(Press-News.org) EDITOR'S PICK: A hunk of a target for treating breast cancer
Among women with breast cancer, approximately 25% have a subtype that is characterized by high levels of expression of the protein HER2. HER2-positive breast cancer tends to be more aggressive than other breast cancer subtypes. Increased molecular understanding of why HER2-positive breast cancer is so aggressive could aid in the development of new therapeutics. By studying mouse models, a team of researchers, led by Lewis Chodosh, at the University of Pennsylvania School of Medicine, Philadelphia, has now identified a key role for the protein Hunk in the formation of tumors driven by overexpression of HER2. As the data also indicate that Hunk is required for HER2-induced tumor cells to maintain their cancerous characteristics, the team suggests that inhibiting Hunk might provide a new approach to treating HER2-positive breast cancer.
TITLE: Hunk is required for HER2/neu-induced mammary tumorigenesis
AUTHOR CONTACT:
Lewis A. Chodosh
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.898.1321; Fax: 215.573.6725; E-mail: chodosh@mail.med.upenn.edu.
View this article at: http://www.jci.org/articles/view/42928?key=0163b99f546167e70104
EDITOR'S PICK: New combination therapy for solid tumors?
Most, if not all, solid tumors contain regions that are not well oxygenated. Tumor cells in these regions, which are known as hypoxic regions, are usually resistant to the death-inducing effects of chemotherapeutics. But now, Caroline Dive and colleagues, at Manchester University, United Kingdom, have identified a compound (ABT-737) that induces human cancer cells exposed to hypoxic conditions in vitro to undergo a form of cell death known as apoptosis. In addition, cells in hypoxic regions of human tumors xenografted in mice were susceptible to ABT-737–induced apoptotic cell death. As ABT-737 synergized with conventional chemotherapeutic agents in tumor-bearing mice, the authors suggest that such a combination of drugs could improve treatment of solid tumors.
TITLE: Hypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1
AUTHOR CONTACT:
Caroline Dive
Paterson Institute for Cancer Research, Manchester, United Kingdom.
Phone: 00.44.161.446.3036; Fax: 00.44.161.446.3109; E-mail: cdive@picr.man.ac.uk.
View this article at: http://www.jci.org/articles/view/43505?key=b39a1fa8ed3af3fab6a0
NEUROBIOLOGY: New function for the protein MEF2D is dysregulated in Parkinson disease
Zixu Mao and colleagues, at Emory University, Atlanta, have identified a new function for the protein MEF2D and determined that this new function is dysregulated in both a mouse model of Parkinson disease and in human patients with the condition.
Members of the MEF2 family of proteins are known to mediate important functions in an increasing number of cell types by working in the nucleus to regulate gene expression. Surprisingly, therefore, Mao and colleagues found MEF2D in the energy-generating compartments (which are known as mitochondria) of rodent nerve cells. More specifically, they found MEF2D bound to the region of mitochondrial DNA that contains the gene ND2, where it induced ND2 expression. Importantly, levels of MEF2D in mitochondria were reduced in affected nerve cells in both a mouse model of Parkinson disease and human patients. Although the authors focused on Parkinson disease in this study, they conclude that mitochondrial MEF2D probably also plays a role in other organ systems and disease processes.
TITLE: Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients
AUTHOR CONTACT:
Zixu Mao
Emory University, Atlanta, Georgia, USA.
Phone: 404.712.8581; Fax: 404.727.3728; E-mail: zmao@pharm.emory.edu.
View this article at: http://www.jci.org/articles/view/43871?key=da6979c39bacbbcf4db8
ONCOLOGY: Understanding genetic cooperation in brain tumors
Glioblastomas are the most common and most aggressive tumors originating in the brain. A subset of glioblastomas show increased expression of the PDGFRA gene and loss of the CDKN2A gene, but whether these genetic events actually drive tumor formation has not been determined. A team of researchers, led by Bo Hu and Shi-Yuan Cheng, at the University of Pittsburgh, Pittsburgh, has now determined that concomitant increases in PDGFR-alpha (the protein templated by PDGFRA) and loss of p16INK4a (one of the proteins templated by CDKN2A gene) can drive mouse and human cells to form glioblastomas in mice. Further analysis revealed that the protein SHP-2 is an important mediator of these tumor-forming effects of PDGFR-alpha and that inhibition of SHP-2 impairs the ability of cells lacking p16INK4a to form glioblastomas. These data lead the team to suggest that SHP-2 could be a good therapeutic target for the treatment of glioblastomas.
