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JCI online early table of contents: August 2, 2010

EDITOR'S PICK: Boosting the efficacy of anticancer vaccines

There are several challenges to be overcome if therapeutic anticancer vaccines, which are designed to boost the patient's anticancer immune response, are to be successfully developed. For example, the viruses used to deliver the tumor protein to the patient's immune system are themselves targeted by the patient's immune system, inducing neutralizing and suppressive responses. But now, a team of researchers, led by Michael Morse, at Duke University Medical Center, Durham, has developed a way to overcome these neutralizing and suppressive responses by using an alphavirus packaged in virus-like replicon particles. Repeated administration of such particles carrying the tumor protein CEA to patients with metastatic cancer expressing CEA induced clinically relevant immune responses targeted to CEA. As the presence of such immune responses was associated with longer overall patient survival, the authors hope their approach might be of therapeutic use in many cancer settings.

TITLE: An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer

Michael A. Morse
Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919.681.3480; Fax: 919.681.7970; E-mail:

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ONCOLOGY: Genetic mutations determine breast cancer subtype

Breast cancers can be divided into different subtypes based on several criteria, including the marker proteins they express. Different tumor subtypes are associated with different clinical outcomes; for example, breast cancers lacking expression of the proteins to which hormones bind (so called triple-negative tumors [TNTs]) are associated with poor clinical outcomes. A team of researchers, led by Eldad Zacksenhaus, at Toronto General Research InstituteUniversity Health Network, Toronto, has generated new insight in mice into the genetic mutations that lead to the formation of different breast cancer subtypes.

Specifically, the team found that loss of the Rb gene in mouse breast tissue progenitor cells led to luminal-B and TNT breast tumor subtypes but that the TNT tumors also had mutations in p53. They therefore conclude that Rb loss can cause breast cancer in mice and that the presence or absence of other mutations, such as mutations in p53, determine the subtype.

TITLE: Rb deletion in mouse mammary progenitors induces luminal-B or basal-like/EMT tumor subtypes depending on p53 status

Eldad Zacksenhaus
Toronto General Research Institute University Health Network, Toronto, Ontario, Canada.
Phone: 416.340.4800, extension 5106; Fax: 416.340.3453; E-mail:

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CARDIOVASCULAR DISEASE: Keeping blood pressure down with the TRPM4 protein

High blood pressure is a risk factor for many diseases of the blood vessels and heart (i.e, cardiovascular diseases), including stroke, heart attack, and heart failure. However, in most patients the cause of high blood pressure is unknown. A team of researchers, led by Marc Freichel, at Universitt des Saarlandes, Germany, has now identified a role for TRPM4 proteins in regulating blood pressure in mice.

The team found that mice lacking TRPM4 had an impaired ability to keep their blood pressure down and that this was because cells in the adrenal gland known as chromaffin cells secreted larger amounts of catecholamines, 'fight-or-flight' hormones such as adrenaline and noradrenaline. The authors therefore conclude that TRPM4 limits catecholamine release from chromaffin cells and that disruption of this control, as in mice lacking TRPM4, increases blood pressure.

TITLE: Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice

Marc Freichel
Universitt des Saarlandes, Homburg, Germany.
Phone: 49.6841.16.26438; Fax: 49.6841.16.26402; E-mail:

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INFECTIOUS DISEASE: New way to control TB?

Tuberculosis is caused by infection with the bacterium M. tuberculosis. The hallmark of infection is the presence of granulomas (small nodular aggregations of inflammatory cells) in the lungs. Some of these cells, known as macrophages, are infected with M. tuberculosis, which they are desperately trying to kill. One mechanism by which macrophages kill M. tuberculosis is to produce nitric oxide. However, for this to be effective it requires high levels of oxygen, and some granulomas are oxygen deficient (hypoxic).

A team of researchers, led by Stephen Reece and Stefan Kaufmann, at the Max Planck Institute for Infection Biology, Germany, has now identified a way in which M. tuberculosis is killed in hypoxic granulomas in mice. Specifically, they found that hypoxic granulomas contained large amounts of proteins known as serine proteases, which function to degrade other proteins, and that inhibiting these proteases increased bacterial growth. The authors suggest that boosting serine protease activity could represent an attractive approach to treat tuberculosis.

TITLE: Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Stephen T. Reece
Max Planck Institute for Infection Biology, Berlin, Germany.
Phone:; Fax:; E-mail:

Stefan H.E. Kaufmann
Max Planck Institute for Infection Biology, Berlin, Germany.
Phone:; Fax:; E-mail:

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VIROLOGY: The real deal: genetically intact human cytomegalovirus can now be studied

A large proportion of adults (approximately 40% worldwide) are infected with human cytomegalovirus (HCMV), a virus that persists lifelong in the body once it has entered it. It is hard to study HCMV because the viruses present in our bodies cannot replicate efficiently in vitro until they have undergone substantial mutation. However, a team of researchers, led by Richard Stanton, at Cardiff University, United Kingdom, has now generated a genetically intact source of HCMV in a BAC. The genes RL13 and UL131A must be repressed while the virus replicates in vitro, but the team engineered the BAC such that these genes can be easily switched on and off. This technological advance will enable researchers to study a clinically relevant HCMV.

TITLE: Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication

Richard J. Stanton
Cardiff University, Cardiff, United Kingdom.
Phone: 44.29.20687319; Fax: 44.29.20742161; E-mail:

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PHYSIOLOGY: Mesenchymal origin for best supporting cell

The supporting tissue of an organ is known as the stroma. It consists largely of cells known as fibroblasts, which have extremely diverse characteristics in different tissues and even within a tissue. Due in part to their extreme diversity, the origin of fibroblasts and the pathways by which they differentiate have been hard to define. However, Jeremy Mao and colleagues, at Columbia University Medical Center, New York, have now determined that the growth factor CTGF is sufficient to induce human bone marrow mesenchymal stem/stromal cells (MSCs) to differentiate into fibroblasts. Furthermore, delivery of CTGF promoted healing in a rat model of connective tissue injury. The authors hope that their demonstration that fibroblasts have a mesenchymal origin will enhance understanding of development, tissue regeneration, dermal healing, organ fibrosis, and cancer stroma.

TITLE: CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model

Jeremy J. Mao
Columbia University Medical Center, New York, New York, USA.
Phone: 212.305.4475; Fax: 212.342.0199; E-mail:

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ENDOCRINOLOGY: The protein MCT8 is the last link in the thyroid hormone chain

The last step of the process by which thyroid hormone is secreted from the thyroid gland into blood has not been characterized. But now, a team of researchers, led by Samuel Refetoff, at the University of Chicago, Chicago, has determined that the protein monocarboxylate transporter 8 (MCT8) is involved in this process. Although the data were generated in mice, the authors suggest that this explains, in part, why humans deficient in MCT8 have low levels of the thyroid hormone thyroxine (T4) in their blood.

TITLE: Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion

Samuel Refetoff
University of Chicago, Chicago, Illinois, USA.
Phone: 773.702.6939; Fax: 773.702.6940; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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