AAV2-mediated in vivo immune gene therapy of solid tumours

Abstract Background Many strategies have been adopted to unleash the potential of gene therapy for cancer, involving a wide range of therapeutic genes delivered by various methods. Immune therapy has become one of the major strategies adopted for cancer gene therapy and seeks to stimulate the immune system to target tumour antigens. In this study, the feasibility of AAV2 mediated immunotherapy of growing tumours was examined, in isolation and combined with anti-angiogenic therapy. Methods Immune-competent Balb/C or C57 mice bearing subcutaneous JBS fibrosarcoma or Lewis Lung Carcinoma (LLC) tumour xenografts respectively were treated by intra-tumoural administration of AAV2 vector encoding the immune up-regulating cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and the co-stimulatory molecule B7-1 to subcutaneous tumours, either alone or in combination with intra-muscular (IM) delivery of AAV2 vector encoding Nk4 14 days prior to tumour induction. Tumour growth and survival was monitored for all animals. Cured animals were re-challenged with tumourigenic doses of the original tumour type. In vivo cytotoxicity assays were used to investigate establishment of cell-mediated responses in treated animals. Results AAV2-mediated GM-CSF, B7-1 treatment resulted in a significant reduction in tumour growth and an increase in survival in both tumour models. Cured animals were resistant to re-challenge, and induction of T cell mediated anti-tumour responses were demonstrated. Adoptive transfer of splenocytes to naïve animals prevented tumour establishment. Systemic production of Nk4 induced by intra-muscular (IM) delivery of Nk4 significantly reduced subcutaneous tumour growth. However, combination of Nk4 treatment with GM-CSF, B7-1 therapy reduced the efficacy of the immune therapy. Conclusions Overall, this study demonstrates the potential for in vivo AAV2 mediated immune gene therapy, and provides data on the inter-relationship between tumour vasculature and immune cell recruitment

Long-Term Effects of Self-Control on Alcohol Use and Sexual Behavior among Urban Minority Young Women

High risk alcohol use and sexual behaviors peak in young adulthood and often occur in the same individuals. Alcohol use has been found to impair decision-making and contribute to high risk sexual activity. However, the association between alcohol use and risky sexual behavior may also reflect enduring individual differences in risk taking, sociability, self-control, and related variables. Both behaviors can serve similar functions related to recreation, interpersonal connection, and the pursuit of excitement or pleasure. The present study examined the extent to which high risk drinking and sexual behavior clustered together in a sample of urban minority young adult women, a demographic group at elevated risk for negative outcomes related to sexual health. We tested whether psychosocial functioning measured at the beginning of high school predicted classes of risk behaviors when girls were tracked longitudinally into young adulthood. Latent class analysis indicated three distinct profiles based on high risk drinking and sexual behavior (i.e., multiple sex partners) in young adulthood. The largest class (73% of the sample) reported low levels of risky drinking and sexual behavior. The next largest class (19%) reported high risk drinking and low risk sexual behavior, and the smallest class (8%) reported high levels of both behaviors. Compared to women from other racial/ethnic groups, black women were more likely to be categorized in the high risk drinking/low risk sex class. Multinomial logistic regression indicated that self-control in adolescence had a broad and enduring protective effect on risk behaviors eight years later and was associated with a greater probability of being in the low risk drinking/low risk sex class. Findings are discussed in terms of understanding the phenotypic expressions of risk behavior as they relate to early psychosocial development and the long-term protective function of self-control in reducing high risk drinking and sexual behaviors

The New Internationalism: Ceding Sovereign Competences to Supranational Organizations and Constitutional Change in the United States and Germany

The United States, which historically has resisted the trend toward ceding sovereign competences to supranational organizations, recently has begun to cede such competences to trade organizations such as the World Trade Organization and the North American Free Trade Agreement. This process has gone largely unchallenged by the courts, yet it may pose unanticipated risks to the structure of our constitutional order. Ceding sovereign competences presents risks precisely because, once they are ceded, neither the legislature nor the judiciary can, as a practical matter, reverse the harm done to the constitutional structure. Through rejection of the traditional invocation of judicial doctrines that are designed to avert judicial review of ceding sovereign competences, the judiciary is the ideal branch to use its discretionary powers to prevent the redistribution of power among the three branches of the federal government. Germany, in its ongoing integration into the European Union, has faced similar challenges and provides a constructive example of how the judiciary can mitigate the constructive amendment of the constitution. The German experience illustrates how the United States may address similar challenges

The Test of Self-Conscious Affect: Internal Structure, Differential Scales and Relationships with Long-Term Affects

Item analyses and confirmatory factor analyses on the Test of Self-Conscious Affect (TOSCA), in a student (N = 723) and an adult (N = 891) sample, supported the theorized four factor structure of proneness to reparation, negative self-evaluation, externalizing blame and unconcern. However, two-fifth of the items did not empirically differentiate between two or more factors. Differential TOSCA scales, including only differentiating TOSCA items, were constructed and related to measures of long-term affect, depression, anxiety, and anger. Both the pattern and size of correlations of the original and the differential TOSCA scales were almost identical. Results of this study, support the interpretation of TOSCA guilt as a measure of a tendency to reparation associated with guilt and TOSCA shame as a measure of a tendency to global negative self-evaluation. Copyright (C) 2001 John Wiley & Sons, Ltd

Viral vectors in cancer immunotherapy: which vector for which strategy?

Gene therapy involves the transfer of genetic information to a target cell to facilitate the production of therapeutic proteins and is now a realistic prospect as a cancer treatment. Gene transfer may be achieved through the use of both viral and non-viral delivery methods and the role of this method in the gene therapy of cancer has been demonstrated. Viruses represent an attractive vehicle for cancer gene therapy due to their high efficiency of gene delivery. Many viruses can mediate long term gene expression, while some are also capable of infecting both dividing and non-dividing cells. Given the broadly differing capabilities of various viral vectors, it is imperative that the functionality of the virus meets the requirements of the specific treatment. A number of immunogene therapy strategies have been undertaken, utilising a range of viral vectors, and studies carried out in animal models and patients have demonstrated the therapeutic potential of viral vectors to carry genes to cancer cells and induce anti-tumour immune responses. This review critically discusses the advances in the viral vector mediated delivery of immunostimulatory molecules directly to tumour cells, the use of viral vectors to modify tumour cells, the creation of whole cell vaccines and the direct delivery of tumour antigens in animal models and clinical trials, specifically in the context of the suitability of vector types for specific strategies

Shame and Guilt Situational Identification in Subclinical Primary Psychopaths

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