Phase II proof-of-concept study of atorvastatin in castration-resistant prostate cancer.

Objectives: To test for evidence of statin-mediated effects in patients with castration-resistant prostate cancer (CRPC) as post-diagnosis use of statins in patients with prostate cancer is associated with favourable survival outcome.

Patients And Methods: The SPECTRE trial was a 6-weeks-long proof-of-concept single-arm Phase II treatment trial, combining atorvastatin and androgen deprivation therapy in patients with CRPC (regardless of metastatic status), designed to test for evidence of statin-mediated effects in patients with CRPC. The primary study endpoint was the proportion of patients achieving a ≥50% drop from baseline in prostate-specific antigen (PSA) levels at any time over the 6-week period of atorvastatin medication (PSA response).

Trauma-focused guided self-help interventions for posttraumatic stress disorder: A meta-analysis of randomized controlled trials.

Trauma-focused guided self-help (TF-GSH) is an important alternative to psychological therapy delivered by a therapist. This meta-analysis evaluates the efficacy of TF-GSH in reducing posttraumatic stress disorder  (PTSD) symptoms and comorbid depressive and anxiety symptoms. A total of 17 trials were included that compared a TF-GSH intervention (N = 610) to various control comparators (N = 570).

Effects of Positive and Negative Emotions on Picture Naming for People With Mild-to-Moderate Aphasia: A Preliminary Investigation.

Purpose: The purpose of the study is to investigate how emotional arousal and valence affect confrontational naming accuracy and response time (RT) in people with mild-to-moderate aphasia compared with adults without aphasia. We hypothesized that negative and positive emotions would facilitate naming for people with aphasia (PWA) but lead to slower responses for adults with no aphasia.

Method: Eight participants with mild-to-moderate aphasia, 15 older adults (OAs), and 17 young adults (YAs) completed a confrontational naming task across three conditions (positive, negative, and neutral) in an ABA (where A = neutral and B = negative) case series design.

Evaluation of the Suitability of RNAscope as a Technique to Measure Gene Expression in Clinical Diagnostics: A Systematic Review.

Objective: To evaluate the application of RNAscope in the clinical diagnostic field compared to the current 'gold standard' methods employed for testing gene expression levels, including immunohistochemistry (IHC), quantitative real time PCR (qPCR), and quantitative reverse transcriptase PCR (qRT-PCR), and to detect genes, including DNA in situ hybridisation (DNA ISH).

Methods: This systematic review searched CINAHL, Medline, Embase and Web of Science databases for studies that were conducted after 2012 and that compared RNAscope with one or more of the 'gold standard' techniques in human samples. QUADAS-2 test was used for the evaluation of the articles' risk of bias.

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration.

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest.

Activation of β-Catenin Cooperates with Loss of Pten to Drive AR-Independent Castration-Resistant Prostate Cancer.

Inhibition of the androgen receptor (AR) is the main strategy to treat advanced prostate cancers. AR-independent treatment-resistant prostate cancer is a major unresolved clinical problem. Patients with prostate cancer with alterations in canonical WNT pathway genes, which lead to β-catenin activation, are refractory to AR-targeted therapies.

Effects of ACA Expansion of Dependent Coverage on Hospital-Based Care of Young Adults With Early Psychosis.

Objective: Since 2010, the Affordable Care Act has required private health plans to extend dependent coverage to adults up to age 26. Because psychosis often begins in young adulthood, expanded private insurance benefits may affect early psychosis treatment. The authors examined changes in insurance coverage and hospital-based service use among young adults with psychosis before and after this change.

STEFs: Activated Vinylogous Protein-Reactive Electrophiles.

Reported here is the synthesis of a class of semi-oxamide vinylogous thioesters, designated STEFs, and the use of these agents as new electrophilic warheads. This work includes preparation of simple probes that contain this reactive motif as well as its installation on a more complex kinase inhibitor scaffold. A key aspect of STEFs is their reactivity towards both thiol and amine groups.

Patient Characteristics and Treatment Patterns Among Psychiatrists Who Do Not Accept Private Insurance.

Objective: Privately insured individuals frequently use out-of-network psychiatrists. Yet, whether treatment provided by psychiatrists who do not accept private insurance differs from treatment provided by those who do has not been studied. The investigators described provider characteristics, patient characteristics, and treatment patterns among psychiatrists who do not accept new patients with private insurance.

Sprouty2 loss-induced IL6 drives castration-resistant prostate cancer through scavenger receptor B1.

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self-sufficient form of CRPC Mechanistically, HER2-IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1-mediated cholesterol uptake in SPRY2-deficient tumours.

Analysis of Nkx3.1:Cre-driven Erk5 deletion reveals a profound spinal deformity which is linked to increased osteoclast activity.

