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JCI online early table of contents: April 8, 2008


Too many gene copies stimulate tumor cell growth

New data, generated by Peter Lichter and colleagues, at the German Cancer Research Center, Heidelberg, have characterized a molecular pathway underlying low-grade forms of a type of brain tumor known as an astrocytoma. The authors therefore suggest that therapeutics targeting this pathway might provide a new approach to treating individuals with low-grade atrocytomas.

Analysis of the DNA of astrocytomas from a large number of children revealed that the most common genetic mutation was the duplication of a region of DNA containing the BRAF gene. Tumors with this genetic mutation showed signs of increased BRAF protein activity. Consistent with the idea that increased BRAF activity had a role in the development of the tumors, mutations in the BRAF gene that caused increased BRAF protein activity were detected in tumors that did not exhibit duplication of the region of DNA containing the BRAF gene. As pharmacologic and genetic silencing of the BRAF signaling pathway and the BRAF gene, respectively, prevented tumor cells from low-grade gliomas growing in culture, it was suggested that inhibiting the signaling pathway downstream of BRAF might be beneficial for individuals with low-grade atrocytomas.

TITLE: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas


Peter Lichter

German Cancer Research Center, Heidelberg, Germany.

Phone: 49-6221-424619; Fax: 49-6221-424639; E-mail:

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Small molecule miRNAs regulate female mouse fertility

Small molecules known as miRNAs, which are generated naturally by the body, regulate the conversion of genetic information into proteins. New data, generated by Jiahuai Han and colleagues, at The Scripps Research Institute, La Jolla, have now indicated that miRNAs can control the fertility of female mice.

The generation of miRNAs is a complex process that involves a protein known as Dicer. In the study, mice expressing substantially lower levels of Dicer than normal mice (Dicerd/d mice) were found to have only one defect the female mice were infertile. Infertility was a result of impaired functioning of the corpus luteum, the structure that forms at the site of release of the fertilized egg and that is required to maintain pregnancy at the early stages. Detailed analysis indicated that the functioning of the corpus luteum was impaired because it was unable to form new blood vessels, and that this was associated with increased expression of the protein TIMP1, which inhibits blood vessel formation. As injection of the miRNAs miR17-5p and let7b into the ovaries of Dicerd/d mice decreased expression of TIMP1 and increased the number of blood vessels in the corpus luteum, the authors concluded that the development and function of the corpus luteum in mice is tightly regulated by miRNAs.

TITLE: Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice


Jiahuai Han

The Scripps Research Institute, La Jolla, California, USA.

Phone: (858) 784-8704; Fax: (858) 784-8665; E-mail:

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Too much of a good thing: high levels of factor VIIa cause problems in mice

Individuals with hemophilia lack either factor VIII or factor IX, proteins crucial for the cascade of events that leads to blood clotting. Although individuals with hemophilia can be treated by intravenous infusion of the factor that they miss, over time, some individuals develop antibodies that prevent the infused factor from working. Intravenous infusion of an activated form of a factor that works earlier in the blood clotting cascade, factor VII (FVIIa), has been used for over a decade to treat individuals who develop antibodies that target factor VIII or factor IX. However, some researchers and clinicians hope that FVIIa gene therapy might provide a simplified way to provide FVIIa to individuals with hemophilia. In a new study, Katherine High and colleagues, at The Childrens Hospital of Philadelphia, have determined a safe and effective level of mouse FVIIa that can be continuously expressed in hemophilia B mice through gene therapy.

The authors observed that continuous expression for up to 16 months of up to 1.5 micrograms per milliliter of mouse FVIIa, either by engineering hemophilia B mice to express this factor throughout life or by treating hemophilia B mice with gene therapy, was safe and corrected the abnormal bleeding of the mice. By contrast, continuous expression of 2 micrograms per milliliter (or more) of mouse FVIIa was associated with early mortality and with heart and lung problems. These data should provide useful information for researchers and clinicians developing gene therapy approaches for the treatment of individuals with hemophilia.

