Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha

Activation of inflammatory pathways may contribute to the beginning and the progression of both atherosclerosis and type 2 diabetes. Here we report a novel interaction between insulin action and control of inflammation, resulting in glucose intolerance and vascular inflammation and amenable to therapeutic modulation. In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. Double heterozygous Insr+/-Timp3+/- mice develop mild hyperglycemia and hyperinsulinemia at 3 months and overt glucose intolerance and hyperinsulinemia at 6 months. A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation.     

Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection

In this study, we demonstrate that the in vitro interactions between a CD56(neg)/CD16(pos) (CD56(neg)) subset of natural killer (NK) cells and autologous dendritic cells (DCs) from HIV-1-infected viremic but not aviremic individuals are markedly impaired and likely interfere with the development of an effective immune response. Among the defective interactions are abnormalities in the process of reciprocal NK-DC activation and maturation as well as a defect in the NK cell-mediated editing or elimination of immature DCs (iDCs). Notably, the lysis of mature DCs (mDCs) by autologous NK cells was highly impaired even after the complete masking of major histocompatibility complex I molecules, suggesting that the defective elimination of autologous iDCs is at the level of activating NK cell receptors. In this regard, the markedly impaired expression/secretion and function of NKp30 and TNF-related apoptosis-inducing ligand, particularly among the CD56(neg) NK cell subset, largely accounts for the highly defective NK cell-mediated lysis of autologous iDCs. Moreover, mDCs generated from HIV-1 viremic but not aviremic patients are substantially impaired in their ability to secrete interleukin (IL)-10 and -12 and to prime the proliferation of neighboring autologous NK cells, which, in turn, fail to secrete adequate amounts of interferon-gamma.     

18F-Fluorodeoxyglucose positron emission tomography in evaluating treatment response to imatinib or other drugs in gastrointestinal stromal tumors: a systematic review

ObjectiveTo systematically review the role of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) in evaluating treatment response to imatinib or other drugs in gastrointestinal stromal tumors (GIST).MethodsA comprehensive literature search of published studies through February 2011 in PubMed/MEDLINE and EMBASE databases was performed.ResultsWe identified 19 studies including 628 patients with GIST. Main findings of included studies are presented.Conclusions¹⁸F-FDG PET has a significant value in assessing treatment response to imatinib or other drugs in GIST patients. ¹⁸F-FDG PET allows an early assessment of treatment response and is a strong predictor of clinical outcome.     

Cancer stem cells: the development of new cancer therapeutics

INTRODUCTION: Cancer stem cells (CSCs) are a subpopulation of tumor cells with indefinite proliferative potential that drive the growth of tumors. CSCs seem to provide a suitable explanation for several intriguing aspects of cancer pathophysiology. AREAS COVERED: An explosion of therapeutic options for cancer treatment that selectively target CSCs has been recorded in the recent years. These include the targeting of cell-surface proteins, various activated signalling pathways, different molecules of the stem cell niche and various drug resistance mechanisms. Importantly, approaching cancer research by investigating the pathogenesis of these intriguing cancer cells is increasing the knowledge of the pathophysiology of the disease, emphasizing certain molecular mechanisms that have been partially neglected. EXPERT OPINION: The characterization of the molecular phenotype of these cancer stem-like cells, associated with an accurate definition of their typical derangement in cell differentiation, can represent a fundamental advance in terms of diagnosis and therapy of cancer. Preliminary results seem to be promising but further studies are required to define the therapeutic index of this new anticancer treatment. Moreover, understanding the pathogenetic mechanisms of CSCs can expand the therapeutic applications of normal adult stem cells by reducing the risk of uncontrolled tumorigenic stem cell differentiation.     

A Comprehensive Map of CNS Transduction by Eight Recombinant Adeno-associated Virus Serotypes Upon Cerebrospinal Fluid Administration in Pigs

Cerebrospinal fluid administration of recombinant adeno-associated viral (rAAV) vectors has been demonstrated to be effective in delivering therapeutic genes to the central nervous system (CNS) in different disease animal models. However, a quantitative and qualitative analysis of transduction patterns of the most promising rAAV serotypes for brain targeting in large animal models is missing. Here, we characterize distribution, transduction efficiency, and cellular targeting of rAAV serotypes 1, 2, 5, 7, 9, rh.10, rh.39, and rh.43 delivered into the cisterna magna of wild-type pigs. rAAV9 showed the highest transduction efficiency and the widest distribution capability among the vectors tested. Moreover, rAAV9 robustly transduced both glia and neurons, including the motor neurons of the spinal cord. Relevant cell transduction specificity of the glia was observed after rAAV1 and rAAV7 delivery. rAAV7 also displayed a specific tropism to Purkinje cells. Evaluation of biochemical and hematological markers suggested that all rAAV serotypes tested were well tolerated. This study provides a comprehensive CNS transduction map in a useful preclinical large animal model enabling the selection of potentially clinically transferable rAAV serotypes based on disease specificity. Therefore, our data are instrumental for the clinical evaluation of these rAAV vectors in human neurodegenerative diseases.