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Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) of 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n = 6) and nonbrain prostate cancer metastases (n = 36). This first whole genome sequencing study of prostate intracranial metastases led to several new insights. First, there was a higher diversity of complex structural alterations in prostate cancer intracranial metastases compared to primary tumor tissues. Chromothripsis and chromoplexy events seemed to dominate, yet there were few enrichments of specific categories of structural variants compared with non-brain metastases. Second, aberrations involving the AR gene, including AR enhancer gain were observed in 7/10 (70%) of intracranial metastases, as well as recurrent loss of function aberrations involving TP53 in 8/10 (80%), RB1 in 2/10 (20%), BRCA2 in 2/10 (20%), and activation of the PI3K/AKT/PTEN pathway in 8/10 (80%). These alterations were frequently present in tumor tissues from other sites of disease obtained concurrently or sequentially from the same individuals. Third, clonality analysis points to genomic factors and evolutionary bottlenecks that contribute to metastatic spread in patients with prostate cancer. These results describe the aggressive molecular features underlying intracranial metastasis that may inform future diagnostic and treatment approaches. [ABSTRACT FROM AUTHOR]

One criticism of published curricula addressing implicit bias is that few achieve skill development in implicit bias recognition and management (IBRM). To inform the development of skills-based curricula addressing IBRM, we conducted a scoping review of the literature inquiring, "What interventions exist focused on IBRM in professions related to social determinants of health: education, law, social work, and the health professions inclusive of nursing, allied health professions, and medicine?"Authors searched eight databases for articles published from 2000 to 2020. Included studies: (1) described interventions related to implicit bias; and (2) addressed knowledge, attitude and/or skills as outcomes. Excluded were interventions solely focused on reducing/neutralizing implicit bias. Article review for inclusion and data charting occurred independently and in duplicate. Investigators compared characteristics across studies; data charting focused on educational and assessment strategies. Fifty-one full-text articles for data charting and synthesis, with more than 6568 learners, were selected. Educational strategies included provocative/engagement triggers, the Implicit Association Test, reflection and discussion, and various active learning strategies. Most assessments were self-report, with fewer objective measures. Eighteen funded studies utilized federal, foundation, institutional, and private sources. This review adds to the literature by providing tangible examples of curricula to complement existing frameworks, and identifying opportunities for further research in innovative skills-based instruction, learner assessment, and development and validation of outcome metrics. Continued research addressing IBRM would enable learners to develop and practice skills to recognize and manage their implicit biases during clinical encounters, thereby advancing the goal of improved, equitable patient outcomes. [ABSTRACT FROM AUTHOR]

Mutations in the LMNA gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The LMNA gene encodes A-type lamins, lamins A/C, intermediate filaments that form a meshwork underlying the inner nuclear membrane. Lamins have a conserved domain structure consisting of a head, coiled-coil rod, and C-terminal tail domain possessing an Ig-like fold. This study identified differences between two mutant lamins that cause distinct clinical diseases. One of the LMNA mutations encodes lamin A/C p.R527P and the other codes lamin A/C p.R482W, which are typically associated with muscular dystrophy and lipodystrophy, respectively. To determine how these mutations differentially affect muscle, we generated the equivalent mutations in the Drosophila Lamin C (LamC) gene, an orthologue of human LMNA. The muscle-specific expression of the R527P equivalent showed cytoplasmic aggregation of LamC, a reduced larval muscle size, decreased larval motility, and cardiac defects resulting in a reduced adult lifespan. By contrast, the muscle-specific expression of the R482W equivalent caused an abnormal nuclear shape without a change in larval muscle size, larval motility, and adult lifespan compared to controls. Collectively, these studies identified fundamental differences in the properties of mutant lamins that cause clinically distinct phenotypes, providing insights into disease mechanisms. [ABSTRACT FROM AUTHOR]

