An N-terminal splice variant of human Stat5a that interacts with different transcription factors is the dominant form expressed in invasive ductal carcinoma

AbstractWe have identified a new variant of human Stat5a, found at higher ratios to full-length Stat5a in invasive ductal carcinoma versus contiguous normal tissue. The variant, missing exon 5, inhibits p21 and Bax production and increases cell number. After prolactin stimulation, only full-length Stat5a interacts with the vitamin D and retinoid X receptors, whereas only Δ5 Stat5a interacts with activating protein 1–2 and specificity protein 1. Prolactin also oppositely regulates interaction of the two Stat5a forms with β-catenin. We propose that a change in splicing leading to upregulation of this new isoform is a pathogenic aspect of invasive ductal carcinoma

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests

Feasibility and Pilot Efficacy Results from the Multi-site Cognitive Remediation in the Schizophrenia Trials Network (CRSTN) Study

The true benefit of pharmacological intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multi-site studies using cognitive remediation at clinical trials sites has not been established

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The Relationship of the Brief Assessment of Cognition in Schizophrenia (BACS) to Functional Capacity and Real-world Functional Outcome

The Brief Assessment of Cognition in Schizophrenia (BACS) assesses five different domains of cognitive function with six tests, and takes about 30-35 minutes to complete in patients with schizophrenia. Previous work has demonstrated the reliability of this measure, and its sensitivity to the deficits of schizophrenia. However, the relationship of this brief cognitive measure to functional outcome has not been determined. Further, future registration trials for potentially cognitive enhancing compounds may not only assess efficacy with cognitive performance measures, but with assessments of real-world functional outcome and functional capacity. The purpose of this study was to determine the relationship between the BACS and a potential co-primary measure for treatment studies of cognition in schizophrenia, and to determine if such a measure accounts for significant variance in functioning beyond that provided by cognitive function. The current study assessed 60 patients with schizophrenia over the course of six months. Cognitive functions were measured with the BACS. Functional capacity was measured with the UCSD Performance-based Skills Assessment (UPSA). Real-world functional outcome was measured with the Independent Living Skills Inventory (ILSI). BACS composite scores were significantly correlated with functional capacity as measured by the UPSA (r = .65, df = 55, p < .001), and real-world functional outcome as assessed by the ILSI (r = .37, df = 56, p = .005). In multiple regression analyses, UPSA scores did not account for additional variance in real-world functioning beyond that accounted for by the BACS. These data suggest that brief cognitive assessments such as the BACS are able to assess aspects of cognition that are related to important functional measures in clinical trials of cognitive enhancement. They also suggest that the measures being considered as potential co-primary indicators of cognitive function for registration trials are significantly correlated with cognition as assessed by brief cognitive assessments

Comprehensive review of the research employing the schizophrenia cognition rating scale (SCoRS)

This review of research utilizing the Schizophrenia Cognition Rating Scale (SCoRS) outlines the development, evaluation, validation, and implementation of the SCoRS to assess whether the scale meets the criteria as a functional co-primary as defined by the MATRICS-CT initiative. Interview-based co-primary assessments should be: 1) practical and easy to administer for a clinician or researcher; 2) validated in individuals with schizophrenia; 3) contain the relevant areas of cognition and functioning applicable to schizophrenia; 4) able to assess all phases and severity levels of schizophrenia; 5) capable of monitoring disease progression; 6) minimal burden to patients; and 7) sensitive to assess treatment effects. A review of the literature was conducted to present information on the development, psychometric properties and usage of the SCoRS. Review of the development of the SCoRS followed the parameters outlined for scale development on content expert validation and feedback. The SCoRS shows good psychometric properties in various studies, and demonstrates low burden on clinicians and patients. The items measure global concepts that do not require notable cultural modification, making international use feasible. While multiple performance-based tests in cognition and functional outcomes are available, there is a need for a multi-domain, interview-based assessment of cognitive progression and treatment response in clinical trials. The SCoRS appears to meet many of the criteria for an optimal co-primary measure for schizophrenia cognition clinical trials as defined in the MATRICS-CT initiative

Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS)

According to the recommendations of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Neurocognition Committee, one of the desired characteristics of a cognitive battery for assessing cognition in schizophrenia studies and clinical trials is the availability of normative data. This report describes normative data collected on the Brief Assessment of Cognition in Schizophrenia (BACS) from 404 healthy controls with demographic characteristics matching the 2005 United States Census of English-speakers. The six test measures demonstrated the expected pattern of correlations with age, gender, and education. Individual test scores were converted into standardized ( T and z) scores and composite scores that were corrected for age and gender. An education-correction factor was calculated and recommended only for non-schizophrenia patients. Eight different verbal memory tests were found to have equivalent levels of difficulty

The Brief Assessment of Cognition In Affective Disorders (BAC-A):Performance of patients with bipolar depression and healthy controls

Cognitive deficits in bipolar disorder are significant enough to impact everyday functioning. A key question for treatments aimed at cognition is which cognitive domains are most affected by bipolar disorder and which cognitive tests have the best psychometric characteristics for this population. Method: 432 patients assessed at study entry in a treatment study of bipolar depression were assessed with a version of a new cognitive measure – the Brief Assessment of Cognition in Affective Disorder (BAC-A), which assesses traditional cognitive constructs with six subtests measuring memory, processing speed, working memory, and reasoning and problem solving, and a new measure of affective processing. From the cohort of 432 patients, 309 were selected based upon their demographic similarities to a previously collected healthy control sample of 309 subjects. Patients and controls completed the traditional cognitive tests and the Affective Processing Test. Results. Patients with bipolar depression and healthy controls differed significantly on all cognitive measures (P<0.001). The two alternate forms of the Affective Processing Test were very similar in both groups. The most robust discriminator of the groups was a composite score that combined the six core cognitive subtests of the Brief Assessment of Cognition (BAC) with two of the measures from the Affective Processing Test. Limitations: Test-retest reliabilities of the individual Affective Processing Test measures were low. Conclusion: The BAC-A is sensitive to the cognitive impairments in bipolar disorder patients in traditional neuropsychological domains and in cognitive processes believed to be specifically impaired in affective disorders