Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer

Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC

Interband mixing between two-dimensional states localized in a surface quantum well and heavy hole states of the valence band in narrow gap semiconductor

Theoretical calculations in the framework of Kane model have been carried out in order to elucidate the role of interband mixing in forming the energy spectrum of two-dimensional carriers, localized in a surface quantum well in narrow gap semiconductor. Of interest was the mixing between the 2D states and heavy hole states in the volume of semiconductor. It has been shown that the interband mixing results in two effects: the broadening of 2D energy levels and their shift, which are mostly pronounced for semiconductors with high doping level. The interband mixing has been found to influence mostly the effective mass of 2D carriers for large their concentration, whereas it slightly changes the subband distribution in a wide concentration range.Comment: 12 pages (RevTEX) and 4 PostScript-figure

GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment

The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting

Negative longitudinal magnetoresistance from anomalous N=0 Landau level in topological materials

Negative longitudinal magnetoresistance (NLMR) is shown to occur in topological materials in the extreme quantum limit, when a magnetic field is applied parallel to the excitation current. We perform pulsed and DC field measurements on Pb1-xSnxSe epilayers where the topological state can be chemically tuned. The NLMR is observed in the topological state, but is suppressed and becomes positive when the system becomes trivial. In a topological material, the lowest N=0 conduction Landau level disperses down in energy as a function of increasing magnetic field, while the N=0 valence Landau level disperses upwards. This anomalous behavior is shown to be responsible for the observed NLMR. Our work provides an explanation of the outstanding question of NLMR in topological insulators and establishes this effect as a possible hallmark of bulk conduction in topological matter.Comment: Accepted in Physical Review Letter

Electron and hole states in quantum-dot quantum wells within a spherical 8-band model

In order to study heterostructures composed both of materials with strongly different parameters and of materials with narrow band gaps, we have developed an approach, which combines the spherical 8-band effective-mass Hamiltonian and the Burt's envelope function representation. Using this method, electron and hole states are calculated in CdS/HgS/CdS/H_2O and CdTe/HgTe/CdTe/H_2O quantum-dot quantum-well heterostructures. Radial components of the wave functions of the lowest S and P electron and hole states in typical quantum-dot quantum wells (QDQWs) are presented as a function of radius. The 6-band-hole components of the radial wave functions of an electron in the 8-band model have amplitudes comparable with the amplitude of the corresponding 2-band-electron component. This is a consequence of the coupling between the conduction and valence bands, which gives a strong nonparabolicity of the conduction band. At the same time, the 2-band-electron component of the radial wave functions of a hole in the 8-band model is small compared with the amplitudes of the corresponding 6-band-hole components. It is shown that in the CdS/HgS/CdS/H_2O QDQW holes in the lowest states are strongly localized in the well region (HgS). On the contrary, electrons in this QDQW and both electron and holes in the CdTe/HgTe/CdTe/H_2O QDQW are distributed through the entire dot. The importance of the developed theory for QDQWs is proven by the fact that in contrast to our rigorous 8-band model, there appear spurious states within the commonly used symmetrized 8-band model.Comment: 15 pages, 5 figures, E-mail addresses: [email protected], [email protected]

Maternal fish and shellfish intake and pregnancy outcomes: A prospective cohort study in Brittany, France

<p>Abstract</p> <p>Background</p> <p>Recommendations about risks and benefits of seafood intake during pregnancy have been published in the last decade, but the specific health effects of the different categories of seafood remain unknown. Fish and shellfish may differ according to their fatty acid content and their concentration of chemical pollutants and toxins. Not taking these particularities into account may result in underestimating of both the positive and negative effects of seafood on birth outcomes and partly explains inconsistent results on the subject.</p> <p>Methods</p> <p>In the PELAGIE cohort study, including 2398 pregnant women from Brittany, we fit multiple linear and logistic regression models to examine associations of fish (salt-water fish only) and shellfish intake before pregnancy with length of gestation, birthweight, and risks of preterm births, low birthweight or small-for-gestational-age (SGA) babies.</p> <p>Results</p> <p>When fish and shellfish consumptions were considered simultaneously, we observed a decrease in the risk of SGA birth with increasing frequency of fish intake: OR = 0.57 (95%CI: 0.31 to 1.05) for women eating fish twice a week or more compared with those eating it less than once a month. The risk of SGA birth was significantly higher among women eating shellfish twice a week or more than among those eating it less than once a month: OR = 2.14 (95%CI: 1.13 to 4.07). Each additional monthly meal including fish was significantly related to an increase in gestational length of 0.02 week (95%CI: 0.002 to 0.035). No association was observed with birthweight or preterm birth.</p> <p>Conclusion</p> <p>These results suggest that different categories of seafood may be differently associated with birth outcomes, fish consumption with increased length of gestation and shellfish consumption with decreased fetal growth.</p

Rationales, design and recruitment for the Elfe longitudinal study

Background Many factors act simultaneously in childhood to influence health status, life chances and well being, including pre-birth influences, the environmental pollutants of early life, health status but also the social influences of family and school. A cohort study is needed to disentangle these influences and explore attribution. Methods Elfe will be a nationally representative cohort of 20 000 children followed from birth to adulthood using a multidisciplinary approach. The cohort will be based on the INSEE Permanent Demographic Panel (EDP) established using census data and civil records. The sample size has been defined in order to match the representativeness criteria and to obtain some prevalence estimation, but also to address the research area of low exposure/rare effects. The cohort will be based on repeated surveys by face to face or phone interview (at birth and each year) as well as medical interview (at 2 years) and examination (at 6 years). Furthermore, biological samples will be taken at birth to evaluate the foetal exposition to toxic substances, environmental sensors will be placed in the child's homes. Pilot studies have been initiated in 2007 (500 children) with an overall acceptance rate of 55% and are currently under progress, the 2-year survey being carried out in October this year. Discussion The longitudinal study will provide a unique source of data to analyse the development of children in their environment, to study the various factors interacting throughout the life course up to adulthood and to determine the impact of childhood experience on the individual's physical, psychological, social and professional development