Functional characterization of circulating tumor cells (CTCs) from metastatic ER+/HER2− breast cancer reveals dependence on HER2 and FOXM1 for endocrine therapy resistance and tumor cell survival: Implications for treatment of ER+/HER2− breast cancer

Mechanisms of acquired endocrine resistance and late recurrence in patients with ER+/HER2− breast cancer are complex and not fully understood. Here, we evaluated mechanisms of acquired resistance in circulating tumor cells (CTCs) from an ER+/HER2− breast cancer patient who initially responded but later progressed under endocrine treatment. We found a switch from ERα-dependent to HER2-dependent and ERα-independent expression of FOXM1, which may enable disseminated ER+/HER2− cells to re-initiate tumor cell growth and metastasis formation in the presence of endocrine treatment. Our results also suggest a role for HER2 in resistance, even in ER+ breast cancer cells that have neither HER2 amplification nor activating HER2 mutations. We found that NFkB signaling sustains HER2 and FOXM1 expression in CTCs in the presence of ERα inhibitors. Inhibition of NFkB signaling blocked expression of HER2 and FOXM1 in the CTCs, and induced apoptosis. Thus, targeting of NFkB and FOXM1 might be an efficient therapeutic approach to prevent late recurrence and to treat endocrine resistance. Collectively our data show that CTCs from patients with endocrine resistance allow mechanisms of acquired endocrine resistance to be delineated, and can be used to test potential drug regimens for combatting resistance

Transvaginal Repair of a Large Chronic Porcine Ventral Hernia with Synthetic Mesh Using NOTES

Transvaginal placement of synthetic mesh to repair large porcine hernia using NOTES technology appears to be a feasible alternative to traditional techniques

Influence of Canopy Disturbances on Runoff and Landslide Disposition after Heavy Rainfall Events

As protective forests have a major control function on runoff and erosion, they directly affect the risk from hydrogeomorphic processes such as sediment transport processes or debris flows. In this context, future scenarios of climate-related canopy disturbances and their influence on the protective effect remain, however, an unsolved problem. With the individual-based forest landscape and disturbance model iLand, an ensemble of forest landscape simulations was carried out and the effects of future changes in natural disturbance regimes were evaluated. To determine peak runoff, hydrological simulations have been conducted, using the conceptual hydrological model ZEMOKOST as well as the deterministic model GEOtop. Effects of forest disturbances on hillslope stability were investigated, based on a modified Coulomb landslide model. Our results suggest no influence of the disturbance regime on the runoff. The climate-related increase in the frequency of disturbances is not reflected in increased runoff during the period under consideration. Contrary, slope stability analyses indicate that the availability of shallow landslides in steep forested torrent catchments might be decreased by the occurrence of disturbances – especially for a warm and dry climate projection. Canopy disturbances seem to accelerate the adaptation of tree species to future climate conditions, which is likely to be accompanied by a change in root systems away from flat roots that currently predominate in torrential catchments. In terms of managing the protective effect of forests against shallow landslides, such natural disturbances can thus be considered as positive interventions in the existing forest ecosystem by promoting natural succession

High Refractive Index Silicone Gels for Simultaneous Total Internal Reflection Fluorescence and Traction Force Microscopy of Adherent Cells

Substrate rigidity profoundly impacts cellular behaviors such as migration, gene expression, and cell fate. Total Internal Reflection Fluorescence (TIRF) microscopy enables selective visualization of the dynamics of substrate adhesions, vesicle trafficking, and biochemical signaling at the cell-substrate interface. Here we apply high-refractive-index silicone gels to perform TIRF microscopy on substrates with a wide range of physiological elastic moduli and simultaneously measure traction forces exerted by cells on the substrate

Limits and barriers to adaptation to climate variability and change in Bangladeshi coastal fishing communities

