Rac1 as a therapeutic target in ovarian cancer

Rac1 is a high value therapeutic target for cancer based on its tumor promoting activities, yet clinical applications targeting Rac1 are in their infancy. High expression and hyperactivation of Rac1 in ovarian cancer, along with our identification of R-ketorolac as a novel Rac1 and Cdc42 selective inhibitor with translational potential, prompt us to test the hypothesis that targeting Rac1 has therapeutic utility for ovarian cancer. Ascites tumor cell samples from ovarian cancer patients in a prospective study receiving racemic ketorolac for clinically indicated use in pain relief were previously reported to show time dependent reduction of Rac1 and Cdc42 activities post-treatment. New RNA seq data of these patient samples reveals significant changes of genes involved in cell adhesion, cytokine-mediated signaling and cytokine production pathways. Conversely, the identified downregulated genes were overexpressed and associated with worse survival in ovarian cancer patients analyzed through The Cancer Genome Atlas (TCGA). Among the downregulated genes in the NOD pathway are chemokines and pro-inflammatory cytokines. Follow-up cytokine panels from patients confirm that racemic ketorolac treatment reduces the levels of immunosuppressive cytokines IL-6, IL-10 and RANTES in ascites fluids. Together, these data indicate there may be a benefit to the anti-inflammatory activity of the S- enantiomer, as well as the GTPase inhibitory activity of the R- enantiomer of ketorolac for ovarian cancer treatment

Overt and relational aggression and victimization: Multiple perspectives within the school setting

The current study involved a comprehensive comparative examination of overt and relational aggression and victimization across multiple perspectives in the school setting (peers, teachers, observers in the lunchroom, self-report). Patterns of results involving sociometic status, ethnicity and gender were explored among 4th graders, with particular emphasis on girls. Controversial and rejected children were perceived as higher on both forms of aggression than other status groups, but only rejected children were reported as victims. Both European American and African American girls showed a greater tendency toward relational aggression and victimization than overt aggression or victimization. Results indicated negative outcomes associated with both relational and overt victimization and especially overt aggression for the target girl sample. Poorer adjustment and a socially unskillful behavioral profile were found to be associated with these three behaviors. However, relational aggression did not evidence a similar negative relation to adjustment nor was it related to many of the behaviors examined in the current study. Implications of these results are discussed

Arene ruthenium dithiolato-carborane complexes for boron neutron capture theory (BNCT)

YesWe report the effect of low-energy thermal neutron irradiation on the antiproliferative activities of a highly hydrophobic organometallic arene ruthenium dithiolatoecarborane complex [Ru(p-cymene) (1,2- dicarba-closo-dodecarborane-1,2-dithiolato)] (1), and of its formulation in Pluronic® triblock copolymer P123 coreeshell micelles (RuMs). Complex 1 was highly active, with and without neutron irradiation, towards human ovarian cancer cells (A2780; IC50 0.14 mM and 0.17 mM, respectively) and cisplatinresistant human ovarian cancer cells (A2780cisR; IC50 0.05 and 0.13 mM, respectively). Complex 1 was particularly sensitive to neutron irradiation in A2780cisR cells (2.6 more potent after irradiation compared to non-irradiation). Although less potent, the encapsulated complex 1 as RuMs nanoparticles resulted in higher cellular accumulation (2.5 ), and was sensitive to neutron irradiation in A2780 cells (1.4 more potent upon irradiation compared to non-irradiation).We thank the Leverhulme Trust (Early Career Fellowship No. ECF-2013-414 to NPEB), the University of Warwick (Grant No. RD14102 to NPEB), the University of Birmingham/EPSRC Follow-on- Fund (Grant No UOBFOF026 to BP), the ERC (Grant No. 247450 to PJS), EPSRC (EP/F034210/1 to PJS)

