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The use of hepatitis C virus (HCV) -positive organs in HCV-negative recipients with posttransplant antiviral treatment has increasingly been studied since the introduction of new direct-acting antivirals. This article reviews existing experience in liver and kidney transplant. Fifteen studies with 218 HCV D+/R- liver transplants, with 182 from viremic donors, show a sustained viral response for 12 weeks (SVR12) rate of 99.5%. Nine studies involving 204 HCV donor-positive recipient-negative kidney transplant recipients had an SVR12 rate of 99.5%. Complications are infrequent. Preemptive treatment in kidney transplant of for only 4 weeks or even 4 days showed surprising success rates.

Supplemental Digital Content is available in the text., Background and aims Liver chemistry abnormalities (LCA) are common in patients with coronavirus disease 2019 (COVID-19), but their causes and clinical impact have not been adequately studied. We assessed the associations between LCA and clinical characteristics, inflammatory serum markers, in-hospital mortality. Methods Ten thousand eight hundred fifty-six adult patients with COVID-19 hospitalized in 13 hospitals in New York (1 March to 27 April 2020) were analyzed retrospectively. Abnormalities of liver chemistries [aspartate aminotransferase (AST), alanine aminotransferase, alkaline phosphatase, or total bilirubin] were defined as absent, mild-moderate (at least one value up to four times elevated), or severe. Results LCA were mild-moderate in 63.9% and severe in 7.6% at admission. Risk factors for severe LCA were male sex and chronic liver disease. Conversely, hypertension and diabetes mellitus were less likely associated with severe LCA. AST elevation correlated weakly to modestly with inflammatory markers. On adjusted analysis, in-hospital mortality was 1.56 times and 1.87 times increased in patients with mild-to-moderate and severe LCA, respectively. Diabetes, hypertension, male sex, and age greater than 60 years was associated with incremental risk of mortality with increase severity of LCA, especially in the first week of hospitalization. HTN was not associated with increased in-hospital mortality unless LCA was present. Conclusion Increasing severity of LCA on hospital admission predicts early in-hospital mortality in COVID-19 patients. Mortality associated with the known risk factors, hypertension, diabetes, male sex, and old age was accentuated in the presence of LCA. AST correlated modestly with inflammatory markers.

INTRODUCTION: Abnormal liver chemistries and elevated CPK (creatinine phosphokinase) levels are known to be associated with COVID-19 infection CPK is a biomarker associated with disease progression with COVID-19 Outcomes related elevated CPK levels in relationship to ALT levels elevation has not been explored Our study assessed the predictive value of the ratio of alanine aminotransferase levels and CPK in a large cohort of COVID-19 patients without known chronic liver disease (CLD) METHODS: We reviewed the charts of 11,265 patients with confirmed COVID-19 infection via nasopharyngeal swabs admitted to our health system from March 1 to April 30, 2020 Baseline ALT and CPK were drawn within 24 hours of presentation After exclusion of patients who did not have an initial RESULTS: CPK to ALT ratio ≥ 1 (CPK/ALT / 5 1) was noted in 91 5% of the patients;8 5% with CPK/ALT≤1, 32% with CPK/ALT >1 and ≤4, 29 5% with CPK/ALT >4 and ≤10, and 29 9% with CPK/ ALT >10 In Kaplan-Meier survival analyses, patients with CPK/ALT ≥1 had an increased in-hospital mortality as compared to patients with CPK/ALT1 and ≤410 compared to patients with CPK/ALT ≤1 CONCLUSION: Our study found that a CPK/ALT >1 on presentation in COVID-19 patients without known chronic liver disease was predictive of increased in-hospital mortality in this large cohort Higher CPK/ ALT (≥1) correlates with increased in-hospital mortality even when adjusted for baseline demographics and the presence of comorbidities Based upon this large study, CPK/ALT ratio should be used to predict inhospital mortality in COVID-19 infection and included in the initial assessment of these patients

