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Abstract Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.

In a good example of translational research, investigators who had initially demonstrated a role for insulin-like growth factor I in the pathogenesis of thyroid eye disease showed that an antibody to the receptor (teprotumumab) produced a meaningful improvement in 83% of patients.

En los últimos años el problema de investigación en el campo de la suplementación deportiva ha cambiado al punto de explicar los mecanismos metabólicos por los cuales la administración de creatina (Cr) incrementa el rendimiento en ciertos deportes o simplemente beneficia la adaptación muscular. Esta revisión analiza por primera vez los mecanismos bioquímicos de la ingesta de Cr desde la perspectiva de señalización celular, enfocándose en la mayor biodisponibilidad energética de Cr y optimización de la acción buffer espacial/ temporal que ofrece el sistema Cr/PCr/CK. Además, se examinan aspectos relacionados con el incremento en los procesos de proliferación y diferenciación de células musculares (IGF-I/PI3K/Akt-PKB, SPHK1/ MAPK/p38/MRFs, mTOR, hinchamiento celular, actividad mitótica de células satélite, polimerización de actina y fusión de mioblastos) y la inactivación y/o reducción en la expresión de proteínas con funciones ergolíticas (GSK3β, miostatina y regulación de AMPK). De esta manera, se explican el aumento de la masa muscular, la fuerza, la resistencia a la fatiga y el rendimiento en ejercicios de alta intensidad, producidos por la suplementación con monohidrato de Cr, desde un punto de vista metabólico.

Background and aims: Insulin-like growth factor (IGF) I receptor (IGF-Ir) signalling is required for carcinogenicity and proliferation of many tumours but this pathway has not been studied in detail in gastric cancer. We have previously shown successful therapy for colorectal, pancreatic, and lung cancer using recombinant adenoviruses expressing dominant negative (dn) IGF-Ir. In this study, we sought to better dissect the role of IGF-Ir on progression of gastric cancer and determine whether IGF-Ir targeted adenoviruses represent potentially effective therapeutics for human gastric cancer. Methods: We assessed the effect of IGF-Ir ligands on proliferation and survival in gastric cancer cells in culture. Then, recombinant adenoviruses expressing truncated IGF-Ir (482 and 950 amino acids long, IGF-Ir/dn) that function as dn inhibitors were studied in the treatment of human gastric cancer xenografts. We characterised the effects of IGF-Ir/dn on signalling blockade, growth, apoptosis induction, and in vivo therapeutic efficacy. Results: IGF-Ir signalling promoted tumour growth and survival in gastric cancer. IGF-Ir/dn expression suppressed tumorigenicity both in vitro and in vivo and upregulated stressor induced apoptosis. IGF-Ir/dn blocked Akt-1 activation induced by IGF-I, IGF-II, and des(1-3)IGF-I, but not by insulin. IGF-Ir/dn expression increased radiation and chemotherapy induced apoptosis and the combination of IGF-Ir/dn and chemotherapy was very effective against tumours in mice. In an intraperitoneal model, IGF-Ir/dn therapy also suppressed peritoneal dissemination. Conclusions: IGF-Ir is involved in the regulation of survival and cell growth in human gastric cancer and may be a good molecular therapeutic target. Adenovirus-IGF-Ir/dn may thus have therapeutic use in gastric cancer.

The insulin-like growth factor signalling system comprises insulin-like growth factors, insulin-like growth factor receptors and insulin-like growth factor-binding proteins. Along with the growth hormones, insulin-like growth factor signalling is very pivotal in the growth and development of all vertebrates. In fishes, insulin-like growth factors play an important role in osmoregulation, besides the neuroendocrine regulation of growth. Insulin-like growth factor concentration in plasma can assess the growth in fishes and shellfishes and therefore widely applied in nutritional research as an indicator to evaluate the performance of selected nutrients. The present review summarizes the role of insulin-like growth factor signalling in fishes and shellfishes, its significance in aquaculture and in evaluating growth, reproduction and development, and discusses the utility of this system as biomarkers for early indication of growth in aquaculture.

Summary Downregulation of insulin-like growth factor (IGF) pathways prolongs lifespan in various species, including mammals. Still, the cellular mechanisms by which IGF signaling controls the aging trajectory of individual organs are largely unknown. Here, we asked whether suppression of IGF-I receptor (IGF-1R) in adult stem cells preserves long-term cell replacement, and whether this may prevent age-related functional decline in a regenerating tissue. Using neurogenesis as a paradigm, we showed that conditional knockout of IGF-1R specifically in adult neural stem cells (NSC) maintained youthful characteristics of olfactory bulb neurogenesis within an aging brain. We found that blocking IGF-I signaling in neural precursors increased cumulative neuroblast production and enhanced neuronal integration into the olfactory bulb. This in turn resulted in neuro-anatomical changes that improved olfactory function. Interestingly, mutants also displayed long-term alterations in energy metabolism, possibly related to IGF-1R deletion in NSCs throughout lifespan. We explored Akt and ERK signaling cascades and revealed differential regulation downstream of IGF-1R, with Akt phosphorylation preferentially decreased in IGF-1R-/- NSCs within the niche, and ERK pathway downregulated in differentiated neurons of the OB. These challenging experimental results were sustained by data from mathematical modeling, predicting that diminished stimulation of growth is indeed optimal for tissue aging. Thus, inhibiting growth and longevity gene IGF-1R in adult NSCs induced a gain-of-function phenotype during aging, marked by optimized management of cell renewal, and enhanced olfactory sensory function.

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer ( EGFR mut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFR mut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFR mut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFR mut-LC. Cancer cells develop resistance to tyrosine kinase inhibitors targeting EGFR. Here, the authors explore the mechanism of resistance to one such inhibitor - osimertinib - and find that resistance is caused by increased expression and activation of the IGF1 receptor and subsequent activation of the donwstream signalling pathway.

BACKGROUNDThe loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC.METHODSA human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion.RESULTSXenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs).CONCLUSIONThe elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.TRIAL REGISTRATIONClinicalTrials.gov (NCT03906253).FUNDINGNational Institutes of Health, Veterans Administration.

In patients with thyroid-associated ophthalmopathy, responses to treatment are rare and usually minor. Teprotumumab, an antibody to the insulin-like growth factor I receptor, led to significant responses in 69% of patients and to decreased proptosis. Medical therapies for moderate-to-severe thyroid-associated ophthalmopathy (Graves’ orbitopathy) that have proved to be effective and safe in adequately powered, prospective, placebo-controlled trials are lacking. This unmet need is due to the incompletely understood pathogenesis of the disease. 1 Current treatments are inconsistently beneficial and often associated with side effects, and their modification of the ultimate disease outcome is uncertain. 1 – 3 Previous clinical trials, which were rarely placebo-controlled, suggest that high-dose glucocorticoids, alone 3 – 5 or with radiotherapy, 6 , 7 can reduce inflammation-related signs and symptoms in patients with active ophthalmopathy. However, glucocorticoids and orbital radiotherapy minimally affect proptosis and can cause dose-limiting adverse . . .