Publications by Year: 2025

PURPOSE: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) improves survival in metastatic castration-resistant prostate cancer. PSMA is also expressed in triple-negative breast cancer (TNBC), a subtype with limited treatment options. This prospective study assessed PSMA uptake on [68Ga]Ga-PSMA-11 PET/CT in patients with metastatic TNBC (mTNBC) to evaluate the feasibility of PSMA-targeted RLT.

METHODS: This single-center prospective study enrolled patients with progressive mTNBC. Each patient underwent [18F]FDG PET/CT followed by [68Ga]Ga-PSMA-11 PET/CT. Visual PSMA positivity was defined as uptake greater than healthy liver in most lesions. For quantitative analysis, target lesions (TLs) ≥ 1.5 cm and PERCIST-measurable on FDG PET/CT were anatomically matched to PSMA PET/CT. SUVmax was measured and compared to liver background.

RESULTS: Twenty patients (median age 53.5 years; median 3 prior systemic therapies) were included. On visual assessment, 50.0% had PSMA uptake exceeding liver in most lesions. Quantitative analysis included 106 FDG-avid TLs; 67.0% showed PSMA SUVmax above liver. On a per-patient basis, 35.0% had all TLs and 30.0% had most TLs above liver SUVmean. However, 65.0% had at least one lesion below liver background, indicating heterogeneity. Higher PSMA uptake was associated with fewer prior treatments, prior immunotherapy, and low androgen receptor expression. PSMA PET/CT identified brain metastases in 10.0% of patients.

CONCLUSION: [68Ga]Ga-PSMA-11 PET/CT revealed clinically relevant PSMA expression in a subset of mTNBC patients. These results support further investigation of PSMA-targeted RLT in this biomarker-defined population.

OBJECTIVE: To quantify opioid and benzodiazepine exposure in extremely preterm neonates and assess variation by gestational age, facility, and clinical factors.

STUDY DESIGN: Cross-sectional study of 1501 neonates born at 23-28 weeks gestation at Kaiser Permanente Northern California (2011-2021). Medication data were extracted from electronic records. Cumulative opioid and benzodiazepine exposures were standardized to morphine and lorazepam equivalents per kg. Logistic regression evaluated associations with clinical comorbidities.

RESULTS: Thirty percent of neonates were exposed to both drug classes, 24% to opioids alone, and 1.5% to benzodiazepines alone. Exposure was inversely related to gestational age and varied widely across facilities. High opioid exposure (≥10 MME/kg) was associated with mechanical ventilation (aOR 3.7), vasopressors (aOR 4.6), oxygen at 36 weeks (aOR 1.7), and severe IVH (aOR 2.5).

CONCLUSIONS: Opioid and benzodiazepine use is common and variable in extremely preterm neonates. Standardized pain management and long-term outcome studies are urgently needed.

As genomic sequencing transitions into mainstream healthcare, critically appraising its value is key to informing evidence-based policy, practice and implementation strategies. Assessing the value of genomics is challenging, as traditional evaluation methods and frameworks do not capture many of the outcomes of genomics. This includes the personal value that genomic information provides individuals and family members, and the potential to reuse sequencing data to improve clinical care and drive research. Evaluation is hampered by lack of standardized outcome measures, small sample sizes, and uncertainties arising from the evolving nature of the technology, its applications and associated costs. Complex health system factors further influence real-world utilization and the value of genomic technologies and services within resource-constrained settings. In this Review, we discuss the need for robust yet agile approaches to evaluating genomic technologies that are dynamically informed by real-world data, and we provide examples of emerging methods and best practices. We emphasize the need for a whole-of-system approach and the need to further advance evaluation and implementation methods, to support health systems to sustainably and equitably integrate genomics into clinical care.

