Loss of Androgen Receptor-Dependent Growth Suppression by Prostate Cancer Cells Can Occur Independently from Acquiring Oncogenic Addiction to Androgen Receptor Signaling

The conversion of androgen receptor (AR) signaling as a mechanism of growth suppression of normal prostate epithelial cells to that of growth stimulation in prostate cancer cells is often associated with AR mutation, amplification and over-expression. Thus, down-regulation of AR signaling is commonly therapeutic for prostate cancer. The E006AA cell line was established from a hormone naïve, localized prostate cancer. E006AA cells are genetically aneuploid and grow equally well when xenografted into either intact or castrated male NOG but not nude mice. These cells exhibit: 1) X chromosome duplication and AR gene amplification, although paradoxically not coupled with increased AR expression, and 2) somatic, dominant-negative Serine-599-Glycine loss-of-function mutation within the dimerization surface of the DNA binding domain of the AR gene. No effect on the growth of E006AA cells is observed using targeted knockdown of endogenous mutant AR, ectopic expression of wild-type AR, or treatment with androgens or anti-androgens. E006AA cells represent a prototype for a newly identified subtype of prostate cancer cells that exhibit a dominant-negative AR loss-of-function in a hormonally naïve patient. Such loss-of-function eliminates AR-mediated growth suppression normally induced by normal physiological levels of androgens, thus producing a selective growth advantage for these malignant cells in hormonally naïve patients. These data highlight that loss of AR-mediated growth suppression is an independent process, and that, without additional changes, is insufficient for acquiring oncogene addiction to AR signaling. Thus, patients with prostate cancer cells harboring such AR loss-of-function mutations will not benefit from aggressive hormone or anti-AR therapies even though they express AR protein

Arterial spin labelling reveals an abnormal cerebral perfusion pattern in Parkinson's disease

There is a need for objective imaging markers of Parkinson's disease status and progression. Positron emission tomography and single photon emission computed tomography studies have suggested patterns of abnormal cerebral perfusion in Parkinson's disease as potential functional biomarkers. This study aimed to identify an arterial spin labelling magnetic resonance-derived perfusion network as an accessible, non-invasive alternative. We used pseudo-continuous arterial spin labelling to measure cerebral grey matter perfusion in 61 subjects with Parkinson's disease with a range of motor and cognitive impairment, including patients with dementia and 29 age- and sex-matched controls. Principal component analysis was used to derive a Parkinson's disease-related perfusion network via logistic regression. Region of interest analysis of absolute perfusion values revealed that the Parkinson's disease pattern was characterized by decreased perfusion in posterior parieto-occipital cortex, precuneus and cuneus, and middle frontal gyri compared with healthy controls. Perfusion was preserved in globus pallidus, putamen, anterior cingulate and post- and pre-central gyri. Both motor and cognitive statuses were significant factors related to network score. A network approach, supported by arterial spin labelling-derived absolute perfusion values may provide a readily accessible neuroimaging method to characterize and track progression of both motor and cognitive status in Parkinson's diseas

Racism, anti-racist practice and social work: articulating the teaching and learning experiences of Black social workers

In the mid 1990s a Black practice teacher programme was established in Manchester and Merseyside with the primary aim to increase the number of Black practice teachers in social work organisations, and in turn provide a supportive and encouraging learning environment for Black student social workers whilst on placement. In the north‐west of England research has been undertaken, to establish the quality of the practice teaching and student learning taking place with Black practice teachers and students. This paper is an exploration of the ideas generated within the placement process that particularly focused on the discourse of racism and ant‐racist practice. Black students and practice teachers explain their understanding of racism and anti‐racist practice within social work. From the research, the paper will critique some of the ideas concerning anti‐racism. In particular, it will question whether anti‐racist social work practice needs to be re‐evaluated in the light of a context with new migrants, asylum seekers and refugees. It will concluded, by arguing that whilst the terms anti‐racism, Black and Minority Ethnic have resonance as a form of political strategic essentialism, it is important to develop more positive representations in the future

Mixed siliciclastic-carbonate-evaporite sedimentation in an arid eolian landscape: The Khor Al Adaid tide-dominated coastal embayment, Qatar

