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A Journal-Level Analysis of Progress in Transplantation.

Tue, 12/12/2017 - 16:48

A Journal-Level Analysis of Progress in Transplantation.

Prog Transplant. 2017 Jan 01;:1526924817746914

Authors: Feeley T, Lee S, Moon SI

Abstract
CONTEXT: Citations to articles published in academic journals represent a proxy for influence in bibliometrics.
OBJECTIVE: To measure the journal impact factor for Progress in Transplantation over time and to also identify related journals indexed in transplantation and surgery.
DESIGN: Data from Journal Citation Reports (ISI web of science) were used to rank Progress in Transplantation compared to peer journals using journal impact and journal relatedness measures. Social network analysis was used to measure relationships between pairs of journals in Progress in Transplantation's relatedness network.
MAIN OUTCOME MEASURES: Journal impact factor and journal relatedness.
RESULTS: Data from 2010 through 2015 indicate the average journal article in PIT was cited 0.87 times (standard deviation [SD] = 0.12) and this estimate was stable over time. Progress in Transplantation most often cited American Journal of Transplantation, Transplantation, American Journal of Kidney Diseases, and Liver Transplantation. In terms of cited data, the journal was most often referenced by Clinical Transplantation, Transplant International, and Current Opinion in Organ Transplantation.
CONCLUSION: The journal is listed both in surgery and transplantation categories of Journal Citation Reports and its impact factors over time fare better with surgery journals than with transplant journals. Network data using betweenness centrality indicate Progress in Transplantation links transplantation-focused journals and journals indexed in health sciences categories.

PMID: 29226776 [PubMed - as supplied by publisher]

A Case Report of Living Donor Liver Transplantation for Fulminant Hepatitis Related to Hepatitis E Virus Infection.

Tue, 12/12/2017 - 16:48

A Case Report of Living Donor Liver Transplantation for Fulminant Hepatitis Related to Hepatitis E Virus Infection.

Prog Transplant. 2017 Jan 01;:1526924817746912

Authors: Shimata K, Sugawara Y, Yamamoto H, Okamoto H, Uchida K, Kawabata S, Isono K, Hayashida S, Inomata Y

Abstract
Hepatitis E virus (HEV) infection which may become fulminant, especially in elderly people is more common than previously recognized in develop countries. Here we report successful living-donor liver transplantation (LDLT) in a case of acute liver failure due to HEV. A 63-year-old Japanese man with no previous history of liver disease was admitted for severe acute hepatitis. Detection of anti-HEV immunoglobulin A established a diagnosis of this virus-related liver failure. The patient suffered from hepatic encephalopathy 10 days after symptom onset and underwent LDLT. The patient had an uneventful course. The HEV RNA showed spontaneous negative conversion 10 weeks after LDLT. LDLT led to a successful outcome in a patient with acute liver failure due to HEV infection and regular testing for HEV RNA should be performed until HEV RNA is undetectable.

PMID: 29226766 [PubMed - as supplied by publisher]

Non-alcoholic Fatty Liver Disease: A Clinical Update.

Tue, 12/12/2017 - 16:48
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Non-alcoholic Fatty Liver Disease: A Clinical Update.

J Clin Transl Hepatol. 2017 Dec 28;5(4):384-393

Authors: Pappachan JM, Babu S, Krishnan B, Ravindran NC

Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in developed countries because of the obesity epidemic. The disease increases liver-related morbidity and mortality, and often increases the risk for other comorbidities, such as type 2 diabetes and cardiovascular disease. Insulin resistance related to metabolic syndrome is the main pathogenic trigger that, in association with adverse genetic, humoral, hormonal and lifestyle factors, precipitates development of NAFLD. Biochemical markers and radiological imaging, along with liver biopsy in selected cases, help in diagnosis and prognostication. Intense lifestyle changes aiming at weight loss are the main therapeutic intervention to manage cases. Insulin sensitizers, antioxidants, lipid lowering agents, incretin-based drugs, weight loss medications, bariatric surgery and liver transplantation may be necessary for management in some cases along with lifestyle measures. This review summarizes the latest evidence on the epidemiology, natural history, pathogenesis, diagnosis and management of NAFLD.

PMID: 29226105 [PubMed]

Hepatitis E: A Literature Review.

Tue, 12/12/2017 - 16:48
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Hepatitis E: A Literature Review.

