Oncologists have known that in order for cancer cells to spread, they must transform themselves so they can detach from a tumor and spread to a distant organ. Now, scientists at Weill Cornell Medical College have revealed critical steps in what happens next -- how these cells reverse the process, morphing back into classical cancer that can now grow into a new tumor.
Their findings, now published online and in a upcoming issue of Cancer Research and funded through a National Cancer Institute grant to the Cornell Center on the Microenvironment and Metastasis and the Neuberger Berman Foundation, show that a single protein, versican, is key to this process in breast cancer, the tumor they studied. When researchers stopped versican from functioning in mice, breast cancer could not "seed" themselves into the lungs and form secondary tumors.
"Our findings both help us understand how breast cancer metastasizes to the lungs and ways to possibly prevent that deadly spread," says the study's senior investigator, Dr. Vivek Mittal, an associate professor of cell and developmental biology in cardiothoracic surgery and director of the Neuberger Berman Lung Cancer Laboratory at Weill Cornell Medical College.
"These are exciting insights into a poorly investigated area," Dr. Mittal says. "There are no clinically approved drugs now that can effectively target metastatic lesions, which is why more than 90 percent of human cancer-related deaths come from spread of the disease from a primary tumor."
"The results of this study are a critical step in deconstructing the process of metastases -- which is critical to curing our patients," says co-author Dr. Linda T. Vahdat, professor of medicine, chief of the Solid Tumor Service and director of the Breast Cancer Research Program at Weill Cornell. "As a direct result of this study, we are working on ways to interrupt the process by which tumors co-opt the infrastructure in our bodies to grow and spread."
This important study starts to unravel the mechanistic basis of cancer metastases, not only in breast cancer but possibly in other types of cancer, says Dr. Nasser Altorki, the David B. Skinner Professor of Thoracic Surgery at Weill Cornell Medical College and director of the division of thoracic surgery at NewYork-Presbyterian/Weill Cornell. "The need for a prepared and receptive soil may be required for cancer cell seeding regardless of the primary cancer's site of origin."
The Seed and the Soil Cancer researchers have believed that for a cancer to spread, its "seed" must find the right "soil" in a distant organ in order to thrive. And they have hypothesized that this seed is formed through a process known as epithelial-mesenchymal transition (EMT), in which cancer cells lose their sticky grip to other cells in a primary tumor and become more mobile, able to travel through the blood to a distant organ.
But what happens next is conjecture. Scientists have speculated that the cells undergo a reverse process, called mesenchymal-epithelial transition (MET), in which the cancer seeds morph back into epithelial cells that can make contact with tissue and integrate in the new organ. Little is known about MET compared to EMT.
In this study, Dr. Mittal, along with his colleagues at Weill Cornell, studied mouse models of spontaneous breast cancer development. They first discovered that primary breast tumors send a signal that forces bone-marrow-derived hematopoietic cells to move into the lungs of the mice. "This appears to be the soil the cancer seeds need," says Dr. Mittal. The next question was obvious: What is it about the soil that helps the seed?
The team found that a subtype of these bone marrow cells expressed versican, which allowed the cancer cells, once they traveled to the lungs, to morph back into epithelial cells. "The primary tumor sets up the lung microenvironment to promote metastasis," he says. "MET resulted not from properties within the cancer cell itself, but due to a unique crosstalk between the microenvironment and tumor cells in the lung."
In their next experiment, the researchers blocked versican production by injecting small interfering RNAs (siRNAs) in the bone marrow that silenced the versican gene, which prevented MET and blocked tumor outgrowth in the lung.
Human Tumors Express Versican Next, they investigated human breast metastases to the lung, utilizing lung samples obtained from breast cancer patients contributed by researchers at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. "We found versican was highly expressed in those lung tumors, which matched what we found in our mice," Dr. Mittal says. "This all made sense to us, because versican has been linked to cancer progression, although no one knew why.
"This is the first study demonstrating the significance of MET in the formation of macrometastases in distant organs," Dr. Mittal says. "Given the findings, we now have a potential strategy to stop cancer spread before it starts, or to shut it down if it has already occurred."
The study was funded by support from the Neuberger Berman Lung Cancer Laboratory, the Robert I. Goldman Foundation and National Cancer Institute support of the Cornell Center on the Microenvironment and Metastasis.
Study co-authors include, from Weill Cornell Medical College: Dingcheng Gao, Natasha Joshi, Hyejin Choi, Seongho Ryu, Mary Hahn, Raul Catena, Patrick Wagner, Linda T. Vahdat, Jeffrey L. Port, Brendon Stiles and Nasser K. Altorki; from Johns Hopkins University: Saraswati Sukumar, Helen Sadik and Pedram Argani; and Shahin Rafii from the Howard Hughes Medical Institute and Weill Cornell Medical College.
New Clues About How Cancer Cells Communicate and Grow
Researchers have shown that the communication signals sent around the body by cancer cells, which are essential for the cancer to grow, may contain pieces of RNA -- these substances, like DNA, are pieces of genetic code that can instruct cells, and ultimately the body, how to form. The same study also found early indications that these genetic instructions can be intercepted and modified by chemotherapy to help prevent cancer cells growing.
The researchers, from St George's, University of London, believe that these findings add to the body of evidence investigating a new wave of cancer treatment that stimulates the body's immune system to fight the disease. Most current treatment attacks the cancerous cells directly. However, the researchers emphasise that this is an early-stage study and there is much more research to be done before patients will benefit.
The findings are published online by the British Journal of Cancer.
It is believed that when tumour cells develop they can, as part of this process, produce chemicals that travel around the body instructing it to create the ideal environment for the tumour to flourish. An element of this is the creation of new blood vessels, which feed the tumour cell in the same way they would healthy cells -- a process known as angiogenesis.
Previously, it has been thought that this angiogenesis process is sparked by chemical messengers called cytokines. But in laboratory-based experiments conducted with human lung cancer cells outside of the body, researchers at St George's discovered the tumour may also send out packets of RNA that, like the cytokines, instruct blood vessels to form and feed the tumour.
The researchers went on to investigate the effects that two frequently prescribed cancer drugs -- cyclophosphamide and oxaliplatin -- had on angiogenesis. They cultivated RNA messages sent by untreated cancer cells as well as those messages sent by cancer cells that had been treated by the drugs.
They found that when lung cancer cells were treated with oxaliplatin, the RNA and cytokine messages produced by the tumours were no longer capable of influencing vessels to grow.
Lung cancer cells treated with cyclophosphamide, however, were still able to instruct vessels to feed the tumour via these chemical messengers.
Lead researcher Dr Wai Liu, from St George's, University of London, says:
"Currently, drugs fight cancer either by attacking the tumour cell itself or by disrupting the physical interaction between the tumour and the body, which can dislodge the cell. Only very few target the signals sent between tumour cells and those that make up the micro-environment. Partly, this is because little is known about the form of these signals. This study tells us a bit more about how cancer forms and provides a further avenue to explore. Plus it suggests that there may also be existing drugs that can help fight cancer in different ways.
"Although these are early findings and more research is needed, they add to the growing interest in training the body's own immune system to fight cancer and will hopefully help to form the foundations for future medications that exploit this approach."
The researchers, from St George's, University of London, believe that these findings add to the body of evidence investigating a new wave of cancer treatment that stimulates the body's immune system to fight the disease. Most current treatment attacks the cancerous cells directly. However, the researchers emphasise that this is an early-stage study and there is much more research to be done before patients will benefit.
The findings are published online by the British Journal of Cancer.
It is believed that when tumour cells develop they can, as part of this process, produce chemicals that travel around the body instructing it to create the ideal environment for the tumour to flourish. An element of this is the creation of new blood vessels, which feed the tumour cell in the same way they would healthy cells -- a process known as angiogenesis.
Previously, it has been thought that this angiogenesis process is sparked by chemical messengers called cytokines. But in laboratory-based experiments conducted with human lung cancer cells outside of the body, researchers at St George's discovered the tumour may also send out packets of RNA that, like the cytokines, instruct blood vessels to form and feed the tumour.
The researchers went on to investigate the effects that two frequently prescribed cancer drugs -- cyclophosphamide and oxaliplatin -- had on angiogenesis. They cultivated RNA messages sent by untreated cancer cells as well as those messages sent by cancer cells that had been treated by the drugs.
They found that when lung cancer cells were treated with oxaliplatin, the RNA and cytokine messages produced by the tumours were no longer capable of influencing vessels to grow.
Lung cancer cells treated with cyclophosphamide, however, were still able to instruct vessels to feed the tumour via these chemical messengers.
Lead researcher Dr Wai Liu, from St George's, University of London, says:
"Currently, drugs fight cancer either by attacking the tumour cell itself or by disrupting the physical interaction between the tumour and the body, which can dislodge the cell. Only very few target the signals sent between tumour cells and those that make up the micro-environment. Partly, this is because little is known about the form of these signals. This study tells us a bit more about how cancer forms and provides a further avenue to explore. Plus it suggests that there may also be existing drugs that can help fight cancer in different ways.
"Although these are early findings and more research is needed, they add to the growing interest in training the body's own immune system to fight cancer and will hopefully help to form the foundations for future medications that exploit this approach."
Buffett millionaires tax raises $47 billion
A proposed 30 percent minimum tax on millionaires backed by President Barack Obama - dubbed the Buffett tax after investor Warren Buffett who supports it - would raise about $47 billion over a decade, according to a congressional report.
The Joint Committee on Taxation, a nonpartisan body that estimates tax changes for lawmakers, on Tuesday updated an earlier report forecasting that the tax would raise $31 billion over the period, citing economic modeling errors.
Either way, the revenue is far less than the $1 trillion or more that would be lost from scrapping the alternative minimum tax. The AMT also is meant to be a minimum tax on the wealthy. Democrats have said the Buffett tax could replace the AMT.
The Buffett tax proposal has little chance of passing with Republicans in charge of the House of Representatives and its prospects in the Democratic-controlled U.S. Senate are murky.
Taxes are a major topic on the campaign trail ahead of Obama's re-election bid this November.
The Joint Committee on Taxation, a nonpartisan body that estimates tax changes for lawmakers, on Tuesday updated an earlier report forecasting that the tax would raise $31 billion over the period, citing economic modeling errors.
Either way, the revenue is far less than the $1 trillion or more that would be lost from scrapping the alternative minimum tax. The AMT also is meant to be a minimum tax on the wealthy. Democrats have said the Buffett tax could replace the AMT.
The Buffett tax proposal has little chance of passing with Republicans in charge of the House of Representatives and its prospects in the Democratic-controlled U.S. Senate are murky.
Taxes are a major topic on the campaign trail ahead of Obama's re-election bid this November.
Estrogen-Targeting Drug Combo May Help Prevent Lung Cancer
A combination of drugs that target estrogen production significantly reduced the number of tobacco carcinogen-induced lung tumors in mice, according to results from a preclinical study.
"Antiestrogens have been shown to prevent breast cancer in some women," said Jill M. Siegfried, Ph.D., professor in the department of pharmacology and chemical biology at University of Pittsburgh Cancer Institute. "If antiestrogens can prevent lung cancer as well, this would be a major advance, because these drugs are safe to give for long periods and there are no approved ways to prevent lung cancer."
Siegfried presented the results at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine, held Jan. 8-11, 2012.
Most lung cancers are positive for a type of estrogen receptor that makes lung tumors grow when exposed to estrogen. In addition, an enzyme in the lung called aromatase produces estrogen. Siegfried and colleagues hoped that by blocking this estrogen receptor and the aromatase enzyme, they might be able to prevent estrogen-sensitive lung tumors.
To test this theory, they conducted a study on two groups of female mice: one group that was currently being exposed to a tobacco carcinogen and one that had past exposure to a tobacco carcinogen and in which some precancerous cells had already formed. The mice were assigned to treatment with a placebo, the aromatase inhibitor anastrozole, the antiestrogen fulvestrant or a combination of anastrozole and fulvestrant.
"The first model asks whether the treatments inhibit the process by which cancer is first started before it is even detectable under the microscope, and the second asks whether the treatments inhibit the process by which microscopic precancers develop into visible tumors," Siegfried said.