TITLE: SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans
AUTHOR CONTACT:
Bo Hu
University of Pittsburgh Cancer Institute and Department of Medicine, Pittsburgh, Pennsylvania, USA.
Phone: 412.623.7791; Fax: 412.623.4840; E-mail: hub@upmc.edu.
Shi-Yuan Cheng
University of Pittsburgh Cancer Institute and Department of Pathology, Pittsburgh, Pennsylvania, USA.
Phone: 412.623.3261; Fax: 412.623.4840; E-mail: chengs@upmc.edu.
View this article at: http://www.jci.org/articles/view/43690?key=4bab71d09e459c4dfe44
ONCOLOGY: Switching over to an aggressive breast cancer
Tumor recurrence and spread to a distant site (a process known as metastasis) are enormous problems in the treatment of cancer. The cellular process epithelial-mesenchymal transition (EMT), which is critical for embryo development, has been linked to both tumor recurrence and metastasis. The mechanisms regulating EMT are therefore potential targets for anticancer therapeutics. In this context, a team of researchers, led by Chonghui Cheng, at Northwestern University, Chicago, has now determined that during EMT, the form of the protein CD44 that is expressed changes. This switch, which was mediated by a process known as alternative splicing, to the CD44s form of the protein was essential for cells to undergo EMT. It was required also for the formation of breast tumors with characteristics of EMT in mice. As expression of CD44s was upregulated in aggressive human breast tumors, the team suggests that targeting this particular form of CD44 might provide a new way to treat advanced breast cancer.
TITLE: CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression
AUTHOR CONTACT:
Chonghui Cheng
Northwestern University, Chicago, Illinois, USA.
Phone: 312.503.5248; Fax: 312.503.0189; E-mail: chengc@northwestern.edu.
View this article at: http://www.jci.org/articles/view/44540?key=b891fe28863fd4d6b3f2
VIROLOGY: Scarring underlies hallmark of HIV-1 infection
Infection with HIV-1 is characterized by loss of immune cells known as CD4+ T cells. When numbers of these cells decline below a critical level, the body becomes susceptible to opportunistic infections and cancers and the patient is said to have developed AIDS. A team of researchers, led by Ashley Haase, at the University of Minnesota, Minneapolis, has now identified a new mechanism by which CD4+ T cells are depleted in HIV-1 infected patients and SIV-infected rhesus macaques. Targeting this mechanism could provide a new approach to treating individuals infected with HIV-1.
The team found that infection with HIV-1 or SIV triggered a cascade of immune system events that led to scarring (fibrosis) of lymphoid tissue (organs and tissues that house immune cells). This in turn, triggered further immune system dysfunction that resulted in CD4+ T cell depletion. The team therefore suggests that early initiation of antiviral therapy, to limit the viral replication-dependent immune cascade that drives lymphoid tissue scarring, along with antifibrotic therapies could limit CD4+ T cell depletion and therefore progression to AIDS.
TITLE: Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections
AUTHOR CONTACT:
Ashley T. Haase
University of Minnesota, Minneapolis, Minnesota, USA.
Phone: 612.624.4442; Fax: 612.626.0623; E-mail: haase001@umn.edu.
View this article at: http://www.jci.org/articles/view/45157?key=6d78c7fd359af0e6f5d0
VIROLOGY: Young versus old: why the immune response to hepatitis B virus is better in adults
Chronic infection with hepatitis B virus (HBV) results in more than half a million deaths annually by causing liver failure and liver cancer. An individual's chance of clearing HBV following infection depends on their age: most individuals infected as adults clear the infection, whereas neonates and children usually develop chronic infection and liver disease. A team of researchers, led by Jody Baron, at UCSF, San Francisco, has now identified a potential reason that adults mount an effective immune response and clear the virus while neonates and children do not by studying an animal model of HBV infection. Specifically, the data suggest that decreased production of the immune mediator IL-21 in younger individuals impairs the development of the cellular immune response required to clear the virus. It might therefore be possible to develop new HBV therapeutic strategies that effectively tilt immune responses toward viral clearance.