The Khor Al Adaid embayment of southern Qatar represents a unique shallow-water mixed siliciclastic‑carbonate coastal depositional system that developed in a hyper-arid climatic setting over the past 6000 years. The embayment, which was formed during the Flandrian transgression as a result of flooding across a partially fault-controlled incised fluvial drainage, is supplied by quartz-rich sands delivered by wind-blown dunes migrating southward across the surface of Qatar. These offshore-migrating eolian-derived sediments are being redistributed by tidal currents in an otherwise low-energy coastal zone, where in situ formation of carbonate mud and a low-diversity skeletal assemblage is ongoing within salinity-restricted environments. Three depositional sectors are delineated: 1) an energetic, linear, fault-controlled Entrance Channel into which the eolian dunes spill directly; 2) a relatively deep (up to 20 m) Outer Lagoon, interpreted to represent a flooded karst-collapse structure; and 3) a sprawling, low-energy, shallow (<2 m) Inner Lagoon occupying low-lying areas between deflated eolian dunes.Physical oceanographic modeling, integrating multi-seasonal current meter and tidal gage measurements, demonstrates tidal current flow velocities are relatively high in both the Entrance Channel and at the constricted entrance to the Inner Lagoon. Associated flow expansion into less confined areas results in deposition of the eolian-derived sands as flood-tidal deltas, one in the Outer, and two in the Inner Lagoon. A weakly-developed ebb-tidal delta occurs where the Entrance Channel debouches into the Arabian Gulf. Flood-tide dominance is also apparent in Entrance Channel deposits, where sand accumulates in seaward-terminating “ebb barbs” along the margins of the flood-dominant thalweg. Such flood-tide dominance of the thalweg is unusual and likely reflects the absence of river discharge. Evidence of significant inverse estuarine circulation (seaward flow of a brine along the embayment floor) is mostly absent in spite of the landward increase of salinity, where concentrations reach more than double normal seawater salinity in the Inner Lagoon. Modeling results show that seaward-flowing brines formed in the Inner Lagoon are trapped in the relatively deep Outer Lagoon, and that mixing by tidal currents in the energetic Entrance Channel precludes the formation of vertical density gradients there. Because siliciclastic mud is essentially absent, and most of the sediment forming the deltas consists of sand, upper intertidal deltaic deposits that would normally consist of mud are absent, resulting in the flood-tide deltas having a pronounced lobate geometry similar to that of fluvial deltas formed predominantly of sand.Away from tidal deltas, low-energy lagoons are floored by carbonate mud of local production, with minor gypsum precipitating in the Inner Lagoon. Wind-generated waves only locally influence sedimentation, forming complex nearshore bars along some lagoonal shorelines. The overall landward increase in salinity is accompanied by a decrease in the diversity of benthic fauna and their skeletal remains. A fairly diverse faunal assemblage is observed in the Entrance Channel near the Arabian Gulf, including colonial corals, whereas the inner lagoon assemblage is dominated gastropods belonging to Pirenella cingulata. The remnants of large eolian dunes are preserved in the low-energy setting of the Inner Lagoon, segmenting the waterbody, and locally increasing restriction. The sedimentology of the arid-zone coastal Khor Al Adaid embayment may serve as an analogue for environmental settings that were perhaps more commonplace in arid zones of flooded continents during greenhouse times

Beta Amyloid Deposition Is Not Associated With Cognitive Impairment in Parkinson's Disease

The extent to which Alzheimer neuropathology, particularly the accumulation of misfolded beta-amyloid, contributes to cognitive decline and dementia in Parkinson's disease (PD) is unresolved. Here, we used Florbetaben PET imaging to test for any association between cerebral amyloid deposition and cognitive impairment in PD, in a sample enriched for cases with mild cognitive impairment. This cross-sectional study used Movement Disorders Society level II criteria to classify 115 participants with PD as having normal cognition (PDN, n = 23), mild cognitive impairment (PD-MCI, n = 76), or dementia (PDD, n = 16). We acquired 18F-Florbetaben (FBB) amyloid PET and structural MRI. Amyloid deposition was assessed between the three cognitive groups, and also across the whole sample using continuous measures of both global cognitive status and average performance in memory domain tests. Outcomes were cortical FBB uptake, expressed in centiloids and as standardized uptake value ratios (SUVR) using the Centiloid Project whole cerebellum region as a reference, and regional SUVR measurements. FBB binding was higher in PDD, but this difference did not survive adjustment for the older age of the PDD group. We established a suitable centiloid cut-off for amyloid positivity in Parkinson's disease (31.3), but there was no association of FBB binding with global cognitive or memory scores. The failure to find an association between PET amyloid deposition and cognitive impairment in a moderately large sample, particularly given that it was enriched with PD-MCI patients at risk of dementia, suggests that amyloid pathology is not the primary driver of cognitive impairment and dementia in most patients with PD