INTRODUCTION: Liver injury has been noted during the disease course of the novel coronavirus infection (COVID-19) We evaluated for ethnic and racial disparities in COVID-19 patients presenting with liver injury METHODS: We reviewed 11,265 individual patient charts with confirmed COVID-19 infection admitted to our 12 hospitals in our health system between March 1 to April 30, 2020 Race and ethnicity data were collected by self-report in pre-specified categories Race categories included white, black, asian, other/multiracial and unknown, while ethnicity included non-Hispanic, Hispanic and unknown Baseline liver chemistries were collected within 24 hours of presentation Exclusion criteria included age less than 18 years and missing baseline data Patients were categorized as having liver injury if they had any elevation above the upper limit of normal set by American Association for the Study of Liver Diseases in alanine aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) or bilirubin Multivariate analysis was performed after adjusting for covariates RESULTS: After exclusion,10,856 patients were included in our study Overall, there was a significant difference of the prevalence of liver injury amongst the various races and ethnicities (Table 1) On adjusted analysis, Asian (OR: 1 65 [95% CI: [1 37-2 02]) and multi-racial patients (OR: 1 65 [95% CI: 1 37-2 02]) were more likely to develop liver injury compared to white patients A non-Hispanic ethnicity had a lower association with sustaining liver injury (OR: 0 77 [95% CI: [0 75-1 03]) (Table 2) CONCLUSION: There are racial and ethnic disparities seen in patients with liver injury during COVID-19 infection Our data suggest that Asian patients are more likely compared to white patients to sustain liver injury Non-Hispanic ethnicity conferred protective effect against liver injury These results may implicate a component underlying genetic predisposition for liver injury during COVID- 19 infection (Table Presented)

INTRODUCTION: There are several reports suggesting abnormal liver enzymes occur in as many as 50% of patients infected by the novel coronavirus-19 (COVID-19) The purpose of our study was to examine the gender disparities in the prevalence of abnormal liver enzymes at initial presentation in COVID-19 patients METHODS: We reviewed the charts of 11,265 adult patients with confirmed COVID-19 infection admitted to any of the 12 hospitals in our health system from March 1 to April 30, 2020 COVID-19 status was confirmed by polymerase chain reaction of a nasopharyngeal swab specimen Labs drawn within 24 hours of presentation were considered baseline Patients that had an age less than 18 or missing baseline data were excluded Abnormalities in liver chemistries for AST (Aspartate Amino Transferase) and ALT (Alanine Amino Transferase) were grouped as follows: (1) within normal limits;(2) mild: greater than the upper limit of normal (ULN) to less than or equal to 4 times the ULN;(3) moderate: greater than 4 times the ULN to less than or equal to 10 times the ULN;and (4) severe: greater than 10 times the ULN RESULTS: After exclusions, 10,856 patients were included in our study There was a significant difference of the prevalence of liver injury between men and women (Table 1) Liver injury was present in 61% male and 40% female (P < 0 001) On univariate analysis, men (OR: 1 77 [95% CI: 1 64-1 92] and OR: 2 56 [95% CI: 2 06-3 17]) were more likely to have mild or moderate increases in AST but the difference was not apparent with ALT levels These results were confirmed using the adjusted analysis after adjusting for baseline demographics and comorbidities (Table 2) CONCLUSION: Males presenting with COVID-19 infection are more likely to have elevated AST levels than females There were no significant differences in ALT levels based upon gender Elevated AST levels have been associated with a poor prognosis in hospitalized COVID-19 patients Further research is needed to understand the mechanism of these gender-based differences in liver enzyme elevations, and their relationship to outcomes in COVID-19 infected patients (Table Presented)

The gut–liver axis is increasingly recognised as a key contributor to chronic liver disease. A failing gut barrier contributes to increased bacterial translocation, which results in an elevated risk of bacterial infection and a chronic inflammatory state that may promote the progression of chronic liver disease and the development of long-term complications such as fibrosis and HCC.1 ,2 The most important clinical consequence of increased translocation is acute bacterial infection, a common cause of hospital admissions and a major contributor to morbidity and mortality in patients with cirrhosis. Moreover, bacterial infections can lead to acute decompensation, often triggering acute-on-chronic liver injury.3 On top of a leaky gut, patients with liver cirrhosis have severe defects in the innate immune system, affecting macrophages, neutrophils and the complement system.4 The liver itself represents an important immunological organ and is the first target of gut-derived bacteria, bacterial pathogen-associated molecular patterns (PAMPs) and food products after they enter the circulation. For this reason, 80% of the body's resident macrophages are found in the liver, where they act as an important component of a firewall, that protects the body from infection from circulating bacteria.5 Following infection, a large proportion of circulating bacteria are phagocytosed by Kupffer cells rather than in the spleen; ablation of macrophages severely hampers clearance of circulating bacteria.5 Together, these findings suggest that the liver rather than the spleen is the main organ involved in the clearance of circulating bacteria. Importantly, the presence of liver fibrosis severely hampers the clearance of circulating bacteria.5 However, the mechanisms that impair the clearance of circulating bacteria in the fibrotic liver remain largely unknown. Better knowledge of the underlying pathways may lead towards novel therapeutic targets for patients with advanced liver disease. In this issue, …

Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IκB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-κB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-κB- and JNK-dependent manner. Blockade of NF-κB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-κB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs.

c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC(50) = 18 nM; K(i) = 1.5 nM) and JNK/substrate association in a displacement assay (IC(50) = 46 nM; K(i) = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell-based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice.

Background/Aims Failure to induce apoptosis triggered by members of the death receptor family has been described in hepatocellular carcinoma (HCC) and sensitization of malignant cells to pro-apoptotic molecules such as TRAIL has been proposed as an alternative cancer therapy. Limiting to this approach are the resistance of many tumor cells to TRAIL and safety concerns about the toxicity of TRAIL in normal hepatocytes. Methods We here explored the possibility that the protooncogene c-Src, known to be overexpressed in a variety of tumors, could be specifically responsible for the loss of response to receptor-mediated apoptosis. Results Cotreatment of several hepatoma cell lines with the Src inhibitor PP2 potently sensitized these cells to TRAIL and CD95, dramatically decreasing effective doses of TRAIL to as low as 1ng/ml. Remarkably, Src-inhibition did not synergize with TRAIL signaling in primary hepatocytes. Specific siRNAs showed that the effect was due to blockade of p60 c-Src and occurred through increased recruitment of caspase 8. Conclusions We provide evidence that p60 c-Src is an important and effective suppressor of receptor-mediated apoptosis in hepatoma cells but not in primary human hepatocytes. Inhibition of Src sensitizes tumor cells to apoptosis and decreases effective doses of TRAIL to therapeutic concentrations.

Loss of susceptibility to apoptosis signals is a crucial step in carcinogenesis. Therefore, sensitization of tumor cells to apoptosis is a promising therapeutic strategy. c-Jun-N-terminal-kinases (JNK) have been implicated in stress-induced apoptosis, but may also contribute to survival signaling. Here we show that CD95-induced apoptosis is augmented by the JNK inhibitor SP600125 and small interfering RNA directed against JNK1/2. SP600125 potently inhibited methyl methane sulfonate–induced phosphorylation of c-Jun, but had minimal effect on apoptosis alone. In contrast, it strongly enhanced CD95-mediated apoptosis in six of eight tumor cell lines and led to a G2/M phase arrest in all cell lines. SP600125 enhanced cleavage of caspase 3 and caspase 8, the most upstream caspase in the CD95 pathway. JNK inhibition up-regulates p53 and its target genes p21Cip1/Waf1 and CD95. However, although HCT116 p53−/− cells and p21+/+ cells were less sensitive to CD95 stimulation than their p53+/+ and p21−/− counterparts, p53 and p21 were not involved in the JNK-mediated effect. JunD, which was described to be protective in tumor necrosis factor–induced apoptosis, was not regulated by JNK inhibition on the protein level. When transcription was blocked by actinomycin D, JNK inhibition still enhanced apoptosis to a comparable extent. We conclude that JNK inhibition has antitumor activity by inducing growth arrest and enhancing CD95-mediated apoptosis by a transcription-independent mechanism.

Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (deltapsim). Loss of deltapsim was only detected in E7, but not in E6 oncogene-expressing cells. HDAC inhibition led to a time-dependent degradation of the pocket proteins pRb, p107 and p130, releasing 'free' E2F-1 following initial G1 arrest. Inhibition of proteasomal proteolysis, but not of caspase activity rescued pRb from degradation and functionally restored its inhibitory effect on the cyclin E gene, known to be suppressed by pRb-E2F-1 in conjunction with HDAC1. Using siRNA targeted against p53, E2F-1 still triggered apoptosis by inducing the E2F-responsive proapoptotic alpha- and beta-isoforms of p73. These data may determine future therapeutic strategies in which HDAC inhibitors can effectively eliminate HPV-positive cells by an apoptotic route that does not rely on the reactivation of the 'classical' p53 pathway through a preceding shut-off of viral gene expression.

