JCI online early table of contents: Dec. 14, 2009

December 14, 2009

EDITOR'S PICK: New suppressor of common liver cancer

Tumor suppressor genes make proteins that help control cell growth. Mutations in these genes that generate nonfunctional proteins can contribute to tumor development and progression. One of the most well-known tumor suppressor genes is BRACA1, mutations in which are linked to breast cancer. Ze-Guang Han and colleagues, at the Chinese National Human Genome Center at Shanghai, People's Republic of China, have now identified SCARA5 as a candidate tumor suppressor gene in human hepatocellular carcinoma (HCC), a form of liver cancer that is the fifth most common cancer worldwide.

While it has been known for a long time that genetic inactivation of tumor suppressor genes can contribute to tumor development and progression, only more recently has it been determined that inactivating tumor suppressor genes by a mechanism known as epigenetic silencing has the same effect. In the study, analysis of HCC tissue samples indicted that SCARA5 was frequently subjected to genetic loss and epigenetic silencing and that SCARA5 protein downregulation was most marked in HCC tissue samples characterized by tumor invasion into the blood vessels (a sign of aggressive disease). Further analysis in HCC cells lines in vitro and after xenotransplantation into mice were consistent with SCARA5 being a tumor suppressor gene. The authors therefore suggest that SCARA5 protein downregulation as a result of SCARA5 genetic loss and epigenetic silencing can contribute to HCC tumor development and progression.

TITLE: Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling

Ze-Guang Han
Chinese National Human Genome Center at Shanghai, Shanghai, People's Republic of China.
Phone: 86-21-50801325; Fax: 86-21-50800402; E-mail: hanzg@chgc.sh.cn.

View this article at: http://www.jci.org/articles/view/38012?key=WYUeOaDgqG3U70r15PKV

EDITOR'S PICK: Genetic link to heart failure

A team of researchers, at Washington University School of Medicine, St Louis, has identified a group of 12 genetic variants in the HSPB7 gene that is associated with heart failure in humans.

The team, led by Gerald Dorn, used an approach they have recently developed that allows ultra-high-throughput targeted DNA sequencing to identify genetic variation in four genes with biological relevance to heart failure. They identified in a large group of Caucasian individuals with heart failure, 129 separate genetic variants in the four genes, including 23 that seemed to be novel. Further analysis of 1117 Caucasian individuals with heart failure and 625 nonaffected Caucasians indicated that a block of 12 genetic variants in the HSPB7 gene was associated with heart failure. Confirmation of this association was provided by analysis of an independent group of individuals. The authors hope to use the same approach to identify further genetic variants associated with heart failure, a disease that is influenced by multiple genetic factors.

TITLE: Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease

Gerald W. Dorn, II
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-4892; Fax: (314) 362-8844; E-mail: gdorn@dom.wustl.edu.

View this article at: http://www.jci.org/articles/view/39085?key=QR23mwtIf19sIud3dWA9

VASCULAR BIOLOGY: Signaling decreased blood pressure

Blood pressure is controlled in part by changes in the radius of blood vessels; when the smooth muscle cells in the wall of a blood vessel contract, the radius of the blood vessel decreases and blood pressure increases. A team of researchers at CSIC-University of Salamanca, Spain, has now identified in mice a new signaling pathway that contributes to relaxation of smooth muscle cells in blood vessel walls triggered by the molecule NO and thereby decreases blood pressure.

Mice lacking the protein Vav2 have elevated blood pressure. By analyzing these mice, the team, led by Xosé Bustelo, identified a Vav2 signaling pathway that normally contributes to NO-triggered relaxation of smooth muscle cells in blood vessel walls. The pathway involves Vav2 activation of the proteins Rac1 and Pak1. Absence of Pak1 activation in Vav2-deficient mice resulted in excessive activity of the protein phosphodiesterase type 5. Consistent with this, treating Vav2-deficient mice with phosphodiesterase type 5 inhibitors reduced their blood pressure to a normal level. As defective blood vessel reactivity to NO contributes to the symptoms of diseases such as atherosclerosis (hardening of the arteries) and diabetes, the authors suggest that stimulating the pathway they have identified might be of therapeutic benefit in patients with these diseases.

TITLE: The Rho/Rac exchange factor Vav2 controls nitric oxide-dependent responses in mouse vascular smooth muscle cells

Xosé R. Bustelo
CSIC-University of Salamanca, Campus Unamuno, Salamanca, Spain.
Phone: 34-923294802; Fax: 34-923294743; E-mail: xbustelo@usal.es.

View this article at: http://www.jci.org/articles/view/38356?key=VFkTwWePlatxwBXqdW3x

ONCOLOGY: How cancer cells protect themselves from low levels of oxygen

Not all regions of a tumor are equal in terms of their oxygen levels. One clinically important implication of this is that tumors with large areas with low levels of oxygen (areas known as hypoxic regions) are associated with poor prognosis and treatment response. A team of researchers, led by Bradly Wouters, at the University of Toronto, Canada, has determined that a cellular response pathway known as the unfolded protein response pathway helps protect human tumor cells from hypoxia and anticancer irradiation treatment. Further analysis indicated that the unfolded response pathway increased expression of two proteins involved in a cellular process known as autophagy, which is known to act to protect cells in times of stress. Importantly, inhibition of autophagy sensitized cultured human tumor cells to hypoxia and sensitized human tumors xenografted into mice to irradiation, leading the authors to suggest that targeting the molecules they identified as important might be of clinical benefit.

