671 results on '"Santiago Ramón y Cajal"'
Search Results
2. Clearance of ctDNA in triple-negative and HER2-positive breast cancer patients during neoadjuvant treatment is correlated with pathologic complete response
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Nikaoly Ciriaco, Esther Zamora, Santiago Escrivá-de-Romaní, Ignacio Miranda Gómez, José Jiménez Flores, Cristina Saura, Hillary Sloane, Anna Starus, Johannes Fredebohm, Lucy Georgieva, Graham Speight, Frederick Jones, Santiago Ramón y Cajal, Martín Espinosa-Bravo, and Vicente Peg
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Although the standard of care is to perform surgery of primary breast cancer (BC) after neoadjuvant chemotherapy (NAC), for certain patients achieving clinical complete response (cCR) and pathologic complete response (pCR), omission of surgical treatment may be an option. Levels of circulating tumor DNA (ctDNA) during and after therapy could identify patients achieving minimal residual disease. In this study, we evaluated whether ctDNA clearance during NAC could be a correlate to effective response in human epidermal growth factor receptor 2 positive (HER2+) and triple-negative (TN) BC patients. Methods: A prospective study was conducted to identify patient-specific PIK3CA and TP53 mutations in tissue using next-generation sequencing, which could then be used to track the presence/absence of mutations prior to, during, and following NAC using Sysmex SafeSEQ technology. All patients underwent a surgical excision after NAC, and pCR was assessed. Results: A total of 29 TN and HER2+ BC patients were examined and 20 that carried mutations in the PIK3CA and/or TP53 genes were recruited. Overall, 19 of these 20 patients harbored at least one tumor-specific mutation in their plasma at baseline. After NAC, 15 patients (75.0%) achieved pCR according to the histopathologic evaluation of the surgical specimen, and 15 patients (75.0%) had a cCR; 18 of 20 patients (90.0%) had concordant pCR and cCR. The status of ‘no mutation detected’ (NMD) following NAC in cCR patients correctly identified the pCR in 14 of 15 patients (93.33%), as well as correctly ruled out pCR in three patients, with an accuracy of 89.47%. During the 12-month follow-up after surgery, 40 plasma samples collected from 15 patients all showed no detectable ctDNA (NMD), and no patient recurred. Conclusion: These findings prompt further research of the value of ctDNA for non-invasive prediction of clinical/pathological response, raising the possibility of sparing surgery following NAC in selected BC patients.
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- 2022
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3. Peripheral and lung resident memory T cell responses against SARS-CoV-2
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Judith Grau-Expósito, Nerea Sánchez-Gaona, Núria Massana, Marina Suppi, Antonio Astorga-Gamaza, David Perea, Joel Rosado, Anna Falcó, Cristina Kirkegaard, Ariadna Torrella, Bibiana Planas, Jordi Navarro, Paula Suanzes, Daniel Álvarez-Sierra, Alfonso Ayora, Irene Sansano, Juliana Esperalba, Cristina Andrés, Andrés Antón, Santiago Ramón y Cajal, Benito Almirante, Ricardo Pujol-Borrell, Vicenç Falcó, Joaquín Burgos, María J. Buzón, and Meritxell Genescà
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Science - Abstract
Lung resident memory T (TRM) cells are important for protection from viral infection in the lungs. Here the authors use paired lung biopsy material and blood to characterize T cell responses in patients with COVID-19 over time and find persistence of antiviral lung TRM cells that might be important to limit reinfection.
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- 2021
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4. Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma
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Laura Escudero, Anna Llort, Alexandra Arias, Ander Diaz-Navarro, Francisco Martínez-Ricarte, Carlota Rubio-Perez, Regina Mayor, Ginevra Caratù, Elena Martínez-Sáez, Élida Vázquez-Méndez, Iván Lesende-Rodríguez, Raquel Hladun, Luis Gros, Santiago Ramón y Cajal, Maria A. Poca, Xose S. Puente, Juan Sahuquillo, Soledad Gallego, and Joan Seoane
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Science - Abstract
Non-invasive and precise methods are critical for monitoring paediatric brain cancers. Here the authors show that the molecular alterations and heterogeneity of paediatric medulloblastomas can be reliably detected in circulating tumour DNA from the cerebrospinal fluid – a routinely collected sample.
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- 2020
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5. ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells
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Pedro Fuentes, Marta Sesé, Pedro J. Guijarro, Marta Emperador, Sara Sánchez-Redondo, Héctor Peinado, Stefan Hümmer, and Santiago Ramón y Cajal
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Science - Abstract
The integrin ITGB3 has been described to play an essential role in breast cancer metastasis, but the precise mechanisms remain undefined. Here the authors describe thus far unknown roles of ITGB3 in the uptake of extracellular vesicles, required for colony growth of breast cancer cells.
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- 2020
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6. Mujer de 58 años con deterioro clínico, anemia grave, y masa tumoral periprotésica 14 años después de una artroplastia de cadera
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Ernesto Guerra-Farfan, Lourdes Salazar-Huayna, Yaiza Garcia-Sanchez, María Villar-Casares, and Santiago Ramón y Cajal
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Medicine (General) ,R5-920 - Published
- 2021
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7. Validation of Cell-Free DNA Collection Tubes for Determination of EGFR Mutation Status in Liquid Biopsy from NSCLC Patients
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Marta Sesé, Rosa Somoza, Inmaculada Maestu, Maria Martín Ureste, Alfredo Sanchez, Juan Felipe Cordoba, Irene Sansano, Griselda Venturas, Santiago Ramón y Cajal, and Javier Hernández-Losa
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Blood collection tubes ,cfDNA ,EGFR mutation analysis ,NSCLC ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Introduction Precision medicine has revolutionized the understanding and treatment of cancer by identifying subsets of patients who are amenable to specific treatments according to their molecular characteristics, as exemplified by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Although tissue biopsy is the gold standard for determining molecular alterations in tumors, its limitations have prompted the development of new techniques for studying tumor biomarkers in liquid biopsies, such as mutation analysis in cell-free DNA (cfDNA). cfDNA analysis can accurately determine tumor progression and prognosis and more effectively identify appropriate targeted therapies. However, cfDNA is vulnerable, particularly during plasma sample shipping. Objective We compared the cell- and DNA-stabilizing properties of cell-free DNA blood collection tubes (BCTs) with those of the traditional shipping method (frozen plasma) for EGFR mutation testing using the cobas® EGFR Mutation Test v2 in a prospective cohort of 49 patients from three different Spanish hospitals. Methods In total, 98 NSCLC samples, two from each patient, were studied; five of the 49 cases were considered invalid by cobas® with one of the two shipping methods analyzed. After excluding these samples, we analyzed 88 samples from 44 patients. Considering the current methodology (frozen plasma) for sending samples as the gold standard, we evaluated the sensitivity and specificity of cfDNA BCT shipment. Results The global agreement between the two methods was 95.4%, with 100% sensitivity and 94.6% specificity for the cfDNA BCTs. cfDNA BCTs had a positive predictive value of 81.8% and negative predictive value of 100%. Conclusion cfDNA BCTs have the same sensitivity for EGFR mutation analysis in liquid biopsy as the current methodology and very high specificity. They also have some additional advantages in terms of collection and further shipment. Therefore, cfDNA BCTs can be perfectly incorporated into the routine practice for EGFR mutation determination. Funding Roche Farma S.A., Spain.
