Researchers Reduce Breast Cancer Spread by Blocking Tissue Scarring

What to fear most if faced by a cancer diagnosis is the spread of the cancer to other parts of the body. This process called metastasis accounts for over 90% of cancer patient deaths and therefore is a strong focus for cancer researchers. Researchers at BRIC, University of Copenhagen have shown that the enzyme Lysyl Oxidase (LOX) can create a "scarred" microenvironment that enhances cancer spreading. By blocking activity of the LOX enzyme, the researchers succeeded in significantly decreasing metastasis in a model of breast cancer.When we inhibit the activity of LOX in our cancer models, we show a dramatic reduction in metastasis. This suggests that therapeutic targeting of LOX can keep the tumour microenvironment "healthy" and thereby decrease metastasis, says Associate Professor Janine Erler from BRIC, who has headed the research.
LOX -- A link between tissue scarring and metastasis
In humans, LOX is an enzyme that is produced in response to tissue injury or chronic inflammation in our organs. It reacts to damage signals and "glues" collagen molecules together to form the scar-like structure. The result can be a fibrotic environment. The new findings from Janine Erler's research group show that persistent injury to lung and liver results in a fibrotic microenvironment that supports the growth of new tumours, and thereby enhances metastasis of breast cancer cells to these organs. Blocking LOX prevents the formation of this fibrotic microenvironment, thereby preventing enhanced metastasis to these organs.
'It is well-known that signals from fibrotic tissues can enhance tumour progression and metastasis, but the underlying mechanisms have remained unclear -- Our new results provide insight into the link between fibrosis and cancer progression. Such a biological understanding is crucial if we are to develop effective therapies preventing tumour metastasis, says PostDoc Thomas Cox from Janine Erler's laboratory, who undertook the experimental investigation.

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Hormones Can Change the Breast's Genetic Material, Study Finds

Melbourne scientists have discovered how female steroid hormones can make dramatic changes to the genetic material in breast cells, changes that could potentially lead to breast cancer.
Researchers from the Walter and Eliza Hall Institute have identified how pregnancy hormones send signals to critical molecules on the DNA to make changes in the epigenome. The epigenome is a series of chemical tags that modify DNA, controlling which genes are switched on and off.
Professor Jane Visvader, Dr Bhupinder Pal, Professor Geoff Lindeman and colleagues from the institute's breast cancer laboratory led the study, which was published today in Cell Reports.
Professor Visvader said the researchers had created a roadmap of the epigenomes of different breast cell types. In collaboration with Professor Gordon Smyth and colleagues from the institute's Bioinformatics division they determined how the epigenomes changed in response to ovarian hormones such as progesterone.
"We found the epigenome was very sensitive to hormonal regulation," Professor Visvader said. "This reveals another way in which female hormones can influence breast cancer risk -- by altering the epigenome through modifications on the DNA."
The epigenome is where the DNA and the environment intersect, communicating signals from the outside world to the DNA. The epigenome doesn't alter the genetic code, but is a layer of proteins or tags that decorates the DNA and provides instructions on whether DNA should be read and 'switched on' to produce proteins.
The research team found that pregnancy hormones activate a molecule called EZH2, which is an important modifier of the epigenome. "We found that hormones including progesterone activate EZH2 to modify the epigenome, leading to global changes in the expression of a huge number of genes," Professor Visvader said.
"In normal tissue, EZH2 is essential for the development of breast tissue including ducts and milk-producing cells, and for maintaining the activity of breast stem cells and their daughter progenitor cells. However, life-long exposure to hormones could lead to breast tumour initiation through increased levels of EZH2 and the changes that it orchestrates in the epigenome."
Breast cancer is the most common cause of cancer in women, accounting for almost 30 per cent of all cancers affecting women. One in nine women in Australia will develop breast cancer by the age of 85.
High levels of EZH2 are a marker of poor prognosis in breast cancer and have been frequently observed in basal-like breast cancers, the most aggressive types of breast cancer. "The link between progesterone, EZH2 and the epigenome, could be crucially important in the very early stages of breast cancer development," Professor Visvader said.

