Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells

Nucleosome positioning at transcription start sites is known to regulate gene expression by altering DNA accessibility to transcription factors; however, its role at enhancers is poorly understood. We investigated nucleosome positioning at the androgen receptor (AR) enhancers of TMPRSS2, KLK2, and KLK3/PSA in prostate cancer cells. Surprisingly, a population of enhancer modules in androgen-deprived cultures showed nucleosome-depleted regions (NDRs) in all three loci. Under androgen-deprived conditions, NDRs at the TMPRSS2 enhancer were maintained by the pioneer AR transcriptional collaborator GATA-2. Androgen treatment resulted in AR occupancy, an increased number of enhancer modules with NDRs without changes in footprint width, increased levels of histone H3 acetylation (AcH3), and dimethylation (H3K4me2) at nucleosomes flanking the NDRs. Our data suggest that, in the absence of ligand, AR enhancers exist in an equilibrium in which a percentage of modules are occupied by nucleosomes while others display NDRs. We propose that androgen treatment leads to the disruption of the equilibrium toward a nucleosome-depleted state, rather than to enhancer de novo “remodeling.” This allows the recruitment of histone modifiers, chromatin remodelers, and ultimately gene activation. The “receptive” state described here could help explain AR signaling activation under very low ligand concentrations

Diploma Privilege and the Constitution

The COVID-19 pandemic and resulting shutdowns are affecting every aspect of society. The legal profession and the justice system have been profoundly disrupted at precisely the time when there is an unprecedented need for legal services to deal with a host of legal issues generated by the pandemic, including disaster relief, health law, insurance, labor law, criminal justice, domestic violence, and civil rights. The need for lawyers to address these issues is great but the prospect of licensing new lawyers is challenging due to the serious health consequences of administering the bar examination during the pandemic. State Supreme Courts are actively considering alternative paths to licensure. One such alternative is the diploma privilege, a path to licensure currently used only in Wisconsin. Wisconsin\u27s privilege, limited to graduates of its two in-state schools, has triggered constitutional challenges never fully resolved by the lower courts. As states consider emergency diploma privileges to address the pandemic, they will face these unresolved constitutional issues. This Article explores those constitutional challenges and concludes that a diploma privilege limited to graduates of in-state schools raises serious Dormant Commerce Clause questions that will require the state to tie the privilege to the particular competencies in-state students develop and avenues they have to demonstrate those competencies to the state\u27s practicing bar over three years. Meeting that standard will be particularly difficult if a state adopts an in-state privilege on an emergency basis. States should consider other options, including privileges that do not prefer in-state schools. The analysis is important both for states considering emergency measures and for those that might restructure their licensing after the pandemic

The Bar Exam and the COVID-19 Pandemic: The Need for Immediate Action

The novel coronavirus COVID-19 has profoundly disrupted life in the United States. Among other challenges, jurisdictions are unlikely to be able to administer the July 2020 bar exam in the usual manner. It is essential, however, to continue licensing new lawyers. Those lawyers are necessary to meet current needs in the legal system. Equally important, the demand for legal services will skyrocket during and after this pandemic. We cannot close doors to the profession at a time when client demand will reach an all-time high.In this brief policy paper, we outline six licensing options for jurisdictions to consider for the Class of 2020. Circumstances will vary from jurisdiction to jurisdiction, but we hope that these options will help courts and regulators make this complex decision. These are unprecedented times: We must work together to ensure we do not leave the talented members of Class of 2020 on the sidelines when we need every qualified professional on the field to keep our justice system moving

ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas.

The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 heterodimerization decreased AKT phosphorylation, cell growth in vitro, and xenograft growth in vivo. Pertuzumab also potentiated the effects of MEK inhibitor on WT/WT melanoma growth in vitro and in vivo. These findings demonstrate that targeting ErbB3-ErbB2 signaling in a cohort of WT/WT melanomas leads to tumor growth reduction. Together, these studies support the rationale to target the NRG1-ErbB3-ErbB2 axis as a novel treatment strategy in a subset of cutaneous melanomas

Relación entre el género y las experiencias de cortejo y actitudes hacia las relaciones románticas en adolescentes bogotanos

This study aims at finding the relation between gender, romantic experiences and love attitudes in a group of 223 adolescences with age of 15 to 18 years old, of two mixed schools in the Bogotá city. This study makes part of a greater work about the romantic relations in Bogotá teenagers. Data were examined by one-way ANOVA and correlation analysis. The study doesn't show significant differences in any of the applied scales, which is not consistent with similar studies. Not significant trends were observed in relation to the involvement in the relationships, the dates by the couple in group and beliefs associated with love at first sight and the perfection of the love. Results could be explained by the cultural variables associated with gender roles and proper contingences and metacontingences of the social group in relation to romantic relations. Data allow extending the comprehension over romantic relations and raising questions about the processes of socialization in this field that can serve as a base for future investigations.El propósito de este estudio fue encontrar las relaciones que existen entre el género, las experiencias de cortejo románticas y las actitudes hacia el amor, en un grupo de 223 adolescentes con edades entre 15 y 18 años, de dos colegios mixtos de la ciudad de Bogotá. Este estudio forma parte de un trabajo más amplio acerca de las relaciones románticas en adolescentes bogotanos. Los datos fueron analizados por medio de ANOVA de una vía y análisis correlacional. No se encontraron diferencias significativas en ninguna de las escalas aplicadas, lo cual no es consistente con estudios similares. Se observaron tendencias no significativas en relación con el involucramiento en las relaciones, las salidas con la pareja en grupo y creencias asociadas al amor a primera vista y a la perfección del amor. Los resultados encontrados pueden ser explicados por variables culturales asociadas a los roles de género y las contingencias y metacontingencias propias del grupo social en relación con las relaciones románticas. Los resultados permiten ampliar la comprensión acerca de las relaciones afectivas y plantean interrogantes acerca de los procesos de socialización en este campo que pueden servir como base para futuras investigaciones

Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome

<p>Abstract</p> <p>Background</p> <p>Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available.</p> <p>Methods</p> <p>Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis.</p> <p>Results</p> <p>Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls.</p> <p>Conclusions</p> <p>Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.</p

Effectiveness guidance document (EGD) for Chinese medicine trials: a consensus document

Background: There is a need for more Comparative Effectiveness Research (CER) on Chinese medicine (CM) to inform clinical and policy decision-making. This document aims to provide consensus advice for the design of CER trials on CM for researchers. It broadly aims to ensure more adequate design and optimal use of resources in generating evidence for CM to inform stakeholder decision-making. Methods: The Effectiveness Guidance Document (EGD) development was based on multiple consensus procedures (survey, written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders, including patients, clinicians, researchers and payers were involved in creating this document. Results: Recommendations were developed for “using available data” and “future clinical studies”. The recommendations for future trials focus on randomized trials and cover the following areas: designing CER studies, treatments, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication. Conclusion: The present EGD provides the first systematic methodological guidance for future CER trials on CM and can be applied to single or multi-component treatments. While CONSORT statements provide guidelines for reporting studies, EGDs provide recommendations for the design of future studies and can contribute to a more strategic use of limited research resources, as well as greater consistency in trial design

Effectiveness guidance document (EGD) for acupuncture research - a consensus document for conducting trials

Abstract Background There is a need for more Comparative Effectiveness Research (CER) to strengthen the evidence base for clinical and policy decision-making. Effectiveness Guidance Documents (EGD) are targeted to clinical researchers. The aim of this EGD is to provide specific recommendations for the design of prospective acupuncture studies to support optimal use of resources for generating evidence that will inform stakeholder decision-making. Methods Document development based on multiple systematic consensus procedures (written Delphi rounds, interactive consensus workshop, international expert review). To balance aspects of internal and external validity, multiple stakeholders including patients, clinicians and payers were involved. Results Recommendations focused mainly on randomized studies and were developed for the following areas: overall research strategy, treatment protocol, expertise and setting, outcomes, study design and statistical analyses, economic evaluation, and publication. Conclusion The present EGD, based on an international consensus developed with multiple stakeholder involvement, provides the first systematic methodological guidance for future CER on acupuncture.http://deepblue.lib.umich.edu/bitstream/2027.42/112870/1/12906_2012_Article_1127.pd

5-SPICE: the application of an original framework for community health worker program design, quality improvement and research agenda setting

Introduction: Despite decades of experience with community health workers (CHWs) in a wide variety of global health projects, there is no established conceptual framework that structures how implementers and researchers can understand, study and improve their respective programs based on lessons learned by other CHW programs. Objective: To apply an original, non-linear framework and case study method, 5-SPICE, to multiple sister projects of a large, international non-governmental organization (NGO), and other CHW projects. Design: Engaging a large group of implementers, researchers and the best available literature, the 5-SPICE framework was refined and then applied to a selection of CHW programs. Insights gleaned from the case study method were summarized in a tabular format named the ‘5×5-SPICE chart’. This format graphically lists the ways in which essential CHW program elements interact, both positively and negatively, in the implementation field. Results: The 5×5-SPICE charts reveal a variety of insights that come from a more complex understanding of how essential CHW projects interact and influence each other in their unique context. Some have been well described in the literature previously, while others are exclusive to this article. An analysis of how best to compensate CHWs is also offered as an example of the type of insights that this method may yield. Conclusions: The 5-SPICE framework is a novel instrument that can be used to guide discussions about CHW projects. Insights from this process can help guide quality improvement efforts, or be used as hypothesis that will form the basis of a program's research agenda. Recent experience with research protocols embedded into successfully implemented projects demonstrates how such hypothesis can be rigorously tested

How Well Do Randomized Trials Inform Decision Making: Systematic Review Using Comparative Effectiveness Research Measures on Acupuncture for Back Pain

Background: For Comparative Effectiveness Research (CER) there is a need to develop scales for appraisal of available clinical research. Aims were to 1) test the feasibility of applying the pragmatic-explanatory continuum indicator summary tool and the six CER defining characteristics of the Institute of Medicine to RCTs of acupuncture for treatment of low back pain, and 2) evaluate the extent to which the evidence from these RCTs is relevant to clinical and health policy decision making. Methods: We searched Medline, the AcuTrials™ Database to February 2011 and reference lists and included full-report randomized trials in English that compared needle acupuncture with a conventional treatment in adults with non-specific acute and/or chronic low back pain and restricted to those with ≥30 patients in the acupuncture group. Papers were evaluated by 5 raters. Principal Findings: From 119 abstracts, 44 full-text publications were screened and 10 trials (4,901 patients) were evaluated. Due to missing information and initial difficulties in operationalizing the scoring items, the first scoring revealed inter-rater and inter-item variance (intraclass correlations 0.02-0.60), which improved after consensus discussions to 0.20-1.00. The 10 trials were found to cover the efficacy-effectiveness continuum; those with more flexible acupuncture and no placebo control scored closer to effectiveness. Conclusion: Both instruments proved useful, but need further development. In addition, CONSORT guidelines for reporting pragmatic trials should be expanded. Most studies in this review already reflect the movement towards CER and similar approaches can be taken to evaluate comparative effectiveness relevance of RCTs for other treatments. © 2012 Witt et al.published_or_final_versio