المؤلفون: Carreira, Mónica, Ruiz de Adana, María Soledad, Pinzón, José Luis, Anarte-Ortiz, María Teresa

مصطلحات موضوعية: Adult, Cognitive Behavioral Therapy, Diabetes Mellitus, Type 1, Humans, Hypoglycemia, Internet, Quality of Life, Randomized Controlled Trials as Topic

الوصف: Professionals need adequate tools to help patients with diabetes and depression. Although web programs integrating cognitive-behavioral therapy with diabetes education have shown good results, no similar approach has been performed as yet in Spain. The objective is to develop an Internet-based program for the treatment of mild-moderate depressive symptomatology in individuals with type 1 diabetes (WEB_TDDI1 study) based on Cognitive-behavioral therapy (CBT) and assess its results. A 2-arm randomized controlled trial will be conducted. Adults with type 1 diabetes and mild-moderate depressive symptoms will be screened to participate in the study and randomly assigned to either the treatment group (TG) that will use a Web-based application for a specific 9-week intervention in depression and type 1 diabetes or the control group (CG) that will be on the waiting list during that time. Data on the primary variable (depressive symptoms) and secondary variables (treatment-related distress, anxiety, fear of hypoglycemia, quality of life, treatment adherence, coping strategies and glycemic control) will be collected from the TG at the beginning/baseline, at the end of treatment and at 3, 6 and 12 months after treatment. The CG will be assessed at the beginning and at the end of the TG intervention. On completion of the program by the TG, the treatment will then be carried out in the CG. The new web application developed is expected to be effective for the treatment of mild-moderate depressive symptoms in adults with type 1 diabetes, reducing depressive symptoms and improving the rest of the analyzed variables. Registry: NCT03473704 (March 21, 2018); ClinicalTrials.gov.

العلاقة: http://hdl.handle.net/10668/20434Test; http://hdl.handle.net/20.500.12105/18817Test; PloS one

الإتاحة: https://doi.org/20.500.12105/18817Test
https://doi.org/10.1371/journal.pone.0274551Test
http://hdl.handle.net/10668/20434Test
https://hdl.handle.net/20.500.12105/18817Test

المؤلفون: Roldan-Romero, Juan María, Santos, María, Lanillos, Javier, Caleiras, Eduardo, Anguera, Georgia, Maroto, Pablo, García-Donas, Jesús, de Velasco, Guillermo, Martinez-Montes, Ángel Mario, Calsina, Bruna, Monteagudo, María, Letón, Rocío, Leandro-García, Luis Javier, Montero-Conde, Cristina, Cascón, Alberto, Robledo Batanero, Mercedes, Rodriguez Antona, Cristina

المساهمون: Ministerio de Economía, Industria y Competitividad (España), Fundación La Caixa, Fundación Rafael del Pino, Asociación Española Contra el Cáncer, Fundación Banco Santander, Agencia Estatal de Investigación (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Ministerio de Educación, Cultura y Deporte (España), Spanish Oncology Genitourinary Group (SOGUG)

مصطلحات موضوعية: Mutation, Adult, Aged, 80 and over, Biomarkers, Tumor, Carcinoma, Renal Cell, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Kidney Neoplasms, Male, Middle Aged, PTEN Phosphohydrolase, Phenotype, Phosphorylation, Ribosomal Protein S6 Kinases, TOR Serine-Threonine Kinases, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Tumor Suppressor Protein p53

