Effect of Gemcitabine based chemotherapy on the immunogenicity of pancreatic tumour cells and T-cells.

PURPOSE: Chemotherapy for advanced pancreatic cancer has limited efficacy due to the difficultly of treating established tumours and the evolution of tumour resistance. Chemotherapies for pancreatic cancer are typically studied for their cytotoxic properties rather than for their ability to increase the immunogenicity of pancreatic tumour cells. In this study Gemcitabine in combination with immune modulatory chemotherapies Oxaliplatin, zoledronic acid and pomalidomide was studied to determine how combination therapy alters the immunogenicity of pancreatic tumour cell lines and subsequent T-cell responses. METHODS: Pancreatic tumour cell lines were stimulated with the chemotherapeutic agents and markers of immune recognition were assessed. The effect of chemotherapeutic agents on DC function was measured using uptake of CFSE-stained PANC-1 cells, changes in markers of maturation and their ability to activate CD8+ T-cells. The effect of chemotherapeutic agents on T-cell priming prior to activation using anti-CD3 and anti-CD28 antibodies was determined by measuring IFN-γ expression and Annexin V staining using flow cytometry. RESULTS: These agents demonstrate both additive and inhibitory properties on a range of markers of immunogenicity. Gemcitabine was notable for its ability to induce the upregulation of human leukocyte antigen and checkpoints on pancreatic tumour cell lines whilst inhibiting T-cell activation. Pomalidomide demonstrated immune modulatory properties on dendritic cells and T-cells, even in the presence of gemcitabine. DISCUSSION: These data highlight the complex interactions of different agents in the modulation of tumour immunogenicity and immune cell activation and emphasise the complexity in rationally designing chemo immunogenic combinations for use with immunotherapy

Factors associated with high‐dose antipsychotic prescriptions in outpatients with schizophrenia: An analysis of claims data from a Japanese prefecture

Abstract Background Antipsychotics are commonly prescribed in high doses in combination with multiple psychotropic drugs. This study focused on the high‐dose antipsychotic prescriptions in patients with schizophrenia, while aiming to identify their associations with patients’ characteristics and concurrent psychotropic prescriptions. Methods This cross‐sectional study used claims data from a prefecture in Japan, between October 2014 and March 2015, to investigate antipsychotic prescriptions in adult outpatients with schizophrenia. The objective variable was the presence/absence of a high‐dose prescription. The explanatory variables included sex, age (category), presence of comorbid conditions, and the use of psychiatrist's therapy. Results After exclusion, a total of 13 471 patients with schizophrenia were analyzed. The frequency of high‐dose prescriptions was higher in men, with chlorpromazine‐equivalent values highest in the age ranges of 45‐54 and 35‐44 years for men and women, respectively. Patients aged below 65 years with cerebrovascular diseases showed a decrease in high‐dose prescriptions. There was a high frequency of polypharmacy psychotropic drug use in combination with a high‐dose antipsychotic prescription in patients aged below 65 years. Conclusion High‐dose antipsychotics are often used in combination with several psychotropic agents in patients with schizophrenia. Our findings emphasize the need to evaluate the prescribing behavior of physicians to avoid high‐dose antipsychotic prescriptions for improved patient care

Hypoxia-mediated prior induction of monocyte-expressed HSP72 and HSP32 provides protection to the disturbances to redox balance associated with human sub-maximal aerobic exercise.

HSP72 is rapidly expressed in response to a variety of stressors in vitro and in vivo (including hypoxia). This project sought a hypoxic stimulus to elicit increases in HSP72 and HSP32 in attempts to confer protection to the sub-maximal aerobic exercise-induced disturbances to redox balance. Eight healthy recreationally active male subjects were exposed to five consecutive days of once-daily hypoxia (2,980 m, 75 min). Seven days prior to the hypoxic acclimation period, subjects performed 60 min of cycling on a cycle ergometer (exercise bout 1-EXB1), and this exercise bout was repeated 1 day post-cessation of the hypoxic period (exercise bout 2-EXB2). Blood samples were taken immediately pre- and post-exercise and 1, 4 and 8 h post-exercise for HSP72 and immediately pre, post and 1 h post-exercise for HSP32, TBARS and glutathione [reduced (GSH), oxidised (GSSG) and total (TGSH)], with additional blood samples obtained immediately pre-day 1 and post-day 5 of the hypoxic acclimation period for the same indices. Monocyte-expressed HSP32 and HSP72 were analysed by flow cytometry, with measures of oxidative stress accessed by commercially available kits. There were significant increases in HSP72 (P < 0.001), HSP32 (P = 0.03), GSSG (t = 9.5, P < 0.001) and TBARS (t = 5.6, P = 0.001) in response to the 5-day hypoxic intervention, whereas no significant changes were observed for GSH (P = 0.22) and TGSH (P = 0.25). Exercise-induced significant increases in HSP72 (P < 0.001) and HSP32 (P = 0.003) post-exercise in EXB1; this response was absent for HSP72 (P ≥ 0.79) and HSP32 (P ≥ 0.99) post-EXB2. The hypoxia-mediated increased bio-available HSP32 and HSP72 and favourable alterations in glutathione redox, prior to exercise commencing in EXB2 compared to EXB1, may acquiesce the disturbances to redox balance encountered during the second physiologically identical exercise bout

Glucose disturbances, cognitive deficits and white matter abnormalities in first-episode drug-naive schizophrenia

Disturbance of glucose metabolism may be implicated in cognitive deficits of schizophrenia in its early phases. Many studies have reported the important role of widespread disruption of white matter (WM) connectivity in pathogenesis, cognitive deficit and psychopathology of schizophrenia. However, no study has investigated their inter-relationships in drug-naive first episode (DNFE) patients with schizophrenia. Glucose metabolism parameters including fasting glucose, insulin and homeostasis model of assessment-insulin resistance (HOMA-IR) index, cognitive performance on the MATRICS Consensus Cognitive Battery (MCCB) and the voxel-wised WM fractional anisotropy (FA) values were examined using DTI in 39 DNFE schizophrenia and 31 control subjects. The Positive and Negative Syndrome Scale was utilized for clinical symptoms. The patients showed significantly greater fasting plasma levels of glucose and insulin and HOMA-IR, and poorer cognitive scores, together with widespread reduced FA values in five brain areas, including left and right corpus callosum, superior longitudinal fasciculus, posterior thalamic radiation, and corona radiata (all p<0.05). Association analysis showed that glucose level was positively associated with Digital Sequence Test and Continuous Performance Test, but negatively with FA values in posterior thalamic radiation and left corpus callosum in patients (all p<0.05). Furthermore, multiple regression analysis revealed that the interactions of glucosexFA in left corpus callosum, longitudinal fasciculus and corona radiata were independent contributors to the Brief Visuospatial Memory Test (BVMT) of MCCB, while the interaction of glucosexFA in left corpus callosum, or in longitudinal fasciculus was associated with MCCB mazes and Trail Making A Test, respectively. Therefore, abnormal glucose metabolism, cognitive impairment and widespread disruption of WM structure occur in an early course of schizophrenia onset. An interaction between glucose metabolism abnormality and the WM dysconnectivity may lead to cognitive impairment