Most studies to date of protein quantitative trait loci (pQTLs) have relied on affinity proteomics platforms, which provide only limited information about the targeted protein isoforms and may be affected by genetic variation in their epitope binding. Here we show that mass spectrometry (MS)-based proteomics can complement these studies and provide insights into the role of specific protein isoform and epitope-altering variants. Using the Seer Proteograph nanoparticle enrichment MS platform, we identified and replicated new pQTLs in a genome-wide association study of proteins in blood plasma samples from two cohorts and evaluated previously reported pQTLs from affinity proteomics platforms. We found that >30% of the evaluated pQTLs were confirmed by MS proteomics to be consistent with the hypothesis that genetic variants induce changes in protein abundance, whereas another 30% could not be replicated and are possibly due to epitope effects, although alternative explanations for nonreplication need to be considered on a case-by-case basis.

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations show substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangle causal proteomic perturbations from TET2 CHIP. Lastly, we identify plasma proteins shared between CHIP and CAD.

Cognition in schizophrenia is difficult to assess in clinical settings due to the time required to administer traditional pen-and-paper tests, among other factors. Digital remote assessments completed on a smartphone offer an alternative that can reduce the burden on healthcare staff and patients, in addition to providing more nuanced cognitive profiles, especially when used in conjunction with smartphone data such as sleep. Building on previous work using the mindLAMP research app in international contexts, this paper presents a global multi-site pilot study to explore the validity of the app's digital cognitive assessments as proxies for traditional in-person assessments such as the gold standard MATRICS Consensus Battery (MCCB). Across one site in the U.S. (Boston) and two sites in India (Bangalore and Bhopal), a total of 56 participants with diagnoses of early-course schizophrenia or schizoaffective disorder were recruited between September 2024 and March 2025 to engage with the mindLAMP app for 30 days. Participants completed 2-3 different cognitive tasks and surveys each day; at the beginning and the end of this period, participants also took the MCCB and surveys related to their diagnosis. mindLAMP cognitive assessments were scored using different metrics that combine speed and accuracy, and correlation analyses were run on these metrics and MCCB domains. Of the scoring metrics used, the Rate-Correct Score (RCS) most consistently correlates with baseline MCCB domains corrected for age, gender, and education. Moderate test-retest reliability was observed across certain cognitive assessments such as a mobile version of Trails-Making Test A and Symbol Digit Substitution, which agrees with previous research done by Keefe et al.; poor test-retest reliability, in contrast, was observed across assessments such as Spatial Span. Additionally, we conducted exploratory mediation analyses using sleep data to see if sleep mediates between the Ecological Momentary Assessment (EMA) survey scores and performance on select digital cognitive assessments on mindLAMP. Our results support the initial accessibility, validity and reliability of using smartphones to assess cognition in schizophrenia. Future research to develop additional smartphone-based cognitive tests, as well as with larger samples and in other psychiatric populations, is warranted.

SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2' site, before membrane fusion can occur. Here, we report a cryo-EM structure of S2 fragment after the S2' cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2' cleavage accelerates membrane fusion, probably by stabilizing membrane fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses.

Vascularized composite allotransplantation (VCA) offers unparalleled reconstructive possibilities in complex cases but remains constrained by high immunogenicity and marked susceptibility to ischemia-reperfusion injury (IRI), particularly in muscle-rich grafts. Static cold storage (SCS), the current clinical standard, preserves grafts only for short durations. In contrast, machine perfusion (MP), already transformative in solid organ transplantation, is emerging as a promising strategy for VCA. This review summarizes the main challenges of ex vivo VCA preservation and current perfusion strategies designed to overcome them. Particular attention is given to physiological and technical factors influencing graft integrity, as well as innovations in perfusate composition and protective additives that mitigate IRI and support tissue preservation. Beyond simple storage, MP platforms enable functional assessment and therapeutic interventions, including graft reconditioning and immune modulation prior to transplantation. Complementary subzero static preservation methods, such as supercooling and cryopreservation, also show promise for substantially extending preservation times. Together with advances in experimental models, these approaches are reshaping the preservation landscape. As the field evolves, MP is poised to become a cornerstone technology in VCA, improving graft quality, extending preservation duration, and enabling pre-implantation modification strategies to reduce rejection and enhance long-term outcomes.