In the first model, the combination treatment given during carcinogen exposure resulted in significantly fewer lung cancer tumors compared with placebo or either treatment alone. The tobacco carcinogen was stopped once treatment began to maximize its ability to halt lung cancer development. Combination treatment also resulted in maximum antitumor effects in the second model, where precancerous cells were already present.
According to Siegfried, these results suggest that antiestrogen treatment combined with an aromatase inhibitor prevents lung cancer development during tobacco carcinogen exposure and after carcinogen damage to the airways has already occurred.
Siegfried said that ultimately, the hope is that this research could lead to an approved treatment that could greatly reduce the risk for an ex-smoker to develop lung cancer.
"We may be able to prevent lung cancer in people who have been previously exposed to tobacco carcinogens using some of the same antiestrogen drugs that can prevent breast cancer," Siegfried said. "A lot of work needs to be done to determine who would benefit from this therapy, and these drugs would need to be tested in clinical trials in those at high risk for lung cancer."
"Antiestrogens have been shown to prevent breast cancer in some women," said Jill M. Siegfried, Ph.D., professor in the department of pharmacology and chemical biology at University of Pittsburgh Cancer Institute. "If antiestrogens can prevent lung cancer as well, this would be a major advance, because these drugs are safe to give for long periods and there are no approved ways to prevent lung cancer."
Siegfried presented the results at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine, held Jan. 8-11, 2012.
Most lung cancers are positive for a type of estrogen receptor that makes lung tumors grow when exposed to estrogen. In addition, an enzyme in the lung called aromatase produces estrogen. Siegfried and colleagues hoped that by blocking this estrogen receptor and the aromatase enzyme, they might be able to prevent estrogen-sensitive lung tumors.
To test this theory, they conducted a study on two groups of female mice: one group that was currently being exposed to a tobacco carcinogen and one that had past exposure to a tobacco carcinogen and in which some precancerous cells had already formed. The mice were assigned to treatment with a placebo, the aromatase inhibitor anastrozole, the antiestrogen fulvestrant or a combination of anastrozole and fulvestrant.
"The first model asks whether the treatments inhibit the process by which cancer is first started before it is even detectable under the microscope, and the second asks whether the treatments inhibit the process by which microscopic precancers develop into visible tumors," Siegfried said.
In the first model, the combination treatment given during carcinogen exposure resulted in significantly fewer lung cancer tumors compared with placebo or either treatment alone. The tobacco carcinogen was stopped once treatment began to maximize its ability to halt lung cancer development. Combination treatment also resulted in maximum antitumor effects in the second model, where precancerous cells were already present.
According to Siegfried, these results suggest that antiestrogen treatment combined with an aromatase inhibitor prevents lung cancer development during tobacco carcinogen exposure and after carcinogen damage to the airways has already occurred.
Siegfried said that ultimately, the hope is that this research could lead to an approved treatment that could greatly reduce the risk for an ex-smoker to develop lung cancer.
"We may be able to prevent lung cancer in people who have been previously exposed to tobacco carcinogens using some of the same antiestrogen drugs that can prevent breast cancer," Siegfried said. "A lot of work needs to be done to determine who would benefit from this therapy, and these drugs would need to be tested in clinical trials in those at high risk for lung cancer."
Major Study Stops Bladder Cancer from Metastasizing to Lungs
The diagnosis of localized bladder cancer carries an 80 percent five-year survival rate, but once the cancer spreads, the survival rate at even three years is only 20 percent. A major study recently published in the Journal of Clinical Investigation not only shows how bladder cancer metastasizes to the lungs but pinpoints a method for stopping this spread.
Specifically, the study shows that versican, a protein involved in cancer cell migration, is a driver of lung metastasis and that high levels of versican are associated with poor prognosis in bladder cancer patients. The study is the first to show how that when a cancer cell makes the protein RhoGDI2, it reduces the cell's production of versican, thus blocking the ability of the cancer cell to grow in the lungs.
"For a decade, we've known that the major challenge of treating bladder cancer is treating or preventing the metastatic form of the disease. This study represents an advance in the latter -- by preventing the spread of bladder cancer to the lungs, we could improve patient survival," says Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center, the paper's senior author.
When a cancer metastasizes from its birth location to another, it's not necessarily that cells suddenly become mobile and thus able to float through the blood or lymph to new homes. In fact, these cancer cells may have been floating through a patient's blood for quite some time, and metastasis occurs only when one of these intrepid cells is finally able to grow in the place where it is attached, such as the lungs.
When the first cancer cells to attach to, say, the lung, they have a tough time -- they become distressed. Cancer cells express this distress in the form of versican. And the more versican they express, the more help they get, which arrives in the form of macrophages, a part of the body's immune response that eat pathogens and other debris.
In most cases, the fact that macrophages benefit distressed cells is good, but in addition to helping healthy cells survive, these arriving macrophages also promote the growth of cancer cells that have landed in distant sites such as the lung, thus promoting metastasis of the disease.
More versican made by the cancer cells calls more macrophages, which aid cancer cells' survival and increase the likelihood that a cancer cell's toehold will develop into a clinically significant tumor in the lung.
Theodorescu and colleagues showed that the protein RhoGDI2 reduces the expression of versican. Cancer cells that make more RhoDI2 produce less versican and thus call fewer macrophages, making it difficult for these high-RhoGDI2 cancer cells to survive.
Sure enough, when Theodorescu and colleagues added RhoGDI2 to tumors, versican went down and with it so did metastasis.
"We believe this study provides an important contribution to the scientific literature by delineating for the first time a new mechanism of metastasis suppression, namely that suppression of metastasis is possible by altering the tumor microenvironment, including reducing the presence macrophages," Theodorescu says.
In fact, this paper also shows for the first time one more step: versican's ability to attract macrophages to the tumor depends on a protein called CCL2. This step is important because drugs that inhibit CCL2 are already in clinical trials for other conditions.
If the effect in humans is the same as the effect in the laboratory -- namely that inhibiting CCL2 reduces versican's ability to attract the macrophages that promote tumor growth at distant sites -- one of these CCL2 inhibitors could soon become part of the treatment regimen for bladder cancer patients with tumors that make low levels of RhoGDI2 and high versican. This approach has the potential to lower the chance of bladder cancer metastasis and thus a significantly improved outcome for patients with high risk bladder cancer.
Specifically, the study shows that versican, a protein involved in cancer cell migration, is a driver of lung metastasis and that high levels of versican are associated with poor prognosis in bladder cancer patients. The study is the first to show how that when a cancer cell makes the protein RhoGDI2, it reduces the cell's production of versican, thus blocking the ability of the cancer cell to grow in the lungs.
"For a decade, we've known that the major challenge of treating bladder cancer is treating or preventing the metastatic form of the disease. This study represents an advance in the latter -- by preventing the spread of bladder cancer to the lungs, we could improve patient survival," says Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center, the paper's senior author.
When a cancer metastasizes from its birth location to another, it's not necessarily that cells suddenly become mobile and thus able to float through the blood or lymph to new homes. In fact, these cancer cells may have been floating through a patient's blood for quite some time, and metastasis occurs only when one of these intrepid cells is finally able to grow in the place where it is attached, such as the lungs.
When the first cancer cells to attach to, say, the lung, they have a tough time -- they become distressed. Cancer cells express this distress in the form of versican. And the more versican they express, the more help they get, which arrives in the form of macrophages, a part of the body's immune response that eat pathogens and other debris.
In most cases, the fact that macrophages benefit distressed cells is good, but in addition to helping healthy cells survive, these arriving macrophages also promote the growth of cancer cells that have landed in distant sites such as the lung, thus promoting metastasis of the disease.
More versican made by the cancer cells calls more macrophages, which aid cancer cells' survival and increase the likelihood that a cancer cell's toehold will develop into a clinically significant tumor in the lung.
Theodorescu and colleagues showed that the protein RhoGDI2 reduces the expression of versican. Cancer cells that make more RhoDI2 produce less versican and thus call fewer macrophages, making it difficult for these high-RhoGDI2 cancer cells to survive.
Sure enough, when Theodorescu and colleagues added RhoGDI2 to tumors, versican went down and with it so did metastasis.
"We believe this study provides an important contribution to the scientific literature by delineating for the first time a new mechanism of metastasis suppression, namely that suppression of metastasis is possible by altering the tumor microenvironment, including reducing the presence macrophages," Theodorescu says.
In fact, this paper also shows for the first time one more step: versican's ability to attract macrophages to the tumor depends on a protein called CCL2. This step is important because drugs that inhibit CCL2 are already in clinical trials for other conditions.
If the effect in humans is the same as the effect in the laboratory -- namely that inhibiting CCL2 reduces versican's ability to attract the macrophages that promote tumor growth at distant sites -- one of these CCL2 inhibitors could soon become part of the treatment regimen for bladder cancer patients with tumors that make low levels of RhoGDI2 and high versican. This approach has the potential to lower the chance of bladder cancer metastasis and thus a significantly improved outcome for patients with high risk bladder cancer.
Precancer Markers Identified in Airway Epithelium Cells of Healthy Smokers
Smoking may be associated with the development of molecular features of cancer in the large airway epithelium. In the small airway epithelium, molecular cancerization is associated with development of chronic obstructive pulmonary disease, according to recent data.
"We are striving to find the earliest molecular changes that are induced by environmental stressors -- in this case, smoking," said Renat Shaykhiev, M.D., Ph.D., assistant professor of genetic medicine at Weill Cornell Medical College, who presented the findings at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine, held Jan. 8-11, 2012. "Our goal is to understand the early pathogenesis of lung cancer and to develop strategies to prevent lung cancer in susceptible individuals."
Shaykhiev and colleagues analyzed the large and small airway epithelia of healthy nonsmokers, healthy smokers and smokers with chronic obstructive pulmonary disease (COPD), which is typically caused by long-term smoking, for expression of so-called "molecular cancerization" features (i.e., the genes upregulated in lung cancer compared with nonmalignant adjacent tissue).
Researchers found significantly more cancer-like gene expression changes in the large airway epithelia of smokers than in those of nonsmokers. When analyzing the small airway epithelium, though, they did not find significant differences between healthy smokers and nonsmokers, but they did find significant overall upregulation of cancerization genes in smokers with COPD. Analysis of these genes in the large and small airway epithelia obtained from the same individuals revealed that molecular cancerization occurs more frequently in the large airway epithelium than in the small airway epithelium.
Shaykhiev and colleagues drew the following conclusions: Smoking is associated with acquisition of molecular cancerization features in the large airway epithelium prior to the development of disease, and the large airway epithelium is likely more susceptible to smoking-induced changes than the small airway epithelium, implying that it may be the primary site of molecular alterations leading to lung cancer in smokers.
These findings could potentially lead to the development of a diagnostic test that would look for these genetic changes in susceptible individuals, the researchers suggested. "Ideally, we would use these genes to do very routine analysis to determine which smokers or even nonsmokers are at risk for development of lung cancer," said Shaykhiev.
"We are striving to find the earliest molecular changes that are induced by environmental stressors -- in this case, smoking," said Renat Shaykhiev, M.D., Ph.D., assistant professor of genetic medicine at Weill Cornell Medical College, who presented the findings at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine, held Jan. 8-11, 2012. "Our goal is to understand the early pathogenesis of lung cancer and to develop strategies to prevent lung cancer in susceptible individuals."
Shaykhiev and colleagues analyzed the large and small airway epithelia of healthy nonsmokers, healthy smokers and smokers with chronic obstructive pulmonary disease (COPD), which is typically caused by long-term smoking, for expression of so-called "molecular cancerization" features (i.e., the genes upregulated in lung cancer compared with nonmalignant adjacent tissue).
Researchers found significantly more cancer-like gene expression changes in the large airway epithelia of smokers than in those of nonsmokers. When analyzing the small airway epithelium, though, they did not find significant differences between healthy smokers and nonsmokers, but they did find significant overall upregulation of cancerization genes in smokers with COPD. Analysis of these genes in the large and small airway epithelia obtained from the same individuals revealed that molecular cancerization occurs more frequently in the large airway epithelium than in the small airway epithelium.
Shaykhiev and colleagues drew the following conclusions: Smoking is associated with acquisition of molecular cancerization features in the large airway epithelium prior to the development of disease, and the large airway epithelium is likely more susceptible to smoking-induced changes than the small airway epithelium, implying that it may be the primary site of molecular alterations leading to lung cancer in smokers.
These findings could potentially lead to the development of a diagnostic test that would look for these genetic changes in susceptible individuals, the researchers suggested. "Ideally, we would use these genes to do very routine analysis to determine which smokers or even nonsmokers are at risk for development of lung cancer," said Shaykhiev.
Collaborative Research Sheds Light On New Cancer Stem Cell Therapies
A collaborative anti-cancer research jointly conducted by The Hong Kong Polytechnic University (PolyU), Peking University Shenzhen Graduate School and Nevada Cancer Institute has led to the development of a novel class of chemical inhibitors that specifically target cancer cells with pluripotency.
This cutting-edge research has combined the effort of three research teams including one led by Dr Tao Ye (葉濤), Associate Professor of PolyU's Department of Applied Biology and Chemical Technology. This breakthrough may help the selective removal of cancer stem cells and potentially provide a novel strategy to eradicate cancers.
Cancer is a major cause of human death in China and all around the world. It is difficult to treat cause of the existence of cancer initiating cells/cancer stem cells. Although they exist in very few in numbers, cancer stem cells (CSCs) can proliferate and self-renew, and are pluripotent and multipotent, which have the capability to differentiate into various more heterogeneous cancer cells that constitute the entire tumor mass. As stem cells, they are more resistant to most conventional cancer therapies such as chemotherapy or radiotherapy due to their differences in the cell cycle regulation and DNA repair processes. They also act as the source for metastasis and recurring drug resistant cancers after conventional cancer therapy. Currently, there are no chemical inhibitors or other agents that can specifically and selectively target cancer stem cells. The development of compounds that target cancer stem cells is an unmet medical demand for the eradication of malignant cancers.
According to Dr Ye, the potential clinical applications of new LSD1 inhibitors include the following:
(1) They can be used to treat malignant germ cell tumors such as teratoma/teratocarcinomas, embryonic carcinomas, seminomas, choriocarcinomas, and tumors of yolk sac. These tumors are usually treated by surgery or cis-platinum, but after initial treatment, these tumors always become resistant to platinum drugs. So far, the LSD1 inhibitors are highly effective towards these pluriptont cancers with stem cell properties.
(2) The LSD1 inhibitors may also be used to remove teratomas/embryonic carcinomas during stem cell-based therapy. One major problem in stem/iPS cell-based therapy is the formation of embryonic carcinomas, teratomas, or teratocarcinomas by incomplete differentiation of ES/iPS cells in the organs of recipients. Because LSD1 selectively inhibit these pluripotent embryonic carcinomas, teratomas, or teratocarcinomas, LSD1 inhibitors may help ensure the successful application of stem cell-based therapy.
(3) More importantly, since teratomas/embryonic carcinomas are pluripotent cancer stem cells, researchers will probe whether cancer stem cells of other types of major organ-specific cancers such as breast, ovarian, lung, and brain cancers are sensitive to these LSD1 inhibitors. Further studies indicated that LSD1 inhibitors can also be used to inhibit many cancer stem cell-like cells such as breast and ovarian cancers.
This cutting-edge research has combined the effort of three research teams including one led by Dr Tao Ye (葉濤), Associate Professor of PolyU's Department of Applied Biology and Chemical Technology. This breakthrough may help the selective removal of cancer stem cells and potentially provide a novel strategy to eradicate cancers.
Cancer is a major cause of human death in China and all around the world. It is difficult to treat cause of the existence of cancer initiating cells/cancer stem cells. Although they exist in very few in numbers, cancer stem cells (CSCs) can proliferate and self-renew, and are pluripotent and multipotent, which have the capability to differentiate into various more heterogeneous cancer cells that constitute the entire tumor mass. As stem cells, they are more resistant to most conventional cancer therapies such as chemotherapy or radiotherapy due to their differences in the cell cycle regulation and DNA repair processes. They also act as the source for metastasis and recurring drug resistant cancers after conventional cancer therapy. Currently, there are no chemical inhibitors or other agents that can specifically and selectively target cancer stem cells. The development of compounds that target cancer stem cells is an unmet medical demand for the eradication of malignant cancers.
According to Dr Ye, the potential clinical applications of new LSD1 inhibitors include the following:
(1) They can be used to treat malignant germ cell tumors such as teratoma/teratocarcinomas, embryonic carcinomas, seminomas, choriocarcinomas, and tumors of yolk sac. These tumors are usually treated by surgery or cis-platinum, but after initial treatment, these tumors always become resistant to platinum drugs. So far, the LSD1 inhibitors are highly effective towards these pluriptont cancers with stem cell properties.
(2) The LSD1 inhibitors may also be used to remove teratomas/embryonic carcinomas during stem cell-based therapy. One major problem in stem/iPS cell-based therapy is the formation of embryonic carcinomas, teratomas, or teratocarcinomas by incomplete differentiation of ES/iPS cells in the organs of recipients. Because LSD1 selectively inhibit these pluripotent embryonic carcinomas, teratomas, or teratocarcinomas, LSD1 inhibitors may help ensure the successful application of stem cell-based therapy.
(3) More importantly, since teratomas/embryonic carcinomas are pluripotent cancer stem cells, researchers will probe whether cancer stem cells of other types of major organ-specific cancers such as breast, ovarian, lung, and brain cancers are sensitive to these LSD1 inhibitors. Further studies indicated that LSD1 inhibitors can also be used to inhibit many cancer stem cell-like cells such as breast and ovarian cancers.
Many People Continue to Smoke After Being Diagnosed With Cancer
A new analysis has found that a substantial number of lung and colorectal cancer patients continue to smoke after being diagnosed. Published early online in CANCER, a peer-reviewed journal of the American Cancer Society, the study provides valuable information on which cancer patients might need help to quit smoking.
When a patient receives a cancer diagnosis, the main focus is to treat the disease. But stopping smoking after a cancer diagnosis is also important because continuing to smoke can negatively affect patients' responses to treatments, their subsequent cancer risk, and, potentially, their survival. Elyse R. Park, PhD, MPH, of the Massachusetts General Hospital/Harvard Medical School in Boston, led a team that looked to see how many patients quit smoking around the time of a cancer diagnosis, and which smokers were most likely to quit.
The investigators determined smoking rates around the time of diagnosis and five months after diagnosis in 5,338 lung and colorectal cancer patients. At diagnosis, 39 percent of lung cancer patients and 14 percent of colorectal cancer patients were smoking; five months later, 14 percent of lung cancer patients and 9 percent of colorectal cancer patients were still smoking. These results indicate that a substantial minority of cancer patients continue to smoke after being diagnosed. Also, although lung cancer patients have higher rates of smoking at diagnosis and following diagnosis, colorectal cancer patients are less likely to quit smoking following diagnosis.
Factors and characteristics that predicted continued smoking differed by cancer type. Lung cancer patients who continued smoking tended to have Medicare or other public health insurance, have a lower body mass index, have low emotional support, not have received chemotherapy, not have had surgery, have had prior heart disease, and have smoked a high number of cigarettes per day at some point during their lives. Colorectal cancer patients who continued to smoke tended to be male, have completed less education, be uninsured, not have had surgery, and have once smoked a high number of cigarettes per day.
"These findings can help cancer clinicians identify patients who are at risk for smoking and guide tobacco counseling treatment development for cancer patients," said Dr. Park.
In an accompanying editorial, Carolyn Dressler, MD, of the Arkansas Department of Health in Little Rock, noted that Dr. Park's research highlights the critical importance of physicians and other caretakers to address tobacco cessation, particularly at the time of diagnosis. "Most clinicians acknowledge the importance of addressing tobacco cessation in their patients; however, few do it," she wrote. "We know enough now to implement effective cessation programs to identify and help cancer patients quit at the time of diagnosis and support them to prevent relapse. By doing so, we maximize patients' response to therapy, their quality of life, and their longevity."
When a patient receives a cancer diagnosis, the main focus is to treat the disease. But stopping smoking after a cancer diagnosis is also important because continuing to smoke can negatively affect patients' responses to treatments, their subsequent cancer risk, and, potentially, their survival. Elyse R. Park, PhD, MPH, of the Massachusetts General Hospital/Harvard Medical School in Boston, led a team that looked to see how many patients quit smoking around the time of a cancer diagnosis, and which smokers were most likely to quit.
The investigators determined smoking rates around the time of diagnosis and five months after diagnosis in 5,338 lung and colorectal cancer patients. At diagnosis, 39 percent of lung cancer patients and 14 percent of colorectal cancer patients were smoking; five months later, 14 percent of lung cancer patients and 9 percent of colorectal cancer patients were still smoking. These results indicate that a substantial minority of cancer patients continue to smoke after being diagnosed. Also, although lung cancer patients have higher rates of smoking at diagnosis and following diagnosis, colorectal cancer patients are less likely to quit smoking following diagnosis.
Factors and characteristics that predicted continued smoking differed by cancer type. Lung cancer patients who continued smoking tended to have Medicare or other public health insurance, have a lower body mass index, have low emotional support, not have received chemotherapy, not have had surgery, have had prior heart disease, and have smoked a high number of cigarettes per day at some point during their lives. Colorectal cancer patients who continued to smoke tended to be male, have completed less education, be uninsured, not have had surgery, and have once smoked a high number of cigarettes per day.
"These findings can help cancer clinicians identify patients who are at risk for smoking and guide tobacco counseling treatment development for cancer patients," said Dr. Park.
In an accompanying editorial, Carolyn Dressler, MD, of the Arkansas Department of Health in Little Rock, noted that Dr. Park's research highlights the critical importance of physicians and other caretakers to address tobacco cessation, particularly at the time of diagnosis. "Most clinicians acknowledge the importance of addressing tobacco cessation in their patients; however, few do it," she wrote. "We know enough now to implement effective cessation programs to identify and help cancer patients quit at the time of diagnosis and support them to prevent relapse. By doing so, we maximize patients' response to therapy, their quality of life, and their longevity."
Study Maps Destructive Path from Cigarette to Emphysema
From the cherry red tip of a lighted cigarette through the respiratory tract to vital lung cells, the havoc created by tobacco smoke seems almost criminal, activating genes and portions of the immune system to create inflammation that results in life-shortening emphysema, said researchers led by those at Baylor College of Medicine and the Michael E. DeBakey Veterans Affairs Medical Center.
In a report online in the journal Science Translational Medicine, the scientists, including two from The University of Texas MD Anderson Cancer Center, described the track toxic smoke takes through the tissues and how it accomplishes its destructive work.
Cause of emphysema identified
"It's like walking into a crime scene," said Dr. Farrah Kheradmand, professor of medicine and immunology at BCM and a senior author of the report. In their current work, the scientists took cells present in the "crime scene" apart, piece by piece to elucidate what occurred when, and how.
It is a complicated story that took more than four years for her, her co-senior author Dr. David Corry and members of their laboratories and colleagues in the Dan L. Duncan Cancer Center at BCM to unravel, she said. Corry is professor and chief of the section of immunology, allergy and rheumatology in the department of medicine at BCM and a member of the faculty at the Michael E. DeBakey VA Medical Center.
"Previously, emphysema was thought to be a non-specific injurious response to long-term smoke exposure," she said. "These studies show for the first time that emphysema is caused by a specific immune response induced by smoke."
Epigenetic factor
"It is a combination of little genes affected by an epigenetic factor," she said. Epigenetics are factors that affect the way genes are expressed after DNA forms. Cigarette smoke is an environmental epigenetic factor.
"DNA is written in pen," said Kheradmand, using a metaphor. "Epigenetics is written in pencil. If you have enough genes affected by epigenetic factors strung together, it can tip you over into lung damage and emphysema. The inflammation that drives emphysema could also drive cancer development, a testable hypothesis that we have begun to pursue."
This study showed that the cigarette recruited antigen-presenting cells (cells that orchestrate the immune system's response to antigens) as co-conspirators in the lung-destroying crime, using specific genes that regulate proteins in their deadly role.
Study methodology
To uncover the cause of tobacco-induced emphysema, they studied mice exposed to conditions that closely simulated how humans smoke. These animals developed the lung disease in three to four months. Certain inflammatory cells and genes proving crucial to the process, she said.
For example, the cytokine interleukin-17 was critical. "When we removed IL-17 from the mice, they did not develop emphysema in the same time span," she said. "The number of a type of immune cell -- the gamma delta T-cell -- would increase dramatically in the crime scene of the lung, she said."
"But when we took them out, the inflammation worsened. The gamma delta T-cells went there to dampen the inflammation," she said. "When they become overwhelmed, the disease ensues."
They confirmed that a subset of antigen-presenting cells (cells that present antigen to activate the immune system) are the key to orchestrating the disease. They had first found these cells in studies of human lung tissue. Then, they duplicated that finding in mice.
Damaging cascade
Dr. Ming Shan, now a postdoctoral associate in Kheradmand's laboratory, then took the cells out of the lungs of the mice with disease and transferred into mice who had never been exposed to cigarette smoke. After three months, these mice showed inflammatory signs indicating that they were on the way to developing lung damage and emphysema.
When they analyzed "gene chips" to screen the disease-causing antigen-presenting cells recovered from lungs with emphysema, they uncovered the gene for osteopontin, which promotes initiation of the inflammatory cascade that damages lungs. Mice that lacked this gene were resistant to emphysema, said Kheradmand.
Others who took part in this work include Xiaoyi Yuan,Li-zhen Song, Luz Roberts, Nazanin Zarinkamar, Alexander Seryshev, Yiqun Zhang and Susan Hilsenbeck, all of BCM and Seon-Hee Chang and Chen Dong of MD Anderson.
Funding for this work came from a Veterans Affairs merit award and the National Institutes of Health.
In a report online in the journal Science Translational Medicine, the scientists, including two from The University of Texas MD Anderson Cancer Center, described the track toxic smoke takes through the tissues and how it accomplishes its destructive work.
Cause of emphysema identified
"It's like walking into a crime scene," said Dr. Farrah Kheradmand, professor of medicine and immunology at BCM and a senior author of the report. In their current work, the scientists took cells present in the "crime scene" apart, piece by piece to elucidate what occurred when, and how.
It is a complicated story that took more than four years for her, her co-senior author Dr. David Corry and members of their laboratories and colleagues in the Dan L. Duncan Cancer Center at BCM to unravel, she said. Corry is professor and chief of the section of immunology, allergy and rheumatology in the department of medicine at BCM and a member of the faculty at the Michael E. DeBakey VA Medical Center.
"Previously, emphysema was thought to be a non-specific injurious response to long-term smoke exposure," she said. "These studies show for the first time that emphysema is caused by a specific immune response induced by smoke."
Epigenetic factor
"It is a combination of little genes affected by an epigenetic factor," she said. Epigenetics are factors that affect the way genes are expressed after DNA forms. Cigarette smoke is an environmental epigenetic factor.
"DNA is written in pen," said Kheradmand, using a metaphor. "Epigenetics is written in pencil. If you have enough genes affected by epigenetic factors strung together, it can tip you over into lung damage and emphysema. The inflammation that drives emphysema could also drive cancer development, a testable hypothesis that we have begun to pursue."
This study showed that the cigarette recruited antigen-presenting cells (cells that orchestrate the immune system's response to antigens) as co-conspirators in the lung-destroying crime, using specific genes that regulate proteins in their deadly role.
Study methodology
To uncover the cause of tobacco-induced emphysema, they studied mice exposed to conditions that closely simulated how humans smoke. These animals developed the lung disease in three to four months. Certain inflammatory cells and genes proving crucial to the process, she said.
For example, the cytokine interleukin-17 was critical. "When we removed IL-17 from the mice, they did not develop emphysema in the same time span," she said. "The number of a type of immune cell -- the gamma delta T-cell -- would increase dramatically in the crime scene of the lung, she said."
"But when we took them out, the inflammation worsened. The gamma delta T-cells went there to dampen the inflammation," she said. "When they become overwhelmed, the disease ensues."
They confirmed that a subset of antigen-presenting cells (cells that present antigen to activate the immune system) are the key to orchestrating the disease. They had first found these cells in studies of human lung tissue. Then, they duplicated that finding in mice.
Damaging cascade
Dr. Ming Shan, now a postdoctoral associate in Kheradmand's laboratory, then took the cells out of the lungs of the mice with disease and transferred into mice who had never been exposed to cigarette smoke. After three months, these mice showed inflammatory signs indicating that they were on the way to developing lung damage and emphysema.
When they analyzed "gene chips" to screen the disease-causing antigen-presenting cells recovered from lungs with emphysema, they uncovered the gene for osteopontin, which promotes initiation of the inflammatory cascade that damages lungs. Mice that lacked this gene were resistant to emphysema, said Kheradmand.
Others who took part in this work include Xiaoyi Yuan,Li-zhen Song, Luz Roberts, Nazanin Zarinkamar, Alexander Seryshev, Yiqun Zhang and Susan Hilsenbeck, all of BCM and Seon-Hee Chang and Chen Dong of MD Anderson.
Funding for this work came from a Veterans Affairs merit award and the National Institutes of Health.
Facebook's Dark Side
When Darth Vader was introduced as the dark side of the Force in the first installment of the original trilogy, "Star Wars Episode IV: A New Hope" (1977), Christopher Carpenter, the 30-year old assistant professor of communication at Western Illinois University, was not yet born.
Now, Carpenter is getting worldwide news coverage for his study of the "dark side," but on the timely subject of Facebook.
Carpenter's study, "Narcissism on Facebook: Self-promotional and Anti-social Behavior," is published in the journal Personality and Individual Differences.
Narcissism is defined in this study as "a pervasive pattern of grandiosity, need for admiration and an exaggerated sense of self-importance," Carpenter said.
For the average narcissist, Facebook "offers a gateway for hundreds of shallow relationships and emotionally detached communication." More importantly, for this study, social networking in general allows the user a great deal of control over how he or she is presented to and perceived by peers and other users, he added.
The narcissistic personality inventory (NPI) survey sample included 292 individuals, which measured self-promoting Facebook behaviors, such as posting status updates, photos of oneself and updating profile information; and several anti-social behaviors, including seeking social support more than providing it, getting angry when others do not comment on status updates and retaliating against negative comments.
Carpenter's research methods class emailed people they knew and asked them to complete the survey. Approximately 75 percent of respondents were college students, he said.
He hypothesized the grandiose exhibitionism (GE) subscale of the NPI would predict the self-promoting behaviors. The entitlement/exploitativeness (EE) subscale was hypothesized to predict the anti-social behaviors. GE includes vanity, superiority, self-absorption and exhibitionistic tendencies. EE includes a sense of deserving respect and a willingness to manipulate and take advantage of others, Carpenter explained.
Results showed grandiose exhibitionism correlated with self-promotion and entitlement/exploitativeness correlated with anti-social behaviors on Facebook. Self-esteem was unrelated to self-promotion behaviors and it was negatively associated with some anti-social behaviors (i.e. self-esteem was related to less of these anti-social behaviors).
"If Facebook is to be a place where people go to repair their damaged ego and seek social support, it is vitally important to discover the potentially negative communication one might find on Facebook and the kinds of people likely to engage in them. Ideally, people will engage in pro-social Facebooking rather than anti-social me-booking.
"In general, the 'dark side' of Facebook requires more research in order to better understand Facebook's socially beneficial and harmful aspects in order to enhance the former and curtail the latter," added Carpenter, who joined the Western Illinois University communication department in Fall 2010.
Now, Carpenter is getting worldwide news coverage for his study of the "dark side," but on the timely subject of Facebook.
Carpenter's study, "Narcissism on Facebook: Self-promotional and Anti-social Behavior," is published in the journal Personality and Individual Differences.
Narcissism is defined in this study as "a pervasive pattern of grandiosity, need for admiration and an exaggerated sense of self-importance," Carpenter said.
For the average narcissist, Facebook "offers a gateway for hundreds of shallow relationships and emotionally detached communication." More importantly, for this study, social networking in general allows the user a great deal of control over how he or she is presented to and perceived by peers and other users, he added.
The narcissistic personality inventory (NPI) survey sample included 292 individuals, which measured self-promoting Facebook behaviors, such as posting status updates, photos of oneself and updating profile information; and several anti-social behaviors, including seeking social support more than providing it, getting angry when others do not comment on status updates and retaliating against negative comments.
Carpenter's research methods class emailed people they knew and asked them to complete the survey. Approximately 75 percent of respondents were college students, he said.
He hypothesized the grandiose exhibitionism (GE) subscale of the NPI would predict the self-promoting behaviors. The entitlement/exploitativeness (EE) subscale was hypothesized to predict the anti-social behaviors. GE includes vanity, superiority, self-absorption and exhibitionistic tendencies. EE includes a sense of deserving respect and a willingness to manipulate and take advantage of others, Carpenter explained.
Results showed grandiose exhibitionism correlated with self-promotion and entitlement/exploitativeness correlated with anti-social behaviors on Facebook. Self-esteem was unrelated to self-promotion behaviors and it was negatively associated with some anti-social behaviors (i.e. self-esteem was related to less of these anti-social behaviors).
"If Facebook is to be a place where people go to repair their damaged ego and seek social support, it is vitally important to discover the potentially negative communication one might find on Facebook and the kinds of people likely to engage in them. Ideally, people will engage in pro-social Facebooking rather than anti-social me-booking.
"In general, the 'dark side' of Facebook requires more research in order to better understand Facebook's socially beneficial and harmful aspects in order to enhance the former and curtail the latter," added Carpenter, who joined the Western Illinois University communication department in Fall 2010.
Smoking May Restore Tapped-Out Self-Control Resources
Researchers at Moffitt Cancer Center in Tampa, Fla., have found that when they deplete a smoker's self control, smoking a cigarette may restore self-control.
The study, published in a recent issue of the Journal of Abnormal Psychology, exposed a test group and a control group -- totaling 132 nicotine dependent smokers -- to an emotional video depicting environmental damage. One group in the study expressed their natural emotional reactions (no depletion of self-control) while the second group suppressed their responses (self-control depletion). Half of the participants in each group were subsequently allowed to smoke a cigarette. Everyone then was asked to complete a frustrating task that required self-control.
"Our goal was to study whether tobacco smoking affects an individual's self-control resources," said lead author Bryan W. Heckman, M.A., a graduate student at the Moffitt Tobacco Research and Intervention Program and the Department of Psychology at the University of South Florida. "We hypothesized that participants who underwent a self-control depletion task would demonstrate less persistence on behavioral tasks requiring self-control as compared to those with self-control intact, when neither group was allowed to smoke. However, we also hypothesized that we would not find this performance decrement among participants who were permitted to smoke."
The investigators' hypotheses were supported.
"We found that smoking did have a restorative effect on an individual's depleted self-control resources," said Heckman. "Moreover, smoking restored self-control, in part, by improving smokers' positive mood."
According to the researchers, evidence is mounting to suggest that self-control is a limited resource that acts like a muscle -- expending self-control on a task has the short-term effect of depleting the resource, making it more difficult to engage in another task that requires self-control. While nicotine has been found to enhance performance on a variety of cognitive activities, such as motor abilities, attention and memory, this study was the first to evaluate the effects of smoking on self-control. It suggests that the desire to restore depleted self-control may contribute to smokers' addiction to tobacco.
"Smoking is obviously a maladaptive way to restore self-control," said study co-author Thomas H. Brandon, Ph.D., chair of the Department of Health Outcomes and Behavior at Moffitt Cancer Center, and psychology professor at USF. "Finding other ways to relax or enhance one's mood would be much healthier alternatives. In fact, even raising glucose level -- perhaps by consuming a sugary drink -- has been shown to restore self-control."
This study suggests that smokers wanting to quit may benefit from learning such alternative self-control restoration strategies as a way to reduce their dependence on tobacco. The authors concluded that smoking cessation treatments would benefit by further research aimed at identifying how smoking restores self-control, as well as identifying additional alternative strategies for strengthening or restoring self-control.
The study, published in a recent issue of the Journal of Abnormal Psychology, exposed a test group and a control group -- totaling 132 nicotine dependent smokers -- to an emotional video depicting environmental damage. One group in the study expressed their natural emotional reactions (no depletion of self-control) while the second group suppressed their responses (self-control depletion). Half of the participants in each group were subsequently allowed to smoke a cigarette. Everyone then was asked to complete a frustrating task that required self-control.
"Our goal was to study whether tobacco smoking affects an individual's self-control resources," said lead author Bryan W. Heckman, M.A., a graduate student at the Moffitt Tobacco Research and Intervention Program and the Department of Psychology at the University of South Florida. "We hypothesized that participants who underwent a self-control depletion task would demonstrate less persistence on behavioral tasks requiring self-control as compared to those with self-control intact, when neither group was allowed to smoke. However, we also hypothesized that we would not find this performance decrement among participants who were permitted to smoke."
The investigators' hypotheses were supported.
"We found that smoking did have a restorative effect on an individual's depleted self-control resources," said Heckman. "Moreover, smoking restored self-control, in part, by improving smokers' positive mood."
According to the researchers, evidence is mounting to suggest that self-control is a limited resource that acts like a muscle -- expending self-control on a task has the short-term effect of depleting the resource, making it more difficult to engage in another task that requires self-control. While nicotine has been found to enhance performance on a variety of cognitive activities, such as motor abilities, attention and memory, this study was the first to evaluate the effects of smoking on self-control. It suggests that the desire to restore depleted self-control may contribute to smokers' addiction to tobacco.
"Smoking is obviously a maladaptive way to restore self-control," said study co-author Thomas H. Brandon, Ph.D., chair of the Department of Health Outcomes and Behavior at Moffitt Cancer Center, and psychology professor at USF. "Finding other ways to relax or enhance one's mood would be much healthier alternatives. In fact, even raising glucose level -- perhaps by consuming a sugary drink -- has been shown to restore self-control."
This study suggests that smokers wanting to quit may benefit from learning such alternative self-control restoration strategies as a way to reduce their dependence on tobacco. The authors concluded that smoking cessation treatments would benefit by further research aimed at identifying how smoking restores self-control, as well as identifying additional alternative strategies for strengthening or restoring self-control.
Autism Risk Gene Linked to Differences in Brain Structure
Healthy individuals who carry a gene variation linked to an increased risk of autism have structural differences in their brains that may help explain how the gene affects brain function and increases vulnerability for autism. The results of this innovative brain imaging study are described in an article in the groundbreaking neuroscience journal Brain Connectivity, a bimonthly peer-reviewed publication from Mary Ann Liebert, Inc. The article is available free online at the Brain Connectivity website.
"This is one of the first papers demonstrating a linkage between a particular gene variant and changes in brain structure and connectivity in carriers of that gene," says Christopher Pawela, PhD, Co-Editor-in-Chief and Assistant Professor, Medical College of Wisconsin. "This work could lead to the creation of an exciting new line of research investigating the impact of genetics on communication between brain regions."
Although carriers of the common gene variant CNTNAP2 -- identified as an autism risk gene -- may not develop autism, there is evidence of differences in brain structure that may affect connections and signaling between brain regions. These disruptions in brain connectivity can give rise to functional abnormalities characteristic of neuropsychological disorders such as autism.
Emily Dennis and coauthors from UCLA School of Medicine and UCLA (Los Angeles, CA) and University of Queensland and Queensland Institute of Medical Research (Brisbane, Australia), used a sophisticated imaging technique to study the brains of healthy young adults who are carriers of CNTNAP2.
"This is one of the first papers demonstrating a linkage between a particular gene variant and changes in brain structure and connectivity in carriers of that gene," says Christopher Pawela, PhD, Co-Editor-in-Chief and Assistant Professor, Medical College of Wisconsin. "This work could lead to the creation of an exciting new line of research investigating the impact of genetics on communication between brain regions."
Although carriers of the common gene variant CNTNAP2 -- identified as an autism risk gene -- may not develop autism, there is evidence of differences in brain structure that may affect connections and signaling between brain regions. These disruptions in brain connectivity can give rise to functional abnormalities characteristic of neuropsychological disorders such as autism.
Emily Dennis and coauthors from UCLA School of Medicine and UCLA (Los Angeles, CA) and University of Queensland and Queensland Institute of Medical Research (Brisbane, Australia), used a sophisticated imaging technique to study the brains of healthy young adults who are carriers of CNTNAP2.
Differences in Brain Function for Children With Math Anxiety
Scientists at the Stanford University School of Medicine have shown for the first time how brain function differs in people who have math anxiety from those who don't.
A series of scans conducted while second- and third-grade students did addition and subtraction revealed that those who feel panicky about doing math had increased activity in brain regions associated with fear, which caused decreased activity in parts of the brain involved in problem-solving.
"The same part of the brain that responds to fearful situations, such as seeing a spider or snake, also shows a heightened response in children with high math anxiety," said Vinod Menon, PhD, the Stanford professor of psychiatry and behavioral sciences who led the research.
In their new study, published online March 20 in Psychological Science, a journal of the Association for Psychological Science, Menon's team performed functional magnetic resonance imaging brain scans on 46 second- and third-grade students with low and high math anxiety. Outside the fMRI scanner, the children were assessed for math anxiety with a modified version of a standardized questionnaire for adults, and also received standard intelligence and cognitive tests.
Menon's lab is now looking for children ages 7 to 12 in the San Francisco Bay Area for several brain studies, including studies of math anxiety, math cognition and memory formation. The researchers are especially seeking second- and third-graders who have difficulty with math for a study in which a month of free math tutoring will be provided.
They are also seeking children with high-functioning autism as well as typically developing children to serve as control subjects for ongoing studies of math, language and social abilities.
Studies involve cognitive assessments and MRI scans. Eligible children will receive pictures of their brain and $50-200 for participation. An MRI scan is a safe, non-invasive procedure that does not use radiation or any injections.
Math anxiety is an under-studied phenomenon, Menon said, which still lacks formally established diagnostic criteria. Tests for math anxiety ask people about their emotional responses to situations and problems involving math. Those with high levels of math anxiety respond to numerical problems with fear and worry, and also say they are anxious about situations such as being asked to solve a math problem in front of a class. Menon noted that it is possible for someone to be good at math, but still suffer from math anxiety. However, over time, people with math anxiety tend to avoid advanced classes, leaving them with deficient math skills and limiting their career options.
While prior research focused on the behavioral aspects of math anxiety, Menon and his team wanted to find biological evidence of its existence.
"It's remarkable that, although the phenomena was first identified over 50 years back, nobody had bothered to ask how math anxiety manifests itself in terms of neural activity," Menon said. His team's observations show that math anxiety is neurobiologically similar to other kinds of anxiety or phobias, he said. "You cannot just wish it away as something that's unreal. Our findings validate math anxiety as a genuine type of stimulus- and situation-specific anxiety."
Identifying the neurologic basis for math anxiety may help to develop new strategies for addressing the problem, such as treatments used for generalized anxiety or phobias.
"The results are a significant step toward our understanding of brain function during math anxiety and will influence development of new academic interventions," said Victor Carrion, MD, a pediatric psychiatrist at Lucile Packard Children's Hospital and an expert on the effects of anxiety in children. Carrion, who was not involved in Menon's research, is also an associate professor of psychiatry and behavioral sciences at Stanford.
Menon's team decided to study young children with math anxiety to gain perspective on the developmental origins of the problem. (Prior behavioral studies had been limited to older children and adults.) First, the researchers modified a questionnaire that measures math anxiety to make it suitable for 7- to 9-year-olds. The study subjects were ranked by their scores and divided into high and low math anxiety groups for comparison. Children in the high and low math anxiety groups had similar IQ scores, working memory, reading and math abilities, and generalized anxiety levels.
The kids performed addition and subtraction problems while their brains were scanned using fMRI. In the children with high math anxiety, the scans showed heightened activity in the amygdala, the brain's main fear center, and also in a section of the hippocampus, a brain structure that helps form new memories. They also had decreased activity in several brain regions associated with working memory and numerical reasoning. Interestingly, analysis of brain connections showed that, in children with high math anxiety, the increased activity in the fear center was driving the reduced function in numerical information-processing regions of the brain. Further, children with high math anxiety also showed greater connections between the amygdala and emotion-regulating regions of the brain.
The two groups also showed differences in performance: Children with high math anxiety were less accurate and significantly slower at solving math problems than children with low math anxiety.
The results suggest that, in math anxiety, math-specific fear interferes with the brain's information-processing capacity and its ability to reason through a math problem. In addition to examining possible treatments and following the trajectory of math anxiety from early childhood throughout schooling, future research could provide insight into how the brain's information-processing capacity is affected by performance anxiety in general, Menon said.
Menon's collaborators at Stanford were research assistants Christina Young and Sarah Wu.
The study was funded by grants from the National Institutes of Health and the National Science Foundation.
A series of scans conducted while second- and third-grade students did addition and subtraction revealed that those who feel panicky about doing math had increased activity in brain regions associated with fear, which caused decreased activity in parts of the brain involved in problem-solving.
"The same part of the brain that responds to fearful situations, such as seeing a spider or snake, also shows a heightened response in children with high math anxiety," said Vinod Menon, PhD, the Stanford professor of psychiatry and behavioral sciences who led the research.
In their new study, published online March 20 in Psychological Science, a journal of the Association for Psychological Science, Menon's team performed functional magnetic resonance imaging brain scans on 46 second- and third-grade students with low and high math anxiety. Outside the fMRI scanner, the children were assessed for math anxiety with a modified version of a standardized questionnaire for adults, and also received standard intelligence and cognitive tests.
Menon's lab is now looking for children ages 7 to 12 in the San Francisco Bay Area for several brain studies, including studies of math anxiety, math cognition and memory formation. The researchers are especially seeking second- and third-graders who have difficulty with math for a study in which a month of free math tutoring will be provided.
They are also seeking children with high-functioning autism as well as typically developing children to serve as control subjects for ongoing studies of math, language and social abilities.
Studies involve cognitive assessments and MRI scans. Eligible children will receive pictures of their brain and $50-200 for participation. An MRI scan is a safe, non-invasive procedure that does not use radiation or any injections.
Math anxiety is an under-studied phenomenon, Menon said, which still lacks formally established diagnostic criteria. Tests for math anxiety ask people about their emotional responses to situations and problems involving math. Those with high levels of math anxiety respond to numerical problems with fear and worry, and also say they are anxious about situations such as being asked to solve a math problem in front of a class. Menon noted that it is possible for someone to be good at math, but still suffer from math anxiety. However, over time, people with math anxiety tend to avoid advanced classes, leaving them with deficient math skills and limiting their career options.
While prior research focused on the behavioral aspects of math anxiety, Menon and his team wanted to find biological evidence of its existence.
"It's remarkable that, although the phenomena was first identified over 50 years back, nobody had bothered to ask how math anxiety manifests itself in terms of neural activity," Menon said. His team's observations show that math anxiety is neurobiologically similar to other kinds of anxiety or phobias, he said. "You cannot just wish it away as something that's unreal. Our findings validate math anxiety as a genuine type of stimulus- and situation-specific anxiety."
Identifying the neurologic basis for math anxiety may help to develop new strategies for addressing the problem, such as treatments used for generalized anxiety or phobias.
"The results are a significant step toward our understanding of brain function during math anxiety and will influence development of new academic interventions," said Victor Carrion, MD, a pediatric psychiatrist at Lucile Packard Children's Hospital and an expert on the effects of anxiety in children. Carrion, who was not involved in Menon's research, is also an associate professor of psychiatry and behavioral sciences at Stanford.
Menon's team decided to study young children with math anxiety to gain perspective on the developmental origins of the problem. (Prior behavioral studies had been limited to older children and adults.) First, the researchers modified a questionnaire that measures math anxiety to make it suitable for 7- to 9-year-olds. The study subjects were ranked by their scores and divided into high and low math anxiety groups for comparison. Children in the high and low math anxiety groups had similar IQ scores, working memory, reading and math abilities, and generalized anxiety levels.
The kids performed addition and subtraction problems while their brains were scanned using fMRI. In the children with high math anxiety, the scans showed heightened activity in the amygdala, the brain's main fear center, and also in a section of the hippocampus, a brain structure that helps form new memories. They also had decreased activity in several brain regions associated with working memory and numerical reasoning. Interestingly, analysis of brain connections showed that, in children with high math anxiety, the increased activity in the fear center was driving the reduced function in numerical information-processing regions of the brain. Further, children with high math anxiety also showed greater connections between the amygdala and emotion-regulating regions of the brain.
The two groups also showed differences in performance: Children with high math anxiety were less accurate and significantly slower at solving math problems than children with low math anxiety.
