Faculty Bibliography

Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge, in part because tau lacks well-defined druggable sites and accumulates as heterogeneous intracellular aggregates that are difficult to access and clear. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance through the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In neurons derived from patients with frontotemporal dementia (FTD) and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 promoted autophagy-lysosome-mediated tau degradation. It readily crossed the blood-brain barrier and improved motor function in JNPL3 tauopathy mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.

BACKGROUND & AIMS/OBJECTIVE:Lipoprotein assembly in the small intestine and liver is critical for the transport of dietary and endogenous lipids. Pla2g12b has recently been shown to play a role in lipoprotein assembly in mice livers and zebrafish larvae. Pla2g12b knockout and mutant (MUT) mice with the C129Y missense mutation have low plasma cholesterol levels. However, the role of Pla2g12b in the intestine and the reason why C129Y mutation decreases plasma lipids are unknown. METHODS:) and WT control mice were used in parallel to study plasma lipids and lipoproteins, lipid absorption and hepatic lipoprotein production studies. Transmission electron microscopy was used to visualize lipid transit through enterocytes. RESULTS:We observed that Pla2g12b expression was the highest in the duodenum. Furthermore, male and female chow fed 3-month-old MUT mice and wildtype (WT) mice expressed similar amounts of Pla2g12b protein and several genes in lipid metabolism. Nonetheless, the MUT mice had significantly lower plasma triglyceride (TG), cholesterol, HDL-C, LDL-C, apoB48, and apoB100 levels than WT mice. Several mechanisms for lower plasma lipids and lipoproteins in MUT mice were investigated. C129Y mutation had no effect on the expression of Pla2g12b and several other proteins necessary for lipid transport. Therefore, the low plasma lipid levels in MUT mice were neither due to the absence of Pla2g12b protein nor due to reductions in critical proteins in lipid transport. Next, we addressed the role of Pla2g12b in hepatic lipid mobilization and intestinal lipid absorption. MUT livers exhibited normal TG synthesis, defective TG secretion, and enhanced fat accumulation. MUT mice also showed defective intestinal TG absorption, intracellular lipid accumulation, and elevated TG excretion in the feces. CONCLUSIONS:We propose that C129 in Pla2g12b is critical for the assembly and secretion of lipoproteins by the liver and intestine.

Pediatric deceased donor kidneys with acute kidney injury (ped-AKI) are at increased risk for non-utilization. To evaluate the post-transplant outcomes of ped-AKI recipients, we conducted a retrospective cohort study, comparing 17,731 adult recipients of kidneys from pediatric donors without AKI (ped-non-AKI, terminal serum creatinine (SCr)<1 mg/dL) to 1,589 ped-AKI recipients (SCr≥2 mg/dL). We used weighted logistic regression to estimate the association between ped-AKI and delayed graft function (DGF), and weighted Cox regression to estimate the association between ped-AKI and primary non-function (PNF) and all-cause graft failure (ACGF). Ped-AKI kidney recipients were at 6.0-fold (aOR=_5.325.98_6.72), 1.9-fold (aHR=_1.361.87_2.58), and 1.4-fold (aHR=_1.161.43_1.76) higher risk of DGF, PNF, and 1-year ACGF compared to ped-non-AKI recipients. En bloc ped-AKI recipients were at 5.6-fold (aOR=_3.295.57_9.43), 3.3-fold (aHR=_1.723.25_6.15), and 2.9-fold (aHR=_1.702.92_5.01) higher risk of DGF, PNF, 1-year ACGF compared to en bloc ped-non-AKI recipients. Among recipients of single kidneys from donors<20kg, ped-AKI recipients were at 8.9-fold (aOR=_4.348.87_18.12), 5-fold (aHR=_1.694.99_14.75), and 3.4-fold (aHR=_1.473.44_8.05) higher risk of DGF, PNF, 1-year ACGF compared to ped-non-AKI recipients. Ped-AKI kidney recipients have higher risks of early graft complications and failure. Risks are greatest for recipients of single kidneys from donors<20kg. Careful recipient selection and counseling are prudent when considering ped-AKI kidney offers.

