Citations

Many neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Polyglutamine disorders are characterized by conformational change in proteins that result in misfolding, aggregation and accumulation of amyloid fibrils. These misfolded species result in toxicity in cells and ultimately lead to the death of specific neuronal populations. The cellular pathways involved in these neurological disorders are still unclear but a large body of evidence suggests that molecular chaperones, regulators of cellular protein quality control, may play a critical role in neurodegeneration. Indeed in patient post-mortem brain, chaperones are found in the hallmark neuronal inclusions. Molecular chaperones are able to inhibit the aggregation of denatured proteins and facilitate refolding of different disease-causing proteins. Experimental approaches in animal and cellular models have shown prevention of protein misfolding and facilitation of clearance mechanisms via up-regulation of molecular chaperones. Therefore manipulating the molecular chaperone system may be a successful strategy to counter the conformational changes occurring in protein misfolding diseases and may offer new therapeutic promise. Here we review the evidence for the involvement of various molecular chaperones in several neurodegenerative disorders and examine the current research investigating the role of the chaperones as novel targets for therapy of these devastating diseases.

Abstract Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1α. Analysis of the mechanism shows that IRE1α endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1α signaling using either siRNA-mediated silencing or a dominant-negative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-α substrate, thereby pointing toward an increased IRE1α activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development. Cancer Res; 73(15); 4732–43. ©2013 AACR.

The Rochester bone trephine is a useful instrument for performing small joint arthrodesis in the foot. The technique involves harvesting a dowel graft from the iliac crest and then inserting the graft into a recipient bed across the small joints in the foot. Minimal surgical trauma and patient discomfort result from this technique. Three cases are presented to illustrate the usefulness and diversity of this system.

Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.

Abstract Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.

Background: Although a gradual increase in heart rate (HR) during dobutamine stress testing (DST) is desired, few data exists regarding whether this is similarly achieved in patients of widely varying body mass index (BMI). Whether difference in BMI contributes to variation in the hemodynamic and symptomatic response to dobutamine is also unknown. Methods: From prospectively acquired data of 2776 consecutive patients who underwent DST according to standard weight-based clinical protocol, we classified patients into 4 groups of BMI (kg/m 2 ): <25 (normal), 25 to 29.9 (overweight), 30 to 39.9 (obese), and ≥40 (severely obese) and compared the rate of increase of HR, mean blood pressure, and development of symptoms for the groups. Results: Age was 68 + 12 years, 52% were men, BMI was 29.8 + 6.6 kg/m 2 (range 14.5-81.4), 198 (7%) had BMI ≥40, and target HR was achieved in 2433 (88%). The rate of increase in HR was similar for each group of BMI after adjustment for age, gender, baseline HR, negative chronotropic use, and atropine administration. The percentage of patients in each group who achieved target HR was similar and the percentage of target HR achieved at each stage of dobutamine was essentially equivalent. Blood pressure responses and development of symptoms were similar in the 4 groups of BMI. Independent predictors of failure to achieve target HR included age, diabetes mellitus, treatment with negative chronotropic medications, and baseline HR; BMI was not a predictor (odds ratio [OR] 0.98, P = .086). Conclusion: The current weight-based protocol of dobutamine dosing for DST results in similar increases in HR and blood pressure for patients of widely varying BMI.