Nature Medicine

The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination.

Publication Date: 2008 May 11 PMID: 18469826
Authors: Chiarle, R. - Martinengo, C. - Mastini, C. - Ambrogio, C. - D'Escamard, V. - Forni, G. - Inghirami, G.
Journal: Nat Med

An ideal vaccination strategy against tumors relies on specific antigens that are required for tumor maintenance. For lymphoma, vaccination with subject-specific immunoglobulin idiotypes has had the most promising results. Here we show that DNA vaccination with plasmids encoding portions of the cytoplasmic domain of anaplastic lymphoma kinase (ALK), which has been translocated in different fusion proteins necessary for the growth of anaplastic large cell lymphoma (ALCL), protects mice from local and systemic lymphoma growth. The protection is potent and long lasting and elicits ALK-specific interferon-gamma responses and CD8(+) T cell-mediated cytotoxicity. A combination of chemotherapy and vaccination significantly enhanced the survival of mice challenged with ALK(+) lymphomas. These findings indicate that ALK represents an ideal tumor antigen for vaccination-based therapies of ALCL and possibly other ALK(+) human tumors.

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Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema.

Publication Date: 2008 May 11 PMID: 18469825
Authors: Savaskan, N. E. - Heckel, A. - Hahnen, E. - Engelhorn, T. - Doerfler, A. - Ganslandt, O. - Nimsky, C. - Buchfelder, M. - Eyupoglu, I. Y.
Journal: Nat Med

Neurodegeneration and brain edema are hallmarks of human malignant brain tumors. Here we show that genetic or pharmacological inhibition of the glutamate transporter xCT (X(c)(-) system, encoded by SLC7a11) in vivo leads to abrogated neurodegeneration, attenuated perifocal edema and prolonged survival. These results show a crucial role for xCT in glioma-induced neurodegeneration and brain edema, corroborating the concept that edema formation may be in part a consequence of peritumoral cell death.

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Corrigendum: Protein kinase CK2 links extracellular growth factor signaling with the control of p27(Kip1) stability in the heart.

Publication Date: 2008 May PMID: 18463663
Authors: Hauck, L. - Harms, C. - An, J. - Rohne, J. - Gertz, K. - Dietz, R. - Endres, M. - von Harsdorf, R.
Journal: Nat Med

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Corrigendum: Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability.

Publication Date: 2008 May PMID: 18463662
Authors: Jones, C. A. - London, N. R. - Chen, H. - Park, K. W. - Sauvaget, D. - Stockton, R. A. - Wythe, J. D. - Suh, W. - Larrieu-Lahargue, F. - Mukouyama, Y. S. - Lindblom, P. - Seth, P. - Frias, A. - Nishiya, N. - Ginsberg, M. H. - Gerhardt, H. - Zhang, K. - Li, D. Y.
Journal: Nat Med

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Erratum: Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy.

Publication Date: 2008 May PMID: 18463661
Authors: Hsiung, P. L. - Hardy, J. - Friedland, S. - Soetikno, R. - Du, C. B. - Wu, A. P. - Sahbaie, P. - Crawford, J. M. - Lowe, A. W. - Contag, C. H. - Wang, T. D.
Journal: Nat Med

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A new penumbra: transitioning from injury into repair after stroke.

Publication Date: 2008 May PMID: 18463660
Authors: Lo, E. H.
Journal: Nat Med

The penumbra is an area of brain tissue that is damaged but not yet dead after focal ischemia. The existence of a penumbra implies that therapeutic salvage is theoretically possible after stroke. The first decade of penumbral science investigated the ischemic regulation of electrophysiology, cerebral blood flow and metabolism. The second decade advanced our understanding of molecular mechanisms that mediate penumbral cell death. And the third decade saw the rapid development of clinical neuroimaging tools that are now increasingly applied in stroke patients. But how can we look ahead as we move into the fourth decade of penumbra research? This author speculates that a paradigm shift is needed. Most molecular targets for therapy have biphasic roles in stroke pathophysiology. During the acute phase, these targets mediate injury. During the recovery phase, the same mediators contribute to neurovascular remodeling. It is this boundary zone that comprises the new penumbra, and future investigations should dissect where, when and how damaged brain makes the transition from injury into repair.

