Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer

PurposeAmplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small-molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that BET bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven NSCLC with BET inhibition.Experimental DesignWe performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cells lines harboring KRAS and/or LKB1 mutations. Furthermore, we evaluated JQ1 in transgenic mouse lung cancer models expressing mutant kras or concurrent mutant kras and lkb1. Effects of bromodomain inhibition on transcriptional pathways were explored and validated by expression analysis.ResultsWhile JQ1 is broadly active in NSCLC cells, activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or genetic knock-down of LKB1. In sensitive NSCLC models, JQ1 treatment results in the coordinate downregulation of the MYC-dependent transcriptional program. We found that JQ1 treatment produces significant tumor regression in mutant kras mice. As predicted, tumors from mutant kras and lkb1 mice did not respond to JQ1.ConclusionBromodomain inhibition comprises a promising therapeutic strategy for KRAS mutant NSCLC with wild-type LKB1, via inhibition of MYC function. Clinical studies of BET bromodomain inhibitors in aggressive NSCLC will be actively pursued

Cosmic CARNage II: the evolution of the galaxy stellar mass function in observations and galaxy formation models

We present a comparison of the observed evolving galaxy stellar mass functions with the predictions of eight semi-analytic models and one halo occupation distribution model. While most models are able to fit the data at low redshift, some of them struggle to simultaneously fit observations at high redshift. We separate the galaxies into 'passive' and 'star-forming' classes and find that several of the models produce too many low-mass star-forming galaxies at high redshift compared to observations, in some cases by nearly a factor of 10 in the redshift range 2.5 < z < 3.0. We also find important differences in the implied mass of the dark matter haloes the galaxies inhabit, by comparing with halo masses inferred from observations. Galaxies at high redshift in the models are in lower mass haloes than suggested by observations, and the star formation efficiency in low-mass haloes is higher than observed. We conclude that many of the models require a physical prescription that acts to dissociate the growth of low-mass galaxies from the growth of their dark matter haloes at high redshift.Facultad de Ciencias Astronómicas y GeofísicasInstituto de Astrofísica de La Plat

Cosmic CARNage II: the evolution of the galaxy stellar mass function in observations and galaxy formation models

We present a comparison of the observed evolving galaxy stellar mass functions with the predictions of eight semi-analytic models and one halo occupation distribution model. While most models are able to fit the data at low redshift, some of them struggle to simultaneously fit observations at high redshift. We separate the galaxies into 'passive' and 'star-forming' classes and find that several of the models produce too many low-mass star-forming galaxies at high redshift compared to observations, in some cases by nearly a factor of 10 in the redshift range 2.5 < z < 3.0. We also find important differences in the implied mass of the dark matter haloes the galaxies inhabit, by comparing with halo masses inferred from observations. Galaxies at high redshift in the models are in lower mass haloes than suggested by observations, and the star formation efficiency in low-mass haloes is higher than observed. We conclude that many of the models require a physical prescription that acts to dissociate the growth of low-mass galaxies from the growth of their dark matter haloes at high redshift.Facultad de Ciencias Astronómicas y GeofísicasInstituto de Astrofísica de La Plat

Cosmic CARNage II: the evolution of the galaxy stellar mass functionin observations and galaxy formation models

We present a comparison of the observed evolving galaxy stellar mass functions with the predictions of eight semi-analytic models and one halo occupation distribution model. While most models are able to fit the data at low redshift, some of them struggle to simultaneously fit observations at high redshift. We separate the galaxies into ‘passive’ and ‘star-forming’ classes and find that several of the models produce too many low-mass star-forming galaxies at high redshift compared to observations, in some cases by nearly a factor of 10 in the redshift range 2.5 < z < 3.0. We also find important differences in the implied mass of the dark matter haloes the galaxies inhabit, by comparing with halo masses inferred from observations. Galaxies at high redshift in the models are in lower mass haloes than suggested by observations, and the star formation efficiency in low-mass haloes is higher than observed. We conclude that many of the models require a physical prescription that acts to dissociate the growth of low-mass galaxies from the growth of their dark matter haloes at high redshift

