Targeted Quantification of Proteoforms in Complex Samples by Proteoform Reaction Monitoring.

Existing mass spectrometric assays used for sensitive and specific measurements of target proteins across multiple samples, such as selected/multiple reaction monitoring (SRM/MRM) or parallel reaction monitoring (PRM), are peptide-based methods for bottom-up proteomics. Here, we describe an approach based on the principle of PRM for the measurement of intact proteoforms by targeted top-down proteomics, termed proteoform reaction monitoring (PfRM). We explore the ability of our method to circumvent traditional limitations of top-down proteomics, such as sensitivity and reproducibility.

Critical Role for the Human Cytomegalovirus Major Immediate Early Proteins in Recruitment of RNA Polymerase II and H3K27Ac To an Enhancer-Like Element in Ori.

Human cytomegalovirus (HCMV) is an opportunistic pathogen that infects most of the population. The complex 236 kbp genome encodes more than 170 open reading frames, whose expression is temporally regulated by both viral transcriptional regulators and cellular factors that control chromatin and transcription. Here, we have used state of the art genomic technologies to investigate the viral transcriptome in conjunction with 2 key transcriptional regulators: Pol II and H3K27Ac.

Preoperative portal vein recanalization-transjugular intrahepatic portosystemic shunt for chronic obliterative portal vein thrombosis: Outcomes following liver transplantation.

High-grade portal vein thrombosis (PVT) is often considered to be a technically challenging scenario for liver transplantation (LT) and in some centers a relative contraindication. This study compares patients with chronic obliterative PVT who underwent portal vein recanalization-transjugular intrahepatic portosystemic shunt (PVR-TIPS) and subsequent LT to those with partial nonocclusive PVT who underwent LT without an intervention. This institutional review board-approved study analyzed 49 patients with cirrhosis with PVT from 2000 to 2020 at our institution.

Donor-derived cell-free DNA levels predict graft injury in liver transplant recipients.

Donor-derived cell-free DNA (dd-cfDNA) has been evaluated as a rejection marker in organ transplantation. This study sought to assess the utility of dd-cfDNA to diagnose graft injury in liver transplant recipients (LTR) and as a predictive biomarker prior to different causes of graft dysfunction. Plasma from single and multicenter LTR cohorts was analyzed for dd-cfDNA.

Prediction of Liver Transplant Rejection With a Biologically Relevant Gene Expression Signature.

Background: Noninvasive biomarkers distinguishing early immune activation before acute rejection (AR) could more objectively inform immunosuppression management in liver transplant recipients (LTRs). We previously reported a genomic profile distinguishing LTR with AR versus stable graft function. This current study includes key phenotypes with other causes of graft dysfunction and uses a novel random forest approach to augment the specificity of predicting and diagnosing AR.

Comparing Real World, Personalized, Multidisciplinary Tumor Board Recommendations with BCLC Algorithm: 321-Patient Analysis.

Purpose: To evaluate hepatocellular carcinoma (HCC) treatment allocation, deviation from BCLC first-treatment recommendation, and outcomes following multidisciplinary, individualized approach.

Methods: Treatment-naïve HCC discussed at multidisciplinary tumor board (MDT) between 2010 and 2013 were included to allow minimum 5 years of follow-up. MDT first-treatment recommendation (resection, transplant, ablation, transarterial radioembolization (Y90), transarterial chemoembolization, sorafenib, palliation) was documented, as were subsequent treatments.

Epigenetic reprogramming of host and viral genes by Human Cytomegalovirus infection in Kasumi-3 myeloid progenitor cells at early times post-infection.

HCMV establishes latency in myeloid cells. Using the Kasumi-3 latency model, we previously showed that lytic gene expression is activated prior to establishment of latency in these cells. The early events in infection may have a critical role in shaping establishment of latency.

Transplant regimen adherence for kidney recipients by engaging information technologies (TAKE IT): Rationale and methods for a randomized controlled trial of a strategy to promote medication adherence among transplant recipients.

