Browsing by Author "Calderón, Juan Francisco"
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Item Current Controversies in Diagnosis and Management of Cleft Palate and Velopharyngeal Insufficiency.(2015 Pablo Antonio Ysunza et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., 2015) Ysunza, Pablo; Repetto, Gabriela; Pamplona, María; Calderón, Juan Francisco; Shaheen, Kenneth; Chaiyasate, Konkgrit; Rontal, MatthewAbstract BACKGROUND: One of the most controversial topics concerning cleft palate is the diagnosis and treatment of velopharyngeal insufficiency (VPI). OBJECTIVE: This paper reviews current genetic aspects of cleft palate, imaging diagnosis of VPI, the planning of operations for restoring velopharyngeal function during speech, and strategies for speech pathology treatment of articulation disorders in patients with cleft palate. MATERIALS AND METHODS: An updated review of the scientific literature concerning genetic aspects of cleft palate was carried out. Current strategies for assessing and treating articulation disorders associated with cleft palate were analyzed. Imaging procedures for assessing velopharyngeal closure during speech were reviewed, including a recent method for performing intraoperative videonasopharyngoscopy. RESULTS: Conclusions from the analysis of genetic aspects of syndromic and nonsyndromic cleft palate and their use in its diagnosis and management are presented. Strategies for classifying and treating articulation disorders in patients with cleft palate are presented. Preliminary results of the use of multiplanar videofluoroscopy as an outpatient procedure and intraoperative endoscopy for the planning of operations which aimed to correct VPI are presented. CONCLUSION: This paper presents current aspects of the diagnosis and management of patients with cleft palate and VPI including 3 main aspects: genetics and genomics, speech pathology and imaging diagnosis, and surgical management.Item Identification of modifier genes/networks of lysosomal biology(Universidad del Desarrollo. Facultad de Medicina, 2023) Durán Mojica, Anyelo Alberto; Klein Posternack, Andrés David; Calderón, Juan FranciscoLysosomal storage diseases (LSDs) are a heterogeneous group of ~70 rare inherited metabolic diseases caused by loss-of-function variants in genes encoding for lysosomal enzymes, their activators, or transport proteins. Clinical symptoms manifest during early childhood or adolescence, causing varying degrees of disability and short life expectancies. At a cellular level, LSD cells show a progressive accumulation of undegraded substrates. In a subset of LSDs, called sphingolipidosis, the primary buildup material corresponds to lipids. These diseases can affect several organs, including the liver, brain, heart, peripheral nervous system, haematologic, skeletal, gastrointestinal system, lung, muscle, and others. On the other hand, defects in processing sphingolipids have also been observed in patients with common diseases such as neurodegenerative disorders and cancer. To date, the phenotypic variability observed in monogenic conditions is thought to be influenced by genomic loci variation other than in the primary disease locus. These genes are called modifiers. We harnessed the natural genetic variation between different strains of healthy mice to identify modifier genes/networks of lysosomal biology. We used a systems genetics approach. We measured the hepatic activity of 12 lysosomal enzymes and several of their natural substrates in livers derived from a panel of inbred mouse strains, followed by genetic regulators mapping by genome-wide association studies (GWAS), transcriptome associations, Bayesian integration, and pathway enrichment analysis. The GWA study identified 137 non-redundant genes associated with changes in lysosomal enzyme activities and 1744 modifiers for GSLs. Among these genes, 30 are shared between the enzymes and lipid groups. They are clustered into three pathways and associated with other nonLSD diseases. Surprisingly, they are under the regulation of ten common transcription factors, suggesting a common regulation of sphingolipid metabolism. In summary, we have identified novel regulators of lysosomal enzymes and GSL levels that may serve as therapeutic targets for LSD and implicated GSL metabolism in other diseases.Item Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome(2019) Gallo MacFarlane, Elena; Parker, Sarah J.; Shin, Josep Y.; Kang, Benjamin E.; Ziegler, Shira G.; Creamer, Tyler J.; Bagirzadeh, Rustam; Bedja, Djahida; Chen, Yichun; Calderón, Juan Francisco; Weissier, Katherine; Frischmeyer-Guerrerio, Pamela A.; Lindsay, Mark E.; Habashi, Jennifer P.; Dietz, Harry C.The aortic root is the predominant site for development of aneurysm caused by heterozygous loss-of-function mutations in positive effectors of the transforming