Sparticle mass hierarchies, simplified models from SUGRA unification, and benchmarks for LHC Run-II SUSY searches

Sparticle mass hierarchies contain significant information regarding the origin and nature of supersymmetry breaking. The hierarchical patterns are severely constrained by electroweak symmetry breaking as well as by the astrophysical and particle physics data. They are further constrained by the Higgs boson mass measurement. The sparticle mass hierarchies can be used to generate simplified models consistent with the high scale models. In this work we consider supergravity models with universal boundary conditions for soft parameters at the unification scale as well as supergravity models with nonuniversalities and delineate the list of sparticle mass hierarchies for the five lightest sparticles. Simplified models can be obtained by a truncation of these, retaining a smaller set of lightest particles. The mass hierarchies and their truncated versions enlarge significantly the list of simplified models currently being used in the literature. Benchmarks for a variety of supergravity unified models appropriate for SUSY searches at future colliders are also presented. The signature analysis of two benchmark models has been carried out and a discussion of the searches needed for their discovery at LHC RUN-II is given. An analysis of the spin independent neutralino-proton cross section exhibiting the Higgs boson mass dependence and the hierarchical patterns is also carried out. It is seen that a knowledge of the spin independent neutralino-proton cross section and the neutralino mass will narrow down the list of the allowed sparticle mass hierarchies. Thus dark matter experiments along with analyses for the LHC Run-II will provide strong clues to the nature of symmetry breaking at the unification scale.Comment: To appear in JHEP; 37 pages, 11 tables, 11 figure

Nanotechnology intervention of the microbiome for cancer therapy

The microbiome is emerging as a key player and driver of cancer. Traditional modalities to manipulate the microbiome (for example, antibiotics, probiotics and microbiota transplants) have been shown to improve efficacy of cancer therapies in some cases, but issues such as collateral damage to the commensal microbiota and consistency of these approaches motivates efforts towards developing new technologies specifically designed for the microbiome–cancer interface. Considering the success of nanotechnology in transforming cancer diagnostics and treatment, nanotechnologies capable of manipulating interactions that occur across microscopic and molecular length scales in the microbiome and the tumour microenvironment have the potential to provide innovative strategies for cancer treatment. As such, opportunities at the intersection of nanotechnology, the microbiome and cancer are massive. In this Review, we highlight key opportunistic areas for applying nanotechnologies towards manipulating the microbiome for the treatment of cancer, give an overview of seminal work and discuss future challenges and our perspective on this emerging area

Sparticle mass hierarchies, simplified models from SUGRA unification, and benchmarks for LHC Run-II SUSY searches

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Sparticle mass hierarchies, simplified models from SUGRA unification, and benchmarks for LHC Run-II SUSY searches

Sparticle mass hierarchies contain significant information regarding the origin and nature of supersymmetry breaking. The hierarchical patterns are severely constrained by electroweak symmetry breaking as well as by the astrophysical and particle physics data. They are further constrained by the Higgs boson mass measurement. The sparticle mass hierarchies can be used to generate simplified models consistent with the high scale models. In this work we consider supergravity models with universal boundary conditions for soft parameters at the unification scale as well as supergravity models with nonuniversalities and delineate the list of sparticle mass hierarchies for the five lightest sparticles. Simplified models can be obtained by a truncation of these, retaining a smaller set of lightest particles. The mass hierarchies and their truncated versions enlarge significantly the list of simplified models currently being used in the literature. Benchmarks for a variety of supergravity unified models appropriate for SUSY searches at future colliders are also presented. The signature analysis of two benchmark models has been carried out and a discussion of the searches needed for their discovery at LHC RUN-II is given. An analysis of the spin independent neutralino-proton cross section exhibiting the Higgs boson mass dependence and the hierarchical patterns is also carried out. It is seen that a knowledge of the spin independent neutralino-proton cross section and the neutralino mass will narrow down the list of the allowed sparticle mass hierarchies. Thus dark matter experiments along with analyses for the LHC Run-II will provide strong clues to the nature of symmetry breaking at the unification scale.Comment: To appear in JHEP; 37 pages, 11 tables, 11 figure

