Tait S.W.G.,St Jude Childrens Research Hospital |
Parsons M.J.,St Jude Childrens Research Hospital |
Llambi F.,St Jude Childrens Research Hospital |
Bouchier-Hayes L.,St Jude Childrens Research Hospital |
And 3 more authors.
Developmental Cell | Year: 2010
During apoptosis, mitochondrial outer membrane permeabilization (MOMP) is often a point-of-no-return; death can proceed even if caspase activation is disrupted. However, under certain conditions, resistance to MOMP-dependent, caspase-independent cell death is observed. Mitochondrial recovery represents a key process in this survival. Live cell imaging revealed that during apoptosis not all mitochondria in a cell necessarily undergo MOMP. This incomplete MOMP (iMOMP) was observed in response to various stimuli and in different cell types regardless of caspase activity. Importantly, the presence of intact mitochondria correlated with cellular recovery following MOMP, provided that caspase activity was blocked. Such intact mitochondria underwent MOMP in response to treatment of cells with the Bcl-2 antagonist ABT-737, suggesting that the resistance of these mitochondria to MOMP lies at the point of Bax or Bak activation. Thus, iMOMP provides a critical source of intact mitochondria that permits cellular survival following MOMP. © 2010 Elsevier Inc.
Serrano J.C.E.,University of Lleida |
Gonzalo-Benito H.,University of Lleida |
Jove M.,University of Lleida |
Fourcade S.,Institute Dinvestigacio Biomedica Of Bellvitge |
And 6 more authors.
Molecular Nutrition and Food Research | Year: 2013
Scope: The intake of food rich in polyphenols is related to a lower incidence in almost all chronic degenerative diseases. However, relatively little is known about the molecular mechanisms involved in its antioxidant properties. The aim of this study was to determine whether the mechanism of action of polyphenols could be related to a modulation in energy uptake and metabolism, and further induced mitochondrial changes. Methods and results: For this purpose, male C57BL6 mice were fed during 3 months with a tea-based beverage rich in polyphenols. Insulin sensitivity, tissue oxidative damage biomarkers, as well as energy-related signaling pathways were determined to evaluate its mechanism of action. As a result, a tissue- and protein-specific subtle reduction in oxidative damage was observed. Skeletal muscle showed mitochondrial changes in respiratory complexes and an increase in AMP-activated protein kinase α levels, suggesting reduced energy availability. These changes were also associated with adipose tissue cellular metabolism. This was confirmed by a decline in the potential of energy uptake, evidenced by a diminished intestinal and systemic absorption of carbohydrates together with an inhibition of insulin sensitivity. Conclusions: Our results suggest that the mechanisms of action of green tea polyphenols may be related to their ability to modulate energy uptake leading to mitochondrial adaptations possibly responsible for the changes in protein oxidative damage. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Lopez-Abad M.,University of Barcelona |
Iglesias-Platas I.,University of Barcelona |
Monk D.,Institute Dinvestigacio Biomedica Of Bellvitge
Frontiers in Genetics | Year: 2016
The cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) gene is expressed from the maternal allele and is located within the centromeric imprinted domain at chromosome 11p15. It is a negative regulator of proliferation, with loss-of-function mutations associated with the overgrowth disorder Beckwith-Wiedemann syndrome. Recently, gain-of-function mutations within the PCNA domain have been described in two disorders characterized by growth failure, namely IMAGe (intra-uterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital abnormalities) syndrome and Silver-Russell syndrome (SRS). Over-expression of CDKN1C by maternally inherited microduplications also results in SRS, suggesting that in addition to activating mutations this gene may regulate growth by changes in dosage. To determine if CDKN1C is involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. We observe higher levels of expression of CDKN1C in IUGR placentas compared to those of controls. All placenta biopsies heterozygous for the PAPA repeat sequence in exon 2 showed appropriate monoallelic expression and no mutations in the PCNA domain were observed. The expression profile was independent of both genetic or methylation variation in the minimal CDKN1C promoter interval and of methylation of the cis-acting maternally methylated region associated with the neighboring KCNQ1OT1 non-coding RNA. Chromatin immunoprecipitation revealed binding sites for CTCF within the unmethylated CDKN1C gene body CpG island and putative enhancer regions, associated with the canonical enhancer histone signature, H3K4me1 and H3K27ac, located ~58 and 360 kb away. Using 3C-PCR we identify constitutive higher-order chromatin loops that occur between one of these putative enhancer regions and CDKN1C in human placenta tissues, which we propose facilitates expression. © 2016 López-Abad, Iglesias-Platas and Monk.
