PAR1-mediated NFΚB activation promotes survival of prostate cancer cells through a Bcl-xL-dependent mechanism

We have previously reported that protease-activated receptor 1 (PAR1 or thrombin receptor) is over-expressed in metastatic prostate cancer cell lines compared to prostate epithelial cells. In this study, we examined 1,074 prostate biopsies by tissue microarray analysis and demonstrated that PAR1 expression is significantly increased in prostate cancer compared to normal prostate epithelial cells and benign prostatic hyperplasia. We hypothesized that PAR1 activation contributed to prostate cancer cell progression. We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide (TRAP6), in androgen-independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFΚB p65 subunit. IL-6 and IL-8 levels were also elevated in conditioned media by at least two-fold within 4–6 h of PAR1 activation. This induction of cytokine production was abrogated by pretreatment of cells with the NFΚB inhibitor caffeic acid phorbol ester. The p38 and ERK1/2 MAPK signaling cascades were also activated by PAR1 stimulation, whereas the SAPK/JNK pathway was unaffected. Inhibition of p38 and ERK1/2 by SB-203589 and PD-098059, respectively, did not abrogate NFΚB activity, suggesting an independent induction of NFΚB by PAR1 stimulation. Furthermore, TUNEL assay showed that activation of PAR1 attenuated docetaxel induced apoptosis through the upregulation of the Bcl-2 family protein Bcl-xL. Akt activation was not observed, suggesting that drug resistance induced by PAR1 was independent of PI3K signaling pathway. Because thrombin and PAR1 are over-expressed in prostate cancer patients, targeting the inhibition of their interaction may attenuate NFΚB signaling transduction resulting in decreased drug resistance and subsequent survival of prostate cancer cells. © 2005 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48764/1/20533_ftp.pd

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Kvinnors erfarenhet av postoperativ smärta och smärtlindring efter kejsarsnitt

Background: Many women experience high levels of pain after caesarean birth. Adequate postoperative pain treatment is important for the mother to be able to breastfeed, take care of the infant and experience a positive birth. Objective: The overall aim is to study women’s experience of postoperative pain and pain relief after caesarean birth. Method: A quantitative retrospective survey. Data were collected thru a questionnaire from Centralsjukhuset in Karlstad and Falu Larsarett in Sweden. Ninety-eight women participated in the study. Data was analysed with descriptive and comparative statistic. Result: Eighty percent of the women rated the pain with VAS = 4 during the first 24 hours post operative. Those who had to undergo acute caesarean birth rated significant higher levels of pain compared with those who had undergone planned caesarean birth. Despite high level of pain the women were satisfied with the pain relief they received. Both the ability to breastfeed and take care of the infant were affected by pain the first 24 hours post operative. Those who had undergone emergency caesarean birth experienced in greater extend the birth in a negative way. Conclusion: Postoperative pain affects the women’s ability to breastfeed and takes care of here infant. Adequate pain management is therefore important. The women who had to undergo emergency caesarean birth have a more negative birth experience. Midwifes have an important role to inform and support the women in processing here experience

Kvinnors erfarenhet av postoperativ smärta och smärtlindring efter kejsarsnitt

Background: Many women experience high levels of pain after caesarean birth. Adequate postoperative pain treatment is important for the mother to be able to breastfeed, take care of the infant and experience a positive birth. Objective: The overall aim is to study women’s experience of postoperative pain and pain relief after caesarean birth. Method: A quantitative retrospective survey. Data were collected thru a questionnaire from Centralsjukhuset in Karlstad and Falu Larsarett in Sweden. Ninety-eight women participated in the study. Data was analysed with descriptive and comparative statistic. Result: Eighty percent of the women rated the pain with VAS = 4 during the first 24 hours post operative. Those who had to undergo acute caesarean birth rated significant higher levels of pain compared with those who had undergone planned caesarean birth. Despite high level of pain the women were satisfied with the pain relief they received. Both the ability to breastfeed and take care of the infant were affected by pain the first 24 hours post operative. Those who had undergone emergency caesarean birth experienced in greater extend the birth in a negative way. Conclusion: Postoperative pain affects the women’s ability to breastfeed and takes care of here infant. Adequate pain management is therefore important. The women who had to undergo emergency caesarean birth have a more negative birth experience. Midwifes have an important role to inform and support the women in processing here experience

The influence of emotional stimuli on attention orienting and inhibitory control in pediatric anxiety

Background: Anxiety disorders are highly prevalent in children and adolescents, and are associated with aberrant emotion-related attention orienting and inhibitory control. While recent studies conducted with high-trait anxious adults have employed novel emotion-modified antisaccade tasks to examine the influence of emotional information on orienting and inhibition, similar studies have yet to be conducted in youths.Methods: Participants were 22 children/adolescents diagnosed with an anxiety disorder, and 22 age-matched healthy comparison youths. Participants completed an emotion-modified antisaccade task that was similar to those used in studies of high-trait anxious adults. This task probed the influence of abruptly appearing neutral, happy, angry, or fear stimuli on orienting (prosaccade) or inhibitory (antisaccade) responses.Results: Anxious compared to healthy children showed facilitated orienting toward angry stimuli. With respect to inhibitory processes, threat-related information improved antisaccade accuracy in healthy but not anxious youth. These findings were not linked to individual levels of reported anxiety or specific anxiety disorders.Conclusions: Findings suggest that anxious relative to healthy children manifest enhanced orienting toward threat-related stimuli. In addition, the current findings suggest that threat may modulate inhibitory control during adolescent development