Pre-Clinical Activity of Amino-Alcohol Dimeric Naphthoquinones as Potential Therapeutics for Acute Myeloid Leukemia.

BACKGROUND: The clinical outcomes of patients with Acute Myeloid Leukemia (AML) remain unsatisfactory. Therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. OBJECTIVE: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate antileukemic activity of the lead compound in vitro and a human AML xenograft mouse model. METHODS: We designed, synthesized, and performed structure-activity relationships of several rationally designed BiQ analogues with amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. RESULTS: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. CONCLUSION: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML.

Trajectories of changes in distress in counseling center clients: a replication study.

Objective: Latent growth mixture modeling (LGMM) and latent class growth analysis (LCGA) are methods of identifying subgroups of individuals with similar trajectories during the course of psychotherapy. Due to inconsistent methodology, previous LGMM/LCGA psychotherapy research has led to inconsistent findings. The purpose of this study was to contribute to our understanding of individual differences in change trajectories during psychotherapy using LGMM/LCGA by attempting to replicate a previous study by Owen et al. (2015. Trajectories of change in psychotherapy. Journal of Clinical Psychology, 71(9), 817-827). Method: This study used LGMM/LCGA to model trajectories of change in a sample of 2538 psychotherapy clients at a university student counseling center. This was a secondary analysis of naturalistically-collected outcome data using The Behavioral Health Measure. Results: LGMM models did not converge. A 2-class LCGA model was selected based on fit statistics and parsimony. One class was labeled as Slow and Steady Change Before Plateau, whereas the other was labeled as Early Rapid Change Before Plateau. We also extended these findings by considering variables associated with class membership. Conclusions: These classes followed similar trajectories to two of the classes identified by Owen et al. These results indicate that latent trajectory modeling may lead to replicable findings. Furthermore, these results have implications for managing expectations about change in psychotherapy.

Moderators of the efficacy of a web-based stress management intervention for college students.

High levels of stress are common among college students. Web-based interventions may be one way to teach students stress management skills. Although previous research has demonstrated the overall efficacy of web-based stress management interventions, little attention has been paid to who might benefit most from these interventions. In this study, we analyzed data from 3 prior studies (N = 782) to examine moderators of the efficacy of a web-based stress management intervention that focused on increasing perceived present control (i.e., aspects of stressors that are controllable in the present). Specific moderators assessed in regression analyses were baseline scores on outcome measures (perceived stress, stress symptoms, anxiety, depression) and the putative mechanism (perceived present control) of the intervention. Baseline symptom levels moderated the effects of the intervention on all outcomes, such that the intervention was more effective for students with more baseline symptoms. Baseline levels of present control had less consistent moderating effects, but significant interactions indicated that the intervention was more effective for those with lower levels of present control. The novel Johnson-Neyman technique was used to identify specific cutoff scores on these measures, below which the effect of the intervention was not significant, and scores on the measures associated with varying effect sizes. Findings from the Johnson-Neyman analyses can inform the development of screening criteria for future research and clinical application. Because the intervention was more effective for students with higher levels of baseline distress, it may be better suited for an indicated rather than universal prevention approach. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Supported Internet-Delivered Cognitive Behavioral Therapy Programs for Depression, Anxiety, and Stress in University Students: Open, Non-Randomised Trial of Acceptability, Effectiveness, and Satisfaction.

BACKGROUND: Many university campuses have limited mental health services that cannot cope with the high demand. One alternative is to use internet-delivered cognitive behavioral therapy (iCBT) as a way of tackling barriers such as lack of availability and scheduling issues. OBJECTIVE: This study aimed to assess feasibility, acceptability, effectiveness, and satisfaction of a supported iCBT intervention offering 3 programs on depression, anxiety, and stress to university students. The design was an open or nonrandomized feasibility trial. METHODS: Participants were recruited from 3 counseling centers at a large midwestern University in the United States. Those agreeing to take part chose 1 of 3 iCBT programs-Space from Depression, Space from Anxiety, or Space from Stress -all comprised 8 modules of media-rich interactive content. Participants were supported throughout the trial by a trained professional. The Patient Health Questionnaire 9 (PHQ-9), Generalized Anxiety Disorder 7 (GAD-7) questionnaire, and stress subscale of the Depression Anxiety and Stress Scale (DASS-21) were completed at baseline, 8 weeks, and 3-month follow-up. A Satisfaction With Treatment (SAT) questionnaire was completed at 8 weeks, and qualitative interviews were completed by a subsample of participants at 3 months. RESULTS: A total of 102 participants were recruited, with 52 choosing Space from Anxiety, 31 choosing Space from Depression, and 19 choosing Space from Stress. Mixed-effects models showed a significant decrease in symptoms of depression (F4=6.36, P<.001), anxiety (F4=7.97, P<.001), and stress (F4=8.50, P<.001) over time across all 3 programs. The largest decreases in PHQ-9 scores at 8 weeks were among participants who chose the Space from Depression program (d=0.84); at 3 months, the largest decreases in PHQ-9 scores were among those who chose the Space from Stress program (d=0.74). The largest decreases in GAD-7 scores were among those who chose the Space from Anxiety program (d=0.74 at 8 weeks and d=0.94 at 3 months). The largest decrease in DASS-21 stress subscale scores was among those who chose the Space from Stress program (d=0.49 at 8 weeks and d=1.16 at 3 months). The mean time spent using the platform per session was 27.4 min (SD 33.8), and participants completed 53% (SD 37.6) of the total program content on average. Most (37/53, 69%) participants found the programs helpful or very helpful and liked the convenience and flexibility of the intervention. Qualitative interviews (n=14) indicated the intervention met students' expectations, and they saw it as a valuable complement to face-to-face treatment. CONCLUSIONS: The iCBT programs tested in our study appear to be feasible, acceptable, and effective in a university environment. Participants described the benefits of having a flexible, supported Web-based intervention available on campus. Larger trials should be conducted to further test the effectiveness of supported Web-based interventions that give students a choice of program depending on their symptom profile.