J Clin Transl Hepatol. 2017 Dec 28;5(4):376-383

Authors: Guerra JAAA, Kampa KC, Morsoletto DGB, Junior AP, Ivantes CAP

Abstract
Hepatitis E is the fifth known form of human viral hepatitis. Although not very common in our clinical practice, the incidence in Western countries is increasing. Infection with the hepatitis E virus (HEV) may be related to acute illness, liver failure, chronic hepatitis and cirrhosis. HEV itself is an RNA virus, with eight described genotypes (HEV 1-8), four of which more commonly affect humans and have, thus, been better studied. Besides liver manifestations, genotype 3 is also related to extra-hepatic manifestations, such as neurological, renal and rheumatological. Evolution to chronic disease occurs especially in patients who underwent transplantation, have hematological malignancies requiring chemotherapy, or have infection with the human immunodeficiency virus. The diagnosis may be difficult because of the low availability of tests and due to low sensibility and specificity. The acute form of illness does not have to be treated, but the chronic one does. We present here a literature review of hepatitis E and the relation between chronic hepatitis E and transplantation.

PMID: 29226104 [PubMed]

Timing of Hepatitis C Virus Treatment in Liver Transplant Candidates in the Era of Direct-acting Antiviral Agents.

Tue, 12/12/2017 - 16:48
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Timing of Hepatitis C Virus Treatment in Liver Transplant Candidates in the Era of Direct-acting Antiviral Agents.

J Clin Transl Hepatol. 2017 Dec 28;5(4):363-367

Authors: Cholankeril G, Joseph-Talreja M, Perumpail BJ, Liu A, Yoo ER, Ahmed A, Goel A

Abstract
Chronic hepatitis C virus (HCV) infection remains the leading indication for liver transplantation (LT) in the United States. While most patients with chronic HCV infection remain asymptomatic, up to one-third develop progressive liver disease resulting in cirrhosis. LT is often the only curative treatment once significant hepatic decompensation develops. However, antiviral therapy for HCV infection has advanced markedly in the past 5 years with the discovery and approval of direct-acting antiviral agents. These new regimens are well tolerated, of short duration and highly effective, unlike the traditional treatment with pegylated-interferon and ribavirin. As achieving sustained virological response becomes increasingly attainable for a majority of HCV-infected patients, concerns have been raised regarding the optimal timing of treatment for HCV infection in the setting of end-stage liver disease and during the peri-transplant period. On one hand, HCV treatment may improve hepatic function and negate the need for LT in some, which is crucial given the scarcity of donor organs and mortality on the waiting list in certain regions. On the other hand, HCV treatment may result in lowering the priority for LT without improving quality of life, thereby delaying potentially curative LT surgery. This review evaluates the evidence supporting the use of direct-acting antiviral agents in the period before and following LT.

PMID: 29226102 [PubMed]

Clinical Food Addiction Is Not Associated with Development of Metabolic Complications in Liver Transplant Recipients.

Tue, 12/12/2017 - 16:48
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Clinical Food Addiction Is Not Associated with Development of Metabolic Complications in Liver Transplant Recipients.

J Clin Transl Hepatol. 2017 Dec 28;5(4):335-342

Authors: Saab S, Sikavi C, Jimenez M, Viramontes M, Allen R, Challita Y, Mai M, Esmailzadeh N, Grotts J, Choi G, Durazo F, El-Kabany M, Han SH, Moreno E

Abstract
Background and Aims: Given the increased risk of post-transplant metabolic syndrome (PTMS; defined by hypertension, diabetes mellitus and hyperlipidemia), we aimed to identify the potential role of food addiction in the development of metabolic complications in the post-liver transplant population. Methods: Inclusion criteria included adult liver transplant recipients followed at our institution between June 2016 and November 2016. Participants were administered a demographic survey as well as the Yale Food Assessment Scale 2.0, a 35-item questionnaire used to assess frequency of food addiction in accordance with the DSM-V guidelines of substance use disorders. Demographic and clinical data were collected. Results: Our study included 236 liver transplant recipients (139 males, 97 females). The median (interquartile range [IQR]) BMI of participants was 26.8 kg/m2 (24.2, 30.4), and median (IQR) time since transplantation was 50.9 months (19.6, 119.8). The prevalence rates of hypertension, hypercholesterolemia and diabetes mellitus were 54.7%, 25.0% and 27.1%, respectively. Twelve participants (5.1%) were found to have a diagnosis of food addiction. A diagnosis of food misuse was made in 94 (39.8%) of the transplant recipients. Conclusions: Our findings are consistent with prior data that indicate high prevalence of metabolic complications among liver transplant recipients. Food addiction was not predictive of metabolic complications within this population. Nevertheless, we found that this population was at high risk of demonstrating symptoms of food misuse, and they were not likely to appreciate the risks of pathologic patterns of eating. Given the increasing risk of cardiovascular morbidity and mortality in this population, efforts should be made to identify risk factors for the development of PTMS.