The results suggest that, in math anxiety, math-specific fear interferes with the brain's information-processing capacity and its ability to reason through a math problem. In addition to examining possible treatments and following the trajectory of math anxiety from early childhood throughout schooling, future research could provide insight into how the brain's information-processing capacity is affected by performance anxiety in general, Menon said.
Menon's collaborators at Stanford were research assistants Christina Young and Sarah Wu.
The study was funded by grants from the National Institutes of Health and the National Science Foundation.
Neurotoxin Resistance in Snakes Around the World
The finding, which appeared in the Proceedings of the National Academy of Sciences, greatly increases scientists' understanding of the genetic basis of adaptation and is a model for understanding the limits to adaptation and the degree to which evolutionary responses are predictable.
Pfrender and colleagues found species of snakes in North, Central and South Americas and Asia that are able to feed on amphibians that secrete a deadly neurotoxic poison, tetrodotoxin or TTX. These snakes have similar mutations in a key sodium-channel gene that makes them highly resistant to TTX. These mutations prevent TTX from blocking the sodium channels in muscle, which would otherwise immobilize the snakes by paralyzing nervous and muscle tissue.
"The key finding is that adaptive evolution is constrained by the functional properties of the genes involved in these evolutionary responses," Pfrender said. "While there are many possible mutations that can improve fitness, in this case resistance to the neurotoxin TTX, many of these mutations have a cost because they change the normal function of the genes. So, when we look at multiple species that have independently adapted to TTX, we see a very similar, and limited, set of mutations involved. The story is one of repeated evolutionary change that occurs through a limited set of changes at the molecular level."
The study stems from Pfrender's interest in understanding how organisms deal with environmental change through adaptive evolution.
"We would like to know what the underlying genetic mechanisms are, and what the limits are to these adaptive responses," he said. "Ultimately, we would like to develop a predictive framework to gauge when natural populations will be able to evolve rapidly enough to persist in a changing environment and when the environmental change is too fast or too strong, leading to local extinction."
An understanding of how organisms deal with environmental change is relevant to the major themes of Notre Dame's Environmental Change Initiative and to the Eck Institute for Global Health, which examines disease resistance coupled with human health.
"Many organisms are exposed to toxic chemicals in their environment, and this system is a model for understanding how they cope with this challenge through evolutionary change," Pfrender said. "A good example of the application of this knowledge is when we are trying to understand how parasites acquire drug resistance. How do they do it and what are the limits to this response? Can we create more effective drug strategies that capitalize on these functional constraints, making it more difficult for parasites to evolve resistance?"
Pfrender and the Utah State researchers plan to study more snake species and to expand their research to a number of other species, including insects that prey on the toxic eggs of salamanders. They also are examining other genes closely related to the sodium channel genes that are the focus of the PNAS study to expand their understanding of how adaptation occurs.
Potential Solution to Melanoma's Resistance to Vemurafenib
Researchers at Moffitt Cancer Center in Tampa, Fla., and colleagues in California have found that the XL888 inhibitor can prevent resistance to the chemotherapy drug vemurafenib, commonly used for treating patients with melanoma.
Vemurafenib resistance is characterized by a diminished apoptosis (programmed cancer cell death) response. According to the researchers, the balance between apoptosis and cell survival is regulated by a family of proteins. The survival of melanoma cells is controlled, in part, by an anti-apoptotic protein (Mcl-1) that is regulated by a particular kind of inhibitor.
Their current findings, tested in six different models of vemurafenib resistance and in both test tube studies and in melanoma patients, demonstrated an induced apoptosis response and tumor regression when the XL888 inhibitor restored the effectiveness of vemurafenib.
The study appeared in a recent issue of Clinical Cancer Research, a publication of the American Association for Cancer Research.
"The impressive clinical response of melanoma patients to vemurafenib has been limited by drug resistance, a considerable challenge for which no management strategies previously existed," said study co-author Keiran S. M. Smalley, Ph.D., of Moffitt's departments of Molecular Oncology and Cutaneous Oncology. "However, we have demonstrated for the first time that the heat shock protein-90 (HSP90) inhibitor XL888 overcomes resistance through a number of mechanisms."
The diversity of resistance mechanism has been expected to complicate the design of future clinical trials to prevent or treat resistance to inhibitors such as vemurafenib.
"That expectation led us to hypothesize that inhibitor resistance might best be managed through broadly targeted strategies that inhibit multiple pathways simultaneously," explained Smalley.
The HSP90 family was known to maintain cancer cells by regulating cancer cells, making it a good target for treatment. According to the authors, the combination of vemurafenib and XL888 overcame vemurafenib resistance by targeting HSP90 through multiple signaling pathways.
There was already evidence that HSP90 inhibitors could overcome multiple drug chemotherapy resistance mechanisms in a number of cancers, including non-small lung cancer and breast cancer. Because XL888 is a novel, orally available inhibitor of HSP90, the researchers hoped that it would arrest the cancer cell cycle in melanoma cell lines.
In their study, the inhibition of HSP90 led to the degradation of the anti-apoptopiuc Mcl-1 protein. The responses to XL888 were characterized as "highly durable with no resistant colonies emerging following four weeks of continuous drug treatment." In other studies not using XL888, resistant colonies "emerged in every case," they reported.
"We have shown for the first time that all of the signaling proteins implicated in vemurafenib resistance are 'clients' of HSP90 and that inhibition of HSP90 can restore sensitivity to vemurafenib," concluded Smalley and his colleagues. "Our study provides the rationale for the dual targeting of HSP90 with XL888 and vemurafenib in treating melanoma patients in order to limit or prevent chemotherapy resistance."
Vemurafenib resistance is characterized by a diminished apoptosis (programmed cancer cell death) response. According to the researchers, the balance between apoptosis and cell survival is regulated by a family of proteins. The survival of melanoma cells is controlled, in part, by an anti-apoptotic protein (Mcl-1) that is regulated by a particular kind of inhibitor.
Their current findings, tested in six different models of vemurafenib resistance and in both test tube studies and in melanoma patients, demonstrated an induced apoptosis response and tumor regression when the XL888 inhibitor restored the effectiveness of vemurafenib.
The study appeared in a recent issue of Clinical Cancer Research, a publication of the American Association for Cancer Research.
"The impressive clinical response of melanoma patients to vemurafenib has been limited by drug resistance, a considerable challenge for which no management strategies previously existed," said study co-author Keiran S. M. Smalley, Ph.D., of Moffitt's departments of Molecular Oncology and Cutaneous Oncology. "However, we have demonstrated for the first time that the heat shock protein-90 (HSP90) inhibitor XL888 overcomes resistance through a number of mechanisms."
The diversity of resistance mechanism has been expected to complicate the design of future clinical trials to prevent or treat resistance to inhibitors such as vemurafenib.
"That expectation led us to hypothesize that inhibitor resistance might best be managed through broadly targeted strategies that inhibit multiple pathways simultaneously," explained Smalley.
The HSP90 family was known to maintain cancer cells by regulating cancer cells, making it a good target for treatment. According to the authors, the combination of vemurafenib and XL888 overcame vemurafenib resistance by targeting HSP90 through multiple signaling pathways.
There was already evidence that HSP90 inhibitors could overcome multiple drug chemotherapy resistance mechanisms in a number of cancers, including non-small lung cancer and breast cancer. Because XL888 is a novel, orally available inhibitor of HSP90, the researchers hoped that it would arrest the cancer cell cycle in melanoma cell lines.
In their study, the inhibition of HSP90 led to the degradation of the anti-apoptopiuc Mcl-1 protein. The responses to XL888 were characterized as "highly durable with no resistant colonies emerging following four weeks of continuous drug treatment." In other studies not using XL888, resistant colonies "emerged in every case," they reported.
"We have shown for the first time that all of the signaling proteins implicated in vemurafenib resistance are 'clients' of HSP90 and that inhibition of HSP90 can restore sensitivity to vemurafenib," concluded Smalley and his colleagues. "Our study provides the rationale for the dual targeting of HSP90 with XL888 and vemurafenib in treating melanoma patients in order to limit or prevent chemotherapy resistance."
To Make a Social Robot, Key Is Satisfying the Human Mind
After years of existing only in fiction, social robots are finally being designed that can more closely emulate how people express themselves, interact and learn – and doing so while performing jobs like teaching social behavior to children with autism or helping stroke patients with their physical rehabilitation exercises.
Recently, The Kavli Foundation brought together three pioneers in Human-Robot Interactions to discuss these advancements, as well as the upcoming technological hurdles. What they say is that, while there are many challenges ahead, the biggest remains getting the robots to match the needs and expectations of the human mind. “How we interact with embodied machines is different than how we interact with a computer, cell phone or other intelligent devices,” says Professor Maja Matarić, University of Southern California. “We need to understand those differences so we can leverage what is important.”
A director of USC’s Center for Robotics and Embedded Systems, Matarić has developed social robots for use in a variety of therapeutic roles. According to Matarić, one of the keys for a successfully designed social robot is considering not only how it communications verbally, but physically through facial expressions and body language. Also important: embedding the right personality. “We found that when we matched the personality of the robot to that of the user, people performed their rehab exercises longer and reported enjoying them more.”
Another key is matching a robot’s appearance to our perception of its abilities. Ayse Saygin is an assistant professor at the University of California San Diego and faculty member of the Kavli Institute of Brain and Mind. Last year, Saygin and her colleagues set out to discover if what they call the “action perception system” in the human brain is tuned more to human appearance or human motion. By using brain scans, they found that as people observed highly humanlike robots compared to less humanlike robots, the brain detected the mismatch and didn’t respond as well. “Making robots more humanlike might seem intuitively like that’s the way to go, but we find it doesn’t work unless the humanlike appearance is equally matched with humanlike actions.”
A social robot also needs the ability to learn socially. Andrea Thomaz is an assistant professor at the Georgia Institute of Technology and director of its Social Intelligent Machines Laboratory. At her lab, they have built a robot designed to learn from humans the way a person would -- along with speech, through observation, demonstration and social interaction. "In my lab, we see human social intelligence as being comprised of four key components – the ability to learn from other people, the ability to collaborate with other people, the ability to apply emotional intelligence, and the ability to perceive and respond to another person’s intentions. We try to build this social intelligence in our robots."
Recently, The Kavli Foundation brought together three pioneers in Human-Robot Interactions to discuss these advancements, as well as the upcoming technological hurdles. What they say is that, while there are many challenges ahead, the biggest remains getting the robots to match the needs and expectations of the human mind. “How we interact with embodied machines is different than how we interact with a computer, cell phone or other intelligent devices,” says Professor Maja Matarić, University of Southern California. “We need to understand those differences so we can leverage what is important.”
A director of USC’s Center for Robotics and Embedded Systems, Matarić has developed social robots for use in a variety of therapeutic roles. According to Matarić, one of the keys for a successfully designed social robot is considering not only how it communications verbally, but physically through facial expressions and body language. Also important: embedding the right personality. “We found that when we matched the personality of the robot to that of the user, people performed their rehab exercises longer and reported enjoying them more.”
Another key is matching a robot’s appearance to our perception of its abilities. Ayse Saygin is an assistant professor at the University of California San Diego and faculty member of the Kavli Institute of Brain and Mind. Last year, Saygin and her colleagues set out to discover if what they call the “action perception system” in the human brain is tuned more to human appearance or human motion. By using brain scans, they found that as people observed highly humanlike robots compared to less humanlike robots, the brain detected the mismatch and didn’t respond as well. “Making robots more humanlike might seem intuitively like that’s the way to go, but we find it doesn’t work unless the humanlike appearance is equally matched with humanlike actions.”
A social robot also needs the ability to learn socially. Andrea Thomaz is an assistant professor at the Georgia Institute of Technology and director of its Social Intelligent Machines Laboratory. At her lab, they have built a robot designed to learn from humans the way a person would -- along with speech, through observation, demonstration and social interaction. "In my lab, we see human social intelligence as being comprised of four key components – the ability to learn from other people, the ability to collaborate with other people, the ability to apply emotional intelligence, and the ability to perceive and respond to another person’s intentions. We try to build this social intelligence in our robots."
Parkinson's Treatment Shows Positive Results in Clinical Testing
Researchers from the University of Florida and 14 additional medical centers reported results in the online version of The Lancet Neurology journal indicating that deep brain stimulation -- also known as DBS -- is effective at improving motor symptoms and quality of life in patients with advanced Parkinson's disease.
