Publications

Individuals with cancer are at increased risk of severe COVID-19 and immunogenicity of SARS-CoV-2 vaccines may be compromised, especially in those receiving systemic anti-cancer treatment. Understanding how treatment affects vaccine-induced humoral responses is critical to optimize vaccination strategies in this vulnerable population. This study evaluated neutralizing antibody responses to SARS-CoV-2 vaccination in cancer cohorts undergoing active treatment or not, measured at multiple timepoints before and after vaccination using a pseudovirus-based neutralization assay. We observed significantly lower seroconversion rates and impaired neutralizing antibody responses in the cancer cohort on active treatment compared to those not on treatment, suggesting an association between active treatment and a compromised functional immune response. Although strong correlations between anti-spike IgG and neutralizing antibodies were observed across all groups, regression analyses revealed potential differences in the relationship between binding and functional antibodies. We also observed the correlation between avidity and neutralizing antibodies varied across groups. These findings suggest that active systemic therapy impaired both the quantity and quality of antibody responses. Tailored vaccination timing and monitoring may be critical in reducing the risk of severe COVID-19 symptoms and improving COVID-19 vaccine efficacy in this population.

We report an 87-year-old female with a history of intellectual disability, severe speech impairment and behavioral issues. She was globally delayed in childhood. In adolescence, she had hallucinations, behavioral issues and was institutionalized. Her behavioral issues were treated, and her medical and behavioral course was stable until her 80's when she began to decline cognitively. She died at age 87. Exome sequencing revealed a novel predicted damaging missense variant (c.1913T>G; p.Met638Arg; NM_001136196.2) in the gene encoding Transportin-2 (TNPO2). Heterozygous variants in TNPO2 have been recently associated with an intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; MIM:619556). Postmortem pathological examination of her brain revealed focal neuronal depletion in the dentate gyrus, CA1, and hilar regions of the hippocampus. These findings are consistent with human gene expression data showing normal to increased expression of TNPO2 in the dentate gyrus and CA1 region of the hippocampus. We suggest that the p.(Met638Arg) variant in TNPO2 is potentially disease-causing and associated with IDDHISD.

The transformation of a two-dimensional epithelial sheet into various three-dimensional structures is a critical process in generating the diversity of animal forms. Previous studies of epithelial folding have revealed diverse mechanisms driven by epithelium-intrinsic or -extrinsic forces. Yet little is known about the biomechanical basis of epithelial splitting, which involves extreme folding and eventually a topological transition breaking the epithelial tube. Here, we leverage tracheal-esophageal separation (TES), a critical and highly conserved morphogenetic event during tetrapod embryogenesis, as a model system for interrogating epithelial tube splitting. We identify an evolutionarily conserved, compressive force exerted by the mesenchyme surrounding the epithelium, as being necessary to drive epithelial constriction and splitting. The compressive force is mediated by localized convergent flow of mesenchymal cells towards the epithelium. Sonic hedgehog (SHH) secreted by the epithelium functions as an attractive cue for mesenchymal cells. Removal of the mesenchyme, inhibition of cell migration, or loss of SHH signaling all abrogate TES, which can be rescued by externally applied pressure. These results unveil the biomechanical basis of epithelial splitting and suggest plausible mesenchymal origins of tracheal-esophageal birth defects.

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.

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.

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare but distinct disease that remains poorly understood, especially at proteome level. We report comprehensive mass spectrometry-based proteomic analyses of SPN (n = 13) and characterize differences from other pancreatic neoplasms, pancreatic ductal adenocarcinoma (n = 11) and neuroendocrine tumor (n = 10). We discovered that the SPN proteome is uniquely distinct from that of other pancreatic neoplasms. Lysosome-related proteins are enriched and upstream lysosomal processes transcriptional regulators, MITF and TFE3, are overexpressed in SPN. MITF protein expression is more specific for SPN than TFE3, previously considered the most specific immunohistochemical marker. Since lysosomal-related processes are connected to biological energy generation processes, we profiled metabolic pathways and found that SPN is characterized by higher fatty acid oxidation and lower glycolysis than PDAC and high proteasome pathway activity with many proteasomal proteins upregulated, suggesting a possible link to metabolic adaptation mechanisms in low-nutrient environments. Proteomics characterizes SPN as an immune-cold tumor with low MHC class I expression. Proteome-based receptor tyrosine kinase (RTK) pathway profiling suggests PDGFRA and ERBB2 (HER2) as potential candidates for targeted therapy. Our results provide unique proteomic contribution to the understanding of SPN biology and highlight differences from other pancreatic tumors.

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.

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.