Based on identified molecular cross-talk between the two contiguous cell populations, a mechanistic model that spurs invasion is proposed, that shows breast cancer invasion proceeds through the acquisition of a motile phenotype in tumor epithelial cells and a reactive phenotype in cancer associated fibroblasts.

Cancer associated fibroblasts (CAFs) are believed to promote tumor growth and progression. Our objective was to measure the effect of TGF-beta1 on fibroblasts isolated from invasive breast cancer patients. Fibroblasts were isolated from tissue obtained at surgery from patients with invasive breast cancer (CAF; n = 28) or normal reduction mammoplasty patients (normal; n = 10). Myofibroblast activation was measured by counting cells immunostained for smooth muscle alpha actin (ACTA2) in cultures +/- TGF-beta 1. Conditioned media (CM) was collected for invasion assays and RNA was isolated from cultures incubated in media +/- TGF-beta1 for 24 h. Q-PCR was used to measure expression of cyclin D1, fibronectin, laminin, collagen I, urokinase, stromelysin-1, and ACTA2 genes. Invasion rate was measured in chambers plated with MDA-MB-231 cells and exposed to CM in the bottom chamber; the number of cells that invaded into the bottom chamber was counted. Wilcox Rank Sum tests were used to evaluate differences in CAFs and normal fibroblasts and the effect of TGF-beta 1. There was no difference in percent myofibroblasts or invasion rate between normal and CAF cultures. However, TGF-beta1 significantly increased the percent of myofibroblasts (P < 0.01) and invasion rate (P = 0.02) in CAF cultures. Stromelysin-1 expression was significantly higher in normal versus CAF cultures (P < 0.01). TGF-beta 1 significantly increased ACTA2 expression in both normal and CAF cultures (P < 0.01). Expression of fibronectin and laminin was significantly increased by TGF-beta in CAF cultures (P < 0.01). CAFs were measurably different from normal fibroblasts in response to TGF-beta 1, suggesting that TGF-beta stimulates changes in CAFs that foster tumor invasion.

Objective To compare maternal characteristics, prenatal care and newborn outcomes in a cohort of opioid-dependent pregnant women treated with methadone vs. buprenorphine. Methods Retrospective cohort study. 609 pregnant, opioid-dependent women were treated with methadone (n=248) or buprenorphine (n=361) between 2000–2012 at a single institution. Results Mothers treated with buprenorphine were more likely to start medication prior to or earlier in pregnancy, had longer gestation and larger infants. Newborns of buprenorphine- vs. methadone-maintained mothers required treatment for neonatal abstinence significantly less often and for a shorter duration. Conclusions These data suggest pregnancy outcomes following buprenorphine to treat opioid dependence during pregnancy in clinical practice are as good and often better than outcomes with methadone. These results are consistent with efficacy data from randomized clinical trials and further support the use of buprenorphine for the treatment of opioid-dependence during pregnancy.

To cite this article: Lakoski SG, Savage PD, Berkman AM, Penalosa L, Crocker A, Ades PA, Kahn SR, Cushman M. The safety and efficacy of early-initiation exercise training after acute venous thromboembolism: a randomized clinical trial. J Thromb Haemost 2015; 13: 1238-44.Summary. Background: Exercise training after myocardial infarction is the standard of care within a cardiac rehabilitation setting. However, there is scant evidence regarding the safety and efficacy of early exercise training following a venous thromboembolism (VTE). Methods: Eligible consenting participants were randomly allocated, on an individual basis, to either a 3-month exercise and behavioral weight loss intervention group or a control group. The primary clinical outcomes were change in health behavior (body weight and physical activity) and objectively measured fitness (VO 2peak ). Results: From 2013 to 2014, 239 patients presented to a community-based specialty clinic after an acute VTE; 43 (18%) of these met the eligibility criteria for inclusion in the study. Of these, 19 (44%) consented to participate (nine in the intervention group; 10 in the control group). There were no adverse events in either group over a 3-month period. The mean difference in body weight between the intervention and control groups was À 4.6 kg (95% confidence interval [CI] À 11.4 to 2.2) in favor of the intervention. The mean difference in duration of physical activity from baseline to 3 months between the intervention and control groups was 133 min (95% CI 7-248) in favor of the intervention. There was a significant change in fitness over a 3-month period for the intervention group (base-Early initiation of exercise training resulted in improvements in physical activity and fitness, and did not result in adverse events while individuals were receiving therapeutic anticoagulation. These are the first data on initiation of an exercise training and behavioral weight loss program in the early post-VTE setting.

