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Resistance to endocrine therapy is a major complication of luminal breast cancer and studies of the biological features of hormonal resistance are limited by the lack of adequate preclinical models. The aim of this study is to establish and characterize a panel of primary human luminal breast carcinoma xenografts, and to evaluate their response to endocrine therapies. Four hundred and twenty-three tumor fragments obtained directly from patients have been grafted in the interscapular fatpad of Swiss nude mice. After stable engraftment with estradiol supplementation, xenografted tumors have been validated by conventional pathology and immunohistochemistry examination, and additional molecular studies. In vivo tumor growth and response to different endocrine treatments were evaluated. We have engrafted 423 tumors including 314 ER+ tumors, and 8 new luminal breast cancer xenografts have been obtained (2.5%). Tumor take was much lower for luminal tumors than for non-luminal tumors (2.5 vs. 24.7%, P  < 0.0001), and was associated with two independent criteria, i.e., ER status ( P  < 0.0001) and a high grade tumor ( P  = 0.05). Histological and immunohistochemical analyses performed on patient’s tumors and xenografts showed striking similarities in the tumor morphology as well as in the expression level of ER, PR, and HER2. Response to hormone therapy, evaluated in 6 luminal models, showed different sensitivities, thus exhibiting heterogeneity similar to what is observed in the clinic. We have established a panel of primary human luminal breast cancer xenografts, recapitulating the biological and clinical behaviors of patient tumors, and therefore suitable for further preclinical experiments.

Deafness is a common sensory defect in human. Our understanding of the molecular bases of this pathology comes from the study of a few genes that have been identified in human and/or in mice. Indeed, deaf mouse mutants are good models for studying and identifying genes involved in human hereditary hearing loss. Among these mouse mutants, twister was initially reported to have abnormal behavior and thereafter to be deaf. The recessive twister (twt) mutation has been mapped on mouse Chromosome (Chr) 7, homologous to the long arm of human Chr 15 (15q11). Otog, the gene encoding otogelin, a glycoprotein specific to all the acellular membranes of the inner ear, is also localized to mouse Chr 7, but in a region more proximal to the twister mutation, homologous to the short arm of human Chr 11 (11p15) carrying the two deafness loci, DFNB 18 and USH C. Mutant mice resulting from the knock-out of Otog, the Otogtm1Prs mice, present deafness and severe imbalance. Although twt had been mapped distally to Otog, these data prompted us to test whether twt could be due to a mutation in the Otog locus. Here, we demonstrate by genetic analysis that twt is actually allelic to Otogtm1Prs. We further extend the phenotypical analysis of twister mice, documenting the association of a severe vestibular phenotype and moderate to severe form of deafness. Molecular analysis of the Otog gene revealed the absence of detectable expression of Otog in the twister mutant. The molecular and phenotypical description of the twt mouse mutation, Otogtwt, reported herein, highlights the importance of the acellular membranes in the inner ear mechanotransduction process.

Genes specifically expressed in the inner ear are candidates to underlie hereditary nonsyndromic deafness1. The gene Otog has been isolated from a mouse subtractive cDNA cochlear library2. It encodes otogelin, an N-glycosylated protein that is present in the acellular membranes covering the six sensory epithelial patches of the inner ear: in the cochlea (the auditory sensory organ), the tectorial membrane (TM) over the organ of Corti; and in the vestibule (the balance sensory organ), the otoconial membranes over the utricular and saccular maculae as well as the cupulae over the cristae ampullares of the three semi-circular canals. These membranes are involved in the mechanotransduction process. Their movement, which is induced by sound in the cochlea or acceleration in the vestibule, results in the deflection of the stereocilia bundle at the apex of the sensory hair cells, which in turn opens the mechanotransduction channels located at the tip of the stereo-cilia3. We sought to elucidate the role of otogelin in the auditory and vestibular functions by generating mice with a targeted disruption of Otog. In Otog−/− mice, both the vestibular and the auditory functions were impaired. Histological analysis of these mutants demonstrated that in the vestibule, otogelin is required for the anchoring of the otoconial membranes and cupulae to the neuroepithelia. In the cochlea, ultrastructural analysis of the TM indicated that otogelin is involved in the organization of its fibrillar network. Otogelin is likely to have a role in the resistance of this membrane to sound stimulation. These results support OTOG as a possible candidate gene for a human nonsyndromic form of deafness.

