Search for anomalous couplings in boosted WW/WZ -> l nu q(q)over-bar production in proton-proton collisions at root s=8TeV

Peer reviewe

High content screening of patient-derived cell lines highlights the potential of non-standard chemotherapeutic agents for the treatment of glioblastoma

<div><p>Background</p><p>Glioblastoma (GBM) is the most common primary brain malignancy in adults, yet survival outcomes remain poor. First line treatment is well established, however disease invariably recurs and improving prognosis is challenging. With the aim of personalizing therapy at recurrence, we have established a high content screening (HCS) platform to analyze the sensitivity profile of seven patient-derived cancer stem cell lines to 83 FDA-approved chemotherapy drugs, with and without irradiation.</p><p>Methods</p><p>Seven cancer stem cell lines were derived from patients with GBM and, along with the established cell line U87-MG, each patient-derived line was cultured in tandem in serum-free conditions as adherent monolayers and three-dimensional neurospheres. Chemotherapeutics were screened at multiple concentrations and cells double-stained to observe their effect on both cell death and proliferation. Sensitivity was classified using high-throughput algorithmic image analysis.</p><p>Results</p><p>Cell line specific drug responses were observed across the seven patient-derived cell lines. Few agents were seen to have radio-sensitizing effects, yet some drug classes showed a marked difference in efficacy between monolayers and neurospheres. <i>In vivo</i> validation of six drugs suggested that cell death readout in a three-dimensional culture scenario is a more physiologically relevant screening model and could be used effectively to assess the chemosensitivity of patient-derived GBM lines.</p><p>Conclusion</p><p>The study puts forward a number of non-standard chemotherapeutics that could be useful in the treatment of recurrent GBM, namely mitoxantrone, bortezomib and actinomycin D, whilst demonstrating the potential of HCS to be used for personalized treatment based on the chemosensitivity profile of patient tumor cells.</p></div

Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis

Abstract Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression

Bland-Altman method comparison of assay models demonstrated no overall bias for potency, whilst highlighting specific drugs to take forward for validation.

<p>All pEC50s were stacked by patient-derived line. Mean difference and lower and upper limits of agreements (95% CI) are indicated by dotted lines. Values outside these limits can be considered real biological differences.</p

pEC50 values highlighted general resistance of GBM cell lines and cell line specific responses to chemotherapeutics and irradiation.

<p>Heat Map was populated using best-fit pEC50 values generated from dose-response curves, then color mapped categorically according to the legend. Each heat map color and corresponding number (1,2,3 etc.), corresponds to a log change in concentration of drug (100,000 μM, 10,000 μM, 1000 μM etc.). Red values of a pEC50 of 9 or above would indicate an EC50 of 1nm or below, indicating high efficacy, whereas any values categorized green-blue or below would likely be poor drug candidates as they correspond to EC50 values above 10μM. Any data Prism was unable to fit was colored black—this was typically due to an inability to generate an EC50 with that drug candidate because of inefficiency at high concentrations.</p

Patient demographics, clinical features and cell line designations.

<p>Patient demographics, clinical features and cell line designations.</p

Cell line characterization demonstrated stem-cell characteristics and tumorigenicity <i>in vivo</i>.

<p>(A-B) U87 neurosphere culture demonstrating Nestin (green) and Sox2 (red) staining in serum-free culture (s.b. = 100μm). (C) U87 orthotopic implantation model showing large well-defined masses within the brain parenchyma, showing staining for anti-human nuclear antigen (green) (s.b. = 1000μm). (D) High power field (x40) of well-demarcated tumour edge showing anti-human nuclear antigen staining of tumour cells (s.b. = 50μm). (E-F) TS18 in serum free neurosphere culture showing uniform Nestin and Sox2 staining (s.b. = 100μm). (G) Orthotopic implantation of TS18-GFP cells with combined GFP (green) and anti-human nuclear antigen (red) staining to show diffuse infiltration of cells both within the parenchyma and across the corpus callosum into the opposite hemisphere (s.b. = 1000μm). (H) High power field (x20) showing area of diffuse infiltration and co-expression of GFP and anti-human nuclear antigen in implanted cells (s.b. = 100μm). (I-J) GS1 neurosphere culture showing uniform Nestin and Sox2 staining in serum free culture. (K) Orthotopic implantation of GS1 cells into the striatum with anti-vimentin staining. Vimentin staining is characteristic of gliosarcoma and is not found in the parenchyma, and was used to trace GS1 cells within the parenchyma (s.b. = 1000μm). (L) High power field (x20) showing diffusely infiltrating vimentin positive cells (green) within the corpus callosum (s.b. = 100μm).</p

<i>In vivo</i> assessment of drug activity demonstrated strong correlation with neurosphere <i>in vitro</i> results.

<p>(A) NSG mice were dosed at sub-maximal tolerated doses with reference to accepted published data^18-24. Tumors were excised seven days post-treatment then measured ex-vivo for accuracy. Results are expressed as the percentage volume compared to the control group (*p < 0.05, **p < 0.01, ***p < 0.001 and **** p < 0.0001). (B) Rank order of drugs based on pEC50 values for the U87 cell line are shown here to facilitate comparison. pEC50s were generated for 66 drugs in one, or both, of the U87 screening models, thus rankings are from 1 to 67, with 1 having the highest pEC50 and therefore the highest cytotoxicity. Mitoxantrone, bortezomib and actinomycin D all ranked in the top 10 in the neurosphere assay, which appears to correlate with the <i>in vivo</i> efficacy seen in these three drugs. Paclitaxel and doxorubicin demonstrated low efficacy <i>in vivo</i>, yet ranked highly in the monolayer assay.</p

Response space analysis identifies highly effective drugs and patient cell–line resistance.

<p>(A) Responses for TS1, TS18, TS9 and GS1 (0Gy) are depicted. Response is plotted onto a response space for each drug by the change in cell death (as measured by DRAQ7 intensity/spheroid cross sectional area), and fold change in neurosphere count. Highly responsive drugs are highlighted in dashed circles, with negative controls sitting at the intersection of the dotted lines (0, 1). (B) Sub -classification of drug response in neurosphere culture. Blue shaded areas represent responsive drugs, and yellow/orange/red areas represent resistance. (C) Summarized neurosphere response sub-classifications. The combined height of the yellow/orange/red columns provides an indication of the overall chemotherapeutic resistance of the cell line.</p

Search for heavy resonances decaying into a vector boson and a Higgs boson in final states with charged leptons, neutrinos, and b quarks

A search for heavy resonances decaying to a Higgs boson and a vector boson is presented. The analysis is performed using data samples collected in 2015 by the CMS experiment at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to integrated luminosities of 2.2-2.5 inverse femtobarns. The search is performed in channels in which the vector boson decays into leptonic final states ($\mathrm{Z} \to \nu\nu$, $\mathrm{W}\to \ell \nu$, and $\mathrm{Z} \to \ell \ell$, with $\ell = \mathrm{e}$, $\mu$), while the Higgs boson decays to collimated b quark pairs detected as a single massive jet. The discriminating power of a jet mass requirement and a b jet tagging algorithm are exploited to suppress the standard model backgrounds. The event yields observed in data are consistent with the background expectation. In the context of a theoretical model with a heavy vector triplet, a resonance with mass less than 2 TeV is excluded at 95% confidence level. The results are also interpreted in terms of limits on the parameters of the model, improving on the reach of previous searches