1,720,966 research outputs found
Novel therapeutic approaches against Head and Neck Squamous Cell Carcinoma
Get PDFPrograma de Doctorat en Genètica / Tesi realitzada a l'lnstitut de Recerca Hospital Universitari Vall d'HebronHead and neck squamous cell carcinoma (HNSCC) is usually diagnosed in advanced stages. The treatment has not changed much on the last decades, being limited to surgery followed by radiotherapy and/or chemotherapy [mainly cisplatin (CDDP) and 5-fluorouracil (5-FU)]. However, the acquisition of chemotherapy resistance is very common, which usually leads to recurrences and metastases. On the other hand, the role of autophagy in HNSCC is not clearly defined. This is the reason why in this thesis we have proposed: 1) to determine the role of autophagy in HNSCC models and its relationship with chemotherapy resistance and other clinical parameters; 2) to identify target proteins involved in the acquisition of chemotherapy resistance in HNSCC models whose modulation of its expression and/or activity could be of clinical and therapeutic interest.
From a retrospective immunohistochemistry (IHC) study, we found that the
expression of the autophagy markers sequestosome-1 (p62/SQSTM1) and microtubule-associated proteins 1A/1B light chain 3B (LC3), as well as prostate tumor-overexpressed gene 1 protein (PTOV1), could be considered markers of poor clinical prognosis in laryngeal cancer patients. We found overexpression of PTOV1 and the autophagy-related protein 5 (ATG5) in HNSCC biopsy-derived cell lines with innate resistance to CDDP. Likewise, in general, autophagy activation and/or PTOV1 overexpression occurred in three non-metastatic HNSCC cell lines in which resistance to CDDP and 5-FU had previously been generated, as well as in cancer stem cells (CSCs). Furthermore, PTOV1 overexpression induced autophagy in JHU029 laryngeal cell line. Finally, we found that autophagy inhibition with hydroxychloroquine (HCQ), alone or in combination with CDDP or 5-FU, could be an attractive therapeutic alternative for HNSCC patients with chemotherapy resistance.
In addition, a comparative proteomic study revealed tetraspanin 1 (TSPAN1) as a
target involved in chemotherapy resistance in HNSCC models. In this sense, TSPAN1 depletion decreased cell proliferation, induced apoptosis, and sensitized HNSCC cell lines and biopsy-derived cell lines to chemotherapeutic agents like CDDP and dasatinib. Moreover, TSPAN1 depletion reduced autophagy and blocked the activation of proto-oncogene tyrosine-protein kinase SRC (SRC), protein kinase B (AKT) and mitogen-activated protein kinase (ERK). In addition, TSPAN1 expression was associated to epithelial–mesenchymal transition (EMT) activation in mice tumors and HNSCC patient biopsies. Overall, TSPAN1 inhibition could be a promising therapeutic strategy to improve the current treatment against HNSCC patients
Targeting Tetraspanin 1: a novel approach for overcoming chemoresistance in head and neck squamous cell carcinoma
No full textEls carcinomes de cèl·lules escamoses de cap i coll (HNSCC) destaquen per la seva alta prevalença i letalitat, degut principalment a: i) diagnòstics tardans, ii) limitada disponibilitat d'opcions terapèutiques, i iii) alta resistència a teràpies convencionals. D'altra banda, el receptor de membrana tetraspanina 1 (TSPAN1) és una proteïna oncogènica implicada en proliferació i metàstasi en diversos tipus de càncer.
La inhibició genètica de TSPAN1 sensibilitza les cèl·lules resistents al cisplatí (CDDP) i les cèl·lules mare canceroses al tractament amb CDDP i dasatinib. Per tant, fent un cribratge virtual amb tres programes de simulació d'acoblament i la base de dades Specs, es van identificar compostos amb capacitat de bloquejar TSPAN1 i les seves vies de senyalització. Vint d'aquests compostos van ser seleccionats per ser validats experimentalment, i els candidats 13 i 14 van mostrar els resultats més prometedors en estudis in vitro i in vivo.
Per millorar la solubilitat en solvents aquosos i crear un compost patentable del compost 14, es van dissenyar variants moleculars mitjançant eines d'intel·ligència artificial i química mèdica. El compost 14-3 va millorar la seva solubilitat respecte al compost 14 original, reduint la proliferació i augmentant la diferenciació de tumors de HNSCC en ratolins (patent europea EP23383269).
