Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its ...success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia‐reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll‐like receptor signalling, alterations in micro‐RNA expression, production of ROS, regulation of autophagy and activation of hypoxia‐inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation – a process that will lead to improved outcomes for patients suffering from end‐stage liver disease.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Technologies for digitizing tissues provide important quantitative data for liver histopathology investigation. We aimed to assess liver fibrosis degree with quantitative morphometric measurements of ...histopathological sections utilizing digital image analysis (DIA) and to further investigate if a correlation with histopathologic scoring (Scheuer staging) exists. A retrospective study of patients with at least two post-liver transplant biopsies having a Scheuer stage of ≤ 2 at baseline were gathered. Portal tract fibrotic percentage (%) and size (μm2) were measured by DIA, while clinical fibrosis score was measured by the Scheuer system. Correlations between DIA measurements and Scheuer scores were computed by Spearman correlation analysis. Differences between mean levels of fibrosis (score, size, and percentage) at baseline versus second visit were computed by Student's t-test. P values < 0.05 were considered significant. Of 22 patients who met the study criteria, 54 biopsies were included for analysis. Average levels ±standard error S.E. of portal tract fibrotic percentage (%) and size (μm2) progressed from 46.5 ± 3.6% at baseline to 61.8 ± 3.8% at the second visit (P = 0.005 by Student's t-test), and from 28,075 ± 3,232 μm2 at base line to 67,146 ± 10,639 μm2 at the second visit (P = 0.002 by Student's t-test), respectively. Average levels of Scheuer fibrosis scores progressed from 0.55±0.19 at baseline to 1.14±0.26 at the second visit (P = 0.02 by Student's t-test). Portal tract fibrotic percentage (%) and portal tract fibrotic size were directly correlated with clinical Scheuer fibrosis stage, with Spearman correlation coefficient and P value computed as r = 0.70, P < 0.0001 and r = 0.41, P = 0.002, respectively. Digital quantitative assessment of portal triad size and fibrosis percentage demonstrates a strong correlation with visually assessed histologic stage of liver fibrosis and complements the standard assessment for allograft monitoring, suggesting the utility of future WSI analysis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate ...gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
Non-small cell lung cancer remains a highly lethal malignancy. Using the tamoxifen inducible Hnf1b:CreER
(H) transgenic mouse crossed to the LsL-Kras
(K) transgenic mouse, we recently discovered that ...an Hnf1b positive cell type in the lung is sensitive to adenoma formation when expressing a mutant Kras
allele. In these mice, we observe adenoma formation over a time frame of three to six months. To study specificity of the inducible Hnf1b:CreER
in the lung, we employed lineage tracing using an mTmG (G) reporter allele. This technique revealed recombined, GFP+ cells were predominantly SPC+. We further employed this technique in HKG mice to determine Hnf1b+ cells give rise to adenomas that express SPC and TTF1. Review of murine lung tissue confirmed a diagnosis of adenoma and early adenocarcinoma, a pathologic subtype of non-small cell lung cancer. Our expanded mouse model revealed loss of Mst1/2 promotes aggressive lung adenocarcinoma and large-scale proteomic analysis revealed upregulation of PKM2 in the lungs of mice with genetic deletion of Mst1/2. PKM2 is a known metabolic regulator in proliferating cells and cancer. Using a human lung adenocarcinoma cell line, we show pharmacologic inhibition of Mst1/2 increases the abundance of PKM2, indicating genetic loss or pharmacologic inhibition of Mst1/2 directly modulates the abundance of PKM2. In conclusion, here we report a novel model of non-small cell lung cancer driven by a mutation in Kras and deletion of Mst1/2 kinases. Tumor development is restricted to a subset of alveolar type II cells expressing Hnf1b. Our data show loss of Mst1/2 regulates levels of a potent metabolic regulator, PKM2.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Since the concept of immunologic tolerance was discovered in the 1940s, the pursuit of tolerance induction in human transplantation has led to a rapid development of pharmacologic and biologic ...agents. Short-term graft survival remains an all-time high, but successful withdrawal of immunosuppression to achieve operational tolerance rarely occurs outside of liver transplantation. Collaborative efforts through the NIH sponsored Immune Tolerance Network and the European Commission sponsored Reprogramming the Immune System for Establishment of Tolerance consortia have afforded researchers opportunity to evaluate the safety and efficacy of tolerogenic strategies, investigate mechanisms of tolerance, and identify molecular and genetic markers that distinguish the tolerance phenotype. In this article, we review traditional and novel approaches to inducing tolerance for organ transplantation, with an emphasis on their translation into clinical trials.