Background Chronic diseases that drive morbidity, mortality, and health care costs are largely influenced by human behavior. Behavioral health conditions such as anxiety, depression, and substance use disorders can often be effectively managed. The majority of patients in need of behavioral health care are seen in primary care, which often has difficulty responding. Some primary care practices are providing integrated behavioral health care (IBH), where primary care and behavioral health providers work together, in one location, using a team-based approach. Research suggests there may be an association between IBH and improved patient outcomes. However, it is often difficult for practices to achieve high levels of integration. The Integrating Behavioral Health and Primary Care study responds to this need by testing the effectiveness of a comprehensive practice-level intervention designed to improve outcomes in patients with multiple chronic medical and behavioral health conditions by increasing the practice’s degree of behavioral health integration. Methods Forty-five primary care practices, with existing onsite behavioral health care, will be recruited for this study. Forty-three practices will be randomized to the intervention or usual care arm, while 2 practices will be considered “Vanguard” (pilot) practices for developing the intervention. The intervention is a 24-month supported practice change process including an online curriculum, a practice redesign and implementation workbook, remote quality improvement coaching services, and an online learning community. Each practice’s degree of behavioral health integration will be measured using the Practice Integration Profile. Approximately 75 patients with both chronic medical and behavioral health conditions from each practice will be asked to complete a series of surveys to measure patient-centered outcomes. Change in practice degree of behavioral health integration and patient-centered outcomes will be compared between the two groups. Practice-level case studies will be conducted to better understand the contextual factors influencing integration. Discussion As primary care practices are encouraged to provide IBH services, evidence-based interventions to increase practice integration will be needed. This study will demonstrate the effectiveness of one such intervention in a pragmatic, real-world setting. Trial registration ClinicalTrials.gov NCT02868983. Registered on August 16, 2016.

Several reports have suggested that breast cancer patients with elevated serum levels of interleukin-6 (IL-6) have a worse prognosis than patients with lower levels. We have studied IL-6 in breast cancer cell lines and have shown that autocrine production of IL-6 can confer multi-drug resistance in vitro by inducing multidrug resistance gene-1 transcription with subsequent overexpression of P-glycoprotein (PGP). Both IL-6 and PGP expression can be measured in malignant cells using immunohistochemical (IHC) techniques. We hypothesized that patients whose tumors expressed higher amounts of IL-6 or PGP would be less likely to respond to paclitaxel, an agent affected by the PGP pathway. If so, then IL-6 could serve as a predictive factor for paclitaxel sensitivity. Both IL-6 and PGP expression were measured in patients treated in a randomized trial that compared three doses of single agent paclitaxel (175, 210, and 250 mg/m(2) over 3 h every 3 weeks) in 469 women with metastatic breast cancer (CALGB 9342). No difference in complete and partial response was found among the three treatment arms. Tissue blocks in this trial were analyzed for IL-6 (154 patients) and PGP (149 patients) in paraffin-embedded sections from tumor samples; clinical characteristics of these patients were similar to the total sample of 469 patients. There were no significant differences among IL-6 or PGP scores whether measured as continuous or dichotomous variables, or by other scoring, and response to paclitaxel. In multivariate analysis neither IL-6 nor PGP was a significant predictor of time to progression or overall survival. IHC expression of IL-6 and PGP levels in tumor cells is not a predictive marker for response to paclitaxel in women with metastatic breast cancer.

Background The opioid epidemic has led to an increase in the number of persons who inject drugs, and this population accounts for 12% of new human immunodeficiency virus (HIV) and 60% of new hepatitis C virus (HCV) infections in the United States annually. While persons who inject drugs disproportionately utilize the emergency department (ED), accurate data is lacking on the prevalence and patterns of injection drug use, and prevalence of co-occurring HIV and HCV infections among ED patients.

Depression is common, places a large burden on the patient, their family and community, and is often difficult to treat. Magnesium supplementation is associated with improved depressive symptoms, but because the mechanism is unknown, it is unclear whether serum magnesium levels act as a biological predictor of the treatment outcome. Therefore, we sought to describe the relationship between serum magnesium and the Patient Health Questionnaire (PHQ, a measure of depression) scores. A cross-sectional analysis of medical records from 3604 adults (mean age 62 years; 42% men) seen in primary care clinics between 2015 and 2018, with at least one completed PHQ were included. The relationship between serum magnesium and depression using univariate analyses showed a significant effect when measured by the PHQ-2 (−0.19 points/mg/dL; 95% CI −0.31, −0.07; P = 0.001) and the PHQ-9 (−0.93 points/mg/dL; 95% CI −1.81, −0.06; P = 0.037). This relationship was strengthened after adjusting for covariates (age, gender, race, time between serum magnesium and PHQ tests, and presence of diabetes and chronic kidney disease) (PHQ-2: −0.25 points/mg/dL; 95% CI −3.33, −0.09; P < 0.001 and PHQ-9: −1.09 95% CI −1.96 −0.21; P = 0.015). For adults seen in primary care, lower serum magnesium levels are associated with depressive symptoms, supporting the use of supplemental magnesium as therapy. Serum magnesium may help identify the biological mechanism of depressive symptoms and identify patients likely to respond to magnesium supplementation.