Hippocampal inactivation enhances taste learning

Learning tasks are typically thought to be either hippocampal-dependent (impaired by hippocampal lesions) or hippocampal-independent (indifferent to hippocampal lesions). Here, we show that conditioned taste aversion (CTA) learning fits into neither of these categories. Rats were trained to avoid two taste stimuli, one novel and one familiar. Muscimol infused through surgically implanted intracranial cannulae temporarily inactivated the dorsal hippocampus during familiarization, subsequent CTA training, or both. As shown previously, hippocampal inactivation during familiarization enhanced the effect of that familiarization on learning (i.e., hippocampal inactivation enhanced latent inhibition of CTA); more novel and surprising, however, was the finding that hippocampal inactivation during training sessions strongly enhanced CTA learning itself. These phenomena were not caused by specific aspects of our infusion technique—muscimol infusions into the hippocampus during familiarization sessions did not cause CTAs, muscimol infusions into gustatory cortex caused the expected attenuation of CTA, and hippocampal inactivation caused the expected attenuation of spatial learning. Thus, we suggest that hippocampal memory processes interfere with the specific learning mechanisms underlying CTA, and more generally that multiple memory systems do not operate independently

Girl Talk: Gossip, Friendship, and Sociometric Status

This study examined the characteristics of gossip among fourth-grade girls and their close friends. Sixty friendship dyads were videotaped as they engaged in conversation, and their gossip was coded. Analyses revealed gossip to be a dominant feature of their interaction and that it was primarily neutral in valence. Sociometrically popular girls and their friends were observed to gossip more about peers, and their gossip was more evaluative than that between rejected girls and their friends. Gossip frequency and valence related to observed friendship closeness and friendship quality. Race differences in the characteristics of gossip were also explored. The study results are important in our efforts to develop a fuller understanding of the important interpersonal process of gossip and the functions that it serves in the context of close friendships

Social Network Centrality and Leadership Status: Links with Problem Behaviors and Tests of Gender Differences

Seventh-grade students (N = 324) completed social cognitive maps to identify peer groups and peer group leaders, sociometric nominations to describe their peers’ behaviors, and questionnaires to assess their own behaviors. Peer group members resembled one another in levels of direct and indirect aggression and substance use; girls’ cliques were more behaviorally homogenous than were boys’ cliques. On average, leaders (especially if they were boys) were perceived as engaging in more problem behaviors than were nonleaders. In girls’ cliques, peripheral group members were more similar to their group leader on indirect aggression than were girls who were more central to the clique. Peer leaders perceived themselves as being more able to influence peers but did not differ from nonleaders in their perceived susceptibility to peer influence. The findings contribute to our understanding of processes through which influence may occur in adolescent peer groups

Perceptions of Friendship Quality and Observed Behaviors with Friends: How do Sociometrically Rejected, Average, and Popular Girls Differ?

This study examined associations between sociometric status and friendship quality using observational and questionnaire data from 139 fourth-grade girls and their friends. Multivariate analyses of covariance (controlling for ethnicity and socioeconomic status) showed that rejected girls and their friends did not differ in their reported friendship quality compared to average or popular girls. However, coded behavioral observations revealed that compared to other girls, rejected girls displayed more negative affect, bossiness, and deviance but less positive gossip, negative gossip, prosocial behavior, and social competence. Furthermore, as a dyad, compared to other girls, rejected girls and their friends exhibited less behavioral maturity and poorer conflict resolution skills. These results are important in advancing understanding of ways in which rejected girls may perpetuate their problems in peer contexts

Dual Actions of Ketorolac in Metastatic Ovarian Cancer

Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the peri-operative window is an under-explored opportunity to mitigate these consequences of surgery and influence the course of metastatic disease to improve patient outcomes. One drug associated with improved survival in cancer patients is ketorolac. Ketorolac is a chiral molecule administered as a 1:1 racemic mixture of the S- and R-enantiomers. The S-enantiomer is considered the active component for its FDA indication in pain management with selective activity against cyclooxygenase (COX) enzymes. The R-enantiomer has a previously unrecognized activity as an inhibitor of Rac1 (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42) GTPases. Therefore, ketorolac differs from other non-steroidal anti-inflammatory drugs (NSAIDs) by functioning as two distinct pharmacologic entities due to the independent actions of each enantiomer. In this review, we summarize evidence supporting the benefits of ketorolac administration for ovarian cancer patients. We also discuss how simultaneous inhibition of these two distinct classes of targets, COX enzymes and Rac1/Cdc42, by S-ketorolac and R-ketorolac respectively, could each contribute to anti-cancer activity