Genome-Wide Associations of Signaling Pathways in Glioblastoma Multiforme

Background: eQTL analysis is a powerful method that allows the identification of causal genomic alterations, providing an explanation of expression changes of single genes. However, genes mediate their biological roles in groups rather than in isolation, prompting us to extend the concept of eQTLs to whole gene pathways. Methods: We combined matched genomic alteration and gene expression data of glioblastoma patients and determined associations between the expression of signaling pathways and genomic copy number alterations with a non-linear machine learning approach. Results: Expectedly, over-expressed pathways were largely associated to tag-loci on chromosomes with signature alterations. Surprisingly, tag-loci that were associated to under-expressed pathways were largely placed on other chromosomes, an observation that held for composite effects between chromosomes as well. Indicating their biological relevance, identified genomic regions were highly enriched with genes having a reported driving role in gliomas. Furthermore, we found pathways that were significantly enriched with such driver genes. Conclusions: Driver genes and their associated pathways may represent a functional core that drive the tumor emergence and govern the signaling apparatus in GBMs. In addition, such associations may be indicative of drug combinations for the treatment of brain tumors that follow similar patterns of common and diverging alterations

Involvement of MicroRNA Families in Cancer

Collecting representative sets of cancer microRNAs (miRs) from the literature we show that their corresponding families are enriched in sets of highly interacting miR families. Targeting cancer genes on a statistically significant level, such cancer miR families strongly intervene with signaling pathways that harbor numerous cancer genes. Clustering miR family-specific profiles of pathway intervention, we found that different miR families share similar interaction patterns. Resembling corresponding patterns of cancer miRs families, such interaction patterns may indicate a miR family’s potential role in cancer. As we find that the number of targeted cancer genes is a naı¨ve proxy for a cancer miR family, we design a simple method to predict candidate miR families based on gene-specific interaction profiles. Assessing the impact of miR families to distinguish between (non-)cancer genes, we predict a set of 84 potential candidate families, including 75% of initially collected cancer miR families. Further confirming their relevance, predicted cancer miR families are significantly indicated in increasing, non-random numbers of tumor types

Large-Scale RNA Interference Screening in Mammalian Cells Identifies Novel Regulators of Mutant Huntingtin Aggregation

In polyglutamine (polyQ) diseases including Huntington's disease (HD), mutant proteins containing expanded polyQ stretch form aggregates in neurons. Genetic or RNAi screenings in yeast, C. elegans or Drosophila have identified multiple genes modifying polyQ aggregation, a few of which are confirmed effective in mammals. However, the overall molecular mechanism underlying polyQ protein aggregation in mammalian cells still remains obscure. We here perform RNAi screening in mouse neuro2a cells to identify mammalian modifiers for aggregation of mutant huntingtin, a causative protein of HD. By systematic cell transfection and automated cell image analysis, we screen ∼12000 shRNA clones and identify 111 shRNAs that either suppress or enhance mutant huntingtin aggregation, without altering its gene expression. Classification of the shRNA-targets suggests that genes with various cellular functions such as gene transcription and protein phosphorylation are involved in modifying the aggregation. Subsequent analysis suggests that, in addition to the aggregation-modifiers sensitive to proteasome inhibition, some of them, such as a transcription factor Tcf20, and kinases Csnk1d and Pik3c2a, are insensitive to it. As for Tcf20, which contains polyQ stretches at N-terminus, its binding to mutant huntingtin aggregates is observed in neuro2a cells and in HD model mouse neurons. Notably, except Pik3c2a, the rest of the modifiers identified here are novel. Thus, our first large-scale RNAi screening in mammalian system identifies previously undescribed genetic players that regulate mutant huntingtin aggregation by several, possibly mammalian-specific mechanisms

An Early and Comprehensive Millimetre and Centimetre Wave and X-ray Study of SN 2011dh: a Non-Equipartition Blast Wave Expanding into a Massive Stellar Wind

Only a handful of supernovae (SNe) have been studied in multiwavelengths from the radio to X-rays, starting a few days after the explosion. The early detection and classification of the nearby Type IIb SN 2011dh/PTF 11eon in M51 provides a unique opportunity to conduct such observations. We present detailed data obtained at one of the youngest phase ever of a core-collapse SN (days 3–12 after the explosion) in the radio, millimetre and X-rays; when combined with optical data, this allows us to explore the early evolution of the SN blast wave and its surroundings. Our analysis shows that the expanding SN shock wave does not exhibit equipartition (ϵe/ϵB ∼ 1000), and is expanding into circumstellar material that is consistent with a density profile falling like R−2. Within modelling uncertainties we find an average velocity of the fast parts of the ejecta of 15 000 ± 1800 km s−1, contrary to previous analysis. This velocity places SN 2011dh in an intermediate blast wave regime between the previously defined compact and extended SN Type IIb subtypes. Our results highlight the importance of early (∼1 d) high-frequency observations of future events. Moreover, we show the importance of combined radio/X-ray observations for determining the microphysics ratio ϵe/ϵB