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Bench to bedside: BRCA: from therapeutic target to therapeutic shield.

Publication Date: 2008 May PMID: 18463659
Authors: Shah, N. P.
Journal: Nat Med

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Bedside to bench: interfering with leukemic stem cells.

Publication Date: 2008 May PMID: 18463658
Authors: Krause, D. S. - Van Etten, R. A.
Journal: Nat Med

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Research Highlights.

Publication Date: 2008 May PMID: 18463657
Authors:
Journal: Nat Med

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Community corner. Striking the balance in multiple sclerosis.

Publication Date: 2008 May PMID: 18463656
Authors: Martin, R. - O'Shea, J. - Birnbaum, L. S. - Luebke, R.
Journal: Nat Med

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A shot in the arm for mast cells.

Publication Date: 2008 May PMID: 18463655
Authors: Pulendran, B. - Ono, S. J.
Journal: Nat Med

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Dust mites' dirty dealings with dendritic cells.

Publication Date: 2008 May PMID: 18463654
Authors: Sheppard, D.
Journal: Nat Med

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Beta-adrenergic signaling in heart failure-adapt or die.

Publication Date: 2008 May PMID: 18463653
Authors: Eschenhagen, T.
Journal: Nat Med

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Assessing fetal nerve cell grafts in Parkinson's disease.

Publication Date: 2008 May PMID: 18463652
Authors: Braak, H. - Del Tredici, K.
Journal: Nat Med

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Progress in therapy: the delicate balance.

Publication Date: 2008 May PMID: 18463651
Authors: Roth, J.
Journal: Nat Med

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Hungry for sleep.

Publication Date: 2008 May PMID: 18463650
Authors: Willyard, C.
Journal: Nat Med

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News in brief: headlines from the past month.

Publication Date: 2008 May PMID: 18463649
Authors:
Journal: Nat Med

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Toaster oven helps researchers toy with microfluidics.

Publication Date: 2008 May PMID: 18463648
Authors: Dove, A.
Journal: Nat Med

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Straight talk with... Maria Freire. Interviewed by Alisa Opar.

Publication Date: 2008 May PMID: 18463647
Authors: Freire, M.
Journal: Nat Med

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Cancer clues fetched from canines.

Publication Date: 2008 May PMID: 18463646
Authors: Brower, V.
Journal: Nat Med

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Scaled-up self-experimentation proposed.

Publication Date: 2008 May PMID: 18463645
Authors: Spinney, L.
Journal: Nat Med

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Harsh spotlight falls on Vytorin.

Publication Date: 2008 May PMID: 18463644
Authors: Wadman, M.
Journal: Nat Med

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Etiology of eating disorders explored as patience for a cure thins.

Publication Date: 2008 May PMID: 18463643
Authors: Gura, T.
Journal: Nat Med

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Return to the basics might breathe life into HIV vaccine pipeline.

Publication Date: 2008 May PMID: 18463642
Authors: Khamsi, R.
Journal: Nat Med

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Haunted house.

Publication Date: 2008 May PMID: 18463641
Authors:
Journal: Nat Med

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Translational moves.

Publication Date: 2008 May PMID: 18463640
Authors:
Journal: Nat Med

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Getting embryonic stem cell therapy right.

Publication Date: 2008 May PMID: 18463639
Authors:
Journal: Nat Med

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Functional roles for C5a receptors in sepsis.