الوصف: Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal tumor. TCGA studies revealed low mutational burden, with only TP53 and PTEN recurrently mutated, and discovered alterations in TERT promoter and in the electron transport chain Complex I genes. However, knowledge on drug targetable genes is limited and treatments at metastatic stage do not follow a molecular rationale. In a large series of 92 chRCC enriched with metastatic cases, we performed an in-depth characterization of mTOR pathway alterations through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin, and PTEN. Mutations in mitochondria, telomere maintenance and other renal cancer related genes and p53 IHC, were also assessed. The impact on metastasis development and disease specific survival was determined, using TCGA-KICH series (n = 65) for validation. mTOR pathway mutations (MTOR, TSC1, TSC2) were present in 17% of primary tumors, most of them being classified as pathogenic. Mutations were associated with positive IHC staining of phospho-S6 and PTEN (P = 0.009 and P = 0.001, respectively) and with chRCC eosinophilic variant (P = 0.039), supporting a biological relevance of the pathway. mTOR pathway mutations were associated with worse clinical outcomes. Survival analysis gave a hazard ratio of 5.5 (P = 0.027), and this association was confirmed in TCGA-KICH (HR = 10.3, P = 0.006). TP53 mutations were enriched in metastatic cases (P = 0.018), and mutations in telomere maintenance genes showed a trend in the same direction. p53 IHC staining pattern was associated with the underlying TP53 defect, and negative PTEN IHC staining (82% of cases) suggested PTEN loss as a chRCC hallmark. In conclusion, our study provides with novel genomic knowledge in chRCC and identifies novel markers of poor survival. Furthermore, this is the first study showing that mTOR pathway mutations correlate with poor prognosis, and may help to identify patients with increased sensitivity to mTOR inhibitors. ...

العلاقة: https://doi.org/10.1038/s41379-020-0607-zTest.; Mod Pathol . 2020;33(12):2580-2590; http://hdl.handle.net/20.500.12105/17510Test; Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

الإتاحة: https://doi.org/20.500.12105/17510Test
https://doi.org/10.1038/s41379-020-0607-zTest
https://hdl.handle.net/20.500.12105/17510Test

المؤلفون: Matamala, Nerea, Gomez-Mariano, Gema Maria, Perez, Jose Antonio, Baladron-Jimenez, Beatriz Isabel, Torres-Durán, María, Michel, Francisco Javier, Saez, Raquel, Hernández-Pérez, Jose María, Belmonte, Irene, Rodriguez-Frias, Francisco, Blanco, Ignacio, Strnad, Pavel, Janciauskiene, Sabina, Martinez-Delgado, Beatriz

المساهمون: Instituto de Salud Carlos III, Deutsche Forschungsgemeinschaft (Alemania)

مصطلحات موضوعية: Alpha-1 antitrypsin, SERPINA 1 genetic mutations, PI*S allele, Polymerization, Adult, Alleles, DNA Mutational Analysis, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Mutation, Phenotype, alpha 1-Antitrypsin, alpha 1-Antitrypsin Deficiency

الوصف: Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing the SERPINA1 gene in three patients who had lower AAT serum levels than expected for the initial genotype. These alleles are the result of combined mutations in cis in a PI*S allele. Sequencing detected the S mutation in cis with Tyr138Cys (S+Tyr138Cys) in two patients, whereas a third one had the S mutation in cis with Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these variants caused strong AAT polymerization and very low AAT secretion to almost undetectable levels. The isoelectric focusing method for plasma AAT phenotyping did not show AAT protein encoded by the novel mutant alleles, behaving as null. We called these alleles PI*S-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demonstrate that the clinical variability observed in AATD can be explained by additional genetic variation, such as dual cis-acting variants in the SERPINA1 gene. The possible existence of other unrevealed variants combined in the PI*S alleles should be considered to improve the genetic diagnosis of the patients. ; Supported by Institute of Health Carlos III grant AESI PI17CIII/00042, and by Deutsche Forschungsgemeinschaft (DFG) grant STR 1095/6-1 (Heisenberg Professorship) (P.S.) and DFG consortium grant SFB/TRR57 “Liver fibrosis” (P.S.). ; Sí

العلاقة: https://doi.org/10.1165/rcmb.2020-0021OCTest; info:fis/Instituto de Salud Carlos III/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/Subprograma Estatal de Generación de Conocimiento/PI17-ISCIII Modalidad Proyectos de Investigacion en Salud Intramurales. (2017)/PI17CIII/00042; Am J Respir Cell Mol Biol. 2020 Oct;63(4):444-451.; http://hdl.handle.net/20.500.12105/17264Test; American journal of respiratory cell and molecular biology

الإتاحة: https://doi.org/20.500.12105/17264Test
https://doi.org/10.1165/rcmb.2020-0021OCTest
https://hdl.handle.net/20.500.12105/17264Test

المؤلفون: Earl, Julie, Galindo-Pumariño, Cristina, Encinas, Jessica, Barreto, Emma, Castillo, Maria E, Pachón, Vanessa, Ferreiro, Reyes, Rodríguez-Garrote, Mercedes, González-Martínez, Silvia, Ramon Y Cajal, Teresa, Diaz, Luis Robles, Chirivella-Gonzalez, Isabel, Rodriguez, Montse, de Castro, Eva Martínez, García-Seisdedos, David, Muñoz, Gloria, Rosa, Juan Manuel Rosa, Marquez, Mirari, Carrato, Alfredo, Malats, Nuria

المساهمون: Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red - CIBERONC (Cáncer), Red Temática de Investigación Cooperativa en Cáncer (RTICC) (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)

مصطلحات موضوعية: Germ-Line Mutation, Adenocarcinoma, Adult, Aged, 80 and over, Cyclin-Dependent Kinase Inhibitor p16, DNA Helicases, DNA-Directed DNA Polymerase, Female, Humans, Male, Middle Aged, MutL Protein Homolog 1, Mutation Rate, Pancreatic Neoplasms, Pedigree

الوصف: The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes. Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC. The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016). ; This study was funded by the Instituto de Salud Carlos III (Plan ...

العلاقة: https://doi.org/10.1016/j.ebiom.2020.102675Test; info:eu-repo/grantAgreement/ES/PI09/02221; Info:eu-repo/grantAgreement/ES/PI12/01635; info:eu-repo/grantAgreement/ES/PI15/02101; info:eu-repo/grantAgreement/ES/PI18/1034; info:eu-repo/grantAgreement/ES/CB16/12/00446; info:eu-repo/grantAgreement/ES/RD12/0036/0073; EBioMedicine.2020;53:102675.; http://hdl.handle.net/20.500.12105/12524Test; EBioMedicine

الإتاحة: https://doi.org/20.500.12105/12524Test
https://doi.org/10.1016/j.ebiom.2020.102675Test
https://hdl.handle.net/20.500.12105/12524Test

المؤلفون: Chalouni, Mathieu, Rodriguez-Centeno, Javier, Samri, Assia, Blanco, Julian, Stella-Ascariz, Natalia, Wallet, Cedrick, Knobel, Hernando, Zucman, David, Autran, Brigitte, Thiebaut, Rodolphe, Raffi, François, Arribas, José Ramón, Alejos, Belén

المساهمون: Red de Investigación Cooperativa en Investigación en Sida (España), Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)

مصطلحات موضوعية: ADP-ribosyl Cyclase 1, Adult, Anti-Retroviral Agents, Antiretroviral Therapy, Highly Active, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Female, HIV Infections, HIV Seropositivity, HIV-1, Humans, Immunologic Memory, Immunophenotyping, Lymphocyte Activation, Male, Middle Aged, T-Lymphocyte Subsets, Telomere, Viral Load

الوصف: In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations. ; This work was supported by NEAT-ID Foundation (not for profit private foundation to promote research and education projects in the HIV field); Red Temática Cooperativa de Investigación en Sida; and Fondo de Investigaciones Sanitarias (supported by FEDER funds; grant number PI13/01467) The NEAT 001/ANRS 143 trial was supported by Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories. French National Institute for Health and Medical Research–France Recherche Nord and Sud Sida- HIV Hepatites (Inserm-ANRS) was the sponsor and a founder of the trial. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the ; Sí

العلاقة: https://doi.org/10.1371/journal.pone.0230772Test; info:eu_repo/grantAgreement/ES/PI13/01467; PLoS One . 2020 Apr 8;15(4):e0230772.; http://hdl.handle.net/20.500.12105/10857Test; PloS one

الإتاحة: https://doi.org/20.500.12105/10857Test
https://doi.org/10.1371/journal.pone.0230772Test
https://hdl.handle.net/20.500.12105/10857Test

المؤلفون: Wolin, Edward, Mita, Alain, Mahipal, Amit, Meyer, Tim, Bendell, Johanna, Nemunaitis, John, Munster, Pam N, Paz Ares, Luis Gonzaga, Filvaroff, Ellen H, Li, Shaoyi, Hege, Kristen, de Haan, Hans, Mita, Monica

مصطلحات موضوعية: Administration, Oral, Adult, Aged, Carcinoid Tumor, Cohort Studies, Female, Gastrointestinal Neoplasms, Humans, Male, Maximum Tolerated Dose, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Middle Aged, Neuroendocrine Tumors, Pyrazines

الوصف: Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development. ; We thank the patients and their families, and the principal investigator study teams, for enabling this study to complete successfully. We also thank the many support staff at ...

العلاقة: Publisher's version; https://doi.org/10.1371/journal.pone.0221994Test.; PLoS One. 2019 ;14(9):e0221994.; http://hdl.handle.net/20.500.12105/9369Test; PloS one

الإتاحة: https://doi.org/20.500.12105/9369Test
https://doi.org/10.1371/journal.pone.0221994Test
https://hdl.handle.net/20.500.12105/9369Test

المؤلفون: Vallejo Mora, María Del Rosario, Carreira, Mónica, Anarte, María Teresa, Linares, Francisca, Olveira, Gabriel, González Romero, Stella

مصطلحات موضوعية: Bolus calculator, Hypoglycemia, Multiple daily injections of insulin, Psychology, Type 1 diabetes, Adolescent, Adult, Blood Glucose, Diabetes Mellitus, Type 1, Fear, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Insulin, Male, Middle Aged, Young Adult

الوصف: In a previous study we demonstrated improvement in metabolic control and reduction in hypoglycemia in people with type 1 diabetes on multiple daily injections, after having used a bolus calculator for 4 months. To demonstrate whether (1) extending its use (2) or introducing it in the control group, previously subjected to treatment intensification, could further improve metabolic control and related psychological issues. After the previous clinical trial, in which the subjects were randomized either to treatment with the calculator or to control group for 4 months, both groups used the calculator during an additional 4-month period. In the previous control group, after using the device, HbA1c did not improve (7.86% ± 0.87% vs. 8.01% ± 0.93%, P 0.215), although a significant decrease in postprandial hypoglycemia was observed (2.3 ± 2 vs. 1.1 ± 1.2/2 weeks, P 0.002). In the group in which the treatment was extended from 4 to 8 months, HbA1c did not improve either (7.61 ± 0.58 vs. 7.73 ± 0.65, P 0.209); however this group had a greater perceived treatment satisfaction (12.03 ± 4.26 vs. 13.71 ± 3.75, P 0.007) and a significant decrease in fear of hypoglycemia (28.24 ± 8.18 basal vs. 25.66 ± 8.02 at 8 months, P 0.026). The extension in the use of the calculator or its introduction in a previously intensified control group did not improve metabolic control, although it did confirm a decrease in hypoglycemic episodes in the short term, while the extension of its use to 8 months was associated with a reduction in fear of hypoglycemia and greater treatment satisfaction.

العلاقة: http://hdl.handle.net/10668/11285Test; http://hdl.handle.net/20.500.12105/17317Test; Diabetes technology & therapeutics

الإتاحة: https://doi.org/20.500.12105/17317Test
https://doi.org/10.1089/dia.2017.0019Test
http://hdl.handle.net/10668/11285Test
https://hdl.handle.net/20.500.12105/17317Test

المؤلفون: Teixido-Tura, Gisela, Forteza, Alberto, Rodríguez-Palomares, Jose, Gonzalez-Mirelis, Jesus, Gutiérrez, Laura, Sánchez, Violeta, Ibáñez, Borja, Garcia-Dorado, David, Evangelista, Artur

المساهمون: Sociedad Española de Cardiología, Centro de Investigación Biomedica en Red - CIBER

مصطلحات موضوعية: Marfan syndrome, aortic aneurysm, losartan, Adrenergic beta-1 Receptor Antagonists, Adult, Aneurysm, Dissecting, Angiotensin II Type 1 Receptor Blockers, Aorta, Atenolol, Dilatation, Pathologic, Disease Progression, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Cine, Male, Young Adult

الوصف: BACKGROUND: Beta-blockers are the standard treatment in Marfan syndrome (MFS). Recent clinical trials with limited follow-up yielded conflicting results on losartan's effectiveness in MFS. OBJECTIVES: The present study aimed to evaluate the benefit of losartan compared with atenolol for the prevention of aortic dilation and complications in Marfan patients over a longer observation period (>5 years). METHODS: A total of 128 patients included in the previous LOAT (LOsartan vs ATenolol) clinical trial (64 in the atenolol and 64 in the losartan group) were followed up for an open-label extension of the study, with the initial treatment maintained. RESULTS: Mean clinical follow-up was 6.7 ± 1.5 years. A total of 9 events (14.1%) occurred in the losartan group and 12 (18.8%) in the atenolol group. Survival analysis showed no differences in the combined endpoint of need for aortic surgery, aortic dissection, or death (p = 0.462). Aortic root diameter increased with no differences between groups: 0.4 mm/year (95% confidence interval: 0.2 to 0.5) in the losartan and 0.4 mm/year (95% confidence interval: 0.3 to 0.6) in the atenolol group. In the subgroup analyses, no significant differences were observed considering age, baseline aortic root diameter, or type of dominant negative versus haploinsufficient FBN1 mutation. CONCLUSIONS: Long-term outcome of Marfan syndrome patients randomly assigned to losartan or atenolol showed no differences in aortic dilation rate or presence of clinical events between treatment groups. Therefore, losartan might be a useful, low-risk alternative to beta-blockers in the long-term management of these patients. ; This work was been funded by a grant of the Spanish Society of Cardiology and CIBERCV. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. ; Sí

العلاقة: https://doi.org/10.1016/j.jacc.2018.07.052Test; J Am Coll Cardiol. 2018; 72(14):1613-1618; http://hdl.handle.net/20.500.12105/9496Test; Journal of the American College of Cardiology

الإتاحة: https://doi.org/20.500.12105/9496Test
https://doi.org/10.1016/j.jacc.2018.07.052Test
https://hdl.handle.net/20.500.12105/9496Test

المؤلفون: Moreno-Santos, Inmaculada, Castellano-Castillo, Daniel, Lara, María Fernanda, Fernandez-Garcia, Jose Carlos, Tinahones, Francisco Jose, Macias-Gonzalez, Manuel

المساهمون: Moreno-Santos, Inmaculada Univ Malaga, Complejo Hosp Malaga Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Unidad Gest Clin Endocrinol & Nutr, Malaga, Spain, Castellano-Castillo, Daniel Univ Malaga, Complejo Hosp Malaga Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Unidad Gest Clin Endocrinol & Nutr, Malaga, Spain, Carlos Fernandez-Garcia, Jose Univ Malaga, Complejo Hosp Malaga Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Unidad Gest Clin Endocrinol & Nutr, Malaga, Spain, Jose Tinahones, Francisco Univ Malaga, Complejo Hosp Malaga Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Unidad Gest Clin Endocrinol & Nutr, Malaga, Spain, Macias-Gonzalez, Manuel Univ Malaga, Complejo Hosp Malaga Virgen de la Victoria, Inst Invest Biomed Malaga IBIMA, Unidad Gest Clin Endocrinol & Nutr, Malaga, Spain, Moreno-Santos, Inmaculada CIBER Pathophysiol Obes & Nutr CB06 03, Malaga, Spain, Castellano-Castillo, Daniel CIBER Pathophysiol Obes & Nutr CB06 03, Malaga, Spain, Carlos Fernandez-Garcia, Jose CIBER Pathophysiol Obes & Nutr CB06 03, Malaga, Spain, Jose Tinahones, Francisco CIBER Pathophysiol Obes & Nutr CB06 03, Malaga, Spain, Macias-Gonzalez, Manuel CIBER Pathophysiol Obes & Nutr CB06 03, Malaga, Spain, Fernanda Lara, Maria Univ Malaga, Complejo Hosp Malaga Virgen de la Victoria, Dept Urol, Malaga, Spain

مصطلحات موضوعية: IGFBP, VDR, insulin resistance, morbid obesity and adipose, vitamin D, Adipose Tissue, Adult, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 2, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Protein 4, Intra-Abdominal Fat, Male, Middle Aged, Obesity, Protein Binding, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptors, Calcitriol, Regression Analysis, Signal Transduction