Comparative oncology: The paradigmatic example of canine and human mast cell neoplasms

In humans, advanced mast cell (MC) neoplasms are rare malignancies with a poor prognosis. Only a few preclinical models are available, and current treatment options are limited. In dogs, MC neoplasms are the most frequent malignant skin tumours. Unlike low-grade MC neoplasms, high-grade MC disorders usually have a poor prognosis with short survival. In both species, neoplastic MCs display activating KIT mutations, which are considered to contribute to disease evolution. Therefore, tyrosine kinase inhibitors against KIT have been developed. Unfortunately, clinical responses are unpredictable and often transient, which remains a clinical challenge in both species. Therefore, current efforts focus on the development of new improved treatment strategies. The field of comparative oncology may assist in these efforts and accelerate human and canine research regarding diagnosis, prognostication, and novel therapies. In this article, we review the current status of comparative oncology approaches and perspectives in the field of MC neoplasms

The merit of high-frequency data in portfolio allocation

This paper addresses the open debate about the usefulness of high-frequency (HF) data in large-scale portfolio allocation. Daily covariances are estimated based on HF data of the S&P 500 universe employing a blocked realized kernel estimator. We propose forecasting covariance matrices using a multi-scale spectral decomposition where volatilities, correlation eigenvalues and eigenvectors evolve on different frequencies. In an extensive out-of-sample forecasting study, we show that the proposed approach yields less risky and more diversified portfolio allocations as prevailing methods employing daily data. These performance gains hold over longer horizons than previous studies have shown

An Early & Comprehensive Millimeter and Centimeter Wave and X-ray Study of Supernova 2011dh: A Non-Equipartition Blastwave Expanding into A Massive Stellar Wind

Only a handful of supernovae (SNe) have been studied in multi-wavelength from radio to X-rays, starting a few days after explosion. The early detection and classification of the nearby type IIb SN2011dh/PTF11eon in M51 provides a unique opportunity to conduct such observations. We present detailed data obtained at the youngest phase ever of a core-collapse supernova (days 3 to 12 after explosion) in the radio, millimeter and X-rays; when combined with optical data, this allows us to explore the early evolution of the SN blast wave and its surroundings. Our analysis shows that the expanding supernova shockwave does not exhibit equipartition (e_e/e_B ~ 1000), and is expanding into circumstellar material that is consistent with a density profile falling like R^-2. Within modeling uncertainties we find an average velocity of the fast parts of the ejecta of 15,000 +/- 1800 km/s, contrary to previous analysis. This velocity places SN 2011dh in an intermediate blast-wave regime between the previously defined compact and extended SN IIb subtypes. Our results highlight the importance of early (~ 1 day) high-frequency observations of future events. Moreover, we show the importance of combined radio/X-ray observations for determining the microphysics ratio e_e/e_B.Comment: 9 pages, 5 figures, submitted to Ap

Fever and hypothermia represent two populations of sepsis patients and are associated with outside temperature

Abstract Background Fever and hypothermia have been observed in septic patients. Their influence on prognosis is subject to ongoing debates. Methods We did a secondary analysis of a large clinical dataset from a quality improvement trial. A binary logistic regression model was calculated to assess the association of the thermal response with outcome and a multinomial regression model to assess factors associated with fever or hypothermia. Results With 6542 analyzable cases we observed a bimodal temperature response characterized by fever or hypothermia, normothermia was rare. Hypothermia and high fever were both associated with higher lactate values. Hypothermia was associated with higher mortality, but this association was reduced after adjustment for other risk factors. Age, community-acquired sepsis, lower BMI and lower outside temperatures were associated with hypothermia while bacteremia and higher procalcitonin values were associated with high fever. Conclusions Septic patients show either a hypothermic or a fever response. Whether hypothermia is a maladaptive response, as indicated by the higher mortality in hypothermic patients, or an adaptive response in patients with limited metabolic reserves under colder environmental conditions, remains an open question. Trial registration The original trial whose dataset was analyzed was registered at ClinicalTrials.gov (NCT01187134) on August 23, 2010, the first patient was included on July 1, 2011

Running of the heavy quark production current and 1/k potential in QCD

The 1/k contribution to the heavy quark potential is first generated at one loop order in QCD. We compute the two loop anomalous dimension for this potential, and find that the renormalization group running is significant. The next-to-leading-log coefficient for the heavy quark production current near threshold is determined. The velocity renormalization group result includes the alpha_s^3 ln^2(alpha_s) ``non-renormalization group logarithms'' of Kniehl and Penin.Comment: 30 pages, journal versio