Jeffrey Everitt

Positions:

Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

D.V.M. 1977

Cornell University

Adjunct Professor of Pathology, College of Veterinary Medicine,, Department Of Pathology

North Carolina State University

Grants:

Molecular Genetics of BBS

Administered By
Institutes and Centers
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Advanced Technologies for Reducing Decompression Obligation and Risk

Administered By
Anesthesiology, General, Vascular, High Risk Transplant & Critical Care
Awarded By
Creare, Inc.
Role
Co Investigator
Start Date
End Date

Combatting Bladder Cancer by Inducing Epithelial Turnover

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Stable therapy in Pompe disease through genome editing

Administered By
Pediatrics, Medical Genetics
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Stable therapy in Pompe disease through genome editing

Administered By
Pediatrics, Medical Genetics
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Publications:

RAS mutation patterns arise from tissue-specific responses to distinct oncogenic signaling

Despite multiple possible oncogenic mutations in the proto-oncogene KRAS , unique subsets of these mutations are detected in different cancer types. As KRAS mutations occur early, if not being initiating, these mutational biases are ostensibly a product of how normal cells respond to the encoded oncoprotein. Oncogenic mutations can impact not only the level of active oncoprotein, but also engagement with effectors and other proteins. To separate these two effects, we generated four novel inducible Kras alleles encoded by the biochemically distinct mutations G12D versus Q61R encoded by native (nat) rare versus common (com) codons to produce either low or high protein levels. Each allele induced a distinct transcriptional response in normal cells. At one end of the spectrum, the Kras natG12D allele induced transcriptional hallmarks suggestive of an expansion of multipotent cells, while at the other end, the Kras comQ61R allele exhibited all the hallmarks of oncogenic stress and inflammation. Further, this dramatic difference in the transcriptomes of normal cells appears to be a product of signaling differences due to increased protein expression as well as the specific mutation. To determine the impact of these distinct responses on RAS mutational patterning in vivo , all four alleles were globally activated, revealing that hematolymphopoietic lesions were sensitive to the level of active oncoprotein, squamous tumors were sensitive to the G12D mutant, while carcinomas were sensitive to both these features. Thus, we identify how specific KRAS mutations uniquely signal to promote the conversion of normal hematopoietic, epithelial, or squamous cells towards a tumorigenic state.
Authors
Erdogan, O; Pershing, NLK; Kaltenbrun, E; Newman, N; Everitt, J; Counter, C
MLA Citation
Erdogan, Ozgun, et al. RAS mutation patterns arise from tissue-specific responses to distinct oncogenic signaling. Dec. 2021. Epmc, doi:10.1101/2021.12.10.472098.
URI
https://scholars.duke.edu/individual/pub1503816
Source
epmc
Published Date
DOI
10.1101/2021.12.10.472098

Whole-slide cytometric feature mapping for distinguishing tumor genomic subtypes in HNSCC whole slide images

Authors
Blocker, S; Morrison, S; Everitt, J; Cook, J; Luo, S; Watts, T; Mowery, Y
MLA Citation
Blocker, Stephanie, et al. “Whole-slide cytometric feature mapping for distinguishing tumor genomic subtypes in HNSCC whole slide images.” Research Square Platform LLC. Crossref, doi:10.21203/rs.3.rs-1785010/v1.
URI
https://scholars.duke.edu/individual/pub1526277
Source
crossref
DOI
10.21203/rs.3.rs-1785010/v1

Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection.

