Faculty Bibliography

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser²⁰²/Thr²⁰⁵-immunoreactivity (AT8-ir) and pTAU-Ser^199/202-ir at 2 days, and pTAU-Thr²³¹-ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.

B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T cells (CAR-Ts) used in multiple myeloma (MM) are rapidly becoming a mainstay in the treatment of relapsed/refractory (R/R) disease, and CAR-T expansion after infusion has been shown to inform depth and duration of response (DoR), but measuring this process remains investigational. This multicenter study describes the kinetics and prognostic impact of absolute lymphocyte count (ALC) in the first 15 days after CAR-T infusion in 156 patients with relapsed MM treated with the BCMA-targeting agents ciltacabtagene autoleucel and idecabtagene vicleucel. Patients with higher maximum ALC (ALCmax) had better depth of response, progression-free survival (PFS), and DoR. Patients with ALCmax >1.0 × 103/μL had a superior PFS (30.5 months vs 6 months; P < .001) compared with those with ≤1.0 × 103/μL, whereas patients with ALCmax ≤0.5 × 103/μL represent a high-risk group with early disease progression and short PFS (hazard ratio, 3.4; 95% confidence interval, 2-5.8; P < .001). In multivariate analysis, ALCmax >1.0 × 103/μL and nonparaskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for international staging systemic staging, age, CAR-T product, high-risk cytogenetics, and the number of previous lines. Moreover, our flow cytometry data suggest that ALC is a surrogate for BCMA CAR-T expansion and can be used as an accessible prognostic marker. We report, to our knowledge, for the first time the association of ALC after BCMA CAR-T infusion with clinical outcomes and its utility in predicting response in patients with R/R MM.

The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data in this patient population. There is a theoretical risk of compromising transplanted organ function with CAR T cell therapy; conversely, organ transplantation-related immunosuppression can alter the function of CAR T cells. Given the prevalence of post-transplantation lymphoproliferative disease, which often can be difficult to treat with conventional chemoimmunotherapy, understanding the risks and benefits of delivering lymphoma-directed CAR T cell therapy in solid organ transplant recipients is of utmost importance. We sought to determine the efficacy of CAR T cell therapy in solid organ transplant recipients as well as the associated adverse effects, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and compromised solid organ transplant function. We conducted a systematic review and meta-analysis of adult recipients of solid organ transplant who received CAR T cell therapy for non-Hodgkin lymphoma. Primary outcomes included efficacy, defined as overall response (OR), complete response (CR), progression-free survival, and overall survival, as well as rates of CRS and ICANS. Secondary outcomes included rates of transplanted organ loss, compromised organ function, and alterations to immunosuppressant regimens. After a systematic literature review and 2-reviewer screening process, we identified 10 studies suitable for descriptive analysis and 4 studies suitable for meta-analysis. Among all patients, 69% (24 of 35) achieved a response to CAR T cell therapy, and 52% (18 of 35) achieved a CR. CRS of any grade occurred in 83% (29 of 35), and CRS grade ≥3 occurred in 9% (3 of 35). Sixty percent of the patients (21 of 35) developed ICANS, and 34% (12 of 35) developed ICANS grade ≥3. The incidence of any grade 5 toxicity among all patients was 11% (4 of 35). Fourteen percent of the patients (5 of 35) experienced loss of the transplanted organ. Immunosuppressant therapy was held in 22 patients but eventually restarted in 68% of them (15 of 22). Among the studies included in the meta-analysis, the pooled OR rate was 70% (95% confidence interval [CI], 29.2% to 100%; I² = 71%) and the pooled CR rate was 46% (95% CI, 25.4% to 67.8%; I² = 29%). The rates of any grade CRS and grade ≥3 CRS were 88% (95% CI, 69% to 99%; I² = 0%) and 5% (95% CI, 0% to 21%; I² = 0%), respectively. The rates of any grade ICANS and ICANS grade ≥3 were 54% (95% CI, 9% to 96%; I² = 68%) and 40% (95% CI, 3% to 85%; I² = 63%), respectively. The efficacy of CAR T cell therapy in solid organ transplant recipients is comparable to that in the general population as reported in prior investigational studies, with an acceptable toxicity profile in terms of CRS, ICANS, and transplanted organ compromise. Further studies are needed to determine long-term effects on organ function, sustained response rates, and best practices peri-CAR T infusion period in this patient population.