Limits and barriers to adaptation restrict people’s ability to address the negative impacts of climate change or manage risks in a way that maximises their wellbeing. There is a lack of evidence of this on small-scale fishing communities in developing countries. This study identifies and characterises limits and barriers to adaptation of fishing activities to cyclones and examines interactions between them in two fishing communities in Bangladesh, using household questionnaires, oral history interviews, vulnerability matrices and focus group discussions. The limits include physical characteristics of climate and sea like higher frequency and duration of cyclones, and hidden sandbars. Barriers include technologically poor boats, inaccurate weather forecast, poor radio signal, lack of access to credit, low incomes, underestimation of cyclone occurrence, coercion of fishermen by the boat owners and captains, lack of education, skills and livelihood alternatives, unfavourable credit schemes, lack of enforcement of fishing regulations and maritime laws, and lack of access to fish markets. These local and wider scale factors interact in complex ways and constrain completion of fishing trips, coping with cyclones at sea, safe return of boats from sea, timely responses to cyclones and livelihood diversification. The findings indicate a need for further detailed research into the determinants and implications of such limits and barriers, in order to move towards an improved characterisation of adaptation and to identify most suitable means to overcome the limits and barriers

The Dark Energy Survey : more than dark energy – an overview

This overview paper describes the legacy prospect and discovery potential of the Dark Energy Survey (DES) beyond cosmological studies, illustrating it with examples from the DES early data. DES is using a wide-field camera (DECam) on the 4 m Blanco Telescope in Chile to image 5000 sq deg of the sky in five filters (grizY). By its completion, the survey is expected to have generated a catalogue of 300 million galaxies with photometric redshifts and 100 million stars. In addition, a time-domain survey search over 27 sq deg is expected to yield a sample of thousands of Type Ia supernovae and other transients. The main goals of DES are to characterize dark energy and dark matter, and to test alternative models of gravity; these goals will be pursued by studying large-scale structure, cluster counts, weak gravitational lensing and Type Ia supernovae. However, DES also provides a rich data set which allows us to study many other aspects of astrophysics. In this paper, we focus on additional science with DES, emphasizing areas where the survey makes a difference with respect to other current surveys. The paper illustrates, using early data (from ‘Science Verification’, and from the first, second and third seasons of observations), what DES can tell us about the Solar system, the Milky Way, galaxy evolution, quasars and other topics. In addition, we show that if the cosmological model is assumed to be +cold dark matter, then important astrophysics can be deduced from the primary DES probes. Highlights from DES early data include the discovery of 34 trans-Neptunian objects, 17 dwarf satellites of the Milky Way, one published z > 6 quasar (and more confirmed) and two published superluminous supernovae (and more confirmed)

BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample

It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling. Recent studies of BDNF gene methylation in relation to maternal care have linked high BDNF methylation levels in the blood of adults to lower quality of received maternal care measured via self-report. Yet the specific mechanisms by which these phenomena occur remain to be established. The present study examines the link between methylation of the BDNF gene promoter region and patterns of neural activity that are associated with maternal response to stressful versus non-stressful child stimuli within a sample that includes mothers with interpersonal violence-related PTSD (IPV-PTSD). 46 mothers underwent fMRI. The contrast of neural activity when watching children-including their own-was then correlated to BDNF methylation. Consistent with the existing literature, the present study found that maternal BDNF methylation was associated with higher levels of maternal anxiety and greater childhood exposure to domestic violence. fMRI results showed a positive correlation of BDNF methylation with maternal brain activity in the anterior cingulate (ACC), and ventromedial prefrontal cortex (vmPFC), regions generally credited with a regulatory function toward brain areas that are generating emotions. Furthermore we found a negative correlation of BDNF methylation with the activity of the right hippocampus. Since our stimuli focus on stressful parenting conditions, these data suggest that the correlation between vmPFC/ACC activity and BDNF methylation may be linked to mothers who are at a disadvantage with respect to emotion regulation when facing stressful parenting situations. Overall, this study provides evidence that epigenetic signatures of stress-related genes can be linked to functional brain regions regulating parenting stress, thus advancing our understanding of mothers at risk for stress-related psychopathology