PMID: 29226100 [PubMed]

Unresectable Undifferentiated Embryonal Sarcoma of the Liver in an Adult Male Treated with Chemotherapy and Orthotopic Liver Transplantation.

Tue, 12/12/2017 - 16:48
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Unresectable Undifferentiated Embryonal Sarcoma of the Liver in an Adult Male Treated with Chemotherapy and Orthotopic Liver Transplantation.

Cureus. 2017 Oct 08;9(10):e1759

Authors: Khan ZH, Ilyas K, Khan HH, Ghazanfar H, Hussain Q, Inayat F, Yasir M, Asim R

Abstract
Undifferentiated embryonal sarcoma of the liver (UESL) is a malignancy of mesenchymal origin observed predominantly in the pediatric population and very rarely in adults. We describe the case of a 21-year-old male who presented with acute onset of right upper quadrant pain and distention. Physical examination of the patient revealed right upper quadrant tenderness with the lower border of the liver palpable, 4 cm below the right costal margin. Laboratory tests performed on admission showed that the patient's liver function tests, urinalysis, complete blood count, and basic metabolic panel were within reference range. The levels of viral hepatitis and tumor serum markers were all within normal limits except for an elevated level of cancer antigen (CA) 19-9. Magnetic resonance imaging (MRI) and a computerized tomography (CT) scan showed two well-circumscribed lesions in the right lobe. The biopsy of the lesion showed UESL. The patient was started on chemotherapy. On his fifth cycle of chemotherapy, the patient was offered orthotopic liver transplantation (OLT). The patient underwent a successful OLT. There were no postoperative complications. Increased survival time and prevention of the recurrence of USEL can be achieved by surgical resection of the tumor combined with adjuvant and neoadjuvant chemotherapy. For unresectable tumors, OLT with chemotherapy can be a potential cure in younger patients.

PMID: 29226049 [PubMed]

Reactivation of Hemophagocytic Lymphohistiocytosis Triggered by Antithymocyte Globulin.

Tue, 12/12/2017 - 16:48
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Reactivation of Hemophagocytic Lymphohistiocytosis Triggered by Antithymocyte Globulin.

Intern Med. 2017 Dec 08;:

Authors: Matsuda K, Toyama K, Toya T, Ikemura M, Nakamura F, Kurokawa M

Abstract
A 16-year-old boy with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (HLH) underwent allogeneic hematopoietic stem cell transplantation after conditioning with fludarabine, melphalan, total body irradiation, and rabbit antithymocyte globulin (ATG). A severe, persistent infusion reaction occurred after the initial administration of ATG. Investigations showed a rapid increase in the levels of liver enzymes and ferritin, and the reactivation of HLH was confirmed by marked hemophagocytosis in the bone marrow. Treatment with pulse glucocorticoid therapy resulted in the improvement of HLH. This is the first case of HLH reactivation triggered by ATG. Physicians should therefore be cautious of HLH reactivation, especially when a severe and prolonged infusion reaction occurs.

PMID: 29225252 [PubMed - as supplied by publisher]

Development of a Predictive Model for Blood Transfusions and Bleeding During Liver Transplantation: An Observational Cohort Study.

Tue, 12/12/2017 - 16:48
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Development of a Predictive Model for Blood Transfusions and Bleeding During Liver Transplantation: An Observational Cohort Study.

J Cardiothorac Vasc Anesth. 2017 Oct 09;:

Authors: Massicotte L, Carrier FM, Denault AY, Karakiewicz P, Hevesi Z, McCormack M, Thibeault L, Nozza A, Tian Z, Dagenais M, Roy A

