1015 Background: Atezolizumab (anti-PD-L1) plus nab-paclitaxel was shown to improve outcomes in mTBNC in a phase III clinical trial. Subjects were required to be > 12 months from curative-intent therapy in this trial. It remains unknown whether non-taxane chemo + anti-PD-1/L1 will be beneficial in mTNBC, or whether this approach is effective in rapidly-progressing patients ( < 12 mo from curative-intent therapy). Methods: mTNBC patients were enrolled in a phase Ib study of anti-PD-1 (pembro, 200mg IV q3w) plus physician’s choice chemo (cape: n = 14, 2000mg BID, 7d on/7d off; or taxol: n = 14, 80mg/m2 q1w). Primary/secondary objectives were to evaluate safety/tolerability (primary) and RECIST1.1 response (w12). The exploratory objective was to explore for differences in immunomodulation according to chemo choice. Mixed effects models were employed to compare the longitudinal effects of chemo on peripheral immune cells (flow cytometry) and T-cell diversity (Immunoseq assay). Results: Enrollment of the trial is complete (n = 28), with 100% of evaluable patients tolerating therapy (n = 22) as of 2/1/2019. Cape ORR was 43% (5 PR, 1 CR, 2 SD) with median PFS = 155d. Taxol ORR was 25% (1 CR, 1 PR, 3 SD) with median PFS = 99d. Subjects enrolled < 12 months from curative-intent therapy had numerically lower response (ORR = 27%, 1 CR, 2 PR, 3 SD) than subjects without rapid progression (ORR = 45%, 1 CR, 4 PR, 2 SD). No significant differences in immunomodulation were observed according to chemo type, however both cape & taxol were associated with declines in T-cell quantity (CD4 p < .02, CD8 p < .04) and Immunoseq T-cell fraction over time. Conclusions: Pembro plus cape or taxol is safe with encouraging efficacy, however activity may be lower in the setting of rapid progression following curative-intent chemo. Cape+pembro efficacy is favorable with no measurable differences in immunomodulation, and therefore cape may be preferred as a chemo backbone in selected patients. Both cape and taxol are associated with iatrogenic declines in T-cell quantity, which may explain the observed dropoff in anti-PD-1/L1 activity in later lines. Clinical trial information: NCT02734290.
Objective: Preventive interventions for postpartum depression (PPD) are critical for women at elevated risk of PPD. Mindfulness based cognitive therapy -perinatal depression (MBCT-PD) is a preventive intervention that has been shown to reduce risk for PPD in women with a prior history of depression. The objective of this clinical trial is to examine two potential mechanisms of action of MBCT-PD, emotion regulation and cognitive control, using behavioral and neuroimaging methods. Method: This baseline protocol describes a randomized control trial (RCT) with two arms, MBCT-PD and treatment as usual (TAU). We plan on enrolling 74 females with a prior history of a major depressive episode, with 37 participants randomized to each arm. Participants in the MBCT-PD arm will receive MBCT-PD during pregnancy, and the TAU group will receive standard prenatal care. All participants will complete the Center for Epidemiological Studies Depression Scale -Revised (CESD-R), Emotion Regulation Questionnaire (ERQ), and classic Stroop task at multiple points from pregnancy through six months postpartum. Participants will also complete an fMRI scan at six weeks postpartum. Results: All primary outcomes are collected at six weeks postpartum. Primary behavioral outcomes include: depressive symptoms on the CESD-R, cognitive reappraisal on the ERQ, and Stroop task performance. In parallel, the primary neurobiological outcomes include whole-brain activation during fMRI tasks when participants 1) regulate emotional responding and 2) engage cognitive control. Conclusions: This results of this innovative RCT will help identify potential behavioral and neurobiological mechanisms of action of preventive interventions for PPD for in-depth examination in larger scale RCTs.
