Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2

Multiple endocrine neoplasia type 2 is an inherited cancer syndrome characterized by tumors of thyroid and adrenal tissues. Germline mutations of the REarranged during Transfection (RET) proto-oncogene, leading to its unregulated activation, are the underlying cause of this disease. Multiple endocrine neoplasia type 2 has been a model in clinical cancer genetics, demonstrating how knowledge of the genetic basis can shape the diagnosis and treatment of the disease. Here, we discuss the nature and effects of the most common recurrent mutations of RET found in multiple endocrine neoplasia type 2. Current understanding of the molecular mechanisms of RET mutations and how they alter the structure and function of the RET protein leading to its aberrant activation, and the effects on RET localization and signaling are described

Neurodevelopmental Correlates of True and False Recognition

The Deese/Roediger–McDermott (DRM) false-memory effect has been extensively documented in psychological research. People falsely recognize critical lures or nonstudied items that are semantically associated with studied items. Behavioral research has provided evidence for age-related increases in the DRM false-recognition effect. The present event-related functional magnetic resonance imaging study was aimed at investigating neurodevelopmental changes in brain regions associated with true- and false-memory recognition in 8-year olds, 12-year olds, and adults. Relative to 8-year olds, adults correctly endorsed more studied items as “old” but also mistakenly endorsed more critical lures. Age-related increases in recollection were associated with changes in the medial temporal lobe (MTL) activation profile. Additionally, age-related increases in false alarms (FAs) to semantically related lures were associated with changes in the activation profile of left ventrolateral prefrontal cortex, a region associated with semantic processing. Additional regions exhibiting age-related changes include posterior parietal and anterior prefrontal cortices. In summary, concomitant changes in the MTL, prefrontal cortex, and parietal cortex underlie developmental increases in true and false recognition during childhood and adolescence

Selecting for BRCA1 testing using a combination of homogeneous selection criteria and immunohistochemical characteristics of breast cancers

<p>Abstract</p> <p>Background</p> <p>BRCA1 gene-related tumours are more frequently estrogen receptor (ER) and progesterone receptor (PR) negative with a lower prevalence of human epidermal growth factor receptor 2 (HER2) overexpression or amplification. We evaluated the effectiveness of a combination of homogeneously selected criteria and immunohistochemical (IHC) characteristics of Familial Breast Cancers (FBCs) in detecting BRCA1 mutation carriers.</p> <p>Methods</p> <p>Primary breast tumours from 93 FBC patients defined by specific eligibility criteria, based on personal and familial tumour history, were evaluated by Allred's method. The BRCA1 molecular analysis, including Multiplex Ligation-dependent Probe Amplification (MLPA), was considered as the gold standard assay.</p> <p>Results</p> <p>A total of 10 BRCA1 pathogenetic mutations was found. With the exclusion of the tumours characterized by double positive receptorial status and/or strong HER2 positivity (3+), we identified 22 patients, 10 of whom resulted as BRCA1 mutation carriers. The sensitivity, specificity, positive and negative predictive values were 100%, 83.3%, 45.4% and 100% respectively.</p> <p>Conclusion</p> <p>Our findings suggest that the IHC analysis by Allred's method improves our ability to select patients for BRCA1 testing.</p

Histone Deacetylase Inhibition Enhances Self Renewal and Cardioprotection by Human Cord Blood-Derived CD34+ Cells

Abstract BACKGROUND: Use of peripheral blood- or bone marrow-derived progenitors for ischemic heart repair is a feasible option to induce neo-vascularization in ischemic tissues. These cells, named Endothelial Progenitors Cells (EPCs), have been extensively characterized phenotypically and functionally. The clinical efficacy of cardiac repair by EPCs cells remains, however, limited, due to cell autonomous defects as a consequence of risk factors. The devise of "enhancement" strategies has been therefore sought to improve repair ability of these cells and increase the clinical benefit. PRINCIPAL FINDINGS: Pharmacologic inhibition of histone deacetylases (HDACs) is known to enhance hematopoietic stem cells engraftment by improvement of self renewal and inhibition of differentiation in the presence of mitogenic stimuli in vitro. In the present study cord blood-derived CD34(+) were pre-conditioned with the HDAC inhibitor Valproic Acid. This treatment affected stem cell growth and gene expression, and improved ischemic myocardium protection in an immunodeficient mouse model of myocardial infarction. CONCLUSIONS: Our results show that HDAC blockade leads to phenotype changes in CD34(+) cells with enhanced self renewal and cardioprotection

Two cases of monomicrobial intraabdominal abscesses due to KPC - 3 Klebsiella pneumoniae ST258 clone

<p>Abstract</p> <p>Background</p> <p>Knowledge of the etiology of pyogenic liver and pancreatic abscesses is an important factor in determining the success of combined surgical and antibiotic treatment. Literature shows geographical variations in the prevalence and distribution of causative organisms, and the spread of <it>Klebsiella pneumoniae </it>carbapenemase-producing bacteria is an emerging cause of abdominal infections.</p> <p>Case presentation</p> <p>We herein describe two cases of intra-abdominal abscesses due to monomicrobial infection by <it>Klebsiella pneumoniae </it>Sequence Type 258 producing <it>K. pneumoniae </it>carbapenemase 3 (KPC-Kp). In case 1, a 50-year-old HIV-negative Italian woman with chronic pancreatitis showed infection of a pancreatic pseudocystic lesion caused by KPC-Kp. In case 2, a 64-year-old HIV- negative Italian woman with pancreatic neoplasm and liver metastases developed a liver abscess due to KPC after surgery. Both women were admitted to our hospital but to different surgical units. The clonal relationship between the two isolates was investigated by pulsed-field gel electrophoresis (PFGE). In case 2, the patient was already colonized at admission and inter-hospital transmission of the pathogen was presumed. A long-term combination regimen of colistin with tigecycline and percutaneous drainage resulted in full recovery and clearance of the multidrug-resistant (MDR) pathogen.</p> <p>Conclusions</p> <p>Timely microbiological diagnosis, the combined use of new and old antibiotics and radiological intervention appeared to be valuable in managing these serious conditions. The emergence and dissemination of MDR organisms is posing an increasing challenge for physicians to develop new therapeutic strategies and control and prevention frameworks.</p

Astrophysical Tests of Dark Matter with Maunakea Spectroscopic Explorer

We discuss how astrophysical observations with the Maunakea Spectroscopic Explorer (MSE), a high-multiplexity (about 4300 fibers), wide field-of-view (1.5 square degree), large telescope aperture (11.25 m) facility, can probe the particle nature of dark matter. MSE will conduct a suite of surveys that will provide critical input for determinations of the mass function, phase-space distribution, and internal density profiles of dark matter halos across all mass scales. N-body and hydrodynamical simulations of cold, warm, fuzzy and self-interacting dark matter suggest that non-trivial dynamics in the dark sector could have left an imprint on structure formation. Analysed within these frameworks, the extensive and unprecedented datasets produced by MSE will be used to search for deviations away from cold and collisionless dark matter model. MSE will provide an improved estimate of the local density of dark matter, critical for direct detection experiments, and will improve estimates of the J-factor for indirect searches through self-annihilation or decay into Standard Model particles. MSE will determine the impact of low mass substructures on the dynamics of Milky Way stellar streams in velocity space, and will allow for estimates of the density profiles of the dark matter halos of Milky Way dwarf galaxies using more than an order of magnitude more tracers. In the low redshift Universe, MSE will provide critical redshifts to pin down the luminosity functions of vast numbers of satellite systems, and MSE will be an essential component of future strong lensing measurements to constrain the halo mass function. Across nearly all mass scales, the improvements offered by MSE, in comparison to other facilities, are such that the relevant analyses are limited by systematics rather than statistics.Comment: 44 pages, 19 figures. To appear as a chapter for "The Detailed Science Case for the Maunakea Spectroscopic Explorer, 2019

Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ.

Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression

The ACS Virgo Cluster Survey. VI. Isophotal Analysis and the Structure of Early-Type Galaxies

(Abridged) We present a detailed analysis of the morphology, isophotal parameters and surface brightness profiles for 100 early-type members of the Virgo Cluster, from dwarfs (M_B = -15.1 mag) to giants (M_B = -21.8 mag). Each galaxy has been imaged in two filters, closely resembling the Sloan g and z passbands, using the Advanced Camera for Surveys on board the Hubble Space Telescope. Dust and complex morphological structures are common, with kiloparsec-scale stellar disks, bars, and nuclear stellar disks seen in 60% of galaxies with intermediate luminosity (-20 < M_B < -17), and dust seen in 42% of galaxies brighter than M_B = -18.9 mag. Dust morphologies range from faint wisps and patches on tens of parsec scales, to regular, highly organized kpc-scale dust disks, often showing evidence of recent star formation. Surface brightness profiles and isophotal parameters are derived typically within 8 kpc from the center for the brightest galaxies, and 1.5 kpc for the faintest systems, with a resolution (FWHM) of 7 pc. Based on a parametrization of the surface brightness profiles in terms of a Sersic or core-Sersic model, we find that 1) there is no evidence of a bimodal behavior of the slope, gamma, of the profile in the innermost regions; 2) although the brightest galaxies have shallow inner profiles, the shallowest profiles (lowest gamma values) are found in faint dwarf systems; 3) the widely adopted separation of early-type galaxies between "core" and "power-law" types, which had originally been prompted by the claim of a clear bimodal distribution of gamma values, is untenable; and 4) there is no evidence of a structural dichothomy between dwarf and regular ellipticals.Comment: Accepted by The Astrophysical Journal Supplement Series. This submission contains low resolution figures; we strongly recommend downloading the original version of the paper from the ACSVCS project website: http://www.cadc.hia.nrc.gc.ca/community/ACSVCS/publications.html#acsvcs

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor