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Volume 18 Issue 6, June 2012

In this issue, Tenbaum et al. (p 892) uncover a malignant crosstalk between activated β-catenin and FOXO signaling that promotes metastasis of colon tumors, a potential negative outcome of targeted therapy. The cover shows a confocal microscopy image of a double immunofluorescence staining for β-catenin (red), FOXO3a (green) and Hoechst (blue) in a paraffin section of a human colon adenoma. Image courtesy of Irene Chicote and Héctor G. Palmer, Stem Cells and Cancer Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Editorial

  • Novartis's recent legal action against the UK National Health Service to prevent the off-label use of Avastin for macular degeneration challenges the current regulatory structures ensuring accountability for the safety and quality of drugs.

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News

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Correction

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News

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News in Brief

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Q&A

  • Since last November, six biopharma buyouts have exceeded $1 billion each, with Gilead Sciences' purchase last year of the hepatitis C specialist Pharmasset topping the charts at a whopping $11.2 billion, the highest ever paid for a clinical-stage biotech and an 89% premium to its share price at the time. Mark Ratner sought out biopharma analyst Joseph Schwartz, a managing director at Leerink Swann in Boston, for his views on what’s behind the recent buyout spending.

    • Mark Ratner
    Q&A
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News Feature

  • Humans and other animals suffer from many of the same ailments. Yet, aside from cases in which diseases cross the species barrier, veterinarians and physicians rarely work together to tackle common health problems. That may soon change. Katharine Gammon profiles one cardiologist who is pioneering a species-spanning approach to biomedical research.

    • Katharine Gammon
    News Feature
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Opinion

  • In the run-up to his reelection, Russian president Vladimir Putin outlined 28 tasks to be undertaken by his administration, including one that commanded the development of weapons based on “genetic principles.” Political pressure must be applied by governments and professional societies to ensure that there is not a modern reincarnation of the Soviet biological warfare program.

    • Raymond A. Zilinskas
    Opinion
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Book Review

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News & Views

  • A new study shows that melanoma-derived exosomes contribute to metastatic invasion by carrying messenger proteins that direct bone marrow–derived cells toward a prometastatic phenotype. This leads to the promotion of proangiogenic events and modification of the extracellular matrix at premetastatic sites (pages 883–891).

    • Rajasekharan Somasundaram
    • Meenhard Herlyn
    News & Views
  • Metastatic colorectal cancer is a largely incurable disease with a pressing need for targeted therapies. A new study sheds light on a surprising interaction between FOXO3a and β-catenin in metastatic colorectal cancer, suggesting new therapeutic avenues for agents targeting the PI3K-AKT pathway (pages 892–901).

    • Yibing Yan
    • Mark R Lackner
    News & Views
  • The link between tobacco use and aneurysms of the abdominal aorta is well established, but the specific mechanisms involved have remained elusive for decades. A new study indicates that nicotine is the major culprit in cigarette smoke and provides a common mechanism of aneurysm formation that may allow the development of drugs to treat this disease, for which currently only surgical treatments exist (pages 902–910).

    • Koichi Sugamura
    • John F Keaney Jr
    News & Views
  • How blood-borne inflammatory cells cause tissue damage in the brain after ischemic stroke remains elusive. Peroxiredoxins, cytosolic antioxidant proteins vital for redox balance, are released extracellularly from ischemic cells, acting as potent 'danger signals' that activate macrophages and lead to a harmful cytokine response, a new study shows. The findings unveil a new culprit in the delayed phase of ischemic injury and suggest new therapeutic approaches (pages 911–917).

    • Lidia Garcia-Bonilla
    • Costantino Iadecola
    News & Views
  • Bariatric surgery to treat obesity can also be effective against type 2 diabetes, but it is unclear how such surgical procedures improve glucose metabolism. A new study in rats suggests that nutrient sensing in the jejunum contributes to the antidiabetic effects of duodenal-jejeunal bypass (pages 950–955).

    • David A Sarruf
    • Susan Bonner-Weir
    • Michael W Schwartz
    News & Views
  • Kaposi's sarcoma–associated herpesvirus is a major oncogenic virus that has been implicated in human cancers. A new study identifies ephrin receptor A2 as a key host receptor for this virus that permits infection of endothelial cells (pages 961–966).