Abstract
OBJECTIVE: Orthotopic liver transplantation (OLT) frequently is associated with major blood loss and considerable transfusion requirements. The goal of this study was to define the risk factors for multiple transfusions and major bleeding during OLT and to help identify higher risk patients that could benefit from targeted interventions.
DESIGN: OLTs were studied for this observational cohort study.
SETTING: Community hospital.
PARTICIPANTS: A total of 800 consecutive OLTs were studied.
INTERVENTION: No intervention.
MEASUREMENTS AND MAIN RESULTS: Baseline and intraoperative data were gathered. Multivariate logistic regression analyses were performed to find variables associated with 2 outcomes: transfusion of more than 2 units of red blood cells (RBC) and bleeding ≥900 mL. Two nomograms were developed to predict individual risks. The overall intraoperative RBC transfusion was 0.6 ± 1.4 units on average, and 61 surgeries (7.6%) received more than 2 units of RBC (4.5 ± 1.9). Some variables were associated with the outcomes: 5 were associated with transfusion of more than 2 units of RBC (patient's height, starting hemoglobin concentration, starting bilirubin value, the use of a phlebotomy, and central venous pressure [CVP] at the time of vena cava clamping) and 3 with blood loss of ≥900 mL (starting hemoglobin value, Child-Turcotte-Pugh score, and CVP at the time of vena cava clamping). Preclamping CVP showed the strongest association with both outcomes. Nomograms were developed to predict the individual OLT recipients' risk of requiring more than 2 units RBC and suffering from major bleeding. Among the variables associated with multiple RBC transfusions and major bleeding, 3 can lead to interventions: baseline hemoglobin value, the use of a phlebotomy, and the preclamping CVP.
CONCLUSION: Some variables were able to predict the risk of multiple transfusions and major bleeding in this low bleeding liver transplantation population. Further studies based on these variables should be done to better define the role of targeted interventions in higher risk liver transplant recipients.

PMID: 29225154 [PubMed - as supplied by publisher]

The Clinical Efficacy of Seasonal Influenza Vaccination - Characteristics of two Outbreaks of Influenza A(H1n1) in Immunocompromised Patients.

Tue, 12/12/2017 - 16:48
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The Clinical Efficacy of Seasonal Influenza Vaccination - Characteristics of two Outbreaks of Influenza A(H1n1) in Immunocompromised Patients.

J Hosp Infect. 2017 Dec 07;:

Authors: Helanterä I, Janes R, Anttila VJ

Abstract
BACKGROUND: Influenza A(H1N1) causes serious complications in immunocompromised patients. The efficacy of seasonal vaccination in these patients has been questioned.
AIMS: We describe two outbreaks of influenza A(H1N1) in immunocompromised patients.
METHODS: Two outbreaks of influenza A(H1N1) occurred in our institution: on the kidney transplant ward in 2014 including patients early after kidney or simultaneous pancreas-kidney transplantation, and on the oncology ward in 2016 including patients receiving chemotherapy for malignant tumors. Factors leading to these outbreaks and the clinical efficacy of seasonal influenza vaccination were analyzed.
FINDINGS: Altogether 86 patients were exposed to influenza A(H1N1) during the outbreaks, among whom the seasonal influenza vaccination status was unknown in ten. Only 3/38 vaccinated patients were infected with influenza A(H1N1), compared to 20/38 unvaccinated patients (P=0.02). 1/38 vaccinated patient died related to influenza, compared to 7/38 unvaccinated patients (P=0.06). Shared factors behind the two outbreaks included old fashioned facilities not designed for the treatment of immunosuppressed patients. Vaccination coverage among patients was low, between 40-70% despite vaccination being offered to all patients free of charge. Vaccination coverage of health care workers on the transplant ward was low (46%), but, despite high coverage on the oncology ward (92%) the outbreak occurred.
CONCLUSIONS: Seasonal influenza vaccination was clinically effective with both a reduced risk of influenza infection and a trend towards reduced mortality in these immunocompromised patients. Several possible causes were identified behind these two outbreaks that require continuous awareness in health care professionals to prevent further outbreaks.

PMID: 29225054 [PubMed - as supplied by publisher]

Subclinical Atherosclerosis in Pediatric Liver Transplant Recipients: Carotid and Aorta Intima-Media Thickness and Their Predictors.

Tue, 12/12/2017 - 16:48
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Subclinical Atherosclerosis in Pediatric Liver Transplant Recipients: Carotid and Aorta Intima-Media Thickness and Their Predictors.

J Pediatr. 2017 Dec 07;:

