Tumor-Derived Extracellular Vesicles Require ß1 Integrins to Promote Anchorage-Independent Growth.

The ß1 integrins, known to promote cancer progression, are abundant in extracellular vesicles (EVs). We investigated whether prostate cancer (PrCa) EVs affect anchorage-independent growth and whether ß1 integrins are required for this effect. Specifically using a cell-line-based genetic rescue and an in vivo PrCa model, we show that gradient-purified small EVs (sEVs) from either cancer cells or blood from tumor-bearing TRAMP (transgenic adenocarcinoma of the mouse prostate) mice promote anchorage-independent growth of PrCa cells. In contrast, sEVs from cultured PrCa cells harboring a short hairpin RNA to ß1, from wild-type mice or from TRAMP mice carrying a ß1 conditional ablation in the prostatic epithelium (ß1pc-/-), do not. We find that sEVs, from cancer cells or TRAMP blood, are functional and co-express ß1 and sEV markers; in contrast, sEVs from ß1pc-/-/TRAMP or wild-type mice lack ß1 and sEV markers. Our results demonstrate that ß1 integrins in tumor-cell-derived sEVs are required for stimulation of anchorage-independent growth.

Prostate cancer sheds the αvß3 integrin in vivo through exosomes.

The αvß3 integrin has been shown to promote aggressive phenotypes in many types of cancers, including prostate cancer. We show that GFP-labeled αvß3 derived from cancer cells circulates in the blood and is detected in distant lesions in NOD scid gamma (NSG) mice. We, therefore, hypothesized that αvß3 travels through exosomes and tested its levels in pools of vesicles, which we designate extracellular vesicles highly enriched in exosomes (ExVs), and in exosomes isolated from the plasma of prostate cancer patients. Here, we show that the αvß3 integrin is found in patient blood exosomes purified by sucrose or iodixanol density gradients. In addition, we provide evidence that the αvß3 integrin is transferred through ExVs isolated from prostate cancer patient plasma to ß3-negative recipient cells. We also demonstrate the intracellular localization of ß3-GFP transferred via cancer cell-derived ExVs. We show that the ExVs present in plasma from prostate cancer patients contain higher levels of αvß3 and CD9 as compared to plasma ExVs from age-matched subjects who are not affected by cancer. Furthermore, using PSMA antibody-bead mediated immunocapture, we show that the αvß3 integrin is expressed in a subset of exosomes characterized by PSMA, CD9, CD63, and an epithelial-specific marker, Trop-2. Finally, we present evidence that the levels of αvß3, CD63, and CD9 remain unaltered in ExVs isolated from the blood of prostate cancer patients treated with enzalutamide. Our results suggest that detecting exosomal αvß3 integrin in prostate cancer patients could be a clinically useful and non-invasive biomarker to follow prostate cancer progression. Moreover, the ability of αvß3 integrin to be transferred from ExVs to recipient cells provides a strong rationale for further investigating the role of αvß3 integrin in the pathogenesis of prostate cancer and as a potential therapeutic target.

Oral contraceptives cause evolutionarily novel increases in hormone exposure: A risk factor for breast cancer.

Background and objectives: In the evolutionary past, women spent most of their reproductive lives either pregnant or in lactational amenorrhea, and rarely menstruated. The current pattern of frequent menses, and the associated increase in endogenous hormonal exposure, has been implicated in the current breast cancer epidemic. It is not known, however, whether oral contraceptives further increase, or actually decrease, hormonal exposure over one menstrual cycle. Here, we examined variation in hormonal exposure across seven oral contraceptive (OC) formulations, and produced the first quantitative comparison of exogenous versus endogenous hormone exposure. Methodology: Data from 12 studies of serum estradiol (E2) and progesterone (P4) were aggregated to create a composite graph of endogenous hormone levels over one menstrual cycle in European or American women (age 19-40 years). Pharmacokinetic package insert data, also from Western women, were used to calculate exposures for hormones in seven different OC formulations. Endogenous and exogenous hormone levels were compared after adjusting for the relative binding affinity (RBA) of progestin to the progesterone receptor and ethinyl estradiol (EE) to the estrogen receptor. Results: After adjusting for RBA, median ethinyl estradiol exposure across 28 days in the OCs was 11.4 nmol/l, similar to median E2 exposure. One formulation, however, was 40% higher in ethinyl estradiol exposure relative to median endogenous estradiol. Median exposure from progestins in OCs (1496 nmol/l) was 4-fold higher than the median endogenous exposure from P4 (364 nmol/l). Exposure from OC progestins ranged from one sixtieth to 8-fold median endogenous P4 over 28 days. Conclusions and implications: Given that breast cancer risk increases with hormonal exposure, our finding that four widely prescribed formulations more than quadruple progestin exposure relative to endogenous progesterone exposure is cause for concern. As not all formulations produce the same exposures, these findings are pertinent to contraceptive choice. We also identify critical gaps in the provision of relevant data on pharmacokinetics and carcinogenicity by drug manufacturers.

