Adenoviral gene therapy of gastrointestinal tumour metastases in the liver

Summary

Gastrointestinal cancers are the second most common cause of cancer death. Once metastasised, 5 year survival is < 5% in gastrointestinal cancer. Because the liver is the preferred site for distant organ metastasis of colon cancer, treatment of hepatic metastases remains a challenge for experimental cancer therapy approaches. Gene therapy provides tools to combat cancer on a molecular level. In contrast to conventional chemotherapy, vectors are used to insert DNA into tumour cells, neighbouring parenchymal cells, or cells involved in the cellular immune defense. The shuttle vectors are of nonviral or viral origin. Adenoviral vectors have been developed for high efficiency in vivo gene transfer and expression. The incorporation of foreign DNA can result in direct tumour cell killing, using suicide genes. Cytokine genes, or genes encoding for tumour-specific antigens recognised by the cellular host immune system, can result in anti-tumoral immune stimulation. Experimental suicide-gene expression in hepatic metastasis of gastrointestinal tumours, utilising thymidine kinase and cytosine deaminase, results in significant tumour necrosis and regression. Intratumoral interleukin-2 and interleukin-12 gene expression can induce a systemic cellular antitumoral immune response, with long-term survival demonstrating the potential of this new therapeutic approach in cancer therapy.     

Terror Suicide: How Is It Possible?

How it is possible for people who apparently do not suffer from distress or pathology to commit violent, cruel suicides? Based on the distinction between causes for suicide and facilitators of suicide, I contend that terror suicide is based largely on processes that facilitate suicide rather than on personal distress. Under this premise, terror suicides are examined in terms of enthusiastic determination to achieve a goal, ideological rage, glorification of the post self, heavenly rewards, materialistic benefits for families, induced dissociative processes, and linguistic mediation. Also described are the processes and preparations by which the idea of terror suicide and its facilitators are induced. Further, a theoretically inferred profile of the suicide attacker is also suggested.     

Ecstatic suicide

Abstract

Suicide is not an epiphenomenon of depression; it occurs in conditions other than major depressive episodes. Some anguished, excited patients in the grips of ecdysial or apotheotic fantasies attempt suicide when reality testing fails, feeling it a thrill. When malignant narcissism colors severe borderline personality disorder such suicides may occur. Three illustrative cases are presented here and are then placed in the perspective of mass suicides and the ecstatic experiences of third century Christian martyrs. Elated, grandiose suicide material is to be found in the lives and writings of Yukio Mishima and Sylvia Plath, and in some perverse sexual fantasies. Some persons kill themselves not feeling depressed in the melancholic sense; they are delighted. Their suicides are acts of omnipotent, death-defying magic. Correct suicide risk assessment must take elation of mood and grandiose beliefs about the nature of death into account, because certain individuals are convinced that suicide is passage to glory.     

Aspects of Qualitative Research in Suicidology

The following article is based on twelve years experience with psychodynamically-oriented psychotherapy for suicidal patients at the Center for Therapy and Studies of Suicidal Behaviour (TZS) at the University Hospital of Eppendorf in Hamburg. Our work in psychotherapy, as well as the accompanying scientific research, is guided by an explicit psychodynamic approach to which, however, an objective quantitative method is also applied. Part I will describe the psychodynamic and experience-oriented research approach employed by the TZS, which can be viewed as a contribution to qualitative research into suicide. In Part II, the specific research interest of the author is described, namely clinical and theoretical investigations into female suicidality.     

Altruistic Suicide: A Look at Some Issues

Examples of recent cases of martyrs are examined in order to identify the basic issues of whether martyrdom can be viewed as altruistic suicide. Several issues are identified: whom does the act have to benefit, does the act have to have its intended consequences or is the intent sufficient, does the martyr have to be thinking rationally, and whether execution by the state can be viewed as altruistic suicide.     

Geographic spatial autocorrelation and United States suicide patterns

Research on aggregated geographical data in such fields as genetics and epidemiology have produced inefficient findings when spatial autocorrelation is present. This inefficiency results from the bias in the standard errors of the regression coefficients for multi-variate studies. It is unclear as to whether the numerous suicide studies that utilize geographical units of analysis am also flawed. The present study employs Odland's test for spatial autocorrelation to ascertain whether this error is present in geographical suicide studies. Two typical studies that employ state and county (parish) data art examined to decide whether spatial autocorrelation limits the findings of these studies. Using a conservative randomization test with Moran's I, it is concluded that for these studies spatial autocorrelation is not a serious problem. However, other weight matrices, and less conservative tests are needed to further support the findings of this paper.     

Serotonin 2c receptor RNA editing in major depression and suicide

Abstract

Objectives. mRNA for serotonin 2C receptor (5-HT_2CR) undergoes editing which results in numerous isoforms. More highly edited isoforms exhibit decreased function. We recently found greater 5-HT_2CR editing in suicide victims with prior bipolar disorder (BPD) or schizophrenia (SZ) compared with non-suicide patients and normal controls (NC). This study compares suicides and non-suicides with major depressive disorder (MDD_Suic and MDD_NoSuic) and non-suicide NC. Methods. mRNA editing was assessed in prefrontal cortex of 24 MDD_Suic, 21 MDD_NoSuic, and 56 NC using next generation sequencing. mRNA expression of 5-HT_2CR and editing enzymes (ADAR1-2) was assessed by real-time PCR. Results. Editing was lower in MDD_NoSuic than in MDD_Suic, which did not differ from NC. No differences in the 5-HT_2CR or ADAR1 expression were detected. ADAR2 expression was higher in NC than in MDD subjects, but did not differ between MDD_NoSuic and MDD_Suic. Conclusions. Our findings suggest the presence of two factors associated with 5-HT_2CR editing. One factor, which probably stems from decreased ADAR2 expression, is linked to MDD and is associated with less editing. The other, seen also in our previous study of suicide in BP and SZ, is linked to suicide alone and is associated with more editing and, therefore, less receptor function.