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Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors. Editor's summary: Radiation therapy (RT) is usually administered as a single dose across a tumor. However, not all radiation doses are created equal. High radiation doses promote immunogenic cell death, medium radiation doses promote type I interferon responses, and low radiation doses promote inflammatory cytokine production and immune cell trafficking. To reap the benefits of all three doses, Jagodinsky et al. treated murine tumors with heterogeneous RT, where different regions of the tumor were treated with different RT doses. The authors found that this heterogeneous approach outperformed homogeneous dose RT in a T cell–dependent manner and could be combined with immune checkpoint inhibition. These data support further clinical development of heterogeneous RT. —Courtney Malo [ABSTRACT FROM AUTHOR]

Insulin sensitivity and glucose effectiveness from three minimal models: effects of energy restriction and body fat in adult male rhesus monkeys. Am J Physiol Regul Integr Comp Physiol 285: R1340-R1354, 2003. First published July 3, 2003; 10.1152/ ajpregu.00651.2002.--The minimal model of glucose disappearance (MINMOD version 3; MM3) and both the one-compartment (1CMM) and the two-compartment (2CMM) minimal models were used to analyze stable isotope-labeled intravenous glucose tolerance test (IVGTT) data from year 10 of a study of the effect of dietary restriction (DR) in male rhesus monkeys. Adult monkeys were energy restricted (R; n = 12) on a semipurified diet to ~70% of control (C) intake (ad libitum-fed monkeys; n = 12). Under ketamine anesthesia, fasting insulin levels were greater among C monkeys. Insulin sensitivity estimates from all models were greater in R than C monkeys, whereas glucose effectiveness estimates were not consistently greater in R monkeys. Fasting plasma glucose as well as hepatic glucose production and clearance rates did not differ between groups. Body fat, in part, statistically mediated the effect of DR to enhance insulin sensitivity indexes. Precision of estimation and intermodel relationships among insulin sensitivity and glucose effectiveness estimates were in the ranges of those reported previously for humans and dogs, suggesting that the models may provide valid estimates for rhesus monkeys as well. The observed insulin sensitivity indexes from all models, elevated among R vs. C monkeys, may be explained, at least in part, by the difference in body fat content between these groups after chronic DR. biological models; body composition; dietary restriction

Using a Head Start program to do pre-school-aged screening for asthma seems to be an effective way of identifying children early in the disease. Focus on social and income groups at high risk, this approach provides a chance for early treatment and preventive measures. Of 2,215 children, physicians diagnosed asthma in 15.8%. A sample of 133 of them were later re-examined and confirmed to be asthmatic at 98.5%., Objective. Asthma is a significant cause of morbidity and mortality in children. The objective of this study was to determine whether the federal program Head Start in Dane County, Wisconsin, could be used as a mechanism to identify preschool-aged children with asthma. Design. Five-year, cross-sectional survey of parents with children enrolled in Head Start. Methods. Investigator-administered asthma screening questionnaire to parents of enrolling Head Start children in Dane County, Wisconsin. Measurements. Asthma prevalence and asthma-related health care use, including emergency department visits, hospitalizations, and medication usage, were measured using an asthma screening questionnaire developed by investigators. Results. Information was gathered on 2215 children. The prevalence of physician-diagnosed asthma in the screened children was 15.8%. Parental reports of physician-diagnosed asthma were validated in a subset of 133 children, with a 98.5% confirmation rate. Independent risk factors for asthma included male gender (relative risk, 1.4) and African-American ethnicity (relative risk, 1.4). Asthma-related morbidity was substantial with 26.7% of identified children hospitalized for asthma and 54.5% with an emergency department visit during their lifetime. The majority of children (46.4%) were treated with intermittent, quick relief medications ([Beta]-agonists) alone, whereas only 6.1% were on daily, long-term controller medications. Conclusions. Asthma screening through a Head Start program provides an effective means of targeting preschool-aged children from socioeconomic groups at high risk for asthma. Identification of children early in the disease course and those at high risk for asthma provides an ideal opportunity for the implementation of preventive and therapeutic interventions. Pediatrics 1998;102: 77-83; asthma, Head Start, epidemiology, health status indicators, health services. ABBREVIATIONS. ED, emergency department; CHS-NHIS, Child Health Supplements to the National Health Interview Survey., Asthma is the most common chronic disease of early childhood, affecting an estimated 3% to 7% of children in the United States.[1-3] Despite advances in the understanding of asthma pathophysiology [...]

