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DNA. --- DNA --- Igf-1 --- Igfbp-1

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This Special Issue of Cells on “Insulin-Like Growth Factors in Development, Cancers and Aging” provides a collection of modern articles dealing with the role of insulin-like growth factors (IGF1) in cancer biology, aging and development. Featured articles explore basic and clinical aspects of the IGF1 system, including post-genomic analyses as well as novel approaches to target the IGF1 receptor (IGF1R) in oncology. The present Special Issue highlights some of the most important topics in the broad area of IGF research, including the role of IGF1 in aging and longevity, attempts to target the IGF1 axis in oncology, the role of IGF-binding proteins, structural aspects of IGF-II, etc. We trust that this assembly of articles will be of great help to students, basic researchers and practitioners.

IGF-I --- IGF-II --- insulin --- IGF-IR --- IRs --- tyrosine kinase receptor --- GPCRs --- hybrids --- phosphorylation --- G-proteins --- β-arrestins --- functional RTK/GPCR hybrid --- nuclear translocation --- IGF-I receptor --- signaling --- targeted therapeutics --- IGF-Trap --- IGF system --- IGFBP-3 --- IGFBP-3R --- TMEM219 --- anti-tumor --- anti-metastatic --- agonists --- mAb therapy --- IGF-1 --- IGFBP-1 --- older adults --- longevity --- health-span --- age-related disease --- cognitive impairment --- diabetes --- mitochondria --- growth hormone --- insulin-like growth factor-1 --- aging --- oxidative stress --- senescence --- longitudinal study --- IGFBP --- mouse models --- skeletal muscle --- MSCs --- myogenesis --- glucose regulated protein (GRP) 94 --- insulin-like growth factor --- obligate chaperone --- hypertrophy --- atrophy --- cachexia --- muscle regeneration --- autophagy --- IGF-1R --- insulin receptor --- IR-A --- structural studies --- receptor activation --- n/a

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This Special Issue of Cells on “Insulin-Like Growth Factors in Development, Cancers and Aging” provides a collection of modern articles dealing with the role of insulin-like growth factors (IGF1) in cancer biology, aging and development. Featured articles explore basic and clinical aspects of the IGF1 system, including post-genomic analyses as well as novel approaches to target the IGF1 receptor (IGF1R) in oncology. The present Special Issue highlights some of the most important topics in the broad area of IGF research, including the role of IGF1 in aging and longevity, attempts to target the IGF1 axis in oncology, the role of IGF-binding proteins, structural aspects of IGF-II, etc. We trust that this assembly of articles will be of great help to students, basic researchers and practitioners.

Research & information: general --- Biology, life sciences --- IGF-I --- IGF-II --- insulin --- IGF-IR --- IRs --- tyrosine kinase receptor --- GPCRs --- hybrids --- phosphorylation --- G-proteins --- β-arrestins --- functional RTK/GPCR hybrid --- nuclear translocation --- IGF-I receptor --- signaling --- targeted therapeutics --- IGF-Trap --- IGF system --- IGFBP-3 --- IGFBP-3R --- TMEM219 --- anti-tumor --- anti-metastatic --- agonists --- mAb therapy --- IGF-1 --- IGFBP-1 --- older adults --- longevity --- health-span --- age-related disease --- cognitive impairment --- diabetes --- mitochondria --- growth hormone --- insulin-like growth factor-1 --- aging --- oxidative stress --- senescence --- longitudinal study --- IGFBP --- mouse models --- skeletal muscle --- MSCs --- myogenesis --- glucose regulated protein (GRP) 94 --- insulin-like growth factor --- obligate chaperone --- hypertrophy --- atrophy --- cachexia --- muscle regeneration --- autophagy --- IGF-1R --- insulin receptor --- IR-A --- structural studies --- receptor activation

