599 research outputs found
Abstract A40: Class IIa HDAC inhibition promotes an anti-tumor macrophage phenotype that induces breast tumor regression and inhibits metastasis
No full textAbstract
While tumor-associated macrophages (TAMs) often have net pro-tumor effects, their embedded location and their untapped potential provide impetus to the discovery of strategies to turn them against tumors. We recently reported that a first in class selective class IIa HDAC inhibitor (TMP195) influenced human monocyte responses to colony stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumor microenvironment and reduces tumor burden and pulmonary metastases through macrophage modulation. TMP195 induces recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumors. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumor reduction. These data introduce class IIa HDAC inhibition as a novel means to harness the anti-tumor potential of macrophages to enhance cancer therapy.
Citation Format: Jennifer L. Guerriero, Alaba Sotayo, Holly Ponichtera, Alexandra Pourzia, Sara Schad, Ruben Carrasco, Lazo Suzan, Roderick Bronson, Anthony Letai. Class IIa HDAC inhibition promotes an anti-tumor macrophage phenotype that induces breast tumor regression and inhibits metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A40.</jats:p
Abstract A31: Biological effects of lutein and kale on the prevention of colonic inflammation and carcinogenesis
No full textAbstract
Ulcerative colitis is a risk factor for colon cancer. Dietary lutein, a nutrient rich in kale, is inversely associated with the risk of developing colon cancer in human observational epidemiologic studies. Besides lutein, kale also contains abundant amounts of other bioactive components with anti-inflammatory, antioxidant, and anti-cancer properties. As a whole food approach, kale may provide more favorable biologic effects on colonic inflammation and neoplasia than lutein alone. Additionally, it is unclear if lutein prevents colon neoplasia via the inhibition of colonic inflammation. Using a dextran sulfate sodium (DSS)-induced colitis and neoplasia mouse model, we evaluated the effects of dietary lutein supplementation and kale on the DSS-induced colorectal inflammation, ulceration, hyperplasia, dysplasia and cancer. Two hundred sixty four 8-week old Swiss-Webster (CFW) mice were assigned to one of ten groups (n = 26 to 27 in each group [13 males and 13 to 14 females]) for 21 weeks as follows: 1) 0.0005% of lutein plus DSS; 2) 0.001% of lutein plus DSS; 3) 0.002% of lutein plus DSS; 4) 0.005% of lutein plus DSS; 5) kale equivalent to 0.0005% of lutein plus DSS; 6) kale equivalent to 0.001% of lutein plus DSS; 7) kale equivalent to 0.002% of lutein plus DSS; 8) kale equivalent to 0.005% of lutein plus DSS; 9) DSS only; and 10) control with no treatment. During the 21-week experimental period, mouse body weights were recorded weekly. At week 7, the mice in groups 1-9 were given DSS for 4 cycles (1 cycle = 1 week 3% of DSS in drinking water followed by 2-week water) to induce colitis and colorectal neoplasia. This report described the findings on the presence of clinical signs of colitis (hemoccult and loose stools, which were evaluated at the end of each week throughout the experiments), and the findings from histopathological evaluations (inflammation, ulceration, hyperplasia, dysplasia, and neoplasia). Dietary lutein and kale, particularly two higher doses (0.002% and 0.005%), reduced the DSS-induced hemoccult and loose stools, as well as the DSS-induced inflammation, ulceration, hyperplasia, dysplasia, and neoplasia. These data suggest that dietary lutein and kale may prevent the DSS-induced colorectal inflammation and associated preneoplastic and neoplastic lesions.
Grant Funding Sources: This project was supported by Agriculture and Food Research Initiative Competitive Grant no. 2014-67017-21754 from the USDA National Institute of Food and Agriculture and by USDA/ARS grant 1950-51000-074S.
Citation Format: Chun Liu, Roderick T. Bronson, Xiang-Dong Wang. Biological effects of lutein and kale on the prevention of colonic inflammation and carcinogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A31.</jats:p
Response and Resistance to NF-κB Inhibitors in Mouse Models of Lung Adenocarcinoma
No full textLung adenocarcinoma is a leading cause of cancer death worldwide. We recently showed that genetic inhibition of the NF-κB pathway affects both the initiation and the maintenance of lung cancer, identifying this pathway as a promising therapeutic target. In this investigation, we tested the efficacy of small-molecule NF-κB inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-κB activity, the proteasome inhibitor bortezomib efficiently reduced nuclear p65, repressed NF-κB target genes, and rapidly induced apoptosis. Bortezomib also induced lung tumor regression and prolonged survival in tumor-bearing KrasLSL-G12D/wt;p53flox/flox mice but not in KrasLSL-G12D/wt mice. After repeated treatment, initially sensitive lung tumors became resistant to bortezomib. A second NF-κB inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired resistance in mice. Our results using preclinical mouse models support the NF-κB pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma.
