Twenty-five years of translational medicine in antiretroviral therapy: promises to keep.

The year 2010 marks the 25th anniversary of modern antiretroviral drug discovery and development. In the early 1980s, AIDS was almost always a lethal disease with an appalling clinical course characterized by severe opportunistic infections and unusual forms of cancer. Since that time, starting with zidovudine (AZT) and related 2',3'-dideoxynucleosides, the causative retrovirus, now called HIV-1, went from being an untreatable infectious agent to being the target of highly active antiretroviral therapy (HAART).

The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic.

In the last 25 years, HIV-1, the retrovirus responsible for the acquired immunodeficiency syndrome (AIDS), has gone from being an "inherently untreatable" infectious agent to one eminently susceptible to a range of approved therapies. During a five-year period, starting in the mid-1980s, my group at the National Cancer Institute played a role in the discovery and development of the first generation of antiretroviral agents, starting in 1985 with Retrovir (zidovudine, AZT) in a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). We focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from the laboratory to the clinic in response to the pandemic of AIDS, then a terrifying and lethal disease.

Multiple variants in toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection.

Background/aims: Seven genomic loci, implicated by single nucleotide polymorphisms (SNPs), have recently been associated with progression to advanced fibrosis (fibrosis risk) in patients with chronic hepatitis C virus. Other variants in these loci have not been examined but may be associated with fibrosis risk independently of or due to linkage disequilibrium with the original polymorphisms.

Methods: We carried out dense genotyping and association testing of additional SNPs in each of the 7 regions in Caucasian case control samples.

A single-tube quantitative assay for mRNA levels of hormonal and growth factor receptors in breast cancer specimens.

Knowledge of estrogen receptor (ER) and progesterone receptor (PR) status has been critical in the evolution of modern targeted therapy of breast cancer and remains essential for making informed therapeutic decisions. Recently, growth factor receptor HER2/neu (ERBB2) status has made it possible to provide another form of targeted therapy linked to the overexpression of this protein. Presently, pathologists determine the receptor status in formalin-fixed, paraffin-embedded sections using subjective, semiquantitative immunohistochemistry (IHC) assays and quantitative fluorescence in situ hybridization for HER2.

Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature.

Background: Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times.

Methods: 197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects.

Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C.

Background & Aims: Previously identified clinical risk factors such as sex, alcohol consumption, and age at infection do not accurately predict which patients with chronic hepatitis C (CHC) will develop advanced fibrosis (bridging fibrosis and cirrhosis). The aim of this study was to identify genetic polymorphisms that can predict the risk of advanced fibrosis in patients with CHC.

Methods: A total of 916 subjects with CHC was enrolled from 2 centers.

Genome-based biomarkers for adverse drug effects, patient enrichment and prediction of drug response, and their incorporation into clinical trial design.

Classic examples of pharmacogenomic biomarkers for drug efficacy include genetic variation in the drug target (including its expression level) and drug metabolizing enzymes (DMEs). Recent US FDA approvals of tests for cytochrome P450 2D6/2C9 and uridine diphosphate glucuronsyltransferase (UGT)1A1 have given regulatory endorsement to biomarkers that can improve drug safety by identifying individuals at risk for drug toxicity. Markers that predict risk for disease can identify patients who will have a greater than average benefit from therapy.

Estrogen receptor genotypes and haplotypes associated with breast cancer risk.

Nearly one in eight US women will develop breast cancer in their lifetime. Most breast cancer is not associated with a hereditary syndrome, occurs in postmenopausal women, and is estrogen and progesterone receptor-positive. Estrogen exposure is an epidemiologic risk factor for breast cancer and estrogen is a potent mammary mitogen.

Implications of new proteomics strategies for biology and medicine.

Advances in proteomics have fundamentally changed the paradigm of discovery for drug targets and novel biomarkers. Proteomics methodologies currently used will be reviewed in this paper, including structural proteomics, quantitative proteomics, and functional proteomics. A strategy to identify differentially expressed cell surface proteins as monoclonal therapeutic targets in oncology will be discussed.

The human genome and comparative genomics: understanding human evolution, biology, and medicine.

The entire 2.9-billion-letter sequence (nucleotide base pairs) of the human genome is available as a resource for scientific discovery. Some of the findings from the completion of the human genome were expected, confirming knowledge anticipated by many years of research and analysis in both human and comparative genetics.

The genome sequence of the malaria mosquito Anopheles gambiae.

Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs.

Therapeutic horizons--the human genome.

The sequence of many genes has been conserved during evolution, offering insights into gene function and new opportunities for research in pharmacology and drug development. The many ethical issues surrounding genetics have the potent tial to halt the genomic revolution unless society strives to understand and resolve these issues. Advances in pharmacogenomics hold significant promise for improved health care, such as by enabling clinicians to select the optimal medications and dosages for individual patients.