The rockefeller university

Background: The incidence and risk of unique toxicities associated with a multi-targeted tyrosine kinase inhibitor sunitinib, such as hypertension and thromboembolic events, have been previously reported. However, the incidence and risk of hematologic toxicities have been less well characterized. We performed an up-to-date meta-analysis of trials to evaluate the risk of sunitinib-related hematologic toxicities. Methods: We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to July 2012 for relevant clinical trials. Eligible studies included phase II and III trials and expanded access programs of sunitinib that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia. The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) were calculated. Results: A total of 8,526 patients from 60 trials of sunitinib as a single agent revealed that the incidence of sunitinib-associated all-grade and high-grade (Grades 3 and 4) hematologic toxicities were, respectively: neutropenia: 42.1% and 12.8%; thrombocytopenia: 44.7% and 10.7% and anemia: 50.4% and 6.2%. Sunitinib-treated patients (2667 subjects from 10 randomized trials) had a significantly increased risk of all-grade (RR = 3.58; 95% CI, 1.71-7.49) and high-grade (RR = 3.32; 95% CI, 1.60-6.90) neutropenia, all-grade (RR = 4.59; 95% CI, 2.76-7.63) and high-grade (RR = 5.84; 95% CI, 2.22-15.41) thrombocytopenia and all-grade anemia (RR = 1.15; 95% CI, 1.00-1.31). Conclusions: Sunitinib is associated with a significant increase in the risk of developing all-grade and high-grade neutropenia and thrombocytopenia and all-grade anemia compared with control. (C) 2013 Elsevier Ltd. All rights reserved.

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.

Defense against infection by Mycobacterium tuberculosis (Mtb) is mediated by CD4 T cells. CCR2(+) inflammatory monocytes (IMs) have been implicated in Mtb-specific CD4 T cell responses but their in vivo contribution remains unresolved. Herein, we show that transient ablation of IMs during infection prevents Mtb delivery to pulmonary lymph nodes, reducing CD4 T cell responses. Transfer of MHC class II-expressing IMs to MHC class II-deficient, monocyte-depleted recipients, while restoring Mtb transport to mLNs, does not enable Mtb-specific CD4 T cell priming. On the other hand, transfer of MHC class II-deficient IMs corrects CD4 T cell priming in monocyte-depleted, MHC class II-expressing mice. Specific depletion of classical DCs does not reduce Mtb delivery to pulmonary lymph nodes but markedly reduces CD4 T cell priming. Thus, although IMs acquire characteristics of DCs while delivering Mtb to lymph nodes, cDCs but not moDCs induce proliferation of Mtb-specific CD4 T cells.

Results are reported from a search for non-standard-model Higgs boson decays to pairs of new light bosons, each of which decays into the mu(+)mu(-) final state. The new bosons may be produced either promptly or via a decay chain. The data set corresponds to an integrated luminosity of 5.3 fb(-1) of proton-proton collisions at root s = 7 TeV, recorded by the CMS experiment at the LHC in 2011. Such Higgs boson decays are predicted in several scenarios of new physics, including supersymmetric models with extended Higgs sectors or hidden valleys. Thus, the results of the search are relevant for establishing whether the new particle observed in Higgs boson searches at the LHC has the properties expected for a standard model Higgs boson. No excess of events is observed with respect to the yields expected from standard model processes. A model-independent upper limit of 0.86 +/- 0.06 fb on the product of the cross section times branching fraction times acceptance is obtained. The results, which are applicable to a broad spectrum of new physics scenarios, are compared with the predictions of two benchmark models as functions of a Higgs boson mass larger than 86 GeV/c(2) and of a new light boson mass within the range 0.25-3.55 GeV/c(2). (C) 2013 CERN. Published by Elsevier B.V. All rights reserved.

Climate warming has been linked to an apparent general decrease in body sizes of ectotherms, both across and within taxa, especially in aquatic systems. Smaller body size in warmer geographical regions has also been widely observed. Since body size is a fundamental determinant of many biological attributes, climate-warming-related changes in size could ripple across multiple levels of ecological organization. Some recent studies have questioned the ubiquity of temperature-size rules, however, and certain widespread and abundant taxa, such as diatoms, may be important exceptions. We tested the hypothesis that diatoms are smaller at warmer temperatures using a system of geothermally heated streams. There was no consistent relationship between size and temperature at either the population or community level. These field data provide important counterexamples to both James' and Bergmann's temperature-size rules, respectively, undermining the widely held assumption that warming favours the small. This study provides compelling new evidence that diatoms are an important exception to temperature-size rules for three reasons: (i) we use many more species than prior work; (ii) we examine both community and species levels of organization simultaneously; (iii) we work in a natural system with a wide temperature gradient but minimal variation in other factors, to achieve robust tests of hypotheses without relying on laboratory setups, which have limited realism. In addition, we show that interspecific effects were a bigger contributor to whole-community size differences, and are probably more ecologically important than more commonly studied intraspecific effects. These findings highlight the need for multispecies approaches in future studies of climate warming and body size.