Publication Date: 2008 May PMID: 18454156
Authors: Rittirsch, D. - Flierl, M. A. - Nadeau, B. A. - Day, D. E. - Huber-Lang, M. - Mackay, C. R. - Zetoune, F. S. - Gerard, N. P. - Cianflone, K. - Kohl, J. - Gerard, C. - Sarma, J. V. - Ward, P. A.
Journal: Nat Med

The function of the C5a receptors, C5ar (encoded by C5ar) and C5l2 (encoded by Gpr77), especially of C5l2, which was originally termed a 'default receptor', remains a controversial topic. Here we investigated the role of each receptor in the setting of cecal ligation and puncture-induced sepsis by using antibody-induced blockade of C5a receptors and knockout mice. In 'mid-grade' sepsis (30-40% survival), blockade or absence of either C5ar or C5l2 greatly improved survival and attenuated the buildup of proinflammatory mediators in plasma. In vivo appearance or in vitro release of high mobility group box 1 protein (HMGB1) required C5l2 but not C5ar. In 'high-grade' sepsis (100% lethality), the only protective condition was the combined blockade of C5l2 and C5ar. These data suggest that C5ar and C5l2 contribute synergistically to the harmful consequences in sepsis and that C5l2 is required for the release of HMGB1. Thus, contrary to earlier speculation, C5l2 is a functional receptor rather than merely a default receptor.

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Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma.

Publication Date: 2008 May PMID: 18454155
Authors: Krishnamoorthy, N. - Oriss, T. B. - Paglia, M. - Fei, M. - Yarlagadda, M. - Vanhaesebroeck, B. - Ray, A. - Ray, P.
Journal: Nat Med

Dendritic cells (DCs) are integral to the differentiation of T helper cells into T helper type 1 T(H)1, T(H)2 and T(H)17 subsets. Interleukin-6 (IL-6) plays an important part in regulating these three arms of the immune response by limiting the T(H)1 response and promoting the T(H)2 and T(H)17 responses. In this study, we investigated pathways in DCs that promote IL-6 production. We show that the allergen house dust mite (HDM) or the mucosal adjuvant cholera toxin promotes cell surface expression of c-Kit and its ligand, stem cell factor (SCF), on DCs. This dual upregulation of c-Kit and SCF results in sustained signaling downstream of c-Kit, promoting IL-6 secretion. Intranasal administration of antigen into c-Kit-mutant mice or neutralization of IL-6 in cultures established from the lung-draining lymph nodes of immunized wild-type mice blunted the T(H)2 and T(H)17 responses. DCs lacking functional c-Kit or those unable to express membrane-bound SCF secreted lower amounts of IL-6 in response to HDM or cholera toxin. DCs expressing nonfunctional c-Kit were unable to induce a robust T(H)2 or T(H)17 response and elicited diminished allergic airway inflammation when adoptively transferred into mice. Expression of the Notch ligand Jagged-2, which has been associated with T(H)2 differentiation, was blunted in DCs from c-Kit-mutant mice. c-Kit upregulation was specifically induced by T(H)2- and T(H)17-skewing stimuli, as the T(H)1-inducing adjuvant, CpG oligodeoxynucleotide, did not promote either c-Kit or Jagged-2 expression. DCs generated from mice expressing a catalytically inactive form of the p110delta subunit of phosphatidylinositol-3 (PI3) kinase (p110(D910A)) secreted lower amounts of IL-6 upon stimulation with cholera toxin. Collectively, these results highlight the importance of the c-Kit-PI3 kinase-IL-6 signaling axis in DCs in regulating T cell responses.

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CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells.

Publication Date: 2008 May PMID: 18438416
Authors: Perruche, S. - Zhang, P. - Liu, Y. - Saas, P. - Bluestone, J. A. - Chen, W.
Journal: Nat Med

Intact CD3-specific antibody transiently depletes large numbers of T cells and subsequently induces long-term immune tolerance. The underlying mechanisms for the systemic tolerance, however, remain unclear. We show here that treatment of normal mice with intact antibody to CD3 increases systemic transforming growth factor-beta (TGF-beta) produced by phagocytes exposed to apoptotic T cells. Among the phagocytes, macrophages and immature dendritic cells (iDCs) secrete TGF-beta upon ingestion of apoptotic T cells, which induces CD4+Foxp3+ regulatory T cells in culture and contributes to immune tolerance mediated by CD3-specific antibody in vivo. In accordance with these results, depletion of macrophages and iDCs not only abrogates CD3-specific antibody-mediated prevention of myelin oligodendrocyte glycoprotein-induced acute experimental autoimmune encephalomyelitis (EAE), but also reverses the therapeutic effects of antibody to CD3 on established disease in a model of relapsing-remitting EAE. Thus, CD3-specific antibody-induced immune tolerance is associated with TGF-beta production in phagocytes involved in clearing apoptotic T cells, which suggests that apoptosis is linked to active suppression in immune tolerance.