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- 2019
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8. The role of clonal communication and heterogeneity in breast cancer
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Ana Martín-Pardillos, Ángeles Valls Chiva, Gemma Bande Vargas, Pablo Hurtado Blanco, Roberto Piñeiro Cid, Pedro J. Guijarro, Stefan Hümmer, Eva Bejar Serrano, Aitor Rodriguez-Casanova, Ángel Diaz-Lagares, Josep Castellvi, Samuel Miravet-Verde, Luis Serrano, María Lluch-Senar, Víctor Sebastian, Ana Bribian, Laura López-Mascaraque, Rafael López-López, and Santiago Ramón y Cajal
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Tumor ,Breast ,Cancer ,Metastasis ,Heterogeneity ,Clone ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Cancer is a rapidly evolving, multifactorial disease that accumulates numerous genetic and epigenetic alterations. This results in molecular and phenotypic heterogeneity within the tumor, the complexity of which is further amplified through specific interactions between cancer cells. We aimed to dissect the molecular mechanisms underlying the cooperation between different clones. Methods We produced clonal cell lines derived from the MDA-MB-231 breast cancer cell line, using the UbC-StarTrack system, which allowed tracking of multiple clones by color: GFP C3, mKO E10 and Sapphire D7. Characterization of these clones was performed by growth rate, cell metabolic activity, wound healing, invasion assays and genetic and epigenetic arrays. Tumorigenicity was tested by orthotopic and intravenous injections. Clonal cooperation was evaluated by medium complementation, co-culture and co-injection assays. Results Characterization of these clones in vitro revealed clear genetic and epigenetic differences that affected growth rate, cell metabolic activity, morphology and cytokine expression among cell lines. In vivo, all clonal cell lines were able to form tumors; however, injection of an equal mix of the different clones led to tumors with very few mKO E10 cells. Additionally, the mKO E10 clonal cell line showed a significant inability to form lung metastases. These results confirm that even in stable cell lines heterogeneity is present. In vitro, the complementation of growth medium with medium or exosomes from parental or clonal cell lines increased the growth rate of the other clones. Complementation assays, co-growth and co-injection of mKO E10 and GFP C3 clonal cell lines increased the efficiency of invasion and migration. Conclusions These findings support a model where interplay between clones confers aggressiveness, and which may allow identification of the factors involved in cellular communication that could play a role in clonal cooperation and thus represent new targets for preventing tumor progression.
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- 2019
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9. ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology
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Elena Arconada-Luque, Jaime Jiménez-Suarez, Raquel Pascual-Serra, Syong Hyun Nam-Cha, Teresa Moline, Francisco J. Cimas, Germán Fliquete, Marta Ortega-Muelas, Olga Roche, Diego M. Fernández-Aroca, Raúl Muñoz Velasco, Natalia García-Flores, Cristina Garnés-García, Adrián Sánchez-Fdez, Sofía Matilla-Almazán, Víctor J. Sánchez-Arévalo Lobo, Javier Hernández-Losa, Borja Belandia, Atanasio Pandiella, Azucena Esparís-Ogando, Santiago Ramón y Cajal, Luis del Peso, Ricardo Sánchez-Prieto, and María José Ruiz-Hidalgo
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ERK5 ,MAPK7 ,soft tissue sarcoma ,leiomyosarcoma ,rhabdomyosarcoma ,KLF2 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5–KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology.
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- 2022
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10. Five microRNAs in Serum Are Able to Differentiate Breast Cancer Patients From Healthy Individuals
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Andrea Feliciano, Lucila González, Yoelsis Garcia-Mayea, Cristina Mir, Mireia Artola, Nieves Barragán, Remedios Martín, Anna Altés, Josep Castellvi, Sergi Benavente, Santiago Ramón y Cajal, Martín Espinosa-Bravo, Javier Cortés, Isabel T. Rubio, and Matilde E. LLeonart
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breast cancer ,serum ,microRNAs ,prognosis ,diagnosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Breast cancer is the cancer with the most incidence and mortality in women. microRNAs are emerging as novel prognosis/diagnostic tools. Our aim was to identify a serum microRNA signature useful to predict cancer development. We focused on studying the expression levels of 30 microRNAs in the serum of 96 breast cancer patients vs. 92 control individuals. Bioinformatic studies provide a microRNA signature, designated as a predictor, based on the expression levels of five microRNAs. Then, we tested the predictor in a group of 60 randomly chosen women. Lastly, a proteomic study unveiled the overexpression and downregulation of proteins differently expressed in the serum of breast cancer patients vs. that of control individuals. Twenty-six microRNAs differentiate cancer tissue from healthy tissue, and 16 microRNAs differentiate the serum of cancer patients from that of the control group. The tissue expression of miR-99a, miR-497, miR-362, and miR-1274, and the serum levels of miR-141 correlated with patient survival. Moreover, the predictor consisting of miR-125b, miR-29c, miR-16, miR-1260, and miR-451 was able to differentiate breast cancer patients from controls. The predictor was validated in 20 new cases of breast cancer patients and tested in 60 volunteer women, assigning 11 out of 60 women to the cancer group. An association of low levels of miR-16 with a high content of CD44 protein in serum was found. Circulating microRNAs in serum can represent biomarkers for cancer prediction. Their clinical relevance and the potential use of the predictor here described are discussed.
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- 2020
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11. DigiPatICS: Digital Pathology Transformation of the Catalan Health Institute Network of 8 Hospitals—Planification, Implementation, and Preliminary Results
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Jordi Temprana-Salvador, Pablo López-García, Josep Castellví Vives, Lluís de Haro, Eudald Ballesta, Matias Rojas Abusleme, Miquel Arrufat, Ferran Marques, Josep R. Casas, Carlos Gallego, Laura Pons, José Luis Mate, Pedro Luis Fernández, Eugeni López-Bonet, Ramon Bosch, Salomé Martínez, Santiago Ramón y Cajal, and Xavier Matias-Guiu
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digital pathology ,computational pathology ,artificial intelligence ,deep learning ,implementation ,workflow ,Medicine (General) ,R5-920 - Abstract
Complete digital pathology transformation for primary histopathological diagnosis is a challenging yet rewarding endeavor. Its advantages are clear with more efficient workflows, but there are many technical and functional difficulties to be faced. The Catalan Health Institute (ICS) has started its DigiPatICS project, aiming to deploy digital pathology in an integrative, holistic, and comprehensive way within a network of 8 hospitals, over 168 pathologists, and over 1 million slides each year. We describe the bidding process and the careful planning that was required, followed by swift implementation in stages. The purpose of the DigiPatICS project is to increase patient safety and quality of care, improving diagnosis and the efficiency of processes in the pathological anatomy departments of the ICS through process improvement, digital pathology, and artificial intelligence tools.
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- 2022
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12. Mesenchymal Stem Cells Delivery in Individuals with Different Pathologies: Multimodal Tracking, Safety and Future Applications
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Carolina Belmar-López, Georges Vassaux, Ana Medel-Martinez, Jerome Burnet, Miguel Quintanilla, Santiago Ramón y Cajal, Javier Hernandez-Losa, Antonio De la Vieja, and Pilar Martin-Duque
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mesenchymal stem cells ,sodium/iodide symporter (NIS) ,transdifferentiation ,therapy ,Imaging PET ,SPECT ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. As most of the individuals joining clinical trials that use MSCs for cancer and other pathologies are carefully recruited and do not suffer from other diseases, here we decided to study the safety and application of iv-injected MSCs in animals simultaneously induced with different inflammatory pathologies (diabetes, wound healing and tumors). We studied this by in vitro and in vivo approaches using different gene reporters (GFP, hNIS, and f-Luc) and non-invasive techniques (PET, BLI, or fluorescence). Our results found that MSCs reached different organs depending on the previously induced pathology. Moreover, we evaluated the property of MSCs to target tumors as vectors to deliver adenoviruses, including the interaction between tumor microenvironment and MSCs on their arrival. Mechanisms such as transdifferentiation, MSC fusion with cells, or paracrine processes after MSCs homing were studied, increasing the knowledge and safety of this new therapy for cancer.
