Kyle Walsh

Overview:

Dr. Walsh is Associate Professor of Neurosurgery and Pathology, Director of the Division of Neuro-epidemiology, and a Senior Fellow in the Duke Center for the Study of Aging and Human Development. He leads Duke’s Neuro-epidemiology Lab, which integrates bench science with statistical methods to study the neurobiology of glial senescence and gliomagenesis. This research interrogates human genomic and epigenomic profiles to identify both heritable and modifiable factors that contribute to neurologic and physical decline, applying these approaches to studying the shared neurobiology of cognition, glial senescence, and gliomagenesis. The lab has a long history studying telomere maintenance in pre-malignant cells and its role in the development of cancer, most notably glioblastoma.

Positions:

Associate Professor in Neurosurgery

Neurosurgery
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Associate Professor in Pediatrics

Pediatrics, Children's Health Discovery Institute
School of Medicine

Associate Professor in Population Health Sciences

Population Health Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2011

Yale University School of Medicine

Grants:

My Childhood Cancer: Survey Series

Administered By
Neurosurgery
Awarded By
Alex's Lemonade Stand
Role
Principal Investigator
Start Date
End Date

Genetic Susceptibility to Pediatric Glioma in Individuals and Diverse populations

Administered By
Neurosurgery
Awarded By
University of Southern California
Role
Principal Investigator
Start Date
End Date

The role of rare and common variants in genetic predisposition to medulloblastoma

Administered By
Neurosurgery
Awarded By
Sontag Foundation
Role
Principal Investigator
Start Date
End Date

Genetic Susceptibility to pediatric Osteosarcoma and Interaction with Measures of Childhood Growth

Administered By
Neurosurgery
Awarded By
Alex's Lemonade Stand
Role
Principal Investigator
Start Date
End Date

Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life ALL Development

Administered By
Pediatrics, Children's Health Discovery Institute
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.

PURPOSE: To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2'-deoxyguanosine (THIO) in gliomas both in vitro and in vivo. EXPERIMENTAL DESIGN: A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO. RESULTS: THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model. CONCLUSIONS: The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.
Authors
Yu, S; Wei, S; Savani, M; Lin, X; Du, K; Mender, I; Siteni, S; Vasilopoulos, T; Reitman, ZJ; Ku, Y; Wu, D; Liu, H; Tian, M; Chen, Y; Labrie, M; Charbonneau, CM; Sugarman, E; Bowie, M; Hariharan, S; Waitkus, M; Jiang, W; McLendon, RE; Pan, E; Khasraw, M; Walsh, KM; Lu, Y; Herlyn, M; Mills, G; Herbig, U; Wei, Z; Keir, ST; Flaherty, K; Liu, L; Wu, K; Shay, JW; Abdullah, K; Zhang, G; Ashley, DM
MLA Citation
Yu, Shengnan, et al. “A Modified Nucleoside 6-Thio-2'-Deoxyguanosine Exhibits Antitumor Activity in Gliomas.Clin Cancer Res, Sept. 2021. Pubmed, doi:10.1158/1078-0432.CCR-21-0374.
URI
https://scholars.duke.edu/individual/pub1497999
PMID
34593527
Source
pubmed
Published In
Clinical Cancer Research
Published Date
DOI
10.1158/1078-0432.CCR-21-0374

The shared genetic architecture between epidemiological and behavioral traits with lung cancer.

The complex polygenic nature of lung cancer is not fully characterized. Our study seeks to identify novel phenotypes associated with lung cancer using cross-trait linkage disequilibrium score regression (LDSR). We measured pairwise genetic correlation (rg) and SNP heritability (h2) between 347 traits and lung cancer risk using genome-wide association study summary statistics from the UKBB and OncoArray consortium. Further, we conducted analysis after removing genomic regions previously associated with smoking behaviors to mitigate potential confounding effects. We found significant negative genetic correlations between lung cancer risk and dietary behaviors, fitness metrics, educational attainment, and other psychosocial traits. Alcohol taken with meals (rg = - 0.41, h2 = 0.10, p = 1.33 × 10-16), increased fluid intelligence scores (rg = - 0.25, h2 = 0.22, p = 4.54 × 10-8), and the age at which full time education was completed (rg = - 0.45, h2 = 0.11, p = 1.24 × 10-20) demonstrated negative genetic correlation with lung cancer susceptibility. The body mass index was positively correlated with lung cancer risk (rg = 0.20, h2 = 0.25, p = 2.61 × 10-9). This analysis reveals shared genetic architecture between several traits and lung cancer predisposition. Future work should test for causal relationships and investigate common underlying genetic mechanisms across these genetically correlated traits.
Authors
Pettit, RW; Byun, J; Han, Y; Ostrom, QT; Edelson, J; Walsh, KM; Bondy, ML; Hung, RJ; McKay, JD; Amos, CI
MLA Citation
Pettit, Rowland W., et al. “The shared genetic architecture between epidemiological and behavioral traits with lung cancer.Sci Rep, vol. 11, no. 1, Sept. 2021, p. 17559. Pubmed, doi:10.1038/s41598-021-96685-x.
URI
https://scholars.duke.edu/individual/pub1495992
PMID
34475455
Source
pubmed
Published In
Scientific Reports
Volume
11
Published Date
Start Page
17559
DOI
10.1038/s41598-021-96685-x

Congenital human cytomegalovirus infection is associated with decreased transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia.