Search for gravitational wave bursts in LIGO's third science run

We report on a search for gravitational wave bursts in data from the three LIGO interferometric detectors during their third science run. The search targets subsecond bursts in the frequency range 100-1100 Hz for which no waveform model is assumed, and has a sensitivity in terms of the root-sum-square (rss) strain amplitude of hrss ~ 10^{-20} / sqrt(Hz). No gravitational wave signals were detected in the 8 days of analyzed data.Comment: 12 pages, 6 figures. Amaldi-6 conference proceedings to be published in Classical and Quantum Gravit

The Mount Perkins block, northwestern Arizona: An exposed cross section of an evolving, preextensional to synextensional magmatic system

This is the published version. Reuse is subject to Society of Exploration Geophysicists terms of use and conditions.The steeply tilted Mount Perkins block, northwestern Arizona, exposes a cross section of a magmatic system that evolved through the onset of regional extension. New 40Ar/39Ar ages of variably tilted (0–90°) volcanic strata bracket extension between 15.7 and 11.3 Ma. Preextensional intrusive activity included emplacement of a composite Miocene laccolith and stock, trachydacite dome complex, and east striking rhyolite dikes. Related volcanic activity produced an ∼18–16 Ma stratovolcano, cored by trachydacite domes and flanked by trachydacite-trachyandesite flows, and ∼16 Ma rhyolite flows. Similar compositions indicate a genetic link between the stratovolcano and granodioritic phase of the laccolith. Magmatic activity synchronous with early regional extension (15.7–14.5 Ma) generated a thick, felsic volcanic sequence, a swarm of northerly striking subvertical rhyolite dikes, and rhyolite domes. Field relations and compositions indicate that the dike swarm and felsic volcanic sequence are cogenetic. Modes of magma emplacement changed during the onset of extension from subhorizontal sheets, east striking dikes, and stocks to northerly striking, subvertical dike swarms, as the regional stress field shifted from nearly isotropic to decidedly anisotropic with an east-west trending, horizontal least principal stress. Preextensional trachydacitic and preextensional to synextensional rhyolitic magmas were part of an evolving system, which involved the ponding of mantle-derived basaltic magmas and ensuing crustal melting and assimilation at progressively shallower levels. Major extension halted this system by generating abundant pathways to the surface (fractures), which flushed out preexisting crustal melts and hybrid magmas. Remaining silicic melts were quenched by rapid, upper crustal cooling induced by tectonic denudation. These processes facilitated eruption of mafic magmas. Accordingly, silicic magmatism at Mount Perkins ended abruptly during peak extension ∼14.5 Ma and gave way to mafic magmatism, which continued until extension ceased

Pelvic and breast examination skills curricula in United States medical schools: a survey of obstetrics and gynecology clerkship directors

Background: Learning to perform pelvic and breast examinations produces anxiety for many medical students. Clerkship directors have long sought strategies to help students become comfortable with the sensitive nature of these examinations. Incorporating standardized patients, simulation and gynecologic teaching associates (GTAs) are approaches gaining widespread use. However, there is a paucity of literature guiding optimal approach and timing. Our primary objective was to survey obstetrics and gynecology (Ob/Gyn) clerkship directors regarding timing and methods for teaching and assessment of pelvic and breast examination skills in United States medical school curricula, and to assess clerkship director satisfaction with current educational strategies at their institutions. Methods: Ob/Gyn clerkship directors from all 135 Liaison Committee on Medical Education accredited allopathic United States medical schools were invited to complete an anonymous 15-item web-based questionnaire. Results: The response rate was 70%. Pelvic and breast examinations are most commonly taught during the second and third years of medical school. Pelvic examinations are primarily taught during the Ob/Gyn and Family Medicine (FM) clerkships, while breast examinations are taught during the Ob/Gyn, Surgery and FM clerkships. GTAs teach pelvic and breast examinations at 72 and 65% of schools, respectively. Over 60% of schools use some type of simulation to teach examination skills. Direct observation by Ob/Gyn faculty is used to evaluate pelvic exam skills at 87% of schools and breast exam skills at 80% of schools. Only 40% of Ob/Gyn clerkship directors rated pelvic examination training as excellent, while 18% rated breast examination training as excellent. Conclusions: Pelvic and breast examinations are most commonly taught during the Ob/Gyn clerkship using GTAs, simulation trainers and clinical patients, and are assessed by direct faculty observation during the Ob/Gyn clerkship. While the majority of Ob/Gyn clerkship directors were not highly satisfied with either pelvic or breast examination training programs, they were less likely to describe their breast examination training programs as excellent as compared to pelvic examination training—overall suggesting an opportunity for improvement. The survey results will be useful in identifying future challenges in teaching such skills in a cost-effective manner. Electronic supplementary material The online version of this article (doi:10.1186/s12909-016-0835-6) contains supplementary material, which is available to authorized users