32 results on '"Albiñana V"'
Search Results
2. Mutation study of Spanish patients with Hereditary Hemorrhagic Telangiectasia
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Blanco Francisco J, Garrido-Martin Eva M, Albiñana Virginia, García-Alegria Eva, Fernandez-L Africa, Fontalba Ana, Zarrabeitia Roberto, Perez-Molino Alfonso, Bernabeu-Herrero Maria E, Ojeda Maria-Luisa, Fernandez-Luna Jose L, Bernabeu Carmelo, and Botella Luisa M
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Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder characterised mainly by mutations in the Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. Methods Here, we have identified 22 ALK1 mutations and 15 ENG mutations, many of which had not previously been reported, in independent Spanish families afflicted with HHT. Results We identified mutations in thirty-seven unrelated families. A detailed analysis of clinical symptoms was recorded for each patient analyzed, with a higher significant presence of pulmonary arteriovenous malformations (PAVM) in HHT1 patients over HHT2. Twenty-two mutations in ALK1 and fifteen in ENG genes were identified. Many of them, almost half, represented new mutations in ALK1 and in ENG. Missense mutations in ENG and ALK1 were localized in a tridimensional protein structure model. Conclusion Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1) in our Spanish population, in agreement with previous data from our country and other Mediterranean countries (France, Italy), but different to Northern Europe or North America. There was a significant increase of PAVM associated with HHT1 over HHT2 in these families.
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- 2008
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3. Endothelial-to-Mesenchymal Transition in an Hereditary Hemorrhagic Telangiectasia-like Pediatric Case of Multiple Pulmonary Arteriovenous Malformations.
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Lorente-Herraiz L, Cuesta AM, Recio-Poveda L, Botella LM, and Albiñana V
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- Humans, Child, Male, Mutation, Arteriovenous Malformations genetics, Arteriovenous Malformations pathology, Arteriovenous Malformations metabolism, Epithelial-Mesenchymal Transition genetics, Lung Transplantation, Arteriovenous Fistula pathology, Arteriovenous Fistula genetics, Lung pathology, Lung blood supply, Female, Telangiectasia, Hereditary Hemorrhagic genetics, Telangiectasia, Hereditary Hemorrhagic pathology, Pulmonary Artery abnormalities, Pulmonary Artery pathology, Pulmonary Veins abnormalities, Pulmonary Veins pathology, Endothelial Cells metabolism, Endothelial Cells pathology
- Abstract
Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connections between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5000/8000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-β pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8-year-old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case under study follows a molecular pattern which is HHT-like. Therefore, molecular- biological and cellular-functional analyses have been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial-to-mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases.
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- 2024
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4. Molecular and Cellular Characterization of Primary Endothelial Cells from a Familial Cavernomatosis Patient.
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Lorente-Herraiz L, Cuesta AM, Granado J, Recio-Poveda L, Botella LM, and Albiñana V
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- Humans, Cell Movement genetics, Exons, Consensus, Endothelial Cells, Intercellular Junctions
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Cerebral cavernous malformation (CCM) or familial cavernomatosis is a rare, autosomal dominant, inherited disease characterized by the presence of vascular malformations consisting of blood vessels with an abnormal structure in the form of clusters. Based on the altered gene ( CCM1/Krit1 , CCM2 , CCM3 ) and its origin (spontaneous or familial), different types of this disease can be found. In this work we have isolated and cultivated primary endothelial cells (ECs) from peripheral blood of a type 1 CCM patient. Differential functional and gene expression profiles of these cells were analyzed and compared to primary ECs from a healthy donor. The mutation of the familial index case consisted of a heterozygous point mutation in the position +1 splicing consensus between exons 15 and 16, causing failure in RNA processing and in the final protein. Furthermore, gene expression analysis by quantitative PCR revealed a decreased expression of genes involved in intercellular junction formation, angiogenesis, and vascular homeostasis. Cell biology analysis showed that CCM1 ECs were impaired in angiogenesis and cell migration. Taken together, the results obtained suggest that the alterations found in CCM1 ECs are already present in the heterozygous condition, suffering from vascular impairment and somewhat predisposed to vascular damage.
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- 2024
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5. Mutation in Chek2 triggers von Hippel-Lindau hemangioblastoma growth.
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Cabrera-Montes J, Aguirre DT, Viñas-López J, Lorente-Herraiz L, Recio-Poveda L, Albiñana V, Pérez-Pérez J, Botella LM, and Cuesta AM
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- Male, Adolescent, Humans, Mutation genetics, Hemangioblastoma genetics, Hemangioblastoma surgery, Hemangioblastoma pathology, von Hippel-Lindau Disease diagnosis, von Hippel-Lindau Disease genetics, von Hippel-Lindau Disease pathology, Carcinoma, Renal Cell, Kidney Neoplasms
- Abstract
Purpose: Von Hippel-Lindau (VHL) is a rare inherited disease mainly characterized by the growth of tumours, predominantly hemangioblastomas (Hbs) in the CNS and retina, and renal carcinomas. The natural history of VHL disease is variable, differing in the age of onset and its penetrance, even among relatives. Unfortunately, sometimes VHL shows more severe than average: the onset starts in adolescence, and surgeries are required almost every year. In these cases, the factor that triggers the appearance and growth of Hbs usually remains unknown, although additional mutations are suspected., Methods: We present the case of a VHL patient whose first surgery was at 13 years of age. Then, along his next 8 years, he has undergone 5 surgeries for resection of 10 CNS Hbs. To clarify this severe VHL condition, DNA from a CNS Hb and white blood cells (WBC) was sequenced using next-generation sequencing technology., Results: Massive DNA sequencing of the WBC (germ line) revealed a pathogenic mutation in CHEK2 and the complete loss of a VHL allele (both tumour suppressors). Moreover, in the tumour sample, several mutations, in BRAF1 and PTPN11 were found. Familiar segregation studies showed that CHEK2 mutation was in the maternal lineage, while VHL was inherited by paternal lineage., Conclusions: Finally, clinical history correlated to the different genotypes in the family, concluding that the severity of these VHL manifestations are due to both, VHL-and-CHEK2 mutations. This case report aims to notice the importance of deeper genetic analyses, in inherited rare diseases, to uncover non-expected mutations., (© 2023. The Author(s).)
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- 2023
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6. Tacrolimus as a Promising Drug for Epistaxis and Gastrointestinal Bleeding in HHT.