This study examined the intensity of activity contributing to physical activity energy expenditure in older adults. In 57 men and women aged > 65, total energy expenditure (TEE) was measured using doubly labeled water and resting metabolic rate was measured using indirect calorimetry to calculate a physical activity index (PAI). Sedentary time and physical activity of light and moderate to vigorous (mod/vig) intensity was measured using an accelerometer. The subjects were 75 + 7 yrs (mean ± SD) of age and 79% female. Subjects spent 66 ± 8, 25 ± 5, and 9 ± 4% of monitor wear time in sedentary, light, and mod/vig activity per day, respectively. In a mixture regression model, both light ([3 = 29.6 [15.6-43.6, 95% Cl]), p < .001) and mod/vig intensity activity ([3 = 28.7 [7.4-50.0,95% CI]),p = .01) were strongly associated with PAI, suggesting that both light and mod/ vig intensity activities are major determinants of their physical activity energy expenditure. [ABSTRACT FROM AUTHOR]

In a longitudinal study of the effects of moderate (70%) dietary restriction (DR) on aging, plasma glucose and insulin concentrations were measured from semiannual, frequently sampled intravenous glucose tolerance tests (FSIGTT) in 30 adult male rhesus monkeys. FSIGTT data were analyzed with Bergman's minimal model, and analysis of covariance revealed that restricted (R) monkeys exhibited increased insulin sensitivity ([S.sub.I], P [is less than] 0.001) and plasma glucose disappearance rate ([K.sub.G], P = 0.015), and reduced fasting plasma insulin ([I.sub.b], P [is less than] 0.001) and insulin response to glucose ([AIR.sub.G], P = 0.023) compared with control (C; ad libitum-fed) monkeys. DR reduced the baseline fasting hyperinsulinemia of two R monkeys, whereas four C monkeys have maintained from baseline, or subsequently developed, fasting hyperinsulinemia; one has progressed to diabetes. Compared with only the normoinsulinemic C monkeys, R monkeys exhibited similarly improved FSIGTT and minimal-model parameters. Thus chronic DR not only has protected against the development of insulin resistance in aging rhesus monkeys, but has also improved glucoregulatory parameters compared with those of otherwise normoinsulinemic monkeys. glucose metabolism; insulin; minimal model; energy restriction

Protein kinase C epsilon (PKCε), a Ca2+-independent phospholipid-dependent serine/threonine kinase, is among the six PKC isoforms (α, δ, ε, η, μ, ζ) expressed in both mouse and human skin. Epidermal PKCε level dictates the susceptibility of PKCε transgenic (TG) mice to the development of cutaneous squamous cell carcinomas (SCC) elicited either by repeated exposure to ultraviolet radiation (UVR) or by using the DMBA initiation-TPA (12-O-tetradecanoylphorbol-13-acetate) tumor promotion protocol (Wheeler,D.L. et al. (2004) Protein kinase C epsilon is an endogenous photosensitizer that enhances ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas. Cancer Res., 64, 7756-7765). Histologically, SCC in TG mice, like human SCC, is poorly differentiated and metastatic. Our earlier studies to elucidate mechanisms of PKCε-mediated development of SCC, using either DMBA-TPA or UVR, indicated elevated release of cytokine TNFα. To determine whether TNFα is essential for the development of SCC in TG mice, we generated PKCε transgenic mice/ TNFα-knockout (TG/TNFαKO) by crossbreeding TNFαKO with TG mice. We now present that deletion of TNFα in TG mice inhibited the development of SCC either by repeated UVR exposures or by the DMBA-TPA protocol. TG mice deficient in TNFα elicited both increase in SCC latency and decrease in SCC incidence. Inhibition of UVR-induced SCC development in TG/TNFαKO was accompanied by inhibition of (i) the expression levels of TNFα receptors TNFRI and TNFRII and cell proliferation marker ornithine decarboxylase and metastatic markers MMP7 and MMP9, (ii) the activation of transcription factors Stat3 and NF-kB and (iii) proliferation of hair follicle stem cells and epidermal hyperplasia. The results presented here provide the first genetic evidence that TNFα is linked to PKCε-mediated sensitivity to DMBA-TPA or UVR-induced development of cutaneous SCC. [ABSTRACT FROM AUTHOR]

