Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint

The ATR-dependent DNA damage response pathway can respond to a diverse group of lesions as well as inhibitors of DNA replication. Using the Xenopus egg extract system, we show that lesions induced by UV irradiation and cis-platinum cause the functional uncoupling of MCM helicase and DNA polymerase activities, an event previously shown for aphidicolin. Inhibition of uncoupling during elongation with inhibitors of MCM7 or Cdc45, a putative helicase cofactor, results in abrogation of Chk1 phosphorylation, indicating that uncoupling is necessary for activation of the checkpoint. However, uncoupling is not sufficient for checkpoint activation, and DNA synthesis by Polalpha is also required. Finally, using plasmids of varying size, we demonstrate that all of the unwound DNA generated at a stalled replication fork can contribute to the level of Chk1 phosphorylation, suggesting that uncoupling amplifies checkpoint signaling at each individual replication fork. Taken together, these observations indicate that functional uncoupling of MCM helicase and DNA polymerase activities occurs in response to multiple forms of DNA damage and that there is a general mechanism for generation of the checkpoint-activating signal following DNA damage.     

Effect of a cognitive behavioral intervention on reducing symptom severity during chemotherapy.

PURPOSE: To describe a randomized trial of a cognitive behavioral intervention on reducing symptom severity among patients diagnosed with solid tumors and undergoing a first course of chemotherapy and to determine whether the intervention had an additive or interactive effect on symptom severity in the presence of supportive care medications. PATIENTS AND METHODS: Patients (N = 237) were accrued from comprehensive and community cancer centers, interviewed, and randomly assigned to either the experimental intervention (n = 118) or conventional care (n = 119). A symptom severity index, based on summed severity scores across 15 symptoms, was the primary outcome. Each patient's site of cancer, stage at diagnosis, chemotherapy protocols, and use of supportive medications were learned from medical records. RESULTS: Groups were equivalent at baseline, and attrition by characteristics by group was not different. The proportion of patients not receiving chemotherapy at 10 and 20 weeks did not differ by group. At the 10- and 20-week observations, there was a significant interaction between the experimental group and baseline symptom severity. Patients in the experimental group who entered the trial with higher symptom severity reported significantly lower severity at 10 and 20 weeks. Controlling for chemotherapy treatment status at follow-up and supportive care medications did not alter the effect of the experimental intervention. CONCLUSION: Compared with conventional care alone, the experimental intervention was effective among patients who entered the trial with higher levels of symptom severity. Age, sex, site or stage of cancer, and supportive medications did not modify the effect of this cognitive behavioral intervention on symptom severity.     

DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome

Juvenile ciliopathy syndromes that are associated with renal cysts and premature renal failure are commonly the result of mutations in the gene encoding centrosomal protein CEP290. In addition to centrosomes and the transition zone at the base of the primary cilium, CEP290 also localizes to the nucleus; however, the nuclear function of CEP290 is unknown. Here, we demonstrate that reduction of cellular CEP290 in primary human and mouse kidney cells as well as in zebrafish embryos leads to enhanced DNA damage signaling and accumulation of DNA breaks ex vivo and in vivo. Compared with those from WT mice, primary kidney cells from Cep290-deficient mice exhibited supernumerary centrioles, decreased replication fork velocity, fork asymmetry, and increased levels of cyclin-dependent kinases (CDKs). Treatment of Cep290-deficient cells with CDK inhibitors rescued DNA damage and centriole number. Moreover, the loss of primary cilia that results from CEP290 dysfunction was rescued in 3D cell culture spheroids of primary murine kidney cells after exposure to CDK inhibitors. Together, our results provide a link between CEP290 and DNA replication stress and suggest CDK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes.     

"Black swan in the kidney": renal involvement in the antiphospholipid antibody syndrome

The antiphosphospholipid antibody syndrome (APS) describes a clinical entity with recurrent thrombosis, fetal loss, thrombocytopenia in the presence of lupus anticoagulant and/or antibodies to cardiolipin. These antibodies may be associated with connective tissue diseases such as systemic lupus erythematosus (secondary APS) or be found in isolation (primary APS). Renal syndromes increasingly being reported in association with these antibodies include thrombotic microangiopathy, renal vein thrombosis, renal infarction, renal artery stenosis and/or malignant hypertension, increased allograft vascular thrombosis, and reduced survival of renal allografts. Although much has been understood concerning the biology of these antibodies and the pathogenesis of thrombosis, the optimal therapy remains to be elucidated. This article presents a historical review of the renal involvement in the antiphospholipid syndrome and discusses therapeutic options. Further research is needed.     