Centella asiatica is an herb used in Ayurvedic and traditional Chinese medicine for its beneficial effects on brain health and cognition. Our group has previously shown that a water extract of Centella asiatica (CAW) elicits cognitive-enhancing effects in animal models of aging and Alzheimer’s disease, including a dose-related effect of CAW on memory in the 5xFAD mouse model of ß-amyloid accumulation. Here, we endeavor to elucidate the mechanisms underlying the effects of CAW in the brain by conducting a metabolomic analysis of cortical tissue from 5xFAD mice treated with increasing concentrations of CAW. Tissue was collected from 8-month-old male and female 5xFAD mice and their wild-type littermates treated with CAW (0, 200, 500, or 1,000 mg/kg/d) dissolved in their drinking water for 5 weeks. High-performance liquid chromatography coupled to high-resolution mass spectrometry analysis was performed and relative levels of 120 annotated metabolites were assessed in the treatment groups. Metabolomic analysis revealed sex differences in the effect of the 5xFAD genotype on metabolite levels compared to wild-type mice, and variations in the metabolomic response to CAW depending on sex, genotype, and CAW dose. In at least three of the four treated groups (5xFAD or wild-type, male or female), CAW (500 mg/kg/d) significantly altered metabolic pathways related to purine metabolism, nicotinate and nicotinamide metabolism, and glycerophospholipid metabolism. The results are in line with some of our previous findings regarding specific mechanisms of action of CAW (e.g., improving mitochondrial function, reducing oxidative stress, and increasing synaptic density). Furthermore, these findings provide new information about additional, potential mechanisms for the cognitive-enhancing effect of CAW, including upregulation of nicotinamide adenine dinucleotide in the brain and modulation of brain-derived neurotrophic factor. These metabolic pathways have been implicated in the pathophysiology of Alzheimer’s disease, highlighting the therapeutic potential of CAW in this neurodegenerative disease.
Impulsivity has been linked to academic performance in the context of Attention Deficit Hyperactivity Disorder, though its influence on a wider spectrum of students remains largely unexplored, particularly in the context of STEM learning (i.e. science, technology, engineering, and math). STEM learning was hypothesized to be more challenging for impulsive students, since it requires the practice and repetition of tasks as well as concerted attention to task performance. Impulsivity was assessed in a cross-sectional sample of 2,476 students in grades 6–12. Results show impulsivity affects a larger population of students, not limited to students with learning disabilities. Impulsivity was associated with lower sources of self-efficacy for science (SSSE), interest in most STEM domains (particularly math), and self-reported STEM skills. The large negative effect size observed for impulsivity was opposed by higher mindset, which describes a student’s belief in the importance of effort when learning is difficult. Mindset had a large positive effect size associated with greater SSSE, STEM interest, and STEM skills. When modeled together, results offer that mindset interventions may benefit impulsive students who struggle with STEM. Together, these data suggest important interconnected roles for impulsivity and mindset that can influence secondary students’ STEM trajectories.
Objective: To test the association of parents' concerns with early intervention (EI) developmental services outcomes including evaluation, eligibility, and enrollment in services. Method: We collected survey data on parents' concerns and EI service use data from a sample of 428 children referred to EI from 2016 to 2018 in 6 Oregon primary care clinics serving lower-income families as part of a developmental and autism spectrum disorder screening intervention. We assessed EI service use trajectories and associations of the presence of parent concern, age of child at the time of parents' concerns, number of concerns, and type of provider concern, with EI evaluation, EI eligibility, and enrollment in EI services, using bivariate testing and multivariable logistic regression. Results: Only 22.9% of children referred to EI were enrolled in services 6 months later. Children whose parents had developmental and/or behavioral concerns were more likely to receive an EI evaluation and were also more likely to be eligible for services, compared with children whose parents had no concerns. There was no association between age, number of concerns, and type of concern with EI evaluation, eligibility, or services enrollment. Conclusion: Although only a minority of children referred to EI enrolled in services, the presence of parent concern is strongly associated with EI services evaluation and eligibility outcomes. Study results suggest that providers should assess the presence of parent concern when deciding on EI referrals and provide more support to parents who are not concerned at all.
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