Myocardial infarction is a form of ischemia/reperfusion (I/R) injury that causes cardiac contractile dysfunction and cell death. I/R injury is mediated, in part, by decreased endothelial-derived nitric oxide (NO) bioavailability and increased reactive oxygen species (ROS) resulting in cell death. Cytokines released from I/R tissue activate G-protein coupled receptors that in turn stimulate NADPH oxidase to produce ROS. Thus, administration of a NADPH oxidase peptide inhibitor, Nox2ds-tat (formerly known as gp91ds-tat), may be a rational approach to attenuate I/R injury. Nox2ds-tat dose-dependently inhibited (10 μM - 80 μM; n=5) phorbol 12-myristate13-acetate (n=21) induced polymorphonuclear leukocyte superoxide production up to 37 ± 7% (p<0.05; Fig. 3). Similarly, Nox2ds-tat dose-dependently attenuated I/R induced cardiac contractile dysfunction as evidenced by improved post-reperfused left ventricular developed pressure (LVDP) which recovered up to 77 ± 7% (5 μM- 80 μM; p<0.05; n=6-7) of initial values (pre-ischemic values) at 45 min post-reperfusion when compared to control I/R hearts (n=14) that only recovered to 46 ± 6% from initial values for LVDP in isolated perfused rat hearts subjected to global I(30 min)/R(45 min) (Table 1). I/R control hearts exhibited an infarct size of 46 ± 2.1%, whereas I/R + Nox2ds-tat hearts exhibited infarct sizes of 30 ± 4% (5 μM), 15 ± 1.4% (10 μM), 23 ± 2.0% (40 μM), and 19 ± 1.6% (80 μM) (p<0.01 vs. control I/R hearts; Figure 4, Panel A-B). Regarding in vivo assessments, Nox2ds-tat (4.1 mg/kg, IV) significantly reduced blood H2O2 (1.4 μM) and increased endothelial-derived blood NO (127 nM) at 45 min reperfusion compared to saline controls (p<0.01) in rat hindlimb I(30 min)/R (45 min). Moreover, Nox2ds-tat (20 μM) dose-dependently and significantly attenuated NG-L-arginine methyl ester (L-NAME) induced leukocyte endothelial interactions up to five-fold compared to L-NAME controls (p<0.01). These results were confirmed by changes seen in the histology of rat mesenteric venules (Figure 7, Panel A-B). The results suggest that Nox2ds-tat attenuates I/R-induced cardiac contractile dysfunction and infarct size by inhibiting ROS release from NADPH oxidase. [ABSTRACT FROM AUTHOR]

The image saturation of contemporary culture has produced a problematic situation for artistic practice, immobilizing the photographic image with cliché and stereotype. The essay considers this dilemma through the practice of Chilean political activist artist Alfredo Jaar and the Lacanian concepts of the sinthome, the Real, and jouissance. Although difficult concepts, even within Jacques Lacan's oeuvre, the sinthome, the Real, and jouissance offer powerful conceptual tools for constructing artistic practice as a challenge to the capture of the image by contemporary media. [ABSTRACT FROM AUTHOR]

A foreword to "Visual Arts Research" is presented.

The author argues for the new approaches to art teaching and learning that center on student engagement with "big ideas," contemporary culture and art. [ABSTRACT FROM AUTHOR]

The increasing dominance of the visual in contemporary society has created new conditions of visuality for art making practice. Using four contemporary artists as exemplars, the article examines visuality—how we learn to see socially—as a significant factor in contemporary art making practice. The investigation reveals considerable trafficking between contemporary art making practice and systems of representation found in mass media and everyday life. The artist's ability to discern and negotiate the visuality that accompanies these various systems of representation, which include perceptual sign systems, time-based systems, fictionalized realities, and consumer display, emerge as important skills for current art making practice and instruction. [ABSTRACT FROM AUTHOR]

Comments on the initiatives and issues concerning educational change. Observations on the implementation of an integrated curriculum; Criticism of the Getty Education Institute-funded project in the Fairfax community schools in Los Angeles County, California; Differences in the interpretation of the meaning of the term system; Analysis of the application of school reform.

Mutations in the LMNA gene cause diseases called laminopathies. LMNA encodes lamins A and C, intermediate filaments with multiple roles at the nuclear envelope. LMNA mutations are frequently single base changes that cause diverse disease phenotypes affecting muscles, nerves, and fat. Disease-associated amino acid substitutions were mapped in silico onto three-dimensional structures of lamin A/C, revealing no apparent genotype–phenotype connections. In silico analyses revealed that seven of nine predicted partner protein binding pockets in the Ig-like fold domain correspond to sites of disease-associated amino acid substitutions. Different amino acid substitutions at the same position within lamin A/C cause distinct diseases, raising the question of whether the nature of the amino acid replacement or genetic background differences contribute to disease phenotypes. Substitutions at R249 in the rod domain cause muscular dystrophies with varying severity. To address this variability, we modeled R249Q and R249W in Drosophila Lamin C, an orthologue of LMNA. Larval body wall muscles expressing mutant Lamin C caused abnormal nuclear morphology and premature death. When expressed in indirect flight muscles, R249W caused a greater number of adults with wing posturing defects than R249Q, consistent with observations that R249W and R249Q cause distinct muscular dystrophies, with R249W more severe. In this case, the nature of the amino acid replacement appears to dictate muscle disease severity. Together, our findings illustrate the utility of Drosophila for predicting muscle disease severity and pathogenicity of variants of unknown significance. [ABSTRACT FROM AUTHOR]

Focuses on the various modes of treatment for hyperactivity in American children. Effect of stimulants on the symptoms; Conditions that can lead to hyperactivity; Lack of scientific sense to suppress hyperactivity with drugs.