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 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.

H.M.’s Brain Yields New Evidence
3D model of famous amnesiac’s brain helps illuminate human memory

During his lifetime, Henry G. Molaison (H.M.) was the best-known and possibly the most-studied patient of modern neuroscience. Now, thanks to the postmortem study of his brain, based on histological sectioning and digital three-dimensional construction led by Jacopo Annese, PhD, at the University of California, San Diego, scientists around the globe will finally have insight into the neurological basis of the case that defined modern studies of human memory. 

The microscopic anatomical model of the whole brain and detailed 3D measurements of the medial temporal lobe (MTL) region are described in a paper to be published online in Nature Communications on January 28.

H.M. was an epileptic patient whose severe and almost total amnesia was the unexpected result of a bilateral surgical ablation of the MTL, including the hippocampus, in 1953. Until his death in 2008, the purity and severity of H.M.’s memory impairment, along with his willingness to participate in continual testing, made his case uniquely influential.

While his intellectual abilities, personality, language and perceptual skills remained intact, he was unable to store information in long-term memory.  After his brain operation, H.M. was profoundly impaired in forming new declarative memories. This unfortunate outcome became the catalyst for over 50 years of scientific discoveries (and thousands of publications) that have radically changed scientists’ basic understanding of memory function. His case was significant because it provided the first conclusive evidence for the involvement of the hippocampus in forming new memories.

In December 2009, Annese and his team dissected H.M.’s brain into 2,401 thin tissue slices that were then preserved cryogenically in serial order. While the brain was being sliced, the researchers collected an unabridged series of digital images of the surface of the block, corresponding to each tissue section. These images were archived and used to create a three-dimensional microscopic model of the whole brain. The model of H.M.’s brain contains clues to help understand the surgery performed in 1953, and the level of sampling and image quality afforded by this study represents a significant advance over the MRI scans performed with H.M.  when he was alive.

More here

Anthony Chetti is one of the beneficiaries of tractography-guided brain surgery. Chetti developed a tumor in the region of the brain called the occipital lobe, the portion of the brain responsible for processing visual information.

“Anytime that you are told that you can potentially lose your vision, you are scared,” said Chetti, a San Diego school teacher. “But when Dr. Chen shared the tractography images with me and showed me how he was going to avoid injury to the connection between my eye and the occipital lobe, I was reassured.”

Chetti underwent a complete excision of the brain tumor without any damage to his vision.

“When I woke up from surgery, I asked for my glasses immediately and began running systems checks. I could see the clock. I could read the words on a sign. It was immediately evident that there were no problems,” said Chetti.

Tractography scans can reveal tiny open paths between nerve fibers to reach brain tumors. The scans are color coded and display tiny neural connections. Other current imaging techniques such as computed tomography (CT) and conventional magnetic resonance imaging (MRI) cannot achieve this type of visual display.

Brain cells of a laboratory mouse glowing with multicolor fluorescent proteins. Image courtesy of Harvard University, Livett-Weissman-Sanes-Lichtman
Early growth factor treatment may help prevent cell loss in Alzheimer’s disease
Brain-derived neurotrophic factor or BDNF has long been a target of interest among Alzheimer’s disease (AD) researchers and the Alzheimer’s community at large.
Four years ago, Mark Tuszynski, MD, PhD, professor of neurosciences at UC San Diego School of Medicine and director of the Center for Neural Repair and colleagues showed that a BDNF-based treatment measurably improved neural dysfunction in animal models of Alzheimer’s disease. The findings garnered international headlines.
Now there is new evidence that BDNF may be effective as a preventive measure for AD. 
In a paper, published yesterday in The Journal of Neuroscience, Tuszynski and colleagues follow up with evidence that early life BDNF treatment prevents neuronal loss in mutant mice genetically predisposed to early-onset familial Alzheimer’s disease.
Specifically, mice engineered to express APP, a protein strongly linked to AD development, received injections of the BDNF gene at two months of age and were examined five months later. The researchers found that BDNF-treated mice exhibited better behavior and brain function than untreated APP mutant mice and suffered significantly less neuron loss in the entorhinal cortex, a region of the brain that helps mediate learning and memory.
In addition, they noted that BDNF did not affect amyloid plaque accumulation, another major indicator of AD, suggesting that direct amyloid reduction is not necessary to achieving significant neuroprotective benefits in mutant amyloid models of AD.
“These findings strengthen the rationale for planning human clinical trials of BDNF therapy in AD,” said Tuszynski. “This is an effort that we are actively engaged in.” 
Tuszynski also noted that there is a possibility that BDNF therapy and anti-amyloid therapies for AD could be combined to yield better treatments than either treatment alone.

Brain cells of a laboratory mouse glowing with multicolor fluorescent proteins. Image courtesy of Harvard University, Livett-Weissman-Sanes-Lichtman

Early growth factor treatment may help prevent cell loss in Alzheimer’s disease

Brain-derived neurotrophic factor or BDNF has long been a target of interest among Alzheimer’s disease (AD) researchers and the Alzheimer’s community at large.

