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Predicting Outcomes for Children with Neuroblastoma

Oncolytic Virotherapy for Neuroblastoma

Abstract: Metastatic neuroblastoma (NB) remains a clinical challenge for pediatric oncologists. Overall survival rates stay less than 40% despite intensive multimodal therapy, with the toll of toxicity being related to high-dose chemotherapy. These rates have shown minor improvements over the last years, and the development of newer therapeutic strategies is necessary. Oncolytic viruses bear the promise of killing cancer cells with low toxicities to healthy tissues. Acting through mechanisms different from chemo- and radiotherapies, a growing arsenal of genetically engineered viruses is being tested in preclinical models of human cancers. Viral infection and selective replication inside tumor cells are achieved by modification of the virus genome in order to target specific molecules or signal transduction pathways of cancer. Cell death may also activate antitumor immune responses to further amplify the beneficial effects. Clinical trials in humans have been conducted and initial results have been reported, giving the first glance of information on safety and efficacy in patients. In this review we will summarize information about how oncolytic virotherapy is being evaluated against NB in preclinical models and recent reports on the use of this new therapy in sporadic cases of children with refractory NB. ... Read more

Pharmacogenetic Mechanisms Underlying Unanticipated Drug Responses

Abstract: Because most medicines have not been encountered by individuals of our species prior to treatment, it follows that treatment could uncover a previously silent genetic predisposition or could interact with a known genetic variation(s) to produce an unintended outcome. Pharmacogenetics encompasses the discovery, testing, and application of genetic variation as applied to therapeutic treatment and outcome. Two broad divisions of pharmacogenetics are recognized: pharmacokinetics, which describes genetic variations that affect drug metabolism, and pharmacodynamics which describes similar processes that have effects on drug targets, including downstream signaling pathways. The genetic mechanisms that underlie an altered drug response recapitulates most known sources of genomic variation. The most commonly encountered is sequence variation. This includes changes in the primary nucleotide sequence of coding, regulatory, and splice regions of a gene, the product of which affects, or is affected by, a drug. Less common forms of variability in the structure and function of the genome have also been found to underlie an individualized response to medicines. Among these are sequence variation in microRNA (miRNA) binding sites, which affects the ability of miRNA to regulate translation; pharmacoepigenetics, which examines heritable chromatin modifications; and copy number variation. Among the 158 currently registered pharmacogenetic clinical trials, the most frequent conditions or disease processes being studied are cancer, psychiatric disorders, and coagulation/thrombosis. From this observation, it is postulated that pharmacogenetics has its greatest potential for optimizing the use of drugs with a high rate of failure or adverse outcomes. ... Read more

The Multidimensional Nature of Epigenetic Information and Its Role in Disease

Abstract: This year marks the 10th anniversary of the publications that reported the initial human genome sequence. In the historic press conference that announced this landmark accomplishment, it was proclaimed that the genome sequence would "revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases." However, subsequent work over the past decade has revealed that "complex diseases" are much more intricate than originally thought. Even with the advent of several new powerful technologies, our understanding of the underlying genetic etiologies of most complex and non-Mendelian diseases is far from complete. These results have raised the possibility that the DNA sequence, i.e., genetic information, may not be the only relevant source of information in order to understand the molecular basis of disease. In this review, we assemble evidence that information encoded beyond the DNA sequence, i.e., epigenetic information, may hold the key to a better understanding of various pathological conditions. Unlike the genetic information encoded within the DNA sequence, epigenetic information can be stored in multiple dimensions, such as in the form of DNA modifications, RNA, or protein. Ideas presented here support the view that to better understand the molecular etiology of diseases, we need to gain a better understanding of both the genetic and epigenetic components of biological information. We hence believe that the fast development of genome-wide technologies will facilitate a better understanding of both genetic and epigenetic dimensions of disease. ... Read more

Epigenetic Regulation of Aging

Abstract: Aging is one of the most challenging and unresolved problems in biology owing to its highly complex nature. Public interest in aging has increased not only because all of us can expect to live to a ripe old age but also because we wish to avoid those age-related changes that lead to physical invalidity or other diseases (cancer, depression) and may ultimately cause social isolation. Aging is a process of genetic and epigenetic interactions at all biological levels, where epigenetics has an important function in determining the phenotypic differences that arise. Epigenetics also plays a key role in the development of diseases associated with aging and explains the relationship between an individual's genetic background, the environment, aging, and disease. DNA plasticity is mediated in part by the epigenetic changes that lead the role of a cell, and can be passed on to future generations. Epigenetics establishes the idea that our health can be affected not only by the interplay of our genes and environment but also by the inherited effects of our ancestors' genes and environment. ... Read more

MicroRNAs in Chromosomal Translocation-associated Solid Tumors: Learning from Sarcomas

Abstract: Sarcomas are malignant solid tumors of mesenchymal origin which consist of 10-15% of all pediatric malignancies and associated with significantly high mortality rates despite current therapies. Oncogenic fusion genes, resulting from non-random chromosomal translocations, characterize a subset of sarcomas including rhabdomyosarcoma, the Ewing's sarcoma family of tumors, and synovial sarcoma. As investigators gain further insight into the role that fusion genes play in the development and progression of sarcomas, we are slowly uncovering novel molecules and pathways that are proving to be essential for the growth and maintenance of sarcomas and other malignancies. MicroRNAs (miRs) have been implicated in a diversity of human diseases including cancer. Only recently, has miR deregulation been shown to be an important component of sarcomagenesis. This review summarizes the recent discoveries tying miR deregulation to sarcoma biology and will discuss the potential and feasibility of miRs as novel therapeutic adjuncts to current therapies. The methodological approaches utilized in the study of miR biology and development of miR-based treatment regimens can serve as a paradigm for future investigations in other translocation-associated solid tumors. ... Read more

