1,723,338 research outputs found
Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2
No full textImproving cord blood transplantation in children
No full textUmbilical cord blood transplantation (UCBT) is widely used to treat children affected by many disorders. In comparison to bone marrow transplantation, the advantages of UCBT are represented by lower incidence and severity of graft-versus-host disease, easier procurement and prompter availability of cord blood cells, and by the possibility of using donors showing human leucocyte antigen disparities with the recipient. Despite these advantages, the large experience gained over the last decade has clearly demonstrated that UCBT patients may be exposed to an increased risk of early fatal complications, due to the lower engraftment rate of donor haematopoiesis, delayed kinetics of neutrophil recovery and lack of adoptive transfer of pathogen-specific memory T-cells. An inverse correlation between the number of nucleated cord blood cells infused per kilogramme recipient body weight and the risk of dying from transplantation-related causes exists. Thus, it is not surprising that strategies aimed at increasing the number of cord blood progenitors, favouring stem cell homing, and transferring pathogen-specific lymphocytes, have been recently investigated. In particular, selection of the richest cord blood units, infusion of 2 units in the same recipient, intrabone injection of cord blood cells, and transplantation of ex-vivo expanded progenitors can contribute to improve the results of UCBT
Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes
Full text linkMultiple myeloma (MM) is a plasma cell malignancy associated with high levels of monoclonal (M) protein in the blood and/or serum. MM can occur de novo or evolve from benign monoclonal gammopathy of undetermined significance (MGUS). Current translational research into MM focuses on the development of combination therapies directed against molecularly defined targets and that are aimed at achieving durable clinical responses. MM cells have a unique ability to evade immunosurveillance through several mechanisms including, among others, expansion of regulatory T cells (Treg), reduced T-cell cytotoxic activity and responsiveness to IL-2, defects in B-cell immunity, and induction of dendritic cell (DC) dysfunction. Immune defects could be a major cause of failure of the recent immunotherapy trials in MM. This article summarizes our current knowledge on the molecular determinants of immune evasion in patients with MM and highlights how these pathways can be targeted to improve patients' clinical outcome
Intestinal dendritic cells in the pathogenesis of inflammatory bowel disease
No full textThe gastrointestinal tract harbors a large number and diverse array of commensal bacteria and is an important entry site for pathogens. For these reasons, the intestinal immune system is uniquely dedicated to protect against infections, while avoiding the development of destructive inflammatory responses to the microbiota. Several models have been proposed to explain how the immune system discriminates between, and appropriately responds to, commensal and pathogenic microorganisms. Dendritic cells (DCs) and regulatory T cells (Treg) are instrumental in maintaining immune homeostasis and tolerance in the gut. DCs are virtually omnipresent and are remarkably plastic, having the ability to adapt to the influences of the microenvironment. Different DC populations with partially overlapping phenotypic and functional properties have been described in different anatomical locations. DCs in the draining mesenteric lymph nodes, in the intestinal lamina propria and in Peyer's patches partake both in the control of intestinal inflammation and in the maintenance of gut tolerance. In this respect, gut-resident DCs and macrophages exert tolerogenic functions as they regularly encounter and sense commensal bacteria. In contrast, migrating DC subsets that are recruited to the gut as a result of pathogenic insults initiate immune responses. Importantly, tolerogenic DCs act by promoting the differentiation and expansion of Treg cells that efficiently modulate gut inflammation, as shown both in pre-clinical models of colitis and in patients with inflammatory bowel disease (IBD). This article reviews the phenotypic and functional features of gut DC subsets and discusses the current evidence underpinning the DC contribution to the pathogenesis of the major clinical subtypes of human IBD. It also addresses the potential clinical benefit derived from DC targeting either in vivo or in vitro. (C) 2011 Baishideng. All rights reserved
Incidence and pathogenesis of tumor lysis syndrome
No full textTumor lysis syndrome (TLS) is a constellation of metabolic disturbances that may be observed in patients with malignancies. Clinically significant TLS can occur spontaneously, but most often is seen 48-72 h after initiation of cancer treatment. The metabolic abnormalities observed in patients with TLS include hyperkalemia, hyperuricemia, and hyperphosphatemia, which leads to secondary hypocalcemia. The precise incidence of TLS is not defined, risk factors being represented by large tumor burden, neoplasms with either high growth fraction or high sensitivity to chemotherapy, and by pre-existing impairment of renal function. Neither racial, nor sex predilection exists. The pathogenesis of TLS is related to the rapid tumor cell turnover or destruction, which may result in release of intracellular ions and metabolic byproducts into the systemic circulation. Acute renal failure (ARF) may frequently complicate TLS and is mainly due to renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine. Hemodynamic changes reducing glomerular flow due to still-undefined mediators are also involved in TLS pathophysiology. Pre-existing volume depletion or renal dysfunction may worsen metabolic derangements and ARE A good comprehension of TLS pathophysiology has provided the basis for an effective and rational treatment of this complication, adversely affecting the outcome of cancer patients. Copyright (c) 2005 S. Karger AG, Basel
Strategies to harness immunity against infectious pathogens after haploidentical stem cell transplantation
No full text: Viral and fungal infections account for significant morbidity and mortality, particularly in pediatric patients with profound immune suppression resulting from allogeneic hematopoietic stem cell transplantation (HSCT). Therapies with anti-viral and anti-fungal drugs are often associated with significant toxicity, are of limited efficacy and can induce drug resistance. One innovative approach to prevent and/or treat viral and fungal infections involves the adoptive transfer of in vitro-expanded or in vitro-generated pathogen-specific T cells. This review summarizes the clinical trials that have been run to date with virus- and fungus-specific T cells, with special emphasis on the clinical context of haploidentical HSCT for pediatric malignancies. It will also discuss initiatives and strategies to overcome the hurdles associated with time-consuming and complex GMP-grade laboratory procedures required to generate pathogen-specific T cells
ADARs: allies or enemies? The importance of A-to-I RNA editing in human disease: from cancer to HIV-1
No full textAdenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosine (A) to inosine (I) in nuclear-encoded RNAs and viral RNAs. The activity of ADARs has been demonstrated to be essential in mammals and serves to fine-tune different proteins and modulate many molecular pathways. Recent findings have shown that ADAR activity is altered in many pathological tissues. Moreover, it has been shown that modulation of RNA editing is important for cell proliferation and migration, and has a protective effect on ischaemic insults. This review summarises available recent knowledge on A-to-I RNA editing and ADAR enzymes, with particular attention given to the emerging role played by these enzymes in cancer, some infectious diseases and immune-mediated disorders
Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease
No full textAllogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment for sickle cell disease (SCD), being successful in around 8590% of patients. Mortality and long-term morbidity (including infertility, gonadal failure, and chronic graft-vs.-host disease) associated with conventional approaches curtail the number of patients who undergo allo-HSCT. Recently, it has been demonstrated that cord blood is as effective as and possibly safer than bone marrow in pediatric patients with SCD. Likewise, transplant strategies based on the use of reduced-intensity regimens and the induction of mixed chimerism have been explored to decrease allo-HSCT short- and long-term complications. Pediatr Blood Cancer 2012;59:372376. (c) 2012 Wiley Periodicals, Inc
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