Adenoviral vector-mediated gene therapy for gliomas: coming of age

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and it carries a dismal prognosis. Adenoviral vector (Ad)-mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates' brain. Importantly, Ads have been safely administered within the tumor resection cavity in humans. AREAS COVERED: This review gives background on GBM and Ads; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally, we discuss the results of the human clinical trials for GBM that have used Ads. EXPERT OPINION: The transduction characteristics of Ads, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases encourage the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although, it is the large randomized Phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM.Fil: Castro, María G.. University of Michigan; Estados UnidosFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Wilson, Thomas J.. University of Michigan; Estados UnidosFil: Calinescu, Alexandra. University of Michigan; Estados UnidosFil: Paran, Christopher. University of Michigan; Estados UnidosFil: Kamran, Neha. University of Michigan; Estados UnidosFil: Koschmann, Carl. University of Michigan; Estados UnidosFil: Moreno Ayala, Mariela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Assi, Hikmat. University Of Michigan Medical School;Fil: Lowenstein, Pedro R.. University of Michigan; Estados Unido

Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding

The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML

COLORECTAL CARCINOGENESIS; ROLE OF OXIDATIVE STRESS AND ANTIOXIDANTS

One of the contributory causes of colon cancer is the negative effect of reactive oxygen species on DNA repair mechanism. Currently, there is a growing support for the concept that oxidative stress may be an important etiological factor for carcinogenesis. The purpose of this review is to elucidate the role of oxidative stress in promoting colorectal carcinogenesis and to highlight the potential protective role of antioxidants. Several studies have documentes the importance of antioxidants in countering oxidative stress and preventing colorectal carcinogenesis. However, there are conflicting data in the literature concerning its proper use in humans, since these studies did not yeld definitive results and were performed mostly in vitro on cell population, or in vivo in experimental animal models

INFLAMMATORY BOWEL DISEASE AND COLORECTAL CANCER, NUTRACEUTICAL ASPECTS

Nutraceuticals constitute a group of functional foods that provide added health benefits for various disorders including inflammatory bowel disease (IBD) and colorectal cancer (CCR). The main groups of nutraceuticals include probiotics, prebiotics omega 3 and antioxidants. Studies on nutraceutical showed that this type of food possessed similar properties to drugs but with the benefit of not having side effects. This mini review shows that probiotics and prebiotics, when administered simultaneously with traditional therapies, reduce IBD symptoms and reduce synthesis of enzymes probably involved in colorectal carcinogenesis. Moreover, Omega 3 reduces the synthesis of inflammation mediators and prevenents carcinogenesis through interaction interaction with the signaling pathway NOTCH1/MMP9. Moreover, antioxidant reduce the inflammatory process by inhibiting the synthesis of inflammatory mediators, and inhibit the mechanisms of cell proliferation by inducing apoptosis. In brief, nutraceuticals have gained a huge clinical interest since they could be used along with traditional therapy. Bioavailability studies of nutracetical supplements guarantee a correct intake of the substance by oral administration, a matter which would not have been posible to have entirely with the consumprtion of regular food only

Assessment of Cytomegalovirus-Specific Cell-Mediated Immunity for the Prediction of Cytomegalovirus Disease in High-Risk Solid-Organ Transplant Recipients: A Multicenter Cohort Study

In high-risk solid-organ transplant recipients receiving antiviral prophylaxis, the measurement of specific cell-mediated immunity using the Quantiferon assay appropriately stratified the individual risk of developing subsequent cytomegalovirus diseas

How can we enhance sexual health outcomes in men who have sex with men in Lebanon?

In Lebanese men who have sex with men (MSM), the prevalence of HIV is 12% and the prevalence of having at least one symptom of a sexually transmitted infection (STI) is 34.9%.1 Low HIV testing rates, unprotected unprotected sexual intercourse, alcohol and substance use contribute to this epidemic.2 Here we present data on the prevalence of STIs in a sample of MSM attending a sexual health clinic in order to identify the correlates of risk-taking behaviour, and of testing behaviour in this population. Addressing these questions is crucial for reducing the incidence of HIV/STIs and, thus, for enhancing sexual health outcomes in this high-risk population in Lebanon

RUNX1 Reshapes the Epigenetic Landscape at the Onset of Haematopoiesis

Cell fate decisions during haematopoiesis are governed by lineage-specific transcription factors, such as RUNX1, SCL/TAL1, FLI1 and C/EBP family members. To gain insight into how these transcription factors regulate the activation of haematopoietic genes during embryonic development, we measured the genome-wide dynamics of transcription factor assembly on their target genes during the RUNX1-dependent transition from haemogenic endothelium (HE) to haematopoietic progenitors. Using a $Runx1^{−/−}$ embryonic stem cell differentiation model expressing an inducible Runx1 gene, we show that in the absence of RUNX1, haematopoietic genes bind SCL/TAL1, FLI1 and C/EBPβ and that this early priming is required for correct temporal expression of the myeloid master regulator PU.1 and its downstream targets. After induction, RUNX1 binds to numerous de novo sites, initiating a local increase in histone acetylation and rapid global alterations in the binding patterns of SCL/TAL1 and FLI1. The acquisition of haematopoietic fate controlled by Runx1 therefore does not represent the establishment of a new regulatory layer on top of a pre-existing HE program but instead entails global reorganization of lineage-specific transcription factor assemblies