Advances in multimodal immunotherapy have significantly reduced acute rejection rates and substantially improved 1‐year graft survival following renal transplantation. However, long‐term (10‐year) ...survival rates have stagnated over the past decade. Recent studies indicate that antibody‐mediated rejection (ABMR) is among the most important barriers to improving long‐term outcomes. Improved understanding of the roles of acute and chronic ABMR has evolved in recent years following major progress in the technical ability to detect and quantify recipient anti‐HLA antibody production. Additionally, new knowledge of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. Still, questions regarding the classification of ABMR, the precision of diagnostic approaches, and the efficacy of various strategies for managing affected patients abound. This review article provides an overview of current thinking and research surrounding the pathophysiology and diagnosis of ABMR, ABMR‐related outcomes, ABMR prevention and treatment, as well as possible future directions in treatment.
This review addresses the spectrum of antibody‐mediated rejection after kidney transplantation, including its pathogenesis, risk factors, phenotypes, the revised Banff 2013 classification, treatment options, and outcomes. Also see meeting report by Haas et al on page 272.
Abstract In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt ...to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.
Pancreas allograft acceptance is markedly more selective than other solid organs. The number of pancreata recovered is insufficient to meet the demand for pancreas transplants (PTx), particularly for ...patients awaiting simultaneous kidney‐pancreas (SPK) transplant. Development of a pancreas donor risk index (PDRI) to identify factors associated with an increased risk of allograft failure in the context of SPK, pancreas after kidney (PAK) or pancreas transplant alone (PTA), and to assess variation in allograft utilization by geography and center volume was undertaken. Retrospective analysis of all PTx performed from 2000 to 2006 (n = 9401) was performed using Cox regression controlling for donor and recipient characteristics. Ten donor variables and one transplant factor (ischemia time) were subsequently combined into the PDRI. Increased PDRI was associated with a significant, graded reduction in 1‐year pancreas graft survival. Recipients of PTAs or PAKs whose organs came from donors with an elevated PDRI (1.57–2.11) experienced a lower rate of 1‐year graft survival (77%) compared with SPK transplant recipients (88%). Pancreas allograft acceptance varied significantly by region particularly for PAK/PTA transplants (p < 0.0001). This analysis demonstrates the potential value of the PDRI to inform organ acceptance and potentially improve the utilization of higher risk organs in appropriate clinical settings.
The Pancreas Donor Risk Index identifies factors associated with graft loss following transplantation which appear to differentially affect pancreas allograft survival in isolated transplants compared with simultaneous kidney‐pancreas transplant.
The signaling mediated by c-MET and its ligand, hepatocyte growth factor (HGF), has been implicated in malignant progression of cancer involving stimulation of proliferation, invasion and metastasis. ...We studied the c-MET/HGF axis as a mediator of tumor-stromal interaction in ovarian cancer and the value of targeting c-MET for the treatment of ovarian cancer. To assess c-MET signaling, we established in vitro models of the microenvironment using primary and immortalized human fibroblasts from normal ovary and tumor samples and epithelial ovarian cancer cell lines. We found that fibroblast from normal ovaries secreted high levels of HGF (1500-3800 pg/ml) as compared with tumor-derived fibroblasts (undetectable level) and could elicit cellular biological responses on c-MET-expressing ovarian cancer cells including increase of cell proliferation and migration (2- to 140-fold increase). HGF secreted by fibroblasts was also found sequestered within extracellular matrices (ECMs) and when degraded this ECM-derived HGF stimulated cancer cell migration (1.5- to 24-fold). In cells containing constitutive c-MET phosphorylation, recombinant HGF and fibroblast-derived HGF negligibly affect c-MET phosphorylation on Tyr(1234) and Tyr(1003). However, both sources of HGF increased the phosphorylation of c-MET on Tyr(1349), the multi-substrate docking site, by more than sixfold and led to activation of downstream signaling transducers. DCC-2701 (Deciphera Pharmaceuticals, LLC), a novel c-MET/TIE-2/VEGFR inhibitor was able to effectively reduce tumor burden in vivo and block c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro. Importantly, DCC-2701's anti-proliferative activity was dependent on c-MET activation induced by stromal human fibroblasts and to a lesser extent exogenous HGF. Our data suggest for the first time that DCC-2701 may be superior to HGF antagonists that are in clinical trials and that pTyr(1349) levels might be a good indicator of c-MET activation and likely response to targeted therapy as a result of signals from the microenvironment.
Background
Before 2012, few studies had addressed pregnancy outcomes following maternal influenza vaccination; however, the number of publications on this topic has increased recently.
Objectives
To ...review comparative studies evaluating fetal death or preterm birth associated with influenza vaccination during pregnancy.
Search strategy
We searched bibliographic databases from inception to April 2014.
Selection criteria
Experimental or observational studies assessing the relationship between influenza vaccination during pregnancy and fetal death or preterm birth.
Data collection and analysis
Two reviewers independently ed data from studies meeting the inclusion criteria.
Main results
We included one randomised clinical trial and 26 observational studies. Meta‐analyses were not considered appropriate because of high clinical and statistical heterogeneity. Three studies of fetal death at any gestational age reported adjusted effect estimates in the range 0.56–0.79, and four of five studies of fetal death at <20 weeks reported adjusted estimates between 0.89 and 1.23, all with confidence intervals including 1.0. Adjusted effect estimates for four of five studies of fetal death at ≥20 weeks ranged from 0.44 to 0.77 (two with confidence intervals not crossing 1.0), whereas a fifth reported a non‐significant effect in the opposite direction. Among 19 studies of preterm birth, there was no strong evidence suggesting any increased risk, and meta‐regression did not explain the moderate between‐study heterogeneity (I2 = 57%).