SARS-CoV-2 entry into cells requires specific host proteases; however, no successful in vivo applications of host protease inhibitors have yet been reported for treatment of SARS-CoV-2 pathogenesis. Here we describe a chemically engineered nanosystem encapsulating CRISPR-Cas13d, developed to specifically target lung protease cathepsin L (Ctsl) messenger RNA to block SARS-CoV-2 infection in mice. We show that this nanosystem decreases lung Ctsl expression in normal mice efficiently, specifically and safely. We further show that this approach extends survival of mice lethally infected with SARS-CoV-2, correlating with decreased lung virus burden, reduced expression of proinflammatory cytokines/chemokines and diminished severity of pulmonary interstitial inflammation. Postinfection treatment by this nanosystem dramatically lowers the lung virus burden and alleviates virus-induced pathological changes. Our results indicate that targeting lung protease mRNA by Cas13d nanosystem represents a unique strategy for controlling SARS-CoV-2 infection and demonstrate that CRISPR can be used as a potential treatment for SARS-CoV-2 infection.
Authors
Cui, Z; Zeng, C; Huang, F; Yuan, F; Yan, J; Zhao, Y; Zhou, Y; Hankey, W; Jin, VX; Huang, J; Staats, HF; Everitt, JI; Sempowski, GD; Wang, H; Dong, Y; Liu, S-L; Wang, Q
MLA Citation
Cui, Zhifen, et al. “Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection.Nat Chem Biol, July 2022. Pubmed, doi:10.1038/s41589-022-01094-4.
URI
https://scholars.duke.edu/individual/pub1528949
PMID
35879545
Source
pubmed
Published In
Nat Chem Biol
Published Date
DOI
10.1038/s41589-022-01094-4

Selected Resources for Pathology Evaluation of Nonhuman Primates in Nonclinical Safety Assessment.

Humans and nonhuman primates (NHPs) share numerous anatomical and physiological characteristics, thereby explaining the importance of NHPs as essential animal models for translational medicine and nonclinical toxicity testing. Researchers, toxicologic pathologists, toxicologists, and regulatory reviewers must be familiar with normal and abnormal NHP biological traits when designing, performing, and interpreting data sets from NHP studies. The current compilation presents a list of essential books, journal articles, and websites that provide context to safety assessment and research scientists working with NHP models. The resources used most frequently by the authors have been briefly annotated to permit readers to rapidly ascertain their applicability to particular research endeavors. The references are aimed primarily for toxicologic pathologists working with cynomolgus and rhesus macaques and common marmosets in efficacy and safety assessment studies.
Authors
Bolon, B; Everitt, JI
MLA Citation
Bolon, Brad, and Jeffrey I. Everitt. “Selected Resources for Pathology Evaluation of Nonhuman Primates in Nonclinical Safety Assessment.Toxicol Pathol, vol. 50, no. 5, July 2022, pp. 725–32. Pubmed, doi:10.1177/01926233221091763.
URI
https://scholars.duke.edu/individual/pub1519553
PMID
35481786
Source
pubmed
Published In
Toxicol Pathol
Volume
50
Published Date
Start Page
725
End Page
732
DOI
10.1177/01926233221091763

Automated Nuclear Segmentation in Head and Neck Squamous Cell Carcinoma Pathology Reveals Relationships between Cytometric Features and ESTIMATE Stromal and Immune Scores.

The tumor microenvironment (TME) plays an important role in the progression of head and neck squamous cell carcinoma (HNSCC). Currently, pathologic assessment of TME is nonstandardized and subject to observer bias. Genome-wide transcriptomic approaches to understanding the TME, while less subject to bias, are expensive and not currently a part of the standard of care for HNSCC. To identify pathology-based biomarkers that correlate with genomic and transcriptomic signatures of TME in HNSCC, cytometric feature maps were generated in a publicly available data set from a cohort of patients with HNSCC, including whole-slide tissue images and genomic and transcriptomic phenotyping (N = 49). Cytometric feature maps were generated based on whole-slide nuclear detection, using a deep-learning algorithm trained for StarDist nuclear segmentation. Cytometric features in each patient were compared to transcriptomic measurements, including Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data (ESTIMATE) scores and stemness scores. With correction for multiple comparisons, one feature (nuclear circularity) demonstrated a significant linear correlation with ESTIMATE stromal score. Two features (nuclear maximum and minimum diameter) correlated significantly with ESTIMATE immune score. Three features (nuclear solidity, nuclear minimum diameter, and nuclear circularity) correlated significantly with transcriptomic stemness score. This study provides preliminary evidence that observer-independent, automated tissue-slide analysis can provide insights into the HNSCC TME which correlate with genomic and transcriptomic assessments.
Authors
Blocker, SJ; Cook, J; Everitt, JI; Austin, WM; Watts, TL; Mowery, YM
MLA Citation
URI
https://scholars.duke.edu/individual/pub1524721
PMID
35718057
Source
pubmed
Published In
The American Journal of Pathology
Published Date
DOI
10.1016/j.ajpath.2022.06.003