Posteriorment, el compost 14-3 es va combinar amb CDDP i docetaxel (DTX) per avaluar-ne l'eficàcia en el tractament de tumors resistents, obtenint-se un efecte sinèrgic in vitro i in vivo. L'èxit del projecte podria revolucionar les estratègies terapèutiques no només contra l'HNSCC, sinó també contra altres càncers agressius que sobreexpressen TSPAN1, en oferir una alternativa cost-efectiva i d'ampli espectre, reduint la càrrega econòmica i social associada al càncer.Los carcinomas de células escamosas de cabeza y cuello (HNSCC) destacan por su alta prevalencia y letalidad, debido principalmente a: i) diagnósticos tardíos, ii) limitada disponibilidad de opciones terapéuticas, y iii) alta resistencia a terapias convencionales. Por otro lado, el receptor de membrana tetraspanina 1 (TSPAN1) es una proteína oncogénica implicada en proliferación y metástasis en varios tipos de cáncer.
La inhibición genética de TSPAN1 sensibiliza las células resistentes al cisplatino (CDDP) y las células madre cancerosas al tratamiento con CDDP y dasatinib. Por tanto, realizando un cribado virtual con tres programas de simulación de acoplamiento y la base de datos Specs, se identificaron compuestos con capacidad de bloquear TSPAN1 y sus vías de señalización. Veinte de estos compuestos fueron seleccionados para ser validados experimentalmente, y los candidatos 13 y 14 mostraron los resultados más prometedores en estudios in vitro e in vivo.
Para mejorar la solubilidad en solventes acuosos y crear un compuesto patentable del compuesto 14, se diseñaron variantes moleculares mediante herramientas de inteligencia artificial y química médica. El compuesto 14-3 mejoró su solubilidad respecto al compuesto 14 original, reduciendo la proliferación y aumentando la diferenciación de tumores de HNSCC en ratones (patente europea EP23383269).
Posteriormente, el compuesto 14-3 se combinó con CDDP y docetaxel (DTX) para evaluar su eficacia en el tratamiento de tumores resistentes, obteniéndose un efecto sinérgico in vitro e in vivo. El éxito del proyecto podría revolucionar las estrategias terapéuticas no solo contra el HNSCC, sino también contra otros cánceres agresivos que sobreexpresan TSPAN1, al ofrecer una alternativa costo-efectiva y de amplio espectro, reduciendo la carga económica y social asociada al cáncer.Head and neck squamous cell carcinomas (HNSCC) were noted for their high prevalence and lethality, primarily due to: i) late diagnosis, ii) limited availability of therapeutic options for these patients, and iii) a high rate of resistance acquisition to conventional therapies. The membrane receptor tetraspanin 1 (TSPAN1) was identified as an oncogenic protein implicated in proliferation and metastasis across various cancer types.
Genetic inhibition of TSPAN1 was shown to sensitize cisplatin (CDDP)-resistant cells and cancer stem cells to CDDP treatment. Utilizing a virtual screening approach based on three different docking simulation programs and the Specs database, potential drugs capable of blocking TSPAN1 and its downstream signalling pathways were identified. 20 compounds exhibited potential activity against the target, representing novel pharmacological entities. Among these, drugs 13 and 14 demonstrated promising results in both in vitro and in vivo studies.
To improve the solubility and create a patentable compound of drug 14, several molecular variants were designed using artificial intelligence tools and medical chemistry. The variant drug 14-3 showed improvements over the original drug 14, as evidenced by the reduced proliferation and increased differentiation of tumors in mice treated with drug 14-3 compared to those treated with drug 14. These characteristics indicated less aggressive tumors (European patent EP23383269).
