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Telomerase as therapeutic target for cancer: Rationale and concerns


How Molecular Profiling Is Transforming Drug Discovery

Abstract: Comparisons of gene and protein profiling between sickness and health offer tremendous opportunities for finding new drug targets and aiding clinical trial design, in addition to fueling promising expansion of advanced diagnostics. ... Read more

Non-coding RNAs and Cancer: New Paradigms in Oncology

Abstract: Over the last decade, a growing number of non-coding transcripts have been found to have roles in gene regulation and RNA processing. The most well known small non-coding RNAs (ncRNAs) are the microRNAs (miRNAs), but the network of long and short non-coding transcripts is complex and is likely to contain as yet unidentified classes of molecules that form transcriptional regulatory networks. miRNAs and some other ncRNAs have been found to be involved in human tumorigenesis, revealing a new layer in the molecular architecture of cancer. Gene expression studies have shown that hundreds of miRNAs are deregulated in cancer cells, and functional studies have clarified that miRNAs are involved in all the molecular and biologic processes that drive tumorigenesis. Here, we summarize the recent advances in understanding miRNAs' and other ncRNAs' involvement in cancer and illustrate how this knowledge may be useful in medical practice. New diagnostic classifiers based on miRNAs will soon be available for medical practitioners, and even more importantly, miRNAs may become novel anti-cancer therapies. ... Read more

Telomerase -- a Gold Mine of Drug Targets

Researchers have recently elucidated the 3-dimentional structure of telomerase, a molecule that plays a key role in such important areas as cancer, aging/longevity, immunology, and stem cells.

Each chromosome (containing a unit of the genome) has a telomere at each of its ends. Telomere, a stretch of DNA, protects the integrity and stability of the genome. A piece of telomere is “clipped” off each time a cell divides. Telomerase is the enzyme that makes more telomere to replenish the shortfall. When a person reaches adulthood, telomerase becomes inactive in most somatic cells (non-sex cells). Consequently, cells stop dividing and regeneration, and ... Read more

Pharmacogenomics in Childhood Rheumatic Disorders: A Foundation for Future Individualized Therapy

Abstract: Investigating the effect of genotype on drug response in children is an evolving field, with many challenges, but there is great potential to optimize safe and effective use of drugs in children. An exponential increase in available medications for use in children with rheumatic disease has opened seemingly endless genotype/phenotype relationships to explore, but challenges inherent in studying rare diseases and the often overlooked role of ontogeny contribute to limitations in pharmacogenomic studies in this population. With careful recognition of the importance of development, improved phenotyping with the incorporation of biomarkers, and expanding collaborative efforts on a national and even international scale, the field of pediatric rheumatology has the opportunity to strategically study the new therapeutic armamentarium available and provide individualized safe and effective therapies to our population of patients. ... Read more

Integration of Genomics into Medical Practice

Abstract: Although some have wondered whether the sequencing of the human genome has led to major advances in medicine, in fact there are multiple examples where genomics has been integrated into medical practice. In the area of prevention, genomic approaches are now used for non-invasive prenatal testing of fetal DNA in the maternal circulation, for expanded preconceptional screening for carrier status, for autosomal recessive disorders, and for assessment of risk of common disease. In the area of diagnosis, major advances have been made in cytogenomics and in use of whole exome or whole genome sequencing. In therapeutics, pharmacogenetic testing is now feasible, tumor genome sequencing is being used to guide cancer therapy, and genomic discoveries are enabling development of new targeted therapies. Ultimately it is possible that genome sequencing may be done for all individuals on a routine basis, though there remain significant technical, ethical, and medical systems challenges to be overcome. It is likely that integration of genomics into medical practice will occur gradually over a long period of time, but the process is now well underway. ... Read more

A Prospective, Randomized, Double-Blind Study Assessing the Clinical Impact of Integrated Pharmacogenomic Testing for Major Depressive Disorder

Abstract: Objective: A prospective double-blind randomized control trial (RCT) to evaluate the benefit of a combinatorial, five gene pharmacogenomic test and interpretive report (GeneSight) for the management of psychotropic medications used in the treatment of major depression in an outpatient psychiatric practice. Methods: Depressed adult outpatients were randomized to a treatment as usual (TAU, n=25) arm or a pharmacogenomic-informed GeneSight (n=26) arm. Subjects were blinded to their treatment group and depression severity was assessed by blinded study raters. Within two days of enrollment, clinicians of subjects in the guided group received the GeneSight report that categorized each of 26 psychotropic medications within a green, yellow, or red "bin" based on the relationship of each medication to a subject's pharmacokinetic and pharmacodynamic combinatorial gene variant profile. Antidepressant medication changes began within 2 weeks after baseline assessments. Depression severity was assessed by blinded study raters using the HAMD-17, PHQ-9, QIDS-SR, and QIDS-CR administered 4, 6, and 10 weeks after baseline assessment. Results: Between-group trends were observed with greater than double the likelihood of response and remission in the GeneSight group measured by HAMD-17 at week 10. Mean percent improvement in depressive symptoms on HAMD-17 was higher for the GeneSight group over TAU (30.8% vs 20.7%; p=0.28). TAU subjects who had been prescribed medications at baseline that were contraindicated based on the individual subject's genotype (i.e., red bin) had almost no improvement (0.8%) in depressive symptoms measured by HAMD-17 at week 10, which was far less than the 33.1% improvement (p=0.06) in the pharmacogenomic guided subjects who started on a red bin medication and the 26.4% improvement in GeneSight subjects overall (p=0.08). Conclusions: Pharmacogenomic-guided treatment with GeneSight doubles the likelihood of response in all patients with treatment resistant depression and identifies 30% of patients with severe gene-drug interactions who have the greatest improvement in depressive symptoms when switched to genetically suitable medication regimens. ... Read more

