Targeting the p53 Pathway in Ewing Sarcoma

The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas. This paper summarizes recent insights into the functional capabilities and regulation of p53 in Ewing Sarcoma, with a particular focus on the cross-talk between p53 and the EWS-FLI1 gene rearrangement frequently associated with this disease. The development of several activators of p53 is discussed, with recent evidence demonstrating the potential of small molecule p53 activators as a promising systemic therapeutic approach for the treatment of Ewing Sarcomas with wild-type p53

An Exact Solution to O(26) Sigma Model coupled to 2-D Gravity

By a mapping to the bosonic string theory, we present an exact solution to the O(26) sigma model coupled to 2-D quantum gravity. In particular, we obtain the exact gravitational dressing to the various matter operators classified by the irreducible representations of O(26). We also derive the exact form of the gravitationally modified beta function for the original coupling constant $e^2$. The relation between our exact solution and the asymptotic solution given in ref[3] is discussed in various aspects.Comment: 10 pages, pupt-144

p53 continues to surprise: High levels of p53 can suppress apoptosis

David F. Calle

Plasmodium Infection Promotes Genomic Instability and AID-Dependent B Cell Lymphoma

SummaryChronic infection with Plasmodium falciparum was epidemiologically associated with endemic Burkitt’s lymphoma, a mature B cell cancer characterized by chromosome translocation between the c-myc oncogene and Igh, over 50 years ago. Whether infection promotes B cell lymphoma, and if so by which mechanism, remains unknown. To investigate the relationship between parasitic disease and lymphomagenesis, we used Plasmodium chabaudi (Pc) to produce chronic malaria infection in mice. Pc induces prolonged expansion of germinal centers (GCs), unique compartments in which B cells undergo rapid clonal expansion and express activation-induced cytidine deaminase (AID), a DNA mutator. GC B cells elicited during Pc infection suffer widespread DNA damage, leading to chromosome translocations. Although infection does not change the overall rate, it modifies lymphomagenesis to favor mature B cell lymphomas that are AID dependent and show chromosome translocations. Thus, malaria infection favors mature B cell cancers by eliciting protracted AID expression in GC B cells.PaperCli

The Oncogenic role of miR-155 in breast cancer

miR-155 is an oncogenic miRNA with well described roles in leukemia. However, additional roles of miR-155 in breast cancer progression have recently been described. A thorough literature search was conducted to review all published data to date, examining the role of miR-155 in breast cancer. Data on all validated miR-155 target genes was collated to identify biologic pathways relevant to miR-155 and breast cancer progression. Publications describing the clinical relevance, functional characterization, and regulation of expression of miR-155 in the context of breast cancer are reviewed. A total of 147 validated miR-155 target genes were identified from the literature. Pathway analysis of these genes identified likely roles in apoptosis, differentiation, angiogenesis, proliferation, and epithelial-mesenchymal transition. The large number of validated miR-155 targets presented here provide many avenues of interest as to the clinical potential of miR-155. Further investigation of these target genes will be required to elucidate the specific mechanisms and functions of miR-155 in breast cancer. This is the first review examining the role of miR-155 in breast cancer progression. The collated data of target genes and biologic pathways of miR-155 identified in this review suggest new avenues of research for this oncogenic miRNA.Sam Mattiske, Rachel J. Suetani, Paul M. Neilsen, and David F. Calle

A First and Second Law for Nonequilibrium Thermodynamics: Maximum Entropy Derivation of the Fluctuation-Dissipation Theorem and Entropy Production Functionals

A theory for non-equilibrium systems is derived from a maximum entropy approach similar in spirit to the equilibrium theory given by Gibbs. Requiring Hamilton's principle of stationary action to be satisfied on average during a trajectory, we add constraints on the transition probability distribution which lead to a path probability of the Onsager-Machlup form. Additional constraints derived from energy and momentum conservation laws then introduce heat exchange and external driving forces into the system, with Lagrange multipliers related to the temperature and pressure of an external thermostatic system. The result is a fully time-dependent, non-local description of a nonequilibrium ensemble. Detailed accounting of the energy exchange and the change in information entropy of the central system then provides a description of the entropy production which is not dependent on the specification or existence of a steady-state or on any definition of thermostatic variables for the central system. These results are connected to the literature by showing a method for path re-weighting, creation of arbitrary fluctuation theorems, and by providing a simple derivation of Jarzynski relations referencing a steady-state. In addition, we identify path free energy and entropy (caliber) functionals which generate a first law of nonequilibrium thermodynamics by relating changes in the driving forces to changes in path averages. Analogous to the Gibbs relations, the variations in the path averages yield fluctuation-dissipation theorems. The thermodynamic entropy production can also be stated in terms of the caliber functional, resulting in a simple proof of our microscopic form for the Clausius statement. We find that the maximum entropy route provides a clear derivation of the path free energy functional, path-integral, Langevin, Brownian, and Fokker-Planck statements of nonequilibrium processes.Comment: 35 page

Construction of an ~700-kb transcript map around the Familial Mediterranean Fever locus on human chromosome 16p13.3

