All Publications


  • Impact of advanced clinical fellowship training on future research productivity and career advancement in adult cardiac surgery. Surgery Wang, H., Bajaj, S. S., Williams, K. M., Pickering, J. M., Heiler, J. C., Manjunatha, K., O'Donnell, C. T., Sanchez, M., Boyd, J. H. 2020

    Abstract

    BACKGROUND: Advanced clinical fellowships are important for training surgeons with a niche expertise. Whether this additional training impacts future academic achievement, however, remains unknown. Here, we investigated the impact of advanced fellowship training on research productivity and career advancement among active, academic cardiac surgeons. We hypothesized that advanced fellowships do not significantly boost future academic achievement.METHODS: Using online sources (eg, department webpages, CTSNet, Scopus, Grantome), we studied adult cardiac surgeons who are current faculty at accredited United States cardiothoracic surgery training programs, and who have practiced only at United States academic centers since 1986 (n= 227). Publicly available data regarding career advancement, research productivity, and grant funding were collected. Data are expressed as counts or medians.RESULTS: In our study, 78 (34.4%) surgeons completed an advanced clinical fellowship, and 149 (65.6%) did not. Surgeons who pursued an advanced fellowship spent more time focused on surgical training (P < .0001), and those who did not were more likely to have completed a dedicated research fellowship (P= .0482). Both groups exhibited similar cumulative total publications (P= .6862), H-index (P= .6232), frequency of National Institutes of Health grant funding (P= .8708), and time to achieve full professor rank (P= .7099). After stratification by current academic rank, or by whether surgeons pursued a dedicated research fellowship, completion of an advanced clinical fellowship was not associated with increased research productivity or accelerated career advancement.CONCLUSION: Academic adult cardiac surgeons who pursue advanced clinical fellowships exhibit similar research productivity and similar career advancement as those who do not pursue additional clinical training.

    View details for DOI 10.1016/j.surg.2020.06.016

    View details for PubMedID 32747139

  • Safety of photosynthetic Synechococcus elongatus for in vivo cyanobacteria-mammalian symbiotic therapeutics. Microbial biotechnology Williams, K. M., Wang, H., Paulsen, M. J., Thakore, A. D., Rieck, M., Lucian, H. J., Grady, F., Hironaka, C. E., Chien, A. J., Farry, J. M., Shin, H. S., Jaatinen, K. J., Eskandari, A., Stapleton, L. M., Steele, A. N., Cohen, J. E., Woo, Y. J. 2020

    Abstract

    The cyanobacterium Synechococcus elongatus (SE) has been shown to rescue ischaemic heart muscle after myocardial infarction by photosynthetic oxygen production. Here, we investigated SE toxicity and hypothesized that systemic SE exposure does not elicit a significant immune response in rats. Wistar rats intravenously received SE (n=12), sterile saline (n=12) or E. coli lipopolysaccharide (LPS, n=4), and a subset (8 SE, 8 saline) received a repeat injection 4weeks later. At baseline, 4h, 24h, 48h, 8days and 4weeks after injection, clinical assessments, blood cultures, blood counts, lymphocyte phenotypes, liver function tests, proinflammatory cytokines and immunoglobulins were assessed. Across all metrics, SE rats responded comparably to saline controls, displaying no clinically significant immune response. As expected, LPS rats exhibited severe immunological responses. Systemic SE administration does not induce sepsis or toxicity in rats, thereby supporting the safety of cyanobacteria-mammalian symbiotic therapeutics using this organism.

    View details for DOI 10.1111/1751-7915.13596

    View details for PubMedID 32476224

  • Multi-phase catheter-injectable hydrogel enables dual-stage protein-engineered cytokine release to mitigate adverse left ventricular remodeling following myocardial infarction in a small animal model and a large animal model. Cytokine Steele, A. N., Paulsen, M. J., Wang, H., Stapleton, L. M., Lucian, H. J., Eskandari, A., Hironaka, C. E., Farry, J. M., Baker, S. W., Thakore, A. D., Jaatinen, K. J., Tada, Y., Hollander, M. J., Williams, K. M., Seymour, A. J., Totherow, K. P., Yu, A. C., Cochran, J. R., Appel, E. A., Woo, Y. J. 2020; 127: 154974

    Abstract

    Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1α (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.

    View details for DOI 10.1016/j.cyto.2019.154974

    View details for PubMedID 31978642

  • Bioengineered analog of stromal cell-derived factor 1α preserves the biaxial mechanical properties of native myocardium after infarction. Journal of the mechanical behavior of biomedical materials Wang, H., Wisneski, A., Paulsen, M. J., Imbrie-Moore, A., Wang, Z., Xuan, Y., Hernandez, H. L., Lucian, H. J., Eskandari, A., Thakore, A. D., Farry, J. M., Hironaka, C. E., von Bornstaedt, D., Steele, A. N., Stapleton, L. M., Williams, K. M., Wu, M. A., MacArthur, J. W., Woo, Y. J. 2019; 96: 165–71