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Álvarez-Hernández P, Patier JL, Marcos S, Gómez Del Olmo V, Lorente-Herraiz L, Recio-Poveda L, Botella LM, Viteri-Noël A, and Albiñana V
- Abstract
Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular autosomically inherited rare disease. Epistaxis (nose bleeds) is the most common symptom in HHT, leading to anemia and affecting the patient's quality of life. In addition to epistaxis, gastrointestinal bleeding (GI), more often at older ages, may lead to severe anemia and the need for blood transfusions. Thus, finding drugs to control both types of bleeding is a primary necessity in HHT., Methods: A cross-sectional observational study was conducted in a series of 11 HHT patients treated with low tacrolimus doses (0.5-2 mg/day) on an off-label prescription basis. Patients showed refractory bleeding to previous treatments. The epistaxis severity score (ESS) and hemoglobin levels were the parameters used to evaluate the impact of tacrolimus. The occurrence of side effects was also recorded., Results: Tacrolimus was well tolerated in all of the patients except 2 (who stopped the treatment). The remaining patients tolerated the treatment, with a general improvement in their health condition. Epistaxis was significantly reduced when comparing the ESS before and after the treatment. Hemoglobin levels significantly increased, overcoming the anemia, during the course of the treatment., Conclusion: Tacrolimus at low doses should be considered as a promising treatment for epistaxis and gastrointestinal bleeding in HHT.
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- 2023
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7. Propranolol: A "Pick and Roll" Team Player in Benign Tumors and Cancer Therapies.
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Albiñana V, Gallardo-Vara E, Casado-Vela J, Recio-Poveda L, Botella LM, and Cuesta AM
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Research on cancer therapies focuses on processes such as angiogenesis, cell signaling, stemness, metastasis, and drug resistance and inflammation, all of which are influenced by the cellular and molecular microenvironment of the tumor. Different strategies, such as antibodies, small chemicals, hormones, cytokines, and, recently, gene editing techniques, have been tested to reduce the malignancy and generate a harmful microenvironment for the tumor. Few therapeutic agents have shown benefits when administered alone, but a few more have demonstrated clear improvement when administered in combination with other therapeutic molecules. In 2008 (and for the first time in the clinic), the therapeutic benefits of the β-adrenergic receptor antagonist, propranolol, were described in benign tumors, such as infantile hemangioma. Propranolol, initially prescribed for high blood pressure, irregular heart rate, essential tremor, and anxiety, has shown, in the last decade, increasing evidence of its antitumoral properties in more than a dozen different types of cancer. Moreover, the use of propranolol in combination therapies with other drugs has shown synergistic antitumor effects. This review highlights the clinical trials in which propranolol is taking part as adjuvant therapy at single administration or in combinatorial human trials, arising as a good pick and roll partner in anticancer strategies.
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- 2022
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8. A Novel Splicing Mutation in the ACVRL1/ALK1 Gene as a Cause of HHT2.
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Errasti Díaz S, Peñalva M, Recio-Poveda L, Vilches S, Casado-Vela J, Pérez Pérez J, Botella LM, Albiñana V, and Cuesta AM
- Abstract
Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disorder of vascular development. Common manifestations include epistaxis, telangiectasias and arteriovenous malformations in multiple organs. Different deletions or nonsense mutations have been described in the ENG (HHT1) or ACVRL1/ALK1 (HHT2) genes, all affecting endothelial homeostasis. A novel mutation in ACVRL1/ALK1 has been identified in a Peruvian family with a clinical history compatible to HHT. Subsequently, 23 DNA samples from oral exchanges (buccal swaps) of the immediate family members were analyzed together with their clinical histories. A routine cDNA PCR followed by comparative DNA sequencing between the founder and another healthy family member showed the presence of the aforementioned specific mutation. The single mutation detected (c.525 + 1G > T) affects the consensus splice junction immediately after exon 4, provokes anomalous splicing and leads to the inclusion of intron IV between exons 4 and 5 in the ACVRL1/ALK1 mRNA and, therefore, to ALK1 haploinsufficiency. Complete sequencing determined that 10 of the 25 family members analyzed were affected by the same mutation. Notably, the approach described in this report could be used as a diagnostic technique, easily incorporated in clinical practice in developing countries and easily extrapolated to other patients carrying such a mutation.
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- 2022
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9. The Role of Propranolol as a Repurposed Drug in Rare Vascular Diseases.
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Cuesta AM, Gallardo-Vara E, Casado-Vela J, Recio-Poveda L, Botella LM, and Albiñana V
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- Adrenergic beta-Antagonists therapeutic use, Drug Repositioning, Humans, Rare Diseases drug therapy, Propranolol therapeutic use, Vascular Diseases drug therapy
- Abstract
Rare Diseases (RD) are defined by their prevalence in less than 5 in 10,000 of the general population. Considered individually, each RD may seem insignificant, but together they add up to more than 7000 different diseases. Research in RD is not attractive for pharmaceutical companies since it is unlikely to recover development costs for medicines aimed to small numbers of patients. Since most of these diseases are life threatening, this fact underscores the urgent need for treatments. Drug repurposing consists of identifying new uses for approved drugs outside the scope of the original medical indication. It is an alternative option in drug development and represents a viable and risk-managed strategy to develop for RDs. In 2008, the "off label" therapeutic benefits of propranolol were described in the benign tumor Infantile Hemangioma. Propranolol, initially prescribed for high blood pressure, irregular heart rate, essential tremor, and anxiety, has, in the last decade, shown increasing evidence of its antiangiogenic, pro-apoptotic, vasoconstrictor and anti-inflammatory properties in different RDs, including vascular or oncological pathologies. This review highlights the finished and ongoing trials in which propranolol has arisen as a good repurposing drug for improving the health condition in RDs.
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- 2022
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10. Blockade of β2-Adrenergic Receptor Reduces Inflammation and Oxidative Stress in Clear Cell Renal Cell Carcinoma.
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Albiñana V, Recio-Poveda L, González-Peramato P, Martinez-Piñeiro L, Botella LM, and Cuesta AM
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- Animals, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Hemangioblastoma drug therapy, Hemangioblastoma metabolism, Humans, Inflammation metabolism, Male, Mice, Propanolamines pharmacology, Propranolol pharmacology, Signal Transduction drug effects, Von Hippel-Lindau Tumor Suppressor Protein metabolism, von Hippel-Lindau Disease drug therapy, von Hippel-Lindau Disease metabolism, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell metabolism, Inflammation drug therapy, Kidney Neoplasms drug therapy, Kidney Neoplasms metabolism, Oxidative Stress drug effects, Receptors, Adrenergic, beta-2 metabolism
- Abstract
Von Hippel-Lindau (VHL) syndrome is a rare inherited cancer disease where the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HBs), CNS-HBs, and clear cell renal cell carcinoma (ccRCC). Since standard therapies in VHL have shown limited response, leaving surgery as the only possible treatment, targeting of the β2-adrenergic receptor (ADRB2) has shown therapeutic antitumor benefits on VHL-retinal HBs (clinical trial), VHL-CNS HBs, and VHL-ccRCC (in vitro and in vivo). In the present study, we wanted to look deep into the effects of the ADRB2 blockers propranolol and ICI-118,551 on two main aspects of cancer progression: (i) the changes on the inflammatory response of ccRCC cells; and (ii) the modulation on the Warburg effect (glycolytic metabolism), concretely, on the expression of genes involved in the cell reactive oxygen species (ROS) balance and levels. Accordingly, in vitro studies with primary VHL-ccRCC and 786-O cells measuring ROS levels, ROS-expression of detoxifying enzymes, and the expression of p65/NF-κB targets by RT-PCR were carried out. Furthermore, histological analyses of ccRCC samples from heterotopic mouse xenografts were performed. The obtained results show that ADRB2 blockade in ccRCC cells reduces the level of oxidative stress and stabilizes the inflammatory response. Thus, these data further support the idea of targeting ADRB2 as a promising strategy for the treatment of VHL and other non-VHL tumors.