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Stromal gene expression predicts clinical outcome in breast cancer.

Publication Date: 2008 May PMID: 18438415
Authors: Finak, G. - Bertos, N. - Pepin, F. - Sadekova, S. - Souleimanova, M. - Zhao, H. - Chen, H. - Omeroglu, G. - Meterissian, S. - Omeroglu, A. - Hallett, M. - Park, M.
Journal: Nat Med

Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.

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Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection.

Publication Date: 2008 May PMID: 18438414
Authors: Sun, K. - Metzger, D. W.
Journal: Nat Med

Secondary bacterial infection often occurs after pulmonary virus infection and is a common cause of severe disease in humans, yet the mechanisms responsible for this viral-bacterial synergy in the lung are only poorly understood. We now report that pulmonary interferon-gamma (IFN-gamma) produced during T cell responses to influenza infection in mice inhibits initial bacterial clearance from the lung by alveolar macrophages. This suppression of phagocytosis correlates with lung IFN-gamma abundance, but not viral burden, and leads to enhanced susceptibility to secondary pneumococcal infection, which can be prevented by IFN-gamma neutralization after influenza infection. Direct inoculation of IFN-gamma can mimic influenza infection and downregulate the expression of the class A scavenger receptor MARCO on alveolar macrophages. Thus, IFN-gamma, although probably facilitating induction of specific anti-influenza adaptive immunity, suppresses innate protection against extracellular bacterial pathogens in the lung.

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Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease.

Publication Date: 2008 May PMID: 18425131
Authors: Bustamante, J. M. - Bixby, L. M. - Tarleton, R. L.
Journal: Nat Med

In this study, we document the development of stable, antigen-independent CD8+ T cell memory after drug-induced cure of a chronic infection. By establishing a system for drug cure of chronic Trypanosoma cruzi infection, we present the first extensively documented case of total parasite clearance after drug treatment of this infection. Cure resulted in the emergence of a stable, parasite-specific CD8+ T cell population with the characteristics of central memory cells, based upon expression of CD62L, CCR7, CD127, CD122, Bcl-2 and a reduced immediate in vivo CTL function. CD8+ T cells from treated and cured mice also expanded more rapidly and provided greater protection following challenge than those from chronically infected mice. These results show that complete pathogen clearance results in stable, antigen-independent and protective T cell memory, despite the potentially exhausting effects of prior long-term exposure to antigen in this chronic infection.

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A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure.

Publication Date: 2008 May PMID: 18425130
Authors: Liggett, S. B. - Cresci, S. - Kelly, R. J. - Syed, F. M. - Matkovich, S. J. - Hahn, H. S. - Diwan, A. - Martini, J. S. - Sparks, L. - Parekh, R. R. - Spertus, J. A. - Koch, W. J. - Kardia, S. L. - Dorn, G. W. 2nd
Journal: Nat Med

Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.

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Mast cell activators: a new class of highly effective vaccine adjuvants.

Publication Date: 2008 May PMID: 18425129
Authors: McLachlan, J. B. - Shelburne, C. P. - Hart, J. P. - Pizzo, S. V. - Goyal, R. - Brooking-Dixon, R. - Staats, H. F. - Abraham, S. N.
Journal: Nat Med

Mast cells (MCs) have recently received recognition as prominent effectors in the regulation of immune cell migration to draining lymph nodes and lymphocyte activation. However, their role in the development of humoral immune responses is not clear. Here, we demonstrate that subcutaneous or nasal administration of small-molecule MC activators with vaccine antigens evokes large increases in antigen-specific serum immunoglobulin G (IgG) responses. These responses were MC dependent and correlated with increased dendritic cell and lymphocyte recruitment to draining lymph nodes. Nasal instillation of these formulations also evoked antigen-specific secretory IgA and provided protection against anthrax lethal toxin challenge in vitro and against vaccinia virus infection in vivo. Collectively, these results define the MC as an integral sensory arm of the adaptive immune system. Moreover, they highlight MC activators as a new class of vaccine adjuvants, capable of inducing protective antigen-specific immune responses through needle-free routes of administration.