Extracellular signal-regulated protein kinase 5 (ERK5) has been implicated during development and carcinogenesis. Nkx3.1-mediated Cre expression is a useful strategy to genetically manipulate the mouse prostate.

Increased T-cell Infiltration Elicited by Deletion in a -Deficient Mouse Model of Prostate Carcinogenesis.

Prostate cancer does not appear to respond to immune checkpoint therapies where T-cell infiltration may be a key limiting factor. Here, we report evidence that ablating the growth regulatory kinase can increase T-cell infiltration in an established -deficient mouse model of human prostate cancer. Mice that were doubly mutant in prostate tissue for and (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared with control -mutant mice, the latter of which exhibited increased mRNA expression.

Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer.

Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)].

Performance on the Farnsworth-Munsell 100-Hue Test Is Significantly Related to Nonverbal IQ.

Purpose: The Farnsworth-Munsell 100-Hue test (FM100) is a standardized measure of chromatic discrimination, based on colored cap-sorting, which has been widely used in both adults and children. Its dependence on seriation ability raises questions as to its universal suitability and accuracy in assessing purely sensory discrimination. This study investigates how general intellectual ability relates to performance on both the FM100 and a new computer-based chromatic discrimination threshold test, across different age groups in both typical and atypical development.

p300-mediated acetylation of COMMD1 regulates its stability, and the ubiquitylation and nucleolar translocation of the RelA NF-κB subunit.

Nucleolar sequestration of the RelA subunit of nuclear factor (NF)-κB is an important mechanism for regulating NF-κB transcriptional activity. Ubiquitylation, facilitated by COMMD1 (also known as MURR1), acts as a crucial nucleolar-targeting signal for RelA, but how this ubiquitylation is regulated, and how it differs from cytokine-mediated ubiquitylation, which causes proteasomal degradation of RelA, is poorly understood. Here, we report a new role for p300 (also known as EP300) in controlling stimulus-specific ubiquitylation of RelA, through modulation of COMMD1.

c-Src dependency of NSAID-induced effects on NF-κB-mediated apoptosis in colorectal cancer cells.

Long-term aspirin or related non-steroidal anti-inflammatory drugs (NSAIDs) ingestion can protect against colorectal cancer (CRC). NSAIDs have a pro-apoptotic activity and we have shown that stimulation of the nuclear factor-kappaB (NF-κB) pathway is a key component of this pro-apoptotic effect. However, the upstream pathways have yet to be fully elucidated.

The 2010 NICE COPD Guidelines: how do they compare with the GOLD guidelines?

The UK National Institute for Health and Clinical Excellence (NICE) has produced a 2010 partial update of its original 2004 Guidelines on COPD management. The definition of airflow obstruction has been altered to a post-bronchodilator FEV1/FVC ratio < 0.7 and the severity of airflow obstruction has been similarly aligned with the Global initiative for Obstructive Lung Disease (GOLD) guideline definition.

What provokes experienced COPD clinical practitioners in the UK to initiate or change medication? A consensus study.

Background: In the absence of clarity in national guidelines, this study aimed to reach a consensus among experts in chronic obstructive pulmonary disease (COPD) regarding when medication should be initiated or changed in patients demonstrating a gradual decline.

Methods: An electronic three-stage Delphi exercise was undertaken with 37 leading UK experts in COPD. The panel submitted criteria which they scored in subsequent rounds.

The sphingosine kinase 1 inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells.

Sphingosine kinase 1 (SK1) is an enzyme that catalyzes the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome.

FTY720 and (S)-FTY720 vinylphosphonate inhibit sphingosine kinase 1 and promote its proteasomal degradation in human pulmonary artery smooth muscle, breast cancer and androgen-independent prostate cancer cells.

Sphingosine kinase 1 (SK1) is an enzyme that catalyses the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that FTY720 (Fingolimod) and (S)-FTY720 vinylphosphonate are novel inhibitors of SK1 catalytic activity and induce the proteasomal degradation of this enzyme in human pulmonary artery smooth muscle cells, MCF-7 breast cancer cells and androgen-independent LNCaP-AI prostate cancer cells. Proteasomal degradation of SK1 in response to FTY720 and (S)-FTY720 vinylphosphonate is associated with the down-regulation of the androgen receptor in LNCaP-AI cells.

Assessment of psychosocial problems in primary care COPD patients.

The emphasis placed on assessing psychosocial needs in nurse-led practice based consultations for chronic obstructive pulmonary disease (COPD) has not been reported. We investigated the frequency with which nurses performed a range of tasks, and explored if the types of tasks performed were related to levels of training or the setting of clinical consultations. Participants were lead COPD nurses based at 500 randomly selected UK general practices.