TITLE: IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B
AUTHOR CONTACT:
Jody L. Baron
University of California at San Francisco, San Francisco, California, USA.
Phone: 415.476.5728; Fax: 415.476.0659; E-mail: jody.baron@ucsf.edu.
View this article at: http://www.jci.org/articles/view/44198?key=a075a2dfd5a4fe18314f
PARASITOLOGY: Genetic link to parasite infection
Amebiasis is a potentially fatal intestinal condition that is caused by infection with the parasite Entamoeba histolytica. In children, malnutrition increases susceptibility to infection and disease severity. As levels of a hormone known as leptin are low in malnourished children, a team of researchers, led by Priya Duggal, at Johns Hopkins Bloomberg School of Public Health, Baltimore, hypothesized that genetic variations that diminished leptin function would increase susceptibility to infection with E. histolytica. The team's observation of a cohort of children living in an urban slum in Dhaka, Bangladesh, through home visits every other day for 9 years, generated data supportive of the hypothesis.
The team specifically identified a common genetic variation in the leptin receptor gene (namely Q223R) as being associated with increased susceptibility to amebiasis. The same genetic variation also associated with amebic liver abscess, a common manifestation of invasive amebiasis, in an independent cohort of adult patients. Consistent with these observations in humans, mice carrying a 223R version of the leptin receptor gene were more susceptible to infection with E. histolytica and developed more severe damage to the lining of the intestines. These data therefore indicate that leptin and the molecule to which it binds are important in the immune response to the dangerous microbe E. histolytica.
TITLE: A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children
AUTHOR CONTACT:
Priya Duggal
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Phone: 410.955.1213; Fax: 410.955.0863; E-mail: pduggal@jhsph.edu.
View this article at: http://www.jci.org/articles/view/45294?key=577c6365071c0453689e
METABOLIC DISEASE: The gene regulator SRF is the STAR(S) of insulin resistance
An individual's risk of developing type 2 diabetes is dramatically increased if their muscle, fat, and liver cells are resistant to the effects of the hormone insulin, which helps keep glucose levels in the blood low. Despite the clinical significance of insulin resistance, little is known about the molecular mechanisms underlying it. A team of researchers, led by Mary-Elizabeth Patti, at the Joslin Diabetes Center, Boston, has now provided insight into this through its demonstration that genes regulated by the protein SRF and its coactivator MLK1 are expressed at higher levels in individuals with a parental family history of diabetes and those with type 2 diabetes than in people with no family history of diabetes. Of potential clinical interest, pharmacological inhibition of SRF enhanced glucose uptake by human and mouse muscle cells in vitro and lowered glucose levels in the blood of insulin-resistant mice. The team therefore suggests that the SRF pathway is a potential therapeutic target for the treatment of insulin resistance and possibly type 2 diabetes.
TITLE: Increased SRF transcriptional activity in human and mouse skeletal muscle is a signature of insulin resistance
AUTHOR CONTACT:
Mary-Elizabeth Patti
Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.735.1966; Fax: 617.732.2593; E-mail: mary.elizabeth.patti@joslin.harvard.edu.
View this article at: http://www.jci.org/articles/view/41940?key=b24c9f3e9f128dea7bb7
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JCI online early table of contents: Feb. 14, 2011
2011-02-15
ELSE PRESS RELEASES FROM THIS DATE:
X-rays show why van Gogh paintings lose their shine
2011-02-15
This release is available in French.
VIDEO:
A microsample is taken from the van Gogh painting "Bank of river Seine " on display at the van Gogh Museum in Amsterdam (Netherlands), and then analyzed at the X-rays microscope...
Click here for more information.
Scientists have identified a complex chemical reaction responsible for the degradation of two paintings by Vincent ...
Medicare costs in last 6 months of life driven by patient variables twice as much as geography
2011-02-15
A study by Mount Sinai School of Medicine finds that Medicare costs at the end of life are influenced more by patient characteristics, such as ability to function, the severity of the illness, and family support than by regional factors, such as the number of hospital beds available. The study will be published February 15 in The Annals of Internal Medicine.
"These new findings show that the reasons for wide variation in Medicare costs across the United States are much more complicated than previously thought," said lead author Amy Kelley, MD, Assistant Professor in ...