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Enzyme Behind Breast Cancer Mutations Identified

Researchers at the University of Minnesota have uncovered a human enzyme responsible for causing DNA mutations found in the majority of breast cancers. The discovery of this enzyme -- called APOBEC3B -- may change the way breast cancer is diagnosed and treated.
The findings from a team of researchers led by Reuben Harris, Ph.D., associate professor of biochemistry, molecular biology and biophysics and also a researcher at the Masonic Cancer Center, University of Minnesota, are published in the latest edition of Nature.
"We strongly believe this discovery will change the way mutations in cancer are viewed and, hopefully, it will allow cancer researchers to develop new treatments approaches that can prevent these mutations before they become harmful," said Harris.
Harris' quest to learn more about mutations in cancer initially began with HIV research. This previous work by Harris' lab and others indicated that APOBEC3B and related enzymes function normally to protect from infectious viruses like HIV-1.
During these studies, Harris' team developed specific tests to quantify the expression of each of the seven APOBEC3 genes, including APOBEC3B.
Harris and his team were able to apply these tests to the problem of mutation in breast cancer, showing only APOBEC3B is over-expressed in patients' breast cancer cell lines and tumors.

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Imaging Biomarker Predicts Response to Rapid Antidepressant

A telltale boost of activity at the back of the brain while processing emotional information predicted whether depressed patients would respond to an experimental rapid-acting antidepressant, a National Institutes of Health study has found.
"We have discovered a potential neuroimaging biomarker that may eventually help to personalize treatment selection by revealing brain-based differences between patients," explained Maura Furey, Ph.D., of NIH's National Institute of Mental Health (NIMH).
Furey, NIMH's Carlos Zarate, M.D., and colleagues, reported on their functional magnetic resonance imaging (fMRI) study of a pre-treatment biomarker for the antidepressant response to scopolamine, Jan. 30, 2013, online in JAMA Psychiatry.
Scopolamine, better known as a treatment for motion sickness, has been under study since Furey and colleagues discovered its fast-acting antidepressant properties in 2006. Unlike ketamine, scopolamine works through the brain's acetylcholine chemical messenger system. The NIMH team's research has demonstrated that by blocking receptors for acetylcholine on neurons, scopolamine can lift depression in many patients within a few days; conventional antidepressants typically take weeks to work. But not all patients respond, spurring interest in a predictive biomarker.

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Significance of Second Trimester Markers for Down's Syndrome Revealed

A new analysis has found that some second trimester markers for Down's syndrome that are detected by ultrasound are more telling than others. Published early online in Ultrasound in Obstetrics & Gynecology, the study's results will help adjust pregnant women's risks for having a child with the condition.
Screening for Down's syndrome is offered to all pregnant women, who start out with a background risk based on their age. Certain features detected during a second trimester ultrasound exam are potential markers for Down's syndrome, and they include dilated brain ventricles, absent or small nose bone, increased thickness of the back of the neck, an abnormal artery to the upper extremities, bright spots in the heart, 'bright' bowels, mild kidney swelling, and shortening of an arm bone or thigh bone.
To determine how these markers affect risk, Kypros Nicolaides, MD, of the Harris Birthright Research Centre for Fetal Medicine at King's College London in England, and his colleagues analyzed all published studies that reported results on second trimester markers for Down's syndrome between 1995 and 2012.
The researchers identified 48 studies, and they discovered that most single markers have only a small effect on modifying the odds for Down's syndrome.. This finding could have important clinical implications because currently in the United States, when a marker such as a short arm or thigh bone is detected, women are told that they are at high risk of having a child with Down's syndrome. Dr. Nicolaides and his team found that a few markers do carry increased risks, though.

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Surgeons Find Better Ways to Treat Nerve Compression Disorder That Can Sideline Athletes, Studies Suggest

