CARM1 and BAF155: an example of how chromatin remodeling factors can be relocalized and contribute to cancer

In a recent article, Wang and colleagues reported the discovery of a mechanism by which CARM1 regulates the genomic localization of BAF155 (a SWI/SNF subunit involved in chromatin remodeling) through post-translational methylation at R1064 arginine residues. This modification leads to the relocalization of BAF155-containing SWI/SNF complexes to regions containing genes involved in the Myc oncogenic pathway. The results presented are evidence that these interactions constitute a mechanism by which the BAF155 chromatin remodeling factor contributes to cancer

First Light of Engineered Diffusers at the Nordic Optical Telescope Reveal Time Variability in the Optical Eclipse Depth of WASP-12b

We present the characterization of two engineered diffusers mounted on the 2.5 meter Nordic Optical Telescope, located at Roque de Los Muchachos, Spain. To assess the reliability and the efficiency of the diffusers, we carried out several test observations of two photometric standard stars, along with observations of one primary transit observation of TrES-3b in the red (R-band), one of CoRoT-1b in the blue (B-band), and three secondary eclipses of WASP-12b in V-band. The achieved photometric precision is in all cases within the sub-millimagnitude level for exposures between 25 and 180 seconds. Along a detailed analysis of the functionality of the diffusers, we add a new transit depth measurement in the blue (B-band) to the already observed transmission spectrum of CoRoT-1b, disfavouring a Rayleigh slope. We also report variability of the eclipse depth of WASP-12b in the V-band. For the WASP-12b secondary eclipses, we observe a secondary-depth deviation of about 5-sigma, and a difference of 6-sigma and 2.5-sigma when compared to the values reported by other authors in similar wavelength range determined from Hubble Space Telescope data. We further speculate about the potential physical processes or causes responsible for this observed variabilityComment: 11 pages, 9 figure

Psychiatric morbidity in epilepsy: a case controlled study of adults receiving disability benefits

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldOBJECTIVE: To compare the prevalence of non-organic psychiatric disorders among disabled patients of normal intelligence with epilepsy with the prevalence of similar psychiatric disorders among age and sex matched disabled patients with other somatic diseases. METHODS: A case-control study was carried out in Iceland among people receiving disability benefits using information available at the State Social Security Institute. There were 344 patients with epilepsy in Iceland 16 to 66 years of age (inclusive) receiving disability benefits in 1995. By excluding mentally retarded patients, autistic patients, and patients with organic psychoses, 241 index cases with epilepsy qualified for the study. For each case two age and sex matched controls were selected from all patients receiving disability benefits who had cardiovascular diseases, respiratory diseases, or arthropathies. The same exclusion criteria were applied to the controls as the index cases. In both patient groups psychiatric diagnoses were classified into one of the four following categories: (1) psychotic illness; (2) neurotic illness or personality disorders; (3) alcohol or drug dependence or misuse; and (4) other mental disorders. RESULTS: Psychiatric diagnosis was present among 35% (85/241) of the cases compared with 30% (143/482) of the controls (p=0.15). There was a difference in the distribution of the two groups into different psychiatric categories (p=0.02). This was mainly due to an excess of men in the index group with psychosis, particularly schizophrenia or paranoid states. CONCLUSION: The results suggest that there is not a difference in the prevalence of non-organic psychiatric disorders among disabled patients of normal intelligence with epilepsy compared with patients with other disabling somatic diseases. However, the data indicate that when psychopathology is present disabled patients with epilepsy are more likely to have psychotic illness than the other disabled patients

Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldTo determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case-control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 Mb NRG1 gene including markers of a seven-marker haplotype at the 5' end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAP(China 1)), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P=0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAP(China 2)) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P=0.003, rr 2.2) and was also significant using parental controls only (P=0.0047, rr 2.1). A four-marker haplotype at the 3' end of the NRG1 gene, HAP(China 3), was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P=0.000042, rr=2.0) but was not significant in the case-control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese

Familial aggregation of atrial fibrillation in Iceland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldAIMS: To examine the heritability of atrial fibrillation (AF) in Icelanders, utilizing a nationwide genealogy database and population-based data on AF. AF is a disorder with a high prevalence, which has been known to cluster in families, but the heritability of the common form has not been well defined. METHODS AND RESULTS: The study population included 5269 patients diagnosed since 1987 and age-sex-matched controls randomly selected from the genealogy database. Kinship coefficients (KC), expressed as genealogical index of familiality (GIF = average KC x 100,000), were calculated before and after exclusion of relatives separated by one to five meiotic events. Risk ratios (RR) were calculated for first- to fifth-degree relatives. The average pairwise GIF among patients with AF was 15.9 (mean GIF for controls 13.9, 95%CI = 13.3, 14.4); this declined to 15.4 (mean GIF for controls 13.6, 95%CI = 13.1, 14.2) after exclusion of relatives separated by one meiosis and to 13.7 (mean GIF for controls 12.6, 95%CI = 12.1, 13.2), 12.7 (mean GIF for controls 11.9, 95%CI = 11.4, 12.4), and 11.3 (mean GIF for controls 10.6, 95%CI = 10.1, 11.1) after exclusion of relatives within two, three, and four meioses, respectively (all P<0.00001). RRs among relative pairs also declined incrementally, from 1.77 in first-degree relatives to 1.36, 1.18, 1.10, and 1.05 in second- through fifth-degree relatives (all P<0.001), consistent with the declining proportion of alleles shared identically by descent. When the analysis was limited to subjects diagnosed with AF before the age of 60, first-degree relatives of the AF cases were nearly five times more likely to have AF than the general population. CONCLUSION: AF shows strong evidence of heritability among unselected patients in Iceland, suggesting that there may be undiscovered genetic variants underlying the risk of the common form of AF

