Tumor Suppressor Mutations Alone Don’t Explain Deadly Cancer Biomarker for head and neck cancers identified
Although mutations in a gene dubbed “the guardian of the genome” are widely recognized as being associated with more aggressive forms of cancer, researchers at the University of California, San Diego School of Medicine have found evidence suggesting that the deleterious health effects of the mutated gene may in large part be due to other genetic abnormalities, at least in squamous cell head and neck cancers.
The study, published online August 3 in the journal Nature Genetics, shows that high mortality rates among head and neck cancer patients tend to occur only when mutations in the tumor suppressor gene coincide with missing segments of genetic material on the cancer genome’s third chromosome.
The link between the two had not been observed before because the mutations co-occur in about 70 percent of head and neck tumors and because full genetic fingerprints of large numbers of cancer tumors have become available only recently.
“These two genetic malfunctions are not two separate stab wounds to the body,” said co-senior author Trey Ideker, PhD, chief of the Division of Genetics. “One exposes the Achilles tendon and the other is a direct blow to it.”
To patients with these cancers, the study’s results mean that there may be therapeutic value in testing tumors for the two genetic identifiers, known as a TP53 mutation (short for tumor protein 53) and a 3p deletion (short for deletions of genetic information on the short arm “p” of the third chromosome).
TP53 plays a key role in regulating cell growth, detecting and fixing DNA, and directing cell apoptosis (death) if the DNA damage is irreparable. Because of this, the TP53 protein is sometimes called the “guardian of the genome.”
The study’s findings suggest that if both markers are present, treatment should be intensified. If only one mutation is present, treatment might be de-intensified because the TP53 mutation alone is less deadly than previously thought. The latter would have immediate benefits in reducing deaths caused by complications related to medical care.
“We are in the early stages of being able to personalize head and neck cancer treatments based on the tumor’s actual biology, the same as what’s done with breast cancers,” said co-senior author Quyen Nguyen, MD, PhD, associate professor of Otolaryngology-Head and Neck Surgery. “In the past, treatments have been based largely on the size and location of the tumor. Now, we know that some large tumors may respond to less aggressive treatment while some small tumors may need intensified treatment. This will have a huge impact for patients.”
The study analyzed the complete genomic signatures of 250 cases of squamous cell head and neck cancer extracted from The Cancer Genome Atlas, a repository of sequenced cancer genomes for more than 20 different types of human cancers maintained by the National Institutes of Cancer. All of the tumors were from patients younger than 85 years of age.
Of these, 179 had both mutations; 50 had one of the two mutations; and 22 had neither mutation. Comparisons with patient outcome data showed that half of patients with both mutations would likely die of cancer within 2 years, while 66 percent of patients with one or neither mutation would be expected to live five years or more. These survival statistics were independent of the patients’ clinical cancer stage.
Besides causing cervical cancer, the human papilloma virus (HPV) is implicated in the growing epidemic of head and neck cancers in otherwise healthy adults. It is believed that the virus can co-opt the activity of TP53, affecting cells in much the same way as a TP53 mutation but without causing a mutation. For this reason, the analysis examined HPV-positive and HPV-negative tumors separately.
One of the study’s more compelling discoveries is that among HPV-positive tumors, the most aggressive cancer cases were also highly linked to the presence of 3p deletions.
“Our findings raise fundamental questions about the role of TP53 in cancer and suggest that some of the deleterious health effects of TP53 mutations might actually be due to something else going on in the third chromosome,” said lead author Andrew Gross, a graduate student in the Bioinformatics and Systems Biology Program.

Tumor Suppressor Mutations Alone Don’t Explain Deadly Cancer
Biomarker for head and neck cancers identified

Although mutations in a gene dubbed “the guardian of the genome” are widely recognized as being associated with more aggressive forms of cancer, researchers at the University of California, San Diego School of Medicine have found evidence suggesting that the deleterious health effects of the mutated gene may in large part be due to other genetic abnormalities, at least in squamous cell head and neck cancers.

The study, published online August 3 in the journal Nature Genetics, shows that high mortality rates among head and neck cancer patients tend to occur only when mutations in the tumor suppressor gene coincide with missing segments of genetic material on the cancer genome’s third chromosome.

The link between the two had not been observed before because the mutations co-occur in about 70 percent of head and neck tumors and because full genetic fingerprints of large numbers of cancer tumors have become available only recently.

“These two genetic malfunctions are not two separate stab wounds to the body,” said co-senior author Trey Ideker, PhD, chief of the Division of Genetics. “One exposes the Achilles tendon and the other is a direct blow to it.”