TITLE: Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality


Katherine A. High

The Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Phone: (215) 590-4521; Fax: (215) 590-3660; E-mail:

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A pox on TLR9: the immune molecule TLR9 is crucial to prevent lethal poxvirus infection in mice

Smallpox is caused by infection with variola virus, a member of a family of viruses known as poxviruses. New data, generated by Hubertus Hochrein and colleagues, at Bavarian Nordic GmbH, Germany, have identified the protein TLR9 as central to immune defense against infection with some poxviruses in mice.

In the study, TLR9 was shown to be essential for mice to mount protective immune responses against infection with the poxvirus that causes mousepox ectromelia virus (ECTV). Indeed, TLR9-deficient mice succumbed to much lower doses of ECTV than did normal mice. By contrast, the strongly attenuated poxvirus modified vaccinia virus Ankara (MVA) induced both TLR9-dependent and TLR9-independent immune responses. It was then found that the ability of MVA to induce TLR9-independent immune responses could be harnessed to protect TLR9-deficient mice from infection with otherwise lethal doses of ECTV, even if the MVA was administered to the TLR9-deficient mice 2 days after they had been exposed to a lethal dose of ECTV. These data led the authors to suggest that administration of MVA might provide a useful immediate and therapeutic intervention against potentially fatal infection with a poxvirus in humans.

TITLE: Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection


Hubertus Hochrein

Bavarian Nordic GmbH, Martinsried, Germany.

Phone: 49-89-8565-1334; Fax: 49-89-8565-1356; E-mail:

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How immune cells get lost in chronic Hepatitis B infection

An immune response that successfully clears an infection with Hepatitis B virus (HBV) includes CD8+ T cells that specifically target cells infected with HBV. The number of these cells is markedly diminished in individuals that fail to clear HBV and become chronically (persistently) infected with the virus. New insight into the mechanisms underlying the decreased number of HBV-specific CD8+ T cells in individuals chronically infected with HBV has now been provided by Mala Maini and colleagues, at University College London, United Kingdom.

In the study, it was found that HBV-specific CD8+ T cells from individuals who had successfully cleared an HBV infection and from individuals chronically infected with HBV expressed different patterns of genes. Specifically, HBV-specific CD8+ T cells from individuals chronically infected with HBV expressed large numbers of genes containing the information for making proteins involved in a form of cell death known as apoptosis. Detailed analysis indicated that CD8+ T cells from individuals chronically infected with HBV expressed the proapoptotic protein Bim and that blocking Bim-mediated apoptosis increased the number of HBV-specific CD8+ T cells both in culture and directly ex vivo. The authors therefore suggest that Bim-mediated apoptosis of HBV-specific CD8+ T cells contributes to the inability of these cells to persist and clear virus in individuals chronically infected with HBV.

TITLE: Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection


Mala K. Maini

University College London, London, United Kingdom.

Phone: 44-0-20-7679-9212; Fax: 44-0-20-7679-9652; E-mail:

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Anticancer agents targeted specifically to tumors

Much effort is being invested in trying to target anticancer therapies more specifically to tumors to decrease harmful side effects. In a new study, Ruth Ganss and colleagues, at the Western Australian Institute for Medical Research, Perth, have used a tumor-homing peptide to engineer two immunotherapeutic anticancer agents, an anti-CD40 antibody and IL-2, such that they selectively targeted spontaneously arising tumors in a transgenic mouse model of cancer of the pancreatic islet cells.

When the engineered agents were injected intravenously, either together or separately, into tumor-bearing mice they were found to accumulate in blood vessels in the tumors. Together, these agents affected the endothelial cells lining the tumor blood vessels, reducing the number of blood vessels and thereby substantially delaying tumor growth. Treating tumor-bearing mice with a combination of the tumor-targeted agents and infusions of preactivated antitumor immune cells led to long-term disease-free survival. The authors believe that this combination was highly effective because the tumor-targeted anti-CD40 antibody modified the endothelial cells lining the tumor blood vessels such that the infused preactivated antitumor immune cells were able to accumulate in the tumor and that the tumor-targeted IL-2 helped the accumulated immune cells persist.