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- 2022
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13. Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis
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Niki Karachaliou, Imane Chaib, Andres Felipe Cardona, Jordi Berenguer, Jillian Wilhelmina Paulina Bracht, Jie Yang, Xueting Cai, Zhigang Wang, Chunping Hu, Ana Drozdowskyj, Carles Codony Servat, Jordi Codony Servat, Masaoki Ito, Ilaria Attili, Erika Aldeguer, Ana Gimenez Capitan, July Rodriguez, Leonardo Rojas, Santiago Viteri, Miguel Angel Molina-Vila, Sai-Hong Ignatius Ou, Morihito Okada, Tony S. Mok, Trever G. Bivona, Mayumi Ono, Jean Cui, Santiago Ramón y Cajal, Peng Cao, and Rafael Rosell
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Medicine ,Medicine (General) ,R5-920 - Abstract
Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p = 0.0407) and overall survival (hazard ratio of 2.23, p = 0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing. Keywords: Lung cancer, EGFR, Resistance, AXL, CDCP1, Combination therapies
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- 2018
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14. Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish
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Inés Martínez-Pena, Pablo Hurtado, Nuria Carmona-Ule, Carmen Abuín, Ana Belén Dávila-Ibáñez, Laura Sánchez, Miguel Abal, Anas Chaachou, Javier Hernández-Losa, Santiago Ramón y Cajal, Rafael López-López, and Roberto Piñeiro
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breast cancer ,metastasis ,circulating tumor cells (CTCs) ,CTC-clusters ,zebrafish ,in vitro models ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.
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- 2021
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15. Spontaneous Cell Detachment and Reattachment in Cancer Cell Lines: An In Vitro Model of Metastasis and Malignancy
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Elena Vargas-Accarino, Carlos Herrera-Montávez, Santiago Ramón y Cajal, and Trond Aasen
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metastasis models ,floating cells ,suspension cells ,anoikis ,NM23 ,mTOR ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
There is an unmet need for simplified in vitro models of malignancy and metastasis that facilitate fast, affordable and scalable gene and compound analysis. “Adherent” cancer cell lines frequently release “free-floating” cells into suspension that are viable and can reattach. This, in a simplistic way, mimics the metastatic process. We compared the gene expression profiles of naturally co-existing populations of floating and adherent cells in SW620 (colon), C33a (cervix) and HeLa (cervix) cancer cells. We found that 1227, 1367 and 1333 genes were at least 2-fold differentially expressed in the respective cell lines, of which 122 were shared among the three cell lines. As proof of principle, we focused on the anti-metastatic gene NM23-H1, which was downregulated both at the RNA and protein level in the floating cell populations of all three cell lines. Knockdown of NM23-H1 significantly increased the number of floating (and viable) cells, whereas overexpression of NM23-H1 significantly reduced the proportion of floating cells. Other potential regulators of these cellular states were identified through pathway analysis, including hypoxia, mTOR (mechanistic target of rapamycin), cell adhesion and cell polarity signal transduction pathways. Hypoxia, a condition linked to malignancy and metastasis, reduced NM23-H1 expression and significantly increased the number of free-floating cells. Inhibition of mTOR or Rho-associated protein kinase (ROCK) significantly increased cell death specifically in the floating and not the adherent cell population. In conclusion, our study suggests that dynamic subpopulations of free-floating and adherent cells is a useful model to screen and identify genes, drugs and pathways that regulate the process of cancer metastasis, such as cell detachment and anoikis.
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- 2021
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16. Interplay Between ncRNAs and Cellular Communication: A Proposal for Understanding Cell-Specific Signaling Pathways
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Santiago Ramón y Cajal, Miguel F. Segura, and Stefan Hümmer
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cancer ,cellular communication ,cell signaling ,long non-coding RNA ,microRNA ,epigenetics ,Genetics ,QH426-470 - Abstract
Intercellular communication is essential for the development of specialized cells, tissues, and organs and is critical in a variety of diseases including cancer. Current knowledge states that different cell types communicate by ligand–receptor interactions: hormones, growth factors, and cytokines are released into the extracellular space and act on receptors, which are often expressed in a cell-type-specific manner. Non-coding RNAs (ncRNAs) are emerging as newly identified communicating factors in both physiological and pathological states. This class of RNA encompasses microRNAs (miRNAs, well-studied post-transcriptional regulators of gene expression), long non-coding RNAs (lncRNAs) and other ncRNAs. lncRNAs are diverse in length, sequence, and structure (linear or circular), and their functions are described as transcriptional regulation, induction of epigenetic changes and even direct regulation of protein activity. They have also been reported to act as miRNA sponges, interacting with miRNA and modulating its availability to endogenous mRNA targets. Importantly, lncRNAs may have a cell-type-specific expression pattern. In this paper, we propose that lncRNA–miRNA interactions, analogous to receptor–ligand interactions, are responsible for cell-type-specific outcomes. Specific binding of miRNAs to lncRNAs may drive cell-type-specific signaling cascades and modulate biochemical feedback loops that ultimately determine cell identity and response to stress factors.
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- 2019
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17. Brain ApoA-I, ApoJ and ApoE Immunodetection in Cerebral Amyloid Angiopathy
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Jessica Camacho, Teresa Moliné, Anna Bonaterra-Pastra, Santiago Ramón y Cajal, Elena Martínez-Sáez, and Mar Hernández-Guillamon
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ApoE ,ApoA-I ,ApoJ ,clusterin ,β-amyloid ,cerebral amyloid angiopathy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Cerebral amyloid angiopathy (CAA) is a common cause of lobar intracerebral hemorrhage (ICH) in elderly individuals and it is the result of the cerebrovascular deposition of beta-amyloid (Aβ) protein. CAA is frequently found in patients with Alzheimer's disease (AD), although it has an independent contribution to the cognitive deterioration associated with age. Specific apolipoproteins (Apo) have been associated with Aβ fibrillization and clearance from the brain. In this regard, in the present study, we analyzed the brain levels of ApoE, ApoA-I, and ApoJ/clusterin in autopsy brains from 20 post-mortem cases with CAA type I, CAA type II, with parenchymal Aβ deposits or without Aβ deposits. Our objective was to find a possible differential pattern of apolipoproteins distribution in the brain depending on the CAA pathological presentation. The protein expression levels were adjusted by the APOE genotype of the patients included in the study. We found that ApoE and ApoJ were abundantly present in meningeal, cortical, and capillary vessels of the brains with vascular Aβ accumulation. ApoE and ApoJ also deposited extracellularly in the parenchyma, especially in cases presenting Aβ diffuse and neuritic parenchymal deposits. In contrast, ApoA-I staining was only relevant in capillary walls in CAA type I cases. On the other hand, ICH was the principal cause of death among CAA patients in our cohort. We found that CAA patients with ICH more commonly had APOEε2 compared with CAA patients without ICH. In addition, patients who suffered an ICH presented higher vascular ApoE levels in brain. However, higher ApoE presence in cortical arteries was the only independent predictor of suffering an ICH in our cohort after adjusting by age and APOE genotype. In conclusion, while ApoE and ApoJ appear to be involved in both vascular and parenchymal Aβ pathology, ApoA-I seems to be mainly associated with CAA, especially in CAA type I pathology. We consider that our study helps to molecularly characterize the distribution subtypes of Aβ deposition within the brain.
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- 2019
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18. Publisher Correction: ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells
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Pedro Fuentes, Marta Sesé, Pedro J. Guijarro, Marta Emperador, Sara Sánchez-Redondo, Héctor Peinado, Stefan Hümmer, and Santiago Ramón y Cajal
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Science - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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- 2020
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19. Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells
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Alexander Tishchenko, Daniel D. Azorín, Laia Vidal-Brime, María José Muñoz, Pol Jiménez Arenas, Christopher Pearce, Henrique Girao, Santiago Ramón y Cajal, and Trond Aasen
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connexin 43 ,gap junctions ,cancer ,intercellular communication ,breast cancer ,cell signaling ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.