To patients with these cancers, the study’s results mean that there may be therapeutic value in testing tumors for the two genetic identifiers, known as a TP53 mutation (short for tumor protein 53) and a 3p deletion (short for deletions of genetic information on the short arm “p” of the third chromosome).

TP53 plays a key role in regulating cell growth, detecting and fixing DNA, and directing cell apoptosis (death) if the DNA damage is irreparable. Because of this, the TP53 protein is sometimes called the “guardian of the genome.”

The study’s findings suggest that if both markers are present, treatment should be intensified. If only one mutation is present, treatment might be de-intensified because the TP53 mutation alone is less deadly than previously thought. The latter would have immediate benefits in reducing deaths caused by complications related to medical care.

“We are in the early stages of being able to personalize head and neck cancer treatments based on the tumor’s actual biology, the same as what’s done with breast cancers,” said co-senior author Quyen Nguyen, MD, PhD, associate professor of Otolaryngology-Head and Neck Surgery. “In the past, treatments have been based largely on the size and location of the tumor. Now, we know that some large tumors may respond to less aggressive treatment while some small tumors may need intensified treatment. This will have a huge impact for patients.”

The study analyzed the complete genomic signatures of 250 cases of squamous cell head and neck cancer extracted from The Cancer Genome Atlas, a repository of sequenced cancer genomes for more than 20 different types of human cancers maintained by the National Institutes of Cancer. All of the tumors were from patients younger than 85 years of age.

Of these, 179 had both mutations; 50 had one of the two mutations; and 22 had neither mutation. Comparisons with patient outcome data showed that half of patients with both mutations would likely die of cancer within 2 years, while 66 percent of patients with one or neither mutation would be expected to live five years or more. These survival statistics were independent of the patients’ clinical cancer stage.

Besides causing cervical cancer, the human papilloma virus (HPV) is implicated in the growing epidemic of head and neck cancers in otherwise healthy adults. It is believed that the virus can co-opt the activity of TP53, affecting cells in much the same way as a TP53 mutation but without causing a mutation. For this reason, the analysis examined HPV-positive and HPV-negative tumors separately.

One of the study’s more compelling discoveries is that among HPV-positive tumors, the most aggressive cancer cases were also highly linked to the presence of 3p deletions.

“Our findings raise fundamental questions about the role of TP53 in cancer and suggest that some of the deleterious health effects of TP53 mutations might actually be due to something else going on in the third chromosome,” said lead author Andrew Gross, a graduate student in the Bioinformatics and Systems Biology Program.

A Moveable Yeast: modeling shows proteins never sit still
Our body’s proteins – encoded by DNA to do the hard work of building and operating our bodies – are forever on the move. Literally, according to new findings reported by Trey Ideker, PhD, chief of the Division of Genetics in the UC San Diego School of Medicine, and colleagues in a recent issue of the Proceedings of the National Academy of Sciences.
Hemoglobin protein molecules, for example, continuously transit through our blood vessels while other proteins you’ve never heard of bustle about inside cells as they grow, develop, respond to stimuli and succumb to disease.
To better understand the role of proteins in biological systems, Ideker and colleagues developed a computer model that can predict a protein’s intracellular wanderings in response to a variety of stress conditions.
To date, the model has been used to predict the effects of 18 different DNA-damaging stress conditions on the sub-cellular locations and molecular functions of more than 5,800 proteins produced by yeasts. They found, for example, that yeast proteins could move from mitochondria to the cell nucleus and from the endoplasmic reticulum to Golgi apparatus.
Though the model debut involved yeasts, researchers said the coding can be adapted to study changes in protein locations for any biological system in which gene expression sequences have been identified, including stem cell differentiation and drug response in humans.
Image courtesy of Material Mavens

A Moveable Yeast: modeling shows proteins never sit still

Our body’s proteins – encoded by DNA to do the hard work of building and operating our bodies – are forever on the move. Literally, according to new findings reported by Trey Ideker, PhD, chief of the Division of Genetics in the UC San Diego School of Medicine, and colleagues in a recent issue of the Proceedings of the National Academy of Sciences.

Hemoglobin protein molecules, for example, continuously transit through our blood vessels while other proteins you’ve never heard of bustle about inside cells as they grow, develop, respond to stimuli and succumb to disease.

To better understand the role of proteins in biological systems, Ideker and colleagues developed a computer model that can predict a protein’s intracellular wanderings in response to a variety of stress conditions.

To date, the model has been used to predict the effects of 18 different DNA-damaging stress conditions on the sub-cellular locations and molecular functions of more than 5,800 proteins produced by yeasts. They found, for example, that yeast proteins could move from mitochondria to the cell nucleus and from the endoplasmic reticulum to Golgi apparatus.

