Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

Gold OAIntroduction: Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. Methods More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. Results The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. Conclusions With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

The “Flexi-Chamber”: A Novel Cost-Effective In Situ Respirometry Chamber for Coral Physiological Measurements

Coral reefs are threatened worldwide, with environmental stressors increasingly affecting the ability of reef-building corals to sustain growth from calcification (G), photosynthesis (P) and respiration (R). These processes support the foundation of coral reefs by directly influencing biogeochemical nutrient cycles and complex ecological interactions and therefore represent key knowledge required for effective reef management. However, metabolic rates are not trivial to quantify and typically rely on the use of cumbersome in situ respirometry chambers and/or the need to remove material and examine ex situ, thereby fundamentally limiting the scale, resolution and possibly the accuracy of the rate data. Here we describe a novel low-cost in situ respirometry bag that mitigates many constraints of traditional glass and plexi-glass incubation chambers. We subsequently demonstrate the effectiveness of our novel "Flexi-Chamber" approach via two case studies: 1) the Flexi-Chamber provides values of P, R and G for the reef-building coral Siderastrea cf. stellata collected from reefs close to Salvador, Brazil, which were statistically similar to values collected from a traditional glass respirometry vessel; and 2) wide-scale application of obtaining P, R and G rates for different species across different habitats to obtain inter- and intra-species differences. Our novel cost-effective design allows us to increase sampling scale of metabolic rate measurements in situ without the need for destructive sampling and thus significantly expands on existing research potential, not only for corals as we have demonstrated here, but also other important benthic groups

The prognostic significance of allelic imbalance at key chromosomal loci in oral cancer

Forty-eight primary oral squamous cell carcinomas (SCC) were screened for allelic imbalance (AI) at 3p24–26, 3p21, 3p13, 8p21–23, 9p21, 9q22 and within the Rb, p53 and DCC tumour suppressor genes. AI was detected at all TNM stages with stage 4 tumours showing significantly more aberrations than stage 1–3. A factional allelic loss (FAL) score was calculated for all tumours and a high score was associated with development of local recurrence (P = 0.033) and reduced survival (P = 0.0006). AI at one or more loci within the 3p24–26, 3p21, 3p13 and 9p21 regions or within the THRB and DCC genes was associated with reduced survival. The hazard ratios for survival analysis revealed that patients with AI at 3p24–26, 3p13 and 9p21 have an approximately 25 times increase in their mortality rate relative to a patient retaining heterozygosity at these loci. AI at specific pairs of loci, D3S686 and D9S171 and involving at least two of D3S1296, DCC and D9S43, was a better predictor of prognosis than the FAL score or TNM stage. These data suggest that it will be possible to develop a molecular staging system which will be a better predict of outcome than conventional clinicopathological features as the molecular events represent fundamental biological characteristics of each tumour. © 1999 Cancer Research Campaig

Quantifying system disturbance and recovery from historical mining-derived metal contamination at Brotherswater, northwest England

The final publication is available at Springer via https://doi.org/10.1007/s10933-016-9907-1Metal ore extraction in historical times has left a legacy of severe contamination in aquatic ecosystems around the world. In the UK, there are ongoing nationwide surveys of present-day pollution discharged from abandoned mines but few assessments of the magnitude of contamination and impacts that arose during historical metal mining have been made. We report one of the first multi-centennial records of lead (Pb), zinc (Zn) and copper (Cu) fluxes into a lake (Brotherswater, northwest England) from point-sources in its catchment (Hartsop Hall Mine and Hogget Gill processing plant) and calculate basin-scale inventories of those metals. The pre-mining baseline for metal contamination has been established using sediment cores spanning the past 1,500 years and contemporary material obtained through sediment trapping. These data enabled the impact of 250 years of local, small-scale mining (1696 – 1942) to be quantified and an assessment of the trajectory towards system recovery to be made. The geochemical stratigraphy displayed in twelve sediment cores show strong correspondence to the documented history of metal mining and processing in the catchment. The initial onset in 1696 was detected, peak Pb concentrations (>10,000 µg g-1) and flux (39.4 g m-2 y-1) corresponded to the most intensive mining episode (1863-1871) and 20th century technological enhancements were reflected as a more muted sedimentary imprint. After careful evaluation, we used these markers to augment a Bayesian age-depth model of the independent geochronology obtained using radioisotope dating (14C, 210Pb, 137Cs and 241Am). Total inventories of Pb, Zn and Cu for the lake basin during the period of active mining were 15,415 kg, 5,897 kg and 363 kg, respectively. The post-mining trajectories for Pb and Zn project a return to pre-mining levels within 54-128 years for Pb and 75-187 years for Zn, although future remobilisation of metal-enriched catchment soils and floodplain sediments could perturb this recovery. We present a transferable paleolimnological approach that highlights flux-based assessments are vital to accurately establish the baseline, impact and trajectory of mining-derived contamination for a lake catchment

ICAR: endoscopic skull‐base surgery

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International meta-analysis of stated preference studies of transportation noise nuisance

The final publication is available at Springer via http://dx.doi.org/10.1007/s11116-014-9527-4This paper reports the first meta-analysis and most extensive review of stated preference studies of transportation noise nuisance. The meta-analysis is based on a newly compiled data set of 258 values from 49 studies and 23 countries and spanning more than 40 years. Contrast this with the most extensive meta-analysis of the more conventional hedonic pricing approach which includes 53 noise valuations. Moreover, the sample compares favourably with the 444 observations from the very first meta-analysis of the value of travel time savings which is by far the most widely examined parameter in transport planning. A particularly significant finding of the study is that the intertemporal income elasticity is close to one, somewhat larger than the cross-sectional income elasticity typically obtained from individual studies. This demonstrates the importance of distinguishing the effects of 2 income variations that occur over time, which tend to drive policy, from variations across individuals at one point in time, and such findings are typical of those observed in other markets. Importantly, the values derived are transferable across countries and may be used to benchmark existing evidence and provide values in contexts where none exist. Other key results are that values for aircraft noise exceed those for other modes, whilst those exposed to higher noise levels and those who are highly annoyed also have higher values in line with expectations. A wide range of design effects were tested but few were significant and these included the consumer surplus measure, the representation of noise and the context

Teaching: Natural or Cultural?

In this chapter I argue that teaching, as we now understand the term, is historically and cross-culturally very rare. It appears to be unnecessary to transmit culture or to socialize children. Children are, on the other hand, primed by evolution to be avid observers, imitators, players and helpers—roles that reveal the profoundly autonomous and self-directed nature of culture acquisition (Lancy in press a). And yet, teaching is ubiquitous throughout the modern world—at least among the middle to upper class segment of the population. This ubiquity has led numerous scholars to argue for the universality and uniqueness of teaching as a characteristically human behavior. The theme of this chapter is that this proposition is unsustainable. Teaching is largely a result of recent cultural changes and the emergence of modern economies, not evolution