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- 2020
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20. Insight into the Role and Regulation of Gap Junction Genes in Lung Cancer and Identification of Nuclear Cx43 as a Putative Biomarker of Poor Prognosis
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Trond Aasen, Irene Sansano, Maria Ángeles Montero, Cleofé Romagosa, Jordi Temprana-Salvador, Alexandre Martínez-Marti, Teresa Moliné, Javier Hernández-Losa, and Santiago Ramón y Cajal
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connexins ,Cx43 ,gap junctions ,lung cancer ,immunohistochemistry ,prognosis ,nuclear ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 73 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival (p = 0.014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p = 0.002) but not in the squamous carcinoma subtype (p = 0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.
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- 2019
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21. Phosphorylation of eIF4E Confers Resistance to Cellular Stress and DNA-Damaging Agents through an Interaction with 4E-T: A Rationale for Novel Therapeutic Approaches.
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Alba Martínez, Marta Sesé, Javier Hernandez Losa, Nathaniel Robichaud, Nahum Sonenberg, Trond Aasen, and Santiago Ramón Y Cajal
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Medicine ,Science - Abstract
Phosphorylation of the eukaryotic translation initiation factor eIF4E is associated with malignant progression and poor cancer prognosis. Accordingly, here we have analyzed the association between eIF4E phosphorylation and cellular resistance to oxidative stress, starvation, and DNA-damaging agents in vitro. Using immortalized and cancer cell lines, retroviral expression of a phosphomimetic (S209D) form of eIF4E, but not phospho-dead (S209A) eIF4E or GFP control, significantly increased cellular resistance to stress induced by DNA-damaging agents (cisplatin), starvation (glucose+glutamine withdrawal), and oxidative stress (arsenite). De novo accumulation of eIF4E-containing cytoplasmic bodies colocalizing with the eIF4E-binding protein 4E-T was observed after expression of phosphomimetic S209D, but not S209A or wild-type eIF4E. Increased resistance to cellular stress induced by eIF4E-S209D was lost upon knockdown of endogenous 4E-T or use of an eIF4E-W73A-S209D mutant unable to bind 4E-T. Cancer cells treated with the Mnk1/2 inhibitor CGP57380 to prevent eIF4E phosphorylation and mouse embryonic fibroblasts derived from Mnk1/2 knockout mice were also more sensitive to arsenite and cisplatin treatment. Polysome analysis revealed an 80S peak 2 hours after arsenite treatment in cells overexpressing phosphomimetic eIF4E, indicating translational stalling. Nonetheless, a selective increase was observed in the synthesis of some proteins (cyclin D1, HuR, and Mcl-1). We conclude that phosphorylation of eIF4E confers resistance to various cell stressors and that a direct interaction or regulation of 4E-T by eIF4E is required. Further delineation of this process may identify novel therapeutic avenues for cancer treatment, and these results support the use of modern Mnk1/2 inhibitors in conjunction with standard therapy.
- Published
- 2015
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22. La Psicología de Don Quijote de la Mancha y el Quijotismo
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Santiago Ramón y Cajal
- Subjects
General Works - Abstract
«Universalmente admirada es la soberbia figura moral del hidalgo manchego. D. Alonso Quijano el bueno, convertido en andante caballero por la sugestión de los disparatados libros de caballería, representa, según se ha dicho mil veces, el más perfecto símbolo del honor y del altruismo. Jamás el genio anglo-sajón, tan dado á imaginar caracteres enérgicos y originales, creó personificación mas exquisita del individualismo indómito y de la abnegación sublime. Pero puntualicemos brevemente los rasgos psicológicos sobresalientes del protagonista de la novela inmortal.…
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- 2004
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23. A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation.
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Rosaura Esteve-Puig, Rosa Gil, Elena González-Sánchez, Joan Josep Bech-Serra, Judit Grueso, Javier Hernández-Losa, Teresa Moliné, Francesc Canals, Berta Ferrer, Javier Cortés, Boris Bastian, Santiago Ramón Y Cajal, Juan Martín-Caballero, Juana Maria Flores, Ana Vivancos, Vicenç García-Patos, and Juan Ángel Recio
- Subjects
Genetics ,QH426-470 - Abstract
Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response.
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- 2014
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24. RPLP1, a crucial ribosomal protein for embryonic development of the nervous system.
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Laura Perucho, Ana Artero-Castro, Sergi Guerrero, Santiago Ramón y Cajal, Matilde E LLeonart, and Zhao-Qi Wang
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Medicine ,Science - Abstract
Ribosomal proteins are pivotal to development and tissue homeostasis. RP Large P1 (Rplp1) overexpression is associated with tumorigenesis. However, the physiological function of Rplp1 in mammalian development remains unknown. In this study, we disrupted Rplp1 in the mouse germline and central nervous system (Rplp1CNSΔ). Rplp1 heterozygosity caused body size reductions, male infertility, systemic abnormalities in various tissues and a high frequency of early postnatal death. Rplp1CNSΔ newborn mice exhibited perinatal lethality and brain atrophy with size reductions of the neocortex, midbrain and ganglionic eminence. The Rplp1 knockout neocortex exhibited progenitor cell proliferation arrest and apoptosis due to the dysregulation of key cell cycle and apoptosis regulators (cyclin A, cyclin E, p21CIP1, p27KIP1, p53). Similarly, Rplp1 deletion in pMEFs led to proliferation arrest and premature senescence. Importantly, Rplp1 deletion in primary mouse embryonic fibroblasts did not alter global protein synthesis, but did change the expression patterns of specific protein subsets involved in protein folding and the unfolded protein response, cell death, protein transport and signal transduction, among others. Altogether, we demonstrated that the translation "fine-tuning" exerted by Rplp1 is essential for embryonic and brain development and for proper cell proliferation.
- Published
- 2014
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25. Clinical validation of a PCR assay for the detection of EGFR mutations in non-small-cell lung cancer: retrospective testing of specimens from the EURTAC trial.
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Susana Benlloch, Maria Luisa Botero, Jordi Beltran-Alamillo, Clara Mayo, Ana Gimenez-Capitán, Itziar de Aguirre, Cristina Queralt, Jose Luis Ramirez, Santiago Ramón y Cajal, Barbara Klughammer, Mariette Schlegel, Walter Bordogna, David Chen, Guili Zhang, Barbara Kovach, Felice Shieh, John F Palma, Lin Wu, H Jeffrey Lawrence, and Miquel Taron
- Subjects
Medicine ,Science - Abstract
The EURTAC trial demonstrated that the tyrosine kinase inhibitor (TKI) erlotinib was superior to chemotherapy as first-line therapy for advanced non-small cell lung cancers (NSCLC) that harbor EGFR activating mutations in a predominantly Caucasian population. Based on EURTAC and several Asian trials, anti-EGFR TKIs are standard of care for EGFR mutation-positive NSCLC. We sought to validate a rapid multiplex EGFR mutation assay as a companion diagnostic assay to select patients for this therapy. Samples from the EURTAC trial were prospectively screened for EGFR mutations using a combination of laboratory-developed tests (LDTs), and tested retrospectively with the cobas EGFR mutation test (EGFR PCR test). The EGFR PCR test results were compared to the original LDT results and to Sanger sequencing, using a subset of specimens from patients screened for the trial. Residual tissue was available from 487 (47%) of the 1044 patients screened for the trial. The EGFR PCR test showed high concordance with LDT results with a 96.3% overall agreement. The clinical outcome of patients who were EGFR-mutation detected by the EGFR PCR test was very similar to the entire EURTAC cohort. The concordance between the EGFR PCR test and Sanger sequencing was 90.6%. In 78.9% of the discordant samples, the EGFR PCR test result was confirmed by a sensitive deep sequencing assay. This retrospective study demonstrates the clinical utility of the EGFR PCR test in the accurate selection of patients for anti-EGFR TKI therapy. The EGFR PCR test demonstrated improved performance relative to Sanger sequencing.