Cosmic CARNage I: on the calibration of galaxy formation models

We present a comparison of nine galaxy formation models, eight semi-analytical, and one halo occupation distribution model, run on the same underlying cold dark matter simulation (cosmological box of comoving width 125h−1 Mpc, with a dark-matter particle mass of 1.24 × 109h−1M) and the same merger trees. While their free parameters have been calibrated to the same observational data sets using two approaches, they nevertheless retain some ‘memory’ of any previous calibration that served as the starting point (especially for the manually tuned models). For the first calibration, models reproduce the observed z = 0 galaxy stellar mass function (SMF) within 3σ. The second calibration extended the observational data to include the z = 2 SMF alongside the z ∼ 0 star formation rate function, cold gas mass, and the black hole–bulge mass relation. Encapsulating the observed evolution of the SMF from z = 2 to 0 is found to be very hard within the context of the physics currently included in the models. We finally use our calibrated models to study the evolution of the stellar-to-halo mass (SHM) ratio. For all models, we find that the peak value of the SHM relation decreases with redshift. However, the trends seen for the evolution of the peak position as well as the mean scatter in the SHM relation are rather weak and strongly model dependent. Both the calibration data sets and model results are publicly available.Instituto de Astrofísica de La PlataFacultad de Ciencias Astronómicas y Geofísica

Cosmic CARNage I: on the calibration of galaxy formation models

We present a comparison of nine galaxy formation models, eight semi-analytical, and one halo occupation distribution model, run on the same underlying cold dark matter simulation (cosmological box of comoving width 125h−1 Mpc, with a dark-matter particle mass of 1.24 × 109h−1M) and the same merger trees. While their free parameters have been calibrated to the same observational data sets using two approaches, they nevertheless retain some ‘memory’ of any previous calibration that served as the starting point (especially for the manually tuned models). For the first calibration, models reproduce the observed z = 0 galaxy stellar mass function (SMF) within 3σ. The second calibration extended the observational data to include the z = 2 SMF alongside the z ∼ 0 star formation rate function, cold gas mass, and the black hole–bulge mass relation. Encapsulating the observed evolution of the SMF from z = 2 to 0 is found to be very hard within the context of the physics currently included in the models. We finally use our calibrated models to study the evolution of the stellar-to-halo mass (SHM) ratio. For all models, we find that the peak value of the SHM relation decreases with redshift. However, the trends seen for the evolution of the peak position as well as the mean scatter in the SHM relation are rather weak and strongly model dependent. Both the calibration data sets and model results are publicly available.Instituto de Astrofísica de La PlataFacultad de Ciencias Astronómicas y Geofísica

Cosmic CARNage I: on the calibration of galaxy formation models

We present a comparison of nine galaxy formation models, eight semi-analytical, and one halo occupation distribution model, run on the same underlying cold dark matter simulation (cosmological box of comoving width 125h−1 Mpc, with a dark-matter particle mass of 1.24 × 109h−1M) and the same merger trees. While their free parameters have been calibrated to the same observational data sets using two approaches, they nevertheless retain some ‘memory’ of any previous calibration that served as the starting point (especially for the manually tuned models). For the first calibration, models reproduce the observed z = 0 galaxy stellar mass function (SMF) within 3σ. The second calibration extended the observational data to include the z = 2 SMF alongside the z ∼ 0 star formation rate function, cold gas mass, and the black hole–bulge mass relation. Encapsulating the observed evolution of the SMF from z = 2 to 0 is found to be very hard within the context of the physics currently included in the models. We finally use our calibrated models to study the evolution of the stellar-to-halo mass (SHM) ratio. For all models, we find that the peak value of the SHM relation decreases with redshift. However, the trends seen for the evolution of the peak position as well as the mean scatter in the SHM relation are rather weak and strongly model dependent. Both the calibration data sets and model results are publicly available.Instituto de Astrofísica de La PlataFacultad de Ciencias Astronómicas y Geofísica