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- 2022
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11. The Endothelial Landscape and Its Role in Von Hippel-Lindau Disease.
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de Rojas-P I, Albiñana V, Taranets L, Recio-Poveda L, Cuesta AM, Popov N, Kronenberger T, and Botella LM
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- Case-Control Studies, Cell Adhesion, Cell Movement, Cell Proliferation, Cells, Cultured, Endothelial Cells immunology, Endothelial Cells metabolism, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mutation, Oxidative Stress, Phenotype, Signal Transduction, Transcriptome, Von Hippel-Lindau Tumor Suppressor Protein genetics, von Hippel-Lindau Disease genetics, von Hippel-Lindau Disease immunology, von Hippel-Lindau Disease metabolism, Endothelial Cells pathology, Neovascularization, Pathologic genetics, von Hippel-Lindau Disease pathology
- Abstract
Von Hippel-Lindau disease (VHL) is a rare hereditary disease characterized by the predisposal to develop different types of highly vascularized tumors. VHL patients carry a VHL mutation that causes partial lack of functional VHL protein (pVHL) in all cells, and a total lack thereof in cells harboring a second hit mutation. Absence of pVHL generates a prolonged state of pseudo-hypoxia in the cell due to accumulation of hypoxia inducible factor, an important transcription factor regulating pro-tumorigenic genes. The work here presented focuses on characterizing the endothelium of VHL patients, by means of blood outgrowth endothelial cells (BOECs). Transcriptome analysis of VHL-derived BOECs, further supported by in vitro assays, shows that these cells are at a disadvantage, as evidenced by loss of cell adhesion capacity, angiogenesis defects, and immune response and oxidative metabolic gene downregulation, which induce oxidative stress. These results suggest that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development. These findings contribute to shedding light on the vascular landscape of VHL patients preceding the second hit mutation in the VHL gene. This knowledge could be useful in searching for new therapies for these patients and other vascular diseases.
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- 2021
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12. Sclerotherapy on Demand with Polidocanol to Treat HHT Nosebleeds.
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Marcos S, Botella LM, Albiñana V, Arbia A, and de Rosales AM
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Epistaxis is the most prevalent clinical symptom in Hereditary Haemorrhagic Telangiectasia (HHT), causing anaemia and decreasing the quality of life (QOL). Since 2013, in Hospital Universitario Fundación Alcorcón, more than 150 HHT patients have been treated by nose sclerotherapy on demand. This study shows the results of 105 patients treated with sclerotherapy between 2017 and 2019. HHT-ESS (epistaxis severity score) was used to measure the severity and frequency of epistaxis. QOL was determined before and after treatment by EuroQol-5D (EQ-5D) and the visual analogue scale (VAS) on the health condition. According to HHT-ESS before treatment, 22 patients presented mild, 35 moderate, and 47 severe epistaxes. Sclerotherapy significantly decreased the frequency and severity of epistaxis, with a significant drop of HHT-ESS in 4.6 points, from 6.23 ± 2.3 to 1.64 ± 1.6. Furthermore, the QOL significantly improved, the EQ-5D scale raised from 0.7 ± 0.26 pre- to 0.92 ± 0.16 post-treatment ( p < 0.05). Additionally, VAS mean value showed a significant increase from 4.38 ± 2.4 to 8.35 ± 1.2. The QOL improvement was correlated with the ESS decrease. In conclusion, this study shows that on-demand sclerotherapy at the office significantly reduces HHT epistaxis as well as improved the patients' QOL.
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- 2021
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13. SARS-CoV-2 Infection in Hereditary Hemorrhagic Telangiectasia Patients Suggests Less Clinical Impact Than in the General Population.
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Marcos S, Albiñana V, Recio-Poveda L, Tarazona B, Verde-González MP, Ojeda-Fernández L, and Botella LM
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At the moment of writing this communication, the health crisis derived from the COVID-19 pandemic has affected more than 120 million cases, with 40 million corresponding to Europe. In total, the number of deaths is almost 3 million, but continuously rising. Although COVID-19 is primarily a respiratory disease, SARS-CoV-2 infects also endothelial cells in the pulmonary capillaries. This affects the integrity of the endothelium and increases vascular permeability. In addition, there are serious indirect consequences, like disruption of endothelial cells' junctions leading to micro-bleeds and uncontrolled blood clotting. The impact of COVID-19 in people with rare chronic cardiovascular diseases is unknown so far, and interesting to assess, because the virus may cause additional complications in these patients. The aim of the present work was to study the COVID-19 infection among the patients with Hereditary Hemorrhagic Telangiectasia (HHT). A retrospective study was carried out in a 138 HHT patients' sample attending an Ear Nose and Throat (ENT) reference consult. The evaluation of the COVID-19 infection in them reveals milder symptoms; among the 25 HHT patients who were infected, only 3 cases were hospitalized, and none of them required ICU or ventilation assistance. The results are discussed in the light of macrophage immune response.
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- 2021
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14. Differential Expression of Circulating Plasma miRNA-370 and miRNA-10a from Patients with Hereditary Hemorrhagic Telangiectasia.
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Ruiz-Llorente L, Albiñana V, Botella LM, and Bernabeu C
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Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disorder that presents with telangiectases and arteriovenous malformations. HHT is a genetically heterogeneous disorder, involving mutations in endoglin ( ENG ; HHT1) and activin receptor-like kinase 1 ( ACVRL1 / ALK1 ; HHT2) genes that account for over 85% of all HHT patients. The current diagnosis of HHT patients remains at the clinical level, but many suspected patients do not have a clear HHT diagnosis or do not show pathogenic mutations in HHT genes. This situation has prompted the search for biomarkers to help in the early diagnosis of the disease. We have analyzed the plasma levels in HHT patients of selected micro-RNAs (miRNAs), small single-stranded RNAs that regulate gene expression at the transcriptional level by interacting with specific RNA targets. A total of 16 HHT1 and 17 HHT2 plasma samples from clinically confirmed patients and 16 controls were analyzed in this study. Total RNA was purified from plasma, and three selected miRNAs (miRNA-10a, miRNA-214, and miRNA-370), related to the pathobiology of cardiovascular diseases and potentially targeting ENG or ALK1 , were measured by quantitative polymerase chain reaction. Compared with controls, levels of miRNA-370, whose putative target is ENG , were significantly downregulated in HHT1, but not in HHT2, whereas the levels of miRNA-10a, whose putative target is ALK1 , were significantly upregulated in HHT2, but not in HHT1. In addition, the levels of miRNA-214, potentially targeting ENG and ALK1, did not change in either HHT1 or HHT2 patients versus control samples. While further studies are warranted, these results suggest that dysregulated plasma levels of miRNA-370 or miRNA-10a could help to identify undiagnosed HHT1 or HHT2 patients, respectively.