    • Chris Boshoff
    News & Views
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Between Bedside and Bench

  • The bone marrow niche keeps puzzling scientists in cancer and regenerative medicine. What elements constitute the niche and how it affects neighbor cells in different disease contexts remain to be a matter of debate and extensive investigation. The translational use of hematopoietic stem cells (HSCs) in transplantation biology poses a challenge, given the propensity of these cells to remain quiescent. Although the niche is a good candidate to exploit for reprogramming HSCs and controlling their expansion, new studies have added to its complexity. In 'Bench to Bedside', Paul S. Frenette and Yuya Kunisaki examine these studies to discuss how new players and their signals are involved in HSC maintenance and what the implications are for the development of HSC-based therapies. Among the alterations occurring in leukemias, metabolic events seem to foster cancer progression but may also be involved in cancer predisposition. Rushdia Z. Yusuf, Ying-Hua Wang and David T. Scadden peruse recent clinical and experimental studies that look at myelodysplastic syndromes and secondary leukemias and argue how metabolic changes in these cancers may not only be cell autonomous but also can emanate from the bone marrow stroma. Targeting this niche may open new avenues to reduce the risk for secondary leukemias in cancer survivors.

    • Yuya Kunisaki
    • Paul S Frenette
    Between Bedside and Bench
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Research Highlights

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Review Article

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Article

  • Exosomes can transfer proteins and nucleic acids from one cell to another, altering the phenotype of the recipient cell. In the case of cancer, tumor-derived exosomes have been shown to promote tumor cell proliferation. Now, in a mouse model of melanoma, Peinado et al. report that exosomes derived from highly metastatic tumor cells can influence bone marrow cells, resulting in increased recruitment of provasculogenic bone marrow progenitors to sites of metastasis, increased primary tumor growth and metastatic spread.

    • Héctor Peinado
    • Maša Alečković
    • David Lyden
    Article
  • The crosstalk between the transcriptional activity of β-catenin and FOXO3a reveals unexpected pro-metastatic cooperative effects of these pathways through concurrent modulation of cell adhesion and motility programs. In tumors with high FOXO3a and β-catenin activity, the proapoptotic effect of FOXO3a is subverted and the pro-proliferative effect of β-catenin is also dampened, but pro-metastatic pathways are activated. These findings suggest that caution should be exerted when using targeted inhibitors that activate FOXO3a in tumors with high β-catenin activity, as coactivation of both pathways also correlates with more aggressive disease in humans.

    • Stephan P Tenbaum
    • Paloma Ordóñez-Morán
    • Héctor G Palmer
    Article
  • Cigarette smoking raises the risk for cardiovascular disease, including the risk for abdominal aortic aneurysm. Shuangxi Wang et al. now show that nicotine itself is a causal factor in promoting abdominal aortic aneurysms in mice and delineate a pathogenic mechanism by which nicotine exposure leads to activation of the enzyme AMP-kinase in vascular smooth muscle cells and increased expression of the metallopeptidase MMP2.

    • Shuangxi Wang
    • Cheng Zhang
    • Ming-Hui Zou
    Article
  • Retinoids and their precursors are known to regulate adipose tissue maturation. Jorge Plutzky and his colleagues now show that an increased endogenous level of retinaldehyde in white adipose tissue, generated by genetic deletion of Raldh1, promotes its 'beiging' in a retinoic acid receptor–dependent manner. They also showed that genetic knockdown of Raldh1 and conversion of white to brown fat leads to weight loss and heightened glucose tolerance in obese mice in a therapeutic manner.

    • Florian W Kiefer
    • Cecile Vernochet
    • Jorge Plutzky
    Article
  • Glucose and its metabolic derivatives are increased the plasma of patients with diabetes. Peter Nawroth and colleagues demonstrate that one such metabolite, methylglyoxal, is increased in patients with painful diabetic neuropathy, and find that it acts by modifying the excitability characteristics of a sodium channel protein.

