Fibroblastic tumour stroma comprising mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs) promotes the invasive and metastatic properties of tumour cells. Here we show that activated CD8+ T cell-derived extracellular vesicles (EVs) interrupt fibroblastic stroma-mediated tumour progression. Activated CD8+ T cells from healthy mice transiently release cytotoxic EVs causing marked attenuation of tumour invasion and metastasis by apoptotic depletion of mesenchymal tumour stromal cells. Infiltration of EV-producing CD8+ T cells is observed in neovascular areas with high mesenchymal cell density, and tumour MSC depletion is associated with preferential engulfment of CD8+ T cell EVs in this setting. Thus, CD8+ T cells have the capacity to protect tumour progression by EV-mediated depletion of mesenchymal tumour stromal cells in addition to their conventional direct cytotoxicity against tumour cells.

ObjectiveWe aimed at investigating factors associated with social isolation and being homebound in older patients with diabetes.DesignCross-sectional study.SettingsThose undergoing outpatient treatments at Ise Red Cross Hospital, Mie Prefecture.ParticipantsPatients with diabetes aged ≥65 years.Primary and secondary outcome measuresSocial isolation was defined as indulging in less than one interaction per week with individuals other than cohabiting family members. We defined homebound as going outside home less than once a day. To identify factors associated with social isolation and being homebound, we performed logistic regression analysis. The dependent variable was social isolation or homebound and independent variables were basic attributes, glycaemic parameters, complications and treatment details.ResultsWe analysed 558 cases (320 men and 238 women). Among these, 174 (31.2%) were socially isolated; meanwhile, 87 (15.6%) were homebound. The glycoalbumin/haemoglobin A1c ratio (OR 4.52; 95% CI 1.07 to 19.1; p=0.040) and the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) scores (OR 0.72; 95% CI 0.57 to 0.90; p=0.006) had significant associations with social isolation. TMIG-IC scores (OR 0.78; 95% CI 0.66 to 0.92; p=0.003) and insulin use (OR 4.29; 95% CI 1.14 to 16.1; p=0.031) were associated with being homebound.ConclusionIn older patients with diabetes, glycaemic fluctuations and insulin use are associated with social isolation and being homebound, respectively. In addition, a decline in higher level functional capacity is a common factor associated with social isolation and being homebound. Thus, it is important to pay attention to social isolation and being homebound when a decline in higher level functional capacity, increased glycaemic fluctuations and insulin use in older patients with diabetes are observed.

Background: When considering the administration of glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, or metformin, it is important to understand their weight loss effect as well as the degree of muscle loss caused by each drug in clinical practice. Objective: To comparatively examine the effects of GLP-1RAs and oral antidiabetic drugs, including SGLT2 inhibitors and metformin, on muscle mass and body weight in patients with type 2 diabetes via a network meta-analysis of randomized controlled trials. Methods: We included randomized controlled trials evaluating the effects of antidiabetic drugs on muscle mass and body weight. Mean difference (MD) and 95% confidence intervals (CIs) were calculated using a random-effects network metaanalysis. Results: Of the studies identified, 18 randomized controlled trials (1, 363 subjects) satisfied the eligibility criteria. In all studies, effects of these drugs on fat-free mass (FFM) were evaluated. Therefore, FFM, which is used as an alternative index of muscle mass, was included in the study. Semaglutide (MD: −1.68, 95% CI: −2.84 to −0.52), dapagliflozin (−0.53, −0.93 to −0.13), and canagliflozin (−0.90, −1.73 to −0.07) showed a significant decrease in FFM compared with the placebo. Metformin did not show a significant decrease in FFM compared with the placebo. When compared with the placebo, semaglutide, dapagliflozin, ipragliflozin, and canagliflozin showed a significant weight loss. Conclusion: Although semaglutide, dapaglifrozin, and canagliflozin have a large weight loss effect, it is important to pay attention to muscle loss because a decrease in FFM was observed.

Adoptive cell therapy with lymphocytes that have been genetically engineered to express tumor-reactive T-cell receptors (TCR) is a promising approach for cancer immunotherapy. We have been exploring the development of TCR gene therapy targeting cancer ⁄ testis antigens, including melanoma-associated antigen (MAGE) family antigens, that are ideal targets for adoptive T-cell therapy. The efficacy of TCR gene therapy targeting MAGE family antigens, however, has not yet been evaluated in vivo. Here, we demonstrate the in vivo antitumor activity in immunodeficient non-obese diabetic ⁄ SCID ⁄ cc null (NOG) mice of human lymphocytes genetically engineered to express TCR specific for the MAGE-A4 antigen. Polyclonal T cells derived from human peripheral blood mononuclear cells were transduced with the ab TCR genes specific for MAGE-A4, then adoptively transferred into NOG mice inoculated with MAGE-A4 expressing human tumor cell lines. The transferred T cells maintained their effector function in vivo, infiltrated into tumors, and inhibited tumor growth in an antigen-specific manner. The combination of adoptive cell therapy with antigen peptide vaccination enhanced antitumor activity, with improved multifunctionality of the transferred cells. These data suggest that TCR gene therapy with MAGE-A4-specific TCR is a promising strategy to treat patients with MAGE-A4-expressing tumors; in addition, the acquisition of multifunctionality in vivo is an important factor to predict the quality of the T-cell response during adoptive therapy with human lymphocytes. (Cancer Sci 2012; 103: 17-25)

The aim of this study was to evaluate the effects of flash glucose monitoring on dietary variety, physical activity, and self-care behavior in patients with diabetes. This study included outpatients with diabetes using insulin who presented at the Department of Diabetes and Metabolism of the Ise Red Cross Hospital. Before initiating flash glucose monitoring and 12 weeks after its initiation, blood glucose-related parameters were assessed and self-administered questionnaires were completed (Dietary Variety Score (DVS), the International Physical Activity Questionnaire (IPAQ), the Summary of Diabetes Self-Care Activities Measure (SDSCA), and the Diabetes Treatment Satisfaction Questionnaire (DTSQ)) and compared between the two time points. We analyzed 42 patients with type 1 diabetes mellitus and 48 patients with type 2 diabetes mellitus. In patients with type 2 diabetes mellitus, but not type 1 diabetes mellitus, there was an increase in moderate/high category scores for IPAQ (P<0.001) and for treatment satisfaction reported via DTSQ. Furthermore, in patients with type 2 diabetes mellitus, the glycemic excursion index improved significantly and HbA1c decreased significantly (from 7.7 (1.2) to 7.4 (0.8), P=0.025). Results showed that standard deviation and mean amplitude of glycemic excursions significantly decreased in patients with type 1 diabetes mellitus (from 71.2 (20.4) to 66.2 (17.5), P=0.033 and from 124.6 (31.9) to 108.1 (28.4), P<0.001, respectively). Flash glucose monitoring is a useful tool to improve physical activity in patients with type 2 diabetes.