Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors.

PurposeTo determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population.Materials and methodsPatients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated.ResultsTwenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m2/dose; and topotecan 0.8 mg/m2/dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 (p=0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline.ConclusionsThe combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen

A Content Analysis of Catholic School Written Discipline Policies

School discipline has traditionally endorsed the use of exclusionary practices (i.e. suspension and expulsion). Such practices can have a negative short- and long-term impact on student lives, and tend to be enforced disproportionately with certain student populations. Although public school discipline policies have received increased scrutiny in recent years, Catholic school policies have received very little attention. This study presents the results of a content analysis of the written discipline policies of 33 Catholic secondary schools from two dioceses within a major metropolitan area. Results suggest that although variability exists in the types of behaviors included in formal written policies, schools in this sample rely heavily on exclusionary practices as possible consequences to many behaviors, even relatively minor ones. Further, they include positive or restorative consequences minimally, if at all. Suggestions for future research related to discipline practices in Catholic schools are made

A novel SARS-CoV-2 (T Cell) vaccine candidate designed using the iVAX platform

EpiVax, Inc., a Rhode Island-based Biotechnology company, develops vaccines that exploit T cell immunity using the innovative iVAX vaccine antigen design platform. The premise of our strategy is the crucial role T cells play in development of protective antibody and cell-mediated immunity in natural infection. Because vaccines aim to recapitulate protective immune responses in infection, a vaccine should effectively harness T cell immunity to be protective. The significance of T cell immunity is underscored by COVID-19. Efficacy trial and real-world COVID-19 vaccine data for different vaccine modalities show a single vaccine dose is as much as 90% effective starting 14 days post-administration, when 100% of vaccinees have functional CD4 and CD8 T cells but no detectable neutralizing antibodies. As T cells support the SARS-CoV-2 antibody response, clear virus-infected cells, and may be required to block transmission, we set out to develop a vaccine designed by iVAX to enhance T cell immunity and provide long lasting protection. Please click Download on the upper right corner to see the full abstract

An Initial Survey of White Dwarfs in the Sloan Digital Sky Survey

An initial assessment is made of white dwarf and hot subdwarf stars observed in the Sloan Digital Sky Survey. In a small area of sky (190 square degrees), observed much like the full survey will be, 269 white dwarfs and 56 hot subdwarfs are identified spectroscopically where only 44 white dwarfs and 5 hot subdwarfs were known previously. Most are ordinary DA (hydrogen atmosphere) and DB (helium) types. In addition, in the full survey to date, a number of WDs have been found with uncommon spectral types. Among these are blue DQ stars displaying lines of atomic carbon; red DQ stars showing molecular bands of C_2 with a wide variety of strengths; DZ stars where Ca and occasionally Mg, Na, and/or Fe lines are detected; and magnetic WDs with a wide range of magnetic field strengths in DA, DB, DQ, and (probably) DZ spectral types. Photometry alone allows identification of stars hotter than 12000 K, and the density of these stars for 15<g<20 is found to be ~2.2 deg^{-2} at Galactic latitudes 29-62 deg. Spectra are obtained for roughly half of these hot stars. The spectra show that, for 15<g<17, 40% of hot stars are WDs and the fraction of WDs rises to ~90% at g=20. The remainder are hot sdB and sdO stars.Comment: Accepted for AJ; 43 pages, including 12 figures and 5 table

Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

Objective: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals. Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. Results: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. Conclusions: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.Grant support for L. Boyle provided by TL1TR001875.info:eu-repo/semantics/publishedVersio

Genome-Wide Discovery of Somatic Regulatory Variants in Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.&nbsp

Understanding the sex difference in vulnerability to adolescent depression: an examination of child and parent characteristics

This study examined sex differences in risk factors associated with adolescent depression in a large sample of boys and girls. Moderation and mediation explanatory models of the sex difference in likelihood of depression were examined. Findings indicate that the factors associated with depression in adolescent boys and girls are quite similar. All of the variables considered were associated with depression, but sex did not moderate the impact of vulnerability factors on likelihood of depression diagnosis. However, negative self-perceptions in the domains of achievement, global self-worth, and physical appearance partially mediated the relationship between sex and depression. Further, girls had higher levels of positive self-perceptions in interpersonal domains that acted as suppressors and reduced the likelihood of depression in girls. These findings suggest that girls' higher incidence of depression is due in part to their higher levels of negative self-perceptions, whereas positive interpersonal factors serve to protect them from depressive episodes

