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

Islands beneath islands: phylogeography of a groundwater amphipod crustacean in the Balearic archipelago

<p>Abstract</p> <p>Background</p> <p>Metacrangonyctidae (Amphipoda, Crustacea) is an enigmatic continental subterranean water family of marine origin (thalassoid). One of the species in the genus, <it>Metacrangonyx longipes</it>, is endemic to the Balearic islands of Mallorca and Menorca (W Mediterranean). It has been suggested that the origin and distribution of thalassoid crustaceans could be explained by one of two alternative hypotheses: (1) active colonization of inland freshwater aquifers by a marine ancestor, followed by an adaptative shift; or (2) passive colonization by stranding of ancestral marine populations in coastal aquifers during marine regressions. A comparison of phylogenies, phylogeographic patterns and age estimations of clades should discriminate in favour of one of these two proposals.</p> <p>Results</p> <p>Phylogenetic relationships within <it>M. longipes </it>based on three mitochondrial DNA (mtDNA) and one nuclear marker revealed five genetically divergent and geographically structured clades. Analyses of cytochrome oxidase subunit 1 (<it>cox1</it>) mtDNA data showed the occurrence of a high geographic population subdivision in both islands, with current gene flow occurring exclusively between sites located in close proximity. Molecular-clock estimations dated the origin of <it>M. longipes </it>previous to about 6 Ma, whereas major cladogenetic events within the species took place between 4.2 and 2.0 Ma.</p> <p>Conclusions</p> <p><it>M. longipes </it>displayed a surprisingly old and highly fragmented population structure, with major episodes of cladogenesis within the species roughly correlating with some of the major marine transgression-regression episodes that affected the region during the last 6 Ma. Eustatic changes (vicariant events) -not active range expansion of marine littoral ancestors colonizing desalinated habitats-explain the phylogeographic pattern observed in <it>M. longipes</it>.</p

Plants and traditional knowledge: An ethnobotanical investigation on Monte Ortobene (Nuoro, Sardinia)

<p>Abstract</p> <p>Background</p> <p>Most of the traditional knowledge about plants and their uses is fast disappearing as a consequence of socio-economic and land use changes. This trend is also occurring in areas that are historically exposed to very few external influences, such as Sardinia (Italy). From 2004 to 2005, an ethnobotanical investigation was carried out in the area of Monte Ortobene, a mountain located near Nuoro, in central Sardinia.</p> <p>Methods</p> <p>Data were collected by means of semi-structured interviews. All the records – defined as 'citations', i.e. a single use reported for a single botanical species by a single informant – were filed in a data base ('analytical table'), together with additional information: i.e. local names of plants, parts used, local frequencies, and habitats of plants, etc. In processing the data, plants and uses were grouped into general ('categories') and detailed ('secondary categories') typologies of use. Some synthetic indexes have also been used, such as Relative Frequency of Citation (RFC), Cultural Importance Index (CI), the Shannon-Wiener Index (H'), and Evenness Index (J).</p> <p>Results</p> <p>Seventy-two plants were cited by the informants as being traditionally used in the area. These 72 'ethnospecies' correspond to 99 botanical taxa (species or subspecies) belonging to 34 families. Three-hundred and one citations, 50 secondary categories of use, and 191 different uses were recorded, most of them concerning alimentary and medicinal plants.</p> <p>For the alimentary plants, 126 citations, 44 species, and 13 different uses were recorded, while for the medicinal plants, there were 106 citations, 40 species, and 12 uses. Few plants and uses were recorded for the remaining categories. Plants and uses for each category of use are discussed. Analyses of results include the relative abundance of botanical families, wild vs. cultivated species, habitats, frequency, parts of plant used, types of use, knowledge distribution, and the different cultural importance of the species in question.</p> <p>Conclusion</p> <p>The study provides examples of several interesting uses of plants in the community, which would seem to show that the custom of using wild plants is still alive in the Monte Ortobene area. However, many practices are no longer in use, and survive only as memories from the past in the minds of elderly people, and often only in one or just a few informants. This rapidly vanishing cultural diversity needs to be studied and documented before it disappears definitively.</p

