Bodyweight and other correlates of symptom detected breast cancers in a population offered screening

Objective: To determine factors associated with symptom detected breast cancers in a population offered screening. Methods We interviewed 1,459 Australian women aged 40–69, 946 with symptom detected and 513 with mammogram detected invasive breast cancers ≥1.1 cm in diameter, about their personal, mammogram and breast histories before diagnosis and reviewed medical records for tumour characteristics and mammogram dates, calculating ORs and 95% confidence intervals (CIs) for symptom- vs mammogram-detected cancers in logistic regression models. Results: Lack of regular mammograms (<2 mammograms in the 4.5 years before diagnosis) was the strongest correlate of symptom detected breast cancer (OR=3.04 for irregular or no mammograms). In women who had regular mammograms (≥2 mammograms in the 4.5 years before diagnosis), the independent correlates of symptom detected cancers were low BMI (OR <25kg/m2 vs ≥30kg/m2=2.18, 95% CI 1.23-3.84; p=0.008), increased breast density (available in 498 women) (OR highest quarter vs lowest =3.50, 95% CI 1.76-6.97; ptrend=0.004), high grade cancer and a larger cancer (each p<0.01). In women who did not have regular mammograms, the independent correlates were age <50 years, a first cancer and a ≥2cm cancer. Smoking appeared to modify the association of symptom detected cancer with low BMI (higher ORs for low BMI in current smokers) and estrogen receptor (ER) status (higher ORs for low BMI in ER− cancers). Conclusion: Women with low BMI may benefit from a tailored approach to breast cancer detection, particularly if they smoke.

The cancer stem-cell hypothesis : its emerging role in lung cancer biology and its relevance for future therapy

The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review.

BSTA Promotes mTORC2-Mediated Phosphorylation of Akt1 to Suppress Expression of FoxC2 and Stimulate Adipocyte Differentiation

Phosphorylation and activation of Akt1 is a crucial signaling event that promotes adipogenesis. However, neither the complex multistep process that leads to activation of Akt1 through phosphorylation at Thr308 and Ser473 nor the mechanism by which Akt1 stimulates adipogenesis is fully understood. We found that the BSD domain–containing signal transducer and Akt interactor (BSTA) promoted phosphorylation of Akt1 at Ser473 in various human and murine cells, and we uncovered a function for the BSD domain in BSTA-Akt1 complex formation. The mammalian target of rapamycin complex 2 (mTORC2) facilitated the phosphorylation of BSTA and its association with Akt1, and the BSTA-Akt1 interaction promoted the association of mTORC2 with Akt1 and phosphorylation of Akt1 at Ser473 in response to growth factor stimulation. Furthermore, analyses of bsta gene-trap murine embryonic stem cells revealed an essential function for BSTA and phosphorylation of Akt1 at Ser473 in promoting adipocyte differentiation, which required suppression of the expression of the gene encoding the transcription factor FoxC2. These findings indicate that BSTA is a molecular switch that promotes phosphorylation of Akt1 at Ser473 and reveal an mTORC2-BSTA-Akt1-FoxC2–mediated signaling mechanism that is critical for adipocyte differentiation.

Reduced Il17a expression distinguishes a Ly6cloMHCIIhi macrophage population promoting wound healing

Macrophages are the main components of inflammation during skin wound healing. They are critical in wound closure and in excessive inflammation, resulting in defective healing observed in chronic wounds. Given the heterogeneity of macrophage phenotypes and functions, we here hypothesized that different subpopulations of macrophages would have different and sometimes opposing effects on wound healing. Using multimarker flow cytometry and RNA expression array analyses on macrophage subpopulations from wound granulation tissue, we identified a Ly6cloMHCIIhi “noninflammatory” subset that increased both in absolute number and proportion during normal wound healing and was missing in Ob/Ob and MYD88−/− models of delayed healing. We also identified IL17 as the main cytokine distinguishing this population from proinflammatory macrophages and demonstrated that inhibition of IL17 by blocking Ab or in IL17A−/− mice accelerated normal and delayed healing. These findings dissect the complexity of the role and activity of the macrophages during wound inflammation and may contribute to the development of therapeutic approaches to restore healing in chronic wounds.

