JCI online early table of contents: Dec. 1, 2011

One of the most common causes of disability in young adults is spinal cord injury. Currently, there is no proven reparative treatment. Hope that a stem cell population, specifically dental pulp stem cells, might be of benefit to individuals with severe spinal cord injury has now been provided by the work of Akihito Yamamoto and colleagues, at Nagoya University Graduate School of Medicine, Japan, in a rat model of this devastating condition.

In the study, when rats with severe spinal cord injury were transplanted with human dental pulp stem cells they showed marked recovery of hind limb function. Detailed analysis revealed that the human dental pulp stem cells mediated their effects in three ways: they inhibited the death of nerve cells and their support cells; they promoted the regeneration of severed nerves; and they replaced lost support cells by generating new ones. Yamamoto and colleagues therefore hope that this approach can be translated into an effective treatment for severe spinal cord injury.

TITLE: Human dental pulp–derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms

AUTHOR CONTACT:
Akihito Yamamoto
Nagoya University Graduate School of Medicine, Nagoya, Japan.
Phone: 81.52.744.1978; Fax: 81.52.744.1978; E-mail: akihito@med.nagoya-u.ac.jp.

View this article at: http://www.jci.org/articles/view/59251?key=2bfc7058185bc571e173

The World Health Organization estimates that one-third of the world's population is currently infected with the microbe that causes tuberculosis, Mycobacterium tuberculosis. The only vaccine, BCG, is largely ineffective; ways to enhance its effectiveness are desperately needed. A team of researchers — led by Peter Andersen, at Statens Serum Institut, Denmark, and JoAnne L. Flynn, at the University of Pittsburgh School of Medicine, Pittsburgh, — has now developed a vaccine that they termed H56 that boosts the effects of vaccination with BCG in cynomolgus monkeys, reducing clinical disease and improving survival.

Importantly, the combination of vaccination with H56 and BCG prevented reactivation of latent Mycobacterium tuberculosis infection in the cynomolgus monkeys. This is important because the majority of individuals infected with Mycobacterium tuberculosis do not show signs of disease because the microbe is hiding in their lungs (in what is called a latent state). However, in many of these people the microbe will "awaken" from this latent state at some point in their life to cause active disease. Andersen, Flynn, and colleagues suggest that this dual effect of H56 on vaccination with BCG — reducing clinical disease and preventing reactivation of latent infection — provide rationale for its clinical development.

TITLE: The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection

AUTHOR CONTACT:
Peter Andersen
Statens Serum Institut, Copenhagen, Denmark.
Phone: 45.32.68.34.62; Fax: 45.32.68.30.35; E-mail: PA@ssi.dk.

JoAnne L. Flynn
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Phone: 412.624.7743; Fax: 412.648.3394; E-mail: joanne@pitt.edu.

View this article at: http://www.jci.org/articles/view/46252?key=b537c011ac7e8cd198b0

Drugs that block L-type Ca2+ channels (LTCCs) are widely used to treat high blood pressure and angina, chest pain caused by restriction of the blood flow to the heart. However, these drugs can have adverse effects in patients with heart failure. It remains unclear how effects on cells comprising the blood vessels versus effects on heart muscle cells contribute to the beneficial and detrimental outcomes seen in different patient populations. A team of researchers led by Jeffery Molkentin, at the University of Cincinnati, Cincinnati, has now investigated this issue in mice. The team found that genetically modifying mice such that they expressed decreased levels of LTCCs only in heart muscle cells made the mice more susceptible to developing thickened heart muscle (cardiac hypertrophy) and heart failure in response to increased stress on the heart. Molkentin and colleagues therefore suggest that blocking LTCCs in heart muscle cells is likely responsible for the detrimental outcomes seen in patients with heart failure upon treatment with drugs that block LTCCs. Thus, they suggest that caution is needed when considering using LTCC blockers for the treatment of such patients.

TITLE: Decreased cardiac L-type Ca2+ channel activity induces hypertrophy and heart failure in mice

AUTHOR CONTACT:
Jeffery D. Molkentin
University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: 513.636.3557; Fax: 513.636.5958; E-mail: jeff.molkentin@cchmc.org.

View this article at: http://www.jci.org/articles/view/58227?key=2e053b4397a6ffb4dfef

Many cancers that affect blood cells, including many leukemias and lymphomas, are characterized by abnormal patterns of DNA methylation — modification of DNA with methyl groups regulates gene expression, in general, low levels of methylation are associated with active gene expression while high levels of methylation are associated with gene silencing. A team of researchers led by Rene Opavsky, at the University of Nebraska Medical Center, Omaha, has now generated data in mice that suggest that the protein Dnmt3b, which adds methyl groups to DNA, acts to suppress lymphoma development. Further analysis indicated that this cancer suppressing effect of Dnmt3b was mediated, in part, via its ability to decrease expression of the protein Ment. Moreover, knocking down Ment expression inhibited the growth of mouse and human lymphoma cell lines. These data likely have clinical significance since the MENT gene was found to be overexpressed in the majority of human lymphomas studied. Opavsky and colleagues therefore suggest that targeting Ment could provide a new antilymphoma approach.

TITLE: Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis

AUTHOR CONTACT:
Rene Opavsky
University of Nebraska Medical Center, Omaha, Nebraska, USA.
Phone: 402.559.5543; Fax: 402.559.4651; E-mail: ropavsky@unmc.edu.

View this article at: http://www.jci.org/articles/view/57292?key=dbf939c1467d037ee256

Rubinstein-Taybi syndrome (RTS) is a rare genetic disease characterized by impaired intellectual function, broad thumbs and toes, short stature, and unusual facial features. Most cases of RTS are caused by mutation of the CBP gene. However, the molecular mechanisms by which these mutations cause the diseases characteristics have not been defined. A team of researchers — led by Laurie Glimcher and Jae-Hyuck Shim, at Harvard School of Public Health, Boston — has now identified a signaling pathway involving CBP that is critical to bone development in mice. Genetic disruption of this pathway at any one of several points caused the mice to develop skeletal defects reminiscent of those seen in individuals with RTS. Of potential therapeutic interest, treating mutant mice destined to develop RTS-like skeletal defects when they were in utero with molecules known as BMPs, which stimulate bone growth, partially reversed their skeletal anomalies at birth. Glimcher, Shim, and colleagues therefore suggest that in utero supplementation with growth factors could provide a new way to treat genetic diseases characterized by skeletal defects.

TITLE: Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome–like skeletal defects induced by Pdk1 or Cbp mutations in mice

AUTHOR CONTACT:
Laurie H. Glimcher
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: 617.432.0622; Fax: 617.432.1223; E-mail: lglimche@hsph.harvard.edu.

Jae-Hyuck Shim
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: 617.432.0622; Fax: 617.432.1223; jshim@hsph.harvard.edu.

View this article at: http://www.jci.org/articles/view/59466?key=7b32ef4307e8dacfdf6d

Many millions of people suffer from asthma and/or another allergic disease. While these conditions can often be managed such that individuals live healthy and active lives, not all individuals respond equally effectively to current treatment options. New treatments are therefore still being developed. A team of researchers, led by Toshiaki Kawakami, at The La Jolla Institute for Allergy and Immunology, La Jolla, has now generated data in mice that suggest that the molecule HRF could provide a good therapeutic target for the treatment of allergic asthma and allergic skin conditions.

TITLE: Histamine-releasing factor has a proinflammatory role in mouse models of asthma and allergy

AUTHOR CONTACT:
Toshiaki Kawakami
The La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Phone: 858.752.6814; Fax: 858.752.6986; E-mail: toshi@liai.org.

View this article at: http://www.jci.org/articles/view/59072?key=c3a5760ec09b3f64a231

Genetic mutations that lead to constitutive activation of the signaling protein Ras as well as those that lead to loss of function of the p53 protein contribute to the development of many cancers. When present together these mutations predict that a limited response to conventional chemotherapeutic agents is likely. Eric Brown and colleagues, at the University of Pennsylvania, Philadelphia, have now shown that decreasing expression of the protein ATR to 10% of normal levels in adult mice inhibits the growth of fibrosarcomas lacking expression of p53 and expressing a constitutively active mutant form of Ras. Similar growth inhibition was observed following reduction of ATR expression in acute myeloid leukemia cells lacking p53 and expressing a constitutively active mutant form of Ras. These mouse data lead Brown and colleagues to suggest that targeting ATR could provide benefit to patients with tumors bearing specific genetic mutations.

TITLE: Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR

AUTHOR CONTACT:
Eric J. Brown
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.746.2805; Fax: 215.573.2486; E-mail: brownej@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/58928?key=5575d171069bbe8189c0

Each year, more than 15,000 children and 15,000 adults are diagnosed with type 1 diabetes in the US. It is caused by the body's immune system attacking and destroying the insulin-producing cells of the pancreas (beta cells). Immune cells known as CTLs are thought to play the predominant role in destroying beta cells. Matthias von Herrath and colleagues, at The La Jolla Institute for Allergy and Immunology, La Jolla, have now visualized the CTL-mediated killing of beta cells in diabetic mice. Their observations indicate that, unexpectedly, diabetogenic CTLs move in a stochastic manner and kill beta cells at a relatively slow rate. Thus, these data provide new insight into the mechanisms underlying type 1 diabetes.

TITLE: Intravital imaging of CTLs killing islet cells in diabetic mice

AUTHOR CONTACT:
Matthias von Herrath
The La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Phone: 858.752.6892; Fax: 858.752.6993; E-mail: matthias@liai.org.

View this article at: http://www.jci.org/articles/view/59285?key=139276cc1d360a5dd12d