Authors: Perito ER, Phelps A, Vase T, Feldstein VA, Lustig RH, Rosenthal P

Abstract
OBJECTIVE: To investigate prevalence and predictors of cardiovascular risk in pediatric liver transplant recipients using noninvasive markers of subclinical atherosclerosis: carotid intima-media thickness (cIMT) and aorta intima-media thickness (aIMT).
STUDY DESIGN: Cross-sectional study of 88 pediatric liver transplant recipients. The cIMT and aIMT were measured by ultrasound imaging using standardized protocol.
RESULTS: Participants were 15.4 ± 4.8 years of age, and 11.2 ± 5.6 years post-transplantation. The cIMT and aIMT were both higher in males than females. In analyses adjusted for sex, age, and height, the cIMT was higher in subjects transplanted for chronic/cirrhotic liver disease and lower in subjects on cyclosporine (n = 9) than tacrolimus (n = 71). The cIMT was not associated with rejection history or current corticosteroid use. The cIMT increased with increasing diastolic blood pressure and triglycerides. The aIMT (n = 83) also increased with age, and its rate of increase post-transplant varied by age at transplantation. In adjusted analyses, aIMT was higher in subjects with glucose intolerance. In analysis of patients ≤20 years of age for whom blood pressure percentiles could be calculated (n = 66), aIMT increased with increasing diastolic blood pressure percentile (0.010 mm per 5-percentile; 95% CI, 0.000-0.021; P = 0.05). Neither the cIMT nor the aIMT was associated with obesity, systolic hypertension, or other dyslipidemia at study visit.
CONCLUSION: Measures of long-term cardiovascular risk were associated with conditions that are more common in pediatric liver transplant recipients than nontransplanted peers, namely, diastolic hypertension and glucose intolerance. Larger, longitudinal studies are warranted to investigate whether cIMT could be useful for stratifying these patients' cardiovascular risk-and potential need for proactive intervention-during long-term follow-up.

PMID: 29224938 [PubMed - as supplied by publisher]

Ammonia modifies enteric neuromuscular transmission through glial γ-aminobutyric acid signaling.

Tue, 12/12/2017 - 16:48
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Ammonia modifies enteric neuromuscular transmission through glial γ-aminobutyric acid signaling.

Am J Physiol Gastrointest Liver Physiol. 2017 Dec 01;313(6):G570-G580

Authors: Fried DE, Watson RE, Robson SC, Gulbransen BD

Abstract
Impaired gut motility may contribute, at least in part, to the development of systemic hyperammonemia and systemic neurological disorders in inherited metabolic disorders, or in severe liver and renal disease. It is not known whether enteric neurotransmission regulates intestinal luminal and hence systemic ammonia levels by induced changes in motility. Here, we propose and test the hypothesis that ammonia acts through specific enteric circuits to influence gut motility. We tested our hypothesis by recording the effects of ammonia on neuromuscular transmission in tissue samples from mice, pigs, and humans and investigated specific mechanisms using novel mutant mice, selective drugs, cellular imaging, and enzyme-linked immunosorbent assays. Exogenous ammonia increased neurogenic contractions and decreased neurogenic relaxations in segments of mouse, pig, and human intestine. Enteric glial cells responded to ammonia with intracellular Ca2+ responses. Inhibition of glutamine synthetase and the deletion of glial connexin-43 channels in hGFAP::CreERT2+/-/connexin43f/f mice potentiated the effects of ammonia on neuromuscular transmission. The effects of ammonia on neuromuscular transmission were blocked by GABAA receptor antagonists, and ammonia drove substantive GABA release as did the selective pharmacological activation of enteric glia in GFAP::hM3Dq transgenic mice. We propose a novel mechanism whereby local ammonia is operational through GABAergic glial signaling to influence enteric neuromuscular circuits that regulate intestinal motility. Therapeutic manipulation of these mechanisms may benefit a number of neurological, hepatic, and renal disorders manifesting hyperammonemia.NEW & NOTEWORTHY We propose that local circuits in the enteric nervous system sense and regulate intestinal ammonia. We show that ammonia modifies enteric neuromuscular transmission to increase motility in human, pig, and mouse intestine model systems. The mechanisms underlying the effects of ammonia on enteric neurotransmission include GABAergic pathways that are regulated by enteric glial cells. Our new data suggest that myenteric glial cells sense local ammonia and directly modify neurotransmission by releasing GABA.

PMID: 28838986 [PubMed - indexed for MEDLINE]

Therapy of primary and metastatic liver cancer by human iPS cell-derived myeloid cells producing interferon-β.

Tue, 12/12/2017 - 16:48
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Therapy of primary and metastatic liver cancer by human iPS cell-derived myeloid cells producing interferon-β.

J Hepatobiliary Pancreat Sci. 2017 Feb;24(2):109-119

Authors: Sakisaka M, Haruta M, Komohara Y, Umemoto S, Matsumura K, Ikeda T, Takeya M, Inomata Y, Nishimura Y, Senju S

