Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Complex posttraumatic stress disorder in intergenerational trauma transmission among Eritrean asylum-seeking mother-child dyads

Background: Traumatic stress among forcibly displaced people has a variety of adverse consequences beyond individual mental health, including implications for poor socioemotional developmental outcomes for their children post-displacement. Objective: This study explored the intergenerational transmission of maternal ICD-11 Complex Posttraumatic Stress Disorder (CPTSD) and depression among asylum-seeking mothers for their children’s internalizing and externalizing difficulties. Method: Participants were 127 trauma-affected Eritrean mothers of preschool-aged children in Israel. The severity of child difficulties was compared between mothers with probable ICD-11 CPTSD (94.5% comorbid depression), ICD-11 PTSD (48.5% comorbid depression), unimorbid depression, and healthy mothers, using multivariate analyses of variance, while controlling for children’s direct exposure to adverse life experiences. Results: Probable ICD-11 CPTSD and PTSD were present in 23.6% and 26.0% of mothers, respectively. Relative to maternal PTSD, CPTSD was significantly and strongly associated with elevated child internalizing symptoms (d = 2.44) and marginally significantly, although strongly, associated with child externalizing symptoms (d = 1.30). Post-hoc exploratory analyses documented that, relative to maternal PTSD and depression, CPTSD and depression comorbidity was marginally significantly but strongly associated with child internalizing (SMD = .67), but not externalizing symptoms (SMD = .35). Conclusions: Findings implicate maternal CPTSD and comorbid depression in child socio-emotional development and inform clinical assessment, prevention, and intervention to attenuate poor development among children in unstable post-displacement settings

Linfoma não-Hodgkin primário do fígado em paciente com SIDA

Non-Hodgkin's lymphomas (NHL) are the second most frequent malignancies in AIDS patients. The majority of NHL associated with AIDS involves extranodal sites, especially the digestive tract and the central nervous system. Primary liver lymphoma (PLL) is an uncommon neoplasm among these patients. Ultrasonography and computed tomography scans may be helpful in the diagnosis of focal hepatic lymphoma. Image-guided fine-needle biopsy with histopathology of the liver lesions is the gold standard for the diagnosis of hepatic lymphoma. We report a case of PLL as the initial manifestation of AIDS in a patient without any previous infection by hepatitis C or B virus, presented as multiple and large hepatic masses.Os linfomas não-Hodgkin (LNH) são as segundas neoplasias mais freqüentes nos pacientes com síndrome da imunodeficiência adquirida (SIDA). A maioria dos LNH associados à AIDS envolvem locais extra-ganglionares, especialmente o trato digestivo e o sistema nervoso central. O linfoma não-Hodgkin primário do fígado (LPF) é uma neoplasia incomum nestes pacientes. A ultrassonografia (US) e a tomografia computadorizada (TC) podem ser úteis no diagnóstico de linfoma não-Hodgkin hepático apresentando-se como lesões multifocais. A biópsia com agulha fina guiada por imagens (US, TC) juntamente com a histopatologia das lesões do fígado constitui o padrão-ouro para o diagnóstico de linfoma hepático. Este trabalho relata um caso de LPF como manifestação inicial de AIDS em um paciente sem infecção prévia pelo vírus da hepatite C e B, que se apresentou como massas hepáticas múltiplas e de grandes dimensões

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

COVID-19, asthma, and biological therapies: What we need to know

Managing patients with severe asthma during the coronavirus pandemic and COVID-19 is a challenge. Authorities and physicians are still learning how COVID-19 affects people with underlying diseases, and severe asthma is not an exception. Unless relevant data emerge that change our understanding of the relative safety of medications indicated in patients with asthma during this pandemic, clinicians must follow the recommendations of current evidence-based guidelines for preventing loss of control and exacerbations. Also, with the absence of data that would indicate any potential harm, current advice is to continue the administration of biological therapies during the COVID-19 pandemic in patients with asthma for whom such therapies are clearly indicated and have been effective. For patients with severe asthma infected by SARS-CoV- 2, the decision to maintain or postpone biological therapy until the patient recovers should be a case-by-case based decision supported by a multidisciplinary team. A registry of cases of COVID- 19 in patients with severe asthma, including those treated with biologics, will help to address a clinical challenge in which we have more questions than answers