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MSTPublications: June 2019

Posted by on Tuesday, June 25, 2019 in New Publications.

p73 regulates epidermal wound healing and induced keratinocyte programming.
Beeler JS, Marshall CB, Gonzalez-Ericsson PI, Shaver TM, Santos Guasch GL, Lea ST, Johnson KN, Jin H, Venters BJ, Sanders ME, Pietenpol JA.
PLoS One. 2019 Jun 19;14(6):e0218458. doi: 10.1371/journal.pone.0218458. eCollection 2019.

p63 is a transcriptional regulator of ectodermal development that is required for basal cell proliferation and stem cell maintenance. p73 is a closely related p53 family member that is expressed in select p63-positive basal cells and can heterodimerize with p63. p73-/- mice lack multiciliated cells and have reduced numbers of basal epithelial cells in select tissues; however, the role of p73 in basal epithelial cells is unknown. Herein, we show that p73-deficient mice exhibit delayed wound healing despite morphologically normal-appearing skin. The delay in wound healing is accompanied by decreased proliferation and increased levels of biomarkers of the DNA damage response in basal keratinocytes at the epidermal wound edge. In wild-type mice, this same cell population exhibited increased p73 expression after wounding. Analyzing single-cell transcriptomic data, we found that p73 was expressed by epidermal and hair follicle stem cells, cell types required for wound healing. Moreover, we discovered that p73 isoforms expressed in the skin (ΔNp73) enhance p63-mediated expression of keratinocyte genes during cellular reprogramming from a mesenchymal to basal keratinocyte-like cell. We identified a set of 44 genes directly or indirectly regulated by ΔNp73 that are involved in skin development, cell junctions, cornification, proliferation, and wound healing. Our results establish a role for p73 in cutaneous wound healing through regulation of basal keratinocyte function.

Leveraging Mathematical Modeling to Quantify Pharmacokinetic and Pharmacodynamic Pathways: Equivalent Dose Metric.
McKenna MT, Weis JA, Quaranta V, Yankeelov TE.
Front Physiol. 2019 May 22;10:616. doi: 10.3389/fphys.2019.00616. eCollection 2019.

Treatment response assays are often summarized by sigmoidal functions comparing cell survival at a single timepoint to applied drug concentration. This approach has a limited biophysical basis, thereby reducing the biological insight gained from such analysis. In particular, drug pharmacokinetic and pharmacodynamic (PK/PD) properties are overlooked in developing treatment response assays, and the accompanying summary statistics conflate these processes. Here, we utilize mathematical modeling to decouple and quantify PK/PD pathways. We experimentally modulate specific pathways with small molecule inhibitors and filter the results with mechanistic mathematical models to obtain quantitative measures of those pathways. Specifically, we investigate the response of cells to time-varying doxorubicin treatments, modulating doxorubicin pharmacology with small molecules that inhibit doxorubicin efflux from cells and DNA repair pathways. We highlight the practical utility of this approach through proposal of the “equivalent dose metric.” This metric, derived from a mechanistic PK/PD model, provides a biophysically-based measure of drug effect. We define equivalent dose as the functional concentration of drug that is bound to the nucleus following therapy. This metric can be used to quantify drivers of treatment response and potentially guide dosing of combination therapies. We leverage the equivalent dose metric to quantify the specific intracellular effects of these small molecule inhibitors using population-scale measurements, and to compare treatment response in cell lines differing in expression of drug efflux pumps. More generally, this approach can be leveraged to quantify the effects of various pharmaceutical and biologic perturbations on treatment response.

Alcohol Use in Pregnancy and Miscarriage: A Systematic Review and Meta-Analysis.
Sundermann AC, Zhao S, Young CL, Lam L, Jones SH, Velez Edwards DR, Hartmann KE.
Alcohol Clin Exp Res. 2019 Jun 13. doi: 10.1111/acer.14124. [Epub ahead of print]