Abstract
BACKGROUND: iPS-ML are myeloid lineage cells with a proliferative capacity derived from induced pluripotent stem (iPS) cells. This study aimed to examine therapeutic effect of iPS-ML producing interferon-β (iPS-ML/IFN-β) towards primary and metastatic liver cancer and investigate the mechanism of that effect.
METHODS: We established a xenograft model of liver metastasis by injecting the spleen of SCID mice with MKN-45 human gastric cancer cells and also a primary liver cancer model by injecting SK-HEP-1 human hepatocellular carcinoma cells into the liver. After cancer lesions were established, iPS-ML/IFN-β was administered by intraperitoneal injection, and therapeutic effect was evaluated.
RESULTS: The i.p. injection of iPS-ML/IFN-β resulted in a significant retardation of cancer progression and prolonged mouse survival. The infiltration of i.p. administered iPS-ML into tumor lesions located below the liver capsule was observed, suggesting tumor-directed migration and penetration of the liver capsule by iPS-ML. The IFN-β concentration in the liver was maintained at levels sufficient to exert an anti-cancer effect for at least 3 days post-injection, accounting for the potent therapeutic effect obtained by injection two to three times per week.
CONCLUSIONS: This study demonstrates the therapeutic potential of the iPS-ML/IFN-β in patients with liver cancer.

PMID: 28008721 [PubMed - indexed for MEDLINE]

Targeting interleukin-1 receptor-associated kinase 1 for human hepatocellular carcinoma.

Tue, 12/12/2017 - 16:48
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Targeting interleukin-1 receptor-associated kinase 1 for human hepatocellular carcinoma.

J Exp Clin Cancer Res. 2016 Sep 13;35(1):140

Authors: Li N, Jiang J, Fu J, Yu T, Wang B, Qin W, Xu A, Wu M, Chen Y, Wang H

Abstract
BACKGROUND: Interleukin-1 receptor associated kinase 1 (IRAK1), as a down-stream of toll-like receptor (TLR) signaling, plays important roles in series of malignancies. However, the role of IRAK1 in hepatocellular carcinoma (HCC) remains little known.
METHODS: In our study, reverse transcription-PCR (RT-PCR), Western Blot, and immunohistochemical staining were used to assess the mRNA and protein levels of IRAK1 in clinical samples and cell lines. Cell counting assay and flow cytometry were employed to analyze the effect of IRAK1 on cell cycle and apoptosis. Transwell assay was used to study the role of IRAK1 in cell migration. Moreover, subcutaneous xenograft tumor models predict the efficacy of targeting IRAK1 against HCC in vivo.
RESULTS: IRAK1 was over-expressed in HCC tissues and cell lines. Suppression of IRAK1 by small interference RNA (siRNA) or a pharmaceutical IRAK1/4 inhibitor impeded cell growth, induced apoptosis and lessened HCC xenograft tumor growth. Particularly, IRAK1/4 inhibitor treatment caused G1/S cell cycle arrest and apoptosis, confirming IRAK1 as a new therapeutic target for HCC.
CONCLUSION: IRAK1 promotes cell proliferation and protects against apoptosis in HCC, and can be a novel target for HCC treatment.

PMID: 27619757 [PubMed - indexed for MEDLINE]

Apoptosis signal-regulating kinase 1 mediates the inhibitory effect of hepatocyte nuclear factor-4α on hepatocellular carcinoma.

Tue, 12/12/2017 - 16:48
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Apoptosis signal-regulating kinase 1 mediates the inhibitory effect of hepatocyte nuclear factor-4α on hepatocellular carcinoma.

Oncotarget. 2016 May 10;7(19):27408-21

Authors: Jiang CF, Wen LZ, Yin C, Xu WP, Shi B, Zhang X, Xie WF

Abstract
Previous studies provided substantial evidence of a striking suppressive effect of hepatocyte nuclear factor 4α (HNF4α) on hepatocellular carcinoma (HCC). Apoptosis signal-regulating kinase 1 (ASK1) is involved in death receptor-mediated apoptosis and may acts as a tumor suppressor in hepatocarcinogenesis. However, the status and function of ASK1 during HCC progression are unclear. In this study, we found that HNF4α increased ASK1 expression by directly binding to its promoter. ASK1 expression was dramatically suppressed and correlated with HNF4α levels in HCC tissues. Reduced ASK1 expression was associated with aggressive tumors and poor prognosis for human HCC. Moreover, ASK1 inhibited the malignant phenotype of HCC cells in vitro. Intratumoral ASK1 injection significantly suppressed the growth of subcutaneous HCC xenografts in nude mice. More interestingly, systemic ASK1 delivery strikingly inhibited the growth of orthotopic HCC nodules in NOD/SCID mice. In addition, inhibition of endogenous ASK1 partially reversed the suppressive effects of HNF4α on HCC. Collectively, this study highlights the suppressive effect of ASK1 on HCC and its biological significance in HCC development. These outcomes broaden the knowledge of ASK1 function in HCC progression, and provide a novel potential prognostic biomarker and therapeutic target for advanced HCC.

