Contents
Pharmacogenetics of Selective Serotonin Reuptake Inhibitor
Response in Major Depression Pp.1-7
Shih-Jen Tsai and
Chen-Jee Hong
[Abstract] [Full text article]
Apoptosis in Drug Response Pp.9-16
Simone Fulda and Klaus-Michael Debatin
[Abstract] [Full text article]
HLA Peptide-mediated Strategies for Modulation of
Cellular and Humoral Immune Response in Transplantation Pp.17-36
A.C. Papassavas
[Abstract] [Full text article]
Genetic Polymorphism and Tumor Immunotherapy Pp.37-57
Rongcun Yang and Richard B.S. Roden
[Abstract] [Full text article]
Genomic and Proteomic Techniques and their Application in
Selenium Research Pp. 59-65
Huawei Zeng
[Abstract] [Full text article]
The Genomic Approaches to Major Depression Pp. 67-74
Chen-Jee Hong, and Shih-Jen Tsai
[Abstract] [Full text article]
Abstracts
[Back to top]
Pharmacogenetics of Selective Serotonin Reuptake Inhibitor Response in Major
Depression
Shih-Jen Tsai and Chen-Jee Hong
As with all antidepressant therapies, there is variability
among major depressed patients in terms of response to selective serotonin
reuptake inhibitor (SSRI) treatment. Of the factors causing this
inter-individual variability in response, differences in genetic components may
play a major role. Some very recent research has focused on the associations
between genetic polymorphisms in candidate genes related to SSRI therapeutic
action. Several genetic polymorphisms have been associated with therapeutic
SSRI response, including genetic variants of the serotonin transporter,
serotonin- 2A-receptor, tryptophan hydroxylase, brain-derived neurotrophic
factor, G-protein beta3 subunit, interleukin-1beta and angiotensin-converting
enzyme, however, these positive findings have not been replicated in all
studies. In this article, the SSRI pharmacogenetic studies for major depression
are reviewed, and recommendations proposed for future study.
[Back to top]
Apoptosis in Drug Response
Simone Fulda and Klaus-Michael Debatin
Apoptosis, the cell’s
intrinsic death program, plays an important role in the regulation of tissue
homeostasis. Imbalances between cell death and survival may result in premature
death, uncontrolled proliferation or tumor formation. Also, killing of cancer
cells by various cytotoxic approaches such as anticancer drugs, g-irradiation,
suicide genes or immunotherapy, is predominantly mediated through induction of
apoptosis in target cells. Thus, defects in apoptosis programs that suppress
cell death can also confer drug resistance. Understanding the molecular events
that regulate apoptosis and how tumor cells evade apoptotic deletion have
provided a paradigm to link cancer genetics and response to cancer therapy.
Insights into the signaling cascades that regulate drug-induced apoptosis
provide rational targets for therapeutic interventions. Also, genetic
variability in apoptosis regulatory genes found in tumors of individual
patients may contribute to variability in drug response. Thus, monitoring
expression profiles of apoptosis genes in tumors of individual patients or in
response to specific pharmacological agents may serve as predictive markers of
drug response.
[Back to top] HLA
Peptide-mediated Strategies for Modulation of Cellular and Humoral Immune
Response in Transplantation
A.C. Papassavas
New insights into the mechanisms of allorecognition
(direct and indirect pathways) and the molecular interactions of the T cell
receptor (TCR) with the human leukocyte antigen (HLA)-peptide complex on
antigen presenting cells (APCs) have stimulated research into peptide-based
strategies of immunosuppression. Although direct recognition of allogeneic
molecules on APCs of the graft may induce a state of tolerance, the continuous
presentation of processed alloantigens by professional APCs of the recipient
does not allow the same phenomenon to occur. It has been demonstrated that
indirect recognition of allogeneic HLA molecules and spread of the T cell
alloreactivity to other epitopes within the allogeneic HLA molecules might play
an important role in provoking graft rejection. Tolerance induction to the
dominant (immunogenic) donor determinants, achieved by administration of
antagonist (nonimmunogenic) synthetic peptide-based treatments, represents a
potential effective strategy for blocking indirect alloresponse and ensuring
long-term graft survival. On the basis of this knowledge, computer based
rational prediction and mapping of the immunogenic and non-immunogenic
determinant on HLA molecules presented during the course of transplantation is
a powerful and promising strategy. Moreover, design of analogues/antagonists of
epitopes critical for normal T cell activation could also be used. Thus,
peptides derived from various regions of HLA class I and II molecules and
structure-based peptides have demonstrated immunomodulatory effects both in
vitro and in vivo. Early downregulation of the antigen specific indirect
alloreactivity, using the various strategies discussed in this review, may allow
long-term survival of human allografts without the need of HLA-compatibility
and without the continuous recipient immunosupression.
