A distinctive requirement for p53 in the genome protective Topoisomerase 2a-dependent G2 arrest in hTERT positive cancer cells

Topoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G2 arrest by determining that p53-p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G2 arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention.SignificanceThe identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality

End-Stage Dementia Spark of Life: Reliability and Validity of the "GATOS" Questionnaire

Background: Fl oor effects are present in most dementia assessment tools as dementia progresses and the in-depth assessment of patients considered more or less on vegetative state is questionable. Objective: To develop a questionnaire (the "Gatos Clinical Test-GCT") for the assessment of end-stage demented patients. Methods: Five hundred patients with dementia of various causes and an MMSE score between 0 and 2 were enrolled in the study. The GCT consists of 14 closed type questions rated on a Likert scale. The total score is used to evaluate patient's dementia. Various aspects of validity and reliability (including face, content and structural validity as well as test-retest reliability) were examined. Results: Three subscales "Autonomy/Alertness", "Gnosias" and "Somatokinetic function" were defined, with a Cronbach equal to 0.851, 0.756 and 0.598 respectively. The GCT subscales and total score were statistically significant higher in patients with MMSE score 1 or 2 compared with those with MMSE score 0 (p < 0.0005). Patients with GCT total score less than 12.5 had 75% probability to have zero MMSE score. Conclusion: The "GATOS" questionnaire is a valid and reliable test for patients with severe dementia, aiming at identification of those patients who could sustain some quality of life. It is a relatively short and easy to administer tool. As dementia prevalence is expected to rise further worldwide we believe that GCT could offer valuable services to health professionals, caregivers and patients

End-stage dementia spark of life: Reliability and validity of the “GATOS” questionnaire

Background: Floor effects are present in most dementia assessment tools as dementia progresses and the in–depth assessment of patients considered more or less on vegetative state is questionable. Objective: To develop a questionnaire (the “Gatos Clinical Test-GCT”) for the assessment of end-stage demented patients. Methods: Five hundred patients with dementia of various causes and an MMSE score between 0 and 2 were enrolled in the study. The GCT consists of 14 closed type questions rated on a Likert scale. The total score is used to evaluate patient’s dementia. Various aspects of validity and reliability (including face, content and structural validity as well as test-retest reliability) were examined. Results: Three subscales “Autonomy/Alertness”, “Gnosias” and “Somatokinetic function” were defined, with a Cronbach equal to 0.851, 0.756 and 0.598 respectively. The GCT subscales and total score were statistically significant higher in patients with MMSE score 1 or 2 compared with those with MMSE score 0 (p&lt;0.0005). Patients with GCT total score less than 12.5 had 75% probability to have zero MMSE score. Conclusion: The “GATOS” questionnaire is a valid and reliable test for patients with severe dementia, aiming at identification of those patients who could sustain some quality of life. It is a relatively short and easy to administer tool. As dementia prevalence is expected to rise further worldwide we believe that GCT could offer valuable services to health professionals, caregivers and patients. © 2015 Bentham Science Publishers

End-stage dementia spark of life: Reliability and validity of the “GATOS” questionnaire

Background: Floor effects are present in most dementia assessment tools as dementia progresses and the in–depth assessment of patients considered more or less on vegetative state is questionable. Objective: To develop a questionnaire (the “Gatos Clinical Test-GCT”) for the assessment of end-stage demented patients. Methods: Five hundred patients with dementia of various causes and an MMSE score between 0 and 2 were enrolled in the study. The GCT consists of 14 closed type questions rated on a Likert scale. The total score is used to evaluate patient’s dementia. Various aspects of validity and reliability (including face, content and structural validity as well as test-retest reliability) were examined. Results: Three subscales “Autonomy/Alertness”, “Gnosias” and “Somatokinetic function” were defined, with a Cronbach equal to 0.851, 0.756 and 0.598 respectively. The GCT subscales and total score were statistically significant higher in patients with MMSE score 1 or 2 compared with those with MMSE score 0 (p<0.0005). Patients with GCT total score less than 12.5 had 75% probability to have zero MMSE score. Conclusion: The “GATOS” questionnaire is a valid and reliable test for patients with severe dementia, aiming at identification of those patients who could sustain some quality of life. It is a relatively short and easy to administer tool. As dementia prevalence is expected to rise further worldwide we believe that GCT could offer valuable services to health professionals, caregivers and patients. © 2015 Bentham Science Publishers