Though the model debut involved yeasts, researchers said the coding can be adapted to study changes in protein locations for any biological system in which gene expression sequences have been identified, including stem cell differentiation and drug response in humans.

Image courtesy of Material Mavens

Cancer Stem Cells Linked to Drug ResistanceDiscovery of previously undefined molecular pathway is step toward novel clinical trial
Most drugs used to treat lung, breast and pancreatic cancers also promote drug-resistance and ultimately spur tumor growth. Researchers at the University of California, San Diego School of Medicine have discovered a molecule, or biomarker, called CD61 on the surface of drug-resistant tumors that appears responsible for inducing tumor metastasis by enhancing the stem cell-like properties of cancer cells.
The findings, published in the April 20, 2014 online issue of Nature Cell Biology, may point to new therapeutic opportunities for reversing drug resistance in a range of cancers, including those in the lung, pancreas and breast.
“There are a number of drugs that patients respond to during their initial cancer treatment, but relapse occurs when cancer cells become drug-resistant,” said David Cheresh, PhD, Distinguished Professor of Pathology and UC San Diego Moores Cancer Center associate director for Innovation and Industry Alliances. “We looked at the cells before and after they became resistant and asked, ‘What has changed in the cells?’”
Cheresh and colleagues investigated how tumor cells become resistant to drugs like erlotinib or lapatinib, known as receptor tyrosine kinase inhibitors and commonly used in standard cancer therapies. They found that as drug resistance occurs, tumor cells acquire stem cell-like properties that give them the capacity to survive throughout the body and essentially ignore the drugs.
Specifically, the scientists delineated the molecular pathway that facilitates both cancer stemness and drug resistance, and were able to identify existing drugs that exploit this pathway. These drugs not only reverse stem cell-like properties of tumors, but also appear to re-sensitize tumors to drugs that the cancer cells had developed resistance to. 
“The good news is that we’ve uncovered a previously undefined pathway that the tumor cells use to transform into cancer stem cells and that enable tumors to become resistant to commonly used cancer drugs,” said Cheresh.
Based on these findings, Hatim Husain, MD, an assistant professor who treats lung and brain cancer patients at Moores Cancer Center, has designed a clinical trial to attack this pathway in patients whose tumors are drug-resistant. The trial will be open to patients with lung cancer who have experienced cancer progression and drug resistance to erlotinib. It is expected to begin in the next year.
“Resistance builds to targeted therapies against cancer, and we have furthered our understanding of the mechanisms by which that happens,” said Husain. “Based on these research findings we now better understand how to exploit the ‘Achilles heel’ of these drug-resistant tumors.  Treatments will evolve into combinational therapies where one may keep the disease under control and delay resistance mechanisms from occurring for extended periods of time.”
Although the trial is expected to begin with patients who have already experienced drug resistance, Husain hopes to extend the study to reach patients in earlier stages to prevent initial resistance.
Pictured: When lung cancer cells become drug resistant, tumor cells return, as shown in brown in the photo on the left. Researchers identified an existing drug, bortezomib, that reverses stem cell-like properties of tumors, resensitizing them to drugs as shown in the photo on the right.

Cancer Stem Cells Linked to Drug Resistance
Discovery of previously undefined molecular pathway is step toward novel clinical trial

Most drugs used to treat lung, breast and pancreatic cancers also promote drug-resistance and ultimately spur tumor growth. Researchers at the University of California, San Diego School of Medicine have discovered a molecule, or biomarker, called CD61 on the surface of drug-resistant tumors that appears responsible for inducing tumor metastasis by enhancing the stem cell-like properties of cancer cells.

The findings, published in the April 20, 2014 online issue of Nature Cell Biology, may point to new therapeutic opportunities for reversing drug resistance in a range of cancers, including those in the lung, pancreas and breast.

“There are a number of drugs that patients respond to during their initial cancer treatment, but relapse occurs when cancer cells become drug-resistant,” said David Cheresh, PhD, Distinguished Professor of Pathology and UC San Diego Moores Cancer Center associate director for Innovation and Industry Alliances. “We looked at the cells before and after they became resistant and asked, ‘What has changed in the cells?’”

Cheresh and colleagues investigated how tumor cells become resistant to drugs like erlotinib or lapatinib, known as receptor tyrosine kinase inhibitors and commonly used in standard cancer therapies. They found that as drug resistance occurs, tumor cells acquire stem cell-like properties that give them the capacity to survive throughout the body and essentially ignore the drugs.

Specifically, the scientists delineated the molecular pathway that facilitates both cancer stemness and drug resistance, and were able to identify existing drugs that exploit this pathway. These drugs not only reverse stem cell-like properties of tumors, but also appear to re-sensitize tumors to drugs that the cancer cells had developed resistance to. 