- Published
- 2014
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26. miR-125b acts as a tumor suppressor in breast tumorigenesis via its novel direct targets ENPEP, CK2-α, CCNJ, and MEGF9.
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Andrea Feliciano, Josep Castellvi, Ana Artero-Castro, Jose A Leal, Cleofé Romagosa, Javier Hernández-Losa, Vicente Peg, Angels Fabra, Francisco Vidal, Hiroshi Kondoh, Santiago Ramón Y Cajal, and Matilde E Lleonart
- Subjects
Medicine ,Science - Abstract
MicroRNAs (miRNAs) play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis and tumor progression. To explore the dysregulation of miRNAs in breast cancer, a genome-wide expression profiling of 939 miRNAs was performed in 50 breast cancer patients. A total of 35 miRNAs were aberrantly expressed between breast cancer tissue and adjacent normal breast tissue and several novel miRNAs were identified as potential oncogenes or tumor suppressor miRNAs in breast tumorigenesis. miR-125b exhibited the largest decrease in expression. Enforced miR-125b expression in mammary cells decreased cell proliferation by inducing G2/M cell cycle arrest and reduced anchorage-independent cell growth of cells of mammary origin. miR-125b was found to perform its tumor suppressor function via the direct targeting of the 3'-UTRs of ENPEP, CK2-α, CCNJ, and MEGF9 mRNAs. Silencing these miR-125b targets mimicked the biological effects of miR-125b overexpression, confirming that they are modulated by miR-125b. Analysis of ENPEP, CK2-α, CCNJ, and MEGF9 protein expression in breast cancer patients revealed that they were overexpressed in 56%, 40-56%, 20%, and 32% of the tumors, respectively. The expression of ENPEP and CK2-α was inversely correlated with miR-125b expression in breast tumors, indicating the relevance of these potential oncogenic proteins in breast cancer patients. Our results support a prognostic role for CK2-α, whose expression may help clinicians predict breast tumor aggressiveness. In particular, our results show that restoration of miR-125b expression or knockdown of ENPEP, CK2-α, CCNJ, or MEGF9 may provide novel approaches for the treatment of breast cancer.
- Published
- 2013
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27. Epithelial-mesenchymal transition markers and HER3 expression are predictors of elisidepsin treatment response in breast and pancreatic cancer cell lines.
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Cristina Teixidó, Rosó Marés, Miguel Aracil, Santiago Ramón y Cajal, and Javier Hernández-Losa
- Subjects
Medicine ,Science - Abstract
Elisidepsin (elisidepsin trifluoroacetate, Irvalec®, PM02734) is a new synthetic depsipeptide, a result of the PharmaMar Development Program that seeks synthetic products of marine origin-derived compounds. Elisidepsin is a drug with antiproliferative activity in a wide range of tumors. In the present work we studied and characterized the mechanisms associated with sensitivity and resistance to elisidepsin treatment in a broad panel of tumor cell lines from breast and pancreas carcinomas, focusing on different factors involved in epithelial-mesenchymal transition (EMT) and the use of HER family receptors in predicting the in vitro drug response. Interestingly, we observed that the basal protein expression levels of EMT markers show a significant correlation with cell viability in response to elisidepsin treatment in a panel of 12 different breast and pancreatic cancer cell lines. In addition, we generated three elisidepsin treatment-resistant cell lines (MCF-7, HPAC and AsPC-1) and analyzed the pattern of expression of different EMT markers in these cells, confirming that acquired resistance to elisidepsin is associated with a switch to the EMT state. Furthermore, a direct correlation between basal HER3 expression and sensitivity to elisidepsin was observed; moreover, modulation of HER3 expression levels in different cancer cell lines alter their sensitivities to the drug, making them more resistant when HER3 expression is downregulated by a HER3-specific short hairpin RNA and more sensitive when the receptor is overexpressed. These results show that HER3 expression is an important marker of sensitivity to elisidepsin treatment.
- Published
- 2013
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28. Ovarian Fibrosarcoma: Clinicopathologic Considerations about the Intraoperative and Post-Surgical Procedures
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Angel García Jiménez, Josep Castellví, Assumpció Pérez Benavente, Isabela Díaz de Corcuera Frutos, and Santiago Ramón y Cajal
- Subjects
Medicine - Abstract
Primary ovarian fibrosarcomas are very uncommon neoplasms. Since the diagnostic criteria were established in 1981, less than one hundred cases have been reported. This diagnosis can be difficult to establish and other similar appearing mesenchymal processes must be ruled out. In every case this diagnosis is under consideration. Multiple sections of the specimen and immunohistochemical stains will be necessary to support this diagnosis. The difficulty of recognition in frozen section in the majority of the situations implies that the diagnosis should be deferred to the definitive study of the permanent sections with immunohistochemical studies. There exists a histological resemblance between a primary ovarian fibrosarcoma and actively mitotic fibroma. In some cases, it can be impossible to separate exactly these two entities. We report a well-differentiated ovarian fibrosarcoma, with less than 1-2 mitosis HPF and low-grade cytological atypia, similar to active mitotic fibromas, developing liver metastasis one year later. Despite having distant metastasis, some cases with long survival rates have been reported in patients who received chemotherapy after surgery; so that the adjuvant chemotherapy should be considered, especially in young females.
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- 2009
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29. Hybrid neurofibroma/schwannoma of the orbit
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Lourdes Salazar-Huayna, Lourdes Naranjo, Cleofé Romagosa, Miguel Ángel Arcediano, Sahyly Siurana, Santiago Ramón y Cajal, and Carme Dinarès
- Subjects
Pathology and Forensic Medicine - Published
- 2023
30. Recuerdos de mi vida (tomo 2 de 2)
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Santiago Ramón y Cajal and Santiago Ramón y Cajal
- Published
- 2019
31. Embarazo gemelar con mola hidatiforme completa y feto vivo asociado: reporte de un caso y revisión bibliográfica
- Author
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Alexandra Navarro, Olivier Moscoso, Marta Garrido-Pontnou, Jessica Camacho, Armando Reques, Itziar García-Ruiz, Joana Madureira, and Santiago Ramón y Cajal
- Subjects
03 medical and health sciences ,030219 obstetrics & reproductive medicine ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pathology and Forensic Medicine - Abstract
Resumen Las gestaciones gemelares de mola hidatiforme completa con feto normal son muy infrecuentes, con unos 300 casos reportados en la literatura. Este tipo de embarazos se consideran de alto riesgo obstetrico debido a las graves complicaciones maternofetales. Los hallazgos clinicos y ecograficos pueden ser altamente indicativos de este tipo de gestaciones, pero el diagnostico de certeza sera habitualmente anatomopatologico. El diagnostico diferencial de esta entidad suele incluir la mola parcial y los embarazos hidropicos, que pueden presentar hallazgos similares, por lo que es importante tener claras las caracteristicas morfologicas que nos pueden permitir diferenciarlas. Para esta tarea es muy util el uso de la inmunohistoquimica para p57, aunque debemos tener en cuenta los casos con expresion aberrante de esta proteina. Presentamos un caso de gestacion gemelar de mola hidatiforme completa con feto vivo, con correlacion radiopatologica, haciendo hincapie en el diagnostico diferencial y la utilidad de la inmunohistoquimica para p57.
