Physician-scientist with broad interests in genetics/genomics, cell biology, developmental biology, cancer, clinical pathology, bioinformatics, and computer vision.
Residency: Stanford University Pathology Residency (2023) CA
Medical Education: Washington University School Of Medicine Registrar (2020) MO
Residency, Stanford Health Care, Clinical Pathology (2023)
MD/PhD, Washington University School of Medicine, Developmental Biology (2020)
BS, Rice University, Ecology and Evolutionary Biology (2011)
BA, Rice University, Psychology (2011)
Cellular and humoral immune response to SARS-CoV-2 vaccination and booster dose in immunosuppressed patients: An observational cohort study.
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
2022; 153: 105217
BACKGROUND: Humoral and cellular immune responses to SARS-CoV-2 vaccination among immunosuppressed patients remain poorly defined, as well as variables associated with poor response.METHODS: We performed a retrospective observational cohort study at a large Northern California healthcare system of infection-naive individuals fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) with clinical SARS-CoV-2 interferon gamma release assay (IGRA) ordered between January through November 2021. Humoral and cellular immune responses were measured by anti-SARS-CoV-2 S1 IgG ELISA (anti-S1 IgG) and IGRA, respectively, following primary and/or booster vaccination.RESULTS: 496 immunosuppressed patients (54% female; median age 50 years) were included. 62% (261/419) of patients had positive anti-S1 IgG and 71% (277/389) had positive IGRA after primary vaccination, with 20% of patients having a positive IGRA only. Following booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Factors associated with low humoral response rates after primary vaccination included anti-CD20 monoclonal antibodies (P<0.001), sphingosine 1-phsophate (S1P) receptor modulators (P<0.001), mycophenolate (P=0.002), and B cell lymphoma (P=0.004); those associated with low cellular response rates included S1P receptor modulators (P<0.001) and mycophenolate (P<0.001). Of patients who had poor humoral response to primary vaccination, 35% (18/52) developed a significantly higher response after the booster. Only 5% (2/42) of patients developed a significantly higher cellular response to the booster dose compared to primary vaccination.CONCLUSIONS: Humoral and cellular response rates to primary and booster SARS-CoV-2 vaccination differ among immunosuppressed patient groups. Clinical testing of cellular immunity is important in monitoring vaccine response in vulnerable populations.
View details for DOI 10.1016/j.jcv.2022.105217
View details for PubMedID 35714462
Case-Control Study of Individuals with Discrepant Nucleocapsid and Spike Protein SARS-CoV-2 IgG Results.
Laboratory-based methods for SARS-CoV-2 antibody detection vary widely in performance. However, there are limited prospectively-collected data on assay performance, and minimal clinical information to guide interpretation of discrepant results.Over a two-week period, 1080 consecutive plasma samples submitted for clinical SARS-CoV-2 IgG testing were tested in parallel for anti-nucleocapsid IgG (anti-N, Abbott) and anti-spike IgG (anti-S1, EUROIMMUN). Chart review was conducted for samples testing positive or borderline on either assay, and for an age/sex-matched cohort of samples negative by both assays. CDC surveillance case definitions were used to determine clinical sensitivity/specificity and conduct receiver operating characteristics curve analysis.There were 52 samples positive by both methods, 2 positive for anti-N only, 34 positive for anti-S1 only, and 27 borderline for anti-S1. Of the 34 individuals positive for anti-S1 alone, 8 (24%) had confirmed COVID-19. No anti-S1 borderline cases were positive for anti-N or had confirmed/probable COVID-19. The anti-N assay was less sensitive (84.2% [95% CI 72.1-92.5%] versus 94.7% [95% CI 85.4-98.9%]) but more specific (99.2% [95% CI 95.5-100%] versus 86.9% [95% CI 79.6-92.3%]) than anti-S1. Abbott anti-N sensitivity could be improved to 96.5% with minimal effect on specificity if the index threshold was lowered from 1.4 to 0.6.Real-world concordance between different serologic assays may be lower than previously described in retrospective studies. These findings have implications for the interpretation of SARS-CoV-2 IgG results, especially with the advent of spike antigen-targeted vaccination, as a subset of patients with true infection are anti-N negative and anti-S1 positive.
View details for DOI 10.1093/clinchem/hvab045
View details for PubMedID 33720347
Analysis ofFGF20-regulated genes in organ of Corti progenitors by translating ribosome affinity purification
2020; 249 (10): 1217-1242
Understanding the mechanisms that regulate hair cell (HC) differentiation in the organ of Corti (OC) is essential to designing genetic therapies for hearing loss due to HC loss or damage. We have previously identified Fibroblast Growth Factor 20 (FGF20) as having a key role in HC and supporting cell differentiation in the mouse OC. To investigate the genetic landscape regulated by FGF20 signaling in OC progenitors, we employ Translating Ribosome Affinity Purification combined with Next Generation RNA Sequencing (TRAPseq) in the Fgf20 lineage.We show that TRAPseq targeting OC progenitors effectively enriched for RNA from this rare cell population. TRAPseq identified differentially expressed genes (DEGs) downstream of FGF20, including Etv4, Etv5, Etv1, Dusp6, Hey1, Hey2, Heyl, Tectb, Fat3, Cpxm2, Sall1, Sall3, and cell cycle regulators such as Cdc20. Analysis of Cdc20 conditional-null mice identified decreased cochlea length, while analysis of Sall1-null and Sall1-ΔZn2-10 mice, which harbor a mutation that causes Townes-Brocks syndrome, identified a decrease in outer hair cell number.We present two datasets: genes with enriched expression in OC progenitors, and DEGs downstream of FGF20 in the embryonic day 14.5 cochlea. We validate select DEGs via in situ hybridization and in vivo functional studies in mice.