Background: Several studies report a high prevalence of non-adherence to prescribed immunosuppressive (IS) medications among kidney transplant recipients (KTRs), yet few interventions have been effective for helping patients sustain appropriate post-transplant adherence. We describe a multifaceted, evidence-based, medication adherence monitoring strategy ('TAKE IT') that leverages available transplant center resources to identify potential medication non-adherence and other concerns earlier to prevent complications that could result from inadequate IS adherence.

Methods: The TAKE IT strategy includes: 1) medication adherence mobile application; 2) routine, online patient self-reported adherence assessments; 3) care alert notifications via the electronic health record (EHR) directed to transplant coordinators; 4) quarterly adherence reports to monitor IS values and summarize adherence trends; 5) deployment of adherence support tools tailored to specific adherence concerns.

Percutaneous Access of the Modified Hutson Loop for Retrograde Cholangiography, Endoscopy, and Biliary Interventions.

Purpose: The purpose of this study was to present the institutional experience of performing endoscopy, cholangiography, and biliary interventions through the modified Hutson loop by interventional radiology.

Materials And Methods: A total of 61 of 64 modified Hutson loop access procedures were successful. This single-center retrospective study included 61 successful procedures of biliary interventions using existing modified Hutson loops (surgically affixed subcutaneous jejunal limb adjacent to biliary anastomosis or anastomoses) for diagnostic or therapeutic purposes in 21 patients.

Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function.

Delayed graft function due to transplant ischemia/reperfusion injury adversely affects up to 50% of deceased-donor kidney transplant recipients. However, key factors contributing to the severity of ischemia/reperfusion injury remain unclear. Here, using a clinically relevant mouse model of delayed graft function, we demonstrated that donor genetic background and kidney-intrinsic MyD88/Trif-dependent innate immunity were key determinants of delayed graft function.

MCMV Dissemination from Latently-Infected Allografts Following Transplantation into Pre-Tolerized Recipients.

Transplantation tolerance is achieved when recipients are unresponsive to donor alloantigen yet mobilize against third-party antigens, including virus. After transplantation, cytomegalovirus (CMV) reactivation in latently-infected transplants reduces allograft viability. To determine if pre-tolerized recipients are resistant to viral dissemination in this setting, we transfused chemically-fixed donor splenocytes (1-ethyl-3- (3'-dimethyl-aminopropyl)-carbo-diimide (ECDI)-treated splenocytes (ECDIsp)) to induce donor antigen tolerance without immunosuppression.

Correction to: Trends and predictors of multidimensional health-related quality of life after living donor kidney transplantation.

In its original publication, an erroneous version of Fig. 2d was included in the manuscript. The corrected figure has now been added.

Acute murine cytomegalovirus disrupts established transplantation tolerance and causes recipient allo-sensitization.

We have previously shown that acute cytomegalovirus (CMV) infection disrupts the induction of transplantation tolerance. However, what impact acute CMV infection would have on the maintenance of established tolerance and on subsequent recipient allo-sensitization is a clinically important unanswered question. Here we used an allogeneic murine islet transplantation tolerance model to examine the impact of acute CMV infection on: (a) disruption of established transplantation tolerance during tolerance maintenance; and (b) the possibility of recipient allo-sensitization by CMV-mediated disruption of stable tolerance.

Kidney Graft Surveillance Biopsy Utilization and Trends: Results From a Survey of High-Volume Transplant Centers.

An e-mail-based market research survey focused on high-volume US adult transplant centers was developed and implemented to assess surveillance based on United Network for Organ Sharing/Scientific Registry of Transplant Recipients data: 51 to 100 transplants, 101 to 200 transplants, and more than 200 transplants. Eighty-three centers responded to the survey. Respondent centers represented 13,837/21,167 (65%) of the total kidney transplants in 2018.

Murine cytomegalovirus dissemination but not reactivation in donor-positive/recipient-negative allogeneic kidney transplantation can be effectively prevented by transplant immune tolerance.

Cytomegalovirus (CMV) reactivation from latently infected donor organs post-transplantation and its dissemination cause significant comorbidities in transplant recipients. Transplant-induced inflammation combined with chronic immunosuppression has been thought to provoke CMV reactivation and dissemination, although sequential events in this process have not been studied. Here, we investigated this process in a high-risk donor CMV-positive to recipient CMV-negative allogeneic murine kidney transplantation model.