Introduction: Limited health literacy has been associated with poor health outcomes in the general population, but there have been few studies investigating the association between functional health ...literacy and kidney transplant listing. The primary objective of this study was to determine if functional health literacy was associated with kidney transplant listing after controlling for demographic, psychosocial, and medical variables, which were secondarily examined for correlation with transplant listing. Design: We retrospectively reviewed 423 kidney transplant candidates who were prospectively administered the Test of Functional Health Literacy in Adults during their transplant evaluation. Results: The functional health literacy scores were found to correlate with transplant listing (P = 0.013). Unexpectedly, a subset of patients (n = 14 out of 36) who had scores < 59 was still able to obtain approval for listing. The probability of approval decreased when functional health literacy scores ranged from 0 to 59 and increased when functional health literacy scores varied between 60 to 100. Multivariable analysis found transplant listing to also be associated with substance use (OR = 0.15, P < 0.001), ESKD etiology other than diabetes or hypertension (OR = 2.62, P < 0.001), time on dialysis (P = 0.012), and pace of transplant evaluation (P < 0.001). Conclusion: Functional health literacy was associated with kidney transplant listing. Programmatic interventions that can help overcome the impact of functional health literacy and improve access to transplantation should be explored.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Coagulation is a critical component in the progression of liver disease. Identification of key molecules involved in the intrahepatic activation of coagulation (IAOC) will be instrumental in the ...development of effective therapies against liver disease. Using a mouse model of concanavalin A (ConA)‐induced hepatitis, in which IAOC plays an essential role in causing liver injury, we uncovered a procoagulant function of chitinase 3‐like 1 (Chi3l1). Chi3l1 expression is dramatically elevated after ConA challenge, which is dependent on ConA‐induced T cell activation and the resulting interferon γ and tumor necrosis factor α productions. Compared with wild‐type mice, Chi3l1−/− mice show less IAOC, reduced tissue factor (TF) expression, and attenuated liver injury. Reconstituting Chi3l1−/− mice with recombinant TF triggers IAOC and augments liver injury. Conclusion: Our data demonstrate that Chi3l1, through induction of TF via mitogen‐activated protein kinase activation, promotes IAOC and tissue injury. (Hepatology 2018;67:2384‐2396).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Introduction:
The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a psychometric instrument designed to assess patient risk for transplant. We investigated the association ...between SIPAT scores and demographic data with psychosocial and medical outcomes within a diverse kidney/kidney–pancreas transplant population.
Design:
The SIPAT was administered to all pretransplant candidates. A retrospective review of transplanted patients who had at least 6 months of follow-up was completed.
Results:
The sample included 136 patients: male (n = 77 57%) with a mean age of 47 years old. Thirty-eight percent were black (n = 51), 55% had less than a high school education (n = 74), and 65% had low socioeconomic status (n = 89). Statistical difference was found among SIPAT scores and substance use and support system instability (P = .035, P = .012). Females (P = .012) and patients with a history of psychopathology (P = .002) developed or had a relapse of psychopathology following transplant. Patients with more than a high school education (P = .025) and who were less than 30 years (P = .026) had higher rejection incidence rates. Risk factors for rehospitalizations included Hispanic race, diabetes, and low socioeconomic status (P = .036, P = .038, P = .014). African American/Black and male patients had higher incidence of infection events (P = .032, P = .049). Mortality and treatment nonadherence were not significantly associated with SIPAT scores or demographic variables.
Conclusion:
The SIPAT was associated with posttransplant substance use and support system instability, while demographic variables were associated with the development and/or relapse of psychopathology, graft loss, rejection, infection events, and medical rehospitalizations. Revision of the SIPAT to include additional demographic components may lend to improved prediction of transplant outcomes.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
BACKGROUNDPrograde flushing (PF) of living donor renal allografts with preservation solution via the renal artery or arteries is standard practice. PF may be difficult and potentially injurious to ...the donor kidney, especially in grafts with small or multiple arteries. In this report, we present our experience with retrograde flushing (RF) of 7 living donor kidneys via the renal vein.
METHODSRetrospective review of 7 consecutive living donor renal transplants performed using the RF technique was performed. The 7 preceding living donor renal transplants performed using the standard arterial PF technique served as a control group.
RESULTSAll 7 recipients of RF kidneys experienced immediate graft function. At postoperative days 3 and 30, there was no difference in estimated glomerular filtration rate between the RF study group and PF controls.
CONCLUSIONSThe RF technique is simple and safe, with results equivalent to the PF technique. The RF technique may be especially useful after recovering kidneys with small and/or multiple arteries.
Objective: Disorders of sex development (DSD) constitutes a small but difficult and equally important area of endocrinology. It is often a social emergency as the decision regarding sex assignment in ...these cases is extremely disturbing and difficult to both families and healthcare professionals. Our study was devised to assess the clinical and chromosomal profile of patients with suspected DSD and classify them according to the new DSD consensus document. Subjects and Methods: This study was a cross-sectional observational study carried out in the department of pediatrics of a tertiary care hospital from August 2012 to August 2014. All patients with suspected DSD in the age group of 0-19 years were included. After detailed history and examination, karyotyping, abdominal sonography, and hormonal analysis were done. Additional studies like gonadal biopsy, laparoscopy, and hormone stimulation tests were done in selected cases. Results: About 41 patients were included in the study. The mean age of presentation was 87 months (1 day to 16 years). Only seven (13.7%) patients presented in neonatal period. In total, 25 patients had ambiguous genitalia; 46, XX DSD were diagnosed in 24 (58.5%) patients, 46, XY DSD in 10 (24.4%) patients, and sex chromosome DSD in 7 (17.1%). Congenital adrenal hyperplasia (CAH) was the commonest disease diagnosed in 21 (51.2%) patients. Turner syndrome, Klinefelter syndrome, androgen insensitivity syndrome, 46, XX ovotesticular disorder, and 46, XY gonadal dysgenesis were diagnosed in 3, 3, 4, 3, and 5 patients, respectively. Eleven patients with CAH presented in shock and six had history of sib deaths. Conclusion: 46, XX DSD were the commonest etiological group in our study and CAH was the commonest individual disease. There is a need for educating general public and practitioners regarding DSD to allow early intervention. Moreover, there is a need to introduce routine neonatal screening for CAH in our country.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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