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. ^

Comparison of Bispectral Index (BIS) and Patient State Index (PSI) as objective measures of sedation and analgesia in critically ill/injured patients

Critically ill and injured patients require pain relief and sedation to reduce the body's stress response and to facilitate painful diagnostic and therapeutic procedures. Presently, the level of sedation and analgesia is guided by the use of clinical scores which can be unreliable. There is therefore, a need for an objective measure of sedation and analgesia. The Bispectral Index (BIS) and Patient State Index (PSI) were recently introduced into clinical practice as objective measures of the depth of analgesia and sedation. ^ Aim. To compare the different measures of sedation and analgesia (BIS and PSI) to the standard and commonly used modified Ramsay Score (MRS) and determine if the monitors can be used interchangeably. ^ Methods. MRS, BIS and PSI values were obtained in 50 postoperative cardiac surgery patients requiring analgesia and sedation from June to December 2004. The MRS, BIS and PSI values were assessed hourly for up to 6-h by a single observer. ^ The relationship between BIS and PSI values were explored using scatter plots and correlation between MRS, BIS and PSI was determined using Spearman's correlation coefficient. Intra-class correlation (ICC) was used to determine the inter-rater reliability of MRS, BIS and PSI. Kappa statistics was used to further evaluate the agreement between BIS and PSI at light, moderate and deep levels of sedation. ^ Results. There was a positive correlation between BIS and PSI values (Rho = 0.731, p<0.001). Intra-class correlation between BIS and PSI was 0.58, MRS and BIS 0.43 and MRS and PSI 0.27. Using Kappa statistics, agreement between MRS and BIS was 0.35 (95% CI: 0.27–0.43) and for MRS and PSI was 0.21 (95% CI: 0.15–0.28). The kappa statistic for BIS and PSI was 0.45 (95% CI: 0.37–0.52). Receiver operating characteristics (ROC) curves constructed to detect undersedation indicated an area under the curve (AUC) of 0.91 (95% CI = 0.87 to 0.94) for the BIS and 0.84 (95% CI = 0.79 to 0.88) for the PSI. For detection of oversedation, AUC for the BIS was 0.89 (95% CI = 0.84 to 0.92) and 0.80 (95% CI = 0.75 to 0.85) for the PSI. ^ Conclusions. There is a statistically significant positive correlation between the BIS and PSI but poor correlation and poor test agreement between the MRS and BIS as well as MRS and PSI. Both the BIS and PSI demonstrated a high level of prediction for undersedation and oversedation; however, the BIS and PSI can not be considered interchangeable monitors of sedation. ^

Use of tabletop exercises for disaster preparedness training

Background. In public health preparedness, disaster preparedness refers to the strategic planning of responses to all types of disasters. Preparation and training for disaster response can be conducted using different teaching modalities, ranging from discussion-based programs such as seminars, drills and tabletop exercises to more complex operation-based programs such as functional exercises and full-scale exercises. Each method of instruction has its advantages and disadvantages. Tabletop exercises are facilitated discussions designed to evaluate programs, policies, and procedures; they are usually conducted in a classroom, often with tabletop props (e.g. models, maps or diagrams). ^ Objective. The overall goal of this project was to determine whether tabletop exercises are effective teaching modalities for disaster preparedness, with an emphasis on intentional chemical exposure. ^ Method. The target audience for the exercise was the Medical Reserve Brigade of the Texas State Guard, a group of volunteer healthcare providers and first responders who prepare for response to local disasters. A new tabletop exercise was designed to provide information on the complex, interrelated organizations within the national disaster preparedness program that this group would interact with in the event of a local disaster. This educational intervention consisted of a four hour multipart program that included a pretest of knowledge, lecture series, an interactive group discussion using a mock disaster scenario, a posttest of knowledge, and a course evaluation. ^ Results. Approximately 40 volunteers attended the intervention session; roughly half (n=21) had previously participated in a full scale drill. There was an 11% improvement in fund of knowledge between the pre- and post-test scores (p=0.002). Overall, the tabletop exercise was well received by those with and without prior training, with no significant differences found between these two groups in terms of relevance and appropriateness of content. However, the separate components of the tabletop exercise were variably effective, as gauged by written text comments on the questionnaire. ^ Conclusions. Tabletop exercises can be a useful training modality in disaster preparedness, as evidenced by improvement in knowledge and qualitative feedback on its value. Future offerings could incorporate recordings of participant responses during the drill, so that better feedback can be provided to them. Additional research should be conducted, using the same or similar design, in different populations that are stakeholders in disaster preparedness, so that the generalizability of these findings can be determined.^

