Assessment of postbrachytherapy sexual function: a comparison of the IIEF-5 and the MSEFS

PURPOSE: This study is to compare the Mount Sinai Erectile Function Score (MSEFS), our brachytherapy program's physician-assigned scale, with patients' independently completed International Index of Erectile Function-5 (IIEF-5). METHODS AND MATERIALS: A total of 1202 patients with T1-T3 prostate cancer were treated with ultrasound-guided radioactive seed implantation +/- EBRT with at least one visit where both MSEFS and IIEF-5 were completed. Spearman rho correlations were performed. RESULTS: The MSEFS significantly correlated with the total IIEF-5 scores on all comparisons. The coefficient was 0.65 for comparisons at initial consultation and 0.76 for all visits. The correlations remained strong, averaging to 0.76 for visits 1 through 10. CONCLUSIONS: In assessing erectile dysfunction after radiation, the MSEFS correlates well with, but cannot be replaced by, the IIEF-5, which is weighted toward one's degree of sexual desire. More insight into patients' erectile function after brachytherapy may be gotten if the IIEF-15 is used instead of the IIEF-5 with our MSEFS.     

Hind limb ischemia-reperfusion in the leptin receptor deficient (db/db) mouse

BACKGROUND: Diabetic patients have high incidence of peripheral vascular disease and limb loss after acute extremity injury. Experiments were designed to test the hypothesis that acute tissue injury in leptin receptor deficient (Db) diabetic (type2) mice would be more severe than in non-diabetic mice. METHODS: Db and wild type (Wt) mice were subjected to 3 h of ischemia followed by either 4 or 24 h of reperfusion (3/4 IR, 3/24 IR). Muscle analyzed for tissue viability (mitochondrial activity), cytokines (KC-murine equivalent of human IL-8, TNFalpha, IL-6), growth factor, and histological evaluation (neutrophils/uninjured muscle fibers). Tissue perfusion was detected during basal and reperfusion conditions using laser Doppler imaging. RESULTS: Mitochondrial activity and histological evaluation for tissue injury did not differ in the Db versus Wt mice at the time intervals studied. When compared with their respective sham animals, both Db and Wt mice had similarly increased levels of KC, IL-6, and VEGF after 3/24 IR. TNFalpha levels increased in Db but not Wt mice after IR. Although absolute increases in TNFalpha and KC were higher in Db mice, VEGF levels were actually lower in the Db mice. CONCLUSION: The patterns of tissue perfusion, cytokines, and growth factors were different in Db versus Wt mice. At the acute time intervals studied, these differences did not correlate with an expected greater degree of acute muscle injury in Db mice.     

Oxidative stress and autophagy in the regulation of lysosome-dependent neuron death

Lysosomes critically regulate the pH-dependent catabolism of extracellular and intracellular macromolecules delivered from the endocytic/heterophagy and autophagy pathways, respectively. The importance of lysosomes to cell survival is underscored not only by their unique ability effectively to degrade metalloproteins and oxidatively damaged macromolecules, but also by the distinct potential for induction of both caspase-dependent and -independent cell death with a compromise in the integrity of lysosome function. Oxidative stress and free radical damage play a principal role in cell death induced by lysosome dysfunction and may be linked to several upstream and downstream stimuli, including alterations in the autophagy degradation pathway, inhibition of lysosome enzyme function, and lysosome membrane damage. Neurons are sensitive to lysosome dysfunction, and the contribution of oxidative stress and free radical damage to lysosome dysfunction may contribute to the etiology of neurodegenerative disease. This review provides a broad overview of lysosome function and explores the contribution of oxidative stress and autophagy to lysosome dysfunction-induced neuron death. Putative signaling pathways that either induce lysosome dysfunction or result from lysosome dysfunction or both, and the role of oxidative stress, free radical damage, and lysosome dysfunction in pediatric lysosomal storage disorders (neuronal ceroid lipofuscinoses or NCL/Batten disease) and in Alzheimer's disease are emphasized.     