Guedan S.,University of Pennsylvania |
Guedan S.,Institute Dinvestigacio Biomedica Of Bellvitge |
Chen X.,New York University |
Madar A.,New York University |
And 11 more authors.
Blood | Year: 2014
With the notable exception of B-cell malignancies, the efficacy of chimeric antigen receptor (CAR) T cells has been limited, and CAR T cells have not been shown to expand and persist in patients with nonlymphoid tumors. Here we demonstrate that redirection of primary human T cells with a CAR containing the inducible costimulator (ICOS) intracellular domain generates tumor-specific IL-17-producing effector cells that show enhanced persistence. Compared with CARs containing the CD3ζ chain alone, or in tandem with the CD28 or the 4-1BB intracellular domains, ICOS signaling increased IL-17A, IL-17F, and IL-22 following antigen recognition. In addition, T cells redirected with an ICOS-based CAR maintained a core molecular signature characteristic of T H17 cells and expressed higher levels of RORC, CD161, IL1R-1, and NCS1. Of note, ICOS signaling also induced the expression of IFN-γ and T-bet, consistent with a TH17/TH1 bipolarization. When transferred into mice with established tumors, TH17 cells that were redirected with ICOS-based CARsmediated efficient antitumor responses and showedenhanced persistence compared with CD28- or 4-1BB-based CAR T cells. Thus, redirection of TH17 cells with a CAR encoding the ICOS intracellular domain is a promising approach to augment the function and persistence of CAR T cells in hematologic malignancies. © 2014 by The American Society of Hematology.
Court F.,Institute Dinvestigacio Biomedica Of Bellvitge |
Tayama C.,National Health Research Institute |
Romanelli V.,Institute Dinvestigacio Biomedica Of Bellvitge |
Martin-Trujillo A.,Institute Dinvestigacio Biomedica Of Bellvitge |
And 19 more authors.
Genome Research | Year: 2014
Differential methylation between the two alleles of a gene has been observed in imprinted regions, where the methylation of one allele occurs on a parent-of-origin basis, the inactive X-chromosome in females, and at those loci whose methylation is driven by genetic variants. We have extensively characterized imprinted methylation in a substantial range of normal human tissues, reciprocal genome-wide uniparental disomies, and hydatidiform moles, using a combination of wholegenome bisulfite sequencing and high-density methylation microarrays. This approach allowed us to define methylation profiles at known imprinted domains at base-pair resolution, as well as to identify 21 novel loci harboring parent-of-origin methylation, 15 of which are restricted to the placenta. We observe that the extent of imprinted differentially methylated regions (DMRs) is extremely similar between tissues, with the exception of the placenta. This extra-embryonic tissue often adopts a different methylation profile compared to somatic tissues. Further, we profiled all imprinted DMRs in sperm and embryonic stem cells derived from parthenogenetically activated oocytes, individual blastomeres, and blastocysts, in order to identify primary DMRs and reveal the extent of reprogramming during preimplantation development. Intriguingly, we find that in contrast to ubiquitous imprints, the majority of placenta-specific imprinted DMRs are unmethylated in sperm and all human embryonic stem cells. Therefore, placental-specific imprinting provides evidence for an inheritable epigenetic state that is independent of DNA methylation and the existence of a novel imprinting mechanism at these loci. © 2014 Court et al.