Deafness is a common sensory defect in human. Our understanding of the molecular bases of this pathology comes from the study of a few genes that have been identified in human and/or in mice. Indeed, deaf mouse mutants are good models for studying and identifying genes involved in human hereditary hearing loss. Among these mouse mutants, twister was initially reported to have abnormal behavior and thereafter to be deaf. The recessive twister (twt) mutation has been mapped on mouse Chromosome (Chr) 7, homologous to the long arm of human Chr 15 (15q11). Otog, the gene encoding otogelin, a glycoprotein specific to all the acellular membranes of the inner ear, is also localized to mouse Chr 7, but in a region more proximal to the twister mutation, homologous to the short arm of human Chr 11 (11p15) carrying the two deafness loci, DFNB18 and USH1C. Mutant mice resulting from the knock-out of Otog, the Otog(tm1Prs) mice, present deafness and severe imbalance. Although twt had been mapped distally to Otog, these data prompted us to test whether twt could be due to a mutation in the Otog locus. Here, we demonstrate by genetic analysis that twt is actually allelic to Otog(tm1Prs). We further extend the phenotypical analysis of twister mice, documenting the association of a severe vestibular phenotype and moderate to severe form of deafness. Molecular analysis of the Otog gene revealed the absence of detectable expression of Otog in the twister mutant. The molecular and phenotypical description of the twt mouse mutation, Otog(twt), reported herein, highlights the importance of the acellular membranes in the inner ear mechanotransduction process.

Our current knowledge of cosmic star-formation history during the first two billion years (corresponding to redshift z >3) is mainly based on galaxies identified in rest-frame ultraviolet light. However, this population of galaxies is known to under-represent the most massive galaxies, which have rich dust content and/or old stellar populations. This raises the questions of the true abundance of massive galaxies and the star-formation-rate density in the early universe. Although several massive galaxies that are invisible in the ultraviolet have recently been confirmed at early epochs, most of them are extreme starbursts with star-formation rates exceeding 1000 solar masses per year, suggesting that they are unlikely to represent the bulk population of massive galaxies. Here we report submillimeter (wavelength 870um) detections of 39 massive star-forming galaxies at z > 3, which are unseen in the spectral region from the deepest ultraviolet to the near-infrared. With a space density of about \\(2 \\times 10^{-5}\\) per cubic megaparsec (two orders of magnitudes higher than extreme starbursts) and star-formation rates of 200 solar masses per year, these galaxies represent the bulk population of massive galaxies that have been missed from previous surveys. They contribute a total star-formation-rate density ten times larger than that of equivalently massive ultraviolet-bright galaxies at z >3. Residing in the most massive dark matter halos at their redshifts, they are probably the progenitors of the largest present-day galaxies in massive groups and clusters. Such a high abundance of massive and dusty galaxies in the early universe challenges our understanding of massive-galaxy formation.

Our current knowledge of cosmic star-formation history during the first two billion years (corresponding to redshift z  > 3) is mainly based on galaxies identified in rest-frame ultraviolet light 1 . However, this population of galaxies is known to under-represent the most massive galaxies, which have rich dust content and/or old stellar populations. This raises the questions of the true abundance of massive galaxies and the star-formation-rate density in the early Universe. Although several massive galaxies that are invisible in the ultraviolet have recently been confirmed at early epochs 2 – 4 , most of them are extreme starburst galaxies with star-formation rates exceeding 1,000 solar masses per year, suggesting that they are unlikely to represent the bulk population of massive galaxies. Here we report submillimetre (wavelength 870 micrometres) detections of 39 massive star-forming galaxies at z  > 3, which are unseen in the spectral region from the deepest ultraviolet to the near-infrared. With a space density of about 2 × 10 −5 per cubic megaparsec (two orders of magnitude higher than extreme starbursts 5 ) and star-formation rates of 200 solar masses per year, these galaxies represent the bulk population of massive galaxies that has been missed from previous surveys. They contribute a total star-formation-rate density ten times larger than that of equivalently massive ultraviolet-bright galaxies at z  > 3. Residing in the most massive dark matter haloes at their redshifts, they are probably the progenitors of the largest present-day galaxies in massive groups and clusters. Such a high abundance of massive and dusty galaxies in the early Universe challenges our understanding of massive-galaxy formation. Submillimetre-wavelength observations reveal a sample of galaxies that have no detectable emission in the ultraviolet-to-near-infrared region, and are probably the progenitors of the largest present-day galaxies in clusters.

