activated B cells (NF‐κB)–dependent immune mechanisms plays a major role in the pathogenesis of cystic fibrosis–associated liver disease and may represent a therapeutic target. Nuclear receptors are transcription factors that regulate several intracellular functions. Some nuclear receptors, including peroxisome proliferator–activated receptor‐γ (PPAR‐γ), may counterregulate inflammation in a tissue‐specific manner. In this study, we explored the anti‐inflammatory effect of PPAR‐γ stimulation in vivo in cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice exposed to dextran sodium sulfate and in vitro in primary cholangiocytes isolated from wild‐type and from Cftr‐knockout mice exposed to lipopolysaccharide. We found that in CFTR‐defective biliary epithelium expression of PPAR‐γ is increased but that this does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR‐γ (pioglitazone and rosiglitazone) up‐regulates PPAR‐γ‐dependent genes, while inhibiting the activation of NF‐κB and the secretion of proinflammatory cytokines (lipopolysaccharide‐induced CXC chemokine, monocyte chemotactic protein‐1, macrophage inflammatory protein‐2, granulocyte colony‐stimulating factor, keratinocyte chemoattractant) in response to lipopolysaccharide. PPAR‐γ agonists modulate NF‐κB‐dependent inflammation by up‐regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF‐κB. Stimulation of PPAR‐γ in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr‐knockout mice exposed to a dextran sodium sulfate–induced portal endotoxemia. Conclusion: These studies unravel a novel function of PPAR‐γ in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR‐γ contributes to the chronic inflammatory state of CFTR‐defective cholangiocytes. (Hepatology 2015;62:1551–1562)
Is cryoablation really more effective than radiofrequency ablation in hepatocellular carcinoma?

Metivier S, et al. Serum tests, liver stiffness and artificial neural networks for diagnosing cirrhosis and portal hypertension. Dig Liver Dis 2015;47:411-416. 5) Amat-Roldan I, Berzigotti A, Gilabert R, Bosch J. Assessment of hepatic vasculature network connectivity with automated graph analysis by dynamic contrast-enhanced US to evaluate portal hypertension in patients with cirrhosis: a pilot study. Radiology 2015; doi:10.1148/radiol.2015141941.
Intracavernous delivery of freshly isolated stromal vascular fraction rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse.

INTRODUCTION Men with diabetic erectile dysfunction (ED) often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. AIM To examine whether and how freshly isolated stromal vascular fraction (SVF) promotes cavernous endothelial regeneration and restores erectile function in diabetic animals. METHODS Eight-week-old C57BL/6J mice were used. Diabetes was induced by intraperitoneal injection of streptozotocin. SVF was isolated from epididymal adipose tissues of green fluorescence protein transgenic mice. At 8 weeks after the induction of diabetes, the animals were divided into six groups: controls, diabetic mice, and diabetic mice treated with a single intracavernous injection of phosphate-buffered saline (PBS) or SVF (1 × 10(4) cells, 1 × 10(5) cells, or 2 × 10(5) cells/20 µL, respectively). MAIN OUTCOME MEASURES Two weeks later, erectile function was measured by cavernous nerve stimulation. The penis was stained with antibodies to CD31, CD34, phosphohistone H3, phospho-endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor-A (VEGF-A). We also performed Western blot for phospho-eNOS and eNOS, and determined cyclic guanosine monophosphate (cGMP) concentration in the corpus cavernosum tissue. RESULTS Significant improvement in erectile function was noted in diabetic mice treated with SVF at concentrations of 1 × 10(5) and 2 × 10(5) cells, which reached up to 82% of the control values. Local delivery of SVF significantly increased cavernous endothelial cell proliferation, eNOS phosphorylation, and cGMP expression compared with that in the untreated group and the PBS-treated diabetic group. Intracavernous injection of SVF increased cavernous VEGF-A expression and induced recruitment of CD34(+)CD31(-) progenitor cells. Some SVF underwent differentiation into cavernous endothelial cells. SVF-induced promotion of cavernous angiogenesis and erectile function was abolished in the presence of VEGF-Trap, a soluble VEGF-A neutralizing antibody. CONCLUSION The results support the concept of cavernous endothelial regeneration by use of SVF as a curative therapy for diabetic ED.
Sexual dysfunction among male veterans returning from Iraq and Afghanistan: prevalence and correlates.