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Replacing PCR with COLD-PCR enriches variant DNA sequences and redefines the sensitivity of genetic testing.

Publication Date: 2008 May PMID: 18408729
Authors: Li, J. - Wang, L. - Mamon, H. - Kulke, M. H. - Berbeco, R. - Makrigiorgos, G. M.
Journal: Nat Med

PCR is widely employed as the initial DNA amplification step for genetic testing. However, a key limitation of PCR-based methods is the inability to selectively amplify low levels of mutations in a wild-type background. As a result, downstream assays are limited in their ability to identify subtle genetic changes that can have a profound impact in clinical decision-making and outcome. Here we describe co-amplification at lower denaturation temperature PCR (COLD-PCR), a novel form of PCR that amplifies minority alleles selectively from mixtures of wild-type and mutation-containing sequences irrespective of the mutation type or position on the sequence. We replaced regular PCR with COLD-PCR before sequencing or genotyping assays to improve mutation detection sensitivity by up to 100-fold and identified new mutations in the genes encoding p53, KRAS and epidermal growth factor in heterogeneous cancer samples that had been missed by the currently used methods. For clinically relevant microdeletions, COLD-PCR enabled exclusive amplification and isolation of the mutants. COLD-PCR will transform the capabilities of PCR-based genetic testing, including applications in cancer, infectious diseases and prenatal identification of fetal alleles in maternal blood.

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Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation.

Publication Date: 2008 May PMID: 18391963
Authors: Li, J. Y. - Englund, E. - Holton, J. L. - Soulet, D. - Hagell, P. - Lees, A. J. - Lashley, T. - Quinn, N. P. - Rehncrona, S. - Bjorklund, A. - Widner, H. - Revesz, T. - Lindvall, O. - Brundin, P.
Journal: Nat Med

Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.

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Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease.

Publication Date: 2008 May PMID: 18391962
Authors: Kordower, J. H. - Chu, Y. - Hauser, R. A. - Freeman, T. B. - Olanow, C. W.
Journal: Nat Med

Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body-like inclusions that stained positively for alpha-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.

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Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years.

Publication Date: 2008 May PMID: 18391961
Authors: Mendez, I. - Vinuela, A. - Astradsson, A. - Mukhida, K. - Hallett, P. - Robertson, H. - Tierney, T. - Holness, R. - Dagher, A. - Trojanowski, J. Q. - Isacson, O.
Journal: Nat Med

Postmortem analysis of five subjects with Parkinson's disease 9-14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.

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Noninvasive in vivo imaging of pancreatic islet cell biology.

Publication Date: 2008 May PMID: 18327249
Authors: Speier, S. - Nyqvist, D. - Cabrera, O. - Yu, J. - Molano, R. D. - Pileggi, A. - Moede, T. - Kohler, M. - Wilbertz, J. - Leibiger, B. - Ricordi, C. - Leibiger, I. B. - Caicedo, A. - Berggren, P. O.
Journal: Nat Med

Advanced imaging techniques have become a valuable tool in the study of complex biological processes at the cellular level in biomedical research. Here, we introduce a new technical platform for noninvasive in vivo fluorescence imaging of pancreatic islets using the anterior chamber of the eye as a natural body window. Islets transplanted into the mouse eye engrafted on the iris, became vascularized, retained cellular composition, responded to stimulation and reverted diabetes. Laser-scanning microscopy allowed repetitive in vivo imaging of islet vascularization, beta cell function and death at cellular resolution. Our results thus establish the basis for noninvasive in vivo investigations of complex cellular processes, like beta cell stimulus-response coupling, which can be performed longitudinally under both physiological and pathological conditions.

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