Quantitative comparison of late effects following photon versus proton external-beam radiation therapies: Toward an evidence-based approach to selecting a treatment modality

Radiation therapy has been used as an effective treatment for malignancies in pediatric patients. However, in many cases, the side effects of radiation diminish these patients’ quality of life. In order to develop strategies to minimize radiogenic complications, one must first quantitatively estimate pediatric patients’ relative risk for radiogenic late effects, which has not become feasible till recently because of the calculational complexity. The goals of this work were to calculate the dose delivered to tissues and organs in pediatric patients during contemporary photon and proton radiotherapies; to estimate the corresponding risk of radiogenic second cancer and cardiac toxicity based on the calculated doses and on dose-risk models from the literature; to test for the statistical significance of the difference between predicted risks after photon versus proton radiotherapies; and to provide a prototype of an evidence-based approach to selecting treatment modalities for pediatric patients, taking second cancer and cardiac toxicity into account. The results showed that proton therapy confers a lower predicted risk of radiogenic second cancer, and lower risks of radiogenic cardiac toxicities, compared to photon therapy. An uncertainty analysis revealed that the qualitative findings of this study are insensitive to changes in a wide variety of host and treatment related factors.

Objective assessment of the built environment and its relationship to physical activity and obesity

The role of physical activity in the promotion of individual and population health has been well documented in research and policy publications. Significant research activities have produced compelling evidence for the support of the positive association between physical activity and improved health. Despite the knowledge about these public health benefits of physical activity, over half of US adults do not engage in physical activity at levels consistent with public health recommendations. Just as physical inactivity is of significant public health concern in the US, the prevalence of obesity (and its attendant co-morbidities) is also increasing among US adults.^ Research suggests racial and ethnic disparities relevant to physical inactivity and obesity in the US. Various studies have shown more favorable outcomes among non-Hispanic whites when compared to other minority groups as far as physical activity and obesity are concerned. The health disparity issue is especially important because Mexican-Americans who are the fastest growing segment of the US population are disproportionately affected by physical inactivity and obesity by a significant margin (when compared to non-Hispanic whites), so addressing the physical inactivity and obesity issues in this group is of significant public health concern. ^ Although the evidence for health benefits of physical activity is substantial, various research questions remain on the potential motivators for engaging in physical activity. One area of emerging interest is the potential role that the built environment may play in facilitating or inhibiting physical activity.^ In this study, based on an ongoing research project of the Department of Epidemiology at the University of Texas M. D. Anderson Cancer Center, we examined the built environment, measured objectively through the use of geographical information systems (GIS), and its association with physical activity and obesity among a cohort of Mexican- Americans living in Harris County, Texas. The overall study hypothesis was that residing in dense and highly connected neighborhoods with mixed land-use is associated with residents’ increased participation in physical activity and lowered prevalence of obesity. We completed the following specific aims: (1) to generate a land-use profile of the study area and create a “walkability index” measure for each block group within the study area; (2) to compare the level of engagement in physical activity between study participants that reside in high walkability index block groups and those from low walkability block groups; (3) to compare the prevalence of obesity between study participants that reside in high walkability index block groups and those from low walkability block groups. ^ We successfully created the walkability index as a form of objective measure of the built environment for portions of Harris County, Texas. We used a variety of spatial and non-spatial dataset to generate the so called walkability index. We are not aware of previous scholastic work of this kind (construction of walkability index) in the Houston area. Our findings from the assessment of relationships among walkability index, physical activity and obesity suggest the following, that: (1) that attempts to convert people to being walkers through health promotion activities may be much easier in high-walkability neighborhoods, and very hard in low-walkability neighborhoods. Therefore, health promotion activities to get people to be active may require supportive environment, walkable in this case, and may not succeed otherwise; and (2) Overall, among individuals with less education, those in the high walkability index areas may be less obese (extreme) than those in the low walkability area. To the extent that this association can be substantiated, we – public health practitioners, urban designers, and policy experts – we may need to start thinking about ways to “retrofit” existing urban forms to conform to more walkable neighborhoods. Also, in this population especially, there may be the need to focus special attention on those with lower educational attainment.^