Browsing by Author "Patel, Neil"

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    Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa
    (2024) Tartaglia, Grace; Fuentes, Ignacia; Patel, Neil; Varughese, Abigail; Israel, Lauren E.; Park, Pyung Hun; Alexander, Michael H.; Poojan, Shiv; Cao, Qingqing; Solomon, Brenda; Padron, Zachary M.; Dyer, Jonathan A.; Mellerio, Jemima E.; McGrath, John A.; Palisson, Francis; Salas-Alanis, Julio; Han, Lin; South, Andrew P.
    Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGF beta pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.
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    Early, Postnatal Pulmonary Hypertension Severity Predicts Inpatient Outcomes in Congenital Diaphragmatic Hernia
    (2021) Munves Ferguson, Dalya; Gupta, Vikas S.; Lally, Pamela A.; Luco Illanes, Matías Fernando; Tsao, KuoJen; Lally, Kevin P.; Patel, Neil; Harting, Matthew T.
    Introduction: Pulmonary hypertension (PH) is the major pathophysiologic consequence of congenital diaphragmatic hernia (CDH). We aimed to evaluate the association between early CDH-associated PH (CDH-PH) and inpatient outcomes. Methods: The CDH Study Group registry was queried for infants born 2015-2019 with echocardiograms before 48h of life. PH was categorized using echocardiographic findings: none, mild (right ventricular systolic pressure <2/3 systemic), moderate (between 2/3 systemic and systemic), or severe (supra-systemic). Univariate and multivariate analyses were performed. Adjusted Poisson regression was used to assess the primary composite outcome of mortality or oxygen support at 30 days. Results: Of 1,472 patients, 86.5% had CDH-PH: 13.9% mild (n = 193), 44.4% moderate (n = 631), and 33.2% severe (n = 468). On adjusted analysis, the primary outcome of mortality or oxygen support at 30 days occurred more frequently in infants with moderate (incidence rate ratio [IRR] 1.8, 95% confidence interval [CI], 1.2-2.6) and severe CDH-PH (IRR 2.0, 95% CI, 1.3-2.9). Extracorporeal life support (ECLS) utilization was associated only with severe CDH-PH after adjustment (IRR 1.8, 95% CI, 1.0-3.3). Discussion/conclusion: Early, postnatal CDH-PH is independently associated with increased risk for mortality or oxygen support at 30 days and utilization of ECLS. Early echocardiogram is a valuable prognostic tool for early, inpatient outcomes in neonates with CDH.