“The good news is that we’ve uncovered a previously undefined pathway that the tumor cells use to transform into cancer stem cells and that enable tumors to become resistant to commonly used cancer drugs,” said Cheresh.

Based on these findings, Hatim Husain, MD, an assistant professor who treats lung and brain cancer patients at Moores Cancer Center, has designed a clinical trial to attack this pathway in patients whose tumors are drug-resistant. The trial will be open to patients with lung cancer who have experienced cancer progression and drug resistance to erlotinib. It is expected to begin in the next year.

“Resistance builds to targeted therapies against cancer, and we have furthered our understanding of the mechanisms by which that happens,” said Husain. “Based on these research findings we now better understand how to exploit the ‘Achilles heel’ of these drug-resistant tumors.  Treatments will evolve into combinational therapies where one may keep the disease under control and delay resistance mechanisms from occurring for extended periods of time.”

Although the trial is expected to begin with patients who have already experienced drug resistance, Husain hopes to extend the study to reach patients in earlier stages to prevent initial resistance.

Pictured: When lung cancer cells become drug resistant, tumor cells return, as shown in brown in the photo on the left. Researchers identified an existing drug, bortezomib, that reverses stem cell-like properties of tumors, resensitizing them to drugs as shown in the photo on the right.

Mutant Protein in Muscle Linked to Neuromuscular DisorderA new therapeutic target for Kennedy’s disease and a potential treatment 
Sometimes known as Kennedy’s disease, spinal and bulbar muscular atrophy (SBMA) is a rare inherited neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy. Researchers have long considered it to be essentially an affliction of primary motor neurons – the cells in the spinal cord and brainstem that control muscle movement.
But in a new study published in the April 16, 2014 online issue of Neuron, a team of scientists at the University of California, San Diego School of Medicine say novel mouse studies indicate that mutant protein levels in muscle cells, not motor neurons, are fundamentally involved in SBMA, suggesting an alternative and promising new avenue of treatment for a condition that is currently incurable.
SBMA is an X-linked recessive disease that affects only males, though females carrying the defective gene have a 50:50 chance of passing it along to a son. It belongs to a group of diseases, such as Huntington’s disease, in which a C-A-G DNA sequence is repeated too many times, resulting in a protein with too many glutamines (an amino acid), causing the diseased protein to misfold and produce harmful consequences for affected cells. Thus far, human clinical trials of treatments to protect against these repeat toxicities have failed.
In the new paper, a team led by principal investigator Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine, and neurosciences, and the associate director of the Institute for Genomic Medicine at UC San Diego, propose a different therapeutic target. After creating a new mouse model of SBMA, they discovered that skeletal muscle was the site of mutant protein toxicity and that measures which mitigated the protein’s influence in muscle suppressed symptoms of SBMA in treated mice, such as weight loss and progressive weakness, and increased survival.   
In a related paper, published in the April 16, 2014 online issue of Cell Reports, La Spada and colleagues describe a potential treatment for SBMA. Currently, there is none.
The scientists developed antisense oligonucleotides – sequences of synthesized genetic material – that suppressed androgen receptor (AR) gene expression in peripheral tissues, but not in the central nervous system. Mutations in the AR gene are the cause of SBMA, a discovery that La Spada made more than 20 years ago while a MD-PhD student.
La Spada said that antisense therapy helped mice modeling SBMA to recover lost muscle weight and strength and extended survival. 
“The main points of these papers is that we have identified both a genetic cure and a drug cure for SBMA – at least in mice. The goal now is to further develop and refine these ideas so that we can ultimately test them in people,” La Spada said.
Pictured: striated human skeletal muscle.

Mutant Protein in Muscle Linked to Neuromuscular Disorder
A new therapeutic target for Kennedy’s disease and a potential treatment

Sometimes known as Kennedy’s disease, spinal and bulbar muscular atrophy (SBMA) is a rare inherited neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy. Researchers have long considered it to be essentially an affliction of primary motor neurons – the cells in the spinal cord and brainstem that control muscle movement.

But in a new study published in the April 16, 2014 online issue of Neuron, a team of scientists at the University of California, San Diego School of Medicine say novel mouse studies indicate that mutant protein levels in muscle cells, not motor neurons, are fundamentally involved in SBMA, suggesting an alternative and promising new avenue of treatment for a condition that is currently incurable.

SBMA is an X-linked recessive disease that affects only males, though females carrying the defective gene have a 50:50 chance of passing it along to a son. It belongs to a group of diseases, such as Huntington’s disease, in which a C-A-G DNA sequence is repeated too many times, resulting in a protein with too many glutamines (an amino acid), causing the diseased protein to misfold and produce harmful consequences for affected cells. Thus far, human clinical trials of treatments to protect against these repeat toxicities have failed.

