MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer

Targeting the PI3K–AKT–mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K–AKT–mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies

The parent?infant dyad and the construction of the subjective self

Developmental psychology and psychopathology has in the past been more concerned with the quality of self-representation than with the development of the subjective agency which underpins our experience of feeling, thought and action, a key function of mentalisation. This review begins by contrasting a Cartesian view of pre-wired introspective subjectivity with a constructionist model based on the assumption of an innate contingency detector which orients the infant towards aspects of the social world that react congruently and in a specifically cued informative manner that expresses and facilitates the assimilation of cultural knowledge. Research on the neural mechanisms associated with mentalisation and social influences on its development are reviewed. It is suggested that the infant focuses on the attachment figure as a source of reliable information about the world. The construction of the sense of a subjective self is then an aspect of acquiring knowledge about the world through the caregiver's pedagogical communicative displays which in this context focuses on the child's thoughts and feelings. We argue that a number of possible mechanisms, including complementary activation of attachment and mentalisation, the disruptive effect of maltreatment on parent-child communication, the biobehavioural overlap of cues for learning and cues for attachment, may have a role in ensuring that the quality of relationship with the caregiver influences the development of the child's experience of thoughts and feelings

Combination of searches for Higgs boson pairs in pp collisions at \sqrts = 13 TeV with the ATLAS detector

This letter presents a combination of searches for Higgs boson pair production using up to 36.1 fb(-1) of proton-proton collision data at a centre-of-mass energy root s = 13 TeV recorded with the ATLAS detector at the LHC. The combination is performed using six analyses searching for Higgs boson pairs decaying into the b (b) over barb (b) over bar, b (b) over barW(+)W(-), b (b) over bar tau(+)tau(-), W+W-W+W-, b (b) over bar gamma gamma and W+W-gamma gamma final states. Results are presented for non-resonant and resonant Higgs boson pair production modes. No statistically significant excess in data above the Standard Model predictions is found. The combined observed (expected) limit at 95% confidence level on the non-resonant Higgs boson pair production cross-section is 6.9 (10) times the predicted Standard Model cross-section. Limits are also set on the ratio (kappa(lambda)) of the Higgs boson self-coupling to its Standard Model value. This ratio is constrained at 95% confidence level in observation (expectation) to -5.0 &lt; kappa(lambda) &lt; 12.0 (-5.8 &lt; kappa(lambda) &lt; 12.0). In addition, limits are set on the production of narrow scalar resonances and spin-2 Kaluza-Klein Randall-Sundrum gravitons. Exclusion regions are also provided in the parameter space of the habemus Minimal Supersymmetric Standard Model and the Electroweak Singlet Model. For complete list of authors see http://dx.doi.org/10.1016/j.physletb.2019.135103</p

Prompt and non-prompt J/psi elliptic flow in Pb plus Pb collisions at root S-NN=5.02 TeV with the ATLAS detector

The elliptic flow of prompt and non-prompt J/ \u3c8 was measured in the dimuon decay channel in Pb+Pb collisions at sNN=5.02&nbsp;TeV with an integrated luminosity of 0.42nb-1 with the ATLAS detector at the LHC. The prompt and non-prompt signals are separated using a two-dimensional simultaneous fit of the invariant mass and pseudo-proper decay time of the dimuon system from the J/ \u3c8 decay. The measurement is performed in the kinematic range of dimuon transverse momentum and rapidity 9 &lt; pT&lt; 30 GeV , | y| &lt; 2 , and 0\u201360% collision centrality. The elliptic flow coefficient, v2, is evaluated relative to the event plane and the results are presented as a function of transverse momentum, rapidity and centrality. It is found that prompt and non-prompt J/ \u3c8 mesons have non-zero elliptic flow. Prompt J/ \u3c8v2 decreases as a function of pT, while for non-prompt J/ \u3c8 it is, with limited statistical significance, consistent with a flat behaviour over the studied kinematic region. There is no observed dependence on rapidity or centrality

Search for squarks and gluinos in final states with hadronically decaying tau-leptons, jets, and missing transverse momentum using pp collisions at root s = 13 TeV with the ATLAS detector

