Kevin Chen

All Publications

• Intramyocardial Hydrogel Delivery Decreases Left Ventricular Remodeling and Increases Angiogenesis Post Myocardial Infarction. Circulation. Cardiovascular imaging Melvinsdottir, I. H., Midgett, D., Lee, S. R., Thorn, S. L., Uman, S., Avendano, R., Lysyy, T., Zohora, F. T., Chen, K., Mamarian, M., Duncan, J. S., Spinale, F. G., Burdick, J. A., Sinusas, A. J. 2025: e018357

  Abstract

  Intramyocardial injection of hydrogel into myocardial infarction (MI) areas can reduce left ventricular remodeling and potentially increase angiogenesis post-MI. The radiotracer 99mTc-Maraciclatide binds to activated αvβ3-integrin, a key factor in angiogenesis, and can be used to evaluate myocardial angiogenesis. This study used multimodality imaging to assess the effects of imageable intramyocardial hydrogel delivery on left ventricular remodeling and angiogenesis after MI.Fourteen pigs (N=14) underwent 90 minutes of balloon occlusion and reperfusion. Five days post-MI, they were randomized to receive either intramyocardial hydrogel (n=8) or control saline injections (n=6). Contrast cine-computed tomography was used to assess biomechanical changes before and after treatment (day 1, day 5, and day 12). 99mTc-Maraciclatide uptake was measured with gamma well counting. Scar burden and angiogenesis were evaluated through histology.Both groups initially showed a decrease in ejection fraction and an increase in end-diastolic volume post-MI. Hydrogel delivery on day 5 led to a reduction in end-diastolic volume and improvement in left ventricular ejection fraction by day 12. The hydrogel group also exhibited decreased compensatory radial strain in remote myocardial segments, but decreased strain in the hydrogel myocardial segments. There was increased uptake of 99mTc-maraciclatide in the infarct segments after hydrogel delivery, associated with increased αvβ3-integrin and factor VIII expression in the hydrogel treatment group on histology. However, there was no difference in regional inflammation or scar size between the groups.Intramyocardial delivery of hydrogel early post-MI resulted in decreased left ventricular remodeling and increased αvβ3-integrin activation associated with an increase in angiogenesis.

  View details for DOI 10.1161/CIRCIMAGING.125.018357

  View details for PubMedID 41017463

• LARP1 haploinsufficiency is associated with an autosomal dominant neurodevelopmental disorder. HGG advances Chettle, J., Louie, R. J., Larner, O., Best, R., Chen, K., Morris, J., Dedeic, Z., Childers, A., Rogers, R. C., DuPont, B. R., Skinner, C., Küry, S., Uguen, K., Planes, M., Monteil, D., Li, M., Eliyahu, A., Greenbaum, L., Mor, N., Besnard, T., Isidor, B., Cogné, B., Blesson, A., Comi, A., Wentzensen, I. M., Vuocolo, B., Lalani, S. R., Sierra, R., Berry, L., Carter, K., Sanders, S. J., Blagden, S. P. 2024; 5 (4): 100345

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. Using lymphocytes collected and immortalized from an index proband who carries a truncating variant in one allele of LARP1, we demonstrated that lower cellular levels of LARP1 protein cause reduced rates of aerobic respiration and glycolysis. As expression of LARP1 increases during neurodevelopment, with higher levels in neurons and astrocytes, we propose that LARP1 haploinsufficiency contributes to ASD or related NDDs through attenuated metabolic activity in the developing fetal brain.

  View details for DOI 10.1016/j.xhgg.2024.100345

  View details for PubMedID 39182167

  View details for PubMedCentralID PMC11418108

• Five questions on how biochemistry can combat climate change. BBA advances Chen, K., Guo, Y., How, K., Acosta, A., Documet, D., Liang, C., Arul, D., Wood, S., Moon, K., Oliver, L. S., Fajardo, E. L., Kopyto, M., Shine, M., Neugebauer, K. M. 2023; 4: 100111

  Abstract

  Global warming is caused by human activity, such as the burning of fossil fuels, which produces high levels of greenhouse gasses. As a consequence, climate change impacts all organisms and the greater ecosystem through changing conditions from weather patterns to the temperature, pH and salt concentrations found in waterways and soil. These environmental changes fundamentally alter many parameters of the living world, from the kinetics of chemical reactions and cellular signaling pathways to the accumulation of unforeseen chemicals in the environment, the appearance and dispersal of new diseases, and the availability of traditional foods. Some organisms adapt to extremes, while others cannot. This article asks five questions that prompt us to consider the foundational knowledge that biochemistry can bring to the table as we meet the challenge of climate change. We approach climate change from the molecular point of view, identifying how cells and organisms - from microbes to plants and animals - respond to changing environmental conditions. To embrace the concept of "one health" for all life on the planet, we argue that we must leverage biochemistry, cell biology, molecular biophysics and genetics to fully understand the impact of climate change on the living world and to bring positive change.