In the new paper, a team led by principal investigator Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine, and neurosciences, and the associate director of the Institute for Genomic Medicine at UC San Diego, propose a different therapeutic target. After creating a new mouse model of SBMA, they discovered that skeletal muscle was the site of mutant protein toxicity and that measures which mitigated the protein’s influence in muscle suppressed symptoms of SBMA in treated mice, such as weight loss and progressive weakness, and increased survival.   

In a related paper, published in the April 16, 2014 online issue of Cell Reports, La Spada and colleagues describe a potential treatment for SBMA. Currently, there is none.

The scientists developed antisense oligonucleotides – sequences of synthesized genetic material – that suppressed androgen receptor (AR) gene expression in peripheral tissues, but not in the central nervous system. Mutations in the AR gene are the cause of SBMA, a discovery that La Spada made more than 20 years ago while a MD-PhD student.

La Spada said that antisense therapy helped mice modeling SBMA to recover lost muscle weight and strength and extended survival. 

“The main points of these papers is that we have identified both a genetic cure and a drug cure for SBMA – at least in mice. The goal now is to further develop and refine these ideas so that we can ultimately test them in people,” La Spada said.

Pictured: striated human skeletal muscle.

Splice Variants Reveal Connections Among Autism Genes 
A team of researchers from the University of California, San Diego School of Medicine and the Center for Cancer Systems Biology (CCSB) at the Dana-Farber Cancer Institute has uncovered a new aspect of autism, revealing that proteins involved in autism interact with many more partners than previously known. These interactions had not been detected earlier because they involve alternatively spliced forms of autism genes found in the brain. 
In their study, published in the April 11, 2014 online issue of Nature Communications, the scientists isolated hundreds of new variants of autism genes from the human brain, and then screened their protein products against thousands of other proteins to identify interacting partners. Proteins produced by alternatively-spliced autism genes and their many partners formed a biological network that produced an unprecedented view of how autism genes are connected. 
"When the newly discovered splice forms of autism genes were added to the network, the total number of interactions doubled," said principal investigator Lilia Iakoucheva, PhD, assistant professor in the Department of Psychiatry at UC San Diego. In some cases, the splice forms interacted with a completely different set of proteins. "What we see from this network is that different variants of the same protein could alter the wiring of the entire system," Iakoucheva said. 
"This is the first proteome-scale interaction network to incorporate alternative splice forms," noted Marc Vidal, PhD, CCSB director and a co-investigator on the study. "The fact that protein variants produce such diverse patterns of interactions is exciting and quite unexpected."
The new network also illuminated how multiple autism genes connect to one another. The scientists found that one class of mutations involved in autism, known as copy number variants, involve genes that are closely connected to each other directly or indirectly through a common partner. “This suggests that shared biological pathways may be disrupted in patients with different autism mutations,” said co-first author Guan Ning Lin, PhD, a postdoctoral fellow in Iakouchevaís laboratory.
Beyond providing greater breadth and depth around autism proteins, the network represents a new resource for future autism studies, according to Iakoucheva. For example, she said the physical collection of more than 400 splicing variants of autism candidate genes could be used by other researchers interested in studying a specific protein variant. Some of the highly connected network partners may also represent potential drug targets. All interaction data will reside in the publicly available National Database of Autism Research.   
"With this assembled autism network, we can begin to investigate how newly discovered mutations from patients may disrupt this network,î said Iakoucheva. "This is an important task because the mechanism by which mutant proteins contribute to autism in 99.9 percent of cases remains unknown."
Pictured: Splicing variants (red) of autism genes were cloned from the brain and screened for interactions. The image on the right represents the network of interactions. Gray lines are interactions from a single isoform; red lines are interactions from additional isoforms of autism candidate genes (yellow circles).

Splice Variants Reveal Connections Among Autism Genes 

A team of researchers from the University of California, San Diego School of Medicine and the Center for Cancer Systems Biology (CCSB) at the Dana-Farber Cancer Institute has uncovered a new aspect of autism, revealing that proteins involved in autism interact with many more partners than previously known. These interactions had not been detected earlier because they involve alternatively spliced forms of autism genes found in the brain. 

In their study, published in the April 11, 2014 online issue of Nature Communications, the scientists isolated hundreds of new variants of autism genes from the human brain, and then screened their protein products against thousands of other proteins to identify interacting partners. Proteins produced by alternatively-spliced autism genes and their many partners formed a biological network that produced an unprecedented view of how autism genes are connected. 