Prediction of the effect of dapagliflozin on kidney and heart failure outcomes based on short-term changes in multiple risk markers

BACKGROUND: Besides improving glucose control, sodium-glucose co-transporter 2 inhibition with dapagliflozin reduces blood pressure, body weight and urinary albumin:creatinine ratio (UACR) in patients with type 2 diabetes (T2DM). The parameter response efficacy (PRE) score was developed to predict how short-term drug effects on cardiovascular risk markers translate into long-term changes in clinical outcomes. We applied the PRE score to clinical trials of dapagliflozin to model the effect of the drug on kidney and heart failure (HF) outcomes in patients with T2DM and impaired kidney function. METHODS: The relationships between multiple risk markers and long-term outcome were determined in a background population of patients with T2DM with a multivariable Cox model. These relationships were then applied to short-term changes in risk markers observed in a pooled database of dapagliflozin trials (n = 7) that recruited patients with albuminuria to predict the drug-induced changes to kidney and HF outcomes. RESULTS: A total of 132 and 350 patients had UACR >200 mg/g and >30 mg/g at baseline, respectively, and were selected for analysis. The PRE score predicted a risk change for kidney events of -40.8% [95% confidence interval (CI) -51.7 to -29.4) and -40.4% (95% CI -48.4 to -31.1) with dapagliflozin 10 mg compared with placebo for the UACR >200 mg/g and >30 mg/g subgroups. The predicted change in risk for HF events was -27.3% (95% CI -47.7 to -5.1) and -21.2% (95% CI -35.0 to -7.8), respectively. Simulation analyses showed that even with a smaller albuminuria-lowering effect of dapagliflozin (10% instead of the observed 35% in both groups), the estimated kidney risk reduction was still 26.5 and 26.8%, respectively. CONCLUSIONS: The PRE score predicted clinically meaningful reductions in kidney and HF events associated with dapagliflozin therapy in patients with diabetic kidney disease. These results support a large long-term outcome trial in this population to confirm the benefits of the drug on these endpoints

Evidence for He I 10830 \AA~ absorption during the transit of a warm Neptune around the M-dwarf GJ 3470 with the Habitable-zone Planet Finder

Understanding the dynamics and kinematics of out-flowing atmospheres of hot and warm exoplanets is crucial to understanding the origins and evolutionary history of the exoplanets near the evaporation desert. Recently, ground based measurements of the meta-stable Helium atom's resonant absorption at 10830 \AA~has become a powerful probe of the base environment which is driving the outflow of exoplanet atmospheres. We report evidence for the He I 10830 \AA~in absorption (equivalent width $\sim$ $0.012 \pm 0.002$ \AA) in the exosphere of a warm Neptune orbiting the M-dwarf GJ 3470, during three transits using the Habitable Zone Planet Finder (HPF) near infrared spectrograph. This marks the first reported evidence for He I 10830 \AA\, atmospheric absorption for a planet orbiting an M-dwarf. Our detected absorption is broad and its blueshifted wing extends to -36 km/sec, the largest reported in the literature to date. We modelled the state of Helium atoms in the exosphere of GJ3470b based on assumptions on the UV and X-ray flux of GJ 3470, and found our measurement of flux-weighted column density of meta-stable state Helium $(N_{He^2_3S} = 2.4 \times 10^{10} \mathrm{cm^{-2}})$, derived from our transit observations, to be consistent with model, within its uncertainties. The methodology developed here will be useful to study and constrain the atmospheric outflow models of other exoplanets like GJ 3470b which are near the edge of the evaporation desert.Comment: Accepted in Ap

Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Inherited mutations in the BRCA2 gene greatly increase the risk of developing breast cancer. Consistent with an important role for BRCA2 in error-free DNA repair, complex genomic changes are frequently observed in tumors derived from BRCA2 mutation carriers. Here, we explore the impact of DNA copy-number changes in BRCA2 tumors with respect to phenotype and clinical staging of the disease. METHODS: Breast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy. RESULTS: Tumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis. CONCLUSIONS: The results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease.Eimskipafelag University Minningarsjodur Bergthoru Magnusdottur and Jakobs J Bjarnasonar Gongum Saman Icelandic Cancer Research Fund SKI Icelandic Centre for Research RANNIS The University of Icelan