UC San Diego biologists gain new insights into brain circuit wiring
2011-02-15
Neurobiologists at UC San Diego have discovered new ways by which nerves are guided to grow in highly directed ways to wire the brain during embryonic development.
Their finding, detailed in a paper in the February 15 issue of the journal Developmental Cell, provides a critical piece of understanding to the longstanding puzzle of how the human brain wires itself into the complex networks that underlie our behavior.
The discovery concerns the movements of a highly sensitive and motile structure at the tips of growing nerves called a growth cone. For more than a century, ...
Less is more when prescribing acid suppressive drugs for non-ICU patients
2011-02-15
BOSTON – Over the last several decades, the prophylactic use of acid-suppressive medications to help prevent gastrointestinal bleeding (GI) in hospitalized patients has increased significantly, with some studies estimating that as many as 40 to 70 percent of all medical inpatients are given these drugs at some point during their hospitalization.
But, for patients who are not critically ill, the actual incidence of GI bleeding has not been well investigated.
Now, a study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and reported in today's on-line ...
Living fast but dying older is possible -- if you're a sheep
2011-02-15
According to Dr Annette Baudisch of the Max Planck Institute for Demographic Research in Rostock, Germany, current methods of comparing patterns of ageing are limited because they confound two different elements of ageing – pace and shape.
"Some organisms live a short time, others live a long time. This is the pace of ageing. Short-lived species have a fast pace of ageing, and long-lived species have a slow pace of ageing. Pace describes how quickly the clock of life ticks away. For humans it ticks slowly, for small songbirds like the robin it ticks very fast," explains ...
Lavender oil has potent antifungal effect
2011-02-15
Lavender oil could be used to combat the increasing incidence of antifungal-resistant infections, according to a study published in the Journal of Medical Microbiology. The essential oil shows a potent antifungal effect against strains of fungi responsible for common skin and nail infections.
Scientists from the University of Coimbra in Portugal distilled lavender oil from the Lavandula viridis L'Hér shrub that grows in southern Portugal. The oil was tested against a range of pathogenic fungi and was found to be lethal to a range of skin-pathogenic strains, known as dermatophytes, ...
Most medical devices recalled because of serious risks did not undergo clinical trials
2011-02-15
Most medical devices recently recalled by the Food and Drug Administration because of very serious risks were initially approved through an expedited process or were exempt from regulatory review, according to a report posted online today that will be published in the June 14 print issue of Archives of Internal Medicine, one of the JAMA/Archives journals.
"Unlike prescription drugs, medical devices are reviewed by the U.S. Food and Drug Administration (FDA) using two alternative regulatory standards: (1) premarket approval, which requires clinical testing and inspections; ...
Obesity is heart disease killer in its own right, irrespective of other risk factors
2011-02-15
Obesity is a killer in its own right, irrespective of other biological or social risk factors traditionally associated with coronary heart disease, suggests research published online in Heart.
Increasing weight is associated with a higher prevalence of known risk factors for coronary artery disease, such as diabetes, high blood pressure and cholesterol. And it has been assumed that these have been responsible for the increased risk of heart disease seen in obesity, say the authors.
The research team tracked the health of more than 6,000 middle aged men with high cholesterol, ...
Portable pedal machines may help counter harmful effects of sedentary jobs
2011-02-15
Portable pedal machines could help counter the harmful effects of prolonged periods spent at a desk or workstation among an increasingly sedentary workforce, suggests a small study published online in the British Journal of Sports Medicine.
The researchers base their findings on 18 full time employees who were given a pedal exercise machine for four weeks, specifically designed to be used while seated at a desk in the workplace.
The mini exercise bike comprised a set of pedals that can be set up in front of most standard office chairs for use while seated, and which ...
Fiber intake associated with reduced risk of death
2011-02-15
Dietary fiber may be associated with a reduced risk of death from cardiovascular, infectious and respiratory diseases, as well as a reduced risk of death from any cause over a nine-year period, according to a report posted online today that will be published in the June 14 print issue of Archives of Internal Medicine, one of the JAMA/Archives journals.
Fiber, the edible part of plants that resist digestion, has been hypothesized to lower risks of heart disease, some cancers, diabetes and obesity, according to background information in the article. It is known to assist ...