"When the newly discovered splice forms of autism genes were added to the network, the total number of interactions doubled," said principal investigator Lilia Iakoucheva, PhD, assistant professor in the Department of Psychiatry at UC San Diego. In some cases, the splice forms interacted with a completely different set of proteins. "What we see from this network is that different variants of the same protein could alter the wiring of the entire system," Iakoucheva said. 

"This is the first proteome-scale interaction network to incorporate alternative splice forms," noted Marc Vidal, PhD, CCSB director and a co-investigator on the study. "The fact that protein variants produce such diverse patterns of interactions is exciting and quite unexpected."

The new network also illuminated how multiple autism genes connect to one another. The scientists found that one class of mutations involved in autism, known as copy number variants, involve genes that are closely connected to each other directly or indirectly through a common partner. “This suggests that shared biological pathways may be disrupted in patients with different autism mutations,” said co-first author Guan Ning Lin, PhD, a postdoctoral fellow in Iakouchevaís laboratory.

Beyond providing greater breadth and depth around autism proteins, the network represents a new resource for future autism studies, according to Iakoucheva. For example, she said the physical collection of more than 400 splicing variants of autism candidate genes could be used by other researchers interested in studying a specific protein variant. Some of the highly connected network partners may also represent potential drug targets. All interaction data will reside in the publicly available National Database of Autism Research.   

"With this assembled autism network, we can begin to investigate how newly discovered mutations from patients may disrupt this network,î said Iakoucheva. "This is an important task because the mechanism by which mutant proteins contribute to autism in 99.9 percent of cases remains unknown."

Pictured: Splicing variants (red) of autism genes were cloned from the brain and screened for interactions. The image on the right represents the network of interactions. Gray lines are interactions from a single isoform; red lines are interactions from additional isoforms of autism candidate genes (yellow circles).

UC San Diego Researcher to Lead a NASA Identical Twin Study
Brinda Rana, PhD, a professor at the University of California, San Diego School of Medicine, has been awarded NASA funding to study the effects of near-zero gravity on fluid flows in the brain.
Her project, one of 10 funded through NASA’s $1.5-million twin astronaut study, will look at how space flight affects fluid pressure in the brain and its implications for vision.
“Our bodies are adapted to an environment in which gravity pools fluids toward our legs,” Rana said. “In space, fluid flows upward. Our project will examine the effects of spaceflight on the proteins that regulate vasoconstriction and dilation, and fluid regulation.”
“Like other NASA innovations, such as memory foam and cordless tools, these studies could potentially impact health care on Earth,” Rana said.
The project that she is leading, for example, may shed light on potential new treatments for traumatic brain injury, glaucoma and “water on the brain.”
Only one set of twins – astronauts Scott and Mark Kelly – has ever been to space, making them “an unprecedented opportunity” for scientists to study the physiological and molecular effects of space flight, NASA officials say.
“Studying identical twins enable us to control for 100 percent of genetic factors and shared environmental factors,” Rana said.
In March 2015, Scott will begin a one-year stay on the International Space Station while his brother, Mark, will remain on Earth and serve as “ground control.”  
Blood and urine samples will be collected from the twins before, during and after the mission to search for genetic, proteomic (protein-related), metabolomic and molecular markers of the effects of – and adaptations to – space flight.
The standard stay on the space station is approximately six months. No human has ever lived in space for an entire year. For those who still dream of manned space explorations of, say, Mars, where evidence of flowing, liquid water was recently reported, the projects will gather the type of information needed for more distant explorations of the solar system.
“NASA needs to understand the long-term impact of these missions in order to identify strategies to monitor health outcomes and reduce health risks,” she said.
Rana is also a co-investigator on a project led by Stuart Lee, a lead research scientist for Wyle Integrated Science and Engineering at NASA Johnson Space Center’s Cardiovascular Laboratory, which focuses on understanding the effects of space on heart health.
Other projects funded through the twin study will examine the effects of near-zero gravity, radiation and other space-related environmental stressors on gut flora, immune function and the aging process.
UC San Diego co-investigators on the projects include Kumar Sharma, MD, Alan Hargens, PhD, Vivian Hook, PhD, Brandon Macias, PhD, and Dorothy Sears, PhD.

UC San Diego Researcher to Lead a NASA Identical Twin Study

Brinda Rana, PhD, a professor at the University of California, San Diego School of Medicine, has been awarded NASA funding to study the effects of near-zero gravity on fluid flows in the brain.

Her project, one of 10 funded through NASA’s $1.5-million twin astronaut study, will look at how space flight affects fluid pressure in the brain and its implications for vision.