    Abstract

    Adverse remodeling of the left ventricle (LV) after myocardial infarction (MI) results in abnormal tissue biomechanics and impaired cardiac function, often leading to heart failure. We hypothesized that intramyocardial delivery of engineered stromal cell-derived factor 1α analog (ESA), our previously-developed supra-efficient pro-angiogenic chemokine, preserves biaxial LV mechanical properties after MI. Male Wistar rats (n = 45) underwent sham surgery (n = 15) or permanent left anterior descending coronary artery ligation. Rats sustaining MI were randomized for intramyocardial injections of either saline (100 μL, n = 15) or ESA (6 μg/kg, n = 15), delivered at four standardized borderzone sites. After 4 weeks, echocardiography was performed, and the hearts were explanted. Tensile testing of the anterolateral LV wall was performed using a displacement-controlled biaxial load frame, and modulus was determined after constitutive modeling. At 4 weeks post-MI, compared to saline controls, ESA-treated hearts had greater wall thickness (1.68 ± 0.05 mm vs 1.42 ± 0.08 mm, p = 0.008), smaller end-diastolic LV internal dimension (6.88 ± 0.29 mm vs 7.69 ± 0.22 mm, p = 0.044), and improved ejection fraction (62.8 ± 3.0% vs 49.4 ± 4.5%, p = 0.014). Histologic analysis revealed significantly reduced infarct size for ESA-treated hearts compared to saline controls (29.4 ± 2.9% vs 41.6 ± 3.1%, p = 0.021). Infarcted hearts treated with ESA exhibited decreased modulus compared to those treated with saline in both the circumferential (211.5 ± 6.9 kPa vs 264.3 ± 12.5 kPa, p = 0.001) and longitudinal axes (194.5 ± 6.5 kPa vs 258.1 ± 14.4 kPa, p < 0.001). In both principal directions, ESA-treated infarcted hearts possessed similar tissue compliance as sham non-infarcted hearts. Overall, intramyocardial ESA therapy improves post-MI ventricular remodeling and function, reduces infarct size, and preserves native LV biaxial mechanical properties.

    View details for PubMedID 31035067

  • Use of a supramolecular polymeric hydrogel as an effective post-operative pericardial adhesion barrier. Nature biomedical engineering Stapleton, L. M., Steele, A. N., Wang, H., Lopez Hernandez, H., Yu, A. C., Paulsen, M. J., Smith, A. A., Roth, G. A., Thakore, A. D., Lucian, H. J., Totherow, K. P., Baker, S. W., Tada, Y., Farry, J. M., Eskandari, A., Hironaka, C. E., Jaatinen, K. J., Williams, K. M., Bergamasco, H., Marschel, C., Chadwick, B., Grady, F., Ma, M., Appel, E. A., Woo, Y. J. 2019; 3 (8): 611–20

    Abstract

    Post-operative adhesions form as a result of normal wound healing processes following any type of surgery. In cardiac surgery, pericardial adhesions are particularly problematic during reoperations, as surgeons must release the adhesions from the surface of the heart before the intended procedure can begin, thereby substantially lengthening operation times and introducing risks of haemorrhage and injury to the heart and lungs during sternal re-entry and cardiac dissection. Here we show that a dynamically crosslinked supramolecular polymer-nanoparticle hydrogel, with viscoelastic and flow properties that enable spraying onto tissue as well as robust tissue adherence and local retention in vivo for two weeks, reduces the formation of pericardial adhesions. In a rat model of severe pericardial adhesions, the hydrogel markedly reduced the severity of the adhesions, whereas commercial adhesion barriers (including Seprafilm and Interceed) did not. The hydrogels also reduced the severity of cardiac adhesions (relative to untreated animals) in a clinically relevant cardiopulmonary-bypass model in sheep. This viscoelastic supramolecular polymeric hydrogel represents a promising clinical solution for the prevention of post-operative pericardial adhesions.

    View details for DOI 10.1038/s41551-019-0442-z

    View details for PubMedID 31391596

  • Asynchronous fate decisions by single cells collectively ensure consistent lineage composition in the mouse blastocyst NATURE COMMUNICATIONS Saiz, N., Williams, K. M., Seshan, V. E., Hadjantonakis, A. 2016; 7

    Abstract

    Intercellular communication is essential to coordinate the behaviour of individual cells during organismal development. The preimplantation mammalian embryo is a paradigm of tissue self-organization and regulative development; however, the cellular basis of these regulative abilities has not been established. Here we use a quantitative image analysis pipeline to undertake a high-resolution, single-cell level analysis of lineage specification in the inner cell mass (ICM) of the mouse blastocyst. We show that a consistent ratio of epiblast and primitive endoderm lineages is achieved through incremental allocation of cells from a common progenitor pool, and that the lineage composition of the ICM is conserved regardless of its size. Furthermore, timed modulation of the FGF-MAPK pathway shows that individual progenitors commit to either fate asynchronously during blastocyst development. These data indicate that such incremental lineage allocation provides the basis for a tissue size control mechanism that ensures the generation of lineages of appropriate size.

    View details for DOI 10.1038/ncomms13463

    View details for Web of Science ID 000387993300001

    View details for PubMedID 27857135

    View details for PubMedCentralID PMC5120222