The taxonomic name resolution service : an online tool for automated standardization of plant names

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in BMC Bioinformatics 14 (2013): 16, doi:10.1186/1471-2105-14-16.The digitization of biodiversity data is leading to the widespread application of taxon names that are superfluous, ambiguous or incorrect, resulting in mismatched records and inflated species numbers. The ultimate consequences of misspelled names and bad taxonomy are erroneous scientific conclusions and faulty policy decisions. The lack of tools for correcting this ‘names problem’ has become a fundamental obstacle to integrating disparate data sources and advancing the progress of biodiversity science. The TNRS, or Taxonomic Name Resolution Service, is an online application for automated and user-supervised standardization of plant scientific names. The TNRS builds upon and extends existing open-source applications for name parsing and fuzzy matching. Names are standardized against multiple reference taxonomies, including the Missouri Botanical Garden's Tropicos database. Capable of processing thousands of names in a single operation, the TNRS parses and corrects misspelled names and authorities, standardizes variant spellings, and converts nomenclatural synonyms to accepted names. Family names can be included to increase match accuracy and resolve many types of homonyms. Partial matching of higher taxa combined with extraction of annotations, accession numbers and morphospecies allows the TNRS to standardize taxonomy across a broad range of active and legacy datasets. We show how the TNRS can resolve many forms of taxonomic semantic heterogeneity, correct spelling errors and eliminate spurious names. As a result, the TNRS can aid the integration of disparate biological datasets. Although the TNRS was developed to aid in standardizing plant names, its underlying algorithms and design can be extended to all organisms and nomenclatural codes. The TNRS is accessible via a web interface at http://tnrs.iplantcollaborative.org/ webcite and as a RESTful web service and application programming interface. Source code is available at https://github.com/iPlantCollaborativeOpenSource/TNRS/ webcite.BJE was supported by NSF grant DBI 0850373 and TR by CSIRO Marine and Atmospheric Research, Australia,. BB and BJE acknowledge early financial support from Conservation International and TEAM who funded the development of early prototypes of taxonomic name resolution. The iPlant Collaborative (http://www.iplantcollaborative.org) is funded by a grant from the National Science Foundation (#DBI-0735191)

Assessment of Virally Vectored Autoimmunity as a Biocontrol Strategy for Cane Toads

BACKGROUND: The cane toad, Bufo (Chaunus) marinus, is one of the most notorious vertebrate pests introduced into Australia over the last 200 years and, so far, efforts to identify a naturally occurring B. marinus-specific pathogen for use as a biological control agent have been unsuccessful. We explored an alternative approach that entailed genetically modifying a pathogen with broad host specificity so that it no longer caused disease, but carried a gene to disrupt the cane toad life cycle in a species specific manner. METHODOLOGY/PRINCIPAL FINDINGS: The adult beta globin gene was selected as the model gene for proof of concept of autoimmunity as a biocontrol method for cane toads. A previous report showed injection of bullfrog tadpoles with adult beta globin resulted in an alteration in the form of beta globin expressed in metamorphs as well as reduced survival. In B. marinus we established for the first time that the switch from tadpole to adult globin exists. The effect of injecting B. marinus tadpoles with purified recombinant adult globin protein was then assessed using behavioural (swim speed in tadpoles and jump length in metamorphs), developmental (time to metamorphosis, weight and length at various developmental stages, protein profile of adult globin) and genetic (adult globin mRNA levels) measures. However, we were unable to detect any differences between treated and control animals. Further, globin delivery using Bohle iridovirus, an Australian ranavirus isolate belonging to the Iridovirus family, did not reduce the survival of metamorphs or alter the form of beta globin expressed in metamorphs. CONCLUSIONS/SIGNIFICANCE: While we were able to show for the first time that the switch from tadpole to adult globin does occur in B. marinus, we were not able to induce autoimmunity and disrupt metamorphosis. The short development time of B. marinus tadpoles may preclude this approach