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Background: Ischemic stroke (IS) is a highly heritable trait, and genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS. Methods: We conducted an exome-wide study using whole-exome sequencing data from 152 058 UK Biobank participants, including 1777 IS cases. We performed single-variant analyses for rare variants and gene-based analyses for loss-of-function and deleterious missense rare variants. We validated these results through (1) gene-based testing using summary statistics from MEGASTROKE—a genome-wide association study of IS that included 67 162 IS cases and 454 450 controls, (2) gene-based testing using individual-level data from 1706 IS survivors, including 142 recurrent IS cases, enrolled in the VISP trial (Vitamin Intervention for Stroke Prevention); and (3) gene-based testing against neuroimaging phenotypes related to cerebrovascular disease using summary-level data from 42 310 UK Biobank participants with available magnetic resonance imaging data. Results: In single-variant association analyses, none of the evaluated variants were associated with IS at genome-wide significance levels ( P −8 ). In the gene-based analysis focused on loss-of-function and deleterious missense variants, rare genetic variation at CYP2R1 was significantly associated with IS risk ( P =2.6×10 −6 ), exceeding the Bonferroni-corrected threshold for 16 074 tests ( P −6 ). Validations analyses indicated that CYP2R1 was associated with IS risk in MEGASTROKE (gene-based test, P =0.003), with IS recurrence in the VISP trial (gene-based test, P =0.001) and with neuroimaging traits (white matter hyperintensity, mean diffusivity, and fractional anisotropy) in the UK Biobank neuroimaging study (all gene-based tests, P Conclusions: Because CYP2R1 plays an important role in vitamin D metabolism and existing observational evidence suggests an association between vitamin D levels and cerebrovascular disease, our results support a role of this pathway in the occurrence of IS.

Background and ObjectivesBlood pressure (BP) is often not at goal in stroke survivors, leaving individuals vulnerable to additional vascular events. Given that BP is a highly heritable trait, we hypothesize that a higher polygenic susceptibility to hypertension (PSH) leads to worse BP control in stroke survivors.MethodsWe conducted a study within the UK Biobank evaluating persons of European ancestry who survived an ischemic or hemorrhagic stroke. To model the PSH, we created polygenic risk scores (PRSs) for systolic and diastolic BP using 732 genetic variants. We divided the PRSs into quintiles and used linear/logistic regression to test whether higher PSH led to higher observed BP, uncontrolled BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg), and resistant BP (uncontrolled BP despite being on ≥3 antihypertensive drugs). We conducted an independent replication using data from the Vitamin Intervention for Stroke Prevention (VISP) trial.ResultsWe analyzed 5,940 stroke survivors. When comparing stroke survivors with very low vs very high PSH, the mean systolic BP was 137 (SD 18) vs 143 (SD 20,p< 0.001), the mean diastolic BP was 81 (SD 10) vs 84 (SD 11,p< 0.001), the prevalence of uncontrolled BP was 42.8% vs 57.2% (p< 0.001), and the prevalence of resistant hypertension was 3.9% vs 11% (p< 0.001). Results remained significant using multivariable models (p< 0.001) and were replicated in the VISP study (all tests withp< 0.05).DiscussionA higher PSH is associated with worse BP control in stroke survivors. These findings point to genetic predisposition as an important determinant of poorly controlled BP in this population.

Supplementary Figures S1-S2 and Supplementary Tables S1-S3.

Purpose: We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer.Experimental Design: Tissue microarrays were constructed from matched normal and tumor tissue derived from patients (n = 253) enrolled in a phase III trial of adjuvant 5-fluorouracil–based chemotherapy versus postoperative observation alone. TRAIL, DR5, caspase 8, and c-FLIP expression levels were determined by immunohistochemistry.Results: Colorectal tumors displayed significantly higher expression levels of c-FLIP (P < 0.001), caspase 8 (P = 0.01), and DR5 (P < 0.001), but lower levels of TRAIL (P < 0.001) compared with matched normal tissue. In univariate analysis, higher TRAIL expression in the tumor was associated with worse overall survival (P = 0.026), with a trend to decreased relapse-free survival (RFS; P = 0.06), and higher tumor c-FLIP expression was associated with a significantly decreased RFS (P = 0.015). Using multivariate predictive modeling for RFS in all patients and including all biomarkers, age, treatment, and stage, we found that the model was significant when the mean tumor c-FLIP expression score and disease stage were included (P < 0.001). As regards overall survival, the overall model was predictive when both TRAIL expression and disease stage were included (P < 0.001).Conclusions: High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III colorectal cancer and might identify patients most at risk of relapse. Clin Cancer Res; 16(13); 3442–51. ©2010 AACR.