A search for a Higgs boson decaying into a Z boson and a photon is described. The analysis is performed using proton-proton collision datasets recorded by the CMS detector at the LHC. Events were collected at center-of-mass energies of 7 TeV and 8 TeV, corresponding to integrated luminosities of 5.0 fb(-1) and 19.6 fb(-1), respectively. The selected events are required to have opposite-sign electron or muon pairs. No excess above standard model predictions has been found in the 120-160 GeV mass range and the first limits on the Higgs boson production cross section times the H -> Z gamma branching fraction at the LHC have been derived. The observed at 95% confidence level limits are between about 4 and 25 times the standard model cross section times the branching fraction. For a standard model Higgs boson mass of 125 GeV the expected limit at the 95% confidence level is 10 and the observed limit is 9.5. Models predicting the Higgs boson production cross section times the H -> Z gamma branching fraction to be larger than one order of magnitude of the standard model prediction are excluded for most of the 125-157 GeV mass range. (C) 2013 CERN. Published by Elsevier B.V. All rights reserved.

We present a measurement of the total decay width of the top quark using events with top-antitop quark pair candidates reconstructed in the final state with one charged lepton and four or more hadronic jets. We use the full Tevatron run II data set of root s = 1.96 TeV proton-antiproton collisions recorded by the CDF II detector. The top quark mass and the mass of the hadronically decaying W boson are reconstructed for each event and compared with distributions derived from simulated signal and background samples to extract the top quark width (Gamma(top)) and the energy scale of the calorimeter jets with in situ calibration. For a top quark mass M-top = 172.5 GeV/c(2), we find 1.10 < Gamma(top) < 4.05 GeV at 68% confidence level, which is in agreement with the standard model expectation of 1.3 GeV and is the most precise direct measurement of the top quark width to date.

We present a measurement of the top-quark pair production cross section in proton-antiproton collisions at root s = 1.96 TeV. The data were collected at the Fermilab Tevatron by the CDF II detector and correspond to an integrated luminosity of 8.8 fb(-1), representing the complete CDF Run II data set. We select events consistent with the production of top-quark pairs by requiring the presence of two reconstructed leptons, an imbalance in the total event transverse momentum, and jets. At least one jet is required to be identified as consistent with the fragmentation of a bottom quark using a secondary-vertex-finding algorithm. The 246 candidate events are estimated to have a signal purity of 91%. We measure a cross section of sigma(t (t) over bar) = 7.09 +/- 0.84 pb, assuming a top-quark mass of 172.5 GeV/c(2). The results are consistent with the standard model as predicted by next-to-leading-order calculations.

Approximately 90% of patients with isolated agammaglob ulinemia and failure of B cell development have mutations in genes required for signaling through the pre-B cell and B cell receptors. The nature of the gene defect in the majority of remaining patients is unknown. We recently identified 4 patients with agatnmaglobulinemia and markedly decreased numbers of peripheral B cells. The B cells that could be detected had an unusual phenotype characterized by the increased expression of CD19 but the absence of a B cell receptor. Genetic studies demonstrated that all 4 patients had the exact same de novo mutation in the broadly expressed transcription factor E47. The mutant protein (E555K) was stable in patient-derived EBV-transformed cell lines and cell lines transfected with expression vectors. E555K in the transfected cells localized normally to the nucleus and resulted in a dominant negative effect when bound to DNA as a homodimer with wild-type E47. Mutant E47 did permit DNA binding by a tissue-specific heteroclimeric DNA-binding partner, myogenic differentiation 1 (MYOD). These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia. Further, they indicate that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors.

De novo protein synthesis is necessary for long-lasting modifications in synaptic strength and dendritic spine dynamics that underlie cognition. Fragile X syndrome (FXS), characterized by intellectual disability and autistic behaviors, holds promise for revealing the molecular basis for these long-term changes in neuronal function. Loss of function of the fragile X mental retardation protein (FMRP) results in defects in synaptic plasticity and cognition in many models of the disease. FMRP is a polyribosome-associated RNA-binding protein that regulates the synthesis of a set of plasticity-reated proteins by stalling ribosomal translocation on target mRNAs. The recent identification of mRNA targets of FMRP and its upstream regulators, and the use of small molecules to stall ribosomes in the absence of FMRP, have the potential to be translated into new therapeutic avenues for the treatment of FXS.