Citations

29 Background: Better biomarkers are needed in prostate cancer (PCa) to predict disease recurrence and guide optimal therapy. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor cancer phenotype impact PCa biology and clinical outcomes in localized disease. Methods: Genes associated with self-renewal, drug resistance, and tumorigenicity were analyzed by qRT-PCR on PCa mRNA from radical prostatectomy (RP) specimens (+/- disease recurrence). Wilcoxon rank sum two-sample test, multivariable recursive partitioning, and bootstrap internal validation measured and confirmed associations with recurrence. Further validation was conducted in external cohorts and in-silico, as well as in vitro and in vivo using siRNA knockdown and lentiviral overexpression to determined the effect of gene expression on PCa proliferation, invasion and tumor growth. Results: Four candidate genes were differentially expressed in PCa recurrence, and of these, low AXIN2 expression was internally validated. Validation in external cohorts demonstrated low AXIN2 expression was associated with more aggressive prostate cancer and was independently associated with biochemical recurrence (BCR) and metastasis-free survival (MFS) after RP. In vitro, low AXIN2 expression was associated with a cancer stem-like cell-surface signature, and siRNA knockdown of AXIN2 resulted in significantly greater invasiveness. Conversely, ectopic overexpression of AXIN2 significantly reduced cell proliferation and tumor growth in mice. Conclusions: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts. AXIN2 expression levels in PCa cells significantly impacted invasiveness, proliferation and tumor growth. AXIN2 represents a putative biomarker and potential therapeutic target in early prostate cancer.

OBJECTIVES: To describe the demographic and clinical characteristics of pediatric multiple sclerosis (MS) in the United States. METHODS: This prospective observational study included children and adolescents with MS. Cases were evaluated across 9 geographically diverse sites as part of the US Network of Pediatric MS Centers. RESULTS: A total of 490 children and adolescents (324 girls, 166 boys) were enrolled; 28% developed symptoms before 12 years of age. The proportion of girls increased with age from 58% (<12 years) to 70% (≥12 years). Race and ethnicity as self-identified were: white, 67%; African American, 21%; and non-Hispanic, 70%. Most (94%) of the cases were born in the United States, and 39% had 1 or both foreign-born parents. Fifty-five percent of cases had a monofocal presentation; 31% had a prodrome (most frequently infectious), most often among those aged <12 years (P < .001). Children aged <12 years presented more commonly with encephalopathy and coordination problems (P < .001). Sensory symptoms were more frequently reported by older children (ie, those aged ≥12 years) (P < .001); 78% of girls had MS onset postmenarche. The initial Expanded Disability Status Scale score for the group was <3.0, and the annualized relapse rate was 0.647 for the first 2 years. Interval from symptom onset to diagnosis and from diagnosis to initiation of disease-modifying therapy was longer among those <12 years of age. CONCLUSIONS: Pediatric MS in the United States is characterized by racial and ethnic diversity, a high proportion of children with foreign-born parents, and differences in clinical features and timing of treatment among those <12 years of age compared with older children.

A lung-protective ventilator strategy significantly reduces mortality in patients with acute lung injury. Substantial progress has been made in understanding how mechanical stress can injure the lung, both in terms of alterations in barrier properties of the pulmonary endothelium and epithelium as well as in stimulating proinflammatory responses of macrophages and neutrophils.

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

AbstractIn order to understand the link between the genetic background of patients and wound clinical outcomes, it is critical to have a reliable method to assess the phenotypic characteristics of healed wounds. In this study, we present a novel imaging method that provides reproducible, sensitive, and unbiased assessments of postsurgical scarring. We used this approach to investigate the possibility that genetic variants in orofacial clefting genes are associated with suboptimal healing. Red‐green‐blue digital images of postsurgical scars of 68 patients, following unilateral cleft lip repair, were captured using the 3dMD imaging system. Morphometric and colorimetric data of repaired regions of the philtrum and upper lip were acquired using ImageJ software, and the unaffected contralateral regions were used as patient‐specific controls. Repeatability of the method was high with intraclass correlation coefficient score > 0.8. This method detected a very significant difference in all three colors, and for all patients, between the scarred and the contralateral unaffected philtrum (p ranging from 1.20−05 to 1.95−14). Physicians’ clinical outcome ratings from the same images showed high interobserver variability (overall Pearson coefficient = 0.49) as well as low correlation with digital image analysis results. Finally, we identified genetic variants in TGFB3 and ARHGAP29 associated with suboptimal healing outcome.

BACKGROUND Platelet-thrombus formation is a complication of arterial wall deep injury by balloon angioplasty that may lead to acute arterial occlusion and may contribute to restenosis. METHODS AND RESULTS Because common platelet-inhibitor drugs with a heparin bolus (100 units/kg) may be effective in inhibiting platelet-thrombus formation after arterial angioplasty, these were compared with a bolus of heparin alone (control), the specific thrombin inhibitor hirudin (1.0 mg/kg), and saline (hirudin control) in normal pigs after angioplasty of the common carotid arteries. In the presence of deep arterial wall injury (injury exposing the media), indium-111-labeled platelet deposition (x 10(6)/cm2) was 68.8 +/- 12.3 and 48.1 +/- 16.9 in the control animals. This was significantly reduced by pretreatment with low-dose aspirin (1 mg/kg/day), by high-dose aspirin (20 mg/kg/day) plus dipyridamole, and especially by thrombin inhibition with hirudin. Treatment regimens with aspirin alone (20 mg/kg/day), dipyridamole alone, or sulfinpyrazone were ineffective. Likewise, the incidence of mural thrombosis was 75% and 80% in deeply injured arteries of controls and was significantly reduced to 46% with aspirin plus dipyridamole, 25% with low-dose aspirin, and 0% with hirudin. The incidence of mural thrombosis was unchanged with high-dose aspirin (69%), dipyridamole (90%), or sulfinpyrazone (92%). This mural thrombosis could not be identified by angiography. In the presence of mild injury (deendothelialization), platelet deposition was low (less than 10 x 10(6)/cm2, a single layer) and was not changed by any therapy, including hirudin. CONCLUSIONS These therapies do not affect platelet adhesion to deeply or mildly injured artery. These data suggest a greater role for thrombin inhibition than with thromboxane or cyclooxygenase inhibition in the pathogenesis of platelet-rich mural thrombosis after deep injury during angioplasty. Antithrombotic therapy for arterial thrombosis by thrombin inhibition appears promising.