TITLE: The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5

Bradly G. Wouters
University of Toronto, Toronto, Ontario, Canada.
Phone: (416) 581-7840; Fax: (416) 581-7840; E-mail: bwouters@uhnresearch.ca.

View this article at: http://www.jci.org/articles/view/40027?key=R0gn8cJB89Pz98D0OF8t

METABOLISM: Bone control of glucose levels

Bone cells known as osteoblasts were recently shown to have a role in controlling the biochemical reactions that generate energy via secretion of the molecule osteocalcin. A team of researchers, led by Stavroula Kousteni, at Columbia University, New York, has now determined that the protein FoxO1 regulates this function of osteoblasts in mice. Specifically, FoxO1 increases expression of osteocalcin and decreases expression of Esp, a gene that makes a protein responsible for decreasing the bioactivity of osteocalcin. This is a new role for FoxO1, which is also involved in regulating glucose levels via effects on cells in the pancreas and liver.

TITLE: FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice

Stavroula Kousteni
Columbia University, New York, New York, USA.
Phone: (212) 851-5223; Fax: (212) 851-5225; E-mail: sk2836@columbia.edu.

View this article at: http://www.jci.org/articles/view/39901?key=IsEkHw3z3h7LJTXqmYDH

NEPHROLOGY: Soluble immune molecules cause acute kidney inflammation in mice

Immune molecules known as cytokines are effectors of immune cell function. The IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways have been linked to autoimmune diseases (i.e, diseases in which the immune system turns on the body). A team of researchers, led by Li Li, at the University of Virginia, Charlottesville, has now determined that these cytokine pathways also contribute to inflammation in a mouse model of acute kidney injury. Specifically, they find that the IL-23/IL-17 pathway works upstream of the IL-12/IFN-gamma pathway, as IL-17A production by immune cells known as neutrophils was required for activation of the IL-12/IFN-gamma pathway. In addition, as the inflammation underlying kidney injury in this model was caused by blood flow returning to the kidney following a period in which the kidney was deprived of blood flow (an event known as reperfusion) and reperfusion injury has a role in brain and heart damage caused by stroke and heart attack, respectively, the authors suggest that the IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways might contribute to reperfusion injury in other organs.

TITLE: IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury

Li Li
University of Virginia, Charlottesville, Virginia, USA.
Phone: (434) 924-2110; Fax: (434) 924-5848; E-mail: ll3m@virginia.edu.

View this article at: http://www.jci.org/articles/view/38702?key=Nwa5Q206lzzoF7Ydyxl4

JCI Journals

Related Heart Failure Articles from Brightsurf:

Top Science Tip Sheet on heart failure, heart muscle cells, heart attack and atrial fibrillation results
Newly discovered pathway may have potential for treating heart failure - New research model helps predict heart muscle cells' impact on heart function after injury - New mass spectrometry approach generates libraries of glycans in human heart tissue - Understanding heart damage after heart attack and treatment may provide clues for prevention - Understanding atrial fibrillation's effects on heart cells may help find treatments - New research may lead to therapy for heart failure caused by ICI cancer medication

Machining the heart: New predictor for helping to beat chronic heart failure
Researchers from Kanazawa University have used machine learning to predict which classes of chronic heart failure patients are most likely to experience heart failure death, and which are most likely to develop an arrhythmic death or sudden cardiac death.

Heart attacks, heart failure, stroke: COVID-19's dangerous cardiovascular complications
A new guide from emergency medicine doctors details the potentially deadly cardiovascular complications COVID-19 can cause.

Autoimmunity-associated heart dilation tied to heart-failure risk in type 1 diabetes
In people with type 1 diabetes without known cardiovascular disease, the presence of autoantibodies against heart muscle proteins was associated with cardiac magnetic resonance (CMR) imaging evidence of increased volume of the left ventricle (the heart's main pumping chamber), increased muscle mass, and reduced pumping function (ejection fraction), features that are associated with higher risk of failure in the general population

Transcendental Meditation prevents abnormal enlargement of the heart, reduces chronic heart failure
A randomized controlled study recently published in the Hypertension issue of Ethnicity & Disease found the Transcendental Meditation (TM) technique helps prevent abnormal enlargement of the heart compared to health education (HE) controls.

Beta blocker use identified as hospitalization risk factor in 'stiff heart' heart failure
A new study links the use of beta-blockers to heart failure hospitalizations among those with the common 'stiff heart' heart failure subtype.

Type 2 diabetes may affect heart structure and increase complications and death among heart failure patients of Asian ethnicity
The combination of heart failure and Type 2 diabetes can lead to structural changes in the heart, poorer quality of life and increased risk of death, according to a multi-country study in Asia.

Preventive drug therapy may increase right-sided heart failure risk in patients who receive heart devices
Patients treated preemptively with drugs to reduce the risk of right-sided heart failure after heart device implantation may experience the opposite effect and develop heart failure and post-operative bleeding more often than patients not receiving the drugs.

How the enzyme lipoxygenase drives heart failure after heart attacks
Heart failure after a heart attack is a global epidemic leading to heart failure pathology.

Novel heart pump shows superior outcomes in advanced heart failure
Severely ill patients with advanced heart failure who received a novel heart pump -- the HeartMate 3 left ventricular assist device (LVAD) -- suffered significantly fewer strokes, pump-related blood clots and bleeding episodes after two years, compared with similar patients who received an older, more established pump, according to research presented at the American College of Cardiology's 68th Annual Scientific Session.

Read More: Heart Failure News and Heart Failure Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.