BACKGROUND: Placentally-transferred maternal IgG protects against pathogens in early life, yet vertically-transmitted infections can interfere with transplacental IgG transfer. Although human cytomegalovirus (HCMV) is the most common placentally-transmitted viral infection worldwide, the impact of congenital HCMV (cCMV) infection on transplacental IgG transfer has been underexplored. METHODS: We evaluated total and antigen-specific maternal and cord blood IgG levels and transplacental IgG transfer efficiency in a U.S-based cohort of 93 mother-infant pairs including 27 cCMV-infected and 66 cCMV-uninfected pairs, of which 29 infants were born to HCMV-seropositive non-transmitting mothers and 37 to HCMV-seronegative mothers. Controls were matched on sex, race/ethnicity, maternal age, and delivery year. RESULTS: Transplacental IgG transfer efficiency was decreased by 23% (95% CI 10-36%, p=0.0079) in cCMV-infected pairs and 75% of this effect (95% CI 28-174%, p=0.0085) was mediated by elevated maternal IgG levels (i.e., hypergammaglobulinemia) in HCMV-transmitting women. Despite reduced transfer efficiency, IgG levels were similar in cord blood from infants with and without cCMV infection. CONCLUSIONS: Our results indicate that cCMV infection moderately reduces transplacental IgG transfer efficiency due to maternal hypergammaglobulinemia; however, infants with and without cCMV infection had similar antigen-specific IgG levels, suggesting comparable protection from maternal IgG acquired via transplacental transfer.
Authors
Semmes, EC; Li, SH; Hurst, JH; Yang, Z; Niedzwiecki, D; Fouda, GG; Kurtzberg, J; Walsh, KM; Permar, SR
MLA Citation
URI
https://scholars.duke.edu/individual/pub1488783
PMID
34260701
Source
pubmed
Published In
Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Published Date
DOI
10.1093/cid/ciab627

Opportunities, barriers, and recommendations in down syndrome research.

BACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.
Authors
Hendrix, JA; Amon, A; Abbeduto, L; Agiovlasitis, S; Alsaied, T; Anderson, HA; Bain, LJ; Baumer, N; Bhattacharyya, A; Bogunovic, D; Botteron, KN; Capone, G; Chandan, P; Chase, I; Chicoine, B; Cieuta-Walti, C; DeRuisseau, LR; Durand, S; Esbensen, A; Fortea, J; Giménez, S; Granholm, A-C; Hahn, LJ; Head, E; Hillerstrom, H; Jacola, LM; Janicki, MP; Jasien, JM; Kamer, AR; Kent, RD; Khor, B; Lawrence, JB; Lemonnier, C; Lewanda, AF; Mobley, W; Moore, PE; Nelson, LP; Oreskovic, NM; Osorio, RS; Patterson, D; Rasmussen, SA; Reeves, RH; Roizen, N; Santoro, S; Sherman, SL; Talib, N; Tapia, IE; Walsh, KM; Warren, SF; White, AN; Wong, GW; Yi, JS
MLA Citation
Hendrix, James A., et al. “Opportunities, barriers, and recommendations in down syndrome research.Transl Sci Rare Dis, vol. 5, no. 3–4, 2021, pp. 99–129. Pubmed, doi:10.3233/trd-200090.
URI
https://scholars.duke.edu/individual/pub1488667
PMID
34268067
Source
pubmed
Published In
Transl Sci Rare Dis
Volume
5
Published Date
Start Page
99
End Page
129
DOI
10.3233/trd-200090

Assisted reproductive technology and association with childhood cancer subtypes

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>Use of assisted reproductive technology (ART) may alter the typical course of fetal development. We sought to investigate the association between ART use and childhood cancer subtype.</jats:p></jats:sec><jats:sec><jats:title>Study design</jats:title><jats:p>We surveyed 1701 parents of children with cancer about ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use and childhood cancer subtypes, birthweight and multiple gestation status.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Among childhood cancer patients, ART use was highest among children with osteosarcoma (OR=2.81; 95% CI=1.2-6.4; P=0.01). ART use was also elevated among children with hepatoblastoma, and this relationship appeared mediated by low birthweight. No specific type of ART appeared to drive these associations. Low birthweight was itself strongly associated with increased hepatoblastoma risk, even after adjustment for ART use, multiple gestation status, sex, and parental income (P&lt;0.001). Birthweight was higher in patients with germ cell tumors (P=0.02) and with neuroblastoma (P=0.06). Multiple gestation status was associated with neuroblastoma among females (OR=3.6, 95% CI=1.2-10.5, P=0.02), but not among males (OR=0.97, 95% CI=0.27-3.4, P=0.96) (P<jats:sub>interaction</jats:sub>=0.02).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Associations between ART use and hepatoblastoma risk may be mediated by birthweight, a strong hepatoblastoma risk factor that was replicated in our study. ART use may also be associated with osteosarcoma independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long-term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.</jats:p></jats:sec>
Authors
Gulrajani, NB; Montes, S; McGough, D; Wimberly, CE; Khattab, A; Semmes, EC; Towry, L; Cohen, JL; Hurst, JH; Landi, D; Hill, SN; Walsh, KM
MLA Citation
Gulrajani, Natalie B., et al. Assisted reproductive technology and association with childhood cancer subtypes. Cold Spring Harbor Laboratory. Crossref, doi:10.1101/2021.04.26.21256117.
URI
https://scholars.duke.edu/individual/pub1481197
Source
crossref
DOI
10.1101/2021.04.26.21256117