Exposure to genotoxic agents is a major cause of human cancer, and cellular responses to genotoxic stress are important defense mechanisms. These responses are very complex, involving many cellular factors that form an extensive signal transduction network. This network includes a protein kinase cascade that connects the detection of DNA damage to the activation of transcription factors, which in turn regulate the expression of genes involved in DNA repair, cell cycle arrest and programmed cell death (apoptosis). The mitogen-activated protein kinases are the best-studied members of the kinase cascade with an acknowledged role in the genotoxic stress response. However, the initial activation of the protein kinase cascade is not fully understood, although several protein kinases, such as ataxia telangiectasia, mutated (ATM), ATM- and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK) in humans, are increasingly recognized for their potential roles in the sensing of DNA damage and initiating the subsequent protein kinase cascade. In this review, the properties of these three kinases are discussed and their functions in the initiation of the genotoxic stress response are explored.

Cellular response to genotoxic stress is a very complex process, and it usually starts with the "sensing" or "detection" of the DNA damage, followed by a series of events that include signal transduction and activation of transcription factors. The activated transcription factors induce expressions of many genes which are involved in cellular functions such as DNA repair, cell cycle arrest, and cell death. There have been extensive studies from multiple disciplines exploring the mechanisms of cellular genotoxic responses, which have resulted in the identification of many cellular components involved in this process, including the mitogen-activated protein kinases (MAPKs) cascade. Although the initial activation of protein kinase cascade is not fully understood, human protein kinases ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) are emerging as potential sensors of DNA damage. Current progresses in ATM/ATR research and related signaling pathways are discussed in this review, in an effort to facilitate a better understanding of genotoxic stress response.

OBJECTIVE -Population-level strategies may improve primary care for diabetes. We designed a controlled study to assess the impact of population management versus usual care on metabolic risk factor testing and management in patients with type 2 diabetes. We also identified potential patient-related barriers to effective diabetes management.RESEARCH DESIGN AND METHODS -We used novel clinical software to rank 910 patients in a diabetes registry at a single primary care clinic and thereby identify the 149 patients with the highest HbA 1c and cholesterol levels. After review of the medical records of these 149 patients, evidence-based guideline recommendations regarding metabolic testing and management were sent via e-mail to each intervention patient's primary care provider (PCP). Over a 3-month follow-up period, we assessed changes in the evidence-based management of intervention patients compared with a matched cohort of control patients receiving usual care at a second primary care clinic affiliated with the same academic medical center.RESULTS -In the intervention cohort, PCPs followed testing recommendations more often (78%) than therapeutic change recommendations (36%, P ϭ 0.001). Compared with the usual care control cohort, population management resulted in a greater overall proportion of evidencebased guideline practices being followed (59 vs. 45%, P ϭ 0.02). Most intervention patients (62%) had potential barriers to effective care, including depression (35%), substance abuse (26%), and prior nonadherence to care plans (18%).CONCLUSIONS -Population management with clinical recommendations sent to PCPs had a modest but statistically significant impact on the evidence-based management of diabetes compared with usual care. Depression and substance abuse are prevalent patient-level adherence barriers in patients with poor metabolic control. Diabetes Care 26:2275-2280, 2003M anagement of type 2 diabetes in the U.S. is expensive (representing 25% of the Medicare budget) (1), complex (patients often have hypertension, hyperlipidemia, and other comorbidities) (2-4), and generally falls short of evidence-based goals (most diabetic patients do not reach recommended levels of glycemic, blood pressure, or cholesterol control) (5,6). Patient-related factors such as adherence to medications and healthy lifestyle changes and societal factors such as costs and access to care are important but difficult-to-modify elements of diabetes management (7-10). In contrast, interventions directed toward primary care providers (PCPs) may be more likely to improve quality of diabetes care (11,12).Prior interventions to improve quality of care by changing physician practice patterns have mostly been either physician-centered (e.g., intensive academic detailing, physician report cards) (13-15) or patient-specific and centered on clinic visits (e.g., computerized reminder systems) (12,16 -20). In contrast, population-based diabetes management takes an overview perspective to monitor and deliver patient care (21,22). Population management...

No abstract