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Michel Demeule Cyndia Charfi Jean-Christophe Currie Alain Larocque Alain Zgheib Sophie Kozelko Richard Béliveau Christian Marsolais Borhane Annabi 《Cancer science》2021,112(10):4317-4334
Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel. 相似文献
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Benoit Peyronnet Emmanuel Oger Zineddine Khene Gregory Verhoest Romain Mathieu Mathieu Roumiguié Jean-Baptiste Beauval Benjamin Pradere Alexandra Masson-Lecomte Christophe Vaessen Hervé Baumert Jean-Christophe Bernhard Nicolas Doumerc Stéphane Droupy Franck Bruyere Alexandre De La Taille Morgan Roupret Karim Bensalah 《World journal of urology》2015,33(11):1815-1820
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Katharina Held Tatjana Kichko Katrien De Clercq Hugo Klaassen Rieta Van Bree Jean-Christophe Vanherck Arnaud Marchand Peter W. Reeh Patrick Chaltin Thomas Voets Joris Vriens 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(11):E1363-E1372
Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin gene-related peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation.Transient receptor potential (TRP) channels represent a large and diverse family of nonselective cation channels that respond to a wide range of chemical and physical stimuli and biophysical properties (1). TRP cation channel subfamily M member 3 (TRPM3), a calcium-permeable nonselective cation channel (2), is a typical example of a polymodally gated TRP channel, in that it can be activated by ligands, such as pregnenolone sulfate (PS) and nifedipine, as well as by heat and membrane depolarization (3, 4). Interestingly, recent evidence indicates that combined stimulation with PS and clotrimazole (Clt) leads to the activation of two distinct permeation pathways in TRPM3: the central pore, which is Ca2+-permeable and carries an outwardly rectifying current, and an alternative ion permeation pathway that mediates an inwardly rectifying monovalent cation current (5).TRPM3 is highly expressed in somatosensory neurons, where it plays decisive roles in the nocifensive response to PS and heat, as well as in the development of heat hyperalgesia during inflammation (3, 6). In these neurons, TRPM3 is frequently coexpressed with TRPA1 and TRPV1, two TRP channels that have emerged as key regulators of neurogenic inflammation by triggering neuropeptide release from sensory nerve endings (7, 8). Whether activation of TRPM3 can also initiate the release of neuropeptides, such as substance P or calcitonin gene-related peptide (CGRP), which elicit vasodilation, vascular leakage, and other responses in peripheral cell types, is unclear, however. In addition, TRPM3 is expressed in pancreatic beta cells, where it is involved in controlling insulin release (4), as well as in various tissues, including brain, pituitary gland, eye, kidney, and adipose tissue (reviewed in ref. 9). The physiological roles of TRPM3 in these tissues remain only poorly understood, owing in part to the lack of potent and specific pharmacologic tools to modulate its action in vitro and in vivo.Here we describe the identification and characterization of a TRPM3 agonist, CIM0216, with a potency that greatly exceeds that of currently used agonists. This compound has the unique property to open both ion permeation pathways of TRPM3 without the requirement of other channel modulators. We further demonstrate that CIM0216 acts in a TRPM3-dependent manner to induce pain and evoke neuropeptide release from sensory nerve terminals in the skin, and also to release insulin from pancreatic islets. Collectively, these findings provide a novel powerful tool for use in further studies of the physiological functions of TRPM3, and identify TRPM3 as a novel player in neurogenic inflammation. 相似文献
6.
