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Influenza during pregnancy is associated with the development of psychopathology in the offspring. We sought to determine whether maternal cytokines produced following administration of viral mimetic polyinosinic-polycytidylic acid (polyI:C) to pregnant rats were predictive of behavioral abnormalities in the adult offspring. Timed-pregnant Sprague Dawley rats received a single intravenous injection of 4-mg/kg polyI:C or saline on gestational day (GD)15. Blood was collected 3 h later for serum analysis of cytokine levels with ELISA. Male offspring were tested in a battery of behavioral tests during adulthood and behavior was correlated with maternal cytokine levels. Maternal serum levels of CXCL1 and interleukin (IL)-6, but not tumor necrosis factor (TNF)-α or CXCL2, were elevated in polyI:C-treated dams. PolyI:C-treated dams experienced post-treatment weight loss and polyI:C pups were smaller than controls at postnatal day (PND)1. Various behavior alterations were seen in the polyI:C-treated offspring. Male polyI:C offspring had enhanced MK-801-induced locomotion, and reduced sociability. PolyI:C offspring failed to display crossmodal and visual memory, and oddity preference was also impaired. Set-shifting, assessed with a lever-based operant conditioning task, was facilitated while touchscreen-based reversal learning was impaired. Correlations were found between maternal serum concentrations of CXCL1, acute maternal temperature and body weight changes, neonatal pup mass, and odd object discrimination and social behavior. Overall, while the offspring of polyI:C-treated rats displayed behavior abnormalities, maternal serum cytokines were not related to the long-term behavior changes in the offspring. Maternal sickness effects and neonatal pup size may be better indicators of later effects of maternal inflammation in the offspring.

The purpose of this study was to investigate the clinical, pathological, and prognostic characteristics of breast cancer patients with diabetes. In total, the study included 1,013 breast cancer patients with diabetes and 4,621 breast cancer patients without diabetes. Patients with diabetes were further divided into the metformin- and nonmetformin-treated subgroups. The percentage of elderly patients (P < 0.001), obese patients (P < 0.001), and menopausal patients (P < 0.001) as well as the percentage of patients with cardio-cerebrovascular complications (P < 0.001), negative PR (P < 0.001) expression, or low Ki67 expression (P = 0.001) tended to be higher in the diabetic group. In addition, these patients had later pathological stages (P < 0.001), more lymph node metastasis (P = 0.014), and a lower percentage of them were on the anthracycline-based chemotherapy regimen (P = 0.003). The diabetic group was further divided into the metformin and nonmetformin-treated subgroups. The pairwise comparison between the metformin-treated subgroup and the control group did not show a significant difference in the pathological stages (P = 0.0079). However, the HER-2 positive rate tended to be lower in the metformin-treated subgroup than in the nonmetformin-treated subgroup (P = 0.002). No significant difference was found in the lymph node status between the nonmetformin-treated subgroup and the control group (P = 0.057), while the nonmetformin-treated subgroup was associated with higher HER-2 positive expression (P = 0.002). The median follow-up time for this study was 68 months (10-120 months). In Kaplan-Meier analysis, The diabetic group predicted worse survival compared with the control group (P < 0.001) with 5-year survival rates of 79 and 82 %, respectively. The breast cancer mortality rates in the metformin-treated subgroup, the nonmetformin-treated subgroup, and the control group were significantly different (long-rank test, P < 0.001), and the 5-year survival rates were 88, 73, and 82 %, respectively. As shown in the multivariate survival analysis using Cox's regression model, compared with the control group, the metformin-treated subgroup was associated with lower mortality risk (HR 0.762; 95 % CI 0.6-0.968; P = 0.026), whereas the nonmetformin-treated subgroup was associated with higher mortality risk (HR 1.708; 95 % CI 1.461-1.997; P < 0.001). In conclusion, the diabetic group is associated with poor prognosis. Compared with the control group, the metformin-treated subgroup is associated with better clinical outcomes, while nonmetformin-treated subgroup with poorer prognosis. The selection of different antidiabetic drugs may impact the prognosis of breast cancer patients with diabetes.

In mouse models of asthma, therapeutic use of allergen-presenting IL-10-differentiated dendritic cells (DCs) can abrogate airway hyperresponsiveness, and reduce other asthma-related responses to near background. Analogous human DCs can suppress human T cell responses in vitro, but the operative mechanisms are poorly defined. We investigated the ability of IL-10-treated human DCs to induce tolerance among autologous T cells of subjects with asthma and the mechanisms by which they do this. CD14(+) monocyte-derived DCs were differentiated in the presence of IL-10 (DC10) ex vivo from 11 donors with asthma and 4 control donors, and characterized for relevant markers. They were pulsed with specific or irrelevant allergen, and cultured with autologous peripheral blood CD4(+) T cells, either alone or together with autologous immunostimulatory DCs (DC-TNF), and the impact of this treatment on the T-cell responses was assessed for each donor. The DC10 expressed reduced levels of some relevant markers (CD40, CD80, human leukocyte antigen-DR) and stimulatory cytokines (IL-6 and IL-12), but augmented levels of Ig-like transcript-22/CD85j and IL-10 relative to DC-TNF. In cocultures, they dampened DC-TNF-driven T helper (Th) type 2 cell proliferation and cytokine (IL-4, -5, and -13) secretion. They also drove the development from atopic CD4(+)CD25(lo)Foxp3(lo) cells of a population of IL-10-secreting CD25(+)Foxp3(+)LAG-3(+)CTLA-4(+) regulatory T cells (Tregs). These Tregs suppressed stimulatory DC-induced autologous Th2 cell proliferation and cytokine secretion in a contact-dependent manner. Our data indicate that IL-10-treated human DCs induce Th2 cell allergen tolerance ex vivo by driving the differentiation of Tregs.