[Back
to top] Genetic Polymorphism and Tumor Immunotherapy
Rongcun Yang and Richard B.S. Roden
Numerous immunotherapeutic strategies have been tested
over the last decade but their success, especially against cancer, has been
both varied and unpredictable. Gene polymorphisms in key immunoregulatory
molecules may contribute to the heterogeneity in outcome between individuals
receiving the same immunotherapeutic treatment. Typically, active cancer
immunotherapy aims to redirect or modulate the function of antigen presenting
cells (APCs), especially dendritc cells (DCs) that play a critical role in both
innate and adaptive immune responses. This includes enhancing the function of
APCs by promoting the growth and differentiation of DCs, potentiating T cell
activation by improving costimulation and engineering vaccine vectors to
significantly enhance the immunogenicity of vaccinogens. Several groups have
investigated the functional consequences of polymorphisms in key
immunoregulatory moleculesincluding antigen presenting molecules, cytokines and
chemokines and their receptors, adhesion and costimulatory molecules, toll-like
receptors and intracellular signaling molecules that play a vital role in
antigen recognition and the control of adaptive immune responses. This review
examines both genetic polymorphisms in these immunoregulatory molecules and
their relationship to immunotherapeutic outcome, especially against carcinoma.
(175 words)
[Back to top]
Genomic and Proteomic Techniques and their Application in Selenium Research
Huawei Zeng
Recent revolutionary changes in molecular biology have
spawned the disciplines of genomics and proteomics that systematically generate
and analyze the information about genomes, gene transcripts, proteins and their
functions in a global, comprehensive manner. The applications of these
approaches present tremendous opportunities in almost every aspect of
bioscience research. One such opportunity concerns selenium, an essential trace
element for humans and many other forms of life, which has been associated with
reduced cancer risk. Interestingly, the biological activities of selenium as a
nutrient, a cancer preventive agent, or even a toxicant, are dependent on the
dose and the chemical form of the element. However, the molecular mechanisms by
which selenium exerts these effects largely remain unknown. This article
outlines the current status of genomic and proteomic techniques and their
application in selenium research, particularly as it relates to the prevention
of tumorigenesis.
[Back to top] The
Genomic Approaches to Major Depression
Chen-Jee Hong, and Shih-Jen Tsai
Major depression is a chronic state of depressed mood with
significant genetic predisposition. Although a lot of efforts has been tried to
localize or associate the genes of major depression, etiological heterogeneity
and complexity of this disorder has greatly hold back the use of traditional
linkage strategies and candidate gene approaches. Recent advances in high
throughput genotyping and microarray techniques have proffered opportunities
for comprehensive investigation on genetic alterations and expressions on a
scale not previously possible. It has become feasible to find genes with small
effect size in major depression using genome-wide association scanning and to
identify new pathways or mechanisms of psychopharmacology by the application of
functional genomics. In the era of genomic approach to the pathophysiology of
major depression, the authors suggest (1) reducing the heterogeneity of major
depression by subgrouping the patients according to biological traits such as
responses to antidepressant treatments, (2) searching for genes with small
effect size using association scanning strategy, genomic control and DNA
pooling techniques in genotyping; and (3) developing animal models with genetic
vulnerability to major depression by ethylnitrosourea (ENU) mutagenesis
technology and efficient behavioral screening tests.