Also Included In: Lymphoma / Leukemia / Myeloma; Bones / Orthopedics; Cancer / Oncology
Article Date: 05 Dec 2011 - 0:00 PST
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CARDIOLOGY: Unraveling the adverse effects of a blood pressure medication
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:
Jeffery D. Molkentin
University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
View this article at: http://www.jci.org/articles/view/58227?key=2e053b4397a6ffb4dfef
HEMATOLOGY: Driving lymphoma de-MENT-ed
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 lymphomagenesisAUTHOR:
Rene Opavsky
University of Nebraska Medical Center, Omaha, Nebraska, USA.
View this article at: http://www.jci.org/articles/view/57292?key=dbf939c1467d037ee256
BONE BIOLOGY: In utero growth factor supplementation corrects mouse skeletal defects
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
AUTHORS:
Laurie H. Glimcher
Harvard School of Public Health, Boston, Massachusetts, USA.
Jae-Hyuck Shim
Harvard School of Public Health, Boston, Massachusetts, USA.
View this article at: http://www.jci.org/articles/view/59466?key=7b32ef4307e8dacfdf6d
ONCOLOGY: Antitumor benefits of lowering, but not eliminating, expression of the protein ATR
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:
Eric J. Brown
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
View this article at: http://www.jci.org/articles/view/58928?key=5575d171069bbe8189c0
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8 Dec. 2011.
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