Glucose Depletion in the Airway Surface Liquid Is Essential for Sterility of the Airways

Diabetes mellitus predisposes the host to bacterial infections. Moreover, hyperglycemia has been shown to be an independent risk factor for respiratory infections. The luminal surface of airway epithelia is covered by a thin layer of airway surface liquid (ASL) and is normally sterile despite constant exposure to bacteria. The balance between bacterial growth and killing in the airway determines the outcome of exposure to inhaled or aspirated bacteria: infection or sterility. We hypothesized that restriction of carbon sources –including glucose– in the ASL is required for sterility of the lungs. We found that airway epithelia deplete glucose from the ASL via a novel mechanism involving polarized expression of GLUT-1 and GLUT-10, intracellular glucose phosphorylation, and low relative paracellular glucose permeability in well-differentiated cultures of human airway epithelia and in segments of airway epithelia excised from human tracheas. Moreover, we found that increased glucose concentration in the ASL augments growth of P. aeruginosa in vitro and in the lungs of hyperglycemic ob/ob and db/db mice in vivo. In contrast, hyperglycemia had no effect on intrapulmonary bacterial growth of a P. aeruginosa mutant that is unable to utilize glucose as a carbon source. Our data suggest that depletion of glucose in the airway epithelial surface is a novel mechanism for innate immunity. This mechanism is important for sterility of the airways and has implications in hyperglycemia and conditions that result in disruption of the epithelial barrier in the lung

Melanoma Spheroids Grown Under Neural Crest Cell Conditions Are Highly Plastic Migratory/Invasive Tumor Cells Endowed with Immunomodulator Function

International audienceBACKGROUND: The aggressiveness of melanoma tumors is likely to rely on their well-recognized heterogeneity and plasticity. Melanoma comprises multi-subpopulations of cancer cells some of which may possess stem cell-like properties. Although useful, the sphere-formation assay to identify stem cell-like or tumor initiating cell subpopulations in melanoma has been challenged, and it is unclear if this model can predict a functional phenotype associated with aggressive tumor cells. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the molecular and functional phenotypes of melanoma spheroids formed in neural crest cell medium. Whether from metastatic or advanced primary tumors, spheroid cells expressed melanoma-associated markers. They displayed higher capacity to differentiate along mesenchymal lineages and enhanced expression of SOX2, NANOG, KLF4, and/or OCT4 transcription factors, but not enhanced self-renewal or tumorigenicity when compared to their adherent counterparts. Gene expression profiling attributed a neural crest cell signature to these spheroids and indicated that a migratory/invasive and immune-function modulating program could be associated with these cells. In vitro assays confirmed that spheroids display enhanced migratory/invasive capacities. In immune activation assays, spheroid cells elicited a poorer allogenic response from immune cells and inhibited mitogen-dependent T cells activation and proliferation more efficiently than their adherent counterparts. Our findings reveal a novel immune-modulator function of melanoma spheroids and suggest specific roles for spheroids in invasion and in evasion of antitumor immunity. CONCLUSION/SIGNIFICANCE: The association of a more plastic, invasive and evasive, thus a more aggressive tumor phenotype with melanoma spheroids reveals a previously unrecognized aspect of tumor cells expanded as spheroid cultures. While of limited efficiency for melanoma initiating cell identification, our melanoma spheroid model predicted aggressive phenotype and suggested that aggressiveness and heterogeneity of melanoma tumors can be supported by subpopulations other than cancer stem cells. Therefore, it could be constructive to investigate melanoma aggressiveness, relevant to patients and clinical transferability

Troisième-irradiation corps comme un traitement palliatif efficace pour les métastases osseuses multiples douloureuses résistantes à la chimiothérapie ou traitement hormonal.

Fifty-three patients had 54 third-body areas irradiated for breast and prostate bone metastases using the third-body irradiation technique during a period of 6 years. These patients were previously treated with chemotherapy, hormonal therapy and limited field irradiation. Seventy percent responded completely and 24% partially. This modality is safe and effective for pain relief.Cinquante-trois patients avaient 54 zones irradiées organisme tiers des cancers du sein et de métastases osseuses de la prostate en utilisant la technique de troisième irradiation corporelle pendant une période de 6 ans. These patients were previously treated with chemotherapy, hormonal therapy and limited field irradiation. Ces patients ont été préalablement traités par chimiothérapie, hormonothérapie et l'irradiation de champ limitée. Seventy percent responded completely and 24% partially. Soixante-dix pour cent ont répondu complètement et 24% partiellement. This modality is safe and effective for pain relief. Cette modalité est sûr et efficace pour le soulagement de la douleur

Endovascular radiation therapy : a new standard

Le traitement des maladies cardiovasculalres, et plus spécifiquement la prise en charge des patients avec des sténoses vasculalres, qu'elles soient cardiaques ou périphériques, est en train d'être modifié de façon radicale. Avec l'Introduction des techniques d'angioplastie par vole transcutanée (PTCA) et la mise en place de « stents », on a certainement amélioré le devenir de ces malades. Toutefois, l'incidence de resténose après ces interventions endovasculaires reste élevée. Ce phénomène d'oblitération vasculaire après angloplastie ou stent s'explique en partie par des mécanismes de prolifération néointimale. On s'est donc logiquement tourné vers les radiations ionisantes comme alternative thérapeutique possible vu leur efficacité sur les processus de prolifération cellulaire, Autant pour les lésions de novo que les resténoses in-stent, on observe l'efficacité des radiations ionisantes. Les résultats des premiers essais randomisés ont été rendus publics et ceci va certainement changer les standards de prise en charge en cardiologie interventionnelle

Consortium for Osteogenesis Imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans

Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones andeasy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identifiedand assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proa1(I)and proa2(I) chains, respectively) that result in OI