Cyclin D as a therapeutic target in cancer

Cyclin D1, and to a lesser extent the other D-type cyclins, is frequently deregulated in cancer and is a biomarker of cancer phenotype and disease progression. The ability of these cyclins to activate the cyclin-dependent kinases (CDKs) CDK4 and CDK6 is the most extensively documented mechanism for their oncogenic actions and provides an attractive therapeutic target. Is this an effective means of targeting the cyclin D oncogenes, and how might the patient subgroups that are most likely to benefit be identified?     

Chitosan hydrogel for localized gene silencing

Objective

To achieve effective delivery of siRNA into target cells in vivo, we have developed a novel approach of siRNA delivery by using local drug delivery systems.

Results

The chitosan hydrogel (CH-HG) displayed a liquid-solid phase transition in a temperature-dependent manner and formed an endothermic hydrogel in tumor tissue after intra-tumoral injection. Additionally, we tested the extent of in vivo delivery following a single intra-tumoral injection of Alexa555 siRNA/CH-HG into A375SM-bearing mice. The Alexa555 siRNA demonstrated higher localization into tumor cells compared to control. The Alexa555 siRNA delivery extends to tumor cells outside of CH-HG and some tumor cells also infiltrated into CH-HG. For therapeutic proof-of-concept studies, CH-HG including TG2-targeted siRNA significantly inhibited tumor growth in melanoma (A375SM) and breast (MDA-MB231) tumor models compared to control (A375SM: 72% reduction and MDA-MB231: 92% reduction, p < 0.001).

Experimental Design

We prepared a CH-HG system loaded with siRNA to enhance localized therapeutic efficacy without risk for systemic side effects. Delivery of siRNA into CH-HG was confirmed by fluorescence microscopy. Antitumor efficacy was examined in mouse models of melanoma (A375SM) and breast (MDA-MD231) cancer.

Conclusions

This study developed a novel local delivery method for siRNA therapy using the CH-HG system. This approach could have broad applications for multiple localized diseases.Key words: RNA interference, chitosan, hydrogel, local delivery     

Circadian Activity Rhythms and Mortality: The Study of Osteoporotic Fractures

OBJECTIVES: To determine whether circadian activity rhythms are associated with mortality in community‐dwelling older women. DESIGN: Prospective study of mortality. SETTING: A cohort study of health and aging. PARTICIPANTS: Three thousand twenty‐seven community‐dwelling women from the Study of Osteoporotic Fractures cohort (mean age 84). MEASUREMENTS: Activity data were collected using wrist actigraphy for a minimum of three 24‐hour periods, and circadian activity rhythms were computed. Parameters of interest included height of activity peak (amplitude), midline estimating statistic of rhythm (mesor), strength of activity rhythm (robustness), and time of peak activity (acrophase). Vital status, with cause of death adjudicated through death certificates, was prospectively ascertained. RESULTS: Over an average of 4.1 years of follow‐up, there were 444 (14.7%) deaths. There was an inverse association between peak activity height and all‐cause mortality rates, with higher mortality rates observed in the lowest activity quartile (hazard ratio (HR)=2.18, 95% confidence interval (CI)=1.63–2.92) than in the highest quartile after adjusting for age, clinic site, race, body mass index, cognitive function, exercise, instrumental activity of daily living impairments, depression, medications, alcohol, smoking, self‐reported health status, married status, and comorbidities. A greater risk of mortality from all causes was observed for those in the lowest quartiles of mesor (HR=1.71, 95% CI=1.29–2.27) and rhythm robustness (HR=1.97, 95% CI=1.50–2.60) than for those in the highest quartiles. Greater mortality from cancer (HR=2.09, 95% CI=1.04–4.22) and stroke (HR=2.64, 95% CI=1.11–6.30) was observed for later peak activity (after 4:33 p.m.; >1.5 SD from mean) than for the mean peak range (2:50–4:33 p.m.). CONCLUSION: Older women with weak circadian activity rhythms have higher mortality risk. If confirmed in other cohorts, studies will be needed to test whether interventions (e.g., physical activity, bright light exposure) that regulate circadian activity rhythms will improve health outcomes in older adults.