Development and characterization of a new inbred transgenic rat strain expressing DsRed monomeric fluorescent protein

The inbred rat is a suitable model for studying human disease and because of its larger size is more amenable to complex surgical manipulation than the mouse. While the rodent fulfills many of the criteria for transplantation research, an important requirement is the ability to mark and track donors cells and assess organ viability. However, tracking ability is limited by the availability of transgenic (Tg) rats that express suitable luminescent or fluorescent proteins. Red fluorescent protein cloned from Discosoma coral (DsRed) has several advantages over other fluorescent proteins, including in vivo detection in the whole animal and ex vivo visualization in organs as there is no interference with autofluorescence. We generated and characterized a novel inbred Tg Lewis rat strain expressing DsRed monomeric (DsRed mono) fluorescent protein under the control of a ubiquitously expressed ROSA26 promoter. DsRed mono Tg rats ubiquitously expressed the marker gene as detected by RT-PCR but the protein was expressed at varying levels in different organs. Conventional skin grafting experiments showed acceptance of DsRed monomeric Tg rat skin on wild-type rats for more than 30 days. Cardiac transplantation of DsRed monomeric Tg rat hearts into wild-type recipients further showed graft acceptance and long-term organ viability (>6 months). The DsRed monomeric Tg rat provides marked cells and/or organs that can be followed for long periods without immune rejection and therefore is a suitable model to investigate cell tracking and organ transplantationFil: Montanari, Sonia. University Health Network. Toronto; Canadá. University of Toronto; Canadá. Princess Margaret Cancer Centre. Toronto; CanadáFil: Wang, Xing-Hua. University Health Network. Toronto; CanadáFil: Yannarelli, Gustavo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University Health Network. Toronto; CanadáFil: Dayan, Victor. University Health Network. Toronto; CanadáFil: Berger, Thorsten. University Health Network. Toronto; CanadáFil: Zocche, Larissa. University Health Network. Toronto; CanadáFil: Kobayashi, Eiji. Jichi Medical School. Tochigi; JapónFil: Viswanathan, Sowmya. University Health Network. Toronto; CanadáFil: Keating, Armand. University of Toronto; Canadá. University Health Network. Toronto; Canad

Systematic versus on-demand early palliative care: results from a multicentre, randomised clinical trial

Background Early palliative care (EPC) in oncology has been shown to have a positive impact on clinical outcome, quality-of-care outcomes, and costs. However, the optimal way for activating EPC has yet to be defined. Methods This prospective, multicentre, randomised study was conducted on 207 outpatients with metastatic or locally advanced inoperable pancreatic cancer. Patients were randomised to receive ‘standard cancer care plus on-demand EPC’ (n = 100) or ‘standard cancer care plus systematic EPC’ (n = 107). Primary outcome was change in quality of life (QoL) evaluated through the Functional Assessment of Cancer Therapy – Hepatobiliary questionnaire between baseline (T0) and after 12 weeks (T1), in particular the integration of physical, functional, and Hepatic Cancer Subscale (HCS) combined in the Trial Outcome Index (TOI). Patient mood, survival, relatives' satisfaction with care, and indicators of aggressiveness of care were also evaluated. Findings The mean changes in TOI score and HCS score between T0 and T1 were −4.47 and −0.63, with a difference between groups of 3.83 (95% confidence interval [CI] 0.10–7.57) (p = 0.041), and −2.23 and 0.28 (difference between groups of 2.51, 95% CI 0.40–4.61, p = 0.013), in favour of interventional group. QoL scores at T1 of TOI scale and HCS were 84.4 versus 78.1 (p = 0.022) and 52.0 versus 48.2 (p = 0.008), respectively, for interventional and standard arm. Until February 2016, 143 (76.9%) of the 186 evaluable patients had died. There was no difference in overall survival between treatment arms. Interpretations Systematic EPC in advanced pancreatic cancer patients significantly improved QoL with respect to on-demand EPC

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

A Heterotopic Heart Transplantation Model to Investigate Cardiac Regeneration

The heart, in contrast to other tissues, exhibits a limited regenerative capacity making it vulnerable to irreparable damage [1]. Despite significant advances in pharmacological and clinical treatment, heart disease remains one of the primary causes of morbidity and mortality worldwide with post - myocardial infarction (MI) heart failure (HF) being one of the major contributors [2]. For the past 25 years, heart transplantation (HT) has been the most effective therapeutic option for patients with end- stage HF [3]. Donor heart ischemia-reperfusion (I/R) injury during the transplantation process can result in primary graft dysfunction. Although the exact sequence of events in the patho-physiology of I/R injury remains unknown, the role of inflammation has become increasingly clear [4]. In this perspective, bone marrow mesenchymal stromal cells (BM-MSCs) are under extensive investigation as potential therapy for I/R injury, since BM-MSCs are able to exert immune regulatory and reparative effects [5].The advent of stem cell biology provided a framework to challenge the notion that the heart is a terminally differentiated organ with recent reports revealing myocardial mitotic activity in both health and disease states [6] and further demonstration of small dividing cells in the heart express cardiac markers with stem cell properties of self-renewal and differentiation [7]. These findings raised questions regarding the identity and origin of these putative cardiac progenitor cells, the paracrine signaling involved in their mobilization and differentiation and whether these cells can repair damaged myocardium [8].Heterotopic heart transplantation (HHT) in rodents is an important and valuable model for studying graft vasculopathy, to evaluate new immunosuppressive strategies, to understand the mechanisms of rejection and tolerance and to monitor tissue regeneration after transplant [9]. The overall goal of this doctoral dissertation was to use a novel cervical HHT in rats as a tool to investigate cardiac regeneration. First, we investigated the therapeutic effects of intravenous delivery of BM-MSCs in the acute phase post-transplant in a HHT model associated with I/R injury. We showed early improvement in cardiac function and subsequent enhanced ventricular remodeling, reduced cardiac fibrosis, augmented neovascularization and decreased cardiomyocyte apoptosis of the transplanted heart.Second, we investigated whether cardiac cells could be mobilized by cardiac injury and, if so, to identify and characterize the putative stem cell type in a HHT model associated with acute MI. We demonstrated that cells expressing a host transgenic marker (GFP) were detectable in the injured recipient six and sixteen days post-MI at higher percentage in the peri-infarcted - and within the infarcted tissue with characteristics of mature adult cardiomyocytes, myofibroblasts, endothelial and smooth muscle cells which significantly contributed to the repopulation of the damaged myocardium.Ph.D

Corpus informatico Belloriano

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