4HPR-X radiation mechanisms of interactions in non-small cell lung cancer (NSCLC) cells in vitro

Lung cancer is the leading cause of cancer death. However, poor survival using conventional therapies fuel the search for more rational interventions. The objective of this study was to design and implement a 4HPR-radiation interaction model in NSCLC, employing a traditional clinical modality (radiation), a relatively new, therapeutically unexplored agent (4HPR) and rationally combining them based on molecular mechanistic findings pertaining to their interactions. To test the hypothesis that 4HPR sensitizes cells to radiation-induced cell death via G2+M accumulation, we designed a working model consisting of H522 adenocarcinoma cells (p53, K-ras mutated) derived from an NSCLC patient; 4HPR at concentrations up to 10 μM; and X radiation up to 6 Gy generated by a patient-dedicated Phillips RT-250 X ray unit at 250 KV, 15 mA, 1.85 Gy/min. We found that 4HPR produced time- and dose-dependent morphological changes, growth inhibition, and DNA damage-inducing enhancement of reactive oxygen species. A transient G2+M accumulation of cells maximal at 24 h of continuous 4HPR exposure was used for irradiation time scheduling. Our data demonstrated enhanced cell death (both apoptotic and necrotic) in irradiated cells pre-treated with 4HPR versus those with either stressor alone. 4HPR's effect of increased NSCLC cells' radioresponse was confirmed by clonogenic assay. To explore these practical findings from a molecular mechanistic perspective, we further investigated and showed that levels of cyclin B1 and p34cdc2 kinase—both components of the mitosis promoting factor (MPF) regulating the G2/M transition—did not change following 4HPR treatment. Likewise, cdc25C phosphatase was not altered. However, enhanced p34cdc2 phosphorylation on its Thr14Tyr15 residues—indicative of its inactivation and increased expression of MPF negative regulators chk1 and wee1 kinases—were supportive of explaining 4HPR-treated cells' accumulation. Hence, p34cdc2 phosphorylation, chk1, and wee1 warrant further evaluation as potential molecular targets for 4HPR-X radiation combination. In summary, we (1) demonstrated that 4HPR not only induces cell death by itself, but also increases NSCLC cells' subsequent radioresponse, indicative of potential clinical applicability, and (2) for the first time, shed light on deciphering 4HPR-X radiation molecular mechanisms of interaction, including the finding of 4HPR's role as a p34cdc2 inactivator via Thr14Tyr15 phosphorylation. ^

Contribution of activity and skin temperature to the risk of developing pressure ulcers in nursing facility residents

Purpose. The central concepts in pressure ulcer risk are exposure to external pressure caused by inactivity and tissue tolerance to pressure, a factor closely related to blood flow. Inactivity measures are effective in predicting pressure ulcer risk. The purpose of the study is to evaluate whether a physiological measure of skin blood flow improves pressure ulcer risk prediction. Skin temperature regularity and self-similarity, as proxy measures of blood flow, and not previously described, may be undefined pressure ulcer risk factors. The specific aims were to determine whether a sample of nursing facility residents at high risk of pressure ulcers classified using the Braden Scale for Pressure Sore Risk© differ from a sample of low risk residents according to (1) exposure to external pressure as measured by resident activity, (2) tissue tolerance to external pressure as measured by skin temperature, and (3) skin temperature fluctuations and recovery in response to a commonly occurring stressor, bathing and additionally whether (4) scores on the Braden Scale mobility subscale score are related to entropy and the spectral exponent. ^ Methods. A two group observational time series design was used to describe activity and skin temperature regularity and self-similarity, calculating entropy and the spectral exponent using detrended fluctuation analysis respectively. Twenty nursing facility residents wore activity and skin temperature monitors for one week. One bathing episode was observed as a commonly occurring stressor for skin temperature.^ Results. Skin temperature multiscale entropy (MSE), F(1, 17) = 5.55, p = .031, the skin temperature spectral exponent, F(1, 17) = 6.19, p = .023, and the activity mean MSE, F(1, 18) = 4.52, p = .048 differentiated the risk groups. The change in skin temperature entropy during bathing was significant, t(16) = 2.55, p = .021, (95% CI, .04-.40). Multiscale entropy for skin temperature was lowest in those who developed pressure ulcers, F(1, 18) = 35.14, p < .001.^ Conclusions. This study supports the tissue tolerance component of the Braden and Bergstrom conceptual framework and shows differences in skin temperature multiscale entropy between pressure ulcer risk categories, pressure ulcer outcome, and during a commonly occurring stressor. ^

Relating one's social support network to one's mid term grade

Much has been written about the relation of social support to health outcomes. Support networks were found to be predictive of health status. Not so clear was the manner in which social support helped the individual to avoid health complications. Whereas some aspects of the support network were protective, others were burdensome. Duties to one's network could serve as a stressor and duties outside one's network might stress the support system itself. Exposure to one's network was associated with certain health risks while disruption in one's social support network was associated with other health risks.^ Many factors contributed to the impact of a social support network upon the individual member: the characteristics of the individual, the individual's role or position within the network, qualities of the network and duties or indebtedness of the individual to the network. This investigation considered the possibility that performance could serve as a stressor in a fashion similar to an exposure to a health hazard.^ Because the literature includes many examples of studies in which the subjects were college students, academic progress is a performance common to most subjects. A profile of the support networks of successful students was contrasted with those of less successful students in this correlational study.^ What was uncovered in this investigation was a very complex web of interrelated constructs. Most aspects of the social support network did not significantly predict academic performance. Only a limited number of characteristics were associated with academic success: the frequency of support, student age, the existence of a 'mentor' within one' s network, and the extent to which one received a predominant source of support. Other factors had a tendency to be negatively correlated with midterm grade, suggesting those factors may impede academic performance.^ Medical status did not predict grades, but was correlated with many aspects of the network. Disruptions in particular parts of one's network were correlated with particular health categories. In fact, disruption in social support was more predictive of academic outcomes than medical complications. Whereas the individual's values were related to the contributing factors, only the individual's satisfaction with certain aspects of the support network were predictive of higher midterm grades in a psychology class. Dissatisfaction was associated with lower grades, suggesting a disruptive effect within the network. Associations among the features of support networks which predicted academic progress were considered. ^