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- 2020
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15. Targeting β2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel-Lindau Disease.
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Albiñana V, Gallardo-Vara E, de Rojas-P I, Recio-Poveda L, Aguado T, Canto-Cano A, Aguirre DT, Serra MM, González-Peramato P, Martínez-Piñeiro L, Cuesta AM, and Botella LM
- Abstract
Von Hippel-Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of β2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL
-/- ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2α, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2α and NFĸB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors.- Published
- 2020
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16. Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding.
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Albiñana V, Cuesta AM, Rojas-P I, Gallardo-Vara E, Recio-Poveda L, Bernabéu C, and Botella LM
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The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. Despite clear knowledge of the symptoms and genes of the disease, we still lack a definite cure for HHT, having just palliative measures and pharmacological trials. Among the former, two strategies are: intervention at "ground zero" to minimize by iron and blood transfusions in order to counteract anemia. Among the later, along the last 15 years, three different strategies have been tested: (1) To favor coagulation with antifibrinolytic agents (tranexamic acid); (2) to increase transcription of ENG and ALK1 with specific estrogen-receptor modulators (bazedoxifene or raloxifene), antioxidants (N-acetylcysteine, resveratrol), or immunosuppressants (tacrolimus); and (3) to impair the abnormal angiogenic process with antibodies (bevacizumab) or blocking drugs like etamsylate, and propranolol. This manuscript reviews the main strategies and sums up the clinical trials developed with drugs alleviating HHT., Competing Interests: The authors declare no conflict of interest.
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- 2020
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17. CLN5 in heterozygosis may protect against the development of tumors in a VHL patient.
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de Rojas-P I, Albiñana V, Recio-Poveda L, Rodriguez-Rufián A, Cuesta ÁM, and Botella LM
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- Endothelial Cells, Female, Humans, Lysosomal Membrane Proteins, Von Hippel-Lindau Tumor Suppressor Protein genetics, Hemangioblastoma, Neoplasms, von Hippel-Lindau Disease genetics
- Abstract
Von Hippel-Lindau syndrome (VHL) is a rare disease of dominant inheritance that increases susceptibility to tumor development, with a complete penetrance at the age of 60. In this report, we present the unprecedented case of a VHL carrier who remains healthy at 72. Under the course of this study, it was discovered that this patient carries a mutation for a second rare disease, Neuronal Ceroid Lipofuscinosis (NCL or CNL). We hypothesize that the CLN mutation she carries offers a protective effect, preventing tumor development in the cells potentially suffering a VHL second hit mutation. To test this hypothesis, we ran a series of molecular experiments and confirmed that cell viability of primary endothelial cells decreases upon CLN5 silencing. Our results further elucidate the cell biology implications of two rare diseases interacting.
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- 2020
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18. 11PS04 is a new chemical entity identified by microRNA-based biosensing with promising therapeutic potential against cancer stem cells.
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Aguado T, Romero-Revilla JA, Granados R, Campuzano S, Torrente-Rodríguez RM, Cuesta ÁM, Albiñana V, Botella LM, Santamaría S, Garcia-Sanz JA, Pingarrón JM, Sánchez-Sancho F, and Sánchez-Puelles JM
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- Animals, Antineoplastic Agents pharmacology, Carcinogenesis drug effects, Carcinogenesis pathology, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Glioma pathology, Magnetic Phenomena, Mammary Glands, Animal drug effects, Mammary Glands, Animal pathology, Mice, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Oxazoles chemistry, Reproducibility of Results, Spheroids, Cellular drug effects, Spheroids, Cellular metabolism, Spheroids, Cellular pathology, Temozolomide pharmacology, Xenograft Model Antitumor Assays, Biosensing Techniques, MicroRNAs metabolism, Neoplastic Stem Cells pathology, Oxazoles pharmacology
- Abstract
Phenotypic drug discovery must take advantage of the large amount of clinical data currently available. In this sense, the impact of microRNAs (miRs) on human disease and clinical therapeutic responses is becoming increasingly well documented. Accordingly, it might be possible to use miR-based signatures as phenotypic read-outs of pathological status, for example in cancer. Here, we propose to use the information accumulating regarding the biology of miRs from clinical research in the preclinical arena, adapting it to the use of miR biosensors in the earliest steps of drug screening. Thus, we have used an amperometric dual magnetosensor capable of monitoring a miR-21/miR-205 signature to screen for new drugs that restore these miRs to non-tumorigenic levels in cell models of breast cancer and glioblastoma. In this way we have been able to identify a new chemical entity, 11PS04 ((3aR,7aS)-2-(3-propoxyphenyl)-7,7a-dihydro-3aH-pyrano[3,4-d]oxazol-6(4H)-one), the therapeutic potential of which was suggested in mechanistic assays of disease models, including 3D cell culture (oncospheres) and xenografts. These assays highlighted the potential of this compound to attack cancer stem cells, reducing the growth of breast and glioblastoma tumors in vivo. These data demonstrate the enhanced chain of translatability of this strategy, opening up new perspectives for drug-discovery pipelines and highlighting the potential of miR-based electro-analytical sensors as efficient tools in modern drug discovery.
- Published
- 2019
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19. Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition).
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Albiñana V, Giménez-Gallego G, García-Mato A, Palacios P, Recio-Poveda L, Cuesta AM, Patier JL, and Botella LM
- Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by recurrent and spontaneous epistaxis (nose bleeds), telangiectases on skin and mucosa, internal organ arteriovenous malformations, and dominant autosomal inheritance. Mutations in Endoglin and ACVRL1 / ALK1 , genes mainly expressed in endothelium, are responsible in 90% of the cases for the pathology. These genes are involved in the transforming growth factor-β(TGF-β) signaling pathway. Epistaxis remains as one of the most common symptoms impairing the quality of life of patients, becoming life-threatening in some cases. Different strategies have been used to decrease nose bleeds, among them is antiangiogenesis. The two main angiogenic pathways in endothelial cells depend on vascular endothelial growth factor and fibroblast growth factor (FGF). The present work has used etamsylate, the diethylamine salt of the 2,5-dihydroxybenzene sulfonate anion, also known as dobesilate, as a FGF signaling inhibitor. In endothelial cells, in vitro experiments show that etamsylate acts as an antiangiogenic factor, inhibiting wound healing and matrigel tubulogenesis. Moreover, etamsylate decreases phosphorylation of Akt and ERK1/2. A pilot clinical trial (EudraCT: 2016-003982-24) was performed with 12 HHT patients using a topical spray of etamsylate twice a day for 4 weeks. The epistaxis severity score (HHT-ESS) and other pertinent parameters were registered in the clinical trial. The significant reduction in the ESS scale, together with the lack of significant side effects, allowed the designation of topical etamsylate as a new orphan drug for epistaxis in HHT (EMA/OD/135/18).