Community-based natural resource use and management of Bigodi Wetland Sanctuary, Uganda, for livelihood benefits

publisher versionConservation and sustainable management of wetlands requires participation of local stakeholders, including communities. The Bigodi Wetland is unusual because it is situated in a common property landscape but the local community has been running a successful community-based natural resource management programme (CBNRM) for the wetland for over a decade. Whilst external visitors to the wetland provide ecotourism revenues we sought to quantify community benefits through the use of wetland goods such as firewood, plant fibres, and the like, and costs associated with wild animals damaging farming activities. We interviewed 68 households living close to the wetland and valued their cash and non-cash incomes from farming and collection of non-timber forest products (NTFPs) and water. The majority of households collected a wide variety of plant and fish resources and water from the wetland for household use and livestock. Overall, 53% of total household cash and non-cash income was from collected products, mostly the wetland, 28% from arable agriculture, 12% from livestock and 7% from employment and cash transfers. Female-headed households had lower incomes than male-headed ones, and with a greater reliance on NTFPs. Annual losses due to wildlife damage were estimated at 4.2% of total gross income. Most respondents felt that the wetland was important for their livelihoods, with more than 80% identifying health, education, craft materials and firewood as key benefits. Ninety-five percent felt that the wetland was in a good condition and that most residents observed the agreed CBNRM rules regarding use of the wetland. This study confirms the success of the locally run CBNRM processes underlying the significant role that the wetland plays in local livelihoods

Timescales of transformational climate change adaptation in sub-Saharan African agriculture

Climate change is projected to constitute a significant threat to food security if no adaptation actions are taken. Transformation of agricultural systems, for example switching crop types or moving out of agriculture, is projected to be necessary in some cases. However, little attention has been paid to the timing of these transformations. Here, we develop a temporal uncertainty framework using the CMIP5 ensemble to assess when and where cultivation of key crops in sub-Saharan Africa becomes unviable. We report potential transformational changes for all major crops during the twenty-first century, as climates shift and areas become unsuitable. For most crops, however, transformation is limited to small pockets (<15% of area), and only for beans, maize and banana is transformation more widespread (â 1/430% area for maize and banana, 60% for beans). We envisage three overlapping adaptation phases to enable projected transformational changes: an incremental adaptation phase focused on improvements to crops and management, a preparatory phase that establishes appropriate policies and enabling environments, and a transformational adaptation phase in which farmers substitute crops, explore alternative livelihoods strategies, or relocate. To best align policies with production triggers for no-regret actions, monitoring capacities to track farming systems as well as climate are needed

Differential livelihood adaptation to social-ecological change in coastal Bangladesh

Social-ecological changes, brought about by the rapid growth of the aquaculture industry and the increased occurrence of climatic stressors, have significantly affected the livelihoods of coastal communities in Asian mega-deltas. This paper explores the livelihood adaptation responses of households of different wealth classes, the heterogeneous adaptation opportunities, barriers and limits (OBLs) faced by these households and the dynamic ways in which these factors interact to enhance or impede adaptive capacities. A mixed methods approach was used to collect empirical evidence from two villages in coastal Bangladesh. Findings reveal that households’ adaptive capacities largely depend on their wealth status, which not only determine their availability of productive resources, but also empower them to navigate social-ecological change in desirable ways. Households operate within a shared response space, which is shaped by the broader socio-economic and political landscape, as well as their previous decisions that can lock them in to particular pathways. While an adaptive response may be effective for one social group, it may cause negative externalities that can undermine the adaptation options and outcomes of another group. Adaptation OBLs interact in complex ways; the extent to which these OBLs affect different households depend on the specific livelihood activities being considered and the differential values and interests they hold. To ensure more equitable and environmentally sustainable livelihoods in future, policies and programs should aim to expand households’ adaptation space by accounting for the heterogeneous needs and complex interdependencies between response processes of different groups

Social Status Affects the Degree of Sex Difference in the Songbird Brain

It is thought that neural sex differences are functionally related to sex differences in the behaviour of vertebrates. A prominent example is the song control system of songbirds. Inter-specific comparisons have led to the hypothesis that sex differences in song nuclei size correlate with sex differences in song behaviour. However, only few species with similar song behaviour in both sexes have been investigated and not all data fit the hypothesis. We investigated the proposed structure – function relationship in a cooperatively breeding and duetting songbird, the white-browed sparrow weaver (Plocepasser mahali). This species lives in groups of 2–10 individuals, with a dominant breeding pair and male and female subordinates. While all male and female group members sing duet and chorus song, a male, once it has reached the dominant position in the group, sings an additional type of song that comprises a distinct and large syllable repertoire. Here we show for both types of male – female comparisons a male-biased sex difference in neuroanatomy of areas of the song production pathway (HVC and RA) that does not correlate with the observed polymorphism in song behaviour. In contrast, in situ hybridisation of mRNA of selected genes expressed in the song nucleus HVC reveals a gene expression pattern that is either similar between sexes in female – subordinate male comparisons or female-biased in female – dominant male comparisons. Thus, the polymorphic gene expression pattern would fit the sex- and status-related song behaviour. However, this implies that once a male has become dominant it produces the duetting song with a different neural phenotype than subordinate males

