The degeneration of photoreceptors in the retina is one of the major causes of adult blindness in humans. Unfortunately, no effective clinical treatments exist for the majority of retinal degenerative disorders. Here we report on the fabrication and functional validation of a fully organic prosthesis for long-term in vivo subretinal implantation in the eye of Royal College of Surgeons rats, a widely recognized model of Retinitis pigmentosa. Electrophysiological and behavioral analyses reveal a prosthesis-dependent recovery of light-sensitivity and visual acuity that persists up to 6-10 months after surgery. The rescue of the visual function is accompanied by an increase in the basal metabolic activity of the primary visual cortex, as demonstrated by positron emission tomography imaging. Our results highlight the possibility of developing a new generation of fully organic, highly biocompatible and functionally autonomous photovoltaic prostheses for subretinal implants to treat degenerative blindness.
The aim of this study was to evaluate how the diagnostic accuracy of a stress echocardiographic procedure, such as a dipyridamole echocardiography test, depends on the specific experience of the physician interpreting the test. Recordings of 50 consecutive dipyridamole echocardiographic tests were selected for the first part of the study. They were analyzed by 20 experienced echocardiographers with different backgrounds in stress echocardiography: 10 beginners (less than 20 stress studies interpreted with trained staff) and 10 experienced observers (greater than or equal to 100 stress studies performed). Diagnostic accuracy (true positive + true negative/total number of tests) versus the angiographic reference standard (greater than 70% coronary stenosis of at least one major coronary artery) was 62 +/- 6% for beginners and 85 +/- 3% for experienced observers (p less than 0.0001). In the second part of the study, 10 observers (5 beginners and 5 experienced observers) evaluated 2 different sets of 50 dipyridamole echocardiographic test studies before and after the training of the beginners. Before training, the accuracy of beginners was lower than that of experienced observers (61 +/- 7% versus 85 +/- 3%; p less than 0.001). After training, the accuracy gap was closed (83 +/- 3% versus 86 +/- 2%; p = NS). Therefore, interpretation of stress echocardiographic tests by an echocardiographer without specific training severely underestimates the diagnostic potential of this technique. One hundred stress echocardiographic studies are more than adequate to build the individual learning curve and reach the plateau of diagnostic accuracy that the test can yield.
Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect.
Dendritic cells (DC) are highly specialized antigen-presenting cells characterized by the ability to prime T-cell responses. Mesenchymal stem cells (MSC) are adult stromal progenitor cells displaying immunomodulatory activities including inhibition of DC maturation in vitro. However, the specific impact of MSC on DC functions, upon in vivo administration, has never been elucidated. Here we show that murine MSC impair Toll-like receptor-4 induced activation of DC resulting in the inhibition of cytokines secretion, down-regulation of molecules involved in the migration to the lymph nodes, antigen presentation to CD4 + T cells, and cross-presentation to CD8 + T cells. These effects are associated with the inhibition of phosphorylation of intracellular mitogen-activated protein kinases. Intravenous administration of MSC decreased the number of CCR7 and CD49dβ1 expressing CFSE-labeled DC in the draining lymph nodes and hindered local antigen priming of DO11.10 ovalbumin-specific CD4 + T cells. Upon labeling of DC with technetium-99m hexamethylpropylene amine oxime to follow their in vivo biodistribution, we demonstrated that intravenous injection of MSC blocks, almost instantaneously, the migration of subcutaneously administered ovalbumin-pulsed DC to the draining lymph nodes. These findings indicate that MSC significantly affect DC ability to prime T cells in vivo because of their inability to home to the draining lymph nodes and further confirm MSC potentiality as therapy for immune-mediated diseases.immunomodulation | tolerance S tromal progenitors of mesodermal cells, referred to as mesenchymal stem cells (MSC) or multipotent mesenchymal stromal cells, are a heterogeneous population of self-renewing and multipotent cells isolated from the bone marrow (BM) (1). MSC raised hopes for their clinical exploitation for tissue-repair strategies and increasing experimental evidence supports their use also for immune-mediated diseases (2). In fact, MSC display a striking capacity of modulating the immune response (3). Despite a large body of experimental studies addressing the in vitro effects of MSC on immune cells, little is known about the mechanisms of MSCmediated inhibition of the in vivo immune response. Dendritic cells (DC) are unique antigen-presenting cells (APCs) endowed with the ability of acquiring and processing antigens, up-regulating costimulatory molecules and therefore priming naive T cells. To present antigens to naive T cells, CCR7-expressing DC must migrate through lymphatic vessels from sites of inflammation to the closest draining lymph node (4). Activation of DC via Toll-like receptors (TLRs) up-regulates the expression of chemokine receptors involved in DC migration to the lymph nodes and enhances their in vivo mobilization properties (5). As a consequence, the total number of DC migrating in the draining lymph nodes deeply affects naive T-cell priming (6). Here we show that murine MSC inhibit in vitro DC effector properties, including antigen processing and presentation to T cells through the inhib...
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