The study, sponsored by St. Jude Medical Inc., tested the safety and effectiveness of a constant current DBS device developed by St. Jude Medical to manage the symptoms of Parkinson's disease. The device aimed to reduce tremors, improve the slowness of movement, decrease the motor disability of the disease and reduce involuntary movements called dyskinesia, which are a common side effect of Parkinson's drugs.
After treatment, analysis of 136 patient diaries revealed longer periods of effective symptom control -- known as "on time" -- without involuntary movements. "On time" for patients who received stimulation increased by an average of 4.27 hours compared with an increase of 1.77 hours in the group without stimulation. Patients also noted overall improvements in the quality of their daily activities, mobility, emotional state, social support and physical comfort.
"I think it is safe to say since dopamine treatment emerged in the 1960s, DBS has been the single biggest symptomatic breakthrough for Parkinson patients who have experienced the fluctuations associated with levodopa therapy," said Dr. Michael S. Okun, first author of the study, administrative director of the UF College of Medicine's Center for Movement Disorders and Neurorestoration, and the National Medical Director for the National Parkinson Foundation. "This study validates the use of mild electrical currents delivered to specific brain structures in order to improve Parkinson's disease in select patients with advanced symptoms, and additionally, it explored a new stimulation paradigm. Future improvements in devices and the delivery systems for DBS will hopefully provide exciting new opportunities for Parkinson's sufferers."
Only patients who have had Parkinson's disease for five years or more were included in the study. They were randomly assigned to a control group that delayed the onset of stimulation for three months, or a group whose stimulation began shortly after surgery. All patients were followed for 12 months.
The deep brain stimulation procedure involves surgeons implanting small electrodes into an area of the patient's brain that controls movement. The electrodes are connected to a device precisely programmed to use mild electrical current to modulate problematic brain signals that result in movement problems.
Today's voltage-controlled DBS devices deliver pulses of current that vary slightly with surrounding tissue changes. The DBS devices tested in this study are intended to provide more accurate delivery and control of the electrical pulses.
"We are committed to driving research that will provide solutions for physicians and their patients whose needs are currently unmet," said Rohan Hoare, president of St. Jude Medical Neuromodulation Division. "These results are significant as they offer evidence that stimulation with the Libra constant current system enabled patients to have better motor control and an improvement in their quality of life when compared to the control group."
The U.S. Food and Drug Administration approved the use of DBS for Parkinson's disease in 2002. At least 500,000 people in the United States suffer from Parkinson's with about 50,000 new cases reported annually, according to the National Institute of Neurological Disorders and Stroke. These numbers are expected to increase as the average age of the population rises.
"The study answered some very important questions concerning cognition and mood with lead implantation (alone) versus implantation with stimulation. It also refutes the hypothesis that DBS increases depressive symptoms," said Dr. Gordon H. Baltuch, a professor of neurosurgery in the Perelman School of Medicine at the University of Pennsylvania and a study author. "The group's results also showed a decrease in the infection rate to 4 percent from previously published 10 percent. It shows that American neurosurgeons and neurologists with their industry partners are improving the safety of this procedure and working in a collaborative fashion."
Comparable with other large DBS studies, the most common serious adverse event revealed was infection, which occurred in five patients. Likewise, some participants also reported an increase in the occurrence of slurred speech, known as dysarthria.
"Technology is on the move, and we expect to see continued improvements to DBS approaches, equipment and materials," said Okun, who is also affiliated with UF's McKnight Brain Institute. "DBS has set the bar high for the development of new therapies for advanced Parkinson's disease patients. DBS will be the standard of care gene therapy and other cell-based therapies that are now being conceived will be measured against, and this will hopefully translate into significant improvements in what we can offer our patients."
The study, sponsored by St. Jude Medical Inc., tested the safety and effectiveness of a constant current DBS device developed by St. Jude Medical to manage the symptoms of Parkinson's disease. The device aimed to reduce tremors, improve the slowness of movement, decrease the motor disability of the disease and reduce involuntary movements called dyskinesia, which are a common side effect of Parkinson's drugs.
After treatment, analysis of 136 patient diaries revealed longer periods of effective symptom control -- known as "on time" -- without involuntary movements. "On time" for patients who received stimulation increased by an average of 4.27 hours compared with an increase of 1.77 hours in the group without stimulation. Patients also noted overall improvements in the quality of their daily activities, mobility, emotional state, social support and physical comfort.
"I think it is safe to say since dopamine treatment emerged in the 1960s, DBS has been the single biggest symptomatic breakthrough for Parkinson patients who have experienced the fluctuations associated with levodopa therapy," said Dr. Michael S. Okun, first author of the study, administrative director of the UF College of Medicine's Center for Movement Disorders and Neurorestoration, and the National Medical Director for the National Parkinson Foundation. "This study validates the use of mild electrical currents delivered to specific brain structures in order to improve Parkinson's disease in select patients with advanced symptoms, and additionally, it explored a new stimulation paradigm. Future improvements in devices and the delivery systems for DBS will hopefully provide exciting new opportunities for Parkinson's sufferers."
Only patients who have had Parkinson's disease for five years or more were included in the study. They were randomly assigned to a control group that delayed the onset of stimulation for three months, or a group whose stimulation began shortly after surgery. All patients were followed for 12 months.
The deep brain stimulation procedure involves surgeons implanting small electrodes into an area of the patient's brain that controls movement. The electrodes are connected to a device precisely programmed to use mild electrical current to modulate problematic brain signals that result in movement problems.
Today's voltage-controlled DBS devices deliver pulses of current that vary slightly with surrounding tissue changes. The DBS devices tested in this study are intended to provide more accurate delivery and control of the electrical pulses.
"We are committed to driving research that will provide solutions for physicians and their patients whose needs are currently unmet," said Rohan Hoare, president of St. Jude Medical Neuromodulation Division. "These results are significant as they offer evidence that stimulation with the Libra constant current system enabled patients to have better motor control and an improvement in their quality of life when compared to the control group."
The U.S. Food and Drug Administration approved the use of DBS for Parkinson's disease in 2002. At least 500,000 people in the United States suffer from Parkinson's with about 50,000 new cases reported annually, according to the National Institute of Neurological Disorders and Stroke. These numbers are expected to increase as the average age of the population rises.
"The study answered some very important questions concerning cognition and mood with lead implantation (alone) versus implantation with stimulation. It also refutes the hypothesis that DBS increases depressive symptoms," said Dr. Gordon H. Baltuch, a professor of neurosurgery in the Perelman School of Medicine at the University of Pennsylvania and a study author. "The group's results also showed a decrease in the infection rate to 4 percent from previously published 10 percent. It shows that American neurosurgeons and neurologists with their industry partners are improving the safety of this procedure and working in a collaborative fashion."
Comparable with other large DBS studies, the most common serious adverse event revealed was infection, which occurred in five patients. Likewise, some participants also reported an increase in the occurrence of slurred speech, known as dysarthria.
"Technology is on the move, and we expect to see continued improvements to DBS approaches, equipment and materials," said Okun, who is also affiliated with UF's McKnight Brain Institute. "DBS has set the bar high for the development of new therapies for advanced Parkinson's disease patients. DBS will be the standard of care gene therapy and other cell-based therapies that are now being conceived will be measured against, and this will hopefully translate into significant improvements in what we can offer our patients."
How Vitamin D Inhibits Inflammation
Researchers at National Jewish Health have discovered specific molecular and signaling events by which vitamin D inhibits inflammation. In their experiments, they showed that low levels of Vitamin D, comparable to levels found in millions of people, failed to inhibit the inflammatory cascade, while levels considered adequate did inhibit inflammatory signaling. They reported their results in the March 1, 2012, issue of The Journal of Immunology.
"This study goes beyond previous associations of vitamin D with various health outcomes. It outlines a clear chain of cellular events, from the binding of DNA, through a specific signaling pathway, to the reduction of proteins known to trigger inflammation," said lead author Elena Goleva, assistant professor of pediatrics at National Jewish Health. "Patients with chronic inflammatory diseases, such as asthma, arthritis and prostate cancer, who are vitamin D deficient, may benefit from vitamin D supplementation to get their serum vitamin D levels above 30 nanograms/milliliter."
Current national guidelines suggest that people should maintain a minimum blood serum level of 20 ng/ml, although there is much scientific debate about optimum levels. Vitamin D has long been known to contribute to bone health by promoting the absorption of calcium. In recent years, much attention has been paid to its possible immune and inflammatory benefits. Low vitamin D levels have been associated with several diseases including asthma, cancer, diabetes, and arthritis.
In the current study researchers examined the specific mechanisms by which vitamin D might act on immune and inflammatory pathways. They incubated human white blood cells with varying levels of vitamin D, then exposed them to lipopolysaccharide (LPS), a molecule associated with bacterial cell walls that is known to promote intense inflammatory responses.
Cells incubated with no vitamin D and in solution containing 15 ng/ml of vitamin D produced high levels of cytokines IL-6 and TNF-alpha, major actors in the inflammatory response. Cells incubated in 30 ng/ml vitamin D and above showed significantly reduced response to the LPS. The highest levels of inflammatory inhibition occurred at 50 ng/ml.
Through a complex series of experiments, the researchers identified a new location where the vitamin-D receptor appears to bind directly to DNA and activate a gene known as MKP-1. MKP-1 interferes with the inflammatory cascade triggered by LPS, which includes a molecule known as p38, and results in higher levels of IL-6 and TNF-alpha.
"This newly identified DNA-binding site for the vitamin-D receptor, and the specific pathways inhibited by higher levels of vitamin D provide a plausible mechanism for many of the benefits that have been associated with vitamin D," said Dr. Goleva. 'The fact that we showed a dose-dependent and varying response to levels commonly found in humans also adds weight to the argument for vitamin D's role in immune and inflammatory conditions."
"This study goes beyond previous associations of vitamin D with various health outcomes. It outlines a clear chain of cellular events, from the binding of DNA, through a specific signaling pathway, to the reduction of proteins known to trigger inflammation," said lead author Elena Goleva, assistant professor of pediatrics at National Jewish Health. "Patients with chronic inflammatory diseases, such as asthma, arthritis and prostate cancer, who are vitamin D deficient, may benefit from vitamin D supplementation to get their serum vitamin D levels above 30 nanograms/milliliter."
Current national guidelines suggest that people should maintain a minimum blood serum level of 20 ng/ml, although there is much scientific debate about optimum levels. Vitamin D has long been known to contribute to bone health by promoting the absorption of calcium. In recent years, much attention has been paid to its possible immune and inflammatory benefits. Low vitamin D levels have been associated with several diseases including asthma, cancer, diabetes, and arthritis.
In the current study researchers examined the specific mechanisms by which vitamin D might act on immune and inflammatory pathways. They incubated human white blood cells with varying levels of vitamin D, then exposed them to lipopolysaccharide (LPS), a molecule associated with bacterial cell walls that is known to promote intense inflammatory responses.
Cells incubated with no vitamin D and in solution containing 15 ng/ml of vitamin D produced high levels of cytokines IL-6 and TNF-alpha, major actors in the inflammatory response. Cells incubated in 30 ng/ml vitamin D and above showed significantly reduced response to the LPS. The highest levels of inflammatory inhibition occurred at 50 ng/ml.
Through a complex series of experiments, the researchers identified a new location where the vitamin-D receptor appears to bind directly to DNA and activate a gene known as MKP-1. MKP-1 interferes with the inflammatory cascade triggered by LPS, which includes a molecule known as p38, and results in higher levels of IL-6 and TNF-alpha.
"This newly identified DNA-binding site for the vitamin-D receptor, and the specific pathways inhibited by higher levels of vitamin D provide a plausible mechanism for many of the benefits that have been associated with vitamin D," said Dr. Goleva. 'The fact that we showed a dose-dependent and varying response to levels commonly found in humans also adds weight to the argument for vitamin D's role in immune and inflammatory conditions."
Scientists Break Through Pancreas Cancer Treatment Barrier
Pancreas cancer tumors spread quickly and are notoriously resistant to treatment, making them among the deadliest of malignancies. Their resistance to chemotherapy stems in part from a unique biological barrier the tumor builds around itself. Now scientists at Fred Hutchinson Cancer Research Center have found a way to break through that defense, and their research represents a potential breakthrough in the treatment of pancreas cancer.
