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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

Next Generation Sequencing and the Management of Diffuse Large B-cell Lymphoma: From Whole Exome Analysis to Targeted Therapy

Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 30-40% of newly diagnosed non-Hodgkin lymphomas. Historically, DLBCL has been thought to involve recurrent translocations of the IGH gene and the deregulation of rearranged oncogenes. Recent advances in next generation sequencing (NGS) have provided a vast and comprehensive catalogue of cancer genes involved in DLBCL pathogenesis. Whole exome sequencing (WES) of more than two hundred DLBCLs has completely redefined the genetic landscape of the disease by identifying recurrent single nucleotide variants and providing new therapeutic opportunities for the germinal center B-cell like (GCB), activated B-cell like (ABC), or primary mediastinal B-cell (PMBL) molecular subtypes. Some of these somatic mutations target genes that play a crucial role in B-cell function (BCR signaling, NF-κB pathway, NOTCH signaling, Toll-like receptor signaling, and the PI3K pathway), immunity, cell cycle/apoptosis, or chromatin modification. In this review, we present an overview of the mutations recently discovered by NGS in DLBCL and discuss their biological relevance and possible impacts on clinical management. ... Read more

The Impact of New Genomic Technologies in Reproductive Medicine

Abstract: Recent advances in the clinical application of genomic technologies have significantly impacted the field of prenatal diagnosis. Central to these advances has been the implementation of chromosomal microarray analysis (CMA). Microdeletions and microduplications, undetectable by traditional karyotyping, have recently been confirmed to play a role in altered neurocognitive development. CMA is now recommended for fetuses with structural anomalies. However, CMA comes with an increased need and role for genetic counseling, because the potential genomic information available is exponentially increased. CMA also can be performed on a small number of preimplantation embryonic cells for assessment of the embryo's reproductive potential. Implementation of these new genomic techniques in an in vitro fertilization setting has already demonstrated significant improvements in reproductive outcome. Techniques are now being developed to eliminate the necessity for invasive prenatal diagnosis procedures. Currently in its infancy, noninvasive prenatal testing using cell-free fetal DNA from maternal blood has already improved the sensitivity for detection of the common aneuploidies and current efforts are focused on identifying select microdeletions. The explosion of new genomic technologies continues to offer great benefits. However, each needs critical assessment prior to adoption in a clinical setting. ... Read more

Inflammatory Disease and the Human Microbiome

Abstract: The human body is a superorganism in which thousands of microbial genomes continually interact with the human genome. A range of physical and neurological inflammatory diseases are now associated with shifts in microbiome composition. Seemingly disparate inflammatory conditions may arise from similar disruption of microbiome homeostasis. Intracellular pathogens long associated with inflammatory disease are able to slow the innate immune response by dysregulating activity of the VDR nuclear receptor. This facilitates the ability of other species to gradually accumulate in tissue and blood, where they generate proteins and metabolites that significantly interfere with the body’s metabolic processes. The microbes that contribute to this dysfunction are often inherited from family members. Immunosuppressive therapies for inflammatory disease allow pathogens driving these processes to spread with greater ease. In contrast to immunosuppression, treatments that stimulate the immune system seem to allow for reversal of this pathogen-induced genomic dysregulation. ... Read more

Rationale for Targeting the Ras/MAPK Pathway in Triple-Negative Breast Cancer

Abstract: "Triple negative" breast cancer (TNBC) is the most aggressive and least common clinical subtype of breast cancer. As its nomenclature implies, TNBC lacks specific biomarker expression marking response to an effective targeted therapy. The incidence of TNBC is higher in young minority women who suffer from high rates of early recurrence and death from their disease. Mounting preclinical evidence supports targeting the Ras/MAPK cell signaling pathway in the TNBC subtype, despite large genomic surveys such as The Cancer Genome Atlas demonstrating infrequent canonical mutations in this pathway. Due to the early spread of TNBC, targeted treatment in the neoadjuvant setting may offer the effective therapeutic punch needed to eliminate micro-metastatic disease and reduce mortality. Herein, we will review the evidence supporting clinical trials of targeted inhibitors of the Ras/MAPK pathway in TNBC, and discuss the obstacles and opportunities of this approach. ... 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

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

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

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