Matching Items (12)

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Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

Description

Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months.

Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months. It is clear that increased survival of brain tumor patients requires the design of new therapeutic modalities, especially those that enhance currently available treatments and/or limit tumor growth. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacological means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). The KD, as the name implies, also provides increased blood ketones to support the energy needs of normal tissues. Preclinical work from a number of laboratories has shown that the KD does indeed reduce tumor growth in vivo. In addition, the KD has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. Furthermore, this diet can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones such as β-hydroxybutyrate (βHB) in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of chemotherapy and radiation. Thus, while we are only beginning to understand the pluripotent mechanisms through which the KD affects tumor growth and response to conventional therapies, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas. This has led to a limited number of clinical trials investigating the use of a KD in patients with primary and recurrent glioma.

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Created

Date Created
  • 2016-11-16

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Enhanced Immunity in a Mouse Model of Malignant Glioma is Mediated by a Therapeutic Ketogenic Diet

Description

Background: Glioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown

Background: Glioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown previously that the therapeutic ketogenic diet (KD) prolongs survival in mouse models of glioma, explained by both direct tumor growth inhibition and suppression of pro-inflammatory microenvironment conditions. The aim of this study is to assess the effects of the KD on the glioma reactive immune response.

Methods: The GL261-Luc2 intracranial mouse model of glioma was used to investigate the effects of the KD on the tumor-specific immune response. Tumor-infiltrating CD8+ T cells, CD4+ T cells and natural killer (NK) cells were analyzed by flow cytometry. The expression of immune inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) on CD8+ T cells were also analyzed by flow cytometry. Analysis of intracellular cytokine production was used to determine production of IFN, IL-2 and IFN- in tumor-infiltrating CD8+ T and natural killer (NK) cells and IL-10 production by T regulatory cells.

Results: We demonstrate that mice fed the KD had increased tumor-reactive innate and adaptive immune responses, including increased cytokine production and cytolysis via tumor-reactive CD8+ T cells. Additionally, we saw that mice maintained on the KD had increased CD4 infiltration, while T regulatory cell numbers stayed consistent. Lastly, mice fed the KD had a significant reduction in immune inhibitory receptor expression as well as decreased inhibitory ligand expression on glioma cells.

Conclusions: The KD may work in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression. This evidence suggests that the KD increases tumor-reactive immune responses, and may have implications in combinational treatment approaches.

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Created

Date Created
  • 2016-05-13

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Combination Immunotherapy with α-CTLA-4 and α-PD-L1 Antibody Blockade Prevents Immune Escape and Leads to Complete Control of Metastatic Osteosarcoma

Description

Background: Osteosarcoma is one of the most common bone cancers in children. Most patients with metastatic osteosarcoma die of pulmonary disease and limited curative therapeutic options exist for such patients. We

Background: Osteosarcoma is one of the most common bone cancers in children. Most patients with metastatic osteosarcoma die of pulmonary disease and limited curative therapeutic options exist for such patients. We have previously shown that PD-1 limits the efficacy of CTL to mediate immune control of metastatic osteosarcoma in the K7M2 mouse model of pulmonary metastatic disease and that blockade of PD-1/PD-L1 interactions can partially improve survival outcomes by enhancing the function of osteosarcoma-specific CTL. However, PD-1/PD-L1 blockade-treated mice eventually succumb to disease due to selection of PD-L1 mAb-resistant tumor cells. We investigated the mechanism of tumor cell resistance after blockade, and additional combinational therapies to combat resistance.

Methods: We used an implantable model of metastatic osteosarcoma, and evaluated survival using a Log-rank test. Cellular analysis of the tumor was done post-mortem with flow cytometry staining, and evaluated using a T-test to compare treatment groups.

Results: We show here that T cells infiltrating PD-L1 antibody-resistant tumors upregulate additional inhibitory receptors, notably CTLA-4, which impair their ability to mediate tumor rejection. Based on these results we have tested combination immunotherapy with α-CTLA-4 and α-PD-L1 antibody blockade in the K7M2 mouse model of metastatic osteosarcoma and show that this results in complete control of tumors in a majority of mice as well as immunity to further tumor inoculation.

Conclusions: Thus, combinational immunotherapy approaches to block additional inhibitory pathways in patients with metastatic osteosarcoma may provide new strategies to enhance tumor clearance and resistance to disease.

