Breast cancer genome heterogeneity: a challenge to personalised medicine?

Implementation of high-throughput genomics sequencing approaches into routine laboratory practice has raised the potential for the identification of multiple breast cancer targets suitable for future therapeutic intervention in order to improve cancer outcomes. Results from these studies have revealed bewildering breast cancer genome complexity with very few aberrations occurring in common between breast cancers. In addition, such complexity is compounded by evidence of genomic heterogeneity occurring within individual breast cancers. Such inter-tumoural and intratumoural heterogeneity is likely to present a challenge to personalised therapeutic approaches that might be circumvented through the definition of genome instability mechanisms governing such diversity and their exploitation using synthetic lethal approaches

Radiological Identification of Near‐Surface Mineralogical Deposits Using Low‐Altitude Unmanned Aerial Vehicle

An ever‐increasing global population and unabating technological growth have resulted in a relentless appetite for mineral resources, namely rare earth elements, fuel minerals and those utilised in electronics applications, with the price of such species continuing to climb. In contrast to more established large‐scale and high‐cost exploration methodologies, this work details the application of novel multi‐rotor unmanned aerial vehicles equipped with miniaturised radiation detectors for the objective of undertaking resource exploration at lower costs, with greater autonomy and at considerably enhanced higher spatial resolutions; utilizing the ore material’s inherent low levels of characteristic radioactivity. As we demonstrate at the former Wooley Mine site in Arizona, USA, a legacy Cu/Fe prospect where the 600 by 275 m ore body (with a maximum deposit depth of 150 m), it is shown that such a fusion of commercially available low‐altitude multi-rotor aerial technology combined with cutting‐edge micro‐electronics and detector materials is capable of accurately assessing the spatial distribution and associated radiogenic signatures of commercially valuable surface/near‐surface ore bodies. This integrated system, deployed at an autonomously controlled consistent survey altitude and using constant grid transects/separations, is shown to be able to delineate the mineral‐containing ore deposits on the site, the location(s) of former mine workings and other surface manifestations. Owing to its advantageous costs alongside its ease of operation and subsequent data‐processing, through the adoption of this system, it is envisaged that less economically developed countries would now possess the means through which to evaluate and appropriately quantify their mineral wealth without the significant initial expenditure needed to equip themselves with otherwise prohibitively expensive technologies

Phenotypic Plasticity and Effects of Selection on Cell Division Symmetry in Escherichia coli

Aging has been demonstrated in unicellular organisms and is presumably due to asymmetric distribution of damaged proteins and other components during cell division. Whether the asymmetry-induced aging is inevitable or an adaptive and adaptable response is debated. Although asymmetric division leads to aging and death of some cells, it increases the effective growth rate of the population as shown by theoretical and empirical studies. Mathematical models predict on the other hand, that if the cells divide symmetrically, cellular aging may be delayed or absent, growth rate will be reduced but growth yield will increase at optimum repair rates. Therefore in nutritionally dilute (oligotrophic) environments, where growth yield may be more critical for survival, symmetric division may get selected. These predictions have not been empirically tested so far. We report here that Escherichia coli grown in oligotrophic environments had greater morphological and functional symmetry in cell division. Both phenotypic plasticity and genetic selection appeared to shape cell division time asymmetry but plasticity was lost on prolonged selection. Lineages selected on high nutrient concentration showed greater frequency of presumably old or dead cells. Further, there was a negative correlation between cell division time asymmetry and growth yield but there was no significant correlation between asymmetry and growth rate. The results suggest that cellular aging driven by asymmetric division may not be hardwired but shows substantial plasticity as well as evolvability in response to the nutritional environment

A Simple Approach to Fourth Generation Effects in B→Xsℓ+ℓ−B\to X_s \ell^+ \ell^- Decay

In a scenario in which fourth generation fermions exist, we study effects of new physics on the differential decay width, forward-backward asymmetry $A_{\text{FB}}$ and integrated branching ratio for $B\to X_s \ell^+ \ell^-$ decay with $(\ell=e,\mu)$. Prediction of the new physics on the mentioned quantities essentially differs from the Standard Model results, in certain regions of the parameter space, enhancement of new physics on the above mentioned physical quantities can yield values as large as two times of the SM predictions, whence present limits of experimental measurements of branching ratio is spanned, contraints of the new physics can be extracted. For the fourth generation CKM factor $V_{t^\prime b}^\ast V_{t^\prime s}$ we use $\pm 10^{-2}$ and $\pm 10^{-3}$ ranges, take into consideration the possibility of a complex phase where it may bring sizable contributions, obtained no significant dependency on the imaginary part of the new CKM factor. For the above mentioned quantities with a new family, deviations from the SM are promising, can be used as a probe of new physics.Comment: 9 pages aps forma

