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"Waterman, Peter"
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Myocardial infarction accelerates atherosclerosis
During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke,
Apoe
−/−
mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.
Myocardial infarction accelerates atherosclerosis through activation of the sympathetic nervous system, and the consequent release of haematopoietic stem and progenitor cells.
Recurrent heart attack risk
Patients who have a myocardial infarction are at high risk of recurrent events. This study shows for the first time that myocardial infarction and stroke accelerate atherosclerosis. The authors were able to demonstrate that myocardial infarction leads to activation of the sympathetic nervous system, which, in turn, leads to the release of haematopoietic stem cells and progenitor cells. These cells seeded in the spleen and augmented the production of monocytes displaying an enhanced atherogenic phenotype. These findings were correlated with patient data showing that prior beta-blocker therapy was associated with a decrease in circulating monocytes after myocardial infarction. These findings suggest that interventions that interrupt the supply of monocytes could attenuate atherosclerosis and may improve long-term patient outcomes.
Journal Article
Long-term declines in nutritional quality of tropical leaves
Global change is affecting plant and animal populations and many of the changes are likely subtle and difficult to detect. Based on greenhouse experiments, changes in temperature and rainfall, along with elevated CO
2
, are expected to impact the nutritional quality of leaves. Here, we show a decline in the quality of tree leaves 15 and 30 years after two previous studies in an undisturbed area of tropical forest in Kibale National Park, Uganda. After 30 years in a sample of multiple individuals of ten tree species, the mature leaves of all but one species increased in fiber concentrations, with a mean increase of 10%; tagged individuals of one species increased 13% in fiber. After 15 years, in eight tree species the fiber of young leaves increased 15%, and protein decreased 6%. Like many folivores, Kibale colobus monkeys select leaves with a high protein-to-fiber ratio, so for these folivores declining leaf quality could have a major impact. Comparisons among African and Asian forests show a strong correlation between colobine biomass and the protein-to-fiber ratio of the mature leaves from common tree species. Although this model, predicts a 31% decline in monkey abundance for Kibale, we have not yet seen these declines.
Journal Article
Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII-expressing artificial antigen presenting cells for adoptive cell therapy for glioma
Glioblastoma multiforme (GBM) is the most aggressive and deadly form of adult brain cancer. Despite of many attempts to identify potential therapies for this disease, including promising cancer immunotherapy approaches, it remains incurable. To address the need of improved persistence, expansion, and optimal antitumor activity of T-cells in the glioma milieu, we have developed an EGFRvIII-specific third generation (G3-EGFRvIII) chimeric antigen receptor (CAR) that expresses both co-stimulatory factors CD28 and OX40 (MR1-CD8TM-CD28-OX40-CD3ζ). To enhance ex vivo target specific activation and optimize T-cell culturing conditions, we generated artificial antigen presenting cell lines (aAPC) expressing the extracellular and transmembrane domain of EGFRvIII (EGFRVIIIΔ654) with costimulatory molecules including CD32, CD80 and 4-1BBL (EGFRVIIIΔ654 aAPC and CD32-80-137L-EGFRVIIIΔ654 aAPC). We demonstrate that the highest cell growth was achieved when G3-EGFRvIII CAR T-cells were cocultured with both co-stimulatory aAPCs and with exposure to EGFRvIII (CD32-80-137L-EGFRVIIIΔ654 aAPCs) in culturing periods of three to six weeks. G3-EGFRvIII CAR T-cells showed an increased level of IFN-γ when cocultured with CD32-80-137L-EGFRVIIIΔ654 aAPCs. Evaluation of G3-EGFRvIII CAR T-cells in an orthotropic human glioma xenograft model demonstrated a prolonged survival of G3-EGFRvIII CAR treated mice compared to control mice. Importantly, we observed survival of G3-EGFRvIII CAR T-cells within the tumor as long as 90 days after implantation in low-dose and single administration, accompanied by a marked tumor stroma demolition. These findings suggest that G3-EGFRvIII CAR cocultured with CD32-80-137L-EGFRVIIIΔ654 aAPCs warrants itself as a potential anti-tumor therapy strategy for glioblastoma.