Authors' conclusions
Most studies reported no association between fetal death or preterm birth and influenza vaccination during pregnancy. Although several reported risk reductions, results may be biased by methodological shortcomings of observational studies of influenza vaccine effectiveness.
Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft ...health. This 1‐year, randomized, controlled, open‐label, exploratory study assessed two belatacept‐based regimens compared to a tacrolimus (TAC)‐based, steroid‐avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept‐mycophenolate mofetil (MMF), belatacept‐sirolimus (SRL), or TAC‐MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty‐nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept‐MMF, belatacept‐SRL and TAC‐MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two‐thirds of patients in the belatacept groups remained on CNI‐ and steroid‐free regimens at 12 months and the calculated glomerular filtration rate was 8–10 mL/min higher with either belatacept regimen than with TAC‐MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC‐based regimen.
Results from this pilot trial suggest that immunosuppression using either of two belatacept‐based regimens that avoid both calcineurin inhibitors and steroids results in acceptable rates of acute rejection and improved renal function relative to a tacrolimus‐based regimen in kidney transplant recipients.
Organs donated after cardiac death (DCD) are used to expand the donor pool. We analyzed the outcomes in the United States of pancreatic transplantation of organs from DCD donors performed between ...1993 and 2003.
We used the OPTN/UNOS Registry to compare outcomes of primary pancreas allografts from DCD donors and donors after brain death (DBD). The primary endpoints were graft failure and patient death. A national survey regarding the use of DCD donors in pancreas transplantation was conducted among the directors of pancreas transplant centers.
Data were obtained on 47 simultaneous pancreas‐kidney transplants (SPK) and 10 solitary pancreas transplants from DCD donors and on 2431 SPK and 1607 solitary pancreas transplants from DBD donors. Recipients of a SPK transplants from DCD and DBD donors had equivalent patient and graft survival rates at 1, 3 and 5 years. For recipients of SPK transplants, the wait for organs from DCD donors was significantly shorter than that for organs from DBD donors. SPK recipients of organs from DCD donors had longer hospital stays than did recipients of organs from DBD donors. With renal allografts, the incidence of delayed graft function was almost four times higher with organs from DCD donors than with organs from DBD donors.
Selective use of organs from DCD donors is safe for pancreas transplantation.
Release 6, the latest reference genome assembly of the fruit fly Drosophila melanogaster, was released by the Berkeley Drosophila Genome Project in 2014; it replaces their previous Release 5 genome ...assembly, which had been the reference genome assembly for over 7 years. With the enormous amount of information now attached to the D. melanogaster genome in public repositories and individual laboratories, the replacement of the previous assembly by the new one is a major event requiring careful migration of annotations and genome-anchored data to the new, improved assembly. In this report, we describe the attributes of the new Release 6 reference genome assembly, the migration of FlyBase genome annotations to this new assembly, how genome features on this new assembly can be viewed in FlyBase (http://flybase.org) and how users can convert coordinates for their own data to the corresponding Release 6 coordinates.
Women who carry germ-line mutations in BRCA1/2 are at very high risk of developing breast and ovarian cancer. Breast conserving therapy is associated with a similar risk of ipsilateral cancer ...recurrence in BRCA carriers compared with non-carriers. However, the risk of subsequent contralateral breast cancer in carriers is markedly increased. Therefore, mastectomy of the diseased breast along with risk reducing mastectomy of the contralateral breast is often advocated for BRCA carriers who are treated for early breast cancer. Yet, many BRCA carriers forgo this option for fear of harmful effects and choose breast conserving treatment and observation instead. In Israel, BRCA-associated breast cancer is relatively common. Accordingly, a national protocol was devised for this enriched population.
In this Institutional Review Board-approved phase II trial, the option of prophylactic irradiation to the contralateral breast, in addition to standard loco-regional treatment, was offered to BRCA carrier patients treated for early breast cancer who declined contralateral mastectomy. The primary end point was contralateral breast cancer.
Between May 2007 and October 2017, 162 patients were enrolled. Eighty-one patients opted for standard loco-regional treatment including surgery and radiation to the involved side (control arm) and 81 patients chose additional contralateral breast irradiation (intervention arm). At a median follow-up of 58 months, 10 patients developed contralateral breast cancer in the control arm at a median of 32 months, as compared with 2 patients in the intervention arm who developed contralateral breast cancer 80 and 105 months after bilateral breast irradiation (log-rank P = 0.011).
Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset.
Phase II, comparative two-arm trial (NCT00496288).
This study compared the effects of using two T‐cell depleting antibodies, alemtuzumab (anti‐CD 52, Campath‐1H®) and rabbit antithymocyte globulin (Thymoglobulin®), as induction immunosuppression for ...recipients of simultaneous pancreas‐kidney transplantation given a prednisone‐free maintenance regimen. We used a single‐center, nonrandomised, retrospective, sequential study design to evaluate the efficacy and safety of alemtuzumab (n = 50) or antithymocyte globulin (n = 38) induction in combination with a prednisone‐free, tacrolimus/sirolimus‐based immunosuppression protocol. Kaplan‐Meier analyses of long‐term patient and graft survivals and rejection rates were determined according to induction agent. Secondary endpoints included the quality of renal allograft function, incidence of infectious and malignant complications, and cost considerations. Overall long‐term patient and graft survival rates did not significantly differ between patients treated with alemtuzumab and antithymocyte globulin. Rejection rates were also nearly equivalent at 1 and 2 years. Viral infectious complications were statistically significantly lower in the alemtuzumab group. The cost of alemtuzumab induction was lower than antithymocyte globulin. Alemtuzumab induction followed by steroid‐free maintenance therapy with a tacrolimus/sirolimus‐based immunosuppression regimen provided an effective, safe and cost‐conscious approach to SPK transplantation.
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