Hematopoietic Cell Transplantation in Chronic Myeloid Leukemia in the Age of Tyrosine Kinase Inhibitors

Abstract: The development and widespread use of tyrosine kinase inhibitors (TKIs) has relegated the use of hematopoietic cell transplant (HCT), in most countries, to chronic myeloid leukemia (CML) patients who fail or are intolerant to TKIs. Its long-term cost effectiveness compared to TKIs, however, has maintained its use as front-line treatment in some areas. Advances in HCT, including the development of intravenous busulfan and plasma assays permitting dose adjustment, have improved results of HCT in CML. Improved supportive care has lowered the incidence of non-relapse mortality and improved survival. The availability of reduced-intensity preparative regimens, molecular typing of unrelated donors, and the use of cord blood and haploidentical donors has expanded the application of HCT to nearly any patient with an appropriate indication. From 2006 to 2010, approximately one thousand HCTs were performed annually in patients with CML. Better understanding of recent advances will improve the appropriate use and results of HCT in patients with CML. ... Read more

CHFR Methylation Strongly Correlates with Methylation of DNA Damage Repair and Apoptotic Pathway Genes in Non-Small Cell Lung Cancer

Abstract: DNA methylation occurs commonly in non-small cell lung cancer (NSCLC). We sought to determine the frequency and relationship of methylation of key genes involved in the pathways of mitotic checkpoint control, DNA damage repair, apoptosis, and growth factor signaling in these patients. We analyzed the DNA methylation status of eight genes (CHFR, FANCF, MGMT, p16, DAPK, ASC or TMS-1, RAR-B, and CRBP1) using nested methylation-specific PCR (MSP) on over 314 paraffin-embedded, human non-small cell lung cancer samples. We determined the methylation frequency of each gene in addition to the association of the methylation of each gene with other members of the panel. Methylation was a common event in these samples. Our methylation analysis showed frequencies of methylation of 10% for CHFR, 14% for FANCF, 30% for MGMT, 29% for p16, 17% for DAPK, 33% for ASC, 38% for RAR-B, and 7% for CRBP1. There was a strong correlation between methylation of the mitotic G2-M checkpoint gene, CHFR, and methylation of other genes in our panel involved in DNA damage repair (FANCF and MGMT) and apoptosis (DAPK and ASC) but not with other genes in our panel, including p16 (the G1-S checkpoint gene), CRBP1, or RAR-B. In addition, MGMT methylation strongly correlated with the pro-apoptotic gene, ASC. There are distinct associations of methylated genes in non-small cell lung cancer involving DNA damage repair, apoptosis, and the G2-M mitotic checkpoint control. Further studies are warranted to determine whether these methylation patterns have implications for prognosis in addition to prediction of response to chemotherapeutic agents commonly used in the treatment of non-small cell lung cancer, such as radiotherapy and platinum- or taxane-based chemotherapy. ... Read more

Epigenetics in Atherosclerosis: a Clinical Perspective

Abstract: Significant progress has been made in understanding in the pathogenesis of atherosclerosis. Nevertheless, atherosclerosis remains a great threat to human health worldwide. Epigenetic mechanisms, which involve DNA methylation, histone modification, and microRNA, have significantly enhanced our understanding of the pathological process of atherosclerosis. More importantly, epigenetic processes (in contrast to genetic alterations) are reversible and thus provide a potential therapeutic target in atherosclerosis treatment. Both in vitro and in vivo studies using drugs targeting enzymes involved in epigenetic modifications have shown considerable promise in atherosclerosis treatment. This review aims to present an overview of current epigenetic mechanisms involved in the pathogenesis of atherosclerosis, and discuss points in these processes where therapeutic interventions likely bear fruition. ... Read more

Exome Sequencing on Malignant Meningiomas Identified Mutations in Neurofibromatosis Type 2 (NF2) and Meningioma 1 (MN1) Genes

Abstract: Background: Meningiomas are tumors originating from the membranous layers surrounding the central nervous system, and are generally regarded as "benign" tumors of the brain. Malignant meningiomas are rare and are typically associated with a higher risk of local tumor recurrence and a poorer prognosis (median survival time <2 years). Previous genome-wide association studies and exome sequencing studies have identified genes that play a role in susceptibility to meningiomas, but these studies did not focus specifically on malignant tumors. Methods: We performed exome sequencing on five malignant meningiomas on the Illumina HiSeq2000 platform using Agilent SureSelect Human All Exon kits. We used wANNOVAR web server to annotate and prioritize variants, identified candidate genes with recurrent mutations, and validated selected mutations by Sanger sequencing. We next designed custom NimbleGen targeted region arrays on five candidate genes, and sequenced four additional malignant meningiomas. Results: From exome sequencing data, we identified several frequently mutated genes including NF2, MN1, ARID1B, SEMA4D, and MUC2, with private mutations in tumors. We sequenced these genes in four additional samples and identified potential driver mutations in NF2 (neurofibromatosis type 2) and MN1 (meningioma 1). Conclusions: We confirmed that mutations in NF2 may play a role in progression of meningiomas, and nominated MN1 as a candidate gene for malignant transformation of meningiomas. Our sample size is limited by the extreme rarity of malignant meningiomas, but our study represents one of the first sequencing studies focusing on the malignant subtype. ... 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

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