- Published
- 2022
32. Cajal: Un grito por la ciencia
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José Ramón Alonso Peña, Juan Andrés Carlos de Segovia, Santiago Ramón y Cajal and José Ramón Alonso Peña, Juan Andrés Carlos de Segovia, Santiago Ramón y Cajal
- Published
- 2018
33. Recuerdos de mi vida (tomo 1 de 2)
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Santiago Ramón y Cajal and Santiago Ramón y Cajal
- Published
- 2018
34. Data from Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay
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Emilio Alba, Vicente Peg, Santiago Ramón y Cajal, Barbara Adamo, Nuria Ribelles, Sean Ferree, Paolo Nuciforo, Catherine Ellis, Sherley Díaz, Martina Álvarez, Maria Vidal, Carl Schaper, H. Arthur Jeiranian, Wesley Buckingham, Begoña Jimenez, Patricia Galván, and Aleix Prat
- Abstract
Purpose: Most hormone receptor (HR)+/HER2− breast cancer patients respond unfavorably to neoadjuvant chemotherapy (NAC); however, genomic tests may identify those patients who are likely to benefit. Using the Prosigna assay, we first evaluated the technical performance of core needle biopsy (CNB) tissues. We then determined whether Prosigna risk of relapse (ROR) score and intrinsic subtype predicted response to NAC in HR+/HER2− patients using CNB samples.Experimental Design: Using the NanoString's nCounter Dx analysis system and a development tissue sample set, we established tissue requirements and assay output variance. We then evaluated the concordance in subtype and correlation in ROR between CNBs and corresponding surgical resection specimens (SRS) in a second independent sample set. Finally, we analyzed 180 independent CNB samples from HR+/HER2− patients who were treated with NAC and correlated ROR and intrinsic subtype with pathologic response.Results: Intra- and interbiopsy variabilities were 2.2 and 6.8 ROR units, respectively. Subtype concordance within multiple CNBs was high for the 4- and 3-subtype classifications (k = 0.885 and 0.889, respectively). Correlation in Prosigna ROR score observed between paired CNBs and SRS was high (r ≥ 0.90), and subtype concordance was also high for the 4- and 3-subtype classifications (kappa = 0.81 and 0.91, respectively). Prosigna results obtained from the HR+/HER2− patient samples showed that both ROR (P = 0.047) and intrinsic subtype (OR LumA vs. non-LumA = 0.341, P = 0.037) were significant predictors of response to NAC.Conclusions: Prosigna ROR and intrinsic subtype are readily obtained from CNB samples in normal practice and reliably predict response to NAC in HR+/HER2− patients. Clin Cancer Res; 22(3); 560–6. ©2015 AACR.
- Published
- 2023
35. Data from Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR
- Author
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Sara C. Kozma, George Thomas, Antonio Zorzano, Santiago Ramón y Cajal, Javier Hernandez-Losa, Hala Elnakat Thomas, María I. Hernández-Álvarez, Carol A. Mercer, Xuemei Ge, and Sónia R. Veiga
- Abstract
Purpose: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mTOR for the treatment of HCC. However, such inhibitors induce hyperglycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor phenformin could reverse both side effects, impose an energetic stress on cancer cells, and suppress the growth of HCC.Experimental Design: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated preclinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival.Results: We found phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with phenformin, was highly efficacious in controlling tumor burden. However, more strikingly, pretreatment with phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival.Conclusions: Treatment of HCC cells in vitro with the biguanide phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC. Clin Cancer Res; 24(15); 3767–80. ©2018 AACR.
- Published
- 2023
36. Suppl.Mat., Suppl. Table, Suppl. Figs Legends from Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR
- Author
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Sara C. Kozma, George Thomas, Antonio Zorzano, Santiago Ramón y Cajal, Javier Hernandez-Losa, Hala Elnakat Thomas, María I. Hernández-Álvarez, Carol A. Mercer, Xuemei Ge, and Sónia R. Veiga
- Abstract
Supplementary data and supplementary table and figures Legends
- Published
- 2023
37. Supplementary Figure S1 and Supplementary Tables S1-S2 from Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay
- Author
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Emilio Alba, Vicente Peg, Santiago Ramón y Cajal, Barbara Adamo, Nuria Ribelles, Sean Ferree, Paolo Nuciforo, Catherine Ellis, Sherley Díaz, Martina Álvarez, Maria Vidal, Carl Schaper, H. Arthur Jeiranian, Wesley Buckingham, Begoña Jimenez, Patricia Galván, and Aleix Prat
- Abstract
Supplementary Figure S1 and Supplementary Tables S1-S2. Supplementary Figure S1. Diagram of tissue block usage for CNB Development Study and Chemo-prediction Validation Study. Supplemental Table S1. Top-10 and bottom-10 Prosigna gene-correlations between paired CNBs and SRS. Supplemental Table S2. Distribution of the Prosigna subtypes within the three main pathology-based groups in 39 independent metastatic samples.
- Published
- 2023
38. Supplementary Figures 1-4, Tables 1-2 from ADAMTS1 Contributes to the Acquisition of an Endothelial-like Phenotype in Plastic Tumor Cells
- Author
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Juan Carlos Rodríguez-Manzaneque, Arjan W. Griffioen, Federico Rojo, Santiago Ramón y Cajal, Estefanía Martino-Echarri, María del Carmen Plaza-Calonge, Antoni Xavier Torres-Collado, and Carmen Casal
- Abstract
Supplementary Figures 1-4, Tables 1-2 from ADAMTS1 Contributes to the Acquisition of an Endothelial-like Phenotype in Plastic Tumor Cells
- Published
- 2023
39. Supplementary Methods from HAVCR/KIM-1 Activates the IL-6/STAT-3 Pathway in Clear Cell Renal Cell Carcinoma and Determines Tumor Progression and Patient Outcome
- Author
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Anna Meseguer, Juan Morote, Emilio Itarte, Santiago Ramón y Cajal, Alex Sánchez, Joan López-Hellin, Mayte Salcedo, Inés de Torres, Jordi Vilardell, Maya R. Vilà, Eduard Sarró, Enric Trilla, and Thaïs Cuadros
- Abstract
PDF file - 116K
- Published
- 2023
40. Data from HAVCR/KIM-1 Activates the IL-6/STAT-3 Pathway in Clear Cell Renal Cell Carcinoma and Determines Tumor Progression and Patient Outcome
- Author
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Anna Meseguer, Juan Morote, Emilio Itarte, Santiago Ramón y Cajal, Alex Sánchez, Joan López-Hellin, Mayte Salcedo, Inés de Torres, Jordi Vilardell, Maya R. Vilà, Eduard Sarró, Enric Trilla, and Thaïs Cuadros
- Abstract
Renal cell carcinoma (RCC), the third most prevalent urological cancer, claims more than 100,000 lives/year worldwide. The clear cell variant (ccRCC) is the most common and aggressive subtype of this disease. While commonly asymptomatic, more than 30% of ccRCC are diagnosed when already metastatic, resulting in a 95% mortality rate. Notably, nearly one-third of organ-confined cancers treated by nephrectomy develop metastasis during follow-up care. At present, diagnostic and prognostic biomarkers to screen, diagnose, and monitor renal cancers are clearly needed. The gene encoding the cell surface molecule HAVCR1/KIM-1 is a suggested susceptibility gene for ccRCC and ectodomain shedding of this molecule may be a predictive biomarker of tumor progression. Microarray analysis of 769-P ccRCC-derived cells where HAVCR/KIM-1 levels have been upregulated or silenced revealed relevant HAVCR/KIM-1–related targets, some of which were further analyzed in a cohort of 98 ccRCC patients with 100 month follow-up. We found that HAVCR/KIM-1 activates the IL-6/STAT-3/HIF-1A axis in ccRCC-derived cell lines, which depends on HAVCR/KIM-1 shedding. Moreover, we found that pSTAT-3 S727 levels represented an independent prognostic factor for ccRCC patients. Our results suggest that HAVCR/KIM-1 upregulation in tumors might represent a novel mechanism to activate tumor growth and angiogenesis and that pSTAT-3 S727 is an independent prognostic factor for ccRCC. Cancer Res; 74(5); 1416–28. ©2014 AACR.