We used a combination of cDNA selection, exon amplification, and computational prediction from genomic sequence to isolate transcribed sequences from genomic DNA surrounding the familial Mediterranean fever (FMF) locus. Eighty-seven kb of genomic DNA around D16S3370, a marker showing a high degree of linkage disequilibrium with FMF, was sequenced to completion, and the sequence annotated. A transcript map reflecting the minimal number of genes encoded within the ∼700 kb of genomic DNA surrounding the FMF locus was assembled. This map consists of 27 genes with discreet messages detectable on Northerns, in addition to three olfactory-receptor genes, a cluster of 18 tRNA genes, and two putative transcriptional units that have typical intron–exon splice junctions yet do not detect messages on Northerns. Four of the transcripts are identical to genes described previously, seven have been independently identified by the French FMF Consortium, and the others are novel. Six related zinc-finger genes, a cluster of tRNAs, and three olfactory receptors account for the majority of transcribed sequences isolated from a 315-kb FMF central region (betweenD16S468/D16S3070 and cosmid 377A12). Interspersed among them are several genes that may be important in inflammation. This transcript map not only has permitted the identification of the FMF gene (MEFV), but also has provided us an opportunity to probe the structural and functional features of this region of chromosome 16.Michael Centola, Xiaoguang Chen, Raman Sood, Zuoming Deng, Ivona Aksentijevich, Trevor Blake, Darrell O. Ricke, Xiang Chen, Geryl Wood, Nurit Zaks, Neil Richards, David Krizman, Elizabeth Mansfield, Sinoula Apostolou, Jingmei Liu, Neta Shafran, Anil Vedula, Melanie Hamon, Andrea Cercek, Tanaz Kahan, Deborah Gumucio, David F. Callen, Robert I. Richards, Robert K. Moyzis, Norman A. Doggett, Francis S. Collins, P. Paul Liu, Nathan Fischel-Ghodsian and Daniel L. Kastne

The next detectors for gravitational wave astronomy

This paper focuses on the next detectors for gravitational wave astronomy which will be required after the current ground based detectors have completed their initial observations, and probably achieved the first direct detection of gravitational waves. The next detectors will need to have greater sensitivity, while also enabling the world array of detectors to have improved angular resolution to allow localisation of signal sources. Sect. 1 of this paper begins by reviewing proposals for the next ground based detectors, and presents an analysis of the sensitivity of an 8 km armlength detector, which is proposed as a safe and cost-effective means to attain a 4-fold improvement in sensitivity. The scientific benefits of creating a pair of such detectors in China and Australia is emphasised. Sect. 2 of this paper discusses the high performance suspension systems for test masses that will be an essential component for future detectors, while sect. 3 discusses solutions to the problem of Newtonian noise which arise from fluctuations in gravity gradient forces acting on test masses. Such gravitational perturbations cannot be shielded, and set limits to low frequency sensitivity unless measured and suppressed. Sects. 4 and 5 address critical operational technologies that will be ongoing issues in future detectors. Sect. 4 addresses the design of thermal compensation systems needed in all high optical power interferometers operating at room temperature. Parametric instability control is addressed in sect. 5. Only recently proven to occur in Advanced LIGO, parametric instability phenomenon brings both risks and opportunities for future detectors. The path to future enhancements of detectors will come from quantum measurement technologies. Sect. 6 focuses on the use of optomechanical devices for obtaining enhanced sensitivity, while sect. 7 reviews a range of quantum measurement options

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Association of a de novo 16q copy number variant with a phenotype that overlaps with Lenz microphthalmia and Townes-Brocks syndromes

<p>Abstract</p> <p>Background</p> <p>Anophthalmia and microphthalmia are etiologically and clinically heterogeneous. Lenz microphthalmia is a syndromic form that is typically inherited in an X-linked pattern, though the causative gene mutation is unknown. Townes-Brocks syndrome manifests thumb anomalies, imperforate anus, and ear anomalies. We present a 13-year-old boy with a syndromic microphthalmia phenotype and a clinical diagnosis of Lenz microphthalmia syndrome.</p> <p>Case Presentation</p> <p>The patient was subjected to clinical and molecular evaluation, including array CGH analysis. The clinical features included left clinical anophthalmia, right microphthalmia, anteriorly placed anus with fistula, chordee, ventriculoseptal defect, patent ductus arteriosus, posteriorly rotated ears, hypotonia, growth retardation with delayed bone age, and mental retardation. The patient was found to have an approximately 5.6 Mb deletion of 16q11.2q12.1 by microarray based-comparative genomic hybridization, which includes the <it>SALL1 </it>gene, which causes Townes-Brocks syndrome.</p> <p>Conclusions</p> <p>Deletions of 16q11.2q12.2 have been reported in several individuals, although those prior reports did not note microphthalmia or anophthalmia. This region includes <it>SALL1</it>, which causes Townes-Brocks syndrome. In retrospect, this child has a number of features that can be explained by the <it>SALL1 </it>deletion, although it is not clear if the microphthalmia is a rare feature of Townes-Brocks syndrome or caused by other mechanisms. These data suggest that rare copy number changes may be a cause of syndromic microphthalmia allowing a personalized genomic medicine approach to the care of patients with these aberrations.</p