Citations

ABSTRACTSaturated fatty acids (SFA) and their toxic metabolites contribute to hepatocyte lipotoxicity in nonalcoholic steatohepatitis (NASH). We previously reported that hepatocytes, under lipotoxic stress, express the potent macrophage chemotactic ligand C‐X‐C motif chemokine 10 (CXCL10), and release CXCL10‐enriched extracellular vesicles (EV) by a mixed lineage kinase (MLK) 3‐dependent mechanism. In the current study, we sought to examine the signaling pathway responsible for CXCL10 induction during hepatocyte lipotoxicity. Here, we demonstrate a role for signal transducer and activator of transcription (STAT) 1 in regulating CXCL10 expression. Huh7 and HepG2 cells were treated with lysophosphatidylcholine (LPC), the toxic metabolite of the SFA palmitate. In LPC‐treated hepatocytes, CXCL10 induction is mediated by a mitogen activated protein kinase (MAPK) signaling cascade consisting of a relay kinase module of MLK3, MKK3/6, and p38. P38 in turn induces STAT1 Ser727 phosphorylation and CXCL10 upregulation in hepatocytes, which is reduced by genetic or pharmacological inhibition of this MAPK signaling cascade. The binding and activity of STAT1 at the CXCL10 gene promoter were identified by chromatin immunoprecipitation and luciferase gene expression assays. Promoter activation was attenuated by MLK3/STAT1 inhibition or by deletion of the consensus STAT1 binding sites within the CXCL10 promoter. In lipotoxic hepatocytes, MLK3 activates a MAPK signaling cascade, resulting in the activating phosphorylation of STAT1, and CXCL10 transcriptional upregulation. Hence, this kinase relay module and/or STAT1 inhibition may serve as a therapeutic target to reduce CXCL10 release, thereby attenuating NASH pathogenesis. J. Cell. Biochem. 118: 3249–3259, 2017. © 2017 Wiley Periodicals, Inc.

Abstract Background: In Minnesota, the 2012 Cancer Report by the Department of Health reported both the incidence of liver cancer and mortality rates due to liver cancer among Blacks were significantly higher than Caucasians. African immigration to Minnesota is the third highest by percentage of state population in the US. Given that viral hepatitis disproportionately affects sub-Saharan Africans and that these individuals are emigrating from countries where childhood HBV vaccination has only recently been implemented on a national scale, we speculate that this unique immigrant community may be a major contributor to the increased burden of viral hepatitis and liver cancer complications in the state. Limited research exists on the burden of viral hepatitis and hepatocellular carcinoma among African immigrants. Thus, we conducted a prospective community-wide screening to assess the rates of chronic HBV and HCV infections among Somali, Liberian and Kenyan immigrants in Minnesota. Methods: Several African community health centers and organizations in Minnesota were selected for the study. Individuals of Somali, Liberian or Kenyan descent were enrolled in a prospective screening study for chronic HBV and HCV infection. Blood samples were collected and tested for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B surface antibody (HBsAb), and anti-hepatitis C virus antibody (anti-HCV). Follow-up testing, health education, counseling, and referral were provided to participants. Results: 853 participants provided blood specimens. 13.5% of participants had chronic HBV infection while 32.4% had prior HBV exposure with spontaneous viral clearance. 7% of participants had chronic HCV infection. Follow up and linkage to care were provided to participants with chronic hepatitis while preventive advice was provided to those who were negative for both infections. In particular, participants susceptible to HBV were informed about the availability of HBV vaccine in order to protect against future HBV infection. Conclusions: Chronic HBV and HCV are major health problems among recent African immigrants in Minnesota. Community-based screening is an effective way to identify and provide health education and linkage to care for individuals with or at risk for viral hepatitis. Citation Format: Essa A. Mohamed, Nasra H. Giama, Hassan M. Shaleh, Abdul M. Oseini, Hager Ahmed Mohammed, Jessica Cvinar, Ibrahim A. Waaeys, Hamdi A. Ali, Loretta K. Allotey, Lewis R. Roberts. Community-wide outreach and screening to reduce hepatitis B, hepatitis C and liver cancer disparities among African immigrants in Minnesota. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C76.

We describe a primary hepatic neuroendocrine tumor of a 57-year-old Thai woman who presented in 2004 with a suspicious mass in the left hepatic lobe. She underwent left hepatectomy for the 10.5-cm mass, calledintermediate grade neuroendocrine carcinoma of unknown origin,likely metastatic. The tumor recurred in 2007, then calledrecurrent primary hepatic neuroendocrine tumor(PHNET), and the patient underwent liver transplant. Because of similarity between the neuroendocrine tumor and a thyroid tumor—specifically, follicular-like characteristics—immunohistochemical stains for thyroglobulin, TTF1, and calcitonin were performed. However, all were negative. All imaging studies revealed no evidence of a primary lesion other than the liver mass. In 2008, the patient’s liver transplant failed because of ischemic cholangiopathy, and she underwent a second liver transplant. Seven years later, in 2015, she presented with metastatic neuroendocrine tumor of intermediate grade to the lung, consistent with metastatic PHNET. She underwent left upper-lobe wedge resection to remove the tumor. The patient is alive with no evidence of disease at 13 years after initial diagnosis. This rare variant of PHNET had thyroid-like morphologic characteristics but there is no evidence of primary thyroid tumor or thyroid markers in the primary and recurrent hepatic tumors and lung metastasis.