Khambay B Nebel JC Bowman J Walker F Hadley DM Ayoub A 《The International journal of adult orthodontics and orthognathic surgery》2002,17(4):331-341
The aim of this study was to register and assess the accuracy of the superimposition method of a 3-dimensional (3D) soft tissue stereophotogrammetric image (C3D image) and a 3D image of the underlying skeletal tissue acquired by 3D spiral computerized tomography (CT). The study was conducted on a model head, in which an intact human skull was embedded with an overlying latex mask that reproduced anatomic features of a human face. Ten artificial radiopaque landmarks were secured to the surface of the latex mask. A stereophotogrammetric image of the mask and a 3D spiral CT image of the model head were captured. The C3D image and the CT images were registered for superimposition by 3 different methods: Procrustes superimposition using artificial landmarks, Procrustes analysis using anatomic landmarks, and partial Procrustes analysis using anatomic landmarks and then registration completion by HICP (a modified Iterative Closest Point algorithm) using a specified region of both images. The results showed that Procrustes superimposition using the artificial landmarks produced an error of superimposition on the order of 10 mm. Procrustes analysis using anatomic landmarks produced an error in the order of 2 mm. Partial Procrustes analysis using anatomic landmarks followed by HICP produced a superimposition accuracy of between 1.25 and 1.5 mm. It was concluded that a stereophotogrammetric and a 3D spiral CT scan image can be superimposed with an accuracy of between 1.25 and 1.5 mm using partial Procrustes analysis based on anatomic landmarks and then registration completion by HICP. 相似文献
7.
Cinquini I Calisti L Fierabracci V Marrapese E Egéa JC Masiello P Giuca MR 《Clinical oral investigations》2002,6(1):21-23
To find evidence of salivary gland involvement in human type I diabetes, we explored the changes in aminotransferase and lactate dehydrogenase activities, as indices of cellular injury, in the whole saliva of diabetic children. Although no significant difference in these enzymatic activities was observed between control and diabetic children as a whole, a negative correlation was found between enzymatic activities and duration of the disease, the highest values being detected in the diabetic subgroup diagnosed for less than 4 years. This suggests that some cell damage could be present in salivary glands of recently diagnosed diabetic children, likely as a result of immune-mediated alterations. In conclusion, these results may support the hypothesis that, as in rodents, the salivary glands could be an additional target of the immunological attack mainly directed against pancreatic beta-cells and resulting in type 1 diabetes. 相似文献
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Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids 总被引:17,自引:0,他引:17 下载免费PDF全文
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Assessment of airway closure from deflation lung volume–pressure curve: sigmoidal equation revisited
Bayle F Guérin C Debord S Badet M Lemasson S Poupelin JC Richard JC 《Intensive care medicine》2006,32(6):894-898
OBJECTIVE: To assess a sigmoidal equation for describing airway closure. DESIGN: Experimental study. SETTING: University laboratory. PARTICIPANTS: Eight piglets mechanically ventilated on zero end-expiratory pressure (ZEEP). INTERVENTIONS: Control and lung saline lavage. MEASUREMENTS AND RESULTS: Lungs were inflated up to transpulmonary pressure of 30 cmH(2)O at constant flow (0.12l s(-1)) then deflated at the same flow rate up to the point at which oesophageal pressure was constant, which was assumed to represent complete airway closure. The deflation volume-transpulmonary pressure curve was fitted to: (1) a sigmoidal equation focusing on inflexion point and pressure at maximal compliance increase and (2) an exponential equation above an inflexion point determined by eyeballing. Data deviate from the exponential equation at the point of airway closure onset. The zero-volume intercept was determined. Complete airway closure was reached at -8.3+/-3.5cmH(2)O in control conditions and at -1.3+/-3.7 cmH(2)O after lavage (p < 0.05). Between control and lavage, onset of airway closure was 3.0+/-1.9 vs. 6.0+/-2.8 cmH(2)O (p <0.05), inflexion point 3.2+/-1.8 vs. 7.7+/-2.6 cmH(2)O (p <0.001), pressure at maximal compliance increase -1.9+/-0.7 vs. -0.03+/-2.1cmH(2)O (p <0.05) and zero-volume intercept -1.5+/-1.4 vs. 0.3+/-2.3cmH(2)O (p <0.05). CONCLUSIONS: During mechanical ventilation airways stay open and close around ZEEP in control but are closed above ZEEP after lavage. Inflexion point might reflect onset of airways closure in control. Pressure at maximal compliance increase was not a marker of complete airways closure. In control and lavage, pressure at maximal compliance increase and zero-volume intercept were reasonably equivalent. 相似文献