  View details for DOI 10.1016/j.bbadva.2023.100111

  View details for PubMedID 38075469

  View details for PubMedCentralID PMC10709155

• Maintenance of Flap Endonucleases for Long-Patch Base Excision DNA Repair in Mouse Muscle and Neuronal Cells Differentiated In Vitro. International journal of molecular sciences Caston, R. A., Fortini, P., Chen, K., Bauer, J., Dogliotti, E., Yin, Y. W., Demple, B. 2023; 24 (16)

  Abstract

  After cellular differentiation, nuclear DNA is no longer replicated, and many of the associated proteins are downregulated accordingly. These include the structure-specific endonucleases Fen1 and DNA2, which are implicated in repairing mitochondrial DNA (mtDNA). Two more such endonucleases, named MGME1 and ExoG, have been discovered in mitochondria. This category of nuclease is required for so-called "long-patch" (multinucleotide) base excision DNA repair (BER), which is necessary to process certain oxidative lesions, prompting the question of how differentiation affects the availability and use of these enzymes in mitochondria. In this study, we demonstrate that Fen1 and DNA2 are indeed strongly downregulated after differentiation of neuronal precursors (Cath.a-differentiated cells) or mouse myotubes, while the expression levels of MGME1 and ExoG showed minimal changes. The total flap excision activity in mitochondrial extracts of these cells was moderately decreased upon differentiation, with MGME1 as the predominant flap endonuclease and ExoG playing a lesser role. Unexpectedly, both differentiated cell types appeared to accumulate less oxidative or alkylation damage in mtDNA than did their proliferating progenitors. Finally, the overall rate of mtDNA repair was not significantly different between proliferating and differentiated cells. Taken together, these results indicate that neuronal cells maintain mtDNA repair upon differentiation, evidently relying on mitochondria-specific enzymes for long-patch BER.

  View details for DOI 10.3390/ijms241612715

  View details for PubMedID 37628896

  View details for PubMedCentralID PMC10454756

• Self-Reported COVID-19 Infections and Social Mixing Behavior at Oncology Meetings. International journal of radiation oncology, biology, physics Talcott, W. J., Chen, K., Peters, G. W., Reddy, K. K., Weintraub, S. M., Mougalian, S. S., Adelson, K., Evans, S. B. 2022; 114 (1): 30-38

  Abstract

  The COVID-19 pandemic largely suspended in-person scientific meetings because of risk of disease spread. In the era of vaccination and social distancing practices, meetings have begun returning to in-person formats. We surveyed attendees and potential attendees of 2 oncology meetings in the United States to identify rates of mixing behavior and the subsequent rate of self-reported COVID-19 infection.We collected via survey reported social mixing behavior and COVID-19 positivity (within 21 days of meeting conclusion) of actual and potential in-person attendees of the American Society of Clinical Oncology (ASCO) Quality Care Symposium held September 24 to 25, 2021, and the American Society for Radiation Oncology (ASTRO) Annual Meeting held October 24 to 27, 2021. Conference speakers and other participants were identified through publicly available meeting materials and targeted via e-mail when possible. Recruitment of additional attendees and potential attendees was also conducted through a sharable link promoted via oncology newsletters and social media. Descriptive statistics alone were performed owing to low COVID-19 event rates.Response rates from targeted conference participants with publicly available e-mails were 27.4% for the ASCO and 14.3% for the ASTRO meetings. The ASCO survey produced 94 responses (48 in-person attendees). The ASTRO survey produced 370 responses (267 in-person attendees). Across both meetings, 3 of 308 (1.0%) in-person attendees versus 2 of 141 (1.4%) nonattendees tested positive for COVID-19. Low COVID-19 positivity rates were reported among in-person attendees spending more (>20) versus fewer (≤20) hours attending live sessions (2.2% vs 0%) and among indoor social event participants versus nonparticipants (0.8% vs 1.9%). Attendees largely felt comfortable attending additional in-person meetings after experiencing ASCO (87.5%) or ASTRO (91.9%) and felt mask compliance was good or excellent at ASCO (100%) and ASTRO (94.6%) meetings.In-person meetings do not seem to be contributing to high rates of new COVID-19 infections in the setting of vaccine and social distancing mandates, supporting paths forward for at least partially in-person conferences as COVID-19 becomes endemic.

  View details for DOI 10.1016/j.ijrobp.2022.05.002

  View details for PubMedID 35598798

  View details for PubMedCentralID PMC9119957

• The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs. Proceedings of the National Academy of Sciences of the United States of America Tesfaye, E., Martinez-Terroba, E., Bendor, J., Winkler, L., Olivero, C., Chen, K., Feldser, D. M., Zamudio, J. R., Dimitrova, N. 2021; 118 (31)

  Abstract

  The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However, knowledge of the downstream mediators of p53 reactivation in different oncogenic contexts has been limited. Here, we utilized a panel of murine cancer cell lines from three distinct tumor types susceptible to alternative outcomes following p53 restoration to define unique and shared p53 transcriptional signatures. While we found that the majority of p53-bound sites and p53-responsive transcripts are tumor-type specific, analysis of shared targets identified a core signature of genes activated by p53 across all contexts. Furthermore, we identified repression of E2F and Myc target genes as a key feature of senescence. Characterization of p53-induced transcripts revealed core and senescence-specific long noncoding RNAs (lncRNAs) that are predominantly chromatin associated and whose production is coupled to cis-regulatory activities. Functional investigation of the contributions of p53-induced lncRNAs to p53-dependent outcomes highlighted Pvt1b, the p53-dependent isoform of Pvt1, as a mediator of p53-dependent senescence via Myc repression. Inhibition of Pvt1b led to decreased activation of senescence markers and increased levels of markers of proliferation. These findings shed light on the core and outcome-specific p53 restoration signatures across different oncogenic contexts and underscore the key role of the p53-Pvt1b-Myc regulatory axis in mediating proliferative arrest.

  View details for DOI 10.1073/pnas.2025539118

  View details for PubMedID 34326251

  View details for PubMedCentralID PMC8346867