Casanovas T.,Hospitalet Of Llobregat |
Argudo A.,Hospitalet Of Llobregat |
Pena-Cala M.C.,Institute Dinvestigacio Biomedica Of Bellvitge
Transplantation Proceedings | Year: 2011
Introduction: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used in acute and chronic treatment of kidney and heart transplants. There is scarce information regarding its use in liver transplant recipients, although everolimus may be a useful alternative for selected cases. Objective: The objective of this study was to study the clinical, biochemical, and pathological features of patients to whom everolimus was added based upon defined clinical profiles. Study Design: This study was prospective observational ongoing study to evaluate the effectiveness and safety of everolimus alone or in combination with low doses of a calcineurin inhibitor (CNI). Chronic liver transplant recipients without contraindications to everolimus were defined based upon 7 profiles of complications. The initial everolimus dose (0.25 mg every 12 hours) was overlapped during conversion, measuring blood levels and evaluating clinical tolerance. Routine monitoring was performed to obtain immunosuppressant blood levels near the lower limit of the therapeutic range. Results: The 35 patients' including 17 men and 18 women, had an overall mean age of 61 ± 10 years with a mean follow-up of 34 months. The everolimus treatment lasted 20 months (range, 660). The indication for everolimus conversion were as follows: renal insufficiency (45.7%), no response to hepatitis C virus (HCV) treatment (42.9%), autoimmune hepatitis associated with interferon (8.5%), de novo autoimmune hepatitis (25.5%), de novo tumor (37.1%), neurotoxicity (14.3%), or side effects to rapamycin treatment (5.7%). Patients may have presented more than one indication. Effectiveness was assessed based upon improved liver (48.6%) or renal function (31.25% with renal insufficiency) or withdrawal of prednisone (100% of 10 patients receiving prednisone). CNI was withdrawn from 48.6% of patients due to de novo tumors or neurotoxicity. The side effect were as follows: anemia, leukopenia, or thrombocytopenia (11.4%) or dyslipidemia (27.3%). The survival rate was 94.3%. Conclusions: Administration of everolimus to chronic liver transplants enhanced therapeutic options in the long term recipients when applied for predefined clinical indications and administrated with dose adjustments based on serial monitoring of exposure. © 2011 by Elsevier Inc. All rights reserved.
Martinez C.,University of California at San Francisco |
Martinez C.,Institute Dinvestigacio Biomedica Of Bellvitge |
Martinez C.,International University of Catalonia |
Guydish J.,University of California at San Francisco |
And 3 more authors.
Addictive Behaviors | Year: 2015
Introduction: This study investigates factors predicting past year quit attempts among smokers enrolled in substance abuse treatment in New York State. Methods: Data were drawn from two prior cross-sectional surveys conducted among clients treated in 10 randomly selected substance abuse treatment programs. Among 820 clients recruited, 542 self-identified as current smokers, and 485 provided information about their quit attempts. The main outcome was reporting a quit smoking attempt in the past year, dichotomized as quit attempters or non-quit attempters. Univariate and multivariate logistic regression analyses were performed to explore predictors of attempting to quit. Results: Half of substance abuse clients in treatment programs reported a past year quit attempt. Quit attempters were more likely to be in a preparation and contemplation stage of change (preparation: OR = 2.68, 95% CI: 1.51-4.77; contemplation: OR = 2.96 95% CI: 1.61-5.42), reported more positive attitudes toward quitting (OR = 1.49; 95% CI: 1.11-1.99) and received more cessation services than non-quit attempters (OR = 1.21; 95% CI: 1.11-1.99). Conclusions: Addressing patient attitudes about quitting smoking, having clinicians address smoking in the course of addiction treatment, and offering interventions to increase readiness to quit may contribute to increased quit attempts in smokers enrolled in addiction treatment programs. © 2014 Elsevier Ltd.
Combined fiber modifications both to target αvβ 6 and detarget the coxsackievirus-adenovirus receptor improve virus toxicity profiles in vivo but fail to improve antitumoral efficacy relative to adenovirus serotype 5
Coughlan L.,University of Glasgow |
Vallath S.,Queen Mary, University of London |
Gros A.,Institute Dinvestigacio Biomedica Of Bellvitge |
Gimenez-Alejandre M.,Institute Dinvestigacio Biomedica Of Bellvitge |
And 6 more authors.
