Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model

Rhabdomyosarcoma is an aggressive childhood malignancy, accounting for more than 50% of all soft-tissue sarcomas in children. Even with extensive therapy, the survival rate among alveolar rhabdomyosarcoma patients with advanced disease is only 20%. The receptor tyrosine kinase Epidermal Growth Factor Receptor (EGFR) has been found to be expressed and activated in human rhabdomyosarcomas. In this study we have used a genetically engineered mouse model for alveolar rhabdomyosarcoma (ARMS) which faithfully recapitulates the human disease by activating the pathognomic Pax3:Fkhr fusion gene and inactivating p53 in the maturing myoblasts. We have demonstrated that tumors from our mouse model of alveolar rhabdomyosarcoma express EGFR at both the mRNA and protein levels. We then tested the EGFR inhibitor, Erlotinib, for its efficacy in this mouse model of alveolar rhabdomyosarcoma. Surprisingly, Erlotinib had no effect on tumor progression, yet mice treated with Erlotinib showed 10–20% loss of body weight. These results suggest that EGFR might not be an a priori monotherapy target in alveolar rhabdomyosarcoma

The Perceptions on Male Circumcision as a Preventive Measure Against HIV Infection and Considerations in Scaling up of the Services: A Qualitative Study Among Police Officers in Dar es Salaam, Tanzania.

\ud In recent randomized controlled trials, male circumcision has been proven to complement the available biomedical interventions in decreasing HIV transmission from infected women to uninfected men. Consequently, Tanzania is striving to scale-up safe medical male circumcision to reduce HIV transmission. However, there is a need to investigate the perceptions of male circumcision in Tanzania using specific populations. The purpose of the present study was to assess the perceptions of male circumcision in a cohort of police officers that also served as a source of volunteers for a phase I/II HIV vaccine (HIVIS-03) trial in Dar es Salaam, Tanzania. In-depth interviews with 24 men and 10 women were conducted. Content analysis informed by the socio-ecological model was used to analyze the data. Informants perceived male circumcision as a health-promoting practice that may prevent HIV transmission and other sexually transmitted infections. They reported male circumcision promotes sexual pleasure, confidence and hygiene or sexual cleanliness. They added that it is a religious ritual and a cultural practice that enhances the recognition of manhood in the community. However, informants were concerned about the cost involved in male circumcision and cleanliness of instruments used in medical and traditional male circumcision. They also expressed confusion about the shame of undergoing circumcision at an advanced age and pain that could emanate after circumcision. The participants advocated for health policies that promote medical male circumcision at childhood, specifically along with the vaccination program. The perceived benefit of male circumcision as a preventive strategy to HIV and other sexually transmitted infections is important. However, there is a need to ensure that male circumcision is conducted under hygienic conditions. Integrating male circumcision service in the routine childhood vaccination program may increase its coverage at early childhood. The findings from this investigation provide contextual understanding that may assist in scaling-up male circumcision in Tanzania.\u

Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing(1,2). Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q - the inheritance of both copies of this material from one parent - and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders(3,4), revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo ( that is, newly arisen and not inherited) single-base substitution, G608G( GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62684/1/nature01629.pd

The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin

Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into T(RM) cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.Supported by National Health and Medical Research Council of Australia and Australian Research Council

A Comparison of Parallel Pyrosequencing and Sanger Clone-Based Sequencing and Its Impact on the Characterization of the Genetic Diversity of HIV-1

