A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors.

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities

Resilience Processes Demonstrated by Young Gay and Bisexual Men Living with HIV: Implications for Intervention

Given the increasing numbers of young gay/bisexual men (YGBM) diagnosed with HIV, it is important to understand the resilience processes enacted by this population in order to develop interventions that support their healthy development. Qualitative interviews were conducted with 54 YGBM (ages 17 to 24; 57% African American, 22% Latino) living with HIV from four geographically diverse clinics in the United States. Resilience processes clustered into four primary thematic areas: (1) engaging in health-promoting cognitive processes; (2) enacting healthy behavioral practices; (3) enlisting social support from others; and (4) empowering other young gay/bisexual men. These data suggest that YGBM living with HIV demonstrate resilience across multiple dimensions, including intrapersonal-level resilience related to individual cognitions and behaviors, as well as interpersonal-level resilience related to seeking support and providing support to others. Implications for the development of culturally-appropriate and strengths-based secondary prevention and other psychosocial interventions for YGBM living with HIV are discussed.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140154/1/apc.2013.0330.pd

Model Independent Predictions of Big Bang Nucleosynthesis from \he4 and \li7: Consistency and Implications

We examine in detail how BBN theory is constrained, and what predictions it can make, when using only the most model-independent observational constraints. We avoid the uncertainties and model-dependencies that necessarily arise when solar neighborhood D and \he3 abundances are used to infer primordial D and \he3 via chemical and stellar evolution models. Instead, we use \he4 and \li7, thoroughly examining the effects of possible systematic errors in each. Via a likelihood analysis, we find near perfect agreement between BBN theory and the most model-independent data. Given this agreement, we then {\it assume} the correctness of BBN to set limits on the single parameter of standard BBN, the baryon-to-photon ratio, and to predict the primordial D and \he3 abundances. We also repeat our analysis including recent measurements of D/H from quasar absorption systems and find that the near perfect agreement between theory and observation of the three isotopes, D, \he4 and \li7 is maintained. These results have strong implications for the chemical and stellar evolution of the light elements, in particular for \he3. In addition, our results (especially if the D/H measurements are confirmed) have implications for the stellar depletion of \li7. Finally, we set limits on the number \nnu\ of neutrino flavors, using an analysis which carefully and systematically includes all available experimental constraints. The value \nnu = 3.0 fits best with BBN and a 95\% CL upper limit of \nnu \la 4 is established.Comment: 28 pages, latex, 10 ps figure

The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells.

Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood brain tumor and remains incurable in about a third of patients. Currently, survivors carry a significant burden of late treatment effects. The p53 tumor suppressor protein plays a crucial role in influencing cell survival in response to cellular stress and while the p53 pathway is considered a key determinant of anti-tumor responses in many tumors, its role in cell survival in MB is much less well defined. Herein, we report that the experimental drug VMY-1-103 acts through induction of a partial DNA damage-like response as well induction of non-survival autophagy. Surprisingly, the genetic or chemical silencing of p53 significantly enhanced the cytotoxic effects of both VMY and the DNA damaging drug, doxorubicin. The inhibition of p53 in the presence of VMY revealed increased late stage apoptosis, increased DNA fragmentation and increased expression of genes involved in apoptosis, including CAPN12 and TRPM8, p63, p73, BIK, EndoG, CIDEB, P27Kip1 and P21cip1. These data provide the groundwork for additional studies on VMY as a therapeutic drug and support further investigations into the intriguing possibility that targeting p53 function may be an effective means of enhancing clinical outcomes in MB

Somatic intronic microsatellite loci differentiate glioblastoma from lower-grade gliomas

Genomic studies of glioma sub-types have amassed new disease specific mutations, yet these only partially explain how mutations are linked to predisposition or progression. We hypothesized that microsatellite variation could expand the understanding of glioma etiology. Furthermore, germline markers for gliomas are typically undetectable; therefore we also hypothesize that the predictability of cancer-associated microsatellite loci in germline DNA may support the current hypothesis of a glioma cell of origin. In this study, “normal” germline exome sequenced DNA from the 1000 Genomes Project (n=390) were compared with exome sequences from germlines of subjects with WHO grade II and III lower-grade glioma (LGG, n=136) and WHO grade IV glioblastoma (GBM, n=252) from The Cancer Genome Atlas to identify microsatellite loci non-randomly associated with glioma. From germline data, we identified 48 GBM-specific loci, 42 Lower-grade glioma specific loci and 29 loci that distinguish GBM from LGG (p≤ 0.01). We then attempted to distinguish WHO grade II glioma (n=67) from GBM resulting in 8 informative loci. Significantly, in all glioma grades, comparisons between tumor and matched germline sequences demonstrated no significant differences in these variants (p≥ 0.01). Therefore, these microsatellite loci are considered to be components of grade-specific signatures for glioma which distinguish germline sequences of individuals with cancer from those of individuals that are “normal”. In order to better understand the significance of these loci, we identified biological processes enriched in genes with these variants. Most strikingly, six helicase genes were enriched in the GBM cohort (p≤ 1.0 x10-3). The preservation of these glioma-specific loci could therefore serve as valuable diagnostic and therapeutic markers; especially since the heterogeneity of tumor cell populations can obscure the identification of mutations preceding a metastatic phenotype

