Pin1: A molecular orchestrator in the heart

Pin1 is an evolutionarily conserved peptidyl–prolyl isomerase that binds and changes the three-dimensional conformation of specific phospho-proteins. By regulating protein structure and folding, Pin1 affects the stability, interaction, and activity of a broad spectrum of target proteins, thus impacting upon diverse cellular processes. This review discusses the pivotal role Pin1 plays in regulating cardiac pathophysiology by functioning as a “molecular orchestrator” of a myriad of signal transduction pathways in the heart.     

Serum Isoform [−2]proPSA Derivatives Significantly Improve Prediction of Prostate Cancer at Initial Biopsy in a Total PSA Range of 2–10 ng/ml: A Multicentric European Study

Background

Strategies to reduce prostate-specific antigen (PSA)–driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary.

Objective

To test the accuracy of serum isoform [−2]proPSA (p2PSA) and its derivatives, percentage of p2PSA to free PSA (fPSA; %p2PSA) and the Prostate Health Index (PHI)—called index tests—in discriminating between patients with and without PCa.

Design, setting, and participants

This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tPSA) range of 2–10 ng/ml who were subjected to initial prostate biopsy for suspected PCa.

Outcome measurements and statistical analysis

The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of fPSA to tPSA (%fPSA) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis.

Results and limitations

Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tPSA (5.7 vs 5.8 ng/ml; p = 0.942) and p2PSA (15.0 vs 14.7 pg/ml) did not differ between groups; conversely, median fPSA (0.7 vs 1 ng/ml; p < 0.001), %fPSA (0.14 vs 0.17; p < 0.001), %p2PSA (2.1 vs 1.6; p < 0.001), and PHI (48.2 vs 38; p < 0.001) did differ significantly between men with and without PCa. In multivariable logistic regression models, p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p < 0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tPSA values.

Conclusions

In patients with a tPSA range of 2–10 ng/ml, %p2PSA and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tPSA and %fPSA.

Trial registration

The study is registered at http://www.controlled-trials.com, ref. ISRCTN04707454.     

Cytotoxicity,cellular uptake and apoptotic responses in human coronary artery endothelial cells exposed to ultrasmall superparamagnetic iron oxide nanoparticles

Ultrasmall superparamagnetic iron oxide nanoparticles (USPION) possess reactive surfaces, are metabolized and exhibit unique magnetic properties. These properties are desirable for designing novel theranostic biomedical products; however, toxicity mechanisms of USPION are not completely elucidated. The goal of this study was to investigate cell interactions (uptake and cytotoxicity) of USPION using human coronary artery endothelial cells as a vascular cell model. Polyvinylpirrolidone-coated USPION were characterized: average diameter 17 nm (transmission electron microscopy [TEM]), average hydrodynamic diameter 44 nm (dynamic light scattering) and zeta potential −38.75 mV. Cells were exposed to 0 (control), 25, 50, 100 or 200 μg/mL USPION. Concentration- and time-dependent cytotoxicity were observed after 3-6 hours through 24 hours of exposure using Alamar Blue and Real-Time Cell Electronic Sensing assays. Cell uptake was evaluated by imaging using live-dead confocal microscopy, actin and nuclear fluorescent staining, and TEM. Phase-contrast, confocal microscopy, and TEM imaging showed significant USPION internalization as early as 3 hours after exposure to 25 μg/mL. TEM imaging demonstrated particle internalization in secondary lysosomes with perinuclear localization. Three orthogonal assays were conducted to assess apoptosis. TUNEL staining demonstrated a marked increase in fragmented DNA, a response pathognomonic of apoptosis, after a 4-hour exposure. Cells subjected to agarose gel electrophoresis exhibited degraded DNA 3 hours after exposure. Caspase-3/7 activity increased after a 3-hour exposure. USPION uptake resulted in cytotoxicity involving apoptosis and these results contribute to further mechanistic understanding of the USPION toxicity in vitro in cardiovascular endothelial cells.     