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Created

Date Created
  • 2015-05-19

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Immunosignaturing Can Detect Products from Molecular Markers in Brain Cancer

Description

Immunosignaturing shows promise as a general approach to diagnosis. It has been shown to detect immunological signs of infection early during the course of disease and to distinguish Alzheimer’s disease

Immunosignaturing shows promise as a general approach to diagnosis. It has been shown to detect immunological signs of infection early during the course of disease and to distinguish Alzheimer’s disease from healthy controls. Here we test whether immunosignatures correspond to clinical classifications of disease using samples from people with brain tumors. Blood samples from patients undergoing craniotomies for therapeutically naïve brain tumors with diagnoses of astrocytoma (23 samples), Glioblastoma multiforme (22 samples), mixed oligodendroglioma/astrocytoma (16 samples), oligodendroglioma (18 samples), and 34 otherwise healthy controls were tested by immunosignature. Because samples were taken prior to adjuvant therapy, they are unlikely to be perturbed by non-cancer related affects. The immunosignaturing platform distinguished not only brain cancer from controls, but also pathologically important features about the tumor including type, grade, and the presence or absence of O[superscript 6]-methyl-guanine-DNA methyltransferase methylation promoter (MGMT), an important biomarker that predicts response to temozolomide in Glioblastoma multiformae patients.

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Created

Date Created
  • 2012-07-16

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Who must die: the state of exception in Rwanda's genocide

Description

The state of exception in Rwanda did not spontaneously occur in Rwanda, it was initially developed by German and Belgian colonizers, adopted by two successive Hutu regimes, and nurtured and

The state of exception in Rwanda did not spontaneously occur in Rwanda, it was initially developed by German and Belgian colonizers, adopted by two successive Hutu regimes, and nurtured and fed for 35 years of Rwandan independence until its final realization in the 1994 genocide. Political theory regarding the development of the "space devoid of law" and necropolitics provide a framework with which to analyze the long pattern of state action that created a milieu in which genocide was an acceptable choice of action for a sovereign at risk of losing power. The study of little-known political theories such as Agamben's and Mbembe's is useful because it provides a lens through which we can analyze current state action throughout the world. As is true in many genocidal regimes, the Rwandan genocide did not just occur as a "descent into hell." Rather, state action over the course of decades in which the subjects of the state (People) were systematically converted into mere flesh beings (people), devoid of political or social value, creates the setting in which it is feasible to seek to eliminate those beings. A question to be posed to political actors and observers around the world today is at what point in the process of one nation's creation of the state of exception and adoption of necropolitics does the world have a right, and a duty, to intervene? Thus far, it has always occurred too late for the "people" in that sovereign to realize their political and social potential to be "People."

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Created

Date Created
  • 2012

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From criminalization to symbolic resiliency: undocumented immigrants "re-imagining success" In the United States

Description

The goal of this exploratory study is to learn how undocumented immigrants remain resilient by adopting new strategies to survive and thrive despite confronting challenges as they legally justify their

The goal of this exploratory study is to learn how undocumented immigrants remain resilient by adopting new strategies to survive and thrive despite confronting challenges as they legally justify their presence in the United States. This study will focus on three research questions: first, what are the demographic factors that describe undocumented immigrant family resiliency in the United States? Second, how are social service providers; perceptions of the challenges faced by their clients modified by the services they provide? Third, how do resiliency factors identified by their social service providers allow undocumented immigrants to overcome the challenges of criminalization in the United States? The theoretical framework for this study was based on two approaches: first, a symbolic interaction approach which was specifically inspired by Benedict Anderson's classic Imagined Communities (1983, 2006). The second approach is Ecological Risk and Resiliency. This study used mixed methods of research: interviews and descriptive analysis. The qualitative data was drawn from ten social service providers from a faith-based agency, and from a narrative analysis of participants enrolled in an ESL program (English as a Second Language). The subjects for the quantitative design were drawn from a group of undocumented first-generation Hispanic immigrants who received social services during the year 2009 from the same faith-based agency. In summary, this exploration discovered that immigrants show great ability for imaginatively developing strategies in order to survive and thrive under their difficult circumstances. Furthermore, undocumented immigrant survival does not completely depend upon food and shelter and even money, but also on a sense of well being. Noted was that women undocumented immigrants show greater resiliency than their male counterparts. Also discovered was that social services do make a difference in the lives of undocumented immigrants but not all social service providers are fully trained and prepared to assist them beyond normal standards. In conclusion, the Hispanic undocumented immigrant displays remarkable resiliency despite tremendous obstacles and personal difficulties and this resiliency could only improve by social service providers' improved understanding of their needs and personal resources.