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- 2019
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20. Evaluation of the safety and effectiveness of oral propranolol in patients with von Hippel-Lindau disease and retinal hemangioblastomas: phase III clinical trial.
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González-Rodríguez B, Villar Gómez de Las Heras K, Aguirre DT, Rodríguez-Padial L, Albiñana V, Recio-Poveda L, Cuesta AM, Botella LM, and Jiménez-Escribano RM
- Abstract
Background: von Hippel-Lindau disease (VHL) is a multisystem cancer syndrome caused by mutations in the VHL gene. Retinal hemangioblastoma is one of the most common tumours, and when it appears near the optic nerve, its treatment is challenging and risky. To date, no treatment has proven effective in changing the course of the disease. This study was designed to evaluate the safety and effectiveness of propranolol in controlling these tumours., Methods: Seven patients were included. All patients took a daily dose of 120 mg of propranolol for 1 year. Clinical variables were assessed at baseline, and at 1, 3, 6, 9 and 12 months. The primary endpoint of the study was the number and size of retinal hemangioblastomas. On every visit, retinal outcomes and blood biomarkers (such as vascular endothelial growth factor (VEGF) and miR210) were analysed., Results: Number and size of retinal hemangioblastomas remained stable in all patients. All of them had initially increased levels of VEGF and miR210. There was a gradual reabsorption of retinal exudation in two patients, correlating with a progressive decrease of both biomarkers. The only adverse effect reported was hypotension in one patient., Conclusions: Propranolol could be used to treat retinal hemangioblastomas in VHL patients, although more studies are needed to determine the ideal dose and long-term effect. VEGF and miR210 should be explored as biomarkers of disease activity. As far as we know, these are the first biomarkers proposed to monitor the VHL disease activity., Trial Registration Number: 2014-003671-30., Competing Interests: Competing interests: None declared.
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- 2019
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21. Case Report: Propranolol increases the therapeutic response to temozolomide in a patient with metastatic paraganglioma.
- Author
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Díaz-Castellanos MA, Gómez de Las Heras KV, Díaz-Redondo T, González-Flores E, Albiñana V, and Botella LM
- Abstract
This case report presents the clinical evolution and management of a patient with a hereditary paraganglioma syndrome. This disease is characterized by rare tumors of neural crest origin that are symmetrically distributed along the paravertebral axis from the base of the skull and neck to the pelvis. In addition, these patients may develop renal cancer, gastrointestinal stromal tumors, pituitary adenomas, and bone metastasis in some cases. To date no successful therapeutic treatment has been reported. Total resection with postoperative radiotherapy and chemotherapy have been advocated, especially for the multiple metastasis. Here we show how the combination of high doses of the beta blocker propranolol (3 mg/Kg/day) and the DNA intercalating agent, temozolomide, has been successful in the treatment of a SDHA metastatic paraganglioma., Competing Interests: No competing interests were disclosed.
- Published
- 2017
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22. Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease.
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Albiñana V, Escribano RMJ, Soler I, Padial LR, Recio-Poveda L, Villar Gómez de Las Heras K, and Botella LM
- Subjects
- Adolescent, Adult, Biomarkers blood, Female, Hemangioblastoma blood, Humans, Male, MicroRNAs blood, Middle Aged, Real-Time Polymerase Chain Reaction, Retinal Diseases blood, Vascular Endothelial Growth Factor A blood, Young Adult, von Hippel-Lindau Disease blood, Hemangioblastoma drug therapy, Propranolol therapeutic use, Retinal Diseases drug therapy, von Hippel-Lindau Disease drug therapy
- Abstract
Background: Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumours. Haemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma and pheochromocytomas are the most common tumours. The absence of treatment for VHL leads to the need of repeated surgeries as the only option for these patients. Targeting VHL-derived tumours with drugs with reduced side effects is urgent to avoid repeated CNS surgeries. Recent reports have demonstrated that propranolol, a β-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control haemangioblastoma growth in VHL disease given its antiangiogenic effects that were recently demonstrated by us. The main objective of the present study was the assessment of the efficacy and safety of propranolol on retinal haemangioblastoma in von Hippel-Lindau disease (VHL)., Methods: 7 VHL patients, from different regions of Spain, affected from juxtapapillary or peripheral haemangioblastomas were administered 120 mg propranolol daily. Patients were evaluated every 3 months for 12 months, at Virgen de la Salud Hospital (Toledo). The patients had juxtapapillary or peripheral haemangioblastomas but had refused standard treatments., Results: Propranolol was initiated with a progressive increase up to a final dose of 120 mg daily. All tumours remained stable, and no new tumours appeared. The reabsorption of retinal exudation was noted in the two patients having exudates. No adverse effects were recorded. VEGF and miRNA 210 levels were monitored in the plasma of patients as possible biomarkers of VHL. These levels decreased in all cases from the first month of treatment., Conclusions: Although more studies are necessary, the results of this work suggest that propranolol is a drug to be considered in the treatment of VHL patients with retinal haemangioblastomas. VEGF and miRNA 210 could be used as biomarkers of the VHL disease activity., Trial Registration: The study has a clinical trial design and was registered at EU Clinical Trials Register and Spanish Clinical Studies Registry, EudraCT Number: 2014-003671-30 . Registered 2 September 2014.
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- 2017
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23. Mutation affecting the proximal promoter of Endoglin as the origin of hereditary hemorrhagic telangiectasia type 1.