A search for supersymmetry in events with large missing transverse momentum, jets, and at least one hadronically decaying τ-lepton is presented. Two exclusive final states with either exactly one or at least two τ-leptons are considered. The analysis is based on proton-proton collisions at √s=13  TeV corresponding to an integrated luminosity of 36.1  fb⁻¹ delivered by the Large Hadron Collider and recorded by the ATLAS detector in 2015 and 2016. No significant excess is observed over the Standard Model expectation. At 95% confidence level, model-independent upper limits on the cross section are set and exclusion limits are provided for two signal scenarios: a simplified model of gluino pair production with τ-rich cascade decays, and a model with gauge-mediated supersymmetry breaking (GMSB). In the simplified model, gluino masses up to 2000 GeV are excluded for low values of the mass of the lightest supersymmetric particle (LSP), while LSP masses up to 1000 GeV are excluded for gluino masses around 1400 GeV. In the GMSB model, values of the supersymmetry-breaking scale are excluded below 110 TeV for all values of tanβ in the range 2 ≤ tanβ ≤ 60, and below 120 TeV for tanβ > 30.M. Aaboud … D. Duvnjak … P. Jackson … J.L. Oliver … A. Petridis … A. Qureshi … A.S. Sharma … M.J. White … et al. [The ATLAS Collaboration

A measurement of material in the ATLAS tracker using secondary hadronic interactions in 7 TeV pp collisions

Knowledge of the material in the ATLAS inner tracking detector is crucial in understanding the reconstruction of charged-particle tracks, the performance of algorithms that identify jets containing b-hadrons and is also essential to reduce background in searches for exotic particles that can decay within the inner detector volume. Interactions of primary hadrons produced in pp collisions with the material in the inner detector are used to map the location and amount of this material. The hadronic interactions of primary particles may result in secondary vertices, which in this analysis are reconstructed by an inclusive vertex-finding algorithm. Data were collected using minimum-bias triggers by the ATLAS detector operating at the LHC during 2010 at centre-of-mass energy √ s = 7 TeV, and correspond to an integrated luminosity of 19 nb−1 . Kinematic properties of these secondary vertices are used to study the validity of the modelling of hadronic interactions in simulation. Secondary-vertex yields are compared between data and simulation over a volume of about 0.7 m3 around the interaction point, and agreement is found within overall uncertainties

A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries

A prospective study on the predictive value of normal sperm morphology as evaluated by computer (IVOS)

Objective: To evaluate the IVOS (Hamilton Thorne Research Version 2.1 Dimension Program, Beverly, MA) system's ability to predict fertilization in vitro in a prospective study. Design: A prospective clinical study. Setting: Hospital-based academic ART program. Patients: Eighty patients from the IVF- GIFT program were evaluated. The same semen sample was analyzed on a day-to- day basis by both laboratory (manual method) and the computerized system for percentage normal morphology, concentration/mL, motility, and forward progression. Only patients with two or more metaphase II (MII) oocytes available were allowed into the study and excluded where the male partner had antisperm antibodies or qualified for intracytoplasmic sperm injection (&lt;500,000 motile spermatozoa obtained after glass wool separation). Statistical Analysis: Logistic regression analysis was used to study predictors of fertilization in vitro. Results: Three hundred thirty-eight oocytes were obtained from 80 patients of which 239 fertilized. The logistic regression analysis of the manual method (percentage normal morphology) and IVOS indicated that both were predictors of fertilization. Sperm morphology as evaluated by IVOS in patients with &lt;10 x 106 motile spermatozoa/mL retrieved after swim-up was a significant predictor of fertilization as was the number of oocytes obtained. Thus, the more oocytes obtained in the lower morphological groups, the better the chance of fertilization. The fertilization rate in the morphology group 0% to 4% normal forms was 45.6% (37/81) and in the group &gt;14% normal forms was 85.2% (69/81). Conclusions: It was shown that in patients where ≤10 x 106 motile spermatozoa were obtained, the role of morphology (evaluated by IVOS) as well as the number of oocytes were important predictors of fertilization. The computer can assist to identify these patient with a poor prognosis for fertilization.Articl

Effects of different staining and washing procedures on the results of human sperm morphology evaluation by manual and computerised methods

The purpose of this study was to investigate the effect of different staining and washing procedures on the results of human sperm morphology evaluation by manual and computerised methods. Furthermore, it was intended to find the staining and washing combination which would provide optimal readability for computer-assisted sperm morphology evaluations. In phase one, four staining methods were evaluated for smears prepared from the resulting samples following a two times washing procedure. In phase two, 20 semen samples were used to compare the Diff-Quik and Papanicolaou staining methods, following one and two washes. All manual readings, of Papanicolaou and Diff-Quik stained smears, were comparable with each other, with means between 7.3% and 7.9% normal spermatozoa. All the manual readings were also comparable to the computer readings of the Diff-Quik slides following one and two washes with means of 9.0% and 5.9%, respectively. However, due to the higher computer readings found for the Papanicolaou stained smears, with means of 13.9% and 13.5% following one and two washes, respectively, a statistically significantly difference between overall computer and manual readings was found (Wilks' Lamda, P=0.0002). Taking all data into consideration, it could be concluded that the one wash Diff-Quik stained smears was the optimal preparation method for computerised sperm morphology evaluation, comparing favourably with manual evaluations.Articl