Although transcriptional activation by NF-κB is well appreciated, physiological importance of transcriptional repression by NF-κB in cancer has remained elusive. Here we show that an HDAC4-RelB-p52 complex maintains repressive chromatin around proapoptotic genes Bim and BMF and regulates multiple myeloma (MM) survival and growth. Disruption of RelB-HDAC4 complex by a HDAC4-mimetic polypeptide blocks MM growth. RelB-p52 also represses BMF translation by regulating miR-221 expression. While the NIK-dependent activation of RelB-p52 in MM has been reported, we show that regardless of the activation status of NIK and the oncogenic events that cause plasma cell malignancy, several genetically diverse MM cells including Bortezomib-resistant MM cells are addicted to RelB-p52 for survival. Importantly, RelB is constitutively phosphorylated in MM and ERK1 is a RelB kinase. Phospho-RelB remains largely nuclear and is essential for Bim repression. Thus, ERK1-dependent regulation of nuclear RelB is critical for MM survival and explains the NIK-independent role of RelB in MM.

Histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A arrest human papillomavirus (HPV)-positive carcinoma cells in G1 to S transition of the cell cycle, which is paralleled by an up-regulation of the cyclin-dependent kinase inhibitors (CKIs) p21CIP1 and p27KIP1 as well as the complete loss of cdk2 activity. Although HPV expression was hitherto thought to be required to maintain a proliferative phenotype of these cells, cdk2 suppression is achieved even in the presence of ongoing viral transcription. While CKIs normally cannot exert their cdk2-inhibitory function in the presence of the viral oncoprotein E7, co-immunoprecipitation experiments revealed that E7 binding is prevented. Increase of p27KIP1 correlates with down-regulation of p45SKP2, a component of the ubiquitin-protein ligase SCF(SKP2) controlling the half-life of regulatory proteins during the cell cycle. HDAC inhibition also triggered an E7-dependent degradation of pRb, while the levels of E2F remained unaffected. The presence of free intracellular E2F and the concomitant up-regulation of CKIs during G1 arrest results in a 'conflicting growth situation', which finally renders the cells to undergo apoptosis. These data provide novel molecular insights into how the transforming potential of HPV can be bypassed and open new therapeutical perspectives for the treatment of cervical cancer.

JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell . In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo , BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.

NF-KappaB/Rel transcription factors are critical regulators of immunity, inflammation, development, and cell survival. Activation of NF-KB inhibits programmed cell death (PCD) triggered by tumor necrosis factor alpha (TNFalpha) and several other stimuli. The prosurvival activity of NF-KB is also crucial to lymphopoiesis, neuroprotection, tumorigenesis, and cancer chemoresistance. The characterization of the downstream targets that mediate the prosurvival activity of NF-KB is therefore a topic of intense investigation. Early screens aimed at identifying these genes were mainly based on expression criteria and so were poised to only isolate genes already known to have protective effects. Here, we describe a new method for the identification of these genes, whereby expression libraries are screened for their ability to halt PCD in NF-KB-deficient cells. This complementation approach provides substantial advantages over other approaches, as it enables functional assessment of isolated genes without any preconceived notion about their sequence or presumed role. Expression libraries are generated from cells that are resistant to TNFalpha-induced cytotoxicity and are then enriched in prosurvival genes upon selection with TNFa in NF-kappaB/RelA-null cells, which are highly susceptible instead to this cytotoxicity. Upon enrichment, libraries are screened through a randomized two-step approach, whereby cDNAs are first tested for cytoprotective function and then for differential expression in NF-kappaB-proficient and NF-KappaB-deficient cells.

