Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice

ADAM10, as the sheddase of the low affinity IgE receptor (CD23), promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J). While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone) WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J) compared to Th1 prone controls. To further understand this regulation, ADAM17 and TNF were studied in C57Bl/6 and Balb/c mice deficient in ADAM10. C57-ADAM10B-/- were more adept at increasing ADAM17 levels and thus TNF cleavage resulting in excess follicular TNF levels and abnormal secondary lymphoid tissue architecture not noted in Balb-ADAM10B-/-. Moreover, the level of B cell ADAM10 as well as Th context is critical for determining IgE production potential. Using a murine house dust mite airway hypersensitivity model, we describe that high B cell ADAM10 level in a Th2 context (Balb/c WT) is optimal for disease induction including bronchoconstriction, goblet cell metaplasia, mucus, inflammatory cellular infiltration, and IgE production. Balb/c mice deficient in B cell ADAM10 have attenuated lung and airway symptoms compared to Balb WT and are actually most similar to C57 WT (Th1 prone). C57-ADAM10B-/- have even further reduced symptomology. Taken together, it is critical to consider both innate B cell levels of ADAM10 and ADAM17 as well as Th context when determining host susceptibility to allergic disease. High B cell ADAM10 and low ADAM17 levels would help diagnostically in predicting Th2 disease susceptibility; and, we provide support for the use ADAM10 inhibitors in treating Th2 disease

Understanding the benefit of metformin use in cancer treatment

Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR) signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed

Targeting insulin-like growth factor pathways

Some cancer cells depend on the function of specific molecules for their growth, survival, and metastatic potential. Targeting of these critical molecules has arguably been the best therapy for cancer as demonstrated by the success of tamoxifen and trastuzumab in breast cancer. This review will evaluate the type I IGF receptor (IGF-IR) as a potential target for cancer therapy. As new drugs come forward targeting this receptor system, several issues will need to be addressed in the early clinical trials using these agents

Insulin and IGF1 signalling pathways in human astrocytes <i>in vitro</i> and <i>in vivo</i>; characterisation, subcellular localisation and modulation of the receptors.

Background The insulin/IGF1 signalling (IIS) pathways are involved in longevity regulation and are dysregulated in neurons in Alzheimer’s disease (AD). We previously showed downregulation in IIS gene expression in astrocytes with AD-neuropathology progression, but IIS in astrocytes remains poorly understood. We therefore examined the IIS pathway in human astrocytes and developed models to reduce IIS at the level of the insulin or the IGF1 receptor (IGF1R). Results We determined IIS was present and functional in human astrocytes by immunoblotting and showed astrocytes express the insulin receptor (IR)-B isoform of Ir. Immunocytochemistry and cell fractionation followed by western blotting revealed the phosphorylation status of insulin receptor substrate (IRS1) affects its subcellular localisation. To validate IRS1 expression patterns observed in culture, expression of key pathway components was assessed on post-mortem AD and control tissue using immunohistochemistry. Insulin signalling was impaired in cultured astrocytes by treatment with insulin + fructose and resulted in decreased IR and Akt phosphorylation (pAkt S473). A monoclonal antibody against IGF1R (MAB391) induced degradation of IGF1R receptor with an associated decrease in downstream pAkt S473. Neither treatment affected cell growth or viability as measured by MTT and Cyquant® assays or GFAP immunoreactivity. Discussion IIS is functional in astrocytes. IR-B is expressed in astrocytes which differs from the pattern in neurons, and may be important in differential susceptibility of astrocytes and neurons to insulin resistance. The variable presence of IRS1 in the nucleus, dependent on phosphorylation pattern, suggests the function of signalling molecules is not confined to cytoplasmic cascades. Down-regulation of IR and IGF1R, achieved by insulin + fructose and monoclonal antibody treatments, results in decreased downstream signalling, though the lack of effect on viability suggests that astrocytes can compensate for changes in single pathways. Changes in signalling in astrocytes, as well as in neurons, may be important in ageing and neurodegeneration

Interactions between Plasma Levels of 25-Hydroxyvitamin D, Insulin-Like Growth Factor (IGF)-1 and C-Peptide with Risk of Colorectal Cancer

