Trial Participation is Not Associated with Better Biochemical Recurrence-free Survival in a Large Cohort of External Beam Radiotherapy-Treated Intermediate- and High-Risk Prostate Cancer Patients.

AIMS: There is a widespread belief that outcomes of cancer patients treated within clinical trials might not be representative of the outcomes obtained within standard clinical settings. We sought to investigate the effect of trial participation on biochemical recurrence (BCR) in localised, D'Amico intermediate- and high-risk prostate cancer patients treated with external beam radiotherapy (EBRT). MATERIALS AND METHODS: We relied on a study population treated with EBRT between January 2001 and January 2021 at a single tertiary care centre, stratified according to trial enrolment. Separate Kaplan-Meier and multivariable Cox regression models tested BCR-free survival at 60 months within intermediate- and high-risk EBRT patients, after adjustment for covariables. Additionally, the analyses were refitted after inverse probability treatment weighting was performed separately for both risk subgroups. RESULTS: Of 932 eligible patients, 635 (68%) and 297 (32%) had intermediate- and high-risk prostate cancer, respectively. Overall, 53% of patients were trial participants. BCR rates were 11 versus 5% (P = 0.27) and 12 versus 14% (P = 0.08) in trial participants versus non-participants for intermediate- and high-risk subgroups, respectively. Differences in patient and clinical characteristics were recorded. Trial participation status failed to reach predictor status in multivariable Cox regression models for BCR in both intermediate-risk (hazard ratio 1.34; 95% confidence interval 0.71-2.49; P = 0.4) and high-risk patients (hazard ratio 1.03; 95% confidence interval 0.45-2.34; P = 0.9). Virtually the same results were recorded in inverse probability treatment weighting cohorts. CONCLUSIONS: Relying on a large cohort of EBRT-treated intermediate- and high-risk patients, no BCR differences were recorded between trial participants and non-participants after accounting for confounders.

Mucosal delivery of human papillomavirus pseudovirus-encapsidated plasmids improves the potency of DNA vaccination.

Mucosal immunization may be important for protection against pathogens whose transmission and pathogenesis target the mucosal tissue. The capsid proteins of human papillomavirus (HPV) confer tropism for the basal epithelium and can encapsidate DNA during self-assembly to form pseudovirions (PsVs). Therefore, we produced mucosal vaccine vectors by HPV PsV encapsidation of DNA plasmids expressing an experimental antigen derived from the M and M2 proteins of respiratory syncytial virus (RSV). Intravaginal (IVag) delivery elicited local and systemic M-M2-specific CD8+ T-cell and antibody responses in mice that were comparable to an approximately 10,000-fold higher dose of naked DNA. A single HPV PsV IVag immunization primed for M-M2-specific-IgA in nasal and vaginal secretions. Based on light emission and immunofluorescent microscopy, immunization with HPV PsV-encapsidated luciferase- and red fluorescent protein (RFP)-expressing plasmids resulted in transient antigen expression (<5 days), which was restricted to the vaginal epithelium. HPV PsV encapsidation of plasmid DNA is a novel strategy for mucosal immunization that could provide new vaccine options for selected mucosal pathogens.

Temperature effects on the breeding distribution of grey seals (Halichoerus grypus).

The metabolic rates of six female grey seal (Halichoerus grypus) pups were measured during their postweaning fast at air temperatures between -15 degrees and 30 degrees C. The composite of their individual thermal neutral zones extended from a mean lower critical temperature of -7.1 degrees +/- 0.7 degree C to a mean upper critical temperature of 23.0 degrees +/- 0.4 degree C. Within the thermal neutral zone, mean standard metabolic rate of the fasting animals was 1,265 +/- 82 kcal d-1, or about 1.1 times the value predicted for an adult animal of similar body mass (mean mass = 40.9 +/- 1.2 kg). For those grey seal populations that reproduce during winter months in the eastern and western Atlantic and in the Baltic Sea, the lower critical temperature of fasting pups corresponds closely with the coldest mean monthly air temperature at the northern end of their breeding ranges. This observation supports the hypothesis that cold ambient air temperatures limit the northern breeding distribution of grey seals, primarily through their thermoregulatory effects on small, fasting pups before they enter the water.

Ontogeny of the thermal limits in the harbor seal (Phoca vitulina).