The Human Genome: Its Modifications and Interactions with Those of the Microbiome, and the Practice of Genomic Medicine

Abstract: In genomic medicine, the nuclear genome is usually the focus of discussion. However, recent developments in genomics show that our interaction with the biological world at large alters our susceptibility to disease and our response to drugs. For example, in addition to causing infection, the trillions of microbial cells that inhabit our bodies (our microbiome), are now known to shape our immune system and our metabolic health. Moreover, mitochondria, the long-assimilated symbionts, are the focus of considerable current genomic research that is making possible, interventions that were at one time in the realms of science fiction. Furthermore, genomics research of the cancer cell is sufficiently refined to enable us to define its genome as a distinct entity suitable for selective drug-targeting. In this contribution we discuss, within their historical contexts, some of these seemingly disparate scientific strands to highlight the importance of embracing a broader multiple-genomic vista when dealing with disease causation, prevention and management. ... Read more

RNA Interference and Personalized Cancer Therapy

Abstract: Despite billions of dollars allocated to cancer research, cancer remains the number 2 cause of death in the United States with less than 50% of advanced cancer patients living one year following standard treatment. Cancer is a complex disease both intrinsically and in relation to its host environment. From a molecular standpoint no two cancers are the same despite histotypic similarity. As evidenced by the recent advances in molecular biology, treatment for advanced cancer is headed towards specific targeting of vulnerable signaling nodes within the reconfigured pathways created by "omic" rewiring. With advancements in proteo-genomics and the capacity of bioinformatics, complex tumor biology can now be more effectively and rapidly analyzed to discover the vulnerable high information transfer nodes within individual tumors. RNA interference (RNAi) technology, with its capability to knock down the expression of targeted genes (the vulnerable nodes), is moving into the clinic to target these nodes, which are integral to tumor maintenance, with a low risk of side-effects and to block intrinsic immunosuppressors thereby priming the tumor for immune attack. An RNAi based sequential approach, a so called "one-two punch," is being advocated comprising tumor volume reduction (ideally to minimal residual disease status) effected by integrated multi-target knockdown followed by immune activation. Examples and recent developments are provided to illustrate this highly powerful approach heralding the future of personalized cancer therapy. ... Read more

Mitochondrial Disease Genetic Diagnostics: Optimized Whole-Exome Analysis for All MitoCarta Nuclear Genes and the Mitochondrial Genome

Abstract: Discovering causative genetic variants in individual cases of suspected mitochondrial disease requires interrogation of both the mitochondrial (mtDNA) and nuclear genomes. Whole-exome sequencing can support simultaneous dual-genome analysis, although currently available capture kits do not target the mtDNA genome and provide insufficient capture for some nuclear-encoded mitochondrial genes. To optimize interrogation of nuclear and mtDNA genes relevant to mitochondrial biology and disease, a custom SureSelect "Mito-Plus" whole-exome library was formulated by blending RNA "baits" from three separate designs: (A) Agilent Technologies SureSelectXT 50 Mb All Exon PLUS Targeted Enrichment Kit, (B) 16-gene nuclear panel targeting sequences for known MitoCarta proteins not included in the 50 Mb All Exon design, and (C) sequences targeting the entire mtDNA genome. The final custom formulations consisted of a 1:1 ratio of nuclear baits to which a 1 to 1,000-fold diluted ratio of mtDNA genome baits were blended. Patient sample capture libraries were paired-end sequenced on an Illumina HiSeq 2000 system using v3.0 SBS chemistry. mtDNA genome coverage varied depending on the mtDNA:nuclear blend ratio, where a 1:100 ratio provided optimal dual-genome coverage with 10X coverage for over 97.5% of all targeted nuclear regions and 1,000X coverage for 99.8% of the mtDNA genome. mtDNA mutations were reliably detected to at least an 8% heteroplasmy level, as discriminated both from sequencing errors and potential contamination from nuclear mtDNA transcripts (Numts). The "1:100 Mito-Plus Whole-Exome" Agilent capture kit offers an optimized tool for whole-exome analysis of nuclear and mtDNA genes relevant to the diagnostic evaluation of mitochondrial disease. ... Read more

The Impact of Antibiotics on the Gut Microbiota as Revealed by High Throughput DNA Sequencing

Abstract: Treatment with broad spectrum antibiotics can have a detrimental impact on the commensal bacteria present in the gut. The extensive nature of the collateral damage caused by such compounds has been revealed more starkly than ever before through the application of high throughput DNA sequencing-based technologies to investigate resulting microbial populations. Here we review the findings of such studies and discuss the strategies available to minimize such negative impacts. ... Read more

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