PMID: 27050273 [PubMed - indexed for MEDLINE]

LGR5 expression is controled by IKKα in basal cell carcinoma through activating STAT3 signaling pathway.

Tue, 12/12/2017 - 16:48
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LGR5 expression is controled by IKKα in basal cell carcinoma through activating STAT3 signaling pathway.

Oncotarget. 2016 May 10;7(19):27280-94

Authors: Jia J, Shi Y, Yan B, Xiao D, Lai W, Pan Y, Jiang Y, Chen L, Mao C, Zhou J, Xi S, Cao Y, Liu S, Tao Y

Abstract
Basal cell carcinomas (BCC) of the skin are the most common of human cancers. The noncanonical NF-κB pathway is dependent on IKKα. However, the role of IKKα in BCC has not been elucidated. We show here that IKKα is expressed in the nucleus in BCC and non-malignant diseases. Nuclear IKKα could directly bind to the promoters of inflammation factors and LGR5, a stem cell marker, in turn, upregulating LGR5 expression through activation of STAT3 signaling pathway during cancer progression. Activation of STAT3 signaling pathway contributes LGR5 expression in dependent of IKKα after the interplay between STAT3 and IKKα. Meanwhile knockdown of IKKα inhibits tumor growth and transition of epithelial stage to mescheme stage. Taken together, we demonstrate that IKKα functions as a bone fide chromatin regulator in BCC, whose promoted expression contributes to oncogenic transformation via promoting expression stemness- and inflammatory- related genes. Our finding reveals a novel viewpoint for how IKKα may involve in BCCs tumor progression in the inflammatory microenvironment.

PMID: 27049829 [PubMed - indexed for MEDLINE]

Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1α: a novel approach for inhibiting angiogenesis in hepatocellular carcinoma.

Tue, 12/12/2017 - 16:48
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Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1α: a novel approach for inhibiting angiogenesis in hepatocellular carcinoma.

Oncotarget. 2016 May 10;7(19):27108-21

Authors: Herzog J, Ehrlich SM, Pfitzer L, Liebl J, Fröhlich T, Arnold GJ, Mikulits W, Haider C, Vollmar AM, Zahler S

Abstract
We recently introduced CDK5 as target in HCC, regulating DNA damage response. Based on this and on our previous knowledge about vascular effects of CDK5, we investigated the role of CDK5 in angiogenesis in HCC, one of the most vascularized tumors. We put a special focus on the transcription factor HIF-1α, a master regulator of tumor angiogenesis.The interaction of CDK5 with HIF-1α was tested by Western blot, PCR, reporter gene assay, immunohistochemistry, kinase assay, co-immunoprecipitation, mass spectrometry, and mutation studies. In vivo, different murine HCC models, were either induced by diethylnitrosamine or subcutaneous injection of HUH7 or HepG2 cells. The correlation of vascular density and CDK5 was assessed by immunostaining of a microarray of liver tissues from HCC patients.Inhibition of CDK5 in endothelial or HCC cells reduced HIF-1α levels in vitro and in vivo, and transcription of HIF-1α target genes (VEGFA, VEGFR1, EphrinA1). Mass spectrometry and site directed mutagenesis revealed a stabilizing phosphorylation of HIF-1α at Ser687 by CDK5. Vascular density was decreased in murine HCC models by CDK5 inhibition.In conclusion, inhibiting CDK5 is a multi-modal systemic approach to treat HCC, hitting angiogenesis, as well as the tumor cells themselves.

PMID: 27027353 [PubMed - indexed for MEDLINE]

[Heart transplantation in an HIV-infected patient].

Mon, 12/11/2017 - 11:05

[Heart transplantation in an HIV-infected patient].

Medicina (B Aires). 2017;77(6):509-511

Authors: Mouras P, Barcán L, Belziti C, Pizarro R, Mañez N, Marenchino R

Abstract
Because of its own unfavourable evolution, HIV infection was until recently considered a contraindication for organ transplantation. The introduction of highly active antiretroviral therapy prolonged the life expectancy of these patients and allowed the manifestation of disorders directly or indirectly related to HIV infection, mainly liver, kidney and cardiovascular diseases. We present a case of cardiac transplantation due to dilated cardiomyopathy that was performed in a patient with a recently detected HIV infection. At 24 month follow-up, the patient is in very good health status, his CD4 are increasing and the viral load is undetectable. He did not present transplant rejection or any other complication. To our knowledge, there is no previous publication on heart transplantation in patients with HIV in South America. In view of the successful outcome of our case and of the few cases reported in the international literature, we consider that heart transplantation is a therapeutic option in correctly selected HIV patients.