TITLE: Vascular targeting of anti-CD40 antibodies and IL-2 into autochthonous tumors enhances immunotherapy in mice


Ruth Ganss

Western Australian Institute for Medical Research, Perth, Western Australia, Australia.

Phone: 61-8-9224-0354; Fax: 61-8-9224-0322; E-mail:

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Understanding why an attack on two fronts has anticancer effects

One mechanism by which a combination therapy that was previously shown to be efficient at clearing tumors in a mouse model of cancer has now been elucidated by Peter Kim and colleagues, at Johns Hopkins University School of Medicine, Baltimore.

Neu-N mice develop spontaneous breast cancer and vaccination with a HER-2/neuexpressing, GM-CSFsecreting whole cell vaccine induces ineffective antitumor immune responses. However, if the vaccination is combined with treatment with a neu-specific antibody, the efficient antitumor response enables mice to remain tumor-free and even eradicates transplanted neu-expressing tumors. In this study, the combination therapy was shown to markedly improve the CD8+ T cell antitumor immune response by enhancing Fc-mediated activation of the immune cells that initiate the CD8+ T cell antitumor immune response. The authors therefore suggest that combination therapies that mount a multifaceted attack on the same tumor protein (in this case neu) might be useful for inducing effective antitumor immune responses targeted to other tumor proteins.

TITLE: Antibody association with HER-2/neu-targeted vaccine enhances CD8+ T cell responses in mice through Fc-mediated activation of DCs


Peter S. Kim

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Phone: (443) 690-4129; Fax: (410) 614-8216; E-mail:

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Understanding how nerves sense chemicals that irritate the lungs

A subset of nerves that terminate in the lining of the airways constantly monitor the air that we breathe for chemicals that might threaten airway function. These sensory nerves are particularly sensitive to the oxidants that form in polluted air and to chlorine, which is often released in industrial accidents, and their stimulation by exposure to such chemicals causes coughing, sneezing, stuffiness, and pain. Although this response is normally protective, it can be dangerous in patients with compromised lung function, such as those suffering from asthma.

In a new study, Sven-Eric Jordt and colleagues from the Yale University School of Medicine, New Haven, have shown that mice lacking the TRPA1 protein, which is involved in signaling inflammatory pain, have decreased depression of the breathing rate and decreased pain following exposure to chlorine and oxidant chemicals. These results indicate that TRPA1 may mediate the response of airway sensory nerves to upper airway irritants. The authors therefore suggest that drugs that inhibit TRPA1 function may help patients with exaggerated responses to chemical irritants, such as those with asthma.

TITLE: TRPA1 is a major oxidant sensor in murine airway sensory neurons


Sven-Eric Jordt

Yale University School of Medicine, New Haven, Connecticut, USA.

Phone: (203) 785-2159; Fax: (203) 737-2027; E-mail:

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Establishing how a genetic mutation can cause disease

Congenital myasthenias are inherited disorders characterized by muscle weakness caused by mutations in genes that contain the information for making proteins that are involved in the communication between nerves and muscle cells. For example, some individuals with congential myasthenia have mutations in the genes that contain the information for making the subunits of a protein that is expressed by muscle cells and that binds a molecule known as acetylcholine, which is the transmitter by which nerves convey signals to the muscle. In a new study, Andrew Engel and colleagues, at the Mayo Clinic, Rochester, determined how a mutation in the gene containing the information for making the delta-subunit of the receptor for acetylcholine, which they detected in a patient with congenital myasthenia, might lead to the disease. The mutation was found to cause a change in the structure of the acetylcholine receptor, leading to slower opening of the receptor, which in turn slowed ion flow through the channel and thus impaired muscular function.

TITLE: Congenital myastheniarelated AChR-delta subunit mutation interferes with intersubunit communication essential for channel gating


Andrew G. Engel

Mayo Clinic, Rochester, Minnesota, USA.

Phone: (507) 284-5102; Fax: (507)284-5831; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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