OBJECTIVE: To systematically review and critically evaluate studies reporting alcohol exposure during pregnancy and miscarriage. METHODS: We searched PubMed, EMBASE, PsycINFO, and ProQuest Theses for publications from January 1970 to January 2019. We identified studies about alcohol exposure during pregnancy and miscarriage. Information about study population, alcohol exposure assessment, outcome definition, covariates, and measures of association were collected. We assessed study quality using an adapted Newcastle-Ottawa Scale. Data were abstracted by two investigators independently. We conducted a random-effects meta-analysis to calculate the association between alcohol exposure and miscarriage risk and performed subgroup analyses to determine robustness of results to study differences. For studies reporting dose-specific effects, a pooled dose-response association was estimated using generalized least squares regression with and without restricted cubic spline terms for number of drinks consumed per week. RESULTS: Of 2,164 articles identified, 24 were eligible for inclusion. Meta-analysis of data from 231,808 pregnant women finds those exposed to alcohol during pregnancy have a greater risk of miscarriage compared to those who abstained (odds ratio [OR] 1.19, 95% confidence intervals [CI] 1.12, 1.28). Estimates did not vary by study design, study country, or method of alcohol ascertainment. For alcohol use of five or fewer drinks per week, each additional drink per week was associated with a six percent increase in miscarriage risk (OR 1.06, 95% CI 1.01, 1.10). Common study limitations reflect challenges inherent to this research, including difficulty recruiting participants early enough in pregnancy to observe miscarriage and collecting and quantifying information about alcohol consumption during pregnancy that accurately reflects use. CONCLUSIONS: This review provides evidence that alcohol consumption during pregnancy is associated with a dose-mediated increase in miscarriage risk. Future studies evaluating change in alcohol use in pregnancy are needed to provide insight into how alcohol consumption prior to pregnancy recognition impacts risk.

Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link.
Thompson PS, Amidon KM, Mohni KN, Cortez D, Eichman BF.
Nat Struct Mol Biol. 2019 Jun 24. doi: 10.1038/s41594-019-0255-5. [Epub ahead of print]

Abasic (AP) sites are one of the most common DNA lesions that block replicative polymerases. 5-hydroxymethylcytosine binding, embryonic stem cell-specific protein (HMCES) recognizes and processes these lesions in the context of single-stranded DNA (ssDNA). A HMCES DNA-protein cross-link (DPC) intermediate is thought to shield the AP site from endonucleases and error-prone polymerases. The highly evolutionarily conserved SOS-response associated peptidase (SRAP) domain of HMCES and its Escherichia coli ortholog YedK mediate lesion recognition. Here we uncover the basis of AP site protection by SRAP domains from a crystal structure of the YedK DPC. YedK forms a stable thiazolidine linkage between a ring-opened AP site and the α-amino and sulfhydryl substituents of its amino-terminal cysteine residue. The thiazolidine linkage explains the remarkable stability of the HMCES DPC, its resistance to strand cleavage and the proteolysis requirement for resolution. Furthermore, its structure reveals that HMCES has specificity for AP sites in ssDNA at junctions found when replicative polymerases encounter the AP lesion.

Molecular form and function of the cytokinetic ring.
Mangione MC, Gould KL.
J Cell Sci. 2019 Jun 17;132(12). pii: jcs226928. doi: 10.1242/jcs.226928. Review.

Chronic rhino-sinusitis treatment in children with cystic fibrosis: A cross-sectional survey of pediatric pulmonologists and otolaryngologists.
Lowery AS, Gallant JN, Woodworth BA, Brown RF, Sawicki GS, Shannon CN, Virgin FW.
Int J Pediatr Otorhinolaryngol. 2019 Jun 1;124:139-142. doi: 10.1016/j.ijporl.2019.05.034. [Epub ahead of print]

Characterization of postsurgical functional connectivity changes in temporal lobe epilepsy.
Morgan VL, Rogers BP, González HFJ, Goodale SE, Englot DJ.
J Neurosurg. 2019 Jun 14:1-11. doi: 10.3171/2019.3.JNS19350. [Epub ahead of print]

A Rapid Allele-Specific Assay for HLA-A*32:01 to Identify Patients at Risk for Vancomycin-Induced Drug Reaction with Eosinophilia and Systemic Symptoms.
Rwandamuriye FX, Chopra A, Konvinse KC, Choo L, Trubiano JA, Shaffer CM, Watson M, Mallal SA, Phillips EJ.
J Mol Diagn. 2019 May 31. pii: S1525-1578(19)30076-5. doi: 10.1016/j.jmoldx.2019.04.006. [Epub ahead of print]

Improved prognosis and increased tumor infiltrating lymphocytes in small cell lung cancer patients with neurologic paraneoplastic syndromes.
Iams WT, Shiuan E, Meador CB, Roth M, Bordeaux J, Vaupel C, Boyd KL, Summitt IB, Wang LL, Schneider JT, Warner JL, Zhao Z, Lovly CM.
J Thorac Oncol. 2019 Jun 12. pii: S1556-0864(19)30463-0. doi: 10.1016/j.jtho.2019.05.042. [Epub ahead of print]