View details for DOI 10.1002/dvdy.211
View details for Web of Science ID 000574938300004
View details for PubMedID 32492250
View details for PubMedCentralID PMC7575056
FGF20-FGFR1signaling throughMAPKandPI3Kcontrols sensory progenitor differentiation in the organ of Corti
2021; 250 (2): 134-144
Fibroblast Growth Factor 20 (FGF20)-FGF receptor 1 (FGFR1) signaling is essential for cochlear hair cell (HC) and supporting cell (SC) differentiation. In other organ systems, FGFR1 signals through several intracellular pathways including MAPK (ERK), PI3K, phospholipase C ɣ (PLCɣ), and p38. Previous studies implicated MAPK and PI3K pathways in HC and SC development. We hypothesized that one or both would be important downstream mediators of FGF20-FGFR1 signaling for HC differentiation.By inhibiting pathways downstream of FGFR1 in cochlea explant cultures, we established that both MAPK and PI3K pathways are required for HC differentiation while PLCɣ and p38 pathways are not. Examining the canonical PI3K pathway, we found that while AKT is necessary for HC differentiation, it is not sufficient to rescue the Fgf20-/- phenotype. To determine whether PI3K functions downstream of FGF20, we inhibited Phosphatase and Tensin Homolog (PTEN) in Fgf20-/- explants. Overactivation of PI3K resulted in a partial rescue of the Fgf20-/- phenotype, demonstrating a requirement for PI3K downstream of FGF20. Consistent with a requirement for the MAPK pathway for FGF20-regulated HC differentiation, we show that treating Fgf20-/- explants with FGF9 increased levels of dpERK.Together, these data provide evidence that both MAPK and PI3K are important downstream mediators of FGF20-FGFR1 signaling during HC and SC differentiation.
View details for DOI 10.1002/dvdy.231
View details for Web of Science ID 000567465800001
View details for PubMedID 32735383
View details for PubMedCentralID PMC8415122
Sox2 and FGF20 interact to regulate organ of Corti hair cell and supporting cell development in a spatially-graded manner
2019; 15 (7): e1008254
The mouse organ of Corti, housed inside the cochlea, contains hair cells and supporting cells that transduce sound into electrical signals. These cells develop in two main steps: progenitor specification followed by differentiation. Fibroblast Growth Factor (FGF) signaling is important in this developmental pathway, as deletion of FGF receptor 1 (Fgfr1) or its ligand, Fgf20, leads to the loss of hair cells and supporting cells from the organ of Corti. However, whether FGF20-FGFR1 signaling is required during specification or differentiation, and how it interacts with the transcription factor Sox2, also important for hair cell and supporting cell development, has been a topic of debate. Here, we show that while FGF20-FGFR1 signaling functions during progenitor differentiation, FGFR1 has an FGF20-independent, Sox2-dependent role in specification. We also show that a combination of reduction in Sox2 expression and Fgf20 deletion recapitulates the Fgfr1-deletion phenotype. Furthermore, we uncovered a strong genetic interaction between Sox2 and Fgf20, especially in regulating the development of hair cells and supporting cells towards the basal end and the outer compartment of the cochlea. To explain this genetic interaction and its effects on the basal end of the cochlea, we provide evidence that decreased Sox2 expression delays specification, which begins at the apex of the cochlea and progresses towards the base, while Fgf20-deletion results in premature onset of differentiation, which begins near the base of the cochlea and progresses towards the apex. Thereby, Sox2 and Fgf20 interact to ensure that specification occurs before differentiation towards the cochlear base. These findings reveal an intricate developmental program regulating organ of Corti development along the basal-apical axis of the cochlea.
View details for DOI 10.1371/journal.pgen.1008254
View details for Web of Science ID 000478689100021
View details for PubMedID 31276493
View details for PubMedCentralID PMC6636783
Dermal Condensate Niche Fate Specification Occurs Prior to Formation and Is Placode Progenitor Dependent
2019; 48 (1): 32-+
Cell fate transitions are essential for specification of stem cells and their niches, but the precise timing and sequence of molecular events during embryonic development are largely unknown. Here, we identify, with 3D and 4D microscopy, unclustered precursors of dermal condensates (DC), signaling niches for epithelial progenitors in hair placodes. With population-based and single-cell transcriptomics, we define a molecular time-lapse from pre-DC fate specification through DC niche formation and establish the developmental trajectory as the DC lineage emerges from fibroblasts. Co-expression of downregulated fibroblast and upregulated DC genes in niche precursors reveals a transitory molecular state following a proliferation shutdown. Waves of transcription factor and signaling molecule expression then coincide with DC formation. Finally, ablation of epidermal Wnt signaling and placode-derived FGF20 demonstrates their requirement for pre-DC specification. These findings uncover a progenitor-dependent niche precursor fate and the transitory molecular events controlling niche formation and function.