We measured metabolic rates (mL O2 h-1, converted to kcal d-1), deep body temperatures (degree C), and skin temperatures (degree C) and calculated whole-animal thermal conductances (mL O2 g-1 h-1 degree C-1) of five 3-yr-old harbor seals (Phoca vitulina concolor) at air temperatures between -20 degrees and 35 degrees C. The mean thermal neutral zone of these seals extended from a lower critical temperature of -12.9 degrees +/- 1.6 degrees C (SD) to an upper critical temperature of 28.6 degrees +/- 1.7 degrees C. Hyperthermia was observed at an ambient air temperature of 35 degrees C. Mean standard metabolic rate was 1,553.6 +/- 168.2 kcal d-1, about 1.2 times the value expected for adult animals of similar body mass (mean mass = 49.2 +/- 7.5 kg). Mean deep body temperature increased from 37.5 degrees +/- 0.30 degrees C at an ambient temperature of 30 degrees C and reached 39.3 degrees +/- 0.33 degrees C at an ambient temperature of 35 degrees C. Skin temperature decreased with decreasing ambient temperature but remained well above ambient temperature. Mean whole-animal thermal conductance decreased from an ambient temperature of 35 degrees C until it reached a minimum value of 0.007 mL O2 g-1 h-1 degree C-1 at -4.0 degrees C; it then increased with a further decrease in ambient temperature. In comparison to the thermal limits of the same seals during their first year of life, the results indicate a broadening of the thermal neutral zone with age: an 11 degrees C decrease in the lower critical temperature and a 3.5 degrees C increase in the upper critical temperature. These findings suggest that warm ambient air temperatures should not pose any particular thermoregulatory problems for larger and older harbor seals, even beyond the limits of their current annual distribution.

Intrinsic rate of increase, body size, and specific metabolic rate in marine mammals.

Hennemann (1983) provided empirical support for McNab's (1980) hypothesis that a higher specific metabolic rate (SMR) in mammals translates into a higher intrinsic rate of increase (r m ). However, the few marine mammals in Hennemann's data base were excluded from any detailed analyses because their "high rates of metabolism but only average or low values of r m " (p. 106) were thought to reflect trade-offs between maintenance and production necessary to compensate for heat loss in aquatic environments (Hennemann 1983, also see McNab 1980).To investigate further the relationships among r m , body size, and specific metabolic rate in marine mammals (pinnepeds, sirenians, and cetaceans), r m was estimated for 37 populations using published life-history data and Cole's (1954) equation (Hennemann 1983). Estimates of r m in relation to body size in marine mammals were generally within the 95% confidence limits calculated for terrestrial mammals using Hennemann's data. Contrary to Hennemann's (1983) observations, eight of these populations had an r m which was higher in relation to body size than predicted by the average terrestrial mammalian relationship. Furthermore, for marine mammal populations where suitable data were available, r m was correlated with specific metabolic rate (r=0.85, P≦0.035) and all the estimates were again within the 95% confidence limits established from data for terrestrial mammals (Hennemann 1983). It is premature, therefore, to reject the hypothesis that marine mammals do not differ significantly from terrestrial mammals in their allocation of energy for maintanance and reproduction.

Reduced fecundity of vitamin D deficient rats.

1. Female rats fed on a vitamin D deplete (D-) diet for 90 days prior to mating gave birth to litters having significantly fewer young than females fed a diet containing vitamin D (2.2 IU/g, D + diet). 2. Neither age nor body weight of females had a significant influence on litter size. 3. Serum calcium and phosphorus levels in D+ and D- dams were not significantly different, nor were serum calcium and phosphorus levels and bone ash of D+ and D- weanlings. 4. The level of 25-hydroxyvitamin D3 [25(OH)D3], the main circulating form of vitamin D, was low in D- dams and was not detected in D- weanlings. 5. These data suggest that vitamin D is required for reproduction in the rat.

Organochlorine and mercury residues in the harp seal (Pagophilus groenlandicus).

Samples of blubber, liver, kidney and brain, obtained from 10 male, 6 female neonatal, and 4 lactating female harp seals (Pagophilus groenlandicus), were analysed for DDT, dieldrin, PCB, and total mercury. Methyl mercury levels in blood were also determined. Biocide deposition was not significantly different in female and male ten day old pups. There were no significant differences in biocide levels in the liver of the 14/+ day old males, but in blubber there were significant differences in dieldrin and DDT. There was no clear relationship between biocide levels in the 6-18 year old lactating adults and their pups. Younger adult seals (6 and 7 years) were found to have higher levels of PCB and sigmaDDT levels in their blubber than did older females (10 and 18 years). Wide intraspecific variation was noted in organochlorine and mercury residue levels. Pups taken in 1973 were found to have lower organochlorine residues than pups taken in the same area in 1971. Preliminary investigation indicates that detectable amounts of organochlorine and mercury residues are capable of crossing the placenta in the harp seal.