Preclinical pharmacology of the pyrrolobenzodiazepine (PBD) monomer DRH-417 (NSC 709119)

The pyrrolobenzodiazepine monomer DRH-417 is a member of the anthramycin group of anti-tumor antibiotics that bind covalently to the N2 of guanine within the minor groove of DNA. DRH-417 emerged from the EORTC-Drug Discovery Committee and NCI 60 cell line in vitro screening programs as a potent antiproliferative agent with differential sensitivity towards certain cancer types such as melanoma, breast and renal cell carcinoma (mean IC(50) = 3 nM). DRH-417 was therefore tested for in vivo activity. The maximum tolerated dose (MTD) was established as 0.5 mg/kg given i.p. Marked anti-tumor activity was seen in two human renal cell cancers, one breast cancer and a murine colon tumor model (p<0.01). A selective HPLC (LC/MS) analytical method was developed and plasma pharmacokinetics determined. At a dose of 0.5 mg kg(-1), the plasma AUC was 540 nM h (197.1 ng h ml(-1)) and the peak plasma concentration (171 nM [62.4 ng ml(-1)]) occurred at 30 min., reaching doses levels well above those needed for in vitro antiproliferative activity. Genomic profiling of in vivo sensitive tumors revealed that the latter have an activated insulin-like growth factor signaling pathway.     

The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth

Anti-angiogenesis therapies have emerged as important treatment options for several types of tumours. To date, these therapies have focused on blocking the vascular endothelial growth factor (VEGF) pathway. A recent series of papers have shown that one ligand for the Notch receptors, Delta-like ligand 4 (DLL4), is normally induced by VEGF and is a negative-feedback regulator that restrains vascular sprouting and branching. Consistent with this role, the deletion or inhibition of DLL4 results in excessive, non-productive angiogenesis. This unrestrained angiogenesis unexpectedly and paradoxically decreases tumour growth, even in tumours resistant to anti-VEGF therapies. Can too much angiogenesis be bad for tumours but good for patients?     

Is susceptibility to prenatal methylmercury exposure from fish consumption non-homogeneous? Tree-structured analysis for the Seychelles Child Development Study

Studies of the association between prenatal methylmercury exposure from maternal fish consumption during pregnancy and neurodevelopmental test scores in the Seychelles Child Development Study have found no consistent pattern of associations through age 9 years. The analyses for the most recent 9-year data examined the population effects of prenatal exposure, but did not address the possibility of non-homogeneous susceptibility. This paper presents a regression tree approach: covariate effects are treated non-linearly and non-additively and non-homogeneous effects of prenatal methylmercury exposure are permitted among the covariate clusters identified by the regression tree. The approach allows us to address whether children in the lower or higher ends of the developmental spectrum differ in susceptibility to subtle exposure effects. Of 21 endpoints available at age 9 years, we chose the Weschler Full Scale IQ and its associated covariates to construct the regression tree. The prenatal mercury effect in each of the nine resulting clusters was assessed linearly and non-homogeneously. In addition we reanalyzed five other 9-year endpoints that in the linear analysis had a two-tailed p-value <0.2 for the effect of prenatal exposure. In this analysis, motor proficiency and activity level improved significantly with increasing MeHg for 53% of the children who had an average home environment. Motor proficiency significantly decreased with increasing prenatal MeHg exposure in 7% of the children whose home environment was below average. The regression tree results support previous analyses of outcomes in this cohort. However, this analysis raises the intriguing possibility that an effect may be non-homogeneous among children with different backgrounds and IQ levels.     

Rapid decrease in tumor perfusion following VEGF blockade predicts long-term tumor growth inhibition in preclinical tumor models

Vascular endothelial growth factor (VEGF) is a key upstream mediator of tumor angiogenesis, and blockade of VEGF can inhibit tumor angiogenesis and decrease tumor growth. However, not all tumors respond well to anti-VEGF therapy. Despite much effort, identification of early response biomarkers that correlate with long-term efficacy of anti-VEGF therapy has been difficult. These difficulties arise in part because the functional effects of VEGF inhibition on tumor vessels are still unclear. We therefore assessed rapid molecular, morphologic and functional vascular responses following treatment with aflibercept (also known as VEGF Trap or ziv-aflibercept in the United States) in preclinical tumor models with a range of responses to anti-VEGF therapy, including Colo205 human colorectal carcinoma (highly sensitive), C6 rat glioblastoma (moderately sensitive), and HT1080 human fibrosarcoma (resistant), and correlated these changes to long-term tumor growth inhibition. We found that an overall decrease in tumor vessel perfusion, assessed by dynamic contrast-enhanced ultrasound (DCE-US), and increases in tumor hypoxia correlated well with long-term tumor growth inhibition, whereas changes in vascular gene expression and microvessel density did not. Our findings support previous clinical studies showing that decreased tumor perfusion after anti-VEGF therapy (measured by DCE-US) correlated with response. Thus, measuring tumor perfusion changes shortly after treatment with VEGF inhibitors, or possibly other anti-angiogenic therapies, may be useful to predict treatment efficacy.     