Later, drug 14-3 was used in combination with CDDP and docetaxel (DTX) to sensitize resistant tumors, resulting in a synergistic effect in vitro and in vivo. The successful development of this project could revolutionize current cancer therapeutic strategies by providing a cost-effective, broad-spectrum alternative, significantly reducing the economic and societal burden of cancer.Universitat Autònoma de Barcelona. Programa de Doctorat en Bioquímica, Biologia Molecular i Biomedicin
Targeting Tetraspanin 1 : a novel approach for overcoming chemoresistance in head and neck squamous cell carcinoma
No full textEls carcinomes de cèl·lules escamoses de cap i coll (HNSCC) destaquen per la seva alta prevalença i letalitat, degut principalment a: i) diagnòstics tardans, ii) limitada disponibilitat d'opcions terapèutiques, i iii) alta resistència a teràpies convencionals. D'altra banda, el receptor de membrana tetraspanina 1 (TSPAN1) és una proteïna oncogènica implicada en proliferació i metàstasi en diversos tipus de càncer. La inhibició genètica de TSPAN1 sensibilitza les cèl·lules resistents al cisplatí (CDDP) i les cèl·lules mare canceroses al tractament amb CDDP i dasatinib. Per tant, fent un cribratge virtual amb tres programes de simulació d'acoblament i la base de dades Specs, es van identificar compostos amb capacitat de bloquejar TSPAN1 i les seves vies de senyalització. Vint d'aquests compostos van ser seleccionats per ser validats experimentalment, i els candidats 13 i 14 van mostrar els resultats més prometedors en estudis in vitro i in vivo. Per millorar la solubilitat en solvents aquosos i crear un compost patentable del compost 14, es van dissenyar variants moleculars mitjançant eines d'intel·ligència artificial i química mèdica. El compost 14-3 va millorar la seva solubilitat respecte al compost 14 original, reduint la proliferació i augmentant la diferenciació de tumors de HNSCC en ratolins (patent europea EP23383269). Posteriorment, el compost 14-3 es va combinar amb CDDP i docetaxel (DTX) per avaluar-ne l'eficàcia en el tractament de tumors resistents, obtenint-se un efecte sinèrgic in vitro i in vivo. L'èxit del projecte podria revolucionar les estratègies terapèutiques no només contra l'HNSCC, sinó també contra altres càncers agressius que sobreexpressen TSPAN1, en oferir una alternativa cost-efectiva i d'ampli espectre, reduint la càrrega econòmica i social associada al càncer.Los carcinomas de células escamosas de cabeza y cuello (HNSCC) destacan por su alta prevalencia y letalidad, debido principalmente a: i) diagnósticos tardíos, ii) limitada disponibilidad de opciones terapéuticas, y iii) alta resistencia a terapias convencionales. Por otro lado, el receptor de membrana tetraspanina 1 (TSPAN1) es una proteína oncogénica implicada en proliferación y metástasis en varios tipos de cáncer. La inhibición genética de TSPAN1 sensibiliza las células resistentes al cisplatino (CDDP) y las células madre cancerosas al tratamiento con CDDP y dasatinib. Por tanto, realizando un cribado virtual con tres programas de simulación de acoplamiento y la base de datos Specs, se identificaron compuestos con capacidad de bloquear TSPAN1 y sus vías de señalización. Veinte de estos compuestos fueron seleccionados para ser validados experimentalmente, y los candidatos 13 y 14 mostraron los resultados más prometedores en estudios in vitro e in vivo. Para mejorar la solubilidad en solventes acuosos y crear un compuesto patentable del compuesto 14, se diseñaron variantes moleculares mediante herramientas de inteligencia artificial y química médica. El compuesto 14-3 mejoró su solubilidad respecto al compuesto 14 original, reduciendo la proliferación y aumentando la diferenciación de tumores de HNSCC en ratones (patente europea EP23383269). Posteriormente, el compuesto 14-3 se combinó con CDDP y docetaxel (DTX) para evaluar su eficacia en el tratamiento de tumores resistentes, obteniéndose un efecto sinérgico in vitro e in vivo. El éxito del proyecto podría revolucionar las estrategias terapéuticas no solo contra el HNSCC, sino también contra otros cánceres agresivos que sobreexpresan TSPAN1, al ofrecer una alternativa costo-efectiva y de amplio espectro, reduciendo la carga económica y social asociada al cáncer.Head and neck squamous cell carcinomas (HNSCC) were noted for their high prevalence and lethality, primarily due to: i) late diagnosis, ii) limited availability of therapeutic options for these patients, and iii) a high rate of resistance acquisition to conventional therapies. The membrane receptor tetraspanin 1 (TSPAN1) was identified as an oncogenic protein implicated in proliferation and metastasis across various cancer types. Genetic inhibition of TSPAN1 was shown to sensitize cisplatin (CDDP)-resistant cells and cancer stem cells to CDDP treatment. Utilizing a virtual screening approach based on three different docking simulation programs and the Specs database, potential drugs capable of blocking TSPAN1 and its downstream signalling pathways were identified. 20 compounds exhibited potential activity against the target, representing novel pharmacological entities. Among these, drugs 13 and 14 demonstrated promising results in both in vitro and in vivo studies. To improve the solubility and create a patentable compound of drug 14, several molecular variants were designed using artificial intelligence tools and medical chemistry. The variant drug 14-3 showed improvements over the original drug 14, as evidenced by the reduced proliferation and increased differentiation of tumors in mice treated with drug 14-3 compared to those treated with drug 14. These characteristics indicated less aggressive tumors (European patent EP23383269). Later, drug 14-3 was used in combination with CDDP and docetaxel (DTX) to sensitize resistant tumors, resulting in a synergistic effect in vitro and in vivo. The successful development of this project could revolutionize current cancer therapeutic strategies by providing a cost-effective, broad-spectrum alternative, significantly reducing the economic and societal burden of cancer
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
- …