Journal Article
Hybrid PET-optical imaging using targeted probes
Fusion imaging of radionuclide-based molecular (PET) and structural data [x-ray computed tomography (CT)] has been firmly established. Here we show that optical measurements [fluorescence-mediated tomography (FMT)] show exquisite congruence to radionuclide measurements and that information can be seamlessly integrated and visualized. Using biocompatible nanoparticles as a generic platform (containing a ¹⁸F isotope and a far red fluorochrome), we show good correlations between FMT and PET in probe concentration (r² > 0.99) and spatial signal distribution (r² > 0.85). Using a mouse model of cancer and different imaging probes to measure tumoral proteases, macrophage content and integrin expression simultaneously, we demonstrate the distinct tumoral locations of probes in multiple channels in vivo. The findings also suggest that FMT can serve as a surrogate modality for the screening and development of radionuclide-based imaging agents.
Journal Article
In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation
Infection by coagulase-positive
Staphylococcus aureus
(
S. aureus
) is the most common cause of acute endocarditis, a destructive and progressive condition of heart valves. Here, Peter Panizzi and his colleagues have developed a targeted, noninvasive fluorescence or positron emission technology imaging strategy that uses an engineered analog of prothrombin that can detect
S. aureus in vivo
in the endocarditic vegetations that form as a result of bacterial colonization.
Coagulase-positive
Staphylococcus aureus
(
S. aureus
) is the major causal pathogen of acute endocarditis, a rapidly progressing, destructive infection of the heart valves. Bacterial colonization occurs at sites of endothelial damage, where, together with fibrin and platelets, the bacteria initiate the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin could be used to detect
S. aureus
in endocarditic vegetations via noninvasive fluorescence or positron emission tomography (PET) imaging. These prothrombin derivatives bound staphylocoagulase and intercalated into growing bacterial vegetations. We also present evidence for bacterial quorum sensing in the regulation of staphylocoagulase expression by
S. aureus.
Staphylocoagulase expression was limited to the growing edge of mature vegetations, where it was exposed to the host and co-localized with the imaging probe. When endocarditis was induced with an
S. aureus
strain with genetic deletion of coagulases, survival of mice improved, highlighting the role of staphylocoagulase as a virulence factor.
Journal Article
Enhanced Antitumor Efficacy of Vasculostatin (Vstat120) Expressing Oncolytic HSV-1
Oncolytic viral (OV) therapy is a promising therapeutic modality for brain tumors. Vasculostatin (Vstat120) is the cleaved and secreted extracellular fragment of brain-specific angiogenesis inhibitor 1 (BAI1), a brain-specific receptor. To date, the therapeutic efficacy of Vstat120 delivery into established tumors has not been investigated. Here we tested the therapeutic efficacy of combining Vstat120 gene delivery in conjunction with OV therapy. We constructed RAMBO (Rapid Antiangiogenesis Mediated By Oncolytic virus), which expresses Vstat120 under the control of the herpes simplex virus (HSV) IE4/5 promoter. Secreted Vstat120 was detected as soon as 4 hours postinfection in vitro and was retained for up to 13 days after OV therapy in subcutaneous tumors. RAMBO-produced Vstat120 efficiently inhibited endothelial cell migration and tube formation in vitro (P = 0.0005 and P = 0.0184, respectively) and inhibited angiogenesis (P = 0.007) in vivo. There was a significant suppression of intracranial and subcutaneous glioma growth in mice treated with RAMBO compared to the control virus, HSVQ (P = 0.0021 and P < 0.05, respectively). Statistically significant reduction in tumor vascular volume fraction (VVF) and microvessel density (MVD) was observed in tumors treated with RAMBO. This is the first study to report the antitumor effects of Vstat120 delivery into established tumors and supports the further development of RAMBO as a possible cancer therapy.
Journal Article
Globalization, social movements and the new internationalisms
One hundred and fifty years ago Marx and Engels produced the Communist Manifesto. This ended with the stirring words \"Workers of all lands unite! You have nothing to lose but your chains. You have a world to win!\" Although this slogan inspired generations of unionists and socialists, the internationalism turned into nationalism, the worlds won did not loosen the chains and even the worlds themselves were lost. This book examines the past internationalism of labour and socialists and the present one of the new radical-democratic social movements (such as womens movements and feminism). It argues for a new global solidarity that relates to a radicalized, globalized, informatized and complex capitalist modernity. This new internationalism addresses multiple global social problems and democratic movements. It both learns from the social theories of today and provides a necessary complement to them.
eBook
Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation
Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using near-infrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic.
Journal Article
Ligation of the Jugular Veins Does Not Result in Brain Inflammation or Demyelination in Mice
An alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and (99m)Tc-exametazime to assess for structural and hemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and hemodynamic disturbances in the brain on Tc99m-exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and hemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis.
Journal Article