Citations

Abstract BackgroundAlternative splicing (AS) is a fundamental process in eukaryotes contributing to the diversity of mRNA isoforms with variable ratios of intron/exon. SF3B1 is a pivotal protein of the spliceosome machinery. Mutations in the SF3B1 gene have prognostic value in Chronic Lymphocytic Leukemia (CLL). Our previous studies have shown that SF3B1 inhibition with macrolides induces apoptosis specifically in CLL compared with normal cells. SF3B1 inhibition is associated with a widespread increase in intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in CLL cells. However, it is unknown how the activity of SF3B1 contributes to the spliceosome activity and the poor clinical prognosis in CLL.MethodsTo better understand this process, we performed a comprehensive analysis to quantify the abundance of individual exonic and intronic mapped reads on annotated RNA-Seq transcripts derived from the B cells of 98 CLL patients and nine healthy volunteers (Normal B cells – NBC). We calculated ratios for intron and exon abundance for each transcript and use this as a measure of intron retention (IR) and a surrogate for alternative splicing (AS).ResultsWe found that 66% of CLL B-cells transcripts had significant IR elevation compared to NBC and that transcripts with high IR were associated with low expression levels and mRNA downregulation. The IR increase in CLL B-cells was independent of prognostic factors such as IgVH or SF3B1 mutations. Transcripts with the highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. Also, we observed a >2-fold increase of active pSF3B1 in CLL B-cells compared to NBC. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein was observed. ConclusionsOur findings suggest that IR/ARS is increased in CLL and that this process is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of AS in carcinogenesis and evidence of pSF3B1 participation in this process.

To describe transverse relaxation of water in fixed tissue, we propose a model of transverse relaxation accelerated by diffusion and exchange (TRADE) that assumes exchange between free (visible) and bound (invisible) water, which relax by the dipole–dipole interaction, chemical exchange, and translation in the field gradient. Depending on the prevailing mechanism, transverse relaxation time (T2) of water in fixed tissue could increase (when dipole–dipole interaction prevails) or decrease with temperature (when diffusion in the field gradient prevails). Chemical exchange can make T2 even temperature independent. Also, variation of resolution from 100 to 15 μm/pxl (or less) affects effective transverse relaxation. T2 steadily decreases with increased resolution ( , is the read direction resolution). TRADE can describe all of these observations (semi)quantitatively. The model has been experimentally verified on water phantoms and on formalin‐fixed zebrafish, mouse brain, and rabbit larynx tissues. TRADE could help predict optimal scanning parameters for high‐resolution MRM from much faster measurements at lower resolution.

AbstractObjectivesPersistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well‐characterized samples of individuals with BD.MethodsThirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived “higher versus lower function” as the dependent variable and selected clinical and demographic variables as predictors.ResultsWe found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning.ConclusionsThe bipolar clinical research community is poised to work together to characterize the multi‐dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large‐scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Background: Ambulatory blood pressure monitoring (ABPM) is important for the diagnosis of hypertension (HTN) as well as variants such as nocturnal HTN (NH), masked HTN and a non-dipping pattern. NH and non-dipping, a failure of the normal circadian drop in blood pressure during sleep, have been associated with all-cause mortality and cardiovascular risk. Obstructive sleep apnea is associated with HTN and a growing body of evidence suggests that limb movement disorders of sleep may also influence cardiovascular morbidity. The present study investigates arousals of sleep disorders, limb movement or respiratory, and their relationship to ABPM measurements. Methods: A retrospective review (January 1, 2010 to December 31, 2014) was performed on patients that underwent both ABPM and polysomnography within a six months of each other. Socio-demographic data, results of 24 hour ABPM and polysomnography, concurrent medication use by class, comorbid conditions and laboratory data were recorded. Patients with incomplete polysomnography or ABPM measurements were excluded. Results: 330 individuals met criterion for inclusion; 59% male, 86% white. 211 (64%) were found to have NH, 106 (32%) had uncontrolled HTN and 202 (61%) had a non-dipping pattern. Patients with NH were more likely to have diabetes, hyperlipidemia and chronic kidney disease. Elevated arousal indices were more prevalent in those with NH, uncontrolled HTN and non-dippers. There was an association of NH with the total number of arousals per hour of sleep (p<0.01), whether related to respiratory disturbances or limb movements. Limb movement index (LMI) was related to age (p<0.0001) and was associated with all type arousals (p<0.0001). Conclusions: ABPM revealed a high prevalence of NH, non-dipping, masked and uncontrolled HTN in patients with sleep disorders. Arousals of all types, whether accompanying respiratory or limb movements, were associated with NH and also with LMI.

Abstract Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency &lt; 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10−8); rs79942605 (OR = 2.17, P = 2.81×10−8) and rs208908 (OR = 0.70, P = 4.54×10−8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.