PMID: 29223945 [PubMed - in process]

Cost Variation Across Centers for the Norwood Operation.

Mon, 12/11/2017 - 11:05

Cost Variation Across Centers for the Norwood Operation.

Ann Thorac Surg. 2017 Dec 06;:

Authors: McHugh KE, Pasquali SK, Hall MA, Scheurer MA

Abstract
BACKGROUND: The Norwood operation is associated with high health care utilization, and prior studies reported substantial variability in Norwood costs across centers. However, specific factors driving this cost variation are unclear. We assessed center variability in Norwood costs and underlying mechanisms in a multicenter cohort.
METHODS: Clinical data from the Pediatric Heart Network Single Ventricle Reconstruction trial were linked with cost data from the Children's Hospital Association Inpatient Essentials database. Center variation was assessed by modeling Norwood costs adjusted for baseline patient characteristics, and the relationship with complications, length of stay (LOS), and specific cost categories was examined. Patients undergoing transplantation or stage 2 palliation during the Norwood admission were excluded.
RESULTS: Nine centers (332 patients) were included. Adjusted mean cost/case varied 4.6-fold across centers (range: $50,559 to $230,851, p < 0.001). In addition, variation was found across centers in the adjusted mean number of complications/case (2.6-fold variation) and adjusted mean LOS/case (1.9-fold variation). Differences in complications explained 63% of the cost variation across centers. After accounting for complications, differences in LOS explained 66% of the remaining cost variation. Seven specific complications were found to occur more frequently at high-cost centers: pleural effusion, seizures, wound infection, thrombus, liver dysfunction, sepsis, necrotizing enterocolitis (all p < 0.001). With regard to types of cost, room and board/supplies and laboratory costs were the primary drivers of cost variation across centers.
CONCLUSIONS: This study identified several factors associated with center variation in Norwood costs, which may be targeted in subsequent initiatives aimed at both improving quality of care and reducing costs.

PMID: 29223416 [PubMed - as supplied by publisher]

Therapeutic efficacy and safety of umbilical cord mesenchymal stem cell transplantation for liver cirrhosis in Chinese population: A meta-analysis.

Mon, 12/11/2017 - 11:05

Therapeutic efficacy and safety of umbilical cord mesenchymal stem cell transplantation for liver cirrhosis in Chinese population: A meta-analysis.

Clin Res Hepatol Gastroenterol. 2017 Dec 06;:

Authors: Sang W, Lv B, Li K, Lu Y

Abstract
BACKGROUND AND OBJECTIVE: Mesenchymal stem cells transfusion has been considered as a promising option for liver cirrhosis (LC). The aim of this study was to systematically evaluate the efficacy and safety of umbilical cord mesenchymal stem cells (UMSC) combined with traditional supportive therapy (TST) for the treatment of patients with LC.
METHODS: Data was extracted from clinical trials published on Web of Science, PubMed, EMBASE, Cochrane Library, Wanfang and CNKI database. The evaluated outcome measurements included liver function, coagulation function, liver fibrosis indexes, clinical symptoms, quality of life (QOL) and adverse events.
RESULTS: A total of 14 trials including 717 LC patients met our selection criteria were involved. The liver function of LC patients was significantly improved after combined therapy (UMSC plus TST), indicated by decreased total bilirubin, alanine aminotransferase and prothrombin time, and increased serum albumin, cholinesterase and prothrombin activity. The QOL of patients was also improved after UMSC therapy. Compared with TST alone, the combined therapy showed better treatment effect based on measurements of hyaluronic acid (OR=-143.20, CI=-181.58 to -104.82, P<0.00001), laminin (OR=-50.65, CI=-53.70 to -47.61, P<0.00001), type III procollagen (OR=-8.68, CI=-9.00 to -8.36, P<0.00001), type IV collagen (OR=-105.79, CI=-132.44 to -79.14, P<0.00001) and plasma prolidase (OR=-876.54, CI=-911.89 to -840.56, P<0.00001). Moreover, the patients' clinical symptoms including fatigue (4th, P=0.003; 8th, P=0.01), appetite (4th, P<0.0001; 8th, P=0.06), ascites (4th, P=0.03; 8th, P=0.17), and abdominal distension (4th, P=0.0008; 8th, P=0.64) were also improved in patients treated by combined therapy without adverse events observed.
CONCLUSION: UMSC and TST combined therapy for LC patients improved their liver function, clinical symptoms and QOL without severe adverse events, therefore is safe and effective in LC therapy.

PMID: 29223366 [PubMed - as supplied by publisher]

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