Cosmic CARNage I: on the calibration of galaxy formation models

We present a comparison of nine galaxy formation models, eight semi-analytical, and one halo occupation distribution model, run on the same underlying cold dark matter simulation (cosmological box of comoving width 125h−1 Mpc, with a dark-matter particle mass of 1.24 × 109h−1M) and the same merger trees. While their free parameters have been calibrated to the same observational data sets using two approaches, they nevertheless retain some ‘memory’ of any previous calibration that served as the starting point (especially for the manually tuned models). For the first calibration, models reproduce the observed z = 0 galaxy stellar mass function (SMF) within 3σ. The second calibration extended the observational data to include the z = 2 SMF alongside the z ∼ 0 star formation rate function, cold gas mass, and the black hole–bulge mass relation. Encapsulating the observed evolution of the SMF from z = 2 to 0 is found to be very hard within the context of the physics currently included in the models. We finally use our calibrated models to study the evolution of the stellar-to-halo mass (SHM) ratio. For all models, we find that the peak value of the SHM relation decreases with redshift. However, the trends seen for the evolution of the peak position as well as the mean scatter in the SHM relation are rather weak and strongly model dependent. Both the calibration data sets and model results are publicly available

Diet quality index as a predictor of treatment efficacy in overweight and obese adolescents: The EVASYON study

Background & aim: A diet quality index (DQI) is a tool that provides an overall score of an individual''s dietary intake when assessing compliance with food-based dietary guidelines. A number of DQIs have emerged, albeit their associations with health-related outcomes are debated. The aim of the present study was to assess whether adherence to dietary intervention, and the overall quality of the diet, can predict body composition changes. Methods: To this purpose, overweight/obese adolescents (n = 117, aged: 13–16 years; 51 males, 66 females) were recruited into a multi-component (diet, physical activity and psychological support) family-based group treatment programme. We measured the adolescents’ compliance and body composition at baseline and after 2 months (intensive phase) and 13 months (extensive phase) of follow-up. Also, at baseline, after 6 months, and at the end of follow-up we calculated the DQI. Results: Global compliance with the dietary intervention was 37.4% during the intensive phase, and 14.3% during the extensive phase. Physical activity compliance was 94.1% at 2-months and 34.7% at 13months and psychological support compliance were growing over the intervention period (10.3% intensive phase and 45.3% during extensive phase). Adolescents complying with the meal frequency criteria at the end of the extensive phase had greater reductions in FMI z-scores than those did not complying (Cohen''s d = 0.53). A statistically significant association was observed with the diet quality index. DQI-A variation explained 98.1% of BMI z-score changes and 95.1% of FMI changes. Conclusions: We conclude that assessment of changes in diet quality could be a useful tool in predicting body composition changes in obese adolescents involved in a diet and physical activity intervention programme backed-up by psychological and family support

HIF2alpha cooperates with RAS to promote lung tumorigenesis in mice.

Members of the hypoxia-inducible factor (HIF) family of transcription factors regulate the cellular response to hypoxia. In non-small cell lung cancer (NSCLC), high HIF2alpha levels correlate with decreased overall survival, and inhibition of either the protein encoded by the canonical HIF target gene VEGF or VEGFR2 improves clinical outcomes. However, whether HIF2alpha is causal in imparting this poor prognosis is unknown. Here, we generated mice that conditionally express both a nondegradable variant of HIF2alpha and a mutant form of Kras (KrasG12D) that induces lung tumors. Mice expressing both Hif2a and KrasG12D in the lungs developed larger tumors and had an increased tumor burden and decreased survival compared with mice expressing only KrasG12D. Additionally, tumors expressing both KrasG12D and Hif2a were more invasive, demonstrated features of epithelial- mesenchymal transition (EMT), and exhibited increased angiogenesis associated with mobilization of circulating endothelial progenitor cells. These results implicate HIF2alpha causally in the pathogenesis of lung cancer in mice, demonstrate in vivo that HIF2alpha can promote expression of markers of EMT, and define HIF2alpha as a promoter of tumor growth and progression in a solid tumor other than renal cell carcinoma. They further suggest a possible causal relationship between HIF2alpha and prognosis in patients with NSCLC