The role of danger signals in tumor elicited inflammation (TUM5P.934)

Abstract Sporadic colorectal cancer (CRC) has traditionally been considered a genetic disease, with inactivation of classic tumor suppressors, such as APC and P53, driving tumorigenesis. Recently, however, it has come to light that inflammation plays a major role in the progression of CRC, and that tumor cells can induce a massive infiltration of immune cells into the tumor. Danger Associated Molecular Patterns (DAMPs) are proteins that are released from dying or stressed cells, which promotes an immune response. While these so called “danger signals” are often up-regulated in cancer, the mechanisms behind their role in tumor progression and inflammation require further exploration. Using a number of mouse models of spontaneous CRC, we are beginning to uncover which inflammatory cues induce danger signals, and which immune cells are the major producers. We have found that S100A8/A9 and HMGB-1 are significantly up-regulated in tumor tissue and mesenteric lymph nodes (MLN) of mice with CRC, compared to adjacent normal colon tissue. Additionally, using FACS to sort individual immune populations within the mouse tissue, intraepithelial monocytes and neutrophils seem to be the major immune cell producers of danger signals. Finally, in a kRas inducible model, to simulate a more aggressive cancer, danger signals are elevated even further in tumor tissue and MLN. Future work will focus on elucidating the precise signaling between immune modulators and danger signals.</jats:p

Abstract 3183: Role of danger signals in tumor elicited inflammation

Abstract Spontaneous colon cancer (CRC) is traditionally thought to arise from a series of genetic mutations to key tumor suppressors and oncogenes that drive its progression. Recently, however, the importance of the immune system and inflammation in exacerbating CRC development has been demonstrated, as seemingly non-inflammatory tumors have massive infiltration of immune cells. This phenomenon has been deemed “Tumor elicited inflammation” (TEI), whereby the tumor cells recruit immune cells to the tumor, promoting tumor development. Danger Associated Molecular Patterns (DAMPs), proteins that are released during cellular stress or oncogenic transformation, promote a robust immune response and are often up-regulated in cancer. Thus, DAMPs may serve as an initial cue to induce TEI. The precise mechanisms of these so-called “danger signals” in CRC development and TEI have not been fully elucidated. Using a number of in vitro and in vivo models, we sought to uncover the major cellular producers of danger signals in the tumor microenvironment, how these danger signals recruit various immune cells to the tumor, and finally their effects on tumor progression. We found an up-regulation of three danger signals, S100A8, S100A9, and HMGB-1, in tumor tissue from mouse models of spontaneous CRC, at the RNA and protein levels. In addition, using FACS, the myeloid compartment of sorted immune cells demonstrated the highest expression levels of S100A8 and S100A9, as measured by qPCR. In order to further explore role of danger signals, lentiviral overexpression of S100A8, S100A9, and HMGB-1 was performed in MC38 colon cancer cells. Subsequently, these new cell lines were injected subcutaneously into C57BL/6 mice and tumor development was followed. S100A8 and S100A9 overexpressing tumors showed accelerated development and a greater influx of myeloid cells into the tumor when compared to GFP overexpressing control cells. Future work will focus on the crosstalk between cancer cells and immune cells, the key cellular pathways affected in cancer cells and immune cells, and finally if blockade of these signals has any therapeutic benefit in the treatment of CRC. Citation Format: Ralph Francescone, Debora Vendramini-Costa, Oxana Dmitrieva, Vivi Hou, David Posocco, Sergei Grivennikov. Role of danger signals in tumor elicited inflammation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3183. doi:10.1158/1538-7445.AM2015-3183</jats:p

Abstract 3186: Role of Interleukin 1 signaling in tumor elicited inflammation and colon cancer