BACKGROUND: Pyrosequencing technology has the potential to rapidly sequence HIV-1 viral quasispecies without requiring the traditional approach of cloning. In this study, we investigated the utility of ultra-deep pyrosequencing to characterize genetic diversity of the HIV-1 gag quasispecies and assessed the possible contribution of pyrosequencing technology in studying HIV-1 biology and evolution. METHODOLOGY/PRINCIPAL FINDINGS: HIV-1 gag gene was amplified from 96 patients using nested PCR. The PCR products were cloned and sequenced using capillary based Sanger fluorescent dideoxy termination sequencing. The same PCR products were also directly sequenced using the 454 pyrosequencing technology. The two sequencing methods were evaluated for their ability to characterize quasispecies variation, and to reveal sites under host immune pressure for their putative functional significance. A total of 14,034 variations were identified by 454 pyrosequencing versus 3,632 variations by Sanger clone-based (SCB) sequencing. 11,050 of these variations were detected only by pyrosequencing. These undetected variations were located in the HIV-1 Gag region which is known to contain putative cytotoxic T lymphocyte (CTL) and neutralizing antibody epitopes, and sites related to virus assembly and packaging. Analysis of the positively selected sites derived by the two sequencing methods identified several differences. All of them were located within the CTL epitope regions. CONCLUSIONS/SIGNIFICANCE: Ultra-deep pyrosequencing has proven to be a powerful tool for characterization of HIV-1 genetic diversity with enhanced sensitivity, efficiency, and accuracy. It also improved reliability of downstream evolutionary and functional analysis of HIV-1 quasispecies

CMB-S4 Science Book, First Edition

This book lays out the scientific goals to be addressed by the next-generation ground-based cosmic microwave background experiment, CMB-S4, envisioned to consist of dedicated telescopes at the South Pole, the high Chilean Atacama plateau and possibly a northern hemisphere site, all equipped with new superconducting cameras. CMB-S4 will dramatically advance cosmological studies by crossing critical thresholds in the search for the B-mode polarization signature of primordial gravitational waves, in the determination of the number and masses of the neutrinos, in the search for evidence of new light relics, in constraining the nature of dark energy, and in testing general relativity on large scales

Inflation and Dark Energy from spectroscopy at z > 2

The expansion of the Universe is understood to have accelerated during two epochs: in its very first moments during a period of Inflation and much more recently, at z < 1, when Dark Energy is hypothesized to drive cosmic acceleration. The undiscovered mechanisms behind these two epochs represent some of the most important open problems in fundamental physics. The large cosmological volume at 2 < z < 5, together with the ability to efficiently target high-$z$ galaxies with known techniques, enables large gains in the study of Inflation and Dark Energy. A future spectroscopic survey can test the Gaussianity of the initial conditions up to a factor of ~50 better than our current bounds, crossing the crucial theoretical threshold of $\sigma(f_{NL}^{\rm local})$ of order unity that separates single field and multi-field models. Simultaneously, it can measure the fraction of Dark Energy at the percent level up to $z = 5$, thus serving as an unprecedented test of the standard model and opening up a tremendous discovery space

Sexual health and COVID-19: protocol for a scoping review.

BACKGROUND: Global responses to the COVID-19 pandemic have exposed and exacerbated existing socioeconomic and health inequities that disproportionately affect the sexual health and well-being of many populations, including people of color, ethnic minority groups, women, and sexual and gender minority populations. Although there have been several reviews published on COVID-19 and health disparities across various populations, none has focused on sexual health. We plan to conduct a scoping review that seeks to fill several of the gaps in the current knowledge of sexual health in the COVID-19 era. METHODS: A scoping review focusing on sexual health and COVID-19 will be conducted. We will search (from January 2020 onwards) CINAHL, Africa-Wide Information, Web of Science Core Collection, Embase, Gender Studies Database, Gender Watch, Global Health, WHO Global Literature on Coronavirus Disease Database, WHO Global Index Medicus, PsycINFO, MEDLINE, and Sociological Abstracts. Grey literature will be identified using Disaster Lit, Google Scholar, governmental websites, and clinical trials registries (e.g., ClinicalTrial.gov , World Health Organization, International Clinical Trials Registry Platform, and International Standard Randomized Controlled Trial Number Registry). Study selection will conform to the Joanna Briggs Institute Reviewers' Manual 2015 Methodology for JBI Scoping Reviews. Only English language, original studies will be considered for inclusion. Two reviewers will independently screen all citations, full-text articles, and abstract data. A narrative summary of findings will be conducted. Data analysis will involve quantitative (e.g., frequencies) and qualitative (e.g., content and thematic analysis) methods. DISCUSSION: Original research is urgently needed to mitigate the risks of COVID-19 on sexual health. The planned scoping review will help to address this gap. SYSTEMATIC REVIEW REGISTRATIONS: Systematic Review Registration: Open Science Framework osf/io/PRX8E

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.