In a paper to be published in the March 20 issue of Cancer Cell, senior author Sunil Hingorani, M.D., Ph.D., an associate member of the Hutchinson Center's Clinical Research and Public Health Sciences divisions, and colleagues describe the biological mechanisms of how the tumor barrier is formed and detail a newly discovered way to break it down. Their research significantly increased the length of survival in a genetically engineered mouse model of the disease. Early clinical trials in humans are under way at a few sites in the U.S. and Europe, including Seattle Cancer Care Alliance, the Hutchinson Center's patient treatment arm.
Using a mouse model developed by Hingorani, the scientists combined gemcitabine, the current standard chemotherapy used to treat pancreatic ductal adenocarcinomas, with an enzyme called PEGPH20. When they infused the combination into specially engineered mice whose pancreas tumors mimic those of human pancreas cancer, the combination broke down the matrix barrier within the tumors and allowed the chemotherapy to permeate freely and spread throughout the cancerous tissue. The result was a 70 percent increase in survival time of the mice after the start of treatment, from 55 to 92 days.
"This represents the largest survival increase we've seen in any of the studies done in a preclinical model, and it rivals the very best results reported in humans," Hingorani said.
Unlike most solid tumors, pancreas tumors use a two-pronged defense to keep small molecules, such as those contained in chemotherapy, from entering: a vastly reduced blood supply and the creation of a strong fibroinflammatory response. The latter includes the production of fibroblasts, immune cells and endothelial cells that become embedded within a dense and complex extracellular matrix throughout the tumor. One major component of this matrix is a substance called hyaluronan, or hyaluronic acid (HA). HA is a glycosaminoglycan, a complex sugar that occurs naturally in the body and is secreted at extremely high levels by pancreas cancer cells.
Hingorani and colleagues discovered that the fibroinflammatory response creates unusually high interstitial fluid pressures that collapse the tumor's blood vessels. This in turn prevents chemotherapy agents from entering the tumors. The researchers found that HA is the main biological cause of the elevated pressures that leads to blood vessel collapse.
"That's the primary reason pancreas cancers are resistant to everything we've thrown at them: because none of the drugs get into the tumor. It's physics first, before we even get to the intrinsic biology," Hingorani said.
Administering the enzyme/gemcitabine combination degrades HA in the tumor barrier and results in rapid reduction of the interstitial fluid pressure. This in turn opens the blood vessels and permits high concentrations of chemotherapy to reach the tumor.
"Being able to deliver the drugs effectively into the tumor resulted in improved survival as well as the realization that pancreas cancer may be more sensitive to conventional chemotherapy than we previously thought," Hingorani said.
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Overall five-year survival is less than 5 percent with a median survival of four to six months.
Grants from the National Cancer Institute, the Giles W. and Elise G. Mead Foundation, Safeway and several individuals supported the research. Collaborators from the University of Washington and the Translational Genomics Research Institute in Scottsdale, Ariz., contributed to the study.
Details about the open clinical trial can be found here: http://clinicaltrials.gov/show/NCT01453153
In a paper to be published in the March 20 issue of Cancer Cell, senior author Sunil Hingorani, M.D., Ph.D., an associate member of the Hutchinson Center's Clinical Research and Public Health Sciences divisions, and colleagues describe the biological mechanisms of how the tumor barrier is formed and detail a newly discovered way to break it down. Their research significantly increased the length of survival in a genetically engineered mouse model of the disease. Early clinical trials in humans are under way at a few sites in the U.S. and Europe, including Seattle Cancer Care Alliance, the Hutchinson Center's patient treatment arm.
Using a mouse model developed by Hingorani, the scientists combined gemcitabine, the current standard chemotherapy used to treat pancreatic ductal adenocarcinomas, with an enzyme called PEGPH20. When they infused the combination into specially engineered mice whose pancreas tumors mimic those of human pancreas cancer, the combination broke down the matrix barrier within the tumors and allowed the chemotherapy to permeate freely and spread throughout the cancerous tissue. The result was a 70 percent increase in survival time of the mice after the start of treatment, from 55 to 92 days.
"This represents the largest survival increase we've seen in any of the studies done in a preclinical model, and it rivals the very best results reported in humans," Hingorani said.
Unlike most solid tumors, pancreas tumors use a two-pronged defense to keep small molecules, such as those contained in chemotherapy, from entering: a vastly reduced blood supply and the creation of a strong fibroinflammatory response. The latter includes the production of fibroblasts, immune cells and endothelial cells that become embedded within a dense and complex extracellular matrix throughout the tumor. One major component of this matrix is a substance called hyaluronan, or hyaluronic acid (HA). HA is a glycosaminoglycan, a complex sugar that occurs naturally in the body and is secreted at extremely high levels by pancreas cancer cells.
Hingorani and colleagues discovered that the fibroinflammatory response creates unusually high interstitial fluid pressures that collapse the tumor's blood vessels. This in turn prevents chemotherapy agents from entering the tumors. The researchers found that HA is the main biological cause of the elevated pressures that leads to blood vessel collapse.
"That's the primary reason pancreas cancers are resistant to everything we've thrown at them: because none of the drugs get into the tumor. It's physics first, before we even get to the intrinsic biology," Hingorani said.
Administering the enzyme/gemcitabine combination degrades HA in the tumor barrier and results in rapid reduction of the interstitial fluid pressure. This in turn opens the blood vessels and permits high concentrations of chemotherapy to reach the tumor.
"Being able to deliver the drugs effectively into the tumor resulted in improved survival as well as the realization that pancreas cancer may be more sensitive to conventional chemotherapy than we previously thought," Hingorani said.
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Overall five-year survival is less than 5 percent with a median survival of four to six months.
Grants from the National Cancer Institute, the Giles W. and Elise G. Mead Foundation, Safeway and several individuals supported the research. Collaborators from the University of Washington and the Translational Genomics Research Institute in Scottsdale, Ariz., contributed to the study.
Details about the open clinical trial can be found here: http://clinicaltrials.gov/show/NCT01453153
Higher Death Risk With Sleeping Pills
People are relying on sleeping pills more than ever to get a good night's rest, but a new study by Scripps Clinic researchers links the medications to a 4.6 times higher risk of death and a significant increase in cancer cases among regular pill users.
The results, published February 27 by the open-access online journal BMJ Open, cast a shadow over a growing segment of the pharmaceutical industry that expanded by 23 percent in the United States from 2006 to 2010 and generated about $2 billion in annual sales.
The possible health hazards
"What our study shows is that sleeping pills are hazardous to your health and might cause death by contributing to the occurrence of cancer, heart disease and other ailments," said author Daniel F. Kripke, MD, of the Viterbi Family Sleep Center at Scripps Health in San Diego.
The research is the first to show that eight of the most commonly used hypnotic drugs were associated with increased hazards of mortality and cancer, including the popularly prescribed medications zolpidem (known by the brand name Ambien) and temazepam (also known as Restoril), Dr. Kripke said. Those drugs had been thought to be safer than older hypnotics because of their shorter duration of action.
Study participants who took sleeping pills were matched with control patients of similar ages, gender and health who received no hypnotics in order to eliminate the possibility that other factors led to the results.
"We tried every practical strategy to make these associations go away, thinking that they could be due to use by people with more health problems, but no matter what we did the associations with higher mortality held," said co-author Robert D. Langer, MD, MPH, of the Jackson Hole Center for Preventive Medicine in Jackson, Wyoming.
Even among patients who were prescribed 1 to 18 sleeping pills per year, the risk of death was 3.6 times higher than among similar participants who did not take the medica-tions. The study looked at patients aged 18 years and older, and found the increased risk in all age groups.
Sleeping pills and cancer
Rates of new cancers were 35 percent higher among patients who were prescribed at least 132 hypnotic doses a year as compared with those who did not take the drugs.
Using data stored in an electronic medical record that has been in place for more than a decade, the researchers obtained information on almost 40,000 patients cared for by a large integrated health system in the northeastern United States.
The study included 10,531 sleeping pill users who were prescribed the medications for an average of 2.5 years and 23,674 control participants who were not prescribed the drugs. Information came from outpatient clinic visits conducted between Jan. 1, 2002, and Sept. 30, 2006.
"It is important to note that our results are based on observational data, so even though we did everything we could to ensure their validity, it's still possible that other factors explain the associations," said co-author Lawrence E. Kline, DO, who is medical director of the Viterbi Family Sleep Center. "We hope our work will spur additional research in this area using information from other populations."
Funding for the study came from the Scripps Health Foundation and other philanthropic sources.
Alternatives to medication
The BMJ Open report should prompt physicians to consider alternatives to hypnotic medications, Dr. Kline said.
Clinicians at the Viterbi Family Sleep Center focus on cognitive therapy that teaches patients to better understand the nature of sleep. For example, some people suffering from insomnia might require less than the eight hours of sleep commonly recommended for each night.
Patients also can benefit from practicing good sleeping habits and relaxation, as well as taking advantage of the body's natural clock, which is driven by the rising and setting of the sun, Dr. Kline said. "Understanding how to use the circadian rhythm is a very powerful tool that doesn't require a prescription," he said.
When insomnia results from emotional problems such as depression, doctors should treat the psychological disorder rather than prescribe sleeping pills that could prove to be harmful, Dr. Kripke said.
The results, published February 27 by the open-access online journal BMJ Open, cast a shadow over a growing segment of the pharmaceutical industry that expanded by 23 percent in the United States from 2006 to 2010 and generated about $2 billion in annual sales.
The possible health hazards
"What our study shows is that sleeping pills are hazardous to your health and might cause death by contributing to the occurrence of cancer, heart disease and other ailments," said author Daniel F. Kripke, MD, of the Viterbi Family Sleep Center at Scripps Health in San Diego.
The research is the first to show that eight of the most commonly used hypnotic drugs were associated with increased hazards of mortality and cancer, including the popularly prescribed medications zolpidem (known by the brand name Ambien) and temazepam (also known as Restoril), Dr. Kripke said. Those drugs had been thought to be safer than older hypnotics because of their shorter duration of action.
Study participants who took sleeping pills were matched with control patients of similar ages, gender and health who received no hypnotics in order to eliminate the possibility that other factors led to the results.
"We tried every practical strategy to make these associations go away, thinking that they could be due to use by people with more health problems, but no matter what we did the associations with higher mortality held," said co-author Robert D. Langer, MD, MPH, of the Jackson Hole Center for Preventive Medicine in Jackson, Wyoming.
Even among patients who were prescribed 1 to 18 sleeping pills per year, the risk of death was 3.6 times higher than among similar participants who did not take the medica-tions. The study looked at patients aged 18 years and older, and found the increased risk in all age groups.
Sleeping pills and cancer
Rates of new cancers were 35 percent higher among patients who were prescribed at least 132 hypnotic doses a year as compared with those who did not take the drugs.
Using data stored in an electronic medical record that has been in place for more than a decade, the researchers obtained information on almost 40,000 patients cared for by a large integrated health system in the northeastern United States.
The study included 10,531 sleeping pill users who were prescribed the medications for an average of 2.5 years and 23,674 control participants who were not prescribed the drugs. Information came from outpatient clinic visits conducted between Jan. 1, 2002, and Sept. 30, 2006.
"It is important to note that our results are based on observational data, so even though we did everything we could to ensure their validity, it's still possible that other factors explain the associations," said co-author Lawrence E. Kline, DO, who is medical director of the Viterbi Family Sleep Center. "We hope our work will spur additional research in this area using information from other populations."
Funding for the study came from the Scripps Health Foundation and other philanthropic sources.
Alternatives to medication
The BMJ Open report should prompt physicians to consider alternatives to hypnotic medications, Dr. Kline said.
Clinicians at the Viterbi Family Sleep Center focus on cognitive therapy that teaches patients to better understand the nature of sleep. For example, some people suffering from insomnia might require less than the eight hours of sleep commonly recommended for each night.
Patients also can benefit from practicing good sleeping habits and relaxation, as well as taking advantage of the body's natural clock, which is driven by the rising and setting of the sun, Dr. Kline said. "Understanding how to use the circadian rhythm is a very powerful tool that doesn't require a prescription," he said.
When insomnia results from emotional problems such as depression, doctors should treat the psychological disorder rather than prescribe sleeping pills that could prove to be harmful, Dr. Kripke said.
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