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Albiñana V, Zafra MP, Colau J, Zarrabeitia R, Recio-Poveda L, Olavarrieta L, Pérez-Pérez J, and Botella LM
- Subjects
- Activin Receptors, Type II genetics, Alleles, Base Sequence, Cell Line, DNA chemistry, DNA isolation & purification, DNA metabolism, Endoglin metabolism, Exons, Genes, Reporter, Genotype, Humans, Monocytes cytology, Monocytes immunology, Monocytes metabolism, Mutation, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Protein Binding, Telangiectasia, Hereditary Hemorrhagic pathology, Transcription Factors chemistry, Transcription Factors metabolism, Endoglin genetics, Promoter Regions, Genetic genetics, Telangiectasia, Hereditary Hemorrhagic genetics
- Abstract
Background: Hereditary hemorrhagic telangiectasia (HHT) is a vascular multi-organ system disorder. Its diagnostic criteria include epistaxis, telangiectases in mucocutaneous sites, arteriovenous malformations (AVMs), and familial inheritance. HHT is transmitted as an autosomal dominant condition, caused in 85% of cases by mutations in either Endoglin (ENG) or Activin receptor-like kinase (ACVRL1/ACVRL1/ALK1) genes. Pathogenic mutations have been described in exons, splice junctions and, in a few cases with ENG mutations, in the proximal promoter, which creates a new ATG start site. However, no mutations affecting transcription regulation have been described to date in HHT, and this type of mutation is rarely identified in the literature on rare diseases., Methods: Sequencing data from a family with HHT lead to single nucleotide change, c.-58G > A. The functionality and pathogenicity of this change was analyzed by in vitro mutagenesis, quantitative PCR and Gel shift assay. Student t test was used for statistical significance., Results: A single nucleotide change, c.-58G > A, in the proximal ENG promoter co-segregated with HHT clinical features in an HHT family. This mutation was present in the proband and in 2 other symptomatic members, whereas 2 asymptomatic relatives did not harbor the mutation. Analysis of RNA from activated monocytes from the probands and the healthy brother revealed reduced ENG mRNA expression in the HHT patient (p = 0.005). Site-directed mutagenesis of the ENG promoter resulted in a three-fold decrease in luciferase activity of the mutant c.-58A allele compared to wild type (p = 0.005). Finally, gel shift assay identified a DNA-protein specific complex., Conclusions: The novel ENG c.-58G > A substitution in the ENG promoter co-segregates with HHT symptoms in a family and appears to affect the transcriptional regulation of the gene, resulting in reduced ENG expression. ENG c.-58G > A may therefore be a pathogenic HHT mutation leading to haploinsufficiency of Endoglin and HHT symptoms. To the best of our knowledge, this is the first report of a pathogenic mutation in HHT involving the binding site for a transcription factor in the promoter of ENG.
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- 2017
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24. Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia.
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Zarrabeitia R, Ojeda-Fernandez L, Recio L, Bernabéu C, Parra JA, Albiñana V, and Botella LM
- Subjects
- Activin Receptors, Type II genetics, Aged, Cells, Cultured, Endoglin genetics, Endothelial Cells drug effects, Endothelial Cells metabolism, Female, Hemorrhage blood, Hemorrhage drug therapy, Hemorrhage etiology, Humans, Middle Aged, Neovascularization, Physiologic drug effects, Orphan Drug Production, Pilot Projects, RNA, Messenger genetics, RNA, Messenger metabolism, Selective Estrogen Receptor Modulators therapeutic use, Telangiectasia, Hereditary Hemorrhagic complications, Telangiectasia, Hereditary Hemorrhagic genetics, Vascular Endothelial Growth Factor A blood, Vascular Endothelial Growth Factor A genetics, Wound Healing drug effects, Indoles therapeutic use, Telangiectasia, Hereditary Hemorrhagic drug therapy
- Abstract
Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is a dominant genetic vascular disorder. In HHT, blood vessels are weak and prone to bleeding, leading to epistaxis and anaemia, severely affecting patients' quality of life. Development of vascular malformations in HHT patients is originated mainly by mutations in ACVRL1/ALK1 (activin receptor-like kinase type I) or Endoglin (ENG) genes. These genes encode proteins of the TGF-β signalling pathway in endothelial cells, controlling angiogenesis. Haploinsufficiency of these proteins is the basis of HHT pathogenicity. It was our objective to study the efficiency of Bazedoxifene, a selective estrogen receptor modulator (SERM) in HHT, looking for a decrease in epistaxis, and understanding the underlying molecular mechanism. Plasma samples of five HHT patients were collected before, and after 1 and 3 months of Bazedoxifene treatment. ENG and ALK1 expression in activated mononuclear cells derived from blood, as well as VEGF plasma levels, were measured. Quantification of Endoglin and ALK1 mRNA was done in endothelial cells derived from HHT and healthy donors, after in vitro treatment with Bazedoxifene. Angiogenesis was also measured by tubulogenesis and wound healing assays. Upon Bazedoxifene treatment, haemoglobin levels of HHT patients increased and the quantity and frequency of epistaxis decreased. Bazedoxifene increased Endoglin and ALK1 mRNA levels, in cells derived from blood samples and in cultured endothelial cells, promoting tube formation. In conclusion, Bazedoxifene seems to decrease bleeding in HHT by partial compensation of haploinsufficiency. The results shown here are the basis of a new orphan drug designation for HHT by the European Medicine Agency (EMA).
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- 2016
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25. Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients.
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Albiñana V, Villar Gómez de Las Heras K, Serrano-Heras G, Segura T, Perona-Moratalla AB, Mota-Pérez M, de Campos JM, and Botella LM
- Subjects
- Adolescent, Adrenergic beta-Antagonists pharmacology, Adrenergic beta-Antagonists therapeutic use, Adult, Apoptosis physiology, Cell Survival physiology, Cerebellar Neoplasms drug therapy, Dose-Response Relationship, Drug, Female, HeLa Cells, Hemangioblastoma drug therapy, Humans, Male, Middle Aged, Propranolol therapeutic use, Tumor Cells, Cultured, Young Adult, von Hippel-Lindau Disease drug therapy, Apoptosis drug effects, Cell Survival drug effects, Cerebellar Neoplasms pathology, Hemangioblastoma pathology, Propranolol pharmacology, von Hippel-Lindau Disease pathology
- Abstract
Background: Von Hippel-Lindau (VHL) disease is a rare oncological disease with an incidence of 1:36,000, and is characterized by the growth of different types of tumors: hemangioblastomas in the central nervous system (CNS) and retina, renal carcinoma, pheochromocytomas, pancreatic serous cystadenoma, and endolymphatic sac tumors. These tumors do not express VHL protein (pVHL). pVHL ubiquitinates hypoxia inducible factor (HIF) protein for degradation by the proteasome; in the absence of VHL, HIF translocates to the nucleus to activate the expression of its target genes. Targeting VHL-derived tumors with drugs that have reduced side effects is urgent to avoid repeat CNS surgeries. Recent reports have shown that propranolol, a β-blocker used for the treatment of hypertension and other cardiac and neurological diseases, is the best option for infantile hemangioma (IH). Propranolol could be an efficient treatment to control hemangioblastoma growth in VHL disease because of its antiangiogenic effects demonstrated in IH and the hypothetical impact on HIF levels., Methods: HeLa 9X (HRE) hypoxia responsive element cell line and primary hemangioblastoma-derived cells were subjected to propranolol treatment and cell viability and apoptosis were evaluated. HIF1-α and Hif-2α expression after propranolol treatment was analyzed by western blotting. Quantitative PCR was performed to study the mRNA expression of HIF target genes. Vascular endothelial growth factor (VEGF) was measured in culture supernatants by immunoassay., Results: Propranolol downregulated HIF-dependent transcription in HeLa 9XHRE cells. Under hypoxic conditions, propranolol decreased the expression of HIF target genes in hemangioblastoma cells, which stopped proliferating and died following long-term treatment. These results suggests that propranolol treatment promoted reduced HIF protein expression and corresponding downregulation of HIF target genes, and inhibited cell proliferation in parallel with induction of cell death by apoptosis., Conclusions: Our results suggest that propranolol could reduce the growth of HIF-dependent tumors and may thus be a promising treatment to delay surgery in VHL patients.