Two new studies from Washington University School of Medicine in St. Louis suggest ways to improve surgical treatment for a debilitating condition caused by compressed nerves in the neck and shoulder.
The condition, neurogenic thoracic outlet syndrome, causes pain, numbness or tingling in the shoulder, arm or hand and is perhaps best known for affecting baseball pitchers and other elite athletes. Patients often describe pain and tension in the neck and upper back, numbness and tingling in the fingers, headaches and perceived muscle weakness in the affected limb.
Treatment begins with physical therapy and sometimes medications such as anti-inflammatory drugs and muscle relaxants. When these treatments fail to improve symptoms and there is substantial disability in the use of the affected upper extremity, surgery can help relieve pressure on the nerves, often by removing the first rib and other structures thought to be causing the compression.
One study reported that adolescents do even better after surgery than adults, but evidence suggests that this may not be due to age alone. In the second study, the researchers found that minimally invasive surgery may be just as good for select patients as the traditional, more extensive approach.
Both studies appear online in the Journal of Vascular Surgery and are important contributions to the field, according to the papers' senior author, Robert W. Thompson, MD, professor of surgery and director of the Washington University Center for Thoracic Outlet Syndrome at Barnes-Jewish Hospital.
The center treats one of the highest volumes of patients in the country, and the paper comparing treatment outcomes by age includes the largest series of adolescent patients reported in the literature to date.
"This is an important message for pediatricians who treat teenagers, especially teenage athletes," Thompson says. "These are patients who can do extremely well if identified early and treated."
The study compared outcomes of the traditional surgery in 189 patients treated from 2008 through 2010. Thirty-five of the patients were under age 21, with an average age of 17. The remaining 154 patients were over age 21, with an average age of 40.
Both groups showed substantial improvement in symptoms and function at three and six months after surgery, but the adolescent group did significantly better. In fact, a combined measure of shoulder, arm and hand function, pain and severity of symptoms was almost four times better in the adolescent group than the adult group six months after surgery. Adults also reported about four times greater use of pain medication after surgery compared to adolescents.
While much of this gap may simply be attributed to age, other differences between the two groups could be useful in identifying ways to improve outcomes for adult patients. For example, duration of pain and use of opiate pain medications before surgery were significantly higher in adults, perhaps contributing to their merely moderate improvement, compared with younger patients. Such evidence suggests that if adults were to seek treatment earlier or use less pain medication, they would perhaps do better following surgery.
"These factors may be related to age to some degree, but we need to sort that out," Thompson says. "Here we have a young group of patients that consistently does very well after surgery. If we can determine which factors contribute to their good outcomes that are independent of age, we may be able to improve the outcomes even further for our adult patients."
The second paper showed that certain patients may do just as well with a minimally invasive procedure done on an outpatient basis as those who require the traditional surgery. The traditional procedure has an average five-day hospital stay.
This study looked at 200 patients treated for neurogenic thoracic outlet syndrome from 2008 through 2011. To determine the best surgical approach for each patient, the doctor examined two locations of potential nerve compression -- the side of the neck above the collarbone and the upper chest just below the collarbone, near the shoulder.
If patients experienced pain and tenderness in both places, they were offered the traditional procedure that includes removing the first rib and scalene muscles in the neck and detaching the tendon of the pectoralis minor muscle, which connects to the top and front of the shoulder blade. Of the 200 patients, 143 underwent this procedure

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Old Drug May Point the Way to New Treatments for Diabetes and Obesity

Researchers at the University of Michigan's Life Sciences Institute have found that amlexanox, an off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes and fatty liver in mice.
The findings from the lab of Alan Saltiel, the Mary Sue Coleman director of the Life Sciences Institute, are scheduled to be published online Feb. 10 in the journal Nature Medicine.
"One of the reasons that diets are so ineffective in producing weight loss for some people is that their bodies adjust to the reduced calories by also reducing their metabolism, so that they are 'defending' their body weight," Saltiel said. "Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice."
Different formulations of amlexanox are currently prescribed to treat asthma in Japan and canker sores in the United States. Saltiel is teaming up with clinical-trial specialists at U-M to test whether amlexanox will be useful for treating obesity and diabetes in humans. He is also working with medicinal chemists at U-M to develop a new compound based on the drug that optimizes its formula.
The study appears to confirm and extend the notion that the genes IKKE and TBK1 play a crucial role for maintaining metabolic balance, a discovery published by the Saltiel lab in 2009 in the journal Cell.
"Amlexanox appears to work in mice by inhibiting two genes -- IKKE and TBK1 -- that we think together act as a sort of brake on metabolism," Saltiel said. "By releasing the brake, amlexanox seems to free the metabolic system to burn more, and possibly store less, energy."
Using high-throughput chemical screening at LSI'

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