Background and Significance. The human genome comprises three billion base pairs of DNA. In order to sequence the entire genome, a phased approach has been implemented by the NIH and DOE. The first requirement is the production of a conceptual array of large contiguous DNA sequences (large insert clones) spanning the 23 chromosomes. These "physical maps" must accurately represent the human genome and be in a form amenable to DNA sequencing. To make these physical maps amenable to sequencing, the individual large-insert clones will be further sub-divided into templates (either physically by subcloning or by primer walking) for direct DNA sequencing. Once the precise sequence of these templates is determined (by Sanger sequencing and fluorescent detection) they will be "assembled" into accurate ("finished" sequence) virtual representations of the original large-insert clones. The sequences of these large-insert clones are then assembled to form the full finished sequence of the human genome.
Background and Significance. Provide supporting information for justifying why the proposed work needs to be done. Provide any preliminary data or other documentation that supports the need for the project actions. If attachments are needed, upload them separately from this work plan.
Background and Significance. The background and significance section responds to PCORI Methodology Standard 1:RQ-1 “Gap analysis to support the need for the proposed study”.1
Background and Significance. 1 Source of exposures to lead, cadmium, and arsenic in children 1 Source of exposures to lead, cadmium, and arsenic in southern Thailand 3 Health effects of lead, cadmium, and arsenic in children 6 Human biomonitoring and biomarkers of lead, cadmium, and arsenic exposures 8 Hypotheses 11
Background and Significance. Type 1 diabetes is the immune mediated form of diabetes. It is an autoimmune disease that is organ specific for the pancreatic beta cells. The disease pathogenesis involves T-cell infiltration into the islets of the pancreas, which subsequently destroy the insulin producing cells, and result in overt symptoms of disease (1). Currently there is no known cure for TID and treatment for the disease consists of lifelong administration of insulin. Despite treatment with insulin therapy long-term complications, including nephropathy, retinopathy, neuropathy, and cardiovascular disease, can result. While the progress to complete insulin dependence can occur quickly after clinical onset, initially after diagnosis the pancreas is able to produce a significant amount of insulin (the “honeymoon” period) (2-5). During this state, the patient will have less glucose variability. The Diabetes Control and Complications Trial (DCCT) found that 20% of patients studied, who were within 5 years of diagnosis, had remaining insulin production (2-5 pmol/ml) (6). At this time immunologic intervention can potentially save beta cell function and reduce reliance on insulin. With the increasing incidence of TID, therapies aimed at altering the underlying autoimmune process need to be investigated. Even partial beta cell function is beneficial as patients that maintain endogenous insulin production have better metabolic control than those who rely solely on exogenous insulin (3), and improved metabolic control reduces the long-term complications from diabetes (7). Therapies that halt beta cell destruction would result in continued endogenous insulin production, greatly improving the metabolic control and prevalence of complications in TID. Currently, there are no treatments available for preservation of insulin production outside of research studies. Previously, the combination of cyclosporine and azothioprine plus glucocorticoids was studied and found to have unfavorable side effect profiles. Studies using anti-CD3 monoclonal antibodies have demonstrated the ability to slow the beta cell destruction in recent onset T1D (8-10). Again, the anti-CD3 studies also had serious adverse events and induce immunosuppression. Several antigen studies are also under way. Previously, antigen therapy with oral insulin demonstrated a delay in onset of T1D in subjects at increased risk for developing T1D (11). Presently, this study is being replicated. Several other antigens are also being studied in ...
Background and Significance. C. Related Previous Studies ..
Background and Significance. Research Design and Methods including statistical analysis ................................ ................................ ................................ ..................
Background and Significance. Briefly sketch the background leading to the present application, critically evaluate existing knowledge, and specifically identify the gaps the proposed project is intended to fill. State concisely the importance and Pediatric Health relevance of the res earch described in this application by relating the specific aims to the broad, long -term objectives.
Background and Significance. Pancreatic adenocarcinoma affects approximately 10 per 100,000 persons annually in the United States, and is the fourth leading cause of cancer related-mortality,1-3 occurring in approximately 43,140 patients per year (2010), with 36,800 patients expected to die in the US from the disease. Pancreatic cancer is generally diagnosed in advanced stages, with a 5-year survival rate of 1.3-3%.4 It is known that 30% of all human cancers have a RAS allele activated by mutation. At least 93% of pancreatic cancers have the identical position 12-activating mutation in the K-RAS gene. We previously discovered that over-activity of RAS signaling sensitizes tumor cells to apoptosis when PKCδ activity is suppressed, and this effect can be exploited as a targeted cancer therapeutic. We have demonstrated that mutated, constitutively-activated RAS is lethal to the cell unless a survival pathway, also driven by Ras, is active.5-14 Over-activity of RAS signaling sensitizes tumor cells to apoptosis when PKCδ activity is suppressed. We have shown that this cancer-specific susceptibility can be exploited as a targeted cancer therapeutic.15 Importantly, PKCδ inhibition is not toxic to cells with normal levels of RAS activity. Unlike the classical PKC isozymes, PKCδ is not required for the survival of normal cells, and its inhibition or down-regulation in normal cells and organisms has no adverse effects.5-8 Inhibition of PKCδ by a variety of means in human and murine cells containing a mutated, activated RAS allelle, however, initiates rapid and profound apoptosis.5 This molecular approach, targeting tumor cells containing a mutated oncogenic protein (and sparing normal cells), by altering a second protein or its activity required for survival of the tumor (“non-oncogene addiction”) is now sometimes termed “synthetic lethality.” While activation of Ras itself renders tumor cells absolutely dependent upon PKCδ activity, aberrant activation of Ras effector pathways such as the Raf/Mek pathway causes the same sensitization. Up to 70% of melanomas have activating mutations of Raf. We have shown that Raf mutant melanoma cells are dependent upon PKCδ for survival and our inhibitors are extremely cytotoxic to these cells. Very recently, a Raf inhibitor has been approved for the treatment of Raf-mutant melanomas. While demonstrating unprecedented activity against these tumors, resistance and relapse invariably occurs within 6-8 months. These resistant tumors have developed activating mut...
Background and Significance. Introduction The systolic and diastolic blood pressures have a strong, continuous and significant effect on the development of cardiovascular disease in the future. This significant association has been proven in many epidemiological studies done on patients with optimal or high blood pressure (Xxxxxxx Xxxxxxxxxxx & Subcommittee, 2015) (Xxxx Xxxxxxx MD, 1988) (Xxxxx
