Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer.

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function. Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner. Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC

Increased Yield of ttbb at Hadron Colliders in Low-Energy Supersymmetry

Light bottom squarks and gluinos have been invoked to explain the b quark pair production excess at the Tevatron. We investigate the associated production of ttbb at hadron colliders in this scenario, and find that the rates for this process are enhanced over the Standard Model prediction. If light gluinos exist, it may be possible to detect them at the Tevatron, and they could easily be observed at the LHC.Comment: 5p, references added, version accepted to PR

Randomized controlled trial of a coordinated care intervention to improve risk factor control after stroke or transient ischemic attack in the safety net: Secondary stroke prevention by Uniting Community and Chronic care model teams Early to End Disparities (SUCCEED).

BackgroundRecurrent strokes are preventable through awareness and control of risk factors such as hypertension, and through lifestyle changes such as healthier diets, greater physical activity, and smoking cessation. However, vascular risk factor control is frequently poor among stroke survivors, particularly among socio-economically disadvantaged blacks, Latinos and other people of color. The Chronic Care Model (CCM) is an effective framework for multi-component interventions aimed at improving care processes and outcomes for individuals with chronic disease. In addition, community health workers (CHWs) have played an integral role in reducing health disparities; however, their effectiveness in reducing vascular risk among stroke survivors remains unknown. Our objectives are to develop, test, and assess the economic value of a CCM-based intervention using an Advanced Practice Clinician (APC)-CHW team to improve risk factor control after stroke in an under-resourced, racially/ethnically diverse population.Methods/designIn this single-blind randomized controlled trial, 516 adults (≥40 years) with an ischemic stroke, transient ischemic attack or intracerebral hemorrhage within the prior 90 days are being enrolled at five sites within the Los Angeles County safety-net setting and randomized 1:1 to intervention vs usual care. Participants are excluded if they do not speak English, Spanish, Cantonese, Mandarin, or Korean or if they are unable to consent. The intervention includes a minimum of three clinic visits in the healthcare setting, three home visits, and Chronic Disease Self-Management Program group workshops in community venues. The primary outcome is blood pressure (BP) control (systolic BP <130 mmHg) at 1 year. Secondary outcomes include: (1) mean change in systolic BP; (2) control of other vascular risk factors including lipids and hemoglobin A1c, (3) inflammation (C reactive protein [CRP]), (4) medication adherence, (5) lifestyle factors (smoking, diet, and physical activity), (6) estimated relative reduction in risk for recurrent stroke or myocardial infarction (MI), and (7) cost-effectiveness of the intervention versus usual care.DiscussionIf this multi-component interdisciplinary intervention is shown to be effective in improving risk factor control after stroke, it may serve as a model that can be used internationally to reduce race/ethnic and socioeconomic disparities in stroke in resource-constrained settings.Trial registrationClinicalTrials.gov Identifier NCT01763203

An Improved Standard Model Prediction Of BR(B -> tau nu) And Its Implications For New Physics

The recently measured B -> tau nu branching ratio allows to test the Standard Model by probing virtual effects of new heavy particles, such as a charged Higgs boson. The accuracy of the test is currently limited by the experimental error on BR(B -> tau nu) and by the uncertainty on the parameters fB and |Vub|. The redundancy of the Unitarity Triangle fit allows to reduce the error on these parameters and thus to perform a more precise test of the Standard Model. Using the current experimental inputs, we obtain BR(B -> tau nu)_SM = (0.84 +- 0.11)x10^{-4}, to be compared with BR(B -> tau nu)_exp = (1.73 +- 0.34)x10^{-4}. The Standard Model prediction can be modified by New Physics effects in the decay amplitude as well as in the Unitarity Triangle fit. We discuss how to disentangle the two possible contributions in the case of minimal flavour violation at large tan beta and generic loop-mediated New Physics. We also consider two specific models with minimal flavour violation: the Type-II Two Higgs Doublet Model and the Minimal Supersymmetric Standard Model.Comment: 7 pages, 13 figures, 1 table. v2: added references and discussion of B -> D tau nu in the 2HDM. v3: added Bs->mumu in the 2HDM. Final version to appear in PL

Electric Dipole Moments in the MSSM at Large tan(beta)

Within the minimal supersymmetric standard model (MSSM), the large tan(beta) regime can lead to important modifications in the pattern of CP-violating sources contributing to low energy electric dipole moments (EDMs). In particular, four-fermion CP-violating interactions induced by Higgs exchange should be accounted for alongside the constituent EDMs of quarks and electrons. To this end, we present a comprehensive analysis of three low energy EDM observables - namely the EDMs of thallium, mercury and the neutron - at large tan(beta), in terms of one- and two-loop contributions to the constituent EDMs and four-fermion interactions. We concentrate on the constrained MSSM as well as the MSSM with non-universal Higgs masses, and include the CP-violating phases of mu and A. Our results indicate that the atomic EDMs receive significant corrections from four-fermion operators, especially when Im(A) is the only CP-violating source, whereas the neutron EDM remains relatively insensitive to these effects. As a consequence, in a large portion of the parameter space, one cannot infer a separate bound on the electron EDM via the experimental constraint on the thallium EDM. Furthermore, we find that the electron EDM can be greatly reduced due to the destructive interference of one- and two-loop contributions with the latter being dominated by virtual staus.Comment: 39 pages, 17 figure

Electric dipole moments as probes of new physics

We review several aspects of flavour-diagonal CP violation, focussing on the role played by the electric dipole moments (EDMs) of leptons, nucleons, atoms and molecules, which consitute the source of several stringent constraints on new CP-violating physics. We dwell specifically on the calculational aspects of applying the hadronic EDM constraints, reviewing in detail the application of QCD sum-rules to the calculation of nucleon EDMs and CP-odd pion-nucleon couplings. We also consider the current status of EDMs in the Standard Model, and on the ensuing constraints on the underlying sources of CP-violation in physics beyond the Standard Model, focussing on weak-scale supersymmetry.Comment: 62 pages, 10 figures, invited review to appear in Annals of Physics; v2: references adde

Searching for hidden sector in multiparticle production at LHC

We study the impact of a hidden sector beyond the Standard Model, e.g. a Hidden Valley model, on factorial moments and cumulants of multiplicity distributions in multiparticle production with a special emphasis on the prospects for LHC results

Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine

Targeted cancer therapy requires the rapid and accurate identification of genetic abnormalities predictive of therapeutic response. We sought to develop a high-throughput genotyping platform that would allow prospective patient selection to the best available therapies, and that could readily and inexpensively be adopted by most clinical laboratories. We developed a highly sensitive multiplexed clinical assay that performs very well with nucleic acid derived from formalin fixation and paraffin embedding (FFPE) tissue, and tests for 120 previously described mutations in 13 cancer genes. Genetic profiling of 250 primary tumours was consistent with the documented oncogene mutational spectrum and identified rare events in some cancer types. The assay is currently being used for clinical testing of tumour samples and contributing to cancer patient management. This work therefore establishes a platform for real-time targeted genotyping that can be widely adopted. We expect that efforts like this one will play an increasingly important role in cancer management