The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.

BACKGROUND:Iron deficiency in patients with heart failure (HF) is underdiagnosed and undertreated. The role of intravenous (IV) iron is well-established to improve quality of life measures. Emerging evidence also supports its role in preventing cardiovascular events in patients with HF. METHODOLOGY:We conducted a literature search of multiple electronic databases. Randomized controlled trials that compared IV iron to usual care among patients with HF and reported cardiovascular (CV) outcomes were included. Primary outcome was the composite of first heart failure hospitalization (HFH) or CV death. Secondary outcomes included HFH (first or recurrent), CV death, all-cause mortality, hospitalization for any cause, gastrointestinal (GI) side effects, or any infection. We performed trial sequential and cumulative meta-analyses to evaluate the effect of IV iron on the primary endpoint, and on HFH. RESULTS: = 0 %; NNT 19). There was no significant difference in the risk of CV death, all-cause mortality, adverse GI events, or any infection among patients receiving IV iron compared to usual care. The observed benefits of IV iron were directionally consistent across trials and crossed both the statistical and trial sequential boundaries of benefit. CONCLUSION:In patients with HF and iron deficiency, the addition of IV iron to usual care reduces the risk of HFH without affecting the risk of CV or all-cause mortality.

How the labor force participation of mothers of young children responds to unconditioned cash support remains an open question in policy debates. Using data from Baby's First Years, a large-scale randomized controlled study, we generate new estimates of the impact of an unconditional monthly cash transfer on maternal employment behavior through a child's first four years of life. We find no overall statistically detectable differences in whether mothers participated in the paid workforce or on total household earnings. Receipt of the cash transfer appears to have reduced hours of maternal work during the height of the pandemic in 2020-21.

BACKGROUND/UNASSIGNED:The burden of pediatric mental disorders in low-and middle-income countries (LMICs) is tremendous, but solutions for addressing the burden remain limited. Although digital solutions have potential to improve prevention services, such solutions have not been systematically tested in these countries. OBJECTIVE/UNASSIGNED:This study explores the use of a digital parenting intervention tool designed for pediatric behavioral health, known as the Pediatric-Behavioral Health Digital Tool, in a preventive service model for low resource communities. We study the feasibility of implementing this new digital health service model and preliminary estimate the potential impacts on parenting and child social emotional outcomes when the program is implemented in faith-based organizations in Uganda. The Pediatric-Behavioral Health Digital Tool is a preventive intervention designed to be implemented by trained community-health-workers to facilitate caregivers' access to the preventive mental health service in community for their young children. The tool is based on the screening, brief intervention, and referral to treatment prevention service model for promoting pediatric behavioral and mental health. METHODS/UNASSIGNED:The evaluation study was designed using a pre-post assessment design. The content in Pediatric-Behavioral Health Digital Tool was co-designed with local expert and iteratively adapted based on parents and caregivers as well as community-health-workers and experts who were invited to provide their feedback and suggestions for improvements in content, functions, and delivery model through a series of focus groups and workshops. This pilot evaluation focuses on the pre-post changes of the intervention families (91 families) and 10 community-health-workers. RESULTS/UNASSIGNED:We found high acceptability, appropriateness, and usefulness of the program based on the intervention families' community-health-workers' report. Intervention parents felt safe in using the digital toolkit. Parents felt comfortable for the CHWs asked them personal questions. In estimating the impacts, we found some expected findings on parenting and child social emotional health. Specifically, we found intervention parents become more mindful in their parenting (d=1.61, p=.049), and felt more effective in discipline their child's misbehavior (d=1.29, p=.003) after they receive the intervention. For children, we found improvement on children's social emotional outcomes, measured by decreased parent-child conflict (d=-1.08, p=.002) and increased child emotional regulation skills (d=1.0, p=.049) after their parents receive the intervention. CONCLUSIONS/UNASSIGNED:Our Pediatric-Behavioral Health Digital Tool has potential to provide a cost-effective service solution to provide preventive mental health care in communities to promote child social-emotional and mental wellbeing in low-resource settings.