Human Gene Therapy | Year: 2012
Achieving high-efficiency tumor targeting after systemic delivery is a considerable challenge facing oncolytic gene therapists. Efficient retargeting should be combined with efforts to improve in vivo safety, reduce hepatotoxicity, minimize off-target interactions, and improve antitumoral potency and efficacy. We previously described the successful retargeting of adenovirus serotype 5 (Ad5) to αvβ6, an integrin that is highly overexpressed in numerous human carcinomas. In this study, we have further modified this construct by introducing mutations that ablate coxsackievirus-adenovirus receptor (CAR) binding and putative interactions with factor IX (FIX)/C4b-binding protein (C4BP). We have found that the resulting vector, Ad5-477dlTAYTA20, displays a desirable in vivo safety profile. This vector does not agglutinate human erythrocytes, fails to cause thrombocytopenia after intravenous delivery, has limited induction of proinflammatory cytokines, and results in low-level toxicity (aspartate aminotransferase/alanine aminotransferase) when compared with Ad5-EGFP WT. Furthermore, it has reduced accumulation in Kupffer cells (1â‰hr) and limited hepatocyte transduction at later time points (24 and 96â‰hr). The parental vector, Ad5-EGFPA20, also displayed many of these desirable properties. As a result of the improved safety profile of both A20-modified vectors, we escalated the dose from 2×1010 to 4×1010 viral particles in an antitumoral efficacy study. We observed improvements in reducing percent tumor growth at early time points (96â‰hr) when compared with Ad5-EGFPWT, although increasing the dose did not affect the therapeutic outcome beneficially. On completion of the experiment, we detected increased E1A staining in the tumors of all A20-treated groups and we determined that E1A expression was localized largely within αvβ 6 + tumor cells. However, in spite of apparently efficient tumor transduction, this did not result in enhanced antitumoral efficacy as the virus failed to disseminate effectively throughout the tumor mass, presumably due to physical intratumoral restrictions. This highlights a remaining challenge that needs to be overcome before such vectors can be developed for future cancer gene therapy applications. © 2012, Mary Ann Liebert, Inc.
Mora J.,Hospital Sant Joan Of Deu |
Modak S.,Sloan Kettering Cancer Center |
Cheung N.-K.,Sloan Kettering Cancer Center |
Meyers P.,Sloan Kettering Cancer Center |
And 7 more authors.
Future Oncology | Year: 2015
Desmoplastic small round cell tumor (DSRCT) was proposed as a distinct disease entity by William L Gerald and Juan Rosai in 1991. Over 850 patients have been reported in the medical literature. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene. DSRCT is composed of nests of small round cells with polyphenotypic differentiation, typically a mixture of epithelial, mesenchymal and neural features, surrounded by a prominent desmoplastic stroma. DSRCT has a predilection for adolescent and young adult males, and primarily involves the abdominal cavity and pelvis. Survival is low despite their initial response to multimodal treatment. Most patients relapse with disseminated disease that is unresponsive to further therapy. © 2015 Future Medicine Ltd.
PubMed | Institute Dinvestigacio Biomedica Of Bellvitge
Type: Comparative Study | Journal: Medicina oral, patologia oral y cirugia bucal | Year: 2015
The aim of this study was to evaluate the clinical and microbiological impact of an antibacterial suture (Monocryl Plus) in the surgical removal of I3M.A split-mouth, prospective pilot clinical study was designed involving 20 patients programmed for the surgical removal of I3M. Each side was randomly sutured with Monocryl Plus or silk suture and removed for microbiological study 72 hours and 7 days after surgery. Presence of SSI, wound bleeding and the degree of discomfort associated with each type of suture material (scored by means of a visual analog scale) were evaluated. The level of contamination of each material was observed under the scanning electron microscope.Wound bleeding upon suture removing was slightly greater after 72 hours and 7 days with black silk suture, though the differences were not statistically significant (p=0.752 and p=0.113, respectively). Patient discomfort was very similar with both types of suture material (p=0.861). Only one case of SSI was recorded with black silk suture after 72 hours. Microbiologically, the antibacterial suture showed a lesser presence of microorganisms (p<0.001, at 72h and p=0.033 at 7th day, respectively). The most common bacterial species included grampositive cocci (Streptococcus viridans group, Neisseria spp., Coagulasenegative Staphylococcus and Peptostreptococcus), gramnegative cocci (Veillonella), grampositive Bacilli (Lactobacillus), and gramnegative Bacilli (Prevotella).The greatest antibacterial effect of Monocryl Plus suture was observed after 72 hours. According to most authors, there is no doubt that this antibacterial suture can provide little safety in the control of SSI.