“Our bodies are adapted to an environment in which gravity pools fluids toward our legs,” Rana said. “In space, fluid flows upward. Our project will examine the effects of spaceflight on the proteins that regulate vasoconstriction and dilation, and fluid regulation.”

“Like other NASA innovations, such as memory foam and cordless tools, these studies could potentially impact health care on Earth,” Rana said.

The project that she is leading, for example, may shed light on potential new treatments for traumatic brain injury, glaucoma and “water on the brain.”

Only one set of twins – astronauts Scott and Mark Kelly – has ever been to space, making them “an unprecedented opportunity” for scientists to study the physiological and molecular effects of space flight, NASA officials say.

“Studying identical twins enable us to control for 100 percent of genetic factors and shared environmental factors,” Rana said.

In March 2015, Scott will begin a one-year stay on the International Space Station while his brother, Mark, will remain on Earth and serve as “ground control.”  

Blood and urine samples will be collected from the twins before, during and after the mission to search for genetic, proteomic (protein-related), metabolomic and molecular markers of the effects of – and adaptations to – space flight.

The standard stay on the space station is approximately six months. No human has ever lived in space for an entire year. For those who still dream of manned space explorations of, say, Mars, where evidence of flowing, liquid water was recently reported, the projects will gather the type of information needed for more distant explorations of the solar system.

“NASA needs to understand the long-term impact of these missions in order to identify strategies to monitor health outcomes and reduce health risks,” she said.

Rana is also a co-investigator on a project led by Stuart Lee, a lead research scientist for Wyle Integrated Science and Engineering at NASA Johnson Space Center’s Cardiovascular Laboratory, which focuses on understanding the effects of space on heart health.

Other projects funded through the twin study will examine the effects of near-zero gravity, radiation and other space-related environmental stressors on gut flora, immune function and the aging process.

UC San Diego co-investigators on the projects include Kumar Sharma, MD, Alan Hargens, PhD, Vivian Hook, PhD, Brandon Macias, PhD, and Dorothy Sears, PhD.

UC San Diego researchers have found clear and direct new evidence that autism begins during pregnancy, reporting that patches of disrupted brain development occur in the womb.

Patches of Cortical Layers Disrupted During Early Brain Development in Autism

Researchers at the University of California, San Diego School of Medicine and the Allen Institute for Brain Science have published a study that gives clear and direct new evidence that autism begins during pregnancy.

The study will be published in the March 27 online edition of the New England Journal of Medicine.  

The researchers – Eric Courchesne, PhD, professor of neurosciences and director of the Autism Center of Excellence at UC San Diego, Ed S. Lein, PhD, of the Allen Institute for Brain Science in Seattle, and first author Rich Stoner, PhD, of the UC San Diego Autism Center of Excellence – analyzed 25 genes in post-mortem brain tissue of children with and without autism. These included genes that serve as biomarkers for brain cell types in different layers of the cortex, genes implicated in autism and several control genes.

“Building a baby’s brain during pregnancy involves creating a cortex that contains six layers,” Courchesne said. “We discovered focal patches of disrupted development of these cortical layers in the majority of children with autism.” Stoner created the first three-dimensional model visualizing brain locations where patches of cortex had failed to develop the normal cell-layering pattern.

“The most surprising finding was the similar early developmental pathology across nearly all of the autistic brains, especially given the diversity of symptoms in patients with autism, as well as the extremely complex genetics behind the disorder,” explained Lein.

During early brain development, each cortical layer develops its own specific types of brain cells, each with specific patterns of brain connectivity that perform unique and important roles in processing information. As a brain cell develops into a specific type in a specific layer with   specific connections, it acquires a distinct genetic signature or “marker” that can be observed.

The study found that in the brains of children with autism, key genetic markers were absent in brain cells in multiple layers. “This defect,” Courchesne said, “indicates that the crucial early developmental step of creating six distinct layers with specific types of brain cells – something that begins in prenatal life – had been disrupted.”

Equally important, said the scientists, these early developmental defects were present in focal patches of cortex, suggesting the defect is not uniform throughout the cortex. The brain regions most affected by focal patches of absent gene markers were the frontal and the temporal cortex, possibly illuminating why different functional systems are impacted across individuals with the disorder.

The frontal cortex is associated with higher-order brain function, such as complex communication and comprehension of social cues. The temporal cortex is associated with language. The disruptions of frontal and temporal cortical layers seen in the study may underlie symptoms most often displayed in autistic spectrum disorders. The visual cortex – an area of the brain associated with perception that tends to be spared in autism – displayed no abnormalities. 

“The fact that we were able to find these patches is remarkable, given that the cortex is roughly the size of the surface of a basketball, and we only examined pieces of tissue the size of a pencil eraser,” said Lein. “This suggests that these abnormalities are quite pervasive across the surface of the cortex.”