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Multicentric phase 2 study of figitumumab (CP-751,871) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.
Background : Insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the growth and apotosis of cancer cells, and is overexpressed in squamous cell carcinoma of the head and the neck. Inhibition of this pathway results in decreased cell growth, inhibition of tumor formation in animals models. Figitumumab blocks the binding of IGF-1 to its receptor and induces the down-regulation in vivo is proportional to figitumumab concentrations in the serum of tumor-bearing mice. In humans, figitumumab has a favourable safety profile and was well tolerated when given in continuous cycles. At the maximal feasible dose of 20 mg/kg, there was a moderate accumulation in plasma exposure, and most of the treated patients experienced stability of disease.
Methods : Patient with palliative squamous cell carcinoma of the head and neck progressing after platinium-based therapy where eligible for this study. They received figitumumab intravenous 20 mg/kg, every 3 weeks. Tumor evaluation was performed every 6-8 weeks. The primary endpoint was disease control rate after 6-8 weeks. A Simon two-stage design was used, wich means that at least 2 out of the first 17 patients should have achieved a stable disease to move on to the second stage.
Results: 17 male patients were studied. According to RECIST, 2 patients with stable disease have an increase in their tumor size after 6-8 weeks and were in progression after 3 months. After a central imaging review, it was decided to stop the trial due to low effectiveness. The most relevant toxicities were hyperglycemia, asthenia, anorexia and anemia. The biopsies of tumor show a low level of IGF-1R and a high level of AKT and EGFR at 6-8 weeks. This leads us to the hypothesis that an overactive vicarious pathway who might bypass the IGF pathway.
Conclusion : Figitumumab monotherapy has no clinically significant activity in squamous cell carcinoma of the head and neck patients. Further investigation with IGF-1R inhibitors should be pursued in combination with chemotherapy or targeted therapies to study potential synergies. According to our analysis, the combination with anti EGFR is the most interesting one Etude multicentrique de phase 2 : Evaluation de l’efficacité et de la toxicité du figitumumab (CP-751,871) après échec d’une chimiothérapie classique dans le cancer épidermoide de la tête et du cou en rechute et/ou métastatique.
Introduction : Le récepteur de l’IGF-1 (IGF-1R) joue un rôle important dans la régulation de la croissance et de l’apoptose des cellules tumorales. Il est surexprimé dans le cancer épidermoide de la tête et du cou. De ce fait ; l’inhibition de la voie de l’IGF favorise une diminution de ma multiplication cellulaire et de la croissance tumorale chez le modèle animal. Le figitumumab est une nouvelle molécule qui bloque la liaison de l’IGF sur son récepteur et induit une diminution de l’IGF-1R in vitro et dans les xénogreffes tumorales. Cette diminution est proportionnelle à la concentration de figitumumab présente dans le sérum des souris. Chez l’humain, le figitumumab a un profil de sécurité favorable et il est bien toléré lorsqu’il est administré en cycles continus. A la dose maximale (20mg/kg), la plupart des patients recevant la médication ont une maladie stable lors des études de phase 1.
Méthode : Les patients avec un cancer épidermoïde de la tête et du cou récurrent et/ou métastasique après une chimiothérapie à base de platine sont éligibles pour cette étude. Ces patients reçoivent du figitumumab en intraveinaux (dose : 20mg/kg) toutes les trois semaines. Une évaluation de la progression tumorale est réalisée toutes les 6-8 semaines. Le design en 2 étapes de Simon est utilisé pour cette étude. Ce design implique qu’à l’analyse intermédiaire, au minimum 2 patients sur 17 doivent présenter une maladie stable pour pouvoir continuer vers la 2e étape de l’étude.
Résultats : 17 patients de sexe masculin sont inclus dans cette étude. Selon les critères RECIST, 2 patients ont une maladie stable et 15 patients ont une maladie progressive lors de la première évaluation à 6-8 semaines confirmée par une maladie progressive à 3 mois. Après l’analyse intermédiaire, le coordinateur de l’étude a décidé de stopper l’étude pour cause de manque d’efficacité du figitumumab. Les toxicités principales de cette molécule sont : l’hyperglycémie, l’asthénie, l’anorexie et l’anémie. Les biopsies réalisées à partir des tumeurs montrent une diminution de l’IGF-1R et une augmentation de l’AKT et de l’EGFR à 6-8 semaines. Ces constatations nous confirment l’inhibition de la voie de l’IGF mais nous font penser qu’il existe un réseau vicariant suractivé qui compense cette inhibition et favorise la progression tumorale. Nous pensons à la voie de l’EGFR.
Conclusion : Le figitumumab en monothérapie n’a pas d’efficacité dans le carcinome épidermoïde de la tête et du cou. Les investigations futures devront porter sur la combinaison de cette molécule avec la chimiothérapie ou avec les thérapies ciblées en espérant prouver une éventuelle synergie des traitements. Selon nos résultats, une co-inhibition de l’IGF-1R et de l’EGFR serait très intéressante à tester

Antibodies, Monoclonal --- Drug Therapy --- Carcinoma, Squamous cell --- Neoplasm Metastasis --- Head and Neck Neoplasms --- figitumumab --- Receptor, IGF Type 1 --- Clinical Trials, Phase II as Topic

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During aging, reductions in hippocampal neurogenesis are associated with memory decline indicating a causal relationship. Indeed, insulin-like growth factor-1 (IGF-1), a major activator of the extracellular receptor kinase pathway that is central in learning and memory processes, is also a key modulator of hippocampal neurogenesis. Previously, we showed that age-related declines in spatial memory tasks can be improved by antioxidant-rich diets containing blueberries. In this study, to begin to understand the mechanisms responsible for the beneficial effects of blueberries, we assessed changes in hippocampal plasticity parameters such as hippocampal neurogenesis, extracellular receptor kinase activation, and IGF-1 and IGF-1R levels in blueberry-supplemented aged animals. Our results show that all these parameters of hippocampal neuronal plasticity are increased in supplemented animals and aspects such as proliferation, extracellular receptor kinase activation and IGF-1 and IGF-1R levels correlate with improvements in spatial memory. Therefore, cognitive improvements afforded by polyphenolic-rich fruits such as blueberries appear, in part, to be mediated by their effects on hippocampal plasticity

Activation. --- Adult dentate gyrus. --- Aged rats. --- Aging. --- Alzheimers-disease. --- Animal. --- Animals. --- Antioxidants. --- Behavior. --- Cognition. --- Diet. --- Dietary supplementation. --- Environmental enrichment. --- Erk. --- Growth-factor-i. --- Growth. --- Hippocampal neurogenesis. --- Hippocampal. --- Human. --- Igf-1. --- Learning and memory. --- Learning. --- Level. --- Mechanisms. --- Medial prefrontal cortex. --- Memory. --- Modulation. --- Neurogenesis. --- Neuronal signal-transduction. --- Neuronal. --- Parameters. --- Plasticity. --- Rat. --- Rats. --- Receptor. --- Reduction. --- Spatial memory. --- Spatial. --- Task. --- Tasks. --- Time. --- Vitamin-e. --- Water maze.