INTRODUCTION Sexual dysfunction (SD) is not well described in the Iraq/Afghanistan veteran population despite high prevalence of multiple risk factors for this issue. AIM To estimate the prevalence and examine the association of various sociodemographic, mental health, comorbid conditions and life style factors with sexual dysfunction in Iraq/Afghanistan veterans. METHODS This exploratory cross-sectional study was conducted using data from the VA administrative database. A total of 4,755 Iraq/Afghanistan veterans were identified who sought treatment from the Michael E. DeBakey Veterans Affairs Medical Center inpatient and outpatient clinic between September 2007 and August 2009. MAIN OUTCOME MEASURES Sexual dysfunction was determined by ICD9-CM codes related to sexual health issues and/or by specific medications, primarily phosphodiesterase-5 inhibitors (PDE5i), prescribed for erectile dysfunction. RESULTS The overall prevalence of sexual dysfunction was 5.5% (N = 265). By age category, it was 3.6% (N = 145) for Iraq/Afghanistan veterans aged 18-40 years and 15.7% (N = 120) for Iraq/Afghanistan veterans aged > 40 years, respectively. A multivariate logistic-regression model revealed that annual income, marital status, post-traumatic stress disorder, and hypertension were significant risk factors of SD (all P < 0.05) among younger Iraq/Afghanistan veterans, whereas among the older Iraq/Afghanistan veterans, being African American and having PTSD and hypertension were significant risk factors of SD (all P < 0.05). There was marked discrepancy between documented erectile dysfunction and prescription of a PDE5i. CONCLUSIONS These data demonstrate that a significant proportion of Iraq/Afghanistan veterans have SD and that the risk factors differ between younger and older veterans. Our findings also suggest that SD is likely under-coded. To better identify the scope of the problem, systematic screening for sexual dysfunction may be appropriate perhaps as part of an initial post-deployment health evaluation.
Psychosocial Well-Being of Young People Who Participated in a Support Group Following the Loss of a Parent to Cancer

ABSTRACT Despite the evidence of unmet support needs among young people who have lost a parent to cancer, only a few support group initiatives have been reported. This observational prospective study explored the psychosocial well-being of young people who participated in support groups at a Swedish specialist palliative care setting. On three occasions, 29 participants, aged 16–28 years, answered questionnaires covering characteristics of the participants, circumstances of the losses, psychosocial well-being of the young people, and their own assessment of the support groups. The support groups attracted mostly young women who were often unprepared for the loss. The living arrangements differed between younger and older participants; however, the loss-related variables did not differ. Significant positive changes were found regarding a sense of meaning in their future life and life satisfaction. The helpfulness of the group was assessed as high/very high and the group brought a valuable fellowship with others in a similar situation. Universality and beneficial interactions were reported and strengthened psychosocial well-being developed over time. This change, according to the young people themselves, may be attributed to the group support. The findings are useful for planning interventions to support young people in bereavement in order to enhance their psychosocial well-being.
Human immunodeficiency virus and liver disease: An update

Human immunodeficiency viral (HIV) infection affects approximately 1.2 million persons in the United States and 35 million worldwide. Progression to advanced liver disease remains a leading cause of death among HIV‐infected persons in the United States and elsewhere. Though mortality from HIV complications has been dramatically reduced wherever effective combination antiretroviral therapy is used, there has been little impact on liver‐related mortality. Causes of liver disease in the setting of HIV infection include viral hepatitis, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, drug‐associated toxicities, and other metabolic/genetic disorders which interact in an environment modulated by persistent immune activation and altered cytokine display. Conclusion: Despite significant advances in treatment of hepatitis C virus and suppression of hepatitis B virus, treatment and management principles for liver disease in HIV‐infected patients remain challenging; limited resources, fragmented health care, and high levels of injection drug use, alcohol use, and depression remain relevant issues in the HIV‐infected patient. (Hepatology 2015;62:1871–1882)
Yes‐associated protein 1 and transcriptional coactivator with PDZ‐binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma

Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes‐associated protein 1 (YAP1) and transcriptional coactivator with PDZ‐binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up‐regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ‐mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism's potential clinical implications for treating hepatocellular carcinoma. Conclusion: YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets. (Hepatology 2016;63:159–172)
Elucidating the composition and conservation of the autophagy pathway in photosynthetic eukaryotes

Aquatic photosynthetic eukaryotes represent highly diverse groups (green, red, and chromalveolate algae) derived from multiple endosymbiosis events, covering a wide spectrum of the tree of life. They are responsible for about 50% of the global photosynthesis and serve as the foundation for oceanic and fresh water food webs. Although the ecophysiology and molecular ecology of some algal species are extensively studied, some basic aspects of algal cell biology are still underexplored. The recent wealth of genomic resources from algae has opened new frontiers to decipher the role of cell signaling pathways and their function in an ecological and biotechnological context. Here, we took a bioinformatic approach to explore the distribution and conservation of TOR and autophagy-related (ATG) proteins (Atg in yeast) in diverse algal groups. Our genomic analysis demonstrates conservation of TOR and ATG proteins in green algae. In contrast, in all 5 available red algal genomes, we could not detect the sequences that encode for any of the 17 core ATG proteins examined, albeit TOR and its interacting proteins are conserved. This intriguing data suggests that the autophagy pathway is not conserved in red algae as it is in the entire eukaryote domain. In contrast, chromalveolates, despite being derived from the red-plastid lineage, retain and express ATG genes, which raises a fundamental question regarding the acquisition of ATG genes during algal evolution. Among chromalveolates, Emiliania huxleyi (Haptophyta), a bloom-forming coccolithophore, possesses the most complete set of ATG genes, and may serve as a model organism to study autophagy in marine protists with great ecological significance.
Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study