BACKGROUND/OBJECTIVE/OBJECTIVE:Juvenile dermatomyositis (JDM) is a systemic autoimmune vasculopathy, which may be complicated by calcinosis of the skin and subcutaneous tissues. Calcinosis is often associated with pain, ulceration, infection, impaired mobility, and reduced quality of life, yet no gold standard exists for its detection and longitudinal monitoring. Current evaluation relies on clinical examination (history plus physical examination) with or without targeted conventional radiography, which may underestimate disease burden and expose children to cumulative doses of ionizing radiation. The EOS 2D/3D imaging system provides rapid, whole-body imaging with substantially reduced radiation exposure. Thus, we sought to explore its utility in assessing calcinosis in JDM. METHODS:In this retrospective case series, we investigated NYU pediatric patients with JDM who underwent EOS imaging for evaluation of calcinosis. EOS images and conventional radiographs were independently reviewed by 2 radiologists blinded to clinical data, with a focus on the anatomic distribution of calcinosis. RESULTS:Seven patients (5 female, 2 male, ages 10 to 17 years) met the inclusion criteria, of whom 6 underwent both EOS and x-ray imaging. EOS imaging accurately identified calcinosis of the trunk and lower extremities in all cases and detected calcinosis not previously appreciated on clinical examination or dedicated radiographs in every patient. In 2 patients, EOS imaging failed to detect all upper-extremity calcinosis, likely due to the use of standard orthopedic positioning. CONCLUSIONS:EOS imaging appears to be a valid alternative to conventional radiography for evaluating calcinosis of the trunk and lower extremities in JDM, while offering the advantages of lower radiation exposure, rapid acquisition, and broader anatomic coverage. Development of JDM-specific positioning protocols may improve the detection of upper-extremity disease.

OBJECTIVES/OBJECTIVE:Much research has documented disruptions to parent well-being and family functioning because of the COVID-19 pandemic in the United States, but little is known about how parents' provision of cognitive stimulation to young children has been affected. This question is of added importance for families with low incomes, who were disproportionately disadvantaged by the pandemic. The current study examined whether and how provision of cognitive stimulation at home, as measured by the parent-reported StimQ2, changed for parents with low incomes after onset of the COVID-19 pandemic. We examined scores on a total scale and subscales tapping multiple aspects of verbal responsivity and reading. DESIGN/METHODS:Data from 7 cohorts of families with low incomes across 3 US cities were de-identified and combined into a single analytic sample for secondary analysis. Cohorts ranged in timing relative to the onset of the pandemic (i.e., as early as 2015 and as late as April 2023). Each study contributed data from families assessed at multiple timepoints between birth and age 4 years. RESULTS:Total scores on the StimQ2 increased after the onset of the COVID-19 pandemic. Subscales reflecting reading stayed the same (quantity) or declined (quality), whereas subscales reflecting verbal responsivity increased. CONCLUSION/CONCLUSIONS:Relative to prepandemic levels, low-income parents' child-directed speech and responsivity increased postpandemic, but the quantity of parent-child reading was unchanged and its quality declined. Findings suggest the possibility of stability or improvement among parents with low incomes during the pandemic and opportunities for intervention.

