Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

Apoptosis induction by (+)alpha-tocopheryl succinate in the absence or presence of all-trans retinoic acid and arsenic trioxide in NB4, NB4-R2 and primary APL cells

We analyzed the effect of (+)alpha-tocopheryl succinate (alpha-TOS) alone or associated with arsenic trioxide (ATO) or all-trans retinoid acid (ATRA) in acute promyelocytic leukemia (APL). alpha-TOS-induced apoptosis in APL clinical samples and in ATRA-sensitive (NB4) and ATRA-resistant (NB4-R2) APL cell lines. The effective dose 50% (ED-50) was calculated to be 71 and 58 mu M, for NB4 and NB4-R2, respectively. a-TOS neither induced nor modified ATRA-induced differentiation of APL cells, and did not affect the proliferation and differentiation of normal CD34(+) hematopoietic progenitors in methylcellulose assays. alpha-TOS exerted a moderate antagonistic effect to ATO-induced apoptosis when treatment was done simultaneously but when alpha-TOS was added 24 h after ATO, an additive effect was observed. Our results support the concept of alpha-TOS as an anti-leukemic compound which spares normal hematopoiesis. (C) 2008 Elsevier Ltd. All rights reserved.

Phosphoinositide-3 Kinase gamma Activity Contributes to Sepsis and Organ Damage by Altering Neutrophil Recruitment

Rationale Sepsis is a leading cause of death in the intensive care unit, characterized by a systemic inflammatory response (SIRS) and bacterial infection, which can often induce multiorgan damage and failure. Leukocyte recruitment, required to limit bacterial spread, depends on phosphoinositide-3 kinase gamma (PI3K gamma) signaling in vitro; however, the role of this enzyme in polymicrobial sepsis has remained unclear. Objectives: This study aimed to determine the specific role of the kinase activity of PI3K gamma in the pathogenesis of sepsis and multiorgan damage. Methods. PI3K gamma wild-type, knockout, and kinase-dead mice were exposed to cecal ligation and perforation induced sepsis and assessed for survival; pulmonary, hepatic, and cardiovascular damage; coagulation derangements; systemic inflammation; bacterial spread; and neutrophil recruitment. Additionally, wild-type mice were treated either before or after the onset of sepsis with a PI3K gamma inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread. Measurements and Main Results: Both genetic and pharmaceutical PI3K gamma kinase inhibition significantly improved survival, reduced multiorgan damage, and limited bacterial decompartmentalization, while modestly affecting SIRS. Protection resulted from both neutrophil-independent mechanisms, involving improved cardiovascular function, and neutrophil-dependent mechanisms, through reduced susceptibility to neutrophil migration failure during severe sepsis by maintaining neutrophil surface expression of the chemokine receptor, CXCR2. Furthermore, PI3K gamma pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock. Conclusions: This study establishes PI3K gamma as a key molecule in the pathogenesis of septic infection and the transition from SIRS to organ damage and identifies it as a novel possible therapeutic target.

Validity of a Brazilian version of the Zung self-rating depression scale for screening of depression in patients with Parkinson`s disease

Introduction: Parkinson`s disease (PD) is a neurodegenerative disorder with prominent motor manifestations and many other non-motor symptoms that significantly decrease quality-of-life and are frequently under-recognized, for example depression. Objective: To study the validity of a Brazilian version of the Zung Self-rating Depression Scale (SDS) for the diagnosis of depression in patients with PD. Methods: We evaluated 78 consecutive non demented patients over the age of 40 with diagnosis of PD at a Movement Disorders Outpatient Clinic, who could read and understand questionnaires. They completed the SIDS and the Geriatric Depression Scale with 15 items (GDS-15). The diagnosis of depression was made after a structured clinical interview based on DSM-IV criteria for the diagnosis of major depression (SCID-CV). Results: The prevalence of major depression was 23.1%. Cronbach`s alpha was 0.73 and the area under the ROC curve was 0.93 for the SDS. The score index of 55 had a sensitivity of 88.9% and a specificity of 83.3% for the diagnosis of depression. The total scores of the SDS and GDS-15 were highly correlated (0.652, p < 0.0001) and correlated weakly with the scores of a motor scale. Discussion: The SIDS is a valid too] for screening depression in patients with PD since the specific SDS index of 55 is adopted. Two shortened versions could be used with good results. (C) 2009 Published by Elsevier Ltd.

The Genome Sequence of Taurine Cattle: A Window to Ruminant Biology and Evolution

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.

Xenooplasmic Transfer between Buffalo and Bovine Enables Development of Homoplasmic Offspring

Nuclear-mitochondrial incompatibilities may be responsible for the development failure reported in embryos and fetuses produced by interspecies somatic cell nuclear transfer (iSCNT). Herein we performed xenooplasmic transfer (XOT) by introducing 10 to 15% of buffalo ooplasm into bovine zygotes to assess its effect on the persistence of buffalo mitochondrial DNA (mtDNA). Blastocyst rates were not compromised by XOT in comparison to both in vitro fertilized embryos and embryos produced by transfer of bovine ooplasm into bovine zygotes. Moreover, offspring were born after transfer of XOT embryos to recipient cows. Buffalo mtDNA introduced in zygotes was still present at the blastocyst stage (8.3 vs. 9.3%, p = 0.11), indicating unaltered heteroplasmy during early development. Nonetheless, no vestige of buffalo mtDNA was found in offspring, indicating a drift to homoplasmy during later stages of development. In conclusion, we show that the buffalo mtDNA introduced by XOT into a bovine zygote do not compromise embryo development. On the other hand, buffalo mtDNA was not inherited by offspring indicating a possible failure in the process of interspecies mtDNA replication.

Deposition of Lead and Cadmium Released by Cigarette Smoke in Dental Structures and Resin Composite

Cigarette smoke is a significant source of cadmium, lead, and toxic elements, which are absorbed into the human organism. In this context, the aim of this study was to investigate in vitro the presence of toxic elements, cadmium, and lead deriving from cigarette smoke in the resin composite, dentine, and dental enamel. Eight cylindrical specimens were fabricated from resin composite, bovine enamel, and root dentin fragments that were wet ground and polished with abrasive paper to obtain sections with 6-mm diameter and 2-mm thickness. All specimens were exposed to the smoke of 10 cigarettes/day during 8 days. After the simulation of the cigarette smoke, the specimens were examined with scanning electron microscopy (SEM) and the energy-dispersive X-ray analysis. In the photomicrographic analysis in SEM, no morphological alterations were found; however, the microanalysis identified the presence of cadmium, arsenic, and lead in the different specimens. These findings suggest that the deposition of these elements derived from cigarette smoke could be favored by dental structures and resin composite. Microsc. Res. Tech. 74:287-291, 2011. (C) 2010 Wiley-Liss, Inc.