Guidance, Navigation, and Control Performance for the GOES-R Spacecraft

The Geostationary Operational Environmental Satellite-R Series (GOES-R) is the first of the next generation geostationary weather satellites. The series represents a dramatic increase in Earth observation capabilities, with 4 times the resolution, 5 times the observation rate, and 3 times the number of spectral bands. GOES-R also provides unprecedented availability, with less than 120 minutes per year of lost observation time. This paper presents the Guidance Navigation & Control (GN&C) requirements necessary to realize the ambitious pointing, knowledge, and Image Navigation and Registration (INR) objectives of GOES-R. Because the suite of instruments is sensitive to disturbances over a broad spectral range, a high fidelity simulation of the vehicle has been created with modal content over 500 Hz to assess the pointing stability requirements. Simulation results are presented showing acceleration, shock response spectra (SRS), and line of sight (LOS) responses for various disturbances from 0 Hz to 512 Hz. Simulation results demonstrate excellent performance relative to the pointing and pointing stability requirements, with LOS jitter for the isolated instrument platform of approximately 1 micro-rad. Attitude and attitude rate knowledge are provided directly to the instrument with an accuracy defined by the Integrated Rate Error (IRE) requirements. The data are used internally for motion compensation. The final piece of the INR performance is orbit knowledge, which GOES-R achieves with GPS navigation. Performance results are shown demonstrating compliance with the 50 to 75 m orbit position accuracy requirements. As presented in this paper, the GN&C performance supports the challenging mission objectives of GOES-R

HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs).

The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation is dispensable for DNA repair since the non-SUMOylatable E316A mutant is as efficient as wt HIC1 in Comet assays. Upon induction of irreparable DSBs, the ATM-mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2. Moreover, irreparable DSBs strongly increase both the interaction of HIC1 with MTA1 and MTA3 and their binding to the SIRT1 promoter. To characterize the molecular mechanisms sustained by this increased repression potential, we established global expression profiles of BJ-hTERT fibroblasts transfected with HIC1-siRNA or control siRNA and treated or not with etoposide. We identified 475 genes potentially repressed by HIC1 with cell death and cell cycle as the main cellular functions identified by pathway analysis. Among them, CXCL12, EPHA4, TGFβR3 and TRIB2, also known as MTA1 target-genes, were validated by qRT-PCR analyses. Thus, our data demonstrate that HIC1 SUMOylation is important for the transcriptional response to non-repairable DSBs but dispensable for DNA repair

Guidance, Navigation, and Control Performance for the GOES-R Spacecraft

The Geostationary Operational Environmental Satellite-R Series (GOES-R) is the first of the next generation geostationary weather satellites, scheduled for delivery in late 2015 and launch in early 2016. Relative to the current generation of GOES satellites, GOES-R represents a dramatic increase in Earth and solar weather observation capabilities, with 4 times the resolution, 5 times the observation rate, and 3 times the number of spectral bands for Earth observations. GOES-R will also provide unprecedented availability, with less than 120 minutes per year of lost observation time. The Guidance Navigation & Control (GN&C) design requirements to achieve these expanded capabilities are extremely demanding. This paper first presents the pointing control, pointing stability, attitude knowledge, and orbit knowledge requirements necessary to realize the ambitious Image Navigation and Registration (INR) objectives of GOES-R. Because the GOES-R suite of instruments is sensitive to disturbances over a broad spectral range, a high fidelity simulation of the vehicle has been created with modal content over 500 Hz to assess the pointing stability requirements. Simulation results are presented showing acceleration, shock response spectrum (SRS), and line of sight responses for various disturbances from 0 Hz to 512 Hz. These disturbances include gimbal motion, reaction wheel disturbances, thruster firings for station keeping and momentum management, and internal instrument disturbances. Simulation results demonstrate excellent performance relative to the pointing and pointing stability requirements, with line of sight jitter of the isolated instrument platform of approximately 1 micro-rad. Low frequency motion of the isolated instrument platform is internally compensated within the primary instrument. Attitude knowledge and rate are provided directly to the instrument with an accuracy defined by the Integrated Rate Error (IRE) requirements. The allowable IRE ranges from 1 to 18.5 micro-rad, depending upon the time window of interest. The final piece of the INR performance is orbit knowledge. Extremely accurate orbital position is achieved by GPS navigation at Geosynchronous Earth Orbit (GEO). Performance results are shown demonstrating compliance with the 50 to 75 m orbit position accuracy requirements of GOES-R, including during station-keeping and momentum management maneuvers. As shown in this paper, the GN&C performance for the GOES-R series of spacecraft supports the challenging mission objectives of the next generation GEO Earth-observation satellites

Cadmium Exposure and Pancreatic Cancer in South Louisiana

Cadmium has been hypothesized to be a pancreatic carcinogen. We test the hypothesis that cadmium exposure is a risk factor for pancreatic cancer with a population-based case-control study sampled from a population with persistently high rates of pancreatic cancer (south Louisiana). We tested potential dietary and nondietary sources of cadmium for their association with urinary cadmium concentrations which reflect long-term exposure to cadmium due to the accumulation of cadmium in the kidney cortex. Increasing urinary cadmium concentrations were significantly associated with an increasing risk of pancreatic cancer (2nd quartile OR = 3.34, 3rd = 5.58, 4th = 7.70; test for trend P ≤ 0.0001). Potential sources of cadmium exposure, as documented in the scientific literature, found to be statistically significantly associated with increased risk of pancreatic cancer included working as a plumber, pipefitter or welder (OR = 5.88) and high consumption levels of red meat (4th quartile OR = 6.18) and grains (4th quartile OR = 3.38). Current cigarette smoking, at least 80 pack years of smoking, occupational exposure to cadmium and paints, working in a shipyard, and high consumption of grains were found to be statistically significantly associated with increased concentrations of urinary cadmium. This study provides epidemiologic evidence that cadmium is a potential human pancreatic carcinogen