Objectives To estimate 10 year decline in cognitive function from longitudinal data in a middle aged cohort and to examine whether age cohorts can be compared with cross sectional data to infer the effect of age on cognitive decline. Design Prospective cohort study. At study inception in 1985-8, there were 10 308 participants, representing a recruitment rate of 73%. Setting Civil service departments in London, United Kingdom. Participants 5198 men and 2192 women, aged 45-70 at the beginning of cognitive testing in 1997-9. Main outcome measure Tests of memory, reasoning, vocabulary, and phonemic and semantic fluency, assessed three times over 10 years. Results All cognitive scores, except vocabulary, declined in all five age categories (age 45-49, 50-54, 55-59, 60-64, and 65-70 at baseline), with evidence of faster decline in older people. In men, the 10 year decline, shown as change/range of test×100, in reasoning was −3.6% (95% confidence interval −4.1% to −3.0%) in those aged 45-49 at baseline and −9.6% (−10.6% to −8.6%) in those aged 65-70. In women, the corresponding decline was −3.6% (−4.6% to −2.7%) and −7.4% (−9.1% to −5.7%). Comparisons of longitudinal and cross sectional effects of age suggest that the latter overestimate decline in women because of cohort differences in education. For example, in women aged 45-49 the longitudinal analysis showed reasoning to have declined by −3.6% (−4.5% to −2.8%) but the cross sectional effects suggested a decline of −11.4% (−14.0% to −8.9%). Conclusions Cognitive decline is already evident in middle age (age 45-49).

Background Myocardial infarction (MI) leads to complex changes in left ventricular (LV) haemodynamics that are linked to clinical outcomes. We hypothesize that LV blood flow kinetic energy (KE) is altered in MI and is associated with LV function and infarct characteristics. This study aimed to investigate the intra-cavity LV blood flow KE in controls and MI patients, using cardiovascular magnetic resonance (CMR) four-dimensional (4D) flow assessment. Methods Forty-eight patients with MI (acute-22; chronic-26) and 20 age/gender-matched healthy controls underwent CMR which included cines and whole-heart 4D flow. Patients also received late gadolinium enhancement imaging for infarct assessment. LV blood flow KE parameters were indexed to LV end-diastolic volume and include: averaged LV, minimal, systolic, diastolic, peak E-wave and peak A-wave KEi EDV . In addition, we investigated the in-plane proportion of LV KE (%) and the time difference (TD) to peak E-wave KE propagation from base to mid-ventricle was computed. Association of LV blood flow KE parameters to LV function and infarct size were investigated in all groups. Results LV KEi EDV was higher in controls than in MI patients (8.5 ± 3 μJ/ml versus 6.5 ± 3 μJ/ml, P  = 0.02). Additionally, systolic, minimal and diastolic peak E-wave KEi EDV were lower in MI ( P  < 0.05). In logistic-regression analysis, systolic KEi EDV (Beta = − 0.24, P  < 0.01) demonstrated the strongest association with the presence of MI. In multiple-regression analysis, infarct size was most strongly associated with in-plane KE ( r  = 0.5, Beta = 1.1, P  < 0.01). In patients with preserved LV ejection fraction (EF), minimal and in-plane KEi EDV were reduced ( P  < 0.05) and time difference to peak E-wave KE propagation during diastole increased ( P  < 0.05) when compared to controls with normal EF. Conclusions Reduction in LV systolic function results in reduction in systolic flow KEi EDV . Infarct size is independently associated with the proportion of in-plane LV KE. Degree of LV impairment is associated with TD of peak E-wave KE. In patient with preserved EF post MI, LV blood flow KE mapping demonstrated significant changes in the in-plane KE, the minimal KEi EDV and the TD. These three blood flow KE parameters may offer novel methods to identify and describe this patient population.

Mitochondrial metabolism is an attractive target for cancer therapy 1 , 2 . Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC) 1 , 3 . Here we show that BTB and CNC homology1 (BACH1) 4 , a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin 5 , 6 , suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours 7 . Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors. The transcription factor BACH1, which targets mitochondrial metabolism, is expressed at high levels in several types of cancer; reducing its expression in tumours makes them more susceptible to treatment with mitochondrial inhibitors.

The nucleus of almost all massive galaxies contains a supermassive black hole (BH) 1 . The feedback from the accretion of these BHs is often considered to have crucial roles in establishing the quiescence of massive galaxies 2 – 14 , although some recent studies show that even galaxies hosting the most active BHs do not exhibit a reduction in their molecular gas reservoirs or star formation rates 15 – 17 . Therefore, the influence of BHs on galaxy star formation remains highly debated and lacks direct evidence. Here, based on a large sample of nearby galaxies with measurements of masses of both BHs and atomic hydrogen (HI), the main component of the interstellar medium 18 , we show that the HI gas mass to stellar masses ratio ( μ HI  =  M HI / M ⋆ ) is more strongly correlated with BH masses ( M BH ) than with any other galaxy parameters, including stellar mass, stellar mass surface density and bulge masses. Moreover, once the μ HI – M BH correlation is considered, μ HI loses dependence on other galactic parameters, demonstrating that M BH serves as the primary driver of μ HI . These findings provide important evidence for how the accumulated energy from BH accretion regulates the cool gas content in galaxies, by ejecting interstellar medium gas and/or suppressing gas cooling from the circumgalactic medium. Supermassive black holes regulate the amount of atomic hydrogen in galaxies and the atomic hydrogen gas mass to stellar masses ratio is more strongly correlated with black hole masses.