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Agent

Created

Date Created
  • 2011

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Social Capital: Two Case Studies of Chinese Small Business in the Greater Phoenix and Los Angeles Areas

Description

As immigrants in the United States, Chinese small business entrepreneurs often encountered social and cultural barriers in the areas of finance, language, and employment in their new environment. This dissertation

As immigrants in the United States, Chinese small business entrepreneurs often encountered social and cultural barriers in the areas of finance, language, and employment in their new environment. This dissertation investigated how they utilized social capital to surmount the embedded disadvantages of an unequal market in their adopted country. The findings presented in this qualitative descriptive multi-case analysis, conducted in the greater metropolitan regions of Phoenix and Los Angeles, demonstrated the importance of social and transnational ties created in the United States within the local Chinese community as well as their social connections brought from China.

Drawing upon the data from in-depth interviews and informal observations, this dissertation was guided by three research questions: (a) What barriers do immigrant small business owners encounter? (b) What social connections provide help for immigrant small business owners to overcome those barriers or intensify their disadvantaged situations? (c) How do social networks influence immigrant small business development? The findings revealed many provocative facts on how social capital stimulated Chinese immigrant small business owners.

The influence of local and strong ties especially provided essential start-up funds, an affordable labor force. Those ties also provided authentication for business information provided by weak ties. Although the governments’ Small Business Administration empowers small business by various programs because it is an important social and economic element in the U.S. market, the Chinese community rarely utilized this support.

Transnational connections played an important role in the relatively mature market found in Los Angeles, but indeed all respondents in both case studies exhibited great interest in utilizing transnational connections to explore business opportunities. Regional connections provided a powerful resource for Chinese small business to create business alliance and increase their market competitiveness. Social capital embeds in a complexity of political, economic, social and personal backgrounds. In summary, social capital was an essential resource for Chinese small business when they encountered the barriers in the local market. From the findings, this dissertation’s scholarly contribution adds to the field of social capital studies by combining the investigation of social capital, embeddedness, intersectionality and transnational connections in respect to study immigrant entrepreneurship.

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Created

Date Created
  • 2019

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First love, then marriage, then a baby carriage?

Description

Above all else, this project is about parentage in the modern American legal system and culture. Advanced reproductive technologies require our courts to reconsider the long-standing presumption that a child

Above all else, this project is about parentage in the modern American legal system and culture. Advanced reproductive technologies require our courts to reconsider the long-standing presumption that a child has only one female mother and one male father. We now have children of choice, rather than chance. Assisted Reproductive Technology and its widespread availability and use and changed the landscape of parentage maybe forever. And the children of such efforts remain largely unprotected by our current legal system that favors reproduction by chance within a recognized marriage or at the least, a traditional two-parent paradigm. However, assisted reproduction calls into question the current legal framework for determinations of parentage based in marriage and/or biology. Based on a long and convoluted history, our current legal system conflates marriage and parentage. Moreover, in many circumstances the law restricts both the number and gender of the parties to a marriage or possible parents. One of the more compelling historical and still salient justifications for doing so is to accord the "Best Interest of the Child" standard which purports to underpin all such determinations. Unfortunately, that standard cannot best be met when weighed in a balance against a constitutionally protected exclusive right to parent vested in an adult either by a determination of a genetic link to the child or marriage to another parent. Children of choice, who result from the affirmative and purposive engagement in assisted reproduction, should be entitled to the same protections as children of chance born to a man and woman who are married. Once we look beyond marriage and biology as determiners of parentage, a better way for our legal system to serve the best interests of children, and their parents, is to identify and protect those adult relationships that are parental in nature and that benefit the child irrespective of a marriage between parents or genetic links to the child. Fortunately, the tools to accomplish this paradigm shift already are in existence. The expansion of our commonly used definitions and broader view of our current statutes will allow the legal system to better protect both children of choice and children of chance by making better parentage determinations. To that end, this project also takes on the ambitious task of praxis; of applying the theories to the law as it stands and demonstrating how the new paradigm might look as it is implemented with all of its far-reaching tentacles.

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Created

Date Created
  • 2012