Rad51 and BRCA2 - New Molecular Targets for Sensitizing Glioma Cells to Alkylating Anticancer Drugs

First line chemotherapeutics for brain tumors (malignant gliomas) are alkylating agents such as temozolomide and nimustine. Despite growing knowledge of how these agents work, patients suffering from this malignancy still face a dismal prognosis. Alkylating agents target DNA, forming the killing lesion O6-alkylguanine, which is converted into DNA double-strand breaks (DSBs) that trigger apoptosis. Here we assessed whether inhibiting repair of DSBs by homologous recombination (HR) or non-homologous end joining (NHEJ) is a reasonable strategy for sensitizing glioma cells to alkylating agents. For down-regulation of HR in glioma cells, we used an interference RNA (iRNA) approach targeting Rad51 and BRCA2, and for NHEJ we employed the DNA-PK inhibitor NU7026. We also assessed whether inhibition of poly(ADP)ribosyltransferase (PARP) by olaparib would enhance the killing effect. The data show that knockdown of Rad51 or BRCA2 greatly sensitizes cells to DSBs and the induction of cell death following temozolomide and nimustine (ACNU). It did not sensitize to ionizing radiation (IR). The expression of O6-methylguanine-DNA methyltransferase (MGMT) abolished all these effects, indicating that O6-alkylguanine induced by these drugs is the primary lesion responsible for the formation of DSBs and increased sensitivity of glioma cells following knockdown of Rad51 and BRCA2. Inhibition of DNA-PK only slightly sensitized to temozolomide whereas a significant effect was observed with IR. A triple strategy including siRNA and the PARP inhibitor olaparib further improved the killing effect of temozolomide. The data provides evidence that down-regulation of Rad51 or BRCA2 is a reasonable strategy for sensitizing glioma cells to killing by O6-alkylating anti-cancer drugs. The data also provide proof of principle that a triple strategy involving down-regulation of HR, PARP inhibition and MGMT depletion may greatly enhance the therapeutic effect of temozolomide

Supersymmetry and Electroweak Breaking in the Interval

Hypermultiplets are considered in the five-dimensional interval where all fields are continuous and the boundary conditions are dynamically obtained from the action principle. The orbifold boundary conditions are obtained as particular cases. We can interpret the Scherk-Schwarz supersymmetry breaking as a misalignment of boundary conditions while a new source of supersymmetry breaking corresponding to a mismatch of different boundary parameters is identified. The latter can be viewed as coming from boundary supersymmetry breaking masses for hyperscalars and the nature of the corresponding supersymmetry breaking parameter is analyzed. For some regions of the parameter space where supersymmetry is broken (either by Scherk-Schwarz boundary conditions or by boundary hyperscalar masses) electroweak symmetry breaking can be triggered at the tree level.Comment: 28 pages, 5 figure

Vacuum Stability with Tachyonic Boundary Higgs Masses in No-Scale Supersymmetry or Gaugino Mediation

No-scale supersymmetry or gaugino mediation augmented with large negative Higgs soft masses at the input scale provides a simple solution to the supersymmetric flavor problem while giving rise to a neutralino LSP. However, to obtain a neutralino LSP it is often necessary to have tachyonic input Higgs soft masses that can give rise to charge-and-color-breaking (CCB) minima and unbounded-from-below (UFB) directions in the low energy theory. We investigate the vacuum structure in these theories to determine when such problematic features are present. When the standard electroweak vacuum is only metastable, we compute its lifetime under vacuum tunneling. We find that vacuum metastability leads to severe restrictions on the parameter space for larger $\tan\beta \sim 30$, while for smaller $\tan\beta\sim 10$, only minor restrictions are found. Along the way, we derive an exact bounce solution for tunneling through an inverted parabolic potential.Comment: 18 Pages, 5 Figure

Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity.

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity

Phenomenology of symmetry breaking from extra dimensions

Motivated by the electroweak hierarchy problem, we consider theories with two extra dimensions in which the four-dimensional scalar fields are components of gauge boson in full space. We explore the Nielsen-Olesen instability for SU(N) on a torus, in the presence of a magnetic background. A field theory approach is developed, computing explicitly the minimum of the complete effective potential, including tri-linear and quartic couplings and determining the symmetries of the stable vacua. We also develop appropriate gauge-fixing terms when both Kaluza-Klein and Landau levels are present and interacting, discussing the interplay between the possible six and four dimensional choices. The equivalence between coordinate dependent and constant Scherk-Schwarz boundary conditions -associated to either continuous or discrete Wilson lines- is analyzed.Comment: 39 pages and 8 eps figures. Few changes in section

The Diboson Excess: Experimental Situation and Classification of Explanations; A Les Houches Pre-Proceeding

We examine the `diboson' excess at $\sim 2$ TeV seen by the LHC experiments in various channels. We provide a comparison of the excess significances as a function of the mass of the tentative resonance and give the signal cross sections needed to explain the excesses. We also present a survey of available theoretical explanations of the resonance, classified in three main approaches. Beyond that, we discuss methods to verify the anomaly, determining the major properties of the various surpluses and exploring how different models can be discriminated. Finally, we give a tabular summary of the numerous explanations, presenting their main phenomenological features.Comment: 37 pages, 9 Figures, 1 Tabl

Systems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species.

peer reviewedThe genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 strains of the BXD mouse population fed chow or high-fat diet and integrated these data with complementary multi-omics datasets. We identified several lipid species and lipid clusters with specific phenotypic and molecular signatures and, in particular, cardiolipin species with signatures of healthy and fatty liver. Genetic analyses revealed quantitative trait loci for 68% of the lipids (lQTL). By multi-layered omics analyses, we show the reliability of lQTLs to uncover candidate genes that can regulate the levels of lipid species. Additionally, we identified lQTLs that mapped to genes associated with abnormal lipid metabolism in human GWASs. This work provides a foundation and resource for understanding the genetic regulation and physiological significance of lipid species