Medicine and Health Sciences Commons^™

Serotonin Reduction In Post-Acute Sequelae Of Viral Infection, Andrea Wong, Ashwarya Devason, Iboro Umana, Timothy Cox, Lenka Dohnalová, Lev Litichevskiy, Jonathan Perla, Patrick Lundgren, Zienab Etwebi, Luke Izzo, Jihee Kim, Monika Tetlak, Hélène Descamps, Simone Park, Stephen Wisser, Aaron Mcknight, Ryan Pardy, Junwon Kim, Niklas Blank, Shaan Patel, Katharina Thum, Sydney Mason, Jean-Christophe Beltra, Michaël Michieletto, Shin Foong Ngiow, Brittany Miller, Megan Liou, Bhoomi Madhu, Oxana Dmitrieva-Posocco, Alex Huber, Peter Hewins, Christopher Petucci, Candice Chu, Gwen Baraniecki-Zwil, Leila Giron, Amy Baxter, Allison Greenplate, Charlotte Kearns, Kathleen Montone, Leslie Litzky, Michael Feldman, Jorge Henao-Mejia, Boris Striepen, Holly Ramage, Kellie Jurado, Kathryn Wellen, Una O'Doherty, Mohamed Abdel-Mohsen, Alan L Landay, Ali Keshavarzian, Timothy Henrich, Steven Deeks, Michael Peluso, Nuala Meyer, E. John Wherry, Benjamin Abramoff, Sara Cherry, Christoph Thaiss, Maayan Levy

Department of Microbiology and Immunology Faculty Papers

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, …

Zinc Treatment Reverses And Anti-Zn-Regulated Mirs Suppress Esophageal Carcinomas In Vivo, Louise Fong, Kay Huebner, Ruiyan Jing, Karl Smalley, Christopher R Brydges, Oliver Fiehn, John Farber, Carlo M Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% …

Trametinib-Induced Epidermal Thinning Accelerates A Mouse Model Of Junctional Epidermolysis Bullosa, Grace Tartaglia, Pyung Hung Park, Michael H. Alexander, Alexander Nyström, Joel Rosenbloom, Andrew P. South

Department of Dermatology and Cutaneous Biology Faculty Papers

Junctional epidermolysis bullosa (JEB) patients experience skin and epithelial fragility due to a pathological deficiency in genes associated with epidermal adhesion. Disease severity ranges from post-natal lethality to localized skin involvement with persistent blistering followed by granulation tissue formation and atrophic scarring. We evaluated the potential of utilizing Trametinib, an MEK inhibitor previously shown to target fibrosis, with and without the documented EB-anti-fibrotic Losartan for reducing disease severity in a mouse model of JEB; Lamc2jeb mice. We found that Trametinib treatment accelerated disease onset and decreased epidermal thickness, which was in large part ameliorated by Losartan treatment. Interestingly, a range …

The Role Of Interleukin-15 In The Development And Treatment Of Hematological Malignancies, Paola Sindaco, Hritisha Pandey, Colleen Isabelle, Nitin Chakravarti, Jonathan Edward Brammer, Pierluigi Porcu, Anjali Mishra

Kimmel Cancer Center Faculty Papers

Cytokines are a vital component of the immune system that controls the activation and growth of blood cells. However, chronic overexpression of cytokines can trigger cellular events leading to malignant transformation. The cytokine interleukin-15 (IL-15) is of particular interest, which has been shown to contribute to the development and progression of various hematological malignancies. This review will provide an overview of the impact of the immunopathogenic function of IL-15 by studying its role in cell survival, proliferation, inflammation, and treatment resistance. We will also review therapeutic approaches for inhibiting IL-15 in blood cancers.

Repression Of Esophageal Neoplasia And Inflammatory Signaling By Anti-Mir-31 Delivery In Vivo., Cristian Taccioli, Michela Garofalo, Hongping Chen, Yubao Jiang, Guidantonio Malagoli Tagliazucchi, Gianpiero Di Leva, Hansjuerg Alder, Paolo Fadda, Justin Middleton, Karl J. Smalley, Tommaso Selmi, Srivatsava Naidu, John L. Farber, Carlo M. Croce, Louise Fong

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined.

METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter …