Página 4 dos resultados de 167 itens digitais encontrados em 0.001 segundos

Insulin resistance: Is it time for primary prevention?

Mercurio, Valentina; Carlomagno, Guido; Fazio, Valeria; Fazio, Serafino
Fonte: Baishideng Publishing Group Co., Limited Publicador: Baishideng Publishing Group Co., Limited
Tipo: Artigo de Revista Científica
EN
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Insulin resistance is a clinical condition characterized by a decrease in sensitivity and responsiveness to the metabolic actions of insulin, so that a given concentration of insulin produces a less-than-expected biological effect. As a result, higher levels of insulin are needed to maintain normal glucose tolerance. Hyperinsulinemia, indeed, is one of the principal characteristics of insulin resistance states. This feature is common in several pathologic conditions, such as type 2 diabetes, obesity, and dyslipidemia, and it is also a prominent component of hypertension, coronary heart disease, and atherosclerosis. The presence of endothelial dysfunction, related to insulin resistance, plays a key role in the development and progression of atherosclerosis in all of these disorders. Insulin resistance represents the earliest detectable abnormality in type 2 diabetes, and is one of the major underlying mechanisms of hypertension and cardiovascular diseases. Its early detection could be of great importance, in order to set a therapeutic attack and to counteract the higher risk of diabetes and cardiovascular diseases.

An NMR-based scoring function improves the accuracy of binding pose predictions by docking by two orders of magnitude

Orts, Julien; Bartoschek, Stefan; Griesinger, Christian; Monecke, Peter; Carlomagno, Teresa
Fonte: Springer Netherlands Publicador: Springer Netherlands
Tipo: Artigo de Revista Científica
EN
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Low-affinity ligands can be efficiently optimized into high-affinity drug leads by structure based drug design when atomic-resolution structural information on the protein/ligand complexes is available. In this work we show that the use of a few, easily obtainable, experimental restraints improves the accuracy of the docking experiments by two orders of magnitude. The experimental data are measured in nuclear magnetic resonance spectra and consist of protein-mediated NOEs between two competitively binding ligands. The methodology can be widely applied as the data are readily obtained for low-affinity ligands in the presence of non-labelled receptor at low concentration. The experimental inter-ligand NOEs are efficiently used to filter and rank complex model structures that have been pre-selected by docking protocols. This approach dramatically reduces the degeneracy and inaccuracy of the chosen model in docking experiments, is robust with respect to inaccuracy of the structural model used to represent the free receptor and is suitable for high-throughput docking campaigns.

A nutraceutical combination improves insulin sensitivity in patients with metabolic syndrome

Affuso, Flora; Mercurio, Valentina; Ruvolo, Antonio; Pirozzi, Concetta; Micillo, Filomena; Carlomagno, Guido; Grieco, Fabrizia; Fazio, Serafino
Fonte: Baishideng Publishing Group Co., Limited Publicador: Baishideng Publishing Group Co., Limited
Tipo: Artigo de Revista Científica
EN
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AIM: To test the efficacy of a proprietary nutraceutical combination in reducing insulin resistance associated with the metabolic syndrome (MetS).

Polyarteritis Nodosa (PAN) in childhood: a report of two siblings with intractable disease controlled by mycophenolate mofetil (MMF)

Falcini, FF; Capannini, CS; Nacci, NF; Indaco, IR; Battagliese, BA; Carlomagno, CR; Alessio, AM
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 15/09/2008 EN
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Guiding protein-ligand docking with different experimental NMR-data

ten Brink, Tim; Onila, Ionut; Mazur, Adam; Korb, Oliver; Möller, Heiko M; Griesinger, Christian; Carlomagno, Teresa; Exner, Thomas E
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 01/05/2012 EN
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Fasting glucose and treatment outcome in breast and colorectal cancer patients treated with targeted agents: results from a historic cohort

Barba, M.; Sperati, F.; Stranges, S.; Carlomagno, C.; Nasti, G.; Iaffaioli, V.; Caolo, G.; Mottolese, M.; Botti, G.; Terrenato, I.; Vici, P.; Serpico, D.; Giordano, A.; D’Aiuto, G.; Crispo, A.; Montella, M.; Capurso, G.; Delle Fave, G.; Fuhrman, B.; Bot
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
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TDP-1/TDP-43 Regulates Stress Signaling and Age-Dependent Proteotoxicity in Caenorhabditis elegans

Vaccaro, Alexandra; Tauffenberger, Arnaud; Ash, Peter E. A.; Carlomagno, Yari; Petrucelli, Leonard; Parker, J. Alex
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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TDP-43 is a multifunctional nucleic acid binding protein linked to several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia. To learn more about the normal biological and abnormal pathological role of this protein, we turned to Caenorhabditis elegans and its orthologue TDP-1. We report that TDP-1 functions in the Insulin/IGF pathway to regulate longevity and the oxidative stress response downstream from the forkhead transcription factor DAF-16/FOXO3a. However, although tdp-1 mutants are stress-sensitive, chronic upregulation of tdp-1 expression is toxic and decreases lifespan. ALS–associated mutations in TDP-43 or the related RNA binding protein FUS activate the unfolded protein response and generate oxidative stress leading to the daf-16–dependent upregulation of tdp-1 expression with negative effects on neuronal function and lifespan. Consistently, deletion of endogenous tdp-1 rescues mutant TDP-43 and FUS proteotoxicity in C. elegans. These results suggest that chronic induction of wild-type TDP-1/TDP-43 by cellular stress may propagate neurodegeneration and decrease lifespan.

KRAS mutation detection by high-resolution melting analysis significantly predicts clinical benefit of cetuximab in metastatic colorectal cancer

Malapelle, U; Carlomagno, C; Salatiello, M; De Stefano, A; De Luca, C; Bianco, R; Marciano, R; Cimminiello, C; Bellevicine, C; De Placido, S; Troncone, G
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
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Addition of erlotinib to fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab: Two sequential phase I trials

CARLOMAGNO, CHIARA; DANIELE, GENNARO; BIANCO, ROBERTO; MARCIANO, ROBERTA; DAMIANO, VINCENZO; MATANO, ELIDE; NAPPI, LUCIA; PEPE, STEFANO; DE PLACIDO, SABINO; TORTORA, GIAMPAOLO
Fonte: D.A. Spandidos Publicador: D.A. Spandidos
Tipo: Artigo de Revista Científica
EN
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The combination of EGFR inhibitors and anti-angiogenic drugs has a strong pre-clinical rationale, yet its use has produced controversial clinical results. We conducted two sequential phase I trials to evaluate the feasibility and the recommended dose of erlotinib when combined with fluoropyrimidine-oxaliplatin-based chemotherapy with or without bevacizumab. A total of 21 metastatic colorectal cancer (mCRC) patients were treated in two sequential phase I trials. In the first trial, 12 patients were treated with escalating doses of erlotinib plus FOLFOX. In the second, 9 patients were treated with escalating doses of erlotinib combined with oxaliplatin, capecitabine and bevacizumab. No MTD was reached in either of the trials. The only dose-limiting toxicities observed were neutropenia and diarrhea. No unexpected toxicities were noted. Hematological toxicity was the most frequently noted adverse event with infusional 5FU therapy, while gastrointestinal toxicity was the most common adverse event. In the second trial most patients withdrew from treatment due to toxicity, and less than half completed the therapeutic program as per protocol, mostly due to toxicity. In conclusion, the present study confirms the disappointing results of the double combination of EGFR inhibitors and anti-angiogenic drugs in mCRC patients.

Adjuvant FOLFOX-4 in patients with radically resected gastric cancer: Tolerability and prognostic factors

CARLOMAGNO, CHIARA; MATANO, ELIDE; BIANCO, ROBERTO; CIMMINIELLO, CAROLINA; PRUDENTE, ANTONELLA; PAGLIARULO, CLORINDO; CRISPO, ANNA; CANNELLA, LUCIA; DE STEFANO, ALFONSO; D’ARMIENTO, FRANCESCO PAOLO; DE PLACIDO, SABINO
Fonte: D.A. Spandidos Publicador: D.A. Spandidos
Tipo: Artigo de Revista Científica
EN
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The aim of the present study was to evaluate the toxicity and efficacy of the FOLFOX-4 regimen as adjuvant chemotherapy in patients with gastric cancer after radical surgery. Fifty-four patients (1 stage Ib, 6 stage II, 22 stage IIIa, 14 stage IIIb and 11 stage IV) received 8-12 cycles of FOLFOX-4 (oxaliplatin 85 mg/m2, Day 1; leucovorin 100 mg/m2 i.v., Days 1 and 2; 5-fluorouracil 400 mg/m2 i.v. bolus, Days 1 and 2 and 600 mg/m2 in 22 h i.v. continuous infusion, Days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the National Cancer Institute Common Toxicity Criteria. Disease-free (DFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Thirty-eight patients (70.4%) completed the prescribed number of cycles of chemotherapy. The toxicity was mild. Grade 3–4 neutropenia occurred in 57% of patients, thrombocytopenia and anemia in 2% of cases. Peripheral neuropathy was experienced by 46% of the patients (grade 4 in 2% of cases). Five patients experienced grade 3 gastrointestinal toxicity. After a median follow-up of 33.1 months, 17 patients relapsed and 17 succumbed to the disease. The mean observed DFS and OS were 49.7 months (range 40.7–58.8) and 57.9 months (range 49.6–66.2)...

The description of protein internal motions aids selection of ligand binding poses by the INPHARMA method

Stauch, Benjamin; Orts, Julien; Carlomagno, Teresa
Fonte: Springer Netherlands Publicador: Springer Netherlands
Tipo: Artigo de Revista Científica
EN
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Protein internal motions influence observables of NMR experiments. The effect of internal motions occurring at the sub-nanosecond timescale can be described by NMR order parameters. Here, we report that the use of order parameters derived from Molecular Dynamics (MD) simulations of two holo-structures of Protein Kinase A increase the discrimination power of INPHARMA, an NMR based methodology that selects docked ligand orientations by maximizing the correlation of back-calculated to experimental data. By including internal motion in the back-calculation of the INPHARMA transfer, we obtain a more realistic description of the system, which better represents the experimental data. Furthermore, we propose a set of generic order parameters, derived from MD simulations of globular proteins, which can be used in the back-calculation of INPHARMA NOEs for any protein–ligand complex, thus by-passing the need of obtaining system-specific order parameters for new protein–ligand complexes.

Structure Prediction and Validation of the ERK8 Kinase Domain

Strambi, Angela; Mori, Mattia; Rossi, Matteo; Colecchia, David; Manetti, Fabrizio; Carlomagno, Francesca; Botta, Maurizio; Chiariello, Mario
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 11/01/2013 EN
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Extracellular signal-regulated kinase 8 (ERK8) has been already implicated in cell transformation and in the protection of genomic integrity and, therefore, proposed as a novel potential therapeutic target for cancer. In the absence of a crystal structure, we developed a three-dimensional model for its kinase domain. To validate our model we applied a structure-based virtual screening protocol consisting of pharmacophore screening and molecular docking. Experimental characterization of the hit compounds confirmed that a high percentage of the identified scaffolds was able to inhibit ERK8. We also confirmed an ATP competitive mechanism of action for the two best-performing molecules. Ultimately, we identified an ERK8 drug-resistant “gatekeeper” mutant that corroborated the predicted molecular binding mode, confirming the reliability of the generated structure. We expect that our model will be a valuable tool for the development of specific ERK8 kinase inhibitors.

Towards Improved Quality of GPCR Models by Usage of Multiple Templates and Profile-Profile Comparison

Latek, Dorota; Pasznik, Pawel; Carlomagno, Teresa; Filipek, Slawomir
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 28/02/2013 EN
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G-protein coupled receptors (GPCRs) are targets of nearly one third of the drugs at the current pharmaceutical market. Despite their importance in many cellular processes the crystal structures are available for less than 20 unique GPCRs of the Rhodopsin-like class. Fortunately, even though involved in different signaling cascades, this large group of membrane proteins has preserved a uniform structure comprising seven transmembrane helices that allows quite reliable comparative modeling. Nevertheless, low sequence similarity between the GPCR family members is still a serious obstacle not only in template selection but also in providing theoretical models of acceptable quality. An additional level of difficulty is the prediction of kinks and bulges in transmembrane helices. Usage of multiple templates and generation of alignments based on sequence profiles may increase the rate of success in difficult cases of comparative modeling in which the sequence similarity between GPCRs is exceptionally low. Here, we present GPCRM, a novel method for fast and accurate generation of GPCR models using averaging of multiple template structures and profile-profile comparison. In particular, GPCRM is the first GPCR structure predictor incorporating two distinct loop modeling techniques: Modeller and Rosetta together with the filtering of models based on the Z-coordinate. We tested our approach on all unique GPCR structures determined to date and report its performance in comparison with other computational methods targeting the Rhodopsin-like class. We also provide a database of precomputed GPCR models of the human receptors from that class.

Molecular Mechanism of 17-Allylamino-17-demethoxygeldanamycin (17-AAG)-induced AXL Receptor Tyrosine Kinase Degradation*

Krishnamoorthy, Gnana Prakasam; Guida, Teresa; Alfano, Luigi; Avilla, Elvira; Santoro, Massimo; Carlomagno, Francesca; Melillo, Rosa Marina
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
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Background: AXL is an established therapeutic target in various cancers. HSP90 chaperoning is critical in maintaining the stability of several oncogenic kinases.

Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy

Clippinger, Amy K.; D’Alton, Simon; Lin, Wen-Lang; Gendron, Tania F.; Howard, John; Borchelt, David R.; Cannon, Ashley; Carlomagno, Yari; Chakrabarty, Paramita; Cook, Casey; Golde, Todd E.; Levites, Yona; Ranum, Laura; Schultheis, Patrick J.; Xu, Guilia
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
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Frontotemporal lobar degeneration (FTLD) has been subdivided based on the main pathology found in the brains of affected individuals. When the primary pathology is aggregated, hyperphosphorylated tau, the pathological diagnosis is FTLD-tau. When the primary pathology is cytoplasmic and/or nuclear aggregates of phosphorylated TAR-DNA-binding protein (TDP-43), the pathological diagnosis is FTLD-TDP. Notably, TDP-43 pathology can also occur in conjunction with a number of neurodegenerative disorders; however, unknown environmental and genetic factors may regulate this TDP-43 pathology. Using transgenic mouse models of several diseases of the central nervous system, we explored whether a primary proteinopathy might secondarily drive TDP-43 proteinopathy. We found abnormal, cytoplasmic accumulation of phosphorylated TDP-43 specifically in two tau transgenic models, but TDP-43 pathology was absent in mouse models of Aβ deposition, α-synucleinopathy or Huntington’s disease. Though tau pathology showed considerable overlap with cytoplasmic, phosphorylated TDP-43, tau pathology generally preceded TDP-43 pathology. Biochemical analysis confirmed the presence of TDP-43 abnormalities in the tau mice, which showed increased levels of high molecular weight...

Oncogenic rearrangements driving ionizing radiation–associated human cancer

Santoro, Massimo; Carlomagno, Francesca
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
EN
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The Chernobyl nuclear disaster has caused a remarkable increase in radiation-induced papillary thyroid carcinoma in children and young adults. In this issue of the JCI, Ricarte-Filho and colleagues demonstrate that chromosomal rearrangements are the oncogenic “drivers” in most post-Chernobyl carcinomas and that they often lead to unscheduled activation of the MAPK signaling pathway. These findings represent a major step forward in our understanding of radiation-induced carcinogenesis and suggest various hypotheses about the mechanisms underlying the formation and selection of gene rearrangements during cancer cell evolution.

Thyroid Cancer: Role of RET and Beyond

Carlomagno, Francesca
Fonte: S. Karger AG Publicador: S. Karger AG
Tipo: Artigo de Revista Científica
EN
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Specific thyroid cancer histotypes, such as papillary and medullary thyroid carcinoma, display genetic rearrangements or point mutations of the RET gene, resulting in its oncogenic conversion. The molecular mechanisms mediating RET rearrangement with other genes and the role of partner genes in tumorigenesis have been described. In addition, the RET protein has become a molecular target for medullary thyroid carcinoma treatment.

Analysis of factors influencing the results of colorectal cancer surgery in the elderly

Saracco, M; Esposito, A; Palmieri, DG; Carlomagno, N; Renda, A
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 16/09/2013 EN
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Diagnostic utility of BRAFV600E mutation testing in thyroid nodules in elderly patients

Guerra, Anna; Di Crescenzo, Vincenzo; Garzi, Alfredo; Cinelli, Mariapia; Carlomagno, Chiara; Pepe, Stefano; Zeppa, Pio; Tonacchera, Massimo; Vitale, Mario
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 08/10/2013 EN
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Cytological diagnosis of adult-type fibrosarcoma of the neck in an elderly patient. Report of one case and review of the literature

Cozzolino, Immacolata; Caleo, Alessia; Di Crescenzo, Vincenzo; Cinelli, Mariapia; Carlomagno, Chiara; Garzi, Alfredo; Vitale, Mario
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 08/10/2013 EN
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