- Published
- 2015
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26. Research on potential biomarkers in hereditary hemorrhagic telangiectasia.
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Botella LM, Albiñana V, Ojeda-Fernandez L, Recio-Poveda L, and Bernabéu C
- Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous disorder, involving mutations in two predominant genes known as Endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2), as well as in some less frequent genes, such as MADH4/SMAD4 (JP-HHT) or BMP9/GDF2 (HHT5). The diagnosis of HHT patients currently remains at the clinical level, according to the "Curaçao criteria," whereas the molecular diagnosis is used to confirm or rule out suspected HHT cases, especially when a well characterized index case is present in the family or in an isolated population. Unfortunately, many suspected patients do not present a clear HHT diagnosis or do not show pathogenic mutations in HHT genes, prompting the need to investigate additional biomarkers of the disease. Here, several HHT biomarkers and novel methodological approaches developed during the last years will be reviewed. On one hand, products detected in plasma or serum samples: soluble proteins (vascular endothelial growth factor, transforming growth factor β1, soluble endoglin, angiopoietin-2) and microRNA variants (miR-27a, miR-205, miR-210). On the other hand, differential HHT gene expression fingerprinting, next generation sequencing of a panel of genes involved in HHT, and infrared spectroscopy combined with artificial neural network patterns will also be reviewed. All these biomarkers might help to improve and refine HHT diagnosis by distinguishing from the non-HHT population.
- Published
- 2015
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27. Copy number variations in endoglin locus: mapping of large deletions in Spanish families with hereditary hemorrhagic telangiectasia type 1.
- Author
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Fontalba A, Fernández-Luna JL, Zarrabeitia R, Recio-Poveda L, Albiñana V, Ojeda-Fernández ML, Bernabéu C, Alcaraz LA, and Botella LM
- Subjects
- Chromosome Mapping, Cyclin-Dependent Kinase 9 genetics, DNA Copy Number Variations, Endoglin, Exons, Gene Deletion, Genetic Association Studies, Genetic Loci, Genotype, Humans, Multiplex Polymerase Chain Reaction, Phenotype, Promoter Regions, Genetic, Spain, Telangiectasia, Hereditary Hemorrhagic pathology, Antigens, CD genetics, Receptors, Cell Surface genetics, Telangiectasia, Hereditary Hemorrhagic genetics, White People genetics
- Abstract
Background: The hereditary hemorrhagic telangiectasia syndrome (HHT), also known as the Rendu-Osler-Weber syndrome is a multiorganic vascular disorder inherited as an autosomal dominant trait. Diagnostic clinical criteria include: epistaxis, telangiectases in mucocutaneous and gastrointestinal sites, arteriovenous malformations (AVMs) most commonly found in pulmonary, hepatic and cerebral circulations, and familial inheritance. HHT is transmitted in 90% of the cases as an autosomal dominant condition due to mutations in either endoglin (ENG), or activin receptor-like kinase 1 (ACVRL1/ALK1) genes (HHT type 1 and 2, respectively)., Methods: We have carried out a genetic analysis of four independent Spanish families with HHT clinical criteria, which has permitted the identification of new large deletions in ENG. These mutations were first detected using the MLPA technique and subsequently, the deletion breakpoints were mapped using a customized copy number variation (CNV) microarray. The array was designed to cover the ENG gene and surrounding areas., Results: All tested families carried large deletions ranging from 3-kb to 100-kb, involving the ENG gene promoter, several ENG exons, and the two downstream genes FGSH and CDK9. Interestingly, common breakpoints coincident with Alu repetitive sequences were found among these families., Conclusions: The systematic hybridization of DNA from HHT families, with deletions or duplications, to custom designed microarrays, could allow the mapping of breakpoints, coincident with repetitive Alu sequences that might act as "hot spots" in the development of chromosomal anomalies.
- Published
- 2013
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28. Propranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia.
- Author
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Albiñana V, Recio-Poveda L, Zarrabeitia R, Bernabéu C, and Botella LM
- Subjects
- Activin Receptors, Type II genetics, Activin Receptors, Type II metabolism, Animals, Antigens, CD genetics, Antigens, CD metabolism, Apoptosis drug effects, Cell Line, Disease Models, Animal, Endoglin, Endothelium, Vascular metabolism, Humans, Mice, Mice, Knockout, Mutation genetics, Neovascularization, Pathologic genetics, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Signal Transduction drug effects, Telangiectasia, Hereditary Hemorrhagic genetics, Adrenergic beta-Antagonists therapeutic use, Angiogenesis Inhibitors therapeutic use, Endothelium, Vascular drug effects, Neovascularization, Pathologic drug therapy, Propranolol therapeutic use, Telangiectasia, Hereditary Hemorrhagic drug therapy
- Abstract
The β-blocker propranolol, originally designed for cardiological indications (angina, cardiac arrhythmias and high blood pressure), is nowadays, considered the most efficient drug for the treatment in infantile haemangiomas (IH), a vascular tumour that affects 5-10% of all infants. However, its potential therapeutic benefits in other vascular anomalies remain to be explored. In the present work we have assessed the impact of propranolol in endothelial cell cultures to test if this drug could be used in the vascular disease hereditary haemorrhagic telangiectasia (HHT). This rare disease is the result of abnormal angiogenesis with epistaxis, mucocutaneous and gastrointestinal telangiectases, as well as arteriovenous malformations in several organs, as clinical manifestations. Mutations in Endoglin (ENG) and ACVLR1 (ALK1) genes, lead to HHT1 and HHT2, respectively. Endoglin and ALK1 are involved in the TGF-β1 signalling pathway and play a critical role for the proper development of the blood vessels. As HHT is due to a deregulation of key angiogenic factors, inhibitors of angiogenesis have been used to normalise the nasal vasculature eliminating epistaxis derived from telangiectases. Thus, the antiangiogenic properties of propranolol were tested in endothelial cells. The drug was able to decrease cellular migration and tube formation, concomitantly with reduced RNA and protein levels of ENG and ALK1. Moreover, the drug showed apoptotic effects which could explain cell death in IH. Interestingly, propranolol showed some profibrinolytic activity, decreasing PAI-1 levels. These results suggest that local administration of propranolol in the nose mucosa to control epistaxis might be a potential therapeutic approach in HHT.
- Published
- 2012
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29. Immunosuppressor FK506 increases endoglin and activin receptor-like kinase 1 expression and modulates transforming growth factor-β1 signaling in endothelial cells.