We examined the effects of dietary restriction (DR) and age on ss-cell function and peripheral insulin sensitivity in rhesus monkeys. A semipurified diet was provided either ad libitum for approximately 8 hours/day to controls (C) or as approximately 70% of baseline intake to restricted (R) animals for 10 years. The minimal model of C-peptide secretion and kinetics and the labeled 2-compartment minimal model of glucose kinetics were identified using plasma glucose, C-peptide, and insulin concentrations during an intravenous glucose tolerance test. R monkeys had less body fat, lower basal ss-cell sensitivity to glucose (Ø(b)), greater insulin sensitivity, and lower first-phase plasma insulin response. DR did not significantly affect first-phase and second-phase ss-cell sensitivity to glucose. Indices of body fatness were highly predictive of the effect of DR on Ø(b), fasting insulin concentration and insulin responses to glucose. Enhanced peripheral insulin sensitivity among R monkeys was strongly correlated with lower Ø(b). [ABSTRACT FROM AUTHOR]

Outlines comments and responses on studies about cancer. Negative results of beta-carotene supplements on cancer; Risk on the use of sunscreen and the incidence of melanocytic lesions; Involvement of the simian virus 40 in the pathogenesis of human malignancies.

Objective: We conducted a pilot survey to evaluate breast cancer patients' willingness to participate in a preoperative chemoprevention (ie, window-of-opportunity) study. Design: A 27-question written survey was developed and administered to participants. Setting: A breast cancer specialty clinic at the University of Wisconsin Hospital and Clinics. Participants: 30 adult patients with newly diagnosed operable breast cancer participated after signing informed consent. Methods: A convenience sample of 30 participants was recruited from July 2005 through January 2006. Participants were administered the survey in clinic. Univariate ordinal logistic regression models were used to identify predictors of willingness to participate in window-of-opportunity trials. Results: Overall, 26.7% of respondents were willing to participate in a research trial between the time of breast cancer diagnosis and surgery. Univariate ordinal logistic regression models identified that women with a prior history of breast cancer (P=0.060), prior research participation (P=0.006), more education (P=0.034), and self-reported breast cancer knowledge (P=0.043) were more willing to participate. On average, women preferred to have surgery 7 days (range 1-14) after their diagnosis, but the actual average wait time between diagnostic biopsy and surgery was 37.5 days (standard deviation = 23.4 days). Conclusion: There is ample time before breast surgery to conduct preoperative window-of- opportunity trials. Interventions aimed at expanding patients' breast cancer knowledge may improve accrual to window-of-opportunity studies. [ABSTRACT FROM AUTHOR]

We performed a clinical trial in non-muscle invasive urothelial cancer (NMIUC) patients randomized (2:1) to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or placebo (either orally once weekly x 3 doses prior to scheduled surgery) to assess for a difference in EGFR phosphorylation in tumor adjacent normal urothelium <24 hours post-study dose and tolerance of weekly erlotinib. Thirty-seven volunteers (6 female/31 male, mean age 70, 35 white/2 non-white) with confirmed or suspected NMIUC were enrolled into either erlotinib (n=24; 900 mg-13, 600 mg-11) or placebo (n=13). Immunohistochemical assessment of phosphorylated and total EGFR in adjacent normal urothelium (20 erlotinib; 9 placebo) or tumor (21 erlotinib and 11 placebo subjects) at study end observed no significant difference between those receiving erlotinib or placebo. This was also true for other assessed tissue biomarkers (phosphorylated ERK, ERK, e-cadherin, p53 and Ki67). Adverse events were more common, in a dose-related fashion, in participants receiving erlotinib, e.g. 38% experienced Grade 1 with rare grade 2 diarrhea and skin toxicity vs 8% in placebo. Clinically insignificant, but statistically significant (p=0.001) elevations in serum total bilirubin and creatinine were observed in erlotinib participants. Serum erlotinib and metabolite concentrations (OSI-420) confirmed compliance in all erlotinib subjects and did not significantly differ between the 600 and 900 mg doses. Despite compelling pre-clinical and clinical data for targeted EGFR inhibition in bladder cancer prevention, these data do not support the use of weekly erlotinib to prevent progression of NMI bladder cancer.