Discovery and validation of a novel blood-based molecular biomarker of rejection following liver transplantation.

Noninvasive biomarker profiles of acute rejection (AR) could affect the management of liver transplant (LT) recipients. Peripheral blood was collected following LT for discovery (Northwestern University [NU]) and validation (National Institute of Allergy and Infectious Diseases Clinical Trials in Organ Transplantation [CTOT]-14 study). Blood gene profiling was paired with biopsies showing AR or ADNR (acute dysfunction no rejection) as well as stable graft function samples (Transplant eXcellent-TX).

Trends and predictors of multidimensional health-related quality of life after living donor kidney transplantation.

Purpose: Living donor kidney transplant (LDKT) imparts the best graft and patient survival for most end-stage kidney disease (ESKD) patients. Yet, there remains variation in post-LDKT health-related quality of life (HRQOL). Improved understanding of post-LDKT HRQOL can help identify patients for interventions to maximize the benefit of LDKT.

Financial Feasibility Analysis of a Culturally and Linguistically Competent Hispanic Kidney Transplant Program.

Background: In 2006, Northwestern Medicine implemented a culturally targeted and linguistically congruent Hispanic Kidney Transplant Program (HKTP). The HKTP has been associated with a reduction in Hispanic/Latino disparities in live donor kidney transplantation. This article assessed the financial feasibility of implementing the HKTP intervention at 2 other transplant centers.

Use of biomarkers to improve immunosuppressive drug development and outcomes in renal organ transplantation: A meeting report.

On September 27-28, 2018 the Food and Drug Administration (FDA) and the Critical Path Institute's Transplant Therapeutics Consortium convened a public workshop titled "Evidence-Based Treatment Decisions in Transplantation: The Right Dose & Regimen for the Right Patient/Individualized Treatment." The workshop facilitated cooperative engagement of transplant community stakeholders, including pharmaceutical industry, academic researchers, clinicians, patients, and regulators to discuss methods to advance the development of novel immunosuppressive drugs for use in solid organ transplantation. Day 1 focused on the utility of biomarkers in drug development with considerations for seeking regulatory endorsement for use in clinical trials.

Correction to: Prognosticating Survival in Hepatocellular Carcinoma with Elevated Baseline Alpha-fetoprotein Treated with Radioembolization Using a Novel Laboratory Scoring System: Initial Development and Validation.

The name of the eleventh author is listed incorrectly in the published article as Nitin Kataraya. The correct name is Nitin Katariya.

New Insights Into the Molecular Mechanisms and Immune Control of Cytomegalovirus Reactivation.

Cytomegalovirus (CMV) is a β-herpesvirus that establishes lifelong latency in infected hosts. Following transplantation of a latently infected organ, reactivation can occur and consists of a spectrum of clinically apparent syndromes from mild symptoms to tissue-invasive, resulting in both direct and indirect sequelae. Before the advent of effective antiviral agents, the primary treatment was reduction in immunosuppression (IS).

A Practical Guide to the Clinical Implementation of Biomarkers for Subclinical Rejection Following Kidney Transplantation.

Noninvasive biomarkers are needed to monitor stable patients following kidney transplantation (KT), as subclinical rejection, currently detectable only with invasive surveillance biopsies, can lead to chronic rejection and graft loss. Several biomarkers have recently been developed to detect rejection in KT recipients, using different technologies as well as varying clinical monitoring strategies defined as "context of use (COU)." The various metrics utilized to evaluate the performance of each biomarker can also vary, depending on their intended COU.

Endovascular Management of Acquired Hepatic Arterial-Portal Venous Malformations.

Purpose: Arteriovenous malformations (AVMs) are typically congenital in origin, but acquired types, such as dural arteriovenous fistula (AVF), have been described. This study aimed to describe the diagnosis and endovascular treatment of acquired hepatic arterial-portal venous (HA-PV) malformations.

Materials And Methods: A retrospective review of suspected acquired HA-PV malformations from 9/2011 to 2/2018 was performed.