الوصف: Adipose tissue has traditionally only been considered as an energy storage organ. Nevertheless, the importance of this tissue in systemic physiology and, especially, in systemic inflammation has been highlighted in recent years. Adipose tissue expresses proteins related to vitamin D (VD) metabolism, and it has been proposed that it can act as a VD storage tissue. The active form of VD, 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃), is able to modify adipocyte and adipose tissue physiology via the VD receptor (VDR), decreasing the expression of pro-inflammatory cytokines in adipose tissue. Moreover, VD deficiency and VDR has been reported to be associated with obesity and diabetes. However, the results of the different studies are not conclusive. Insulin growth binding proteins (IGFBPs) have been identified in adipose tissue, but their roles are poorly understood. Therefore, the objective of this study was to analyze the plasma levels of VD and the gene expression of VDR in the adipose tissue of subjects with morbid obesity (MO) and with different degrees of insulin resistance (IR), as well as the functionality of direct interaction between IGFBP-3 and VDR, which could explain its inhibitory role in adipogenesis. Our results show a novel role of the VD system in the regulation and activation of IGFBP-3 in visceral adipose tissue (VAT) of patients with MO, as a new and alternative mechanism proposed in the insulin signaling associated with obesity.

العلاقة: http://hdl.handle.net/10668/11776Test; http://hdl.handle.net/20.500.12105/17345Test; International journal of molecular sciences

الإتاحة: https://doi.org/20.500.12105/17345Test
https://doi.org/10.3390/ijms18112349Test
http://hdl.handle.net/10668/11776Test
https://hdl.handle.net/20.500.12105/17345Test

المؤلفون: LLanos, Susana, García-Pedrero, Juana M, Morgado-Palacin, Lucia, Rodrigo, Juan P, Serrano Marugan, Manuel

المساهمون: Unión Europea. Comisión Europea. European Research Council (ERC), Botín Foundation, Fundación Ramón Areces, Fundación AXA, Ministerio de Economía y Competitividad (España)

مصطلحات موضوعية: Adaptor Proteins, Signal Transducing, Adult, Aged, 80 and over, Carcinoma, Squamous Cell, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Head and Neck Neoplasms, Humans, Male, Mechanistic Target of Rapamycin Complex 1, Middle Aged, Multiprotein Complexes, Phosphoproteins, TOR Serine-Threonine Kinases

الوصف: The levels, regulation and prognostic value of p21 in head and neck squamous cell carcinomas (HNSCC) has been puzzling for years. Here, we report a new mechanism of regulation of p21 by the mTORC1/4E-BP1 pathway. We find that non-phosphorylated 4E-BP1 interacts with p21 and induces its degradation. Accordingly, hyper-activation of mTORC1 results in phosphorylation of 4E-BP1 and stabilization of p21. In HNSCC, p21 levels strongly correlate with mTORC1 activity but not with p53 status. Finally, clinical data indicate that HNSCC patients with p21 and phospho-S6-double-positive tumours present a better disease-specific survival. We conclude that over-activation of the mTORC1/4E-BP1/p21 pathway is a frequent and clinically relevant alteration in HNSCC. ; We are grateful to Reidar Grenman, Silvio Gutkind, Nahum Sonenberg, Gordon Peters, David Sabatini and Mariano Barbacid for sharing critical reagents. We also thank Aurora Astudillo, Aitana Vallina, Laura Alonso-Dura ́n and Eva Allonca for excellent technical assistance. Work in the laboratory of M.S. is funded by the CNIO and by grants from the Spanish Ministry of Economy (SAF) co-funded by the European Regional Development Fund, the European Research Council (ERC Advanced Grant), the Regional Government of Madrid co-funded by the European Social Fund, the Botin Foundation and BancoSantander (Santander Universities Global Division), the Ramon Areces Foundation an the AXA Foundation. Work in the laboratory of J.M.G.-P. and J.P.R. was supported bygrants from Plan Nacional de DþI 2013–2016 ISCIII (CP13/00013 andPI13/00259),RD12/0036/0015 of Red Tematica de Investigacio ́n Cooperativa en Cancer (RTICC), Spain and the FEDER Funding Program from the European Union ; Sí

العلاقة: https://doi.org/10.1038/10.1038/ncomms10438Test.; info:eu-repo/grantAgreement/ES/CP13/00013; info:eu-repo/grantAgreement/ES/ PI13/00259; Nat Commun. 2016;7:10438.; http://hdl.handle.net/20.500.12105/7870Test; Nature communications

الإتاحة: https://doi.org/20.500.12105/7870Test
https://doi.org/10.1038/ncomms10438Test
https://doi.org/10.1038/10.1038/ncomms10438Test
https://hdl.handle.net/20.500.12105/7870Test