Use of cyclin-dependent kinase (CDK) 4/6 inhibitors for hormone receptor-positive, human epidermal growth factor receptor 2-negative, metastatic breast cancer: a roundtable discussion by The Breast Cancer Therapy Expert Group (BCTEG)

Purpose: To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community. Methods: A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice. Results: Level 1 evidence now supports use of a CDK 4/6 inhibitor in combination with endocrine therapy for patients with HR+, HER2−, mBC. Currently, there are no biomarkers that reliably define patients who will, or will not, benefit from the addition of a CDK 4/6 inhibitor to their endocrine therapy. Additional research is needed to identify the optimal sequencing of CDK 4/6 inhibitors in relation to other therapies as well as the optimal duration of therapy; at present, evidence suggests that use in the upfront setting is better than waiting for a later line of therapy, or adding after endocrine therapy has started. Conclusions: Thus far, three CDK 4/6 inhibitors—palbociclib, ribociclib, and more recently, abemaciclib—have been approved for use in the setting of HR+, HER2−, mBC. The degrees to which these agents differ in terms of CDK4/6 affinity, side-effect profiles, dosing, degree of central nervous system (CNS) penetration, optimal use in combination with antiestrogen therapy, and across other subsets of breast cancer, remain an active area of investigation

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe

Measurement of isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV

Isolated photon production is measured in proton-proton and lead-lead collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80 GeV with the CMS detector at the LHC. The measured ET spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon ET-differential yields, scaled by the number of incoherent nucleon-nucleon collisions, is consistent with unity for all PbPb reaction centralities.Comment: Submitted to Physics Letters

Measurement of the Lambda(b) cross section and the anti-Lambda(b) to Lambda(b) ratio with Lambda(b) to J/Psi Lambda decays in pp collisions at sqrt(s) = 7 TeV

The Lambda(b) differential production cross section and the cross section ratio anti-Lambda(b)/Lambda(b) are measured as functions of transverse momentum pt(Lambda(b)) and rapidity abs(y(Lambda(b))) in pp collisions at sqrt(s) = 7 TeV using data collected by the CMS experiment at the LHC. The measurements are based on Lambda(b) decays reconstructed in the exclusive final state J/Psi Lambda, with the subsequent decays J/Psi to an opposite-sign muon pair and Lambda to proton pion, using a data sample corresponding to an integrated luminosity of 1.9 inverse femtobarns. The product of the cross section times the branching ratio for Lambda(b) to J/Psi Lambda versus pt(Lambda(b)) falls faster than that of b mesons. The measured value of the cross section times the branching ratio for pt(Lambda(b)) > 10 GeV and abs(y(Lambda(b))) < 2.0 is 1.06 +/- 0.06 +/- 0.12 nb, and the integrated cross section ratio for anti-Lambda(b)/Lambda(b) is 1.02 +/- 0.07 +/- 0.09, where the uncertainties are statistical and systematic, respectively.Comment: Submitted to Physics Letters

Search for new physics in events with opposite-sign leptons, jets, and missing transverse energy in pp collisions at sqrt(s) = 7 TeV

A search is presented for physics beyond the standard model (BSM) in final states with a pair of opposite-sign isolated leptons accompanied by jets and missing transverse energy. The search uses LHC data recorded at a center-of-mass energy sqrt(s) = 7 TeV with the CMS detector, corresponding to an integrated luminosity of approximately 5 inverse femtobarns. Two complementary search strategies are employed. The first probes models with a specific dilepton production mechanism that leads to a characteristic kinematic edge in the dilepton mass distribution. The second strategy probes models of dilepton production with heavy, colored objects that decay to final states including invisible particles, leading to very large hadronic activity and missing transverse energy. No evidence for an event yield in excess of the standard model expectations is found. Upper limits on the BSM contributions to the signal regions are deduced from the results, which are used to exclude a region of the parameter space of the constrained minimal supersymmetric extension of the standard model. Additional information related to detector efficiencies and response is provided to allow testing specific models of BSM physics not considered in this paper.Comment: Replaced with published version. Added journal reference and DO

Error sources and data limitations for the prediction ofsurface gravity: a case study using benchmarks

Gravity-based heights require gravity values at levelled benchmarks (BMs), whichsometimes have to be predicted from surrounding observations. We use EGM2008 andthe Australian National Gravity Database (ANGD) as examples of model and terrestrialobserved data respectively to predict gravity at Australian national levelling network(ANLN) BMs. The aim is to quantify errors that may propagate into the predicted BMgravity values and then into gravimetric height corrections (HCs). Our results indicatethat an approximate ±1 arc-minute horizontal position error of the BMs causesmaximum errors in EGM2008 BM gravity of ~ 22 mGal (~55 mm in the HC at ~2200 melevation) and ~18 mGal for ANGD BM gravity because the values are not computed atthe true location of the BM. We use RTM (residual terrain modelling) techniques toshow that ~50% of EGM2008 BM gravity error in a moderately mountainous regioncan be accounted for by signal omission. Non-representative sampling of ANGDgravity in this region may cause errors of up to 50 mGals (~120 mm for the Helmertorthometric correction at ~2200 m elevation). For modelled gravity at BMs to beviable, levelling networks need horizontal BM positions accurate to a few metres, whileRTM techniques can be used to reduce signal omission error. Unrepresentative gravitysampling in mountains can be remedied by denser and more representative re-surveys,and/or gravity can be forward modelled into regions of sparser gravity

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function