BACKGROUND:Solid organ transplant recipients (SOTRs) face frequent advanced cutaneous malignancies, yet data guiding systemic therapy are limited. MATERIALS AND METHODS/METHODS:We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review of immune checkpoint inhibitors (ICIs), talimogene laherparepvec (T-VEC), and Sonic Hedgehog Pathway Inhibitors (HPIs) for locally advanced or metastatic cutaneous squamous cell carcinoma, melanoma, Merkel cell carcinoma, and basal cell carcinoma in SOTRs, including a novel case from our institution. Outcomes included tumor response, graft rejection, and graft failure. RESULTS:Among 196 SOTRs treated with ICIs (101 cutaneous squamous cell carcinoma, 83 melanoma, 12 Merkel cell carcinoma), the overall response rate (ORR) was 39.3%, and lack of progression occurred in 58.0%. Graft rejection occurred in 36.9% and graft failure in 22.3%. A higher number of baseline immunosuppressive agents decreased odds of rejection (OR 0.55) and failure (OR 0.38). Tacrolimus was associated with reduced tumor response (OR 0.41), whereas mTOR-based regimens and cemiplimab were associated with fewer transplant rejection. T-VEC was reported in 10 SOTRs with an ORR of 90% and no graft rejection or failure. HPIs in six SOTRs with basal cell carcinoma demonstrated ORR of 83% without graft loss. CONCLUSION/CONCLUSIONS:ICIs provide antitumor activity but substantial graft-related risk, while T-VEC and HPIs show high response rates with no reported rejection.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Most patients with high-risk localized prostate cancer (HRLPC) do not undergo stereotactic body radiotherapy (SBRT) in part because of the limited evidence of long-term outcomes. We report long-term efficacy and toxicity outcomes for men treated with SBRT for HRLPC. METHODS:Individual patient data from ten prospective clinical studies evaluating SBRT for HRLPC across nine institutions were pooled in the Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate consortium. The Kaplan-Meier method was used to estimate 5-yr biochemical recurrence (BCR) and distant metastasis (DM), stratified by receipt of intensified treatment (≥12 mo of androgen deprivation therapy [ADT] with extremely dose-escalated [≥8 Gy/fraction] prostate-directed SBRT). The impact of intensified treatment on BCR-free survival and DM-free survival was evaluated using multivariable Cox proportional hazards models. Late Common Terminology Criteria for Adverse Events grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity was analyzed using time-to-event models. KEY FINDINGS AND LIMITATIONS/UNASSIGNED:In 440 patients with a median follow-up time of 60.4 mo, 5-yr BCR and DM rates were 22% (95% confidence interval [CI] = 17-26%] and 9.2% (95% CI = 6.2-12%), respectively. In the 93 patients (21%) who received intensified treatment, 5-yr BCR and DM rates were 7.4% (95% CI = 1.7-13%) and 3.7% (95% CI = 0-7.9%), respectively. Receipt of intensified therapy was associated with a significant reduction in both BCR (hazard ratio [HR] = 0.38 [95% CI = 0.20-0.74], p = 0.005) and DM (HR = 0.43 [95% CI = 0.18-0.99], p = 0.049). For the overall cohort, 5-yr rates of grade ≥2 GU and GI toxicity were 23% (95% CI = 19-27%) and 10% (95% CI = 7-13%), respectively. Limitations include heterogeneous treatment techniques and the nonrandomized nature of the study. CONCLUSIONS AND CLINICAL IMPLICATIONS/CONCLUSIONS:The safety and efficacy profile of SBRT for HRLPC remains favorable at long-term follow-up, and SBRT should be integrated into shared decision-making for treatment of HRLPC.

INTRODUCTION/UNASSIGNED:We synthesized evidence on racial disparities in perinatal toxicology testing among Black and White women and their infants in the United States, including testing practices and downstream consequences such as child welfare involvement. METHODS/UNASSIGNED:We systematically searched PubMed and PsycINFO for peer-reviewed studies published before January 2023 that examined perinatal toxicology testing and reported racial outcomes. Eligible studies assessed testing practices or related consequences. A random-effects meta-analysis estimated pooled rate ratios (RRs) and 95% confidence intervals (CIs) for disparities in testing. Thematic synthesis summarized qualitative findings on downstream outcomes. Sixteen studies (1993-2023) met inclusion criteria; six contributed to the meta-analysis, encompassing over 50 000 pregnant women and/or their infants. RESULTS/UNASSIGNED:Black women and their infants were significantly more likely to be tested than their White counterparts (RR = 2.58; 95% CI: 2.03-3.29). While recent studies suggest disparities in referral to child welfare services after positive tests may be narrowing, earlier research indicates disproportionate reporting and child removal among Black and Hispanic families. CONCLUSION/UNASSIGNED:Racial inequities in perinatal and infant toxicology testing persist, with implications for maternal and child health. Future research should investigate multilevel drivers of these disparities and inform equitable policy and practice.