View details for DOI 10.1016/j.devcel.2018.11.034
View details for Web of Science ID 000455007100010
View details for PubMedID 30595537
View details for PubMedCentralID PMC6370312
Sculpting the skull through neurosensory epithelial-mesenchymal signaling
2019; 248 (1): 88-97
The vertebrate skull is a complex structure housing the brain and specialized sensory organs, including the eye, the inner ear, and the olfactory system. The close association between bones of the skull and the sensory organs they encase has posed interesting developmental questions about how the tissues scale with one another. Mechanisms that regulate morphogenesis of the skull are hypothesized to originate in part from the encased neurosensory organs. Conversely, the developing skull is hypothesized to regulate the growth of neurosensory organs, through mechanical forces or molecular signaling. Here, we review studies of epithelial-mesenchymal interactions during inner ear and olfactory system development that may coordinate the growth of the two sensory organs with their surrounding bone. We highlight recent progress in the field and provide evidence that mechanical forces arising from bone growth may affect olfactory epithelium development. Developmental Dynamics 248:88-97, 2019. © 2018 Wiley Periodicals, Inc.
View details for DOI 10.1002/dvdy.24664
View details for Web of Science ID 000454597700009
View details for PubMedID 30117627
View details for PubMedCentralID PMC6312752
FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area
2018; 46 (5): 564-+
The olfactory epithelium (OE) is a neurosensory organ required for the sense of smell. Turbinates, bony projections from the nasal cavity wall, increase the surface area within the nasal cavity lined by the OE. Here, we use engineered fibroblast growth factor 20 (Fgf20) knockin alleles to identify a population of OE progenitor cells that expand horizontally during development to populate all lineages of the mature OE. We show that these Fgf20-positive epithelium-spanning progenitor (FEP) cells are responsive to Wnt/β-Catenin signaling. Wnt signaling suppresses FEP cell differentiation into OE basal progenitors and their progeny and positively regulates Fgf20 expression. We further show that FGF20 signals to the underlying mesenchyme to regulate the growth of turbinates. These studies thus identify a population of OE progenitor cells that function to scale OE surface area with the underlying turbinates.
View details for DOI 10.1016/j.devcel.2018.07.010
View details for Web of Science ID 000444088200007
View details for PubMedID 30100263
View details for PubMedCentralID PMC7271766
Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles
GENES & DEVELOPMENT
2013; 27 (4): 450-458
In hair follicle development, a placode-derived signal is believed to induce formation of the dermal condensation, an essential component of ectodermal organs. However, the identity of this signal is unknown. Furthermore, although induction and patterning of hair follicles are intimately linked, it is not known whether the mesenchymal condensation is necessary for inducing the initial epithelial pattern. Here, we show that fibroblast growth factor 20 (Fgf20) is expressed in hair placodes and is induced by and functions downstream from epithelial ectodysplasin (Eda)/Edar and Wnt/β-Catenin signaling to initiate formation of the underlying dermal condensation. Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles and subsequent formation of guard, awl, and auchene hairs. Although primary dermal condensations are absent in Fgf20 mutant mice, a regular array of hair placodes is formed, demonstrating that the epithelial patterning process is independent of known histological and molecular markers of underlying mesenchymal patterns during the initial stages of hair follicle development.
View details for DOI 10.1101/gad.198945.112
View details for Web of Science ID 000315286300010
View details for PubMedID 23431057
View details for PubMedCentralID PMC3589561
Analysis of FGF-Dependent and FGF-Independent Pathways in Otic Placode Induction
2013; 8 (1): e55011
The inner ear develops from a patch of thickened cranial ectoderm adjacent to the hindbrain called the otic placode. Studies in a number of vertebrate species suggest that the initial steps in induction of the otic placode are regulated by members of the Fibroblast Growth Factor (FGF) family, and that inhibition of FGF signaling can prevent otic placode formation. To better understand the genetic pathways activated by FGF signaling during otic placode induction, we performed microarray experiments to estimate the proportion of chicken otic placode genes that can be up-regulated by the FGF pathway in a simple culture model of otic placode induction. Surprisingly, we find that FGF is only sufficient to induce about 15% of chick otic placode-specific genes in our experimental system. However, pharmacological blockade of the FGF pathway in cultured chick embryos showed that although FGF signaling was not sufficient to induce the majority of otic placode-specific genes, it was still necessary for their expression in vivo. These inhibitor experiments further suggest that the early steps in otic placode induction regulated by FGF signaling occur through the MAP kinase pathway. Although our work suggests that FGF signaling is necessary for otic placode induction, it demonstrates that other unidentified signaling pathways are required to co-operate with FGF signaling to induce the full otic placode program.
View details for DOI 10.1371/journal.pone.0055011
View details for Web of Science ID 000314021500153
View details for PubMedID 23355906
View details for PubMedCentralID PMC3552847