Effectiveness and Tolerability of Istradefylline for the Treatment of Restless Legs Syndrome: An Exploratory Study in Five Female Patients

Background: Studies of istradefylline (KW6002), an adenosine A_2A-receptor antagonist, have provided evidence of its efficacy as a nondopaminergic antiparkinsonian drug. Antiparkinsonian drugs have also had efficacy in treating restless legs syndrome (RLS).Objectives: The aims of this study were to assess the effectiveness and tolerability of istradefylline in the treatment of RLS.Methods: This was a single-center, multiparametric, prospective trial of istradefylline as a treatment for moderate to severe idiopathic RLS. It was conducted at the Shands/Jacksonville Sleep Disorders Center, University of Florida, Jacksonville, Florida, from March 2003 to October 2003. Patients received a single PO 80-mg dose QD of istradefylline in the late afternoon or early evening for 6 weeks. Appropriate tolerability evaluations (ie, vital assessments, physical examination, clinical laboratory tests, and electrocardiogram) were performed at screening, while on study drug, and after withdrawal of study drug.Results: Fifteen participants (mean [SD] age, 61 [7.1] years; range, 50-69 years) were screened for enrollment. The mean duration of RLS was 18 years. Of the 15 potential patients, 6 did not meet entry criteria, 2 withdrew consent, 1 had not completed baseline procedures at the time of study suspension, and 1 was excluded for administrative reasons. Therefore, a total of 5 patients received the study drug. Of these, 3 (60%) patients responded favorably to istradefylline treatment. Improvement in the periodic limb movement index was observed in 3 patients compared with baseline (patients 2, 4, and 5 [index score: 6, 4, 9 vs 50, 35, 18, respectively]). Improvement in the International RLS Rating Scale scores was observed in 3 patients compared with baseline (patients 2, 4, and 5 [index score: 7, 23, 9 vs 35, 25, 20, respectively]). There was a return to baseline severity in 2 of the 3 patients after withdrawal of study drug. Improvement in RLS symptoms was observed in 3 patients treated with istradefylline for 6 weeks. A clinical worsening of baseline insomnia was observed in 2 patients.Conclusions: Although we could not definitively conclude a beneficial effect based on this small exploratory trial, we found the data to be encouraging. The study drug was well tolerated. Further study of this compound in the treatment of RLS is justified.     

The Sequential Relation Between Changes in Catastrophizing and Changes in Posttraumatic Stress Disorder Symptom Severity

Catastrophizing has been discussed as a cognitive precursor to the emergence of posttraumatic stress disorder (PTSD) symptoms following the experience of stressful events. Implicit in cognitive models of PTSD is that treatment-related reductions in catastrophizing should yield reductions in PTSD symptoms. The tenability of this prediction has yet to be tested. The present study investigated the sequential relation between changes in a specific form of catastrophizing—symptom catastrophizing—and changes in PTSD symptom severity in a sample of 73 work-disabled individuals enrolled in a 10-week behavioral activation intervention. Measures of symptom catastrophizing and PTSD symptom severity were completed at pre-, mid-, and posttreatment assessment points. Cross-sectional analyses of pretreatment data revealed that symptom catastrophizing accounted for significant variance in PTSD symptom severity, β = .40, p < .001, sr = .28 (medium effect size), even when controlling for known correlates of symptom catastrophizing, such as pain and depression. Significant reductions in symptom catastrophizing and PTSD symptoms were observed during treatment, with large effect sizes, ds = 1.42 and 0.94, respectively, ps < .001. Cross-lagged analyses revealed that early change in symptom catastrophizing predicted later change in PTSD symptoms; early changes in PTSD symptom severity did not predict later change in symptom catastrophizing. These findings are consistent with the conceptual models that posit a causal relation between catastrophizing and PTSD symptom severity. The clinical implications of the findings are discussed.     

巨噬细胞迁移抑制因子通过CC趋化因子配体2诱导巨噬细胞聚集

巨噬细胞迁移抑制因子最初是由于能抑制体外巨噬细胞随机迁移而被发现,现在它作为一种重要的调节因子参与一系列炎症性疾病过程.我们最近发现,巨噬细胞迁移抑制因子的缺失使一些由炎症介质诱发的白细胞-内皮细胞相互作用减弱,提示巨噬细胞迁移抑制因子在炎症反应中起作用的机制之一是促进白细胞聚集.……