Supplementary Tables 1-2 from The ΔNp63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer

Little is known about the origin of basal-like breast cancers, an aggressive disease that is highly similar to BRCA1-mutant breast cancers. p63 family proteins that are structurally related to the p53 suppressor protein are known to function in stem cell regulation and stratified epithelia development in multiple tissues, and p63 expression may be a marker of basal-like breast cancers. Here we report that ΔNp63 isoforms of p63 are transcriptional targets for positive regulation by BRCA1. Our analyses of breast cancer tissue microarrays and BRCA1-modulated breast cancer cell lines do not support earlier reports that p63 is a marker of basal-like or BRCA1 mutant cancers. Nevertheless, we found that BRCA1 interacts with the specific p63 isoform ΔNp63γ along with transcription factor isoforms AP-2α and AP-2γ. BRCA1 required ΔNp63γ and AP-2γ to localize to an intronic enhancer region within the p63 gene to upregulate transcription of the ΔNp63 isoforms. In mammary stem/progenitor cells, siRNA-mediated knockdown of ΔNp63 expression resulted in genomic instability, increased cell proliferation, loss of DNA damage checkpoint control, and impaired growth control. Together, our findings establish that transcriptional upregulation of ΔNp63 proteins is critical for BRCA1 suppressor function and that defects in BRCA1-ΔNp63 signaling are key events in the pathogenesis of basal-like breast cancer. Cancer Res; 71(5); 1933–44. ©2011 AACR.

Supplementary Methods from The ΔNp63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)–microdystrophin (μDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 10 13 vector genomes per kilogram (vg/kg), 1 × 10 14 vg/kg, and 2 × 10 14 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-μDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day −7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; μDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.

In many economic decisions, people estimate probabilities, such as the likelihood that a risk materializes or that a job applicant will be a productive employee, by retrieving experiences from memory. We model this process based on two established regularities of selective recall: similarity and interference. We show that the similarity structure of a hypothesis and the way it is described (not just its objective probability) shape the recall of experiences and thus probability assessments. The model accounts for and reconciles a variety of empirical findings, such as overestimation of unlikely events when these are cued versus neglect of noncued ones, the availability heuristic, the representativeness heuristic, conjunction and disjunction fallacies, and over- versus underreaction to information in different situations. The model yields several new predictions, for which we find strong experimental support.

The understanding of the molecular and cellular basis of aging has grown exponentially over recent years, and it is now accepted within the scientific community that aging is a malleable process; just as it can be accelerated, it can also be slowed and even reversed. This has far-reaching implications for our attitude and approach toward aging, presenting the opportunity to enter a new era of cellular regenerative medicine to not only manage the external signs of aging but also to develop therapies that support the body to repair and restore itself back to a state of internal well-being. A wealth of evidence now demonstrates that a decline in cellular nicotinamide adenine dinucleotide (NAD+) is a feature of aging and may play a role in the process. NAD+ plays a pivotal role in cellular metabolism and is a co-substrate for enzymes that play key roles in pathways that modify aging. Thus, interventions that increase NAD+ may slow aspects of the aging trajectory, and there is great interest in methods for cellular NAD+ restoration. Given these recent advancements in understanding the cellular aging process, it is important that there is an integration between the basic scientists who are investigating the underlying mechanisms of cellular aging and the surgeons and aesthetic practitioners who are providing antiaging therapies. This will allow the effective translation of this vastly complex area of biology into clinical practice so that people can continue to not only stay looking younger for longer but also experience improved health and wellness.