Data collected for the Allen Brain Atlas, as well as the BrainSpan Atlas of the Developing Human Brain was developed by a consortium of partners and funded by the National Institute of Mental Health. It allowed scientists to identify specific genes in the developing human brain that could be used as biomarkers for the different layer cell types.

Researching the origins of autism is challenging because it typically relies upon studying adult brains and attempting to extrapolate backwards. “In this case,” Lein noted, “we were able to study autistic and control cases at a young age, giving us a unique insight into how autism presents in the developing brain.”

“The finding that these defects occur in patches rather than across the entirety of cortex gives hope as well as insight about the nature of autism,” added Courchesne.

According to the scientists, such patchy defects, as opposed to uniform cortical pathology, may help explain why many toddlers with autism show clinical improvement with early treatment and over time. The findings support the idea that in children with autism the brain can sometimes rewire connections to circumvent early focal defects, raising hope that understanding these patches may eventually open new avenues to explore how that improvement occurs.

A coronary aneurysm is an abnormal ballooning of a portion of the coronary artery and a potential consequence of Kawasaki disease. If untreated, it may result in irreversible heart damage and death. This angiography of an 18-year-old patient reveals a massive aneurysm in the right coronary artery compared to the normal left. Image courtesy of Tomio Kobayashi, Gunma University School of Medicine, Japan.
Study Evaluates Role of Infliximab in Treating Kawasaki DiseaseAntibody treatment helps children with dangerous heart disorder
Kawasaki Disease (KD) is a severe childhood disease that many parents, even some doctors, mistake for an inconsequential viral infection. If not diagnosed or treated in time, it can lead to irreversible heart damage.
Signs of KD include prolonged fever associated with rash, red eyes, mouth, lips and tongue, and swollen hands and feet with peeling skin. The disease causes damage to the coronary arteries in a quarter of untreated children and may lead to serious heart problems in early adulthood. There is no diagnostic test for Kawasaki disease, and current treatment fails to prevent coronary artery damage in at least one in 10 to 20 children and death in one in 1,000 children. 
Between 10 and 20 percent of patients with KD experience fever relapse following the standard therapy with a single infusion of intravenous immunoglobulin (IVIG) and aspirin. It is known that IVIG resistance increases the risk of heart damage, most commonly a ballooning of the coronary arteries called aneurysms. These children require additional therapy to interrupt the inflammatory process that can lead to damage of the coronary arteries.
A study led by physicians at the University of California, San Diego School of Medicine and Rady Children’s Hospital-San Diego looked at intensification of initial therapy for all children with KD in order to prevent IVIG-resistance and associated coronary artery abnormalities by assessing the addition of the medication infliximab to current standard therapy. The results of their study will be published in the February 24, 2014 online issue of the medical journal Lancet. 
More here

A coronary aneurysm is an abnormal ballooning of a portion of the coronary artery and a potential consequence of Kawasaki disease. If untreated, it may result in irreversible heart damage and death. This angiography of an 18-year-old patient reveals a massive aneurysm in the right coronary artery compared to the normal left. Image courtesy of Tomio Kobayashi, Gunma University School of Medicine, Japan.

Study Evaluates Role of Infliximab in Treating Kawasaki Disease
Antibody treatment helps children with dangerous heart disorder

Kawasaki Disease (KD) is a severe childhood disease that many parents, even some doctors, mistake for an inconsequential viral infection. If not diagnosed or treated in time, it can lead to irreversible heart damage.

Signs of KD include prolonged fever associated with rash, red eyes, mouth, lips and tongue, and swollen hands and feet with peeling skin. The disease causes damage to the coronary arteries in a quarter of untreated children and may lead to serious heart problems in early adulthood. There is no diagnostic test for Kawasaki disease, and current treatment fails to prevent coronary artery damage in at least one in 10 to 20 children and death in one in 1,000 children. 

Between 10 and 20 percent of patients with KD experience fever relapse following the standard therapy with a single infusion of intravenous immunoglobulin (IVIG) and aspirin. It is known that IVIG resistance increases the risk of heart damage, most commonly a ballooning of the coronary arteries called aneurysms. These children require additional therapy to interrupt the inflammatory process that can lead to damage of the coronary arteries.

A study led by physicians at the University of California, San Diego School of Medicine and Rady Children’s Hospital-San Diego looked at intensification of initial therapy for all children with KD in order to prevent IVIG-resistance and associated coronary artery abnormalities by assessing the addition of the medication infliximab to current standard therapy. The results of their study will be published in the February 24, 2014 online issue of the medical journal Lancet

More here

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