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Savaryn J.P.,Northwestern University | Toby T.K.,Northwestern University | Catherman A.D.,Northwestern University | Fellers R.T.,Northwestern University | And 7 more authors.
Proteomics | Year: 2016

Recent studies utilizing transcriptomics, metabolomics, and bottom up proteomics have identified molecular signatures of kidney allograft pathology. Although these results make significant progress toward non-invasive differential diagnostics of dysfunction of a transplanted kidney, they provide little information on the intact, often modified, protein molecules present during progression of this pathology. Because intact proteins underpin diverse biological processes, measuring the relative abundance of their modified forms promises to advance mechanistic understanding, and might provide a new class of biomarker candidates. Here, we used top down proteomics to inventory the modified forms of whole proteins in peripheral blood mononuclear cells (PBMCs) taken at the time of kidney biopsy for 40 kidney allograft recipients either with healthy transplants or those suffering acute rejection. Supported by gas-phase fragmentation of whole protein ions during tandem mass spectrometry, we identified 344 proteins mapping to 2905 distinct molecular forms (proteoforms). Using an initial implementation of a label-free approach to quantitative top down proteomics, we obtained evidence suggesting relative abundance changes in 111 proteoforms between the two patient groups. Collectively, our work is the first to catalog intact protein molecules in PBMCs and suggests differentially abundant proteoforms for further analysis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Source

Fischer-Frohlich C.-L.,Region Baden Wurttemberg | Konigsrainer A.,University Hospital of Tuebingen | Schaffer R.,Scripps Center for Organ and Cell Transplantation | Schaub F.,Deutsche Stiftung Organtransplantation | And 4 more authors.
Transplant International | Year: 2012

Although more than 2300 intestinal transplantations (IT) have been performed worldwide, a description of intestinal donor criteria is still missing. This causes confusion among transplant coordinators, OPOs, physicians at intensive care unit and transplant surgeons. A Med-line search looking for publications about donor criteria or donor selection in human IT was performed in December 2011. Retrospective analysis of 39 deceased donors from whom, in the period January 2006-December 2011, 20 isolated intestinal grafts and 19 multivisceral grafts were recovered and successfully transplanted. Review of the Literature: Among 3504 publications about IT, no study reported specifically about intestinal donor profile. The most commonly cited donor criterion was age, while all other criteria were inconsistently discussed. Based on the collected data, we suggest following inclusion criteria for donation of IT grafts: age 0-50 years, ICU-stay <1 week, no blunt abdominal trauma, most recent Sodium <155 mmol/l, no severe ongoing transfusion requirements, standard donor therapy including early enteral nutrition and a compatible donor-recipient size match. By providing simple criteria for intestinal donation from deceased donor, we may help to properly utilize the limited donor pool. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation. Source

Fisher J.S.,Scripps Center for Organ and Cell Transplantation | Butt Z.,Northwestern University | Friedewald J.,Northwestern University | Fry-Revere S.,American Solutions | And 9 more authors.
American Journal of Transplantation | Year: 2015

New approaches to address the kidney scarcity in the United States are urgently needed. The greatest potential source of kidneys is from living donors. Proposals to offer financial incentives to increase living kidney donation rates remain highly controversial. Despite repeated calls for a pilot study to assess the impact of financial compensation on living kidney donation rates, many fear that financial incentives will exploit vulnerable individuals and cast the field of transplantation in a negative public light, ultimately reducing donation rates. This paper provides an ethical justification for conducting a pilot study of a federally regulated approach to providing financial incentives to living kidney donors, with the goal of assessing donors' perceptions. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons. Source

Crissien A.M.,Scripps Green Hospital | Frenette C.,Scripps Center for Organ and Cell Transplantation
Gastroenterology and Hepatology | Year: 2014

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Despite efforts for prevention and screening as well as development of new technologies for diagnosis and treatment, the incidence of HCC has doubled, and mortality rates have increased in recent decades. A variety of important risk factors are associated with the development of HCC, with any type of cirrhosis, regardless of etiology, being the major contributor. Hepatitis C virus infection with bridging fibrosis or cirrhosis and hepatitis B virus infection are independent risk factors. The diagnosis of HCC is made without liver biopsy in over 90% of cases. Screening with ultrasound and alpha-fetoprotein (AFP) at 6-month intervals is advised; however, it is not adequate for patients on the orthotopic liver transplantation (OLT) list. Triple-phase computed tomography and/or magnetic resonance imaging are used in combination with the detection of AFP, AFP-L3%, and/or des-gamma-carboxy prothrombin due to their superior sensitivities and specificities. Several treatment modalities are available, but only surgical resection and OLT are curative. OLT is available only for patients who meet or are downstaged into Milan or University of California, San Francisco criteria. Other treatment options include radiofrequency ablation, microwave ablation, percutaneous ethanol injection, transarterial chemoembolization, radioembolization, cryoablation, radiation therapy, stereotactic radiotherapy, systemic chemotherapy, and molecularly targeted therapies. The management of HCC is based on tumor size and location, extrahepatic spread, and underlying liver function. Given the complexity of the disease, patients are often best served in centers with experience in HCC management, where a multidisciplinary approach can take place. Source

Modena B.D.,Scripps Research Institute | Kurian S.M.,Scripps Research Institute | Gaber L.W.,The Methodist Hospital | Waalen J.,Scripps Research Institute | And 21 more authors.
American Journal of Transplantation | Year: 2016

Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons Source

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