Spatial modelling of population health screening : the role of accessibility in predicting expected patient flows

This paper describes a generalised linear mixed model (GLMM) approach for understanding spatial patterns of participation in population health screening, in the presence of multiple screening facilities. The models presented have dual focus, namely the prediction of expected patient flows from regions to services and relative rates of participation by region- service combination, with both outputs having meaningful implications for the monitoring of current service uptake and provision. The novelty of this paper lies with the former focus, and an approach for distributing expected participation by region based on proximity to services is proposed. The modelling of relative rates of participation is achieved through the combination of different random effects, as a means of assigning excess participation to different sources. The methodology is applied to participation data collected from a government-funded mammography program in Brisbane, Australia.

Baby-friendly hospital accreditation, in-hospital care practices and breastfeeding : a population based survey

OBJECTIVES: To investigate the effect of Baby-Friendly Hospital Initiative (BFHI) accreditation and hospital care practices on breastfeeding rates at 1 and 4 months. METHODS: All women who birthed in Queensland, Australia, from February 1 to May 31, 2010, received a survey 4 months postpartum. Maternal, infant, and hospital characteristics; pregnancy and birth complications; and infant feeding outcomes were measured. RESULTS: Sample size was 6752 women. Breastfeeding initiation rates were high (96%) and similar in BFHI-accredited and nonaccredited hospitals. After adjustment for significant maternal, infant, clinical, and hospital variables, women who birthed in BFHI-accredited hospitals had significantly lower odds of breastfeeding at 1 month (adjusted odds ratio 0.72, 95% confidence interval 0.58–0.90) than those who birthed in non–BFHI-accredited hospitals. BFHI accreditation did not affect the odds of breastfeeding at 4 months or exclusive breastfeeding at 1 or 4 months. Four in-hospital practices (early skin-to-skin contact, attempted breastfeeding within the first hour, rooming-in, and no in-hospital supplementation) were experienced by 70% to 80% of mothers, with 50.3% experiencing all 4. Women who experienced all 4 hospital practices had higher odds of breastfeeding at 1 month (adjusted odds ratio 2.20, 95% confidence interval 1.78–2.71) and 4 months (adjusted odds ratio 2.93, 95% confidence interval 2.40–3.60) than women who experienced fewer than 4. CONCLUSIONS: When breastfeeding-initiation rates are high and evidence-based practices that support breastfeeding are common within the hospital environment, BFHI accreditation per se has little effect on both exclusive or any breastfeeding rates.C

Computational experiments involving population size for FPGA-based implementation of a GA for the TSP

The feasibility of using an in-hardware implementation of a genetic algorithm (GA) to solve the computationally expensive travelling salesman problem (TSP) is explored, especially in regard to hardware resource requirements for problem and population sizes. We investigate via numerical experiments whether a small population size might prove sufficient to obtain reasonable quality solutions for the TSP, thereby permitting relatively resource efficient hardware implementation on field programmable gate arrays (FPGAs). Software experiments on two TSP benchmarks involving 48 and 532 cities were used to explore the extent to which population size can be reduced without compromising solution quality, and results show that a GA allowed to run for a large number of generations with a smaller population size can yield solutions of comparable quality to those obtained using a larger population. This finding is then used to investigate feasible problem sizes on a targeted Virtex-7 vx485T-2 FPGA platform via exploration of hardware resource requirements for memory and data flow operations.

Organotypic culture of normal, dysplastic and squamous cell carcinoma-derived oral cell lines reveals loss of spatial regulation of CD44 and p75(NTR) in malignancy

Oral squamous cell carcinomas (OSCC) often arise from dysplastic lesions. The role of cancer stem cells in tumour initiation is widely accepted, yet the potential existence of pre-cancerous stem cells in dysplastic tissue has received little attention. Cell lines from oral diseases ranging in severity from dysplasia to malignancy provide opportunity to investigate the involvement of stem cells in malignant progression from dysplasia. Stem cells are functionally defined by their ability to generate hierarchical tissue structures in consortium with spatial regulation. Organotypic cultures readily display tissue hierarchy in vitro; hence, in this study, we compared hierarchical expression of stem cell-associated markers in dermis-based organotypic cultures of oral epithelial cells from normal tissue (OKF6-TERT2), mild dysplasia (DOK), severe dysplasia (POE-9n) and OSCC (PE/CA P J15). Expression of CD44, p75NTR, CD24 and ALDH was studied in monolayers by flow cytometry and in organotypic cultures by immunohistochemistry. Spatial regulation of CD44 and p75NTR was evident for organotypic cultures of normal (OKF6-TERT2) and dysplasia (DOK and POE-9n) but was lacking for OSCC (PE/CA PJ15)-derived cells. Spatial regulation of CD24 was not evident. All monolayer cultures exhibited CD44, p75NTR, CD24 antigens and ALDH activity (ALDEFLUOR® assay), with a trend towards loss of population heterogeneity that mirrored disease severity. In monolayer, increased FOXA1 and decreased FOXA2 expression correlated with disease severity, but OCT3/4, Sox2 and NANOG did not. We conclude that dermis-based organotypic cultures give opportunity to investigate the mechanisms that underlie loss of spatial regulation of stem cell markers seen with OSCC-derived cells.