NF-kappaB/Rel transcription factors have recently emerged as crucial regulators of cell survival. Activation of NF-kappaB antagonizes programmed cell death (PCD) induced by tumor necrosis factor-receptors (TNF-Rs) and several other triggers. This prosurvival activity of NF-kappaB participates in a wide range of biological processes, including immunity, lymphopoiesis and development. It is also crucial for pathogenesis of various cancers, chronic inflammation and certain hereditary disorders. This participation of NF-kappaB in survival signaling often involves an antagonism of PCD triggered by TNF-R-family receptors, and is mediated through a suppression of the formation of reactive oxygen species (ROS) and a control of sustained activation of the Jun-N-terminal kinase (JNK) cascade. Effectors of this antagonistic activity of NF-kappaB on this ROS/JNK pathway have been recently identified. Indeed, further delineating the mechanisms by which NF-kappaB promotes cell survival might hold the key to developing new highly effective therapies for treatment of widespread human diseases.

Background & Aims: Portopulmonary hypertension (PPHTN), a severe complication of portal hypertension is observed in 3%–6% of patients evaluated for liver transplantation. Endothelin-1, a potent vasoconstrictor, is likely to play a role in the pathogenesis of primary pulmonary hypertension, and, in 2 recent trials, the dual endothelin receptor antagonist bosentan has shown beneficial effects in this disease. A role for endothelins in the development of both pulmonary hypertension and cirrhosis has been suggested. We therefore hypothesized that endothelin receptor blockade may be beneficial in the treatment of PPHTN. Methods: We report a case of a 42-year-old patient with PPHTN and alcoholic cirrhosis treated with the mixed endothelin receptor antagonist bosentan. Results: The patient rapidly improved from NYHA IV to stage II, experienced a remarkable improvement of 6-minute walking distance from 0 to 590 m within 6 months, and resumed working full-time as a locksmith after 7 months of treatment. Improvement of cardiovascular parameters included a reduction of pulmonary vascular resistance by 60%, a decrease of mean pulmonary artery pressure (mPAP) from 55 to 44 mm Hg at 9 months, and a decline of plasma B-type natriuretic peptide (BNP) from 339 pg/mL to 19 pg/mL after 1 year. There were no adverse events except for a transient decrease in systemic blood pressure. Conclusions: To our knowledge, this is the first report of a patient with PPHTN treated with an endothelin receptor antagonist. The marked and sustained improvement supports the undertaking of controlled studies of the safety and efficacy of bosentan in PPHTN.

Inhibitors of histone deacetylase (HDAC) are capable of arresting growth in cervical carcinoma cells in the G1 phase of the cell cycle. Although HPV E6/E7 mRNA steady-state levels appeared to be constant after prolonged treatment, time-course experiments revealed that viral transcription was transiently down-regulated between 7–10 h prior to cdk2 suppression. To test whether transitory suppression was a prerequisite for the biological outcome after HDAC inhibition, we took advantage of two immortalized human keratinocyte cell lines in which E6/E7 oncogene expression was controlled by different regulatory regions. After treatment with sodium butyrate (NaB) or trichostatin A (TSA), HPV16 upstream regulatory region (URR)-directed transcription was down-regulated, showing kinetics similar to those in cervical carcinoma cells. In contrast, β-actin promoter controlled E6/E7 transcription was even temporarily increased and finally declined to levels initially detected in the untreated controls. Both cell lines, however, were arrested in G1 and showed complete suppression of cdk2 activity that was preceded by a strong up-regulation of the cdk2 inhibitors p21CIP1 and p27KIP1. These results demonstrate that growth of HPV16/18-positive cells can be arrested by HDAC inhibitors despite ongoing HPV transcription and thus independently of any potential position effects uncoupling URR-directed gene expression by adjacent cellular promoters or by downstream 3′-polyadenylation sites after viral integration into the host genome during multistep carcinogenesis.

The NF-kappaB activating kinase IKKbeta suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKbeta's role in late tumor promotion and progression, we developed a transplant system that allows initiated mouse hepatocytes to form hepatocellular carcinomas (HCC) in host liver after a long latency. Deletion of IKKbeta long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKbeta/NF-kappaB were cell autonomous and correlated with increased accumulation of reactive oxygen species that led to JNK and STAT3 activation. Hepatocyte-specific STAT3 ablation prevented HCC development. The negative crosstalk between NF-kappaB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.