Integrating Bar-Code Medication Administration Competencies in the Curriculum: Implications for Nursing Education and Interprofessional Collaboration.

This article describes an innovative project involving the integration of bar-code medication administration technology competencies in the nursing curriculum through interprofessional collaboration among nursing, pharmacy, and computer science disciplines. A description of the bar-code medication administration technology project and lessons learned are presented.

Effect of a brief, regular telephone intervention by paraprofessionals for type 2 diabetes.

Brief, cost-effective interventions to promote diabetes self-management are needed. This study evaluated the effects of a brief, regular, proactive, telephone "coaching" intervention delivered by paraprofessionals on diabetes adherence, glycemic control, diabetes-related medical symptoms, and depressive symptoms. Therapeutic mechanisms underlying the intervention's effect on the primary outcomes were also examined. Adults diagnosed with type 2 diabetes (N = 62) were randomly assigned to receive the "coaching" intervention and treatment as usual, or only treatment as usual. The intervention increased frequency of exercise and feet inspection, improved diet, reduced diabetes medical symptoms, and lowered depressive symptoms. Self-efficacy, reinforcement, and awareness of self-care goals mediated the treatment effect on depression, exercise, and feet inspection, respectively. A brief telephone intervention delivered by paraprofessionals had positive effects on type 2 diabetes patients.

Adherence, body mass index, and depression in adults with type 2 diabetes: the mediational role of diabetes symptoms and self-efficacy.

OBJECTIVE: Evidence indicates that depression is linked to the development and worsening of diabetes, but the mechanisms underlying this link are not well understood. The authors examined the hypothesis that diabetes-related symptoms mediate the effect of both behavioral adherence and body mass index (BMI) on depression. In addition, they examined whether a prior finding that self-efficacy mediates the effect of behavioral adherence and BMI on depression would replicate with a larger sample size (W. P. Sacco, K. J. Wells, C. A. Vaughan, A. Friedman, S. Perez, & R. Morales, 2005). Also, the relative contributions of diabetes-related symptoms and self-efficacy to depression were evaluated. DESIGN AND PARTICIPANTS: Cross-sectional design involving adults diagnosed with Type 2 diabetes (N = 99). MAIN OUTCOME MEASURES: The primary outcome measure was depression (Patient Health Questionnaire: Nine Symptom Depression Checklist). Predictors of depression were diet and exercise adherence (Summary of Diabetes Self-Care Activities Questionnaire), diet and exercise self-efficacy (Multidimensional Diabetes Questionnaire), diabetes symptoms (Diabetes Symptom Checklist), and BMI (based on height and weight data from medical records). RESULTS: Path and mediation analyses indicated that adherence and BMI each contributed to depression indirectly, via their effects on self-efficacy and diabetes-related medical symptoms. CONCLUSION: Results provide evidence consistent with two independent pathways by which BMI and adherence could increase depression in people with Type 2 diabetes. The first pathway indicates that the effects of higher BMI and poor adherence on depression are mediated by lower self-efficacy perceptions. The second pathway indicates that the effect of higher BMI on depression is mediated by increased diabetes symptoms.

Depression in adults with type 2 diabetes: the role of adherence, body mass index, and self-efficacy.

Considerable evidence links depression with the development and worsening of diabetes, but the factors contributing to this link have not been established. The authors examined the role of adherence, body mass index (BMI), and self-efficacy. Adult patients with Type 2 diabetes (N = 56) completed self-report measures of diet and exercise adherence, diet and exercise self-efficacy, and depression. BMI was obtained from medical records. Path and mediation analyses indicated that both adherence and BMI independently contributed to self-efficacy. Self-efficacy mediated both the association between adherence and depression and the association between BMI and depression. These findings are consistent with the proposal that lower self-efficacy in reaction to adherence failure and higher BMI contributes to depression in adults with diabetes.