- Published
- 2023
41. Supplementary Figures 1 - 2 from HAVCR/KIM-1 Activates the IL-6/STAT-3 Pathway in Clear Cell Renal Cell Carcinoma and Determines Tumor Progression and Patient Outcome
- Author
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Anna Meseguer, Juan Morote, Emilio Itarte, Santiago Ramón y Cajal, Alex Sánchez, Joan López-Hellin, Mayte Salcedo, Inés de Torres, Jordi Vilardell, Maya R. Vilà, Eduard Sarró, Enric Trilla, and Thaïs Cuadros
- Abstract
PDF file - 701K, Figure S1. RT-qPCR performed in independent clones confirmed that HAVCR/KIM-1 overexpressing 769-P cells exhibited increased mRNA IL-6 levels. Figure S2. As for 769-P cells, HAVCR/KIM-1 overexpression in 786-O cells (FUW-HAVCR) correlated with increased pSTAT-3 S727 levels when compared to 786-O control cells (FUW).
- Published
- 2023
42. Charlas de café: Pensamientos, anécdotas y confidencias
- Author
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Santiago Ramón y Cajal, Francisco Fuster and Santiago Ramón y Cajal, Francisco Fuster
- Published
- 2017
43. Tumor vulvar similar a lipoblastoma: descripción de un nuevo caso y revisión de la literatura
- Author
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Domingo Bodet, Claudia Valverde, Carmen Vásquez-Dongo, Antoni Rivas, Santiago Ramón y Cajal, Cleofé Romagosa, Clara Delbene, and Berta Ferrer
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pathology and Forensic Medicine - Abstract
Resumen El tumor vulvar similar a lipoblastoma (LBLTV) fue descrito inicialmente como una neoplasia mesenquimal benigna. Desde entonces, se han reportado unicamente 19 casos. Ademas, esta entidad no ha sido reconocida aun como diagnostico separado en la clasificacion de la OMS (2013) de los tumores de tejido blando. El diagnostico diferencial de LBLTV incluye otros tumores de la region vulvoperineal, asi como tumores con diferenciacion adipocitica, la mayoria de ellos benignos. Por tanto, un diagnostico erroneo aporta pocas consecuencias clinicas. Sin embargo, LBLTV puede imitar tambien algunas neoplasias lipomatosas agresivas. Describimos aqui un nuevo caso de LBLTV en una mujer de 28 anos, asi como una revision de la literatura.
- Published
- 2022
44. Myosin Vb as a tumor suppressor gene in intestinal cancer
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Fernando Cartón-García, Bruno Brotons, Estefanía Anguita, Higinio Dopeso, Jordi Tarragona, Rocio Nieto, Elia García-Vidal, Irati Macaya, Zsuzsanna Zagyva, Mariona Dalmau, Manuel Sánchez-Martín, Sven C. D. van Ijzendoorn, Stefania Landolfi, Javier Hernandez-Losa, Simo Schwartz Jr, Xavier Matias-Guiu, Santiago Ramón y Cajal, Águeda Martínez-Barriocanal, Diego Arango, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
- Subjects
Mice, Knockout ,Cancer Research ,Myosin Heavy Chains ,Myosin Type V ,Myosins ,Mice ,Enterocytes ,Colonic Neoplasms ,Genetics ,Animals ,Humans ,Genes, Tumor Suppressor ,Colorectal Neoplasms ,Molecular Biology - Abstract
Colorectal cancer causes >900,000 deaths every year and a deeper understanding of the molecular mechanisms underlying this disease will contribute to improve its clinical management and survival. Myosin Vb (MYO5B) regulates intracellular vesicle trafficking, and inactivation of this myosin disrupts the polarization and differentiation of intestinal epithelial cells causing microvillous inclusion disease (MVID), a rare congenital disorder characterized by intractable life-threatening diarrhea. Here, we show that the loss Myosin Vb interfered with the differentiation/polarization of colorectal cancer cells. Although modulation of Myosin Vb expression did not affect the proliferation of colon cancer cells, MYO5B inactivation increased their migration, invasion, and metastatic potential. Moreover, Myo5b inactivation in an intestine-specific knockout mouse model caused a >15-fold increase in the number of azoxymethane-initiated small intestinal tumors. Consistently, reduced expression of Myosin Vb in a cohort of 155 primary colorectal tumors was associated with shorter patient survival. In conclusion, we show here that loss of Myosin Vb reduces polarization/differentiation of colon cancer cells while enhancing their metastatic potential, demonstrating a tumor suppressor function for this myosin. Moreover, reduced expression of Myosin Vb in primary tumors identifies a subset of poor prognosis colorectal cancer patients that could benefit from more aggressive therapeutic regimens.
- Published
- 2022
45. La necesidad de la coordinación técnica en los servicios de Anatomía Patológica. Documento de posicionamiento de la Sociedad Española de Anatomía Patológica
- Author
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Mar García-García, Ramiro Álvarez Alegret, Belen Perez-Mies, Mar Iglesias, Santiago Ramón y Cajal, Xavier Matías-Guiu, and José Luis Rodríguez Peralto
- Subjects
Pathology and Forensic Medicine - Published
- 2022
46. Las redes neuronales visuales de Ramón y Cajal: comentarios sobre el facsímil de uno de sus dibujos manuscritos expuesto en el Museo de Historia de la Medicina de la Academia Nacional de Medicina de Colombia
- Author
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Alberto Gómez Gutiérrez, Mercedes Olaya Contreras, Juan Andrés De Carlos Segovia, and Santiago Ramón Y Cajal Agüeras
- Abstract
La obra de Santiago Ramón y Cajal ha sido ampliamente comentada en biografías y artículos científicos. El presente texto busca aportar información historiográfica sobre una ilustración facsimilar donada a la Academia Nacional de Medicina de Colombia, que se encuentra expuesta en su Museo de la Historia de la Medicina en Bogotá. Para el efecto, se recurrió a los archivos del Instituto Cajal en Madrid, España, en donde se conserva su legado original.
- Published
- 2021
47. Diffuse trophoblast damage is the hallmark of SARS-CoV-2-associated fetal demise
- Author
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Jessica Camacho, Itziar Garcia Ruíz, Santiago Ramón y Cajal, Berta Serrano, Paula Garcia-Aguilar, Marina Alguacil-Guillén, Fatima Crispi, Joan Carles Ferreres, Anna Moreno-Baró, Alexandra Navarro, Anna Suy, Marta Sesé, Javier Hernández-Losa, Alfons Nadal, and Marta Garrido-Pontnou
- Subjects
0301 basic medicine ,Adult ,Pathology ,medicine.medical_specialty ,Necrosis ,In situ hybridization ,Article ,Pathology and Forensic Medicine ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Placenta ,Medicine ,Humans ,Pregnancy Complications, Infectious ,skin and connective tissue diseases ,Fetal Death ,reproductive and urinary physiology ,Fetus ,business.industry ,SARS-CoV-2 ,fungi ,Trophoblast ,COVID-19 ,Intervillous space ,Trophoblasts ,body regions ,030104 developmental biology ,medicine.anatomical_structure ,Viral infection ,030220 oncology & carcinogenesis ,embryonic structures ,Immunohistochemistry ,Female ,Urogenital reproductive disorders ,medicine.symptom ,business ,Infection - Abstract
Placental pathology in SARS-CoV-2-infected pregnancies seems rather unspecific. However, the identification of the placental lesions due to SARS-CoV-2 infection would be a significant advance in order to improve the management of these pregnancies and to identify the mechanisms involved in a possible vertical transmission. The pathological findings in placentas delivered from 198 SARS-CoV-2-positive pregnant women were investigated for the presence of lesions associated with placental SARS-CoV-2 infection. SARS-CoV-2 infection was investigated in placental tissues through immunohistochemistry, and positive cases were further confirmed by in situ hybridization. SARS-CoV-2 infection was also investigated by RT-PCR in 33 cases, including all the immunohistochemically positive cases. Nine cases were SARS-CoV-2-positive by immunohistochemistry, in situ hybridization, and RT-PCR. These placentas showed lesions characterized by villous trophoblast necrosis with intervillous space collapse and variable amounts of mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition. Such lesions ranged from focal to massively widespread in five cases, resulting in intrauterine fetal death. Two of the stillborn fetuses showed some evidence of SARS-CoV-2 positivity. The remaining 189 placentas did not show similar lesions. The strong association between trophoblastic damage and placenta SARS-CoV-2 infection suggests that this lesion is a specific marker of SARS-CoV-2 infection in placenta. Diffuse trophoblastic damage, massively affecting chorionic villous tissue, can result in fetal death associated with COVID-19 disease.