    • Angelika Bierhaus
    • Thomas Fleming
    • Peter P Nawroth
    Article
  • It is believed that lipid accumulation in the liver, or fatty liver disease, contributes to insulin resistance in this organ and, thus, poorly controlled gluconeogenesis and hyperglycemia during type 2 diabetes. Mitch Lazar and colleagues now show that deletion of the chromatin modifier Hdac3 in mice results in increased fatty liver disease but improved hepatic insulin sensitivity because metabolic flux in the liver is increased toward lipid synthesis and storage and away from gluconeogenesis.

    • Zheng Sun
    • Russell A Miller
    • Mitchell A Lazar
    Article
  • Hepatic glucose production is elevated in obesity and type 2 diabetes, contributing to the hyperglycemia that occurs in these conditions. In a new study, Liangyou Rui and colleagues show that NF-κB–inducing kinase (NIK) is abnormally activated in states of obesity, resulting in elevated hepatic glucose production. When they inhibit NIK activity in the liver, hyperglycemia is lowered, suggesting NIK as a potential therapeutic target in the management of type 2 diabetes.

    • Liang Sheng
    • Yingjiang Zhou
    • Liangyou Rui
    Article
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Letter

  • Tony Lam and his colleagues show that the middle intestine senses glucose and has a role in a gut-brain-liver axis to regulate hepatic glucose production. They also show that an experimental form of bariatric surgery quickly ameliorates hyperglycemia in two rat models of type 1 diabetes, and the intestinal sensing of glucose they have identified probably contributes to this metabolic effect.

    • Danna M Breen
    • Brittany A Rasmussen
    • Tony K T Lam
    Letter
  • Entamoeba histolytica causes human amebiasis. Although antibiotic therapy for this infection exists, there are limited treatment options for this potentially fatal invasive disease. Anjan Debnath and colleagues now report their identification of auranofin, an approved treatment for rheumatoid arthritis, as a candidate new drug for combating E. histolytica infection.

    • Anjan Debnath
    • Derek Parsonage
    • Sharon L Reed
    Letter
  • Kaposi's sarcoma–associated herpesvirus (KSHV) can infect endothelial cells, leading to the development of Kaposi's sarcoma in some individuals. The mechanisms underlying cell entry by KSHV are not fully elucidated. ahn et al. now report that ephrin receptor tyrosine kinase A2 (EphA2) acts as a cellular receptor for KSHV and show that blocking EphA2 inhibits infection of endothelial cells.

    • Alexander S Hahn
    • Johanna K Kaufmann
    • Frank Neipel
    Letter
  • High concentrations of some types of plasma lipoproteins, such as low-density lipoprotein, promote atherosclerosis and a wide range of vascular-related diseases. These pathogenic lipoproteins have in common the protein component apolipoprotein B. Through study of the effects of modulating lipoprotein levels in experiments involving zebrafish, mice and cultured human endothelial cells, Inbal Avraham-Davidi et al. uncover a potentially deleterious role of apolipoprotein B–containing lipoproteins as direct inhibitors of the angiogenic behavior of vascular endothelial cells.

    • Inbal Avraham-Davidi
    • Yona Ely
    • Karina Yaniv
    Letter
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Technical Report

  • For years, manufacturers have used one of only two chemicals to inactivate viruses for vaccine production: formaldehyde or β-propiolactone, and formaldehyde can damage key antigenic epitopes, leading to reduced immunogenicity or exacerbated disease. Ian Amanna and his colleagues have now found a third, the oxidizing agent hydrogen peroxide (H2O2), which they show can be more effective than the conventional approaches. Utility of the H2O2-based approach is demonstrated in three model systems.

    • Ian J Amanna
    • Hans-Peter Raué
    • Mark K Slifka
    Technical Report
  • T cell receptor (TCR)-based immunotherapeutic approaches have so far had limited success because of a lack of specific immune recognition and activation by the TCR. Here Nathaniel Liddy and his colleagues describe the generation, optimization and characterization of a new set of reagents—immune-mobilizing monoclonal TCRs against cancer (or ImmTACs)—designed to overcome some of these limitations. The ImmTACs were used to redirect and activate T cells to lyse tumor cells both in vitro and in vivo, even those expressing very low epitope numbers on the cell surface.

    • Nathaniel Liddy
    • Giovanna Bossi
    • Bent K Jakobsen
    Technical Report
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