Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

"I'm the Momma": Using photo-elicitation to understand matrilineal influence on family food choice

<p>Abstract</p> <p>Background</p> <p>Many complex and subtle aspects relating to mothers and food choice are not well understood. Mothers play a primary role in their children's food choices, but research has not specifically examined how matrilineal family members who do not reside in the same household, such as a mother's mother, aunt, or grandmother, influence the current family's food choices.</p> <p>Methods</p> <p>Seven participants were recruited from the Household Food Inventory (HFI) Study in the Bryan/College Station, Texas. All participants completed an in-depth interview, photographed food-related activities, and discussed photographs in a follow-up in-depth interview. Interviews were transcribed verbatim from audio recordings. Transcripts were analyzed using several qualitative approaches including grounded theory to identify themes and subthemes.</p> <p>Results</p> <p>Participants discussed the following themes relating to the influence of their mother or other female relation (Mom) on their families' food choices: Relationship with Mom, Just like Mom, 'Kinda' like Mom, Different than Mom, and Mom's Influence on Children's Food Choices. Overall, participants used the photographs to illustrate how they were similar or different to their mothers, or other female family member, as well as how their mothers either supported or undermined control over their children's food choices. The "Mom effect" or matrilineal influence of mothers, aunts, and grandmothers on a mother's food choices was omnipresent, even though Mom was no longer living with the participants.</p> <p>Conclusions</p> <p>We found a matrilineal influence to have a residual and persistent influence on a family's food choices. This finding may be helpful for understanding the contextual elements of food choice and explaining why it is sometimes difficult to change mothers' food habits.</p

Effects of branching spatial structure and life history on the asymptotic growth rate of a population

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Theoretical Ecology 3 (2010): 137-152, doi:10.1007/s12080-009-0058-0.The dendritic structure of a river network creates directional dispersal and a hierarchical arrangement of habitats. These two features have important consequences for the ecological dynamics of species living within the network.We apply matrix population models to a stage-structured population in a network of habitat patches connected in a dendritic arrangement. By considering a range of life histories and dispersal patterns, both constant in time and seasonal, we illustrate how spatial structure, directional dispersal, survival, and reproduction interact to determine population growth rate and distribution. We investigate the sensitivity of the asymptotic growth rate to the demographic parameters of the model, the system size, and the connections between the patches. Although some general patterns emerge, we find that a species’ mode of reproduction and dispersal are quite important in its response to changes in its life history parameters or in the spatial structure. The framework we use here can be customized to incorporate a wide range of demographic and dispersal scenarios.Funding for this work came from the James S. McDonnell Foundation (EEG, HJL, WFF). MGN was supported by grants from the National Science Foundation (CMG-0530830, OCE-0326734, ATM-0428122)

Estrogen receptor transcription and transactivation: Basic aspects of estrogen action

Estrogen signaling has turned out to be much more complex and exciting than previously thought; the paradigm shift in our understanding of estrogen action came in 1996, when the presence of a new estrogen receptor (ER), ERβ, was reported. An intricate interplay between the classical ERα and the novel ERβ is of paramount importance for the final biological effect of estrogen in different target cells

A systematic review of grandparents’ influence on grandchildren’s cancer risk factors

Many lifestyle patterns are established when children are young. Research has focused on the potential role of parents as a risk factor for non communicable disease in children, but there is limited investigation of the role of other caregivers, such as grandparents. The aim of this review was to identify and synthesise evidence for any influence grandparents&rsquo; care practices may have on their grandchildren&rsquo;s long term cancer risk factors. A systematic review was carried out with searches across four databases (MEDLINE, Embase, Web of Science, PsycINFO) as well as searches of reference lists and citing articles, and Google Scholar. Search terms were based on six areas of risk that family care could potentially influence&ndash;weight, diet, physical activity, tobacco, alcohol and sun exposure. All study designs were included, as were studies that provided an indication of the interaction of grandparents with their grandchildren. Studies were excluded if grandparents were primary caregivers and if children had serious health conditions. Study quality was assessed using National Institute for Health and Care Excellence checklists. Grandparent impact was categorised as beneficial, adverse, mixed or as having no impact. Due to study heterogeneity a meta-analysis was not possible. Qualitative studies underwent a thematic synthesis of their results. Results from all included studies indicated that there was a sufficient evidence base for weight, diet, physical activity and tobacco studies to draw conclusions about grandparents&rsquo; influence. One study examined alcohol and no studies examined sun exposure. Evidence indicated that, overall, grandparents had an adverse impact on their grandchildren&rsquo;s cancer risk factors. The theoretical work in the included studies was limited. Theoretically underpinned interventions designed to reduce these risk factors must consider grandparents&rsquo; role, as well as parents&rsquo;, and be evaluated robustly to inform the evidence base further

ERrrr…Where are the Progenitors? Hormone Receptors and Mammary Cell Heterogeneity

The mammary epithelium is a highly heterogenous and dynamic tissue that includes a range of cell types with varying levels of proliferative capacity and differentiation potential, from stem to committed progenitor and mature cells. Generation of mature cells through expansion and specification of immature precursors is driven by hormonal and local stimuli. Intriguingly, although circulating hormones can be directly sensed only by a subset of mammary cells, they also regulate the behaviour of cells lacking their cognate receptors through paracrine mechanisms. Thus, mapping the hormonal signalling network on to the emerging mammary cell hierarchy appears to be a difficult task. Nevertheless, a first step towards a better understanding is the characterization of the hormone receptor expression pattern across individual cell types in the mammary epithelium. Here we review the most relevant findings on the cellular distribution of hormone receptors in the mammary gland, taking into account differences between mice and humans, the methods employed to assess receptor expression as well as the variety of approaches used to resolve the mammary cell heterogeneity

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402