Cumulative meta-analysis of the relationship between useful field of view and driving performance in older adults: current and future implications.

PURPOSE: Driving is a complex behavior that requires the utilization of a wide range of individual abilities. Identifying assessments that not only capture individual differences, but also are related to older adults' driving performance would be beneficial. This investigation examines the relationship between the Useful Field of View (UFOV) assessment and objective measures of retrospective or concurrent driving performance, including state-recorded accidents, on-road driving, and driving simulator performance. METHOD: The PubMed and PsycINFO databases were searched to retrieve eight studies that reported bivariate relationships between UFOV and these objective driving measures. Cumulative meta-analysis techniques were used to combine the effect sizes in an attempt to determine whether the strength of the relationship was stable across studies and to assess whether a sufficient number of studies have been conducted to validate the relationship between UFOV and driving performance. RESULTS: A within-group homogeneity of effect sizes test revealed that the samples could be thought of as being drawn from the same population, Q [7] = 11.29, p (one-tailed) = 0.13. Therefore, the effect sizes of eight studies were combined for the present cumulative meta-analysis. The weighted mean effect size across the studies revealed a large effect (Cohen's d = 0.945), with poorer UFOV performance associated with negative driving outcomes. This relationship was robust across multiple indices of driving performance and several research laboratories. CONCLUSIONS: This convergence of evidence across numerous studies using different methodologies confirms the importance of the UFOV assessment as a valid and reliable index of driving performance and safety. Recent prospective studies have confirmed a relationship between UFOV performance and future crashes, further supporting the use of this instrument as a potential screening measure for at-risk older drivers.     

Taking CHARGE: A self-management program for women following breast cancer treatment

The purpose of the study was to develop and evaluate Taking CHARGE, a self-management intervention designed to facilitate successful transitions to survivorship after breast cancer treatment. The Taking CHARGE intervention involves a two-pronged approach building on self-regulation principles to (1) equip women with self-management skills to address concerns following breast cancer treatment, and (2) provide information about common survivorship topics. The program involved four intervention contacts, two small group meetings and two individualized telephone sessions, delivered by nurse/health educators. This paper focuses on the process evaluation findings from a preliminary test of the Taking CHARGE intervention conducted with 25 women, aged 34-66 years, completing breast cancer treatment, who were randomly assigned to the intervention group. The process evaluation was conducted to obtain systematic information about the relevance and usefulness of the self-regulation approach, informational aspects, and program delivery. The findings indicated that intervention group participants found the Taking CHARGE program to be timely, relevant, and to have high utility in dealing with concerns that exist following breast cancer treatment. The process evaluation findings provide early evidence of the usefulness of the Taking CHARGE intervention for successful transition to survivorship following breast cancer treatment.     

Reliability and validity of useful field of view test scores as administered by personal computer

The Useful Field of View test (UFOV(1)) is a measure of processing speed that predicts driving performance and other functional abilities in older adults. In comparison to a number of other visual and cognitive measures, the UFOV measure has consistently been found to be the strongest predictor of motor vehicle crashes of older adults. This measure has valuable applications in that computerized, performance-based measures that are predictive of crashes in the elderly population can provide an objective criterion for determining the need for driver restriction or rehabilitation. Administration of the UFOV test has evolved from the standard version (administered via touch-screen with the Visual Attention Analyzer) to two briefer versions, which are administered on a personal desktop computer (PC) using either a touch screen or mouse response option. These new versions of the test are briefer and require less specialized equipment, making the test more portable and practical for use in clinical settings. This study examined the reliability and validity of the scores from these two new versions. Results indicate that test-retest reliabilities of the scores from the UFOV PC versions are high (r's= 0 .884 for mouse and 0.735 for touch), and performance on both PC versions correlates well with performance on the standard version (r's = 0.658 for mouse and 0.746 for touch). Furthermore, scores were highly correlated (r = 0.916) when participants used either a touch screen or a mouse to input responses. In conclusion, the reliability and validity coefficients are of sufficient magnitude to make the touch and mouse PC versions of the UFOV practical for use in clinical evaluations.