growth factor-β (TGF-β) pathway. Using a mouse model of Loeys-Dietz syndrome (LDS) that carries a heterozygous kinase-inactivating mutation in TGF-β receptor I, we found that the effects of this mutation depend on the lineage of origin of vascular smooth muscle cells (VSMCs). Secondary heart field–derived (SHF-derived), but not neighboring cardiac neural crest–derived (CNC-derived), VSMCs showed impaired Smad2/3 activation in response to TGF-β, increased expression of angiotensin II (AngII) type 1 receptor (Agtr1a), enhanced responsiveness to AngII, and higher expression of TGF-β ligands. The preserved TGF-β signaling potential in CNC-derived VSMCs associated, in vivo, with increased Smad2/3 phosphorylation. CNC-, but not SHF-specific, deletion of Smad2 preserved aortic wall architecture and reduced aortic dilation in this mouse model of LDS. Taken together, these data suggest that aortic root aneurysm predisposition in this LDS mouse model depends both on defective Smad signaling in SHF-derived VSMCs and excessive Smad signaling in CNC-derived VSMCs. This work highlights the importance of considering the regional microenvironment and specifically lineage-dependent variation in the vulnerability to mutations in the development and testing of pathogenic models for aortic aneurysm.Item NPC1 as a Modulator of Disease Severity and Viral Entry of SARS-CoV-2(2020) Vial, Cecilia; Calderón, Juan Francisco; Klein, AndrésThe COVID-19 plague is hitting mankind. Several viruses, including SARS-CoV-1, MERS-CoV, EBOV, and SARS-CoV-2, use the endocytic machinery to enter the cell. Genomic variants in NPC1, which encodes for the endo-lysosomal Niemann-Pick type C1 protein, restricts the host-range of viruses in bats and susceptibility to infections in humans. Lack of NPC1 and its pharmacological suppression inhibits many viral infections including SARS-CoV-1 and Type I Feline Coronavirus Infection. Antiviral effects of NPC1-inhibiting drugs for COVID-19 treatment should be explored.Item Regulation of Connexins Expression Levels by MicroRNAs, an Update(Frontiers Research Foundation, 2016) Calderón, Juan Francisco; Retamal, MauricioControl of cell-cell coordination and communication is regulated by several factors, including paracrine and autocrine release of biomolecules, and direct exchange of soluble factors between cells through gap junction channels. Additionally, hemichannels also participate in cell-cell coordination through the release of signaling molecules, such as ATP and glutamate. A family of transmembrane proteins named connexins forms both gap junction channels and hemichannels. Because of their importance in cell and tissue coordination, connexins are controlled both by post-translational and post-transcriptional modifications. In recent years, non-coding RNAs have garnered research interest due to their ability to exert post-transcriptional regulation of gene expression. One of the most recent, well-documented control mechanisms of protein synthesis is found through the action of small, single-stranded RNA, called micro RNAs (miRNAs or miRs). Put simply, miRNAs are negative regulators of the expression of a myriad proteins involved in many physiological and pathological processes. This mini review will briefly summarize what is currently known about the action of miRNAs over Cxs expression/function in different organs under some relevant physiological and pathological conditions.Item Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer(Impact Journals, 2017) Weber, Helga; Valbuena, Jose R.; Barbhuiya, Mustafa A; Stein, Stefan; Kunkel, Hana; Garcia, Patricia; Bizama, Carolina; Riquelme, Ismael; Espinoza, Jaime; Kurtz, Stephen; Tyner, Jeffrey; Calderón, Juan Francisco; Corvalan, Alejandro; Grez, Manuel; Pandey, Akhilesh; Leal-Rojas, Pamela; Roa, Juan C.Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.Item Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome(American Society for Clinical Investigation., 2020-02) Bowen, Caitlin; Calderón, Juan Francisco; Burger, Zachary; Rykiel, Graham; Davis, Elaine; Helmers, Mark; Benke, Kelly; Gallo, Elena; Dietz, HarryVascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-α 1 chain of collagen III. Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. We created 2 mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glycine substitutions analogous to those found in patients, and we showed that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase) are major mediators of vascular pathology. Treatment with pharmacologic inhibitors of ERK1/2 or PKCβ prevented death due to spontaneous aortic rupture. Additionally, we found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, was rescued by attenuation of oxytocin and androgen signaling, respectively. Taken together, our results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.