A pilot study of the impact of bovine spongiform encephalopathy on the futures of rural youth and Canadian farming

There is an abundance of literature examining the economic impact of Canada's bovine spongiform encephalopathy (BSE) outbreak, but few studies examined the impact of such a crisis on health at the individual, family, or community levels. In particular, rural youth represent an under-researched population despite being at risk for a unique set of social and health concerns. In this pilot study, our objectives were to explore how rural youth responded to Canada's BSE crisis and how they perceived themselves, their families, and their communities to have been impacted. Seven youths (n = 7), recruited from within a university setting using a snowball sampling method, were interviewed. They represent a segment of rural, agriculturally based youth who are resilient due to good parental support. Although they reported high stress in their families during the immediate crisis in 2003, they did not report lasting high levels of stress or negative health effects due to BSE. They did report a decline in rural community health, identifying a reduction in community activities and in the participation of families in community activities. Participants identified elements that discourage youth from pursuing farming as a career and expressed concern for the future of family farming. The results are discussed in terms of the ability of agriculturally based youth to make the transition to adulthood. The implications have importance for future research and policy that addresses the structural supports for choice making, the long-term success for rural youth in transitioning to adult status, and the future of agriculture.     

Distributed lag analyses of daily hospital admissions and source-apportioned fine particle air pollution

Background

Past time-series studies of the health effects of fine particulate matter [aerodynamic diameter ≤ 2.5 μm (PM_2.5)] have used chemically nonspecific PM_2.5 mass. However, PM_2.5 is known to vary in chemical composition with source, and health impacts may vary accordingly.

Objective

We tested the association between source-specific daily PM_2.5 mass and hospital admissions in a time-series investigation that considered both single-lag and distributed-lag models.

Methods

Daily PM_2.5 speciation measurements collected in midtown Manhattan were analyzed via positive matrix factorization source apportionment. Daily and distributed-lag generalized linear models of Medicare respiratory and cardiovascular hospital admissions during 2001–2002 considered PM_2.5 mass and PM_2.5 from five sources: transported sulfate, residual oil, traffic, steel metal works, and soil.

Results

Source-related PM_2.5 (specifically steel and traffic) was significantly associated with hospital admissions but not with total PM_2.5 mass. Steel metal works–related PM_2.5 was associated with respiratory admissions for multiple-lag days, especially during the cleanup efforts at the World Trade Center. Traffic-related PM_2.5 was consistently associated with same-day cardiovascular admissions across disease-specific subcategories. PM_2.5 constituents associated with each source (e.g., elemental carbon with traffic) were likewise associated with admissions in a consistent manner. Mean effects of distributed-lag models were significantly greater than were maximum single-day effect models for both steel- and traffic-related PM_2.5.

Conclusions

Past analyses that have considered only PM_2.5 mass or only maximum single-day lag effects have likely underestimated PM_2.5 health effects by not considering source-specific and distributed-lag effects. Differing lag structures and disease specificity observed for steel-related versus traffic-related PM_2.5 raise the possibility of distinct mechanistic pathways of health effects for particles of differing chemical composition.     

Fine particulate matter constituents associated with cardiovascular hospitalizations and mortality in New York City

Background

Recent time-series studies have indicated that both cardiovascular disease (CVD)mortality and hospitalizations are associated with particulate matter (PM). However, seasonal patterns of PM associations with these outcomes are not consistent, and PM components responsible for these associations have not been determined. We investigated this issue in New York City (NYC), where PM originates from regional and local combustion sources.

Objective

In this study, we examined the role of particulate matter with aerodynamic diameter ≤ 2.5 μm (PM_2.5) and its key chemical components on both CVD hospitalizations and on mortality in NYC.

Methods

We analyzed daily deaths and emergency hospitalizations for CVDs among persons ≥ 40 years of age for associations with PM_2.5, its chemical components, nitrogen dioxide (NO₂), carbon monoxide, and sulfur dioxide for the years 2000–2006 using a Poisson time-series model adjusting for temporal and seasonal trends, temperature effects, and day of the week. We estimated excess risks per interquartile-range increases at lags 0 through 3 days for warm (April through September) and cold (October through March) seasons.

Results

The CVD mortality series exhibit strong seasonal trends, whereas the CVD hospitalization series show a strong day-of-week pattern. These outcome series were not correlated with each other but were individually associated with a number of PM_2.5 chemical components from regional and local sources, each with different seasonal patterns and lags. Coal-combustion–related components (e.g., selenium) were associated with CVD mortality in summer and CVD hospitalizations in winter, whereas elemental carbon and NO₂ showed associations with these outcomes in both seasons.

Conclusion

Local combustion sources, including traffic and residual oil burning, may play a year-round role in the associations between air pollution and CVD outcomes, but transported aerosols may explain the seasonal variation in associations shown by PM_2.5 mass.     

Access to palliative care services in hospital: a matter of being in the right hospital. Hospital charts study in a Canadian city

Access to palliative care (PC) is a major need worldwide. Using hospital charts of all patients who died over one year (April 2008-March 2009) in two mid-sized hospitals of a large Canadian city, similar in size and function and operated by the same administrative group, this study examined which patients who could benefit from PC services actually received these services and which ones did not, and compared their care characteristics. A significantly lower proportion (29%) of patients dying in hospital 2 (without a PC unit and reliant on a visiting PC team) was referred to PC services as compared to in hospital 1 (with a PC unit; 68%). This lower referral likelihood was found for all patient groups, even among cancer patients, and remained after controlling for patient mix. Referral was strongly associated with having cancer and younger age. Referral to PC thus seems to depend, at least in part, on the coincidence of being admitted to the right hospital. This finding suggests that establishing PC units or a team of committed PC providers in every hospital could increase referral rates and equity of access to PC services. The relatively lower access for older and non-cancer patients and technology use in hospital PC services require further attention.