Abstract Colorectal cancer (CRC) is the 2nd most common cause of cancer deaths in the United States and other developed countries, despite important advances in detection, surgery and chemotherapy. It becomes increasingly clear that not only cell autonomous events in cancer cells are required for tumor growth and progression. Growing CRC tumors possess the ability to recruit inflammatory cells and upregulate inflammatory cytokines - a phenomenon recently introduced as “Tumor elicited inflammation”(TEI). The mechanisms of TEI induction and tumor promotion are not yet well defined. IL23/IL17 pathway is one of the established regulators of TEI. While in mice the ablation of IL-23 signaling results in a uniform loss of IL-17 response and in a decrease in tumor growth; in humans IL23/IL-23R gene expression signature is not always consistent with elevated IL-17 signature, implicating that there should be other regulators of IL-17 and TEI induction in tumors. IL-1 pathway is important for the induction of T helper IL-17 producing cells (Th17) and for the production of IL-17 by innate lymphoid cells (ILC), both in mice and in humans. IL-1 pathway is also implicated in host defense, immunity and tumorigenesis, with some of its functional characteristics similar to IL-23 pathway. In addition, IL-1, much alike IL-23, can be also induced by various microbial derived and host derived ‘danger signals’ readily available within the tumor microenvironment. Our own data suggests that components of IL-1 pathway are upregulated in CRC tumors. Therefore, we hypothesized, that IL-1 pathway might be an important regulator of TEI and CRC tumorigenesis. Using genetic tools and animal models, we examined if IL-1 has the potential role in different stage of CRC and whether it serves as an important regulator of TEI and CRC tumor cells proliferation and survival. Citation Format: Oxana Dmitrieva, David Possoco, Ralph A. Francescone, Vivianty Hou, Debora B. Vendramini-Costa, Sergey Grivennikov. Role of Interleukin 1 signaling in tumor elicited inflammation and colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3186. doi:10.1158/1538-7445.AM2015-3186</jats:p

Abstract 2799: Goniothalamin, a natural product, modulates the inflammatory microenvironment on colitis and colitis-associated cancer

Abstract Despite anticancer drug discovery advances, the worldwide cancer incidence is remarkable. Thus, there is continuous necessity on new therapies development and tumor microenvironment offers multiple targets for cancer therapy, including inflammation. Nature has been a source of new therapeutic and preventive agents and the styryl-lactone goniothalamin (GTN) has shown to be a promising anti-proliferative and anti-inflammatory agent. In previous studies we showed that GTN has pro-apoptotic activity, gastroprotective effects and inhibits tumor development and acute inflammation in mice. Thus, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on colitis and colitis-associate cancer (CAC) models, focusing on the elucidation of the relationship between the anti-proliferative and anti-inflammatory activities. GTN was synthesized and evaluated in vitro in LPS-stimulated RAW 264.7 murine macrophages. Cells were pre-treated with GTN (20 μM) for 3 hours and then stimulated with LPS (1 μg/mL) for 4 hours. Gene expression was analyzed by real-time PCR and cytokines production by ELISA. Experimental colitis was induced by 3.5% dextran sulfate sodium (DSS) for 7 days and animals (mice, C57-BL/6) were treated with GTN daily by oral route (30 and 100 mg/kg). CAC was induced by Azoxymethane (AOM, 10 mg/kg) followed by 3 cycles of DSS (3.0%) and treatments with GTN (30 mg/kg) were conducted by oral route, twice week. Body weight was checked every week and in the end of experiments, colon tissues were collected and processed for microscopic, biochemical and gene expression evaluations. GTN significantly reduced IL-1β, IL-6, TNF-α, IL-23, CXCL2 and iNOS expression on RAW cells, as well as levels of secreted IL-6 and TNF-α. Treatments with GTN also reduced inflammation severity on DSS-induced colitis model by reducing cytokines expression, thus suggesting a modulatory activity of the inflammatory environment. GTN treatment modulated tumor development in a mouse model of CAC. Together with previous data, these results highlight that goniothalamin can be used as a preventive and therapeutic agent to inhibit inflammation in colitis and cancer. Citation Format: Débora Barbosa Vendramini Costa, Ralph A. Francescone, Oxana Dmitrieva, Vivi Hou, David Posocco, Ronaldo A. Pilli, Sergei Grivennikov. Goniothalamin, a natural product, modulates the inflammatory microenvironment on colitis and colitis-associated cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2799. doi:10.1158/1538-7445.AM2015-2799</jats:p