We assessed the association between the single‐nucleotide polymorphism (SNP) rs58542926 in the transmembrane 6 superfamily member 2 (TM6SF2) gene and fatty liver disease in obese youth. We genotyped the TM6SF2 rs58542926 SNP in a multiethnic cohort of 957 obese children and adolescents (42% Caucasians, 28% African Americans, 30% Hispanics). All underwent an oral glucose tolerance test, a liver panel, and a lipid profile. Of them, 454 children underwent a magnetic resonance imaging study to assess hepatic fat content and 11 underwent liver biopsy to assess the degree of disease severity. The minor allele of the rs58542926 SNP was associated with high hepatic fat content in Caucasians and African Americans (all P < 0.05), with high alanine aminotransferase levels in Hispanics (P < 0.05) and a more favorable lipoprotein profile (lower low‐density lipoprotein, small dense low‐density lipoprotein, and very small low‐density lipoprotein) in Caucasians and Hispanics (all P < 0.05). The liver biopsy showed a higher prevalence of fibrosis (P = 0.04) and a higher nonalcoholic fatty liver disease activity score (P = 0.05) in subjects carrying the minor allele than in those homozygous for the common allele. Moreover, we observed a joint effect among the TM6SF2 rs58542926, the PNPLA3 rs738409, and the GCKR rs1260326 SNPs in determining intrahepatic fat accumulation (P < 0.05). Conclusion: The rs58542926 SNP in the TM6SF2 gene is associated with pediatric nonalcoholic fatty liver disease but may confer protection against cardiovascular risk. (Hepatology 2016;63:117–125)
Macrophage autophagy protects against liver fibrosis in mice

Autophagy is a lysosomal degradation pathway of cellular components that displays antiinflammatory properties in macrophages. Macrophages are critically involved in chronic liver injury by releasing mediators that promote hepatocyte apoptosis, contribute to inflammatory cell recruitment and activation of hepatic fibrogenic cells. Here, we investigated whether macrophage autophagy may protect against chronic liver injury. Experiments were performed in mice with mutations in the autophagy gene Atg5 in the myeloid lineage (Atg5fl/fl LysM-Cre mice, referred to as atg5−/−) and their wild-type (Atg5fl/fl, referred to as WT) littermates. Liver fibrosis was induced by repeated intraperitoneal injection of carbon tetrachloride. In vitro studies were performed in cultures or co-cultures of peritoneal macrophages with hepatic myofibroblasts. As compared to WT littermates, atg5−/− mice exposed to chronic carbon tetrachloride administration displayed higher hepatic levels of IL1A and IL1B and enhanced inflammatory cell recruitment associated with exacerbated liver injury. In addition, atg5−/− mice were more susceptible to liver fibrosis, as shown by enhanced matrix and fibrogenic cell accumulation. Macrophages from atg5−/− mice secreted higher levels of reactive oxygen species (ROS)-induced IL1A and IL1B. Moreover, hepatic myofibroblasts exposed to the conditioned medium of macrophages from atg5−/− mice showed increased profibrogenic gene expression; this effect was blunted when neutralizing IL1A and IL1B in the conditioned medium of atg5−/− macrophages. Finally, administration of recombinant IL1RN (interleukin 1 receptor antagonist) to carbon tetrachloride-exposed atg5−/− mice blunted liver injury and fibrosis, identifying IL1A/B as central mediators in the deleterious effects of macrophage autophagy invalidation. These results uncover macrophage autophagy as a novel antiinflammatory pathway regulating liver fibrosis.
Phosphorylation of Atg9 regulates movement to the phagophore assembly site and the rate of autophagosome formation

ABSTRACT Macroautophagy is primarily a degradative process that cells use to break down their own components to recycle macromolecules and provide energy under stress conditions, and defects in macroautophagy lead to a wide range of diseases. Atg9, conserved from yeast to mammals, is the only identified transmembrane protein in the yeast core macroautophagy machinery required for formation of the sequestering compartment termed the autophagosome. This protein undergoes dynamic movement between the phagophore assembly site (PAS), where the autophagosome precursor is nucleated, and peripheral sites that may provide donor membrane for expansion of the phagophore. Atg9 is a phosphoprotein that is regulated by the Atg1 kinase. We used stable isotope labeling by amino acids in cell culture (SILAC) to identify phosphorylation sites on this protein and identified an Atg1-independent phosphorylation site at serine 122. A nonphosphorylatable Atg9 mutant showed decreased autophagy activity, whereas the phosphomimetic mutant enhanced activity. Electron microscopy analysis suggests that the different levels of autophagy activity reflect differences in autophagosome formation, correlating with the delivery of Atg9 to the PAS. Finally, this phosphorylation regulates Atg9 interaction with Atg23 and Atg27.