- Author
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Albiñana V, Sanz-Rodríguez F, Recio-Poveda L, Bernabéu C, and Botella LM
- Subjects
- Base Sequence, Blotting, Western, Cell Line, DNA Primers, Endoglin, Endothelium, Vascular enzymology, Endothelium, Vascular metabolism, Humans, Reverse Transcriptase Polymerase Chain Reaction, Activin Receptors, Type I genetics, Antigens, CD genetics, Endothelium, Vascular drug effects, Gene Expression Regulation drug effects, Immunosuppressive Agents pharmacology, Receptors, Cell Surface genetics, Signal Transduction drug effects, Tacrolimus pharmacology, Transforming Growth Factor beta1 metabolism
- Abstract
Hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal-dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in internal organs. Patients show severe epistaxis, and/or gastrointestinal bleeding, both of which notably interfere with their quality of life. There are two predominant types of HHT caused by mutations in endoglin (ENG) and ACVRL1/activin receptor-like kinase 1 (ALK1) genes, named HHT1 and HHT2, respectively. ENG and ALK1 code for proteins involved in the transforming growth factor (TGF)-β1 signaling pathway, and it is widely accepted that HHT pathogenicity results from haploinsufficiency. No cure for HHT has been found, so identification of drugs able to increase the expression of these genes is essential when proposing new therapies. We report the efficacy of tacrolimus (FK506) in increasing ENG and ALK1 expression. The rationale comes from a case report of a patient with HHT who received a liver transplantation after hepatic failure due to a liver arteriovenous malformation. The liver was transplanted, and the immunosuppressor FK506 was used to prevent the rejection. After the first month of FK506 treatment, the internal and external telangiectases, epistaxes, and anemia disappeared. Here, we find that the immunosuppressor FK506 increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells and enhances the TGF-β1/ALK1 signaling pathway and endothelial cell functions like tubulogenesis and migration. These results suggest that the mechanism of action of FK506 involves a partial correction of endoglin and ALK1 haploinsufficiency and may therefore be an interesting drug for use in patients with HHT who undergo transplantation.
- Published
- 2011
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30. A review on clinical management and pharmacological therapy on hereditary haemorrhagic telangiectasia (HHT).
- Author
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Zarrabeitia R, Albiñana V, Salcedo M, Señaris-Gonzalez B, Fernandez-Forcelledo JL, and Botella LM
- Subjects
- Epistaxis drug therapy, Epistaxis etiology, Epistaxis therapy, Gastrointestinal Hemorrhage etiology, Gastrointestinal Hemorrhage therapy, Humans, Hypertension, Pulmonary etiology, Hypertension, Pulmonary therapy, Telangiectasia, Hereditary Hemorrhagic complications, Telangiectasia, Hereditary Hemorrhagic genetics, Telangiectasia, Hereditary Hemorrhagic drug therapy, Telangiectasia, Hereditary Hemorrhagic therapy
- Abstract
Hereditary Haemorrhagic Telangiectasia (HHT) or Rendu-Osler-Weber syndrome, is an autosomal dominant rare disease characterized by localized angiodysplasia. This is manifested as epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in the pulmonary, cerebral or hepatic circulation. The prevalence is between 1 in 5,000 to 8,000, although it is higher in some regions. The most frequent clinical manifestation of HHT is epistaxis, normally from light to moderate from the 4(th) decade of life. However, many patients show severe epistaxis which may interfere with their quality of life. The epistaxis is due to telangiectasia on the nasal mucosa. These are focally dilated postcapilar venules, which in advanced phases show many layers of smooth muscle cells without elastic fibers, and very frequently directly connect with dilated arterioles. As a consequence of these vascular alterations, telangiectases are very sensitive to slight trauma and even to the friction with the air when breathing, which gives rise to nose bleeds. Unfortunately, there is no optimal pharmacological treatment for the epistaxis in HHT. The use of antifibrinolytic agents for the treatment of HHT has been studied recently by our group as an effective relief for nasal and gastric haemorrhages. This work represents a systematic review and the beginning of a systematic laboratory work we are now conducting in our lab to screen for "orphan drugs" as therapeutic agents in HHT. In this context, the use of hormones, immunosuppresants and anti-angiogenic agents are under preclinical study in our laboratory.
- Published
- 2010
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31. Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells.
- Author
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Albiñana V, Bernabeu-Herrero ME, Zarrabeitia R, Bernabéu C, and Botella LM
- Subjects
- Activin Receptors, Type II genetics, Aged, Antigens, CD genetics, Cell Line, Endoglin, Endothelial Cells drug effects, Endothelium, Vascular cytology, Epistaxis drug therapy, Estrogens pharmacology, Estrogens therapeutic use, Female, Humans, Menopause, Middle Aged, Prospective Studies, Raloxifene Hydrochloride therapeutic use, Receptors, Cell Surface genetics, Selective Estrogen Receptor Modulators, Transcription, Genetic drug effects, Activin Receptors, Type II drug effects, Antigens, CD drug effects, Raloxifene Hydrochloride pharmacology, Receptors, Cell Surface drug effects, Telangiectasia, Hereditary Hemorrhagic drug therapy
- Abstract
Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor beta pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploinsufficiency of ENG and ALK1.
- Published
- 2010
- Full Text
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32. Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia.
- Author
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Fontalba A, Fernandez-L A, García-Alegria E, Albiñana V, Garrido-Martin EM, Blanco FJ, Zarrabeitia R, Perez-Molino A, Bernabeu-Herrero ME, Ojeda ML, Fernandez-Luna JL, Bernabeu C, and Botella LM
- Subjects
- Endoglin, Exons, Humans, Mutation, Missense, Pedigree, Spain, Activin Receptors, Type II genetics, Antigens, CD genetics, Mutation, Receptors, Cell Surface genetics, Telangiectasia, Hereditary Hemorrhagic genetics
- Abstract
Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder characterised mainly by mutations in the Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes., Methods: Here, we have identified 22 ALK1 mutations and 15 ENG mutations, many of which had not previously been reported, in independent Spanish families afflicted with HHT., Results: We identified mutations in thirty-seven unrelated families. A detailed analysis of clinical symptoms was recorded for each patient analyzed, with a higher significant presence of pulmonary arteriovenous malformations (PAVM) in HHT1 patients over HHT2. Twenty-two mutations in ALK1 and fifteen in ENG genes were identified. Many of them, almost half, represented new mutations in ALK1 and in ENG. Missense mutations in ENG and ALK1 were localized in a tridimensional protein structure model., Conclusion: Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1) in our Spanish population, in agreement with previous data from our country and other Mediterranean countries (France, Italy), but different to Northern Europe or North America. There was a significant increase of PAVM associated with HHT1 over HHT2 in these families.
- Published
- 2008
- Full Text
- View/download PDF
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