The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo

Background  

Breast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM) derived from premenopausal African-American (AA) or Caucasian-American (CAU) breast tissue would affect the tumorigenicity of cancer cells in vitro and in vivo. We chose these two populations because of the well documented predisposition of AA women to develop aggressive, highly metastatic breast cancer compared to CAU women.     

Morning compared with evening induction of labor: a nested randomized controlled trial. A nested randomized controlled trial

OBJECTIVE: To test the hypothesis that commencing induction of labor in the morning more closely reflects the physiologic timing of onset of labor and is associated with fewer women who remain undelivered 24 hours after cervical ripening and induction begins. METHODS: This was a nested randomized clinical trial, conducted between April 2001 and December 2004. Pregnant women at more than 36+6 weeks gestation with a cephalic presentation who were scheduled for prostaglandin induction of labor were eligible to participate. Women were randomly assigned to either admission in the morning (0800 hours) or admission in the evening (2,000 hours). The primary outcome measures were vaginal birth not achieved in 24 hours, uterine hyperstimulation with associated fetal heart rate changes, and cesarean delivery. RESULTS: A total of 620 women were entered in the trial, with 280 women in the morning admission group and 340 women in the evening admission group. There were no statistically significant differences between the timing of admission for induction and the primary trial outcomes. However, women admitted in the morning were less likely to require oxytocin infusion (morning admission 126 of 280 [45.0%] compared with evening admission 184 of 340 [54.1%]; relative risk 0.83, 95% confidence interval 0.70-0.97; P=.022). Nulliparous women admitted in the morning were less likely to require operative vaginal birth (morning admission 10 of 62 [16.1%] compared with evening admission 28 of 82 [34.2%]; relative risk 0.47, 95% confidence interval 0.25-0.90; P=.015). CONCLUSION: For women who require induction of labor, consideration should be given to admission in the morning rather than admission in the evening. CLINICAL TRIAL REGISTRATION: Australian Clinical Trials Registry, www.actr.org.au, 12606000156583.     

Innate immune activation in neutrophilic asthma and bronchiectasis

BACKGROUND: The role of the innate immune system in the pathogenesis of asthma is unclear. Activation of innate immune receptors in response to bacterial lipopolysaccharide, viral infection and particulate matter triggers a pre-programmed inflammatory response, which involves interleukin (IL)8 and neutrophil influx. The inflammatory response in asthma is heterogeneous. AIM: To test the hypothesis that innate immune activation may be a relevant inflammatory mechanism in neutrophilic asthma where IL8 levels are increased. METHODS: Induced sputum was obtained from non-smoking adults with asthma (n = 49), healthy controls (n = 13) and a positive reference group with bronchiectasis (n = 9). Subjects with asthma were classified into inflammatory subtypes using induced sputum cell counts. Sputum was examined for mRNA expression of the innate immune receptors toll-like receptor (TLR)2, TLR4 and CD14, and inflammatory cytokines. A separate sputum portion was dispersed and the supernatant assayed for surfactant protein A, IL8, soluble CD14 and endotoxin. RESULTS: Expression of innate immune receptors was increased in subjects with bronchiectasis and neutrophilic asthma compared with other asthma subtypes and controls. Increased expression of the receptors TLR2, TLR4 and CD14, as well as the pro-inflammatory cytokines IL8 and IL1beta, was observed. Subjects with neutrophilic asthma had higher airway levels of endotoxin than the other groups studied. CONCLUSION: There is evidence of activation of the innate immune system in asthma which results in the production of pro-inflammatory cytokines and may contribute to the pathogenesis of neutrophilic asthma.     

Inflaming the CD8+ T cell response

Although inflammatory cytokines induced by infection or vaccination with adjuvants have long been known to stimulate optimal antigen-presenting cell function, recent evidence indicates that some inflammatory cytokines also act directly on the responding T cells to control their response to infection. Here, we review the evidence that specific inflammatory cytokines act to control the magnitude of expansion, the degree of contraction, and the rate of memory cell development. These data may suggest new strategies for manipulating vaccine efficacy in the quest to protect against pathogenic microbes.     

Variations of the Amnionless gene in recurrent spontaneous abortions

Recurrent spontaneous abortions (RSA) are estimated to affect 0.5-1% of couples trying to have a child. The causes of RSA are unknown in the majority of cases. This study aimed to determine whether homozygous mutations in the AMN gene in a fetus cause spontaneous abortions in humans, as they are known to cause spontaneous abortions in mice. The study was conducted by screening 40 couples and 5 women with three or more unexplained spontaneous abortions for heterozygous mutations in the AMN gene using denaturing high-performance liquid chromatography. Altogether, 3 exonic and 11 intronic sequence variations were found. There were no significant differences in the frequencies of the variations between the patients and a control group. One of the exonic variations was non-synonymous, and three of the variations may affect gene splicing. None of the putative phenotype-affecting variations were found in both partners in any couple. These results indicate that RSA in the couples studied cannot be explained by homozygous AMN mutations in the fetus. However, two couples had different, potentially deleterious variations in both partners. If these variations have a phenotypic effect, the RSA experienced by these couples may be caused by mutations in the AMN gene. In addition, birthplaces of the patients' ancestors revealed some clustering, suggesting that some patients may carry a founder mutation in another gene which may contribute to RSA.     

A randomized clinical trial of an activity and exercise adherence intervention in chronic pulmonary disease

Steele BG, Belza B, Cain KC, Coppersmith J, Lakshminarayan S, Howard J, Haselkorn JK. A randomized clinical trial of an activity and exercise adherence intervention in chronic pulmonary disease.

Objectives

To evaluate the effectiveness of an exercise adherence intervention to maintain daily activity, adherence to exercise, and exercise capacity over 1 year after completion of an outpatient pulmonary rehabilitation program.

Design

A 2-group, experimental design was used with randomization into intervention and usual care groups.

Setting

Outpatient pulmonary rehabilitation program in a university-affiliated medical center.

Participants

One hundred six subjects (98 men; 98 with chronic obstructive pulmonary disease) with a mean age of 67 years and chronic lung disease.

Intervention

Twelve-week adherence intervention (weekly phone calls and home visit) including counseling on establishing, monitoring, and problem-solving in maintaining a home exercise program.

Main Outcome Measures

Primary outcomes included daily activity (accelerometer), exercise adherence (exercise diary), and exercise capacity (six-minute walk test). All measures were performed at baseline, after the pulmonary rehabilitation program (8wk), after the adherence intervention (20wk), and at 1 year.

Results

A rank-based analysis of covariance showed less decline at 20 weeks in exercise adherence (intervention mean, +3min; control mean, −13min; P=.015) and exercise capacity (intervention mean, −10.7m; control mean, −35.4m; P=.023). There were no differences in daily activity at 20 weeks or any differences in any primary variable at 1 year.

Conclusions

The intervention enhanced exercise adherence and exercise capacity in the short term but produced no long-term benefit. These findings are in part attributed to the disappointing measurement characteristics of the accelerometer used to measure daily activity. The intervention was acceptable to participants. Further study is needed to fashion interventions that have more persistent benefit.