A Model for Damage Load and Its Implications for the Evolution of Bacterial Aging

Deleterious mutations appearing in a population increase in frequency until stopped by natural selection. The ensuing equilibrium creates a stable frequency of deleterious mutations or the mutational load. Here I develop the comparable concept of a damage load, which is caused by harmful non-heritable changes to the phenotype. A damage load also ensues when the increase of damage is opposed by selection. The presence of a damage load favors the evolution of asymmetrical transmission of damage by a mother to her daughters. The asymmetry is beneficial because it increases fitness variance, but it also leads to aging or senescence. A mathematical model based on microbes reveals that a cell lineage dividing symmetrically is immortal if lifetime damage rates do not exceed a threshold. The evolution of asymmetry allows the lineage to persist above the threshold, but the lineage becomes mortal. In microbes with low genomic mutation rates, it is likely that the damage load is much greater than the mutational load. In metazoans with higher genomic mutation rates, the damage and the mutational load could be of the same magnitude. A fit of the model to experimental data shows that Escherichia coli cells experience a damage rate that is below the threshold and are immortal under the conditions examined. The model estimates the asymmetry level of E. coli to be low but sufficient for persisting at higher damage rates. The model also predicts that increasing asymmetry results in diminishing fitness returns, which may explain why the bacterium has not evolved higher asymmetry

How Grandparents Matter: Support for the Cooperative Breeding Hypothesis in a Contemporary Dutch Population

Low birth rates in developed societies reflect women’s difficulties in combining work and motherhood. While demographic research has focused on the role of formal childcare in easing this dilemma, evolutionary theory points to the importance of kin. The cooperative breeding hypothesis states that the wider kin group has facilitated women’s reproduction during our evolutionary history. This mechanism has been demonstrated in pre-industrial societies, but there is no direct evidence of beneficial effects of kin’s support on parents’ reproduction in modern societies. Using three-generation longitudinal data anchored in a sample of grandparents aged 55 and over in 1992 in the Netherlands, we show that childcare support from grandparents increases the probability that parents have additional children in the next 8 to 10 years. Grandparental childcare provided to a nephew or niece of childless children did not significantly increase the probability that those children started a family. These results suggest that childcare support by grandparents can enhance their children’s reproductive success in modern societies and is an important factor in people’s fertility decisions, along with the availability of formal childcare

Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy

How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful

Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer

In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer

Childhood adversity, attachment security, and adult relationships: A preliminary study

Several evolutionary theorists have linked early rearing context to later reproductive strategy, hypothesizing that strategies differentiate during development as functional responses to ecological characteristics, by individuals or through parental manipulation. Attachment security has been proposed as a mediator. In this study, 40 young adults were given a multidimensional assessment, including the Hazen and Shaver Adult Attachment Questionnaire. Twenty-four subjects were classified as having secure attachment styles, 16 as nonsecure. The magnitude and predictability of parental investment during childhood was classified as lower if there was a brief intersibling interval, parental divorce, fewer economic resources, or less nurturing parents (i.e., more childhood adversity). Several such indicators were present for 17 people, 12 of whom were nonsecure, compared to only 4 of the 23 others. The nonsecurely attached subjects were less likely to have attained enduring marriages. The 6/16 nonsecure who had a marriage or cohabitation began them at a younger age and after a shorter courtship period than did the 15/24 secure with such relationships. Separations or divorces had already occurred in the relationships of 4/6 nonsecure versus 5/15 secure. Attachment security was associated with childhood adversity and adult relationships for both men and women, when analyzed separately. A retrospective study cannot address cause and effect, because poor adult relationship outcomes might bias recall of parental behavior. However, results are consistent with theories that unpredictable early environments foster short-term rather than long-term mating strategies, possibly through affecting attachment styles.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31362/1/0000274.pd

Therapy for metastatic melanoma: the past, present, and future

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise