MSTPublications: April & May 2017
Congratulations to all of our MSTP students on their successful publications! Take a look at the great work our students are doing.
First Author Original Research:
BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.
Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CE, Mittal MK, Naik RD, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Brand T, Bader DM, Tansey WP, Chen R, Brentnall TA, Grady WM, Williams CS.
Gut. 2017 May;66(5):852-862. doi: 10.1136/gutjnl-2015-310255. Epub 2016 Jan 14.
Before I joined the lab, it was known that Blood Vessel Epicardial Substance (BVES), a tight-junction associated protein, was underexpressed in a variety of epithelial malignancies (including colorectal, gastric, and breast), but our understanding of BVES at the molecular level was incomplete. Using a yeast-two-hybrid screen as a starting point, we discovered that BVES interacts with PPP2R5A, a phosphatase subunit, to promote the destruction of c-Myc, the oncogene hyperactive in over 50% of cancers. In collaboration with William Grady and Andrew Katz, physician-scientists at the University of Washington, we analyzed samples from patients with inflammatory bowel disease who had colorectal cancer and showed that BVES promoter hypermethylation status could possibly be used as biomarker for patients who are at high risk for developing cancer. This paper was the culmination of my graduate school work (four years of countless failed experiments, a few lucky breaks, and many helpful thesis committee meetings) and would not have been possible without fantastic collaborators and a wonderfully supportive lab. (By Bobak Parang, 2017 Vanderbilt MSTP Graduate)
Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution.
Puccetti MV, Fischer MA, Arrate MP, Boyd KL, Duszynski RJ, Bétous R, Cortez D, Eischen CM.
Oncogene. 2017 May 4;36(18):2553-2564. doi: 10.1038/onc.2016.408. Epub 2016 Oct 31.
SMARCAL1 is a DNA replication stress response protein that functions to maintain genomic integrity by stabilizing and remodeling stalled replication forks. Patients with mutations in SMARCAL1 suffer from Schimke Immuno-osseus Dysplasia (SIOD); a rare genetic disorder which is characterized, in part, by a severe, progressive immunodeficiency. While the biochemical functions of SMARCAL1 have been partially described, its in vivo, biological functions remained unknown. In this study, we sought to evaluate how SMARCAL1 influences hematopoietic cancer development and hematopoietic stem cell (HSPC) function. Using a Smarcal1 knockout mouse model, we demonstrated Smarcal1 is critical for maintaining the function and viability of HSPCs, as loss of Smarcal1 lead to HSPC attrition during forced proliferation. Moreover, we showed that this reduction in HSPCs inhibited radiation-induced lymphoma development as increased HSPC apoptosis reduced the pool of cells with the potential to undergo transformation. Overall, our data provides a potential biological mechanism for the immunodeficiency observed in SIOD patients as well as establishing Smarcal1 as an important factor in the development of lymphoid malignancies. (By Matthew Puccetti G4)
Membrane protein contact and structure prediction using co-evolution in conjunction with machine learning.
Teixeira PL, Mendenhall JL, Heinze S, Weiner B, Skwark MJ, Meiler J.
PLoS One. 2017 May 24;12(5):e0177866. doi: 10.1371/journal.pone.0177866. eCollection 2017.
De novo membrane protein structure prediction is limited to small proteins due to the conformational search space quickly expanding with length. Long-range contacts (24+ amino acid separation)-residue positions distant in sequence, but in close proximity in the structure, are arguably the most effective way to restrict this conformational space. Inverse methods for co-evolutionary analysis predict a global set of position-pair couplings that best explain the observed amino acid co-occurrences, thus distinguishing between evolutionarily explained co-variances and these arising from spurious transitive effects. Here, we show that applying machine learning approaches and custom descriptors improves evolutionary contact prediction accuracy, resulting in improvement of average precision by 6 percentage points for the top 1L non-local contacts. Further, we demonstrate that predicted contacts improve protein folding with BCL::Fold. The mean RMSD100 metric for the top 10 models folded was reduced by an average of 2 Å for a benchmark of 25 membrane proteins. (By Pedro Teixeira M4)
Co-authorships, Case Studies, and Reviews:
HIV integration sites in latently infected cell lines: evidence of ongoing replication.
Symons J, Chopra A, Malantinkova E, De Spiegelaere W, Leary S, Cooper D, Abana CO, Rhodes A, Rezaei SD, Vandekerckhove L, Mallal S, Lewin SR, Cameron PU.
Retrovirology. 2017 Jan 13;14(1):2. doi: 10.1186/s12977-016-0325-2.
Azithromycin Causes a Novel Proarrhythmic Syndrome.
Yang Z, Prinsen JK, Bersell KR, Shen W, Yermalitskaya L, Sidorova T, Luis PB, Hall L, Zhang W, Du L, Milne G, Tucker P, George AL Jr, Campbell CM, Pickett RA, Shaffer CM, Chopra N, Yang T, Knollmann BC, Roden DM, Murray KT.
Circ Arrhythm Electrophysiol. 2017 Apr;10(4). pii: e003560. doi: 10.1161/CIRCEP.115.003560.
Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults.
Wells QS, Veatch OJ, Fessel JP, Joon AY, Levinson RT, Mosley JD, Held EP, Lindsay CS, Shaffer CM, Weeke PE, Glazer AM, Bersell KR, Van Driest SL, Karnes JH, Blair MA, Lagrone LW, Su YR, Bowton EA, Feng Z, Ky B, Lenihan DJ, Fisch MJ, Denny JC, Roden DM.
Pharmacogenet Genomics. 2017 May 24. doi: 10.1097/FPC.0000000000000284. [Epub ahead of print]
Dysfunctional T cell metabolism in the tumor microenvironment.
Beckermann KE, Dudzinski SO, Rathmell JC.
Cytokine Growth Factor Rev. 2017 Apr 23. pii: S1359-6101(17)30052-7. doi: 10.1016/j.cytogfr.2017.04.003. [Epub ahead of print] Review.
Does Intrawound Vancomycin Application During Spine Surgery Create Vancomycin-Resistant Organism?
Chotai S, Wright PW, Hale AT, Jones WA, McGirt MJ, Patt JC, Devin CJ.
Neurosurgery. 2017 Apr 6. doi: 10.1093/neuros/nyw097. [Epub ahead of print]
Global Diversity and Academic Success of Foreign-Trained Academic Neurosurgeons in the United States.
Mistry AM, Kumar NG, Reynolds RA, Hale AT, Wellons JC 3rd, Naftel RP.
World Neurosurg. 2017 Apr 29. pii: S1878-8750(17)30657-5. doi: 10.1016/j.wneu.2017.04.149. [Epub ahead of print]
Healthcare Resource Utilization and Patient-Reported Outcomes Following Elective Surgery for Intradural Extramedullary Spinal Tumors.
Chotai S, Zuckerman SL, Parker SL, Wick JB, Stonko DP, Hale AT, McGirt MJ, Cheng JS, Devin CJ.Neurosurgery. 2017 May 10. doi: 10.1093/neuros/nyw126. [Epub ahead of print]
Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice.
Peter JG, Lehloenya R, Dlamini S, Risma K, White KD, Konvinse KC, Phillips EJ.
J Allergy Clin Immunol Pract. 2017 May - Jun;5(3):547-563. doi: 10.1016/j.jaip.2017.01.025
SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer.
Ichihara E, Westover D, Meador CB, Yan Y, Bauer JA, Lu P, Ye F, Kulick A, De Stanchina E, McEwen R, Ladanyi M, Cross D, Pao W, Lovly CM.
Cancer Res. 2017 Apr 17. pii: canres.2300.2016. doi: 10.1158/0008-5472.CAN-16-2300. [Epub ahead of print]
Draft Genome Sequences of 13 Colombian Helicobacter pylori Strains Isolated from Pacific Coast and Andean Residents.
Pazos A, Kodaman N, Piazuelo MB, Romero-Gallo J, Sobota RS, Israel DA, Bravo LE, Morgan DR, Wilson KT, Correa P, Peek RM Jr, Williams SM, Schneider BG.
Genome Announc. 2017 Apr 13;5(15). pii: e00113-17. doi: 10.1128/genomeA.00113-17.
Genetic Effects on the Correlation Structure of CVD Risk Factors: Exome-Wide Data From a Ghanaian Population.
Kodaman N, Sobota RS, Asselbergs FW, Oetjens MT, Moore JH, Brown NJ, Aldrich MC, Williams SM.
Glob Heart. 2017 Apr 10. pii: S2211-8160(17)30013-3. doi: 10.1016/j.gheart.2017.01.013. [Epub ahead of print] Review.