Significance: Using small-molecule compounds that inhibit NF-κB activity, we provide evidence that NF-κB inhibition has therapeutic efficacy in the treatment of lung cancer. Our results also illustrate the value of mouse models in validating new drug targets in vivo and indicate that acquired chemoresistance may later influence bortezomib treatment in lung cancer.Howard Hughes Medical InstituteNational Cancer Institute (U.S.) (Cancer Center Support grant from the NCI (P30-CA14051))American Association for Cancer ResearchLeukemia & Lymphoma Society of AmericaHuman Frontier Science Program (Strasbourg, France) (Fellowship)American Society for Pharmacology and Experimental TherapeuticsMerck Research LaboratoriesDamon Runyon Cancer Research FoundationGenentech, Inc
Pathologic phenotyping of mutant mice.
No full textThe easiest and cheapest way to analyze the phenotype of most knockout mice is to do a comprehensive necropsy and histopathologic examination of slides of all tissues. Once any lesion is found in a knockout mouse a vast contemporary and traditional literature can be searched for occurrences of similar lesions in other species, including human beings. This may provide further insights into the molecular and cellular pathogenesis of the lesion. In this chapter we will focus on the best way to turn a mouse into a set of slides which can thereafter be studied by investigators and pathologists. Some techniques suggested are not generally used in conventional histology laboratories. Most are decidedly old fashioned. They have all been used successfully in many diverse studies of mice of all ages with all kinds of lesions
M.Aikawa, J.R.Broderson, I.Ikuo, G.Jakobs, M.Pappaioanou, W.E.Collins, and C.C.Campbell, An Atlas of Renal Disease in Aotus Monkeys with Experimental Plasmodial Infection. American Institute of Biological Sciences, Arlington, VA1988.
No full text
Economics of Management Zone Delineation in Cotton Precision Agriculture
No full textThis paper develops a management zone delineation procedure based on a spatial statistics approach and evaluates its economic impact for the case of Texas cotton production. With the use of an optimization model that utilizes a yield response function estimated through spatial econometric methods, we found that applying variable N rates based on the management zones delineated would result in higher cotton yields and higher net returns, above Nitrogen cost, relative to uniformly applying a single N rate for the whole field. In addition, a variable rate N application using the delineated management zones produced higher net returns, above Nitrogen cost, relative to a variable N rate system where the zones are based solely on landscape position. This is indicative of the potential economic value of using a spatial statistics approach to management zone delineation.Management Zones, Exploratory Spatial Data Analysis, Site-Specific Nitrogen Management, Cotton Precision Agriculture., Crop Production/Industries, Q1, Q16,
Repair of endogenous DNA base lesions modulate lifespan in mice
No full textThe accumulation of DNA damage is thought to contribute to the physiological decay associated with the aging process. Here, we report the results of a large-scale study examining longevity in various mouse models defective in the repair of DNA alkylation damage, or defective in the DNA damage response. We find that the repair of spontaneous DNA damage by alkyladenine DNA glycosylase (Aag/Mpg)-initiated base excision repair and O[superscript 6]-methylguanine DNA methyltransferase (Mgmt)-mediated direct reversal contributes to maximum life span in the laboratory mouse. We also uncovered important genetic interactions between Aag, which excises a wide variety of damaged DNA bases, and the DNA damage sensor and signaling protein, Atm. We show that Atm plays a role in mediating survival in the face of both spontaneous and induced DNA damage, and that Aag deficiency not only promotes overall survival, but also alters the tumor spectrum in Atm[superscript −/−] mice. Further, the reversal of spontaneous alkylation damage by Mgmt interacts with the DNA mismatch repair pathway to modulate survival and tumor spectrum. Since these aging studies were performed without treatment with DNA damaging agents, our results indicate that the DNA damage that is generated endogenously accumulates with age, and that DNA alkylation repair proteins play a role in influencing longevity.National Institutes of Health (U.S.) (Grant R01-CA075576)National Institutes of Health (U.S.) (Grant R01-ES022872)National Institutes of Health (U.S.) (Grant R01-CA149261)National Institutes of Health (U.S.) (Grant P30-ES002109
A genetic platform to model sarcomagenesis from primary adult mesenchymal stem cells
No full textThe regulatory factors governing adult mesenchymal stem cell (MSC) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal forms of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here, we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSC transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma, with important therapeutic implications
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