Modeling Evolutionary Dynamics of Epigenetic Mutations in Hierarchically Organized Tumors

The cancer stem cell (CSC) concept is a highly debated topic in cancer research. While experimental evidence in favor of the cancer stem cell theory is apparently abundant, the results are often criticized as being difficult to interpret. An important reason for this is that most experimental data that support this model rely on transplantation studies. In this study we use a novel cellular Potts model to elucidate the dynamics of established malignancies that are driven by a small subset of CSCs. Our results demonstrate that epigenetic mutations that occur during mitosis display highly altered dynamics in CSC-driven malignancies compared to a classical, non-hierarchical model of growth. In particular, the heterogeneity observed in CSC-driven tumors is considerably higher. We speculate that this feature could be used in combination with epigenetic (methylation) sequencing studies of human malignancies to prove or refute the CSC hypothesis in established tumors without the need for transplantation. Moreover our tumor growth simulations indicate that CSC-driven tumors display evolutionary features that can be considered beneficial during tumor progression. Besides an increased heterogeneity they also exhibit properties that allow the escape of clones from local fitness peaks. This leads to more aggressive phenotypes in the long run and makes the neoplasm more adaptable to stringent selective forces such as cancer treatment. Indeed when therapy is applied the clone landscape of the regrown tumor is more aggressive with respect to the primary tumor, whereas the classical model demonstrated similar patterns before and after therapy. Understanding these often counter-intuitive fundamental properties of (non-)hierarchically organized malignancies is a crucial step in validating the CSC concept as well as providing insight into the therapeutical consequences of this model

Female house sparrows "count on" male genes: experimental evidence for MHC-dependent mate preference in birds

<p>Abstract</p> <p>Background</p> <p>Females can potentially assess the quality of potential mates using their secondary sexual traits, and obtain "good genes" that increase offspring fitness. Another potential indirect benefit from mating preferences is genetic compatibility, which does not require extravagant or viability indicator traits. Several studies with mammals and fish indicate that the genes of the major histocompatibility complex (MHC) influence olfactory cues and mating preferences, and such preferences confer genetic benefits to offspring. We investigated whether individual MHC diversity (class I) influences mating preferences in house sparrows (<it>Passer domesticus</it>).</p> <p>Results</p> <p>Overall, we found no evidence that females preferred males with high individual MHC diversity. Yet, when we considered individual MHC allelic diversity of the females, we found that females with a low number of alleles were most attracted to males carrying a high number of MHC alleles, which might reflect a mating-up preference by allele counting.</p> <p>Conclusions</p> <p>This is the first experimental evidence for MHC-dependent mating preferences in an avian species to our knowledge. Our findings raise questions about the underlying mechanisms through which birds discriminate individual MHC diversity among conspecifics, and they suggest a novel mechanism through which mating preferences might promote the evolution of MHC polymorphisms and generate positive selection for duplicated MHC loci.</p

Melanism in Peromyscus Is Caused by Independent Mutations in Agouti

Identifying the molecular basis of phenotypes that have evolved independently can provide insight into the ways genetic and developmental constraints influence the maintenance of phenotypic diversity. Melanic (darkly pigmented) phenotypes in mammals provide a potent system in which to study the genetic basis of naturally occurring mutant phenotypes because melanism occurs in many mammals, and the mammalian pigmentation pathway is well understood. Spontaneous alleles of a few key pigmentation loci are known to cause melanism in domestic or laboratory populations of mammals, but in natural populations, mutations at one gene, the melanocortin-1 receptor (Mc1r), have been implicated in the vast majority of cases, possibly due to its minimal pleiotropic effects. To investigate whether mutations in this or other genes cause melanism in the wild, we investigated the genetic basis of melanism in the rodent genus Peromyscus, in which melanic mice have been reported in several populations. We focused on two genes known to cause melanism in other taxa, Mc1r and its antagonist, the agouti signaling protein (Agouti). While variation in the Mc1r coding region does not correlate with melanism in any population, in a New Hampshire population, we find that a 125-kb deletion, which includes the upstream regulatory region and exons 1 and 2 of Agouti, results in a loss of Agouti expression and is perfectly associated with melanic color. In a second population from Alaska, we find that a premature stop codon in exon 3 of Agouti is associated with a similar melanic phenotype. These results show that melanism has evolved independently in these populations through mutations in the same gene, and suggest that melanism produced by mutations in genes other than Mc1r may be more common than previously thought