- Published
- 2021
48. Nodal metastatic load in papillary thyroid carcinoma. Morphological and molecular analysis with one-step nucleic acid amplification on more than 550 lymph nodes
- Author
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Santiago Ramón y Cajal, Oscar Gonzalez, Carles Zafon, Jordi Temprana-Salvador, Enric Caubet, Amparo García-Burillo, and Carmela Iglesias
- Subjects
Oncology ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Metastasis ,Thyroid carcinoma ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Cytology ,medicine ,Humans ,Prospective Studies ,RNA, Messenger ,Thyroid Neoplasms ,Prospective cohort study ,Lymph node ,Keratin-19 ,Nutrition and Dietetics ,business.industry ,medicine.disease ,Molecular analysis ,medicine.anatomical_structure ,Thyroid Cancer, Papillary ,Lymphatic Metastasis ,030220 oncology & carcinogenesis ,Lymph ,NODAL ,business - Abstract
The risk of recurrence in papillary thyroid carcinoma (PTC) is likely related to the amount of tumour in the metastatic lymph node (LN). Therefore, the current TNM classification (N0/N1) make it necessary to find a method to quantify the LN metastasis (LNM). We propose that the quantitative molecular assay One-Step Nucleic-Acid Amplification (OSNA), which measures the number of cytokeratin-19 (CK-19) mRNA copies as a marker of LNM, could play this role. Our objective was to describe the characteristics of the LNs from PTC, and to compare the morphological characteristics that have been claimed as criteria for metastatic burden with OSNA.Prospective study of LNs from 42 patients. All of the LNs were measured, weighed and analysed by OSNA and also by imprint cytology.A total of 573 LNs were included, 187 (32.6%) of them were OSNA-positives. The global consistency between cytology and OSNA was 87.4%. Significant differences were observed in the CK-19 copy number between the LNMs0.2cm and those3cm, as well as between those from 0.2 to 3cm with respect to those3cm, but not between those0.2cm and those between 0.2 and 3cm. The total tumour load per neck dissection showed no differences based on whether there were ≤5 or5 LNMs.In our series the LNMs3cm show an increased tumour load, but it is unclear if it is necessary to sub-classify the smaller ones as well as the relevance of the number of metastatic nodes according to the cut-off of 5 nodes. We consider that the OSNA analysis avoids the bias of nodal histology and allows for a greater understanding of its real oncological potential.
- Published
- 2021
49. Vulvar Adenocarcinoma of Intestinal Type: A Case Report of an Uncommon Entity
- Author
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Santiago Ramón y Cajal, Adela Saco, Josep Castellví, Ángel García, Natalia R. Gómez-Hidalgo, Olivier Moscoso, and Armando Reques
- Subjects
Pathology ,medicine.medical_specialty ,Keratin-20 ,Adenocarcinoma ,Vulva ,Pathology and Forensic Medicine ,Lesion ,Cytokeratin ,Dermis ,medicine ,Humans ,CDX2 Transcription Factor ,Papillomaviridae ,Aged ,Pruritus vulvae ,Vulvar Neoplasms ,integumentary system ,business.industry ,Obstetrics and Gynecology ,Vulvar cancer ,medicine.disease ,Immunohistochemistry ,Dissection ,medicine.anatomical_structure ,Carcinoma, Squamous Cell ,Female ,medicine.symptom ,business ,Rare disease - Abstract
Vulvar cancer is rare and accounts for only 5% of all gynecologic cancers. Squamous cell carcinoma is the most common and makes up 90% of the cases. Vulvar adenocarcinoma usually arises in Bartholin and other vulvar glands. Primary vulvar intestinal-type adenocarcinoma is an extremely rare disease with an unclear prognosis and treatment. Its origin is still unknown, the most accepted theory suggests cloacal remnants as the source of origin. Only a few cases have been reported in the literature. We present a case of a 66-yr-old female who presented with vulvar pruritus and local discomfort, showing a 2 cm tumor located in the left labium minor in the region of vulvar fourchette. Wide vulvar excision and bilateral lymph nodes dissection were performed. Other concomitant lesions and distant extension of tumor were ruled out by positron emission tomography. Pathologic study revealed a colonic-type adenocarcinoma with typical villoglandular architecture with an irregular glandular structure composed of atypical columnar epithelium. The lesion had direct contact with epidermal surface and mainly was external without involving the dermis. Immunohistochemical analysis revealed positive staining for cytokeratin 20 and CDX2. p16 showed an abnormal diffuse and strong immunoexpression. The presence of a low-risk human papillomavirus was detected by polymerase chain reaction, therefore, the expression of p16 cannot be explained in this case by the presence of human papillomavirus. Additional studies are needed to be performed in further cases to clarify the role of human papillomavirus in this kind of tumors.
- Published
- 2021
50. Actualización de la recomendación para la determinación de biomarcadores en el carcinoma colorrectal. Consenso Nacional de la Sociedad Española de Oncología Médica y de la Sociedad Española de Anatomía Patológica
- Author
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Santiago Ramón y Cajal, Miriam Cuatrecasas, Eva Musulen, Pilar García-Alfonso, Stefania Landolfi, Javier Hernández-Losa, Jesus Garcia-Foncillas, Ramon Salazar, Samuel Navarro, Rocio Garcia-Carbonero, Pedro Pérez-Segura, and Ruth Vera
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pathology and Forensic Medicine - Abstract
Resumen En esta actualizacion del consenso de la Sociedad Espanola de Oncologia Medica (SEOM) y la Sociedad Espanola de Anatomia Patologica (SEAP) se revisan los avances producidos en el analisis de biomarcadores en cancer colorrectal (CCR) avanzado, asi como en los marcadores de susceptibilidad del CCR hereditario y los biomarcadores moleculares del CCR localizado. Tambien se evaluan la informacion publicada recientemente sobre la determinacion imprescindible de las mutaciones de KRAS, NRAS y BRAF y la conveniencia de determinar la amplificacion del receptor del factor de crecimiento epidermico 2 (HER2), la expresion de las proteinas de la via reparadora de ADN y el estudio de las fusiones de NTRK. Desde el punto de vista anatomopatologico, se revisa la importancia de analizar la presencia de celulas tumorales aisladas o en pequenos grupos de menos de 5 en el frente invasivo tumoral del CCR y su valor pronostico en el CCR. Tambien se revisa la incorporacion de tecnologias pangenomicas, como la secuenciacion de nueva generacion (next-generation sequencing [NGS]) y la biopsia liquida, en el manejo clinico del paciente con CCR. Todos estos aspectos se desarrollan en la presente guia que, como la anterior, permanecera abierta a cualquier revision necesaria en el futuro.
- Published
- 2021
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