Why we need a population-based approach to clinical indicators for cancer: a case study using microscopic confirmation of lung cancer in Queensland

An important function of clinical cancer registries is to provide feedback to clinicians on various performance measures. To date, most clinical cancer registries in Australia are located in tertiary academic hospitals, where adherence to guidelines is probably already high. Microscopic confirmation is an important process measure for lung cancer care. We found that the proportion of patients with lung cancer without microscopic confirmation was much higher in regional public hospitals (27.1%) than in tertiary hospitals (7.5%), and this disparity remained after adjusting for age, sex and comorbidities. The percentage was also higher in the private than in the public sector. This case study shows that we need a population-based approach to measuring clinical indicators that includes regional public hospitals as a matter of priority and should ideally include the private sector.

Can we deliver both population-based and personalized approaches to cancer care?

Responding to the individual needs of the person affected by cancer is a fundamental tenet of nursing care. The evidence base to enable highly personalized approaches to the way we provide care has grown enormously in recent years. Today, we have a much better understanding of the mechanisms underpinning health needs of people with cancer, as well as the wide range of environmental, sociocultural, psychological, and biological influences on these needs. This growing evidence base enables us to better target and tailor interventions in increasingly sophisticated ways.

Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia

Context: The benefits of high serum levels of 25-hydroxyvitamin D [25(OH)D] are unclear. Trials are needed to establish an appropriate evidence base. Objective: We plan to conduct a large-scale trial of vitamin D supplementation for the reduction of cancer incidence and overall mortality and report here the methods and results of a pilot trial established to inform its design. Design: Pilot D-Health was a randomized trial carried out in a general community setting with 12 months intervention and follow-up. Participants: Participants were 60- to 84-yr-old residents of one of the four eastern Australian states who did not have any vitamin D-related disorders and who were not taking more than 400 IU supplementary vitamin D per day. A total of 644 participants were randomized, and 615 completed the study (two persons withdrew because of nonserious adverse events). Interventions: The interventions were monthly doses of placebo or 30,000 or 60,000 IU vitamin D3. Main Outcomes: The main outcomes were the recruitment rate and changes in serum 25(OH)D. Results: Ten percent of those approached were recruited. At baseline, the mean 25(OH)D was 42 nmol/liter in all three study arms. The mean change in 25(OH)D in the placebo group was 0.12 nmol/liter, compared with changes of 22 and 36 nmol/liter in the 30,000- and 60,000-IU groups, respectively. Conclusions: The D-Health pilot has shown that a large trial is feasible in Australia and that a dose of 2000 IU/d will be needed to ensure that a large proportion of the population reaches the target serum 25(OH)D level. Copyright © 2012 by The Endocrine Society.

Estimation of reference values for dioxin, furan, and PCB congener concentrations for the Australian population

Population-representative data for dioxin and PCB congener concentrations are available for the Australian population based on measurements in age- and gender-specific serum pools.1 Such data provide a basis for characterizing the mean concentrations of these compounds in the population, but do not provide information on the inter-individual variation in serum concentrations that may exist in the population within an age- and gender-specific group. Such variation may occur due to inter-individual differences in long-term exposure levels or elimination rates. Reference values are estimates of upper percentiles (often the 95th percentile) of measured values in a defined population that can be used to evaluate data from individuals in the population in order to identify concentrations that are elevated, for example, from occupational exposures.2 The objective of this analysis is to estimate reference values corresponding to the 95th percentile (RV95s) for Australia on an age-specific basis for individual dioxin-like congeners based on measurements in serum pools from Toms and Mueller (2010).