BACKGROUNDTo evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post‐transplantation.METHODSWe analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre‐HCT depression requiring treatment versus those without pre‐HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post‐HCT using Poisson models. We also compared the incidence of grade 2‐4 acute and chronic graft‐versus‐host disease (GVHD) in allogeneic HCT.RESULTSThe study included 1116 (15%) patients with pre‐transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre‐transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04‐1.23; P = 0.004) and a higher incidence of grade 2‐4 acute GVHD (HR, 1.25; 95% CI, 1.14‐1.37; P < 0.0001), but similar incidence of chronic GVHD. Pre‐transplant depression was associated with fewer days‐alive‐and‐out‐of‐the hospital (means ratio [MR] = 0.97; 95% CI, 0.95‐0.99; P = 0.004). There were 512 (13.5%) patients with Pre‐transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre‐transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98‐1.34; P = 0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97‐0.99; P = 0.002).CONCLUSIONPre‐transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre‐transplant depression represent a population that is at risk for post‐transplant complications. Cancer 2017;123:1828–1838. © 2017 American Cancer Society.

The purpose of this work was to investigate the performance of currently available magnetic resonance imaging (MRI) for detecting kidney stones, compared to computed tomography (CT) results, and to determine the characteristics of successfully detected stones. Patients who had undergone both abdominal/pelvic CT and MRI exams within 30 days were studied. The images were reviewed by two expert radiologists blinded to the patients’ respective radiological diagnoses. The study consisted of four steps: (1) reviewing the MRI images and determining whether any kidney stone(s) are identified; (2) reviewing the corresponding CT images and confirming whether kidney stones are identified; (3) reviewing the MRI images a second time, armed with the information from the corresponding CT, noting whether any kidney stones are positively identified that were previously missed; (4) for all stones MRI-confirmed on previous steps, the radiologist experts being asked to answer whether in retrospect, with knowledge of size and location on corresponding CT, these stones would be affirmed as confidently identified on MRI or not. In this best-case scenario involving knowledge of stones and their locations on concurrent CT, radiologist experts detected 19% of kidney stones on MRI, with stone size being a major factor for stone identification.

Background and objectives Delayed graft function is a form of AKI resulting from ischemia-reperfusion injury. Our aim was to study the effect of delayed graft function on the progression of interstitial fibrosis after deceased donor kidney transplantation. Design, setting, participants, & measurements Our study is a retrospective study of all patients transplanted at our center between July of 2003 and September of 2014 using a kidney from a deceased donor. The primary outcome was the progression of interstitial fibrosis on serial protocol biopsies done during the first year post-transplant. We analyzed the distribution of the change in the Banff interstitial fibrosis (ci) score between the delayed graft function and nondelayed graft function groups for all of the paired biopsies done at time 0 and 12 months post-transplant ( Δ fibrosis). We also performed a linear mixed model analyzing the difference in the slopes for the progression of mean Banff ci score for all of the biopsies done at time 0 and 1, 4, and 12 months post-transplant. Results There were 343 (36.7%) in the delayed graft function group and 591 in the control group. The biopsy rates for the delayed graft function and nondelayed graft function groups at time 0 were 65.3% ( n =224) and 67.0% ( n =396), respectively, and at 12 months, they were 64.4% ( n =221) and 68.4% ( n =404), respectively. Paired biopsies were available for 155 in the delayed graft function group and 283 in the control group. In a risk-adjusted model, Banff ci score >0 on the time 0 biopsy had a higher odds of delayed graft function (odds ratio, 1.70; 95% confidence interval, 1.03 to 2.82). The distribution of the Δ fibrosis between 0 and 12 months was similar in delayed graft function and control groups ( P =0.91). The slopes representing the progression of fibrosis were also similar between the groups ( P =0.66). Conclusions Donor-derived fibrosis may increase the odds of delayed graft function; however, delayed graft function does not seem to increase the progression of fibrosis during the first year after transplantation.

Extracellular vesicles (EVs) are nanometer‐sized, membrane‐bound vesicles released by cells into the extracellular milieu. EVs are now recognized to play a critical role in cell‐to‐cell communication. EVs contain important cargo in the form of proteins, lipids, and nucleic acids and serve as vectors for delivering this cargo from donor to acceptor or target cell. EVs are released under both physiologic and pathologic conditions, including liver diseases, and exert a wide range of effects on target cells. This review provides an overview on EV biogenesis, secretion, cargo, and target cell interactions in the context of select liver diseases. Specifically, the diverse roles of EVs in nonalcoholic steatohepatitis, alcoholic liver disease, viral hepatitis, cholangiopathies, and hepatobiliary malignancies are emphasized. Liver diseases often result in an increased release of EVs and/or in different cargo sorting into these EVs. Either of these alterations can drive disease pathogenesis. Given this fact, EVs represent a potential target for therapeutic intervention in liver disorders. Because altered EV composition may reflect the underlying disease condition, circulating EVs can be exploited for diagnostic and prognostic purposes as a liquid biopsy. Furthermore, ex vivo modified or synthesized EVs can be engineered as therapeutic nano‐shuttles. Finally, we highlight areas that merit further investigation relevant to understanding how EVs regulate liver disease pathogenesis. (H epatology 2016;64:2219‐2233).