Background: Vitamin D status and levels of insulin-like growth factor (IGF)-1 and C-peptide have been implicated in colorectal carcinogenesis. However, in contrast to vitamin D IGF-1 is not an easily modifiable risk factor. Methods: Combining data from the Health Professionals Follow up Study (HPFS) and the Nurses' Health Study cohort (NHS) additive and multiplicative interactions were examined between plasma 25-hydroxyvitamin D (25(OH)D) and IGF-1, IGFBP-3 as well as C-peptide levels in 499 cases and 992 matched controls. For the various analytes, being high or low was based on being either above (or equal) or below the medians, respectively. Results: Compared to participants with high 25(OH)D and low IGF-1/IGFBP-3 ratio (reference group), participants with a high IGF-1/IGFBP-3 ratio were at elevated risk of colorectal cancer when 25(OH)D was low (odds ratio (OR): 2.05 (95% CI: 1.43 to 2.92), but not when 25(OH)D was high (OR:1.20 (95% CI: 0.84 to 1.71, p(interaction): additive = 0.06, multiplicative = 0.25). Similarly, compared to participants with high 25(OH)D and low molar IGF-1/IGFBP-3 ratio and low C-peptide levels (reference group), participants with a combination of either high IGF-1/IGFBP-3 ratio or high C-peptide were at elevated risk for colorectal cancer when 25(OH)D was low (OR = 1.90, 95% CI: 1.22 to 2.94) but not when 25(OH)D was high (OR = 1.15, 95% CI: 0.74 to 1.77, p(interaction): additive = 0.004; multiplicative = 0.04). Conclusion: The results from this study suggest that improving vitamin D status may help lower risk of colorectal cancer associated with higher IGF-1/IGFBP-3 ratio or C-peptide levels

Patterns, trends and sex differences in HIV/AIDS reported mortality in Latin American countries: 1996-2007

<p>Abstract</p> <p>Background</p> <p>International cohort studies have shown that antiretroviral treatment (ART) has improved survival of HIV-infected individuals. National population based studies of HIV mortality exist in industrialized settings but few have been presented from developing countries. Our objective was to investigate on a population basis, the regional situation regarding HIV mortality and trends in Latin America (LA) in the context of adoption of public ART policies and gender differences.</p> <p>Methods</p> <p>Cause of death data from vital statistics registries from 1996 to 2007 with "good" or "average" quality of mortality data were examined. Standardized mortality rates and Poisson regression models by country were developed and differences among countries assessed to identify patterns of HIV mortality over time occurring in Latin America.</p> <p>Results</p> <p>Standardized HIV mortality following the adoption of public ART policies was highest in Panama and El Salvador and lowest in Chile. During the study period, three overall patterns were identified in HIV mortality trends- following the adoption of the free ART public policies; a remarkable decrement, a remarkable increment and a slight increment. HIV mortality was consistently higher in males compared to females. Mean age of death attributable to HIV increased in the majority of countries over the study period.</p> <p>Conclusions</p> <p>Vital statistics registries provide valuable information on HIV mortality in LA. While the introduction of national policies for free ART provision has coincided with declines in population-level HIV mortality and increasing age of death in some countries, in others HIV mortality has increased. Barriers to effective ART implementation and uptake in the context of free ART public provision policies should be further investigated.</p

Change & Maintaining Change in School Cafeterias: Economic and Behavioral-Economic Approaches to Increasing Fruit and Vegetable Consumption

Developing a daily habit of consuming fruits and vegetables (FV) in children is an important public-health goal. Eating habits acquired in childhood are predictive of adolescent and adult dietary patterns. Thus, healthy eating patterns developed early in life can protect the individual against a number of costly health deficits and may reduce the prevalence of obesity. At present, children in the United States (US) under-consume FV despite having access to them through the National School Lunch Program. Because access is an obstacle to developing healthy eating habits, particularly in low-income households, targeting children’s FV consumption in schools has the advantage of near-universal FV availability among more than 30 million US children. This chapter reviews economic and behavioral-economic approaches to increasing FV consumption in schools. Inclusion criteria include objective measurement of FV consumption (e.g., plate waste measures) and minimal demand characteristics. Simple but effective interventions include (a) increasing the variety of vegetables served, (b) serving sliced instead of whole fruits, (c) scheduling lunch after recess, and (d) giving children at least 25 minutes to eat. Improving the taste of FV and short-term incentivizing consumption of gradually increasing amounts can produce large increases in consumption of these foods. Low-cost game-based incentive program may increase the practicality of the latter strategy

Increasing vegetable intakes: rationale and systematic review of published interventions

Purpose While the health benefits of a high fruit and vegetable consumption are well known and considerable work has attempted to improve intakes, increasing evidence also recognises a distinction between fruit and vegetables, both in their impacts on health and in consumption patterns. Increasing work suggests health benefits from a high consumption specifically of vegetables, yet intakes remain low, and barriers to increasing intakes are prevalent making intervention difficult. A systematic review was undertaken to identify from the published literature all studies reporting an intervention to increase intakes of vegetables as a distinct food group. Methods Databases—PubMed, PsychInfo and Medline—were searched over all years of records until April 2015 using pre-specified terms. Results Our searches identified 77 studies, detailing 140 interventions, of which 133 (81 %) interventions were conducted in children. Interventions aimed to use or change hedonic factors, such as taste, liking and familiarity (n = 72), use or change environmental factors (n = 39), use or change cognitive factors (n = 19), or a combination of strategies (n = 10). Increased vegetable acceptance, selection and/or consumption were reported to some degree in 116 (83 %) interventions, but the majority of effects seem small and inconsistent. Conclusions Greater percent success is currently found from environmental, educational and multi-component interventions, but publication bias is likely, and long-term effects and cost-effectiveness are rarely considered. A focus on long-term benefits and sustained behaviour change is required. Certain population groups are also noticeably absent from the current list of tried interventions