Four years ago, Mark Tuszynski, MD, PhD, professor of neurosciences at UC San Diego School of Medicine and director of the Center for Neural Repair and colleagues showed that a BDNF-based treatment measurably improved neural dysfunction in animal models of Alzheimer’s disease. The findings garnered international headlines.

Now there is new evidence that BDNF may be effective as a preventive measure for AD. 

In a paper, published yesterday in The Journal of Neuroscience, Tuszynski and colleagues follow up with evidence that early life BDNF treatment prevents neuronal loss in mutant mice genetically predisposed to early-onset familial Alzheimer’s disease.

Specifically, mice engineered to express APP, a protein strongly linked to AD development, received injections of the BDNF gene at two months of age and were examined five months later. The researchers found that BDNF-treated mice exhibited better behavior and brain function than untreated APP mutant mice and suffered significantly less neuron loss in the entorhinal cortex, a region of the brain that helps mediate learning and memory.

In addition, they noted that BDNF did not affect amyloid plaque accumulation, another major indicator of AD, suggesting that direct amyloid reduction is not necessary to achieving significant neuroprotective benefits in mutant amyloid models of AD.

“These findings strengthen the rationale for planning human clinical trials of BDNF therapy in AD,” said Tuszynski. “This is an effort that we are actively engaged in.” 

Tuszynski also noted that there is a possibility that BDNF therapy and anti-amyloid therapies for AD could be combined to yield better treatments than either treatment alone.

Human astrocyte progenitors and immature astrocytes, created from induced pluripotent stem cells, form an “astrosphere” inside a Petri dish. Image courtesy of the University of Wisconsin-Madison. 
A star (cell) is born
Astrocytes are star-shaped (the name derives from the Greek words for star and cell) glial cells. They are the most abundant cell type in the human brain, and for good reason: They have a lot of jobs, from providing biochemical support of the endothelial cells that form the blood-brain barrier to delivering nutrients to nervous system tissue to helping repair the spinal cord after traumatic injury.
Neurons attract most of the attention, but researchers are increasingly investigating the roles and potential of astrocytes in treating a host of neurological harms and diseases.
For example, a CIRM-supported “disease team” of scientists at UC San Diego School of Medicine and the Salk Institute for Biological Studies is investigating the possibility of transplanting healthy astrocytes derived from stem cells into patients suffering from amytrophic lateral sclerosis or Lou Gehrig’s disease. The work is based, in part, upon encouraging findings in an ALS mouse model, conducted by Don Cleveland, PhD, and colleagues.
More recently, UC Davis scientists underscored the potential therapeutic value of astrocytes, reporting in the journal Nature Communications that the cells’ “calm” nature may make them best suited for some future stem cell-based neurological therapies.
“Astrocytes are often considered just ‘housekeeping’ cells because of their supportive roles to neurons, but they’re actually much more sophisticated,” said study co-author Wenbin Deng in a news release. 
“They are critical to several brain functions and are believed to protect neurons from injury and death. They are not excitable cells like neurons and are easier to harness. We wanted to explore their potential in treating neurological disorders, beginning with stroke.”
Of course, success is neither guaranteed nor looming, but if it happens, astrocytes will have a starring role.

Human astrocyte progenitors and immature astrocytes, created from induced pluripotent stem cells, form an “astrosphere” inside a Petri dish. Image courtesy of the University of Wisconsin-Madison.

A star (cell) is born

Astrocytes are star-shaped (the name derives from the Greek words for star and cell) glial cells. They are the most abundant cell type in the human brain, and for good reason: They have a lot of jobs, from providing biochemical support of the endothelial cells that form the blood-brain barrier to delivering nutrients to nervous system tissue to helping repair the spinal cord after traumatic injury.

Neurons attract most of the attention, but researchers are increasingly investigating the roles and potential of astrocytes in treating a host of neurological harms and diseases.

For example, a CIRM-supported “disease team” of scientists at UC San Diego School of Medicine and the Salk Institute for Biological Studies is investigating the possibility of transplanting healthy astrocytes derived from stem cells into patients suffering from amytrophic lateral sclerosis or Lou Gehrig’s disease. The work is based, in part, upon encouraging findings in an ALS mouse model, conducted by Don Cleveland, PhD, and colleagues.

More recently, UC Davis scientists underscored the potential therapeutic value of astrocytes, reporting in the journal Nature Communications that the cells’ “calm” nature may make them best suited for some future stem cell-based neurological therapies.

“Astrocytes are often considered just ‘housekeeping’ cells because of their supportive roles to neurons, but they’re actually much more sophisticated,” said study co-author Wenbin Deng in a news release

“They are critical to several brain functions and are believed to protect neurons from injury and death. They are not excitable cells like neurons and are easier to harness. We wanted to explore their potential in treating