Browsing by Author "Salas, Julio"
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Publication Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa(2024) Tartaglia, Grace; Fuentes, María; Pate,Neil; Varughese, Abigail; Pyung, Lauren; Pyung, Israel; Alexander, Michael; Poojan, Shiv; Cao, Qingqing; Solomon, Brenda; Padron, Zachary; Dyer, Jonathan; Mellerio, Jemima; McGrath, John; Palisson, Francis; Salas, Julio; Han, Lin; South, AndrewRecessive 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 TGFβ 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.Item Outcomes and Predictors for Re-stenosis of Esophageal Stricture in Epidermolysis Bullosa: A Multicenter Cohort Study(2020-09) Pope, Elena; Mansour, Mark; Berseneva, María; Liy-Wong, Carmen; Salas, Julio; Fuentes, Ignacia; Yubero, Maria Joao; Palisson, Francis; Martinez, Anna; Mellerio, Jemima; Lara-Corrales, Irene; Yang, Anes; Murrell, Dedee; Torres-Pradilla, Mauricio; Lucky, AnneBackground: Esophageal strictures are the common gastrointestinal complications in patients with epidermolysis bullosa (EB) requiring dilation. There is limited information on the best type of intervention, outcomes, and predictors for re-stenosis. Objectives: We aimed to investigate the frequency, clinical presentation of esophageal strictures in EB patients, and to ascertain the predictors of re-stenosis. Methods: We conducted a retrospective, multicenter cohort study involving 7 specialized, international EB centers on patients who were 0 to 50 years of age. Descriptive statistics and hazard risks for re-stenosis were calculated. Results: We identified 125 patients with 497 esophageal stricture episodes over a mean period of observation of 17 (standard deviation [SD]¼ 11.91) years. Dilations were attempted in 90.74% of episodes, using guided fluoroscopy 45.23%, retrograde endoscopy 33.04%, and antegrade endoscopy 19.07%. Successful dilation was accomplished in 99.33% of attempts. Patients experienced a median of 2 (interquartile range [IQR]: 1–7) stricture episodes with a median interval between dilations of 7 (IQR: 4–12) months. Predictors for re-stenosis included: number of strictures (2 vs 1 stricture:x2¼ 4.293,P¼ 0.038, hazard ratio [HR]¼ 1.294 (95% confidence interval [CI]: 1.014–1.652 and 3 vs 1 stricture:x2¼ 7.986, P¼ 0.005, HR¼ 1.785 [95% CI: 1.194, 2.667]) and a long (1 cm) segment stricture (x2¼ 4.599, P¼ 0.032, HR¼ 1.347 (95% CI: 1.026– 1.769). Complications were more common with the endoscopic approach (8/86, antegrade endoscopy; 2 /149, retrograde endoscopy vs 2/204, fluoroscopy; x2¼ 17.39, P-value <0.000). Conclusions: We found excellent dilation outcomes irrespective of the dilation procedure; however, with higher complications in the endoscopic approach. Long (>1 cm) segment involvement and multiple locations were predictive of stricture reoccurrence.Publication Phytochemical variation of wild and farmed populations of boldo (Peumus boldus Molina)(2023) Fuentes, Gonzalo; Echeverría, Javier; Mattar, Cesar; Liberona, Leonel; Giordano, Ady; Suarez, Cristian; Salas, Julio; Gonzalez, Antonia; Cassels, Bruce; Castro, SebastianThe phytochemical profile of six wild and one cultivated Peumus boldus (boldo) populations from different regions of north-central, central and south-central Chile was studied. In leaves, wood, and bark, alkaloids and phenolics were analyzed by UHPLC-MS-MS and leaf essential oils by GC-MS. In each population, compounds were found to exhibit high variability, but important differences were recorded at the population level. The north-central wild populations showed higher concentrations of alkaloids and polyphenols in leaves and alkaloids in the bark compared to more southern populations. Saplings farmed under different shade conditions contained higher species-characteristic leaf polyphenolic concentrations with increasing light while most alkaloids increased with the shade. When analyzed the following year, higenamine, boldine, isocorydine and N- methyllaurotetanine increased. The principal components of the leaf essential oils from the wild populations were p-cymene, ascaridole and 1,8-cineole, while in the farmed trees ascaridole was replaced by its precursor α-terpinene as the second most abundant constituent. Although multiple factors may affect the concentration of secondary metabolites and geographic provenances with its attending differences in sunlight and rainfall has been suggested as one of these, the present work shows that latitude by itself cannot explain differences that have a clear impact on quality from the medicinal standpoint.Item Pro-inflammatory chemokines and cytokines dominate the blister fluid molecular signature in patients with epidermolysis bullosa and affect leukocyte and stem cell migration(Elsevier, 2017) Alexeev, Vitali; Salas, Julio; Palisson, Francis; Mukhtarzada, Lila; Fortuna, Giulio; Uitto, Jouni; South, Andrew; Igoucheva, OlgaHereditary epidermolysis bullosa (EB) is associated with skin blistering and the development of chronic nonhealing wounds. Although clinical studies have shown that cell-based therapies improve wound healing, the recruitment of therapeutic cells to blistering skin and to more advanced skin lesions remains a challenge. Here, we analyzed cytokines and chemokines in blister fluids of patients affected by dystrophic, junctional, and simplex EB. Our analysis revealed high levels of CXCR1, CXCR2, CCR2, and CCR4 ligands, particularly dominant in dystrophic and junctional EB. In vitro migration assays demonstrated the preferential recruitment of CCR4+ lymphocytes and CXCR1+ , CXCR2+ , and CCR2+ myeloid cells toward EB-derived blister fluids. Immunophenotyping of skininfiltrating leukocytes confirmed substantial infiltration of EB-affected skin with resting (CD45RA+ ) and activated (CD45RO+ ) T cells and CXCR2+ CD11b+ cells, many of which were identified as CD16b+ neutrophils. Our studies also showed that abundance of CXCR2 ligand in blister fluids also creates a favorable milieu for the recruitment of the CXCR2+ stem cells, as validated by in vitro and in-matrix migration assays. Collectively, this study identified several chemotactic pathways that control the recruitment of leukocytes to the EB-associated skin lesions. These chemotactic axes could be explored for the refinement of the cutaneous homing of the therapeutic stem cells.