Background. The role of kidney volume measurement in predicting the donor and recipient kidney function is not clear. Methods. We measured kidney volume bilaterally in living kidney donors using CT angiography and assessed the association with the donor remaining kidney and recipient kidney (donated kidney) function at 1 year after kidney transplantation. Donor volume was categorized into tertiles based on lowest, middle, and highest volume. Results. There were 166 living donor and recipient pairs. The mean donor age was 44.8 years (SD ± 10.8), and donor mean BMI was 25.5 (SD ± 2.9). The recipients of living donor kidneys were 64% male and had a mean age of 43.5 years (SD ± 13.3). Six percent of patients experienced an episode of cellular rejection and were maintained on dialysis for a mean of 18 months (13–32) prior to transplant. Kidney volume was divided into tertiles based on lowest, middle, and highest volume. Kidney volume median (range) in tertiles 1, 2, and 3 was 124 (89–135 ml), 155 (136–164 ml), and 184 (165–240 ml) with donor eGFR ml/min (adjusted for body surface area expressed as ml/min/1.73 m2) at the time of donation in each tertile, 109 (93–129), 110 (92–132), and 101 ml/min (84–117). The median (IQR) eGFR in tertiles 1 to 3 in kidney recipients at 1 year after donation was 54 (44–67), 62 (50–75), and 63 ml/min (58–79), respectively. The median (IQR) eGFR in tertiles 1 to 3 in the remaining kidney of donors at 1 year after donation was 59 (53–66), 65 (57–72), and 65 ml/min (56–73), respectively. Conclusion. Bigger kidney volume was associated with better eGFR at 1 year after transplant in the recipient and marginally in the donor remaining kidney.

Chronic inflammation, long implicated in the genesis of malignancy, is now understood to underlie an estimated 25% of all cancers. The most pertinent malignancies, to the plastic surgeon, associated with the degeneration of chronic inflammation include Marjolin's ulcer, breast implant-associated large cell lymphoma, radiation-induced sarcoma, and Kaposi's sarcoma. The cellular and genetic damage incurred by a prolonged inflammatory reaction is controlled by an increasingly understood cytokinetic system. Advances in understanding the chronic inflammatory cascade have yielded new therapeutics and therapeutic targets.

Background Podocyte dysfunction is the main pathologic mechanism driving the development of FSGS and other morphologic types of steroid-resistant nephrotic syndrome (SRNS). Despite significant progress, the genetic causes of most cases of SRNS have yet to be identified. Methods Whole-genome sequencing was performed on 320 individuals from 201 families with familial and sporadic NS/FSGS with no pathogenic mutations in any known NS/FSGS genes. Results Two variants in the gene encoding regulator of calcineurin type 1 (RCAN1) segregate with disease in two families with autosomal dominant FSGS/SRNS. In vitro, loss of RCAN1 reduced human podocyte viability due to increased calcineurin activity. Cells expressing mutant RCAN1 displayed increased calcineurin activity and NFAT activation that resulted in increased susceptibility to apoptosis compared with wild-type RCAN1. Treatment with GSK-3 inhibitors ameliorated this elevated calcineurin activity, suggesting the mutation alters the balance of RCAN1 regulation by GSK-3β, resulting in dysregulated calcineurin activity and apoptosis. Conclusions These data suggest mutations in RCAN1 can cause autosomal dominant FSGS. Despite the widespread use of calcineurin inhibitors in the treatment of NS, genetic mutations in a direct regulator of calcineurin have not been implicated in the etiology of NS/FSGS before this report. The findings highlight the therapeutic potential of targeting RCAN1 regulatory molecules, such as GSK-3β, in the treatment of FSGS.

Data scientists are among the highest-paid and most in-demand employees in the 21st century. This gives them opportunities to switch jobs quite easily. In this paper, we follow the Cross-Industry Standard Process for Data Mining (CRISP-DM) approach and the data science life cycle process to analyze factors which predict whether a data scientist is looking for a new job or not. Specifically, we use machine learning techniques to analyze data from Kaggle.com. We find that features that have the highest impact on whether a data scientist wants to change his/her job include the city development index, company size, and company type. When we examine the city development index more carefully, we find evidence suggesting that employees move from cities with lower to higher development indexes, as they become more experienced. The predictive analysis system we use is able to predict with average accuracy rates of higher than 78%.