Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment anti-tumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL-2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T cell response. Given the T cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared to combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T cell checkpoint blockade, with immediate implications for clinical evaluation.
Objectives-To determine if odor identification ability is associated with the 5-year incidence of cognitive impairment in a large population of older adults with normal cognition at baseline and if olfactory impairment contributes to the prediction of cognitive decline in a population.Design-Population-based longitudinal study. Setting-Beaver Dam, WI.Participants-1920 participants in the Epidemiology of Hearing Loss Study (mean age = 66.9 years). Measurements-Olfaction was measured by the San Diego Odor Identification Test (SDOIT).Incident cognitive impairment was defined as a Mini-Mental State Exam Score (MMSE) < 24 or reported diagnosis of dementia or Alzheimer's disease (AD) at the follow-up among people with MMSE ≥ 24 and no diagnosis of dementia or AD at baseline.Results-There was a significant association between olfactory impairment at baseline and the 5-year incidence of cognitive impairment (Odds Ratio (O.R.) = 6.62, 95% Confidence Interval (C.I.) = 4.36, 10.05). The association remained significant after adjusting for possible confounders (O.R. = 3.72, 95% C.I. = 2.31, 5.99). The Positive Predictive Value of the SDOIT was 15.9%, the Negative Predictive Value was 97.2% and the sensitivity and specificity were 55.1% and 84.4%, respectively, for the 5-year incidence of cognitive impairment.Conclusion-Olfactory impairment at baseline was strongly associated with the 5-year incidence of cognitive impairment as measured by the MMSE. Odor identification testing may be useful in high risk settings, but not in the general population, to identify patients at risk for cognitive decline.
vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. .
BackgroundHigh food insecurity has been demonstrated in rural American Indian households, but little is known about American Indian families in urban settings or the association of food insecurity with diet for these families. The purpose of this study was to examine the prevalence of food insecurity in American Indian households by urban-rural status, correlates of food insecurity in these households, and the relationship between food insecurity and diet in these households.MethodsDyads consisting of an adult caregiver and a child (2–5 years old) from the same household in five urban and rural American Indian communities were included. Demographic information was collected, and food insecurity was assessed using two validated items from the USDA Household Food Security Survey. Factors associated with food insecurity were examined using logistic regression. Child and adult diets were assessed using food screeners. Coping strategies were assessed through focus group discussions. These cross-sectional baseline data were collected from 2/2013 through 4/2015 for the Healthy Children, Strong Families 2 randomized controlled trial of a healthy lifestyles intervention for American Indian families.ResultsA high prevalence of food insecurity was determined (61%) and was associated with American Indian ethnicity, lower educational level, single adult households, WIC participation, and urban settings (p = 0.05). Food insecure adults had significantly lower intake of vegetables (p < 0.05) and higher intakes of fruit juice (<0.001), other sugar-sweetened beverages (p < 0.05), and fried potatoes (p < 0.001) than food secure adults. Food insecure children had significantly higher intakes of fried potatoes (p < 0.05), soda (p = 0.01), and sports drinks (p < 0.05). Focus group participants indicated different strategies were used by urban and rural households to address food insecurity.ConclusionsThe prevalence of food insecurity in American Indian households in our sample is extremely high, and geographic designation may be an important contributing factor. Moreover, food insecurity had a significant negative influence on dietary intake for families. Understanding strategies employed by households may help inform future interventions to address food insecurity.Trial registration (NCT01776255). Registered: January 16, 2013. Date of enrollment: February 6, 2013.
Changes in hearing thresholds over a 10-year period in a large population of older adults (2130) ranging in age from 48 to 92 years were documented. Pure-tone thresholds at frequencies from 0.5 to 8 kHz were evaluated at a baseline examination and 2.5, 5, and 10 years later. For younger age groups (50-69 years of age), threshold changes were generally greatest for higher frequencies; in older age groups (70-89 years of age), threshold changes were generally greatest for lower frequencies due to a ceiling effect at higher frequencies. At frequencies of 0.5, 1, 2, and 8 kHz, the pattern of 10-year changes in thresholds across audiometric frequencies was generally similar for men and women. Threshold changes at 4 and 6 kHz were relatively constant for all ages in men across the 10-year examination period; threshold changes at the same frequencies in women increased for the 48-59 and 60-69 years age groups and then tended to level off. Other than age and gender, the best baseline examination predictors of 10-year thresholds at a specific audiometric frequency were the baseline threshold at that frequency followed by the baseline threshold for the next higher test frequency. KeywordsAging; hearing loss; hearing sensitivity; presbyacusis Presbyacusis (age-related hearing loss) is probably the most prevalent basis for sensorineural hearing loss in older adults (Sajjadi et al, 2000) and ranks among the top three or four chronic conditions affecting adults over 65 years of age (National Center for Health Statistics, 1990). Although there are a number of studies documenting the prevalence and degree of hearing loss with advancing age (Moscicki et al, 1985;Gates et al, 1990;Cruickshanks et al, 1998), there are considerably fewer studies that have documented the progression of age-related hearing loss. Further, many of the earlier studies on the progression of hearing loss with advancing age were restricted to selected age groups (e.g., Eisdorfer and Wilkie, 1972;Moller, 1981;Rahko et al, 1985;Ostri et al, 1986;Pedersen et al, 1989;Ostri and Parving, 1991) and typically were based on relatively small samples, particularly for older age groups (e.g., Eisdorfer and Wilkie, 1972;Milne, 1977;Keay and Murray, 1988;Davis et al, 1991 The three largest contemporary studies of hearing loss progression in older adults were conducted within the Epidemiology of Hearing Loss Study (Cruickshanks et al, 2003), the Framingham Heart Study (Gates et al, 1990;Gates and Cooper, 1991), and the Baltimore Longitudinal Study of Aging (BLSA [Brant and Fozard, 1990;Pearson et al, 1995;Morrell et al, 1996]). Cruickshanks and colleagues (2003) documented the incidence and progression of hearing loss in a large population of older adults. Progression of hearing loss was defined as a change greater than 5 dB in the pure-tone average (0.5, 1, 2, and 4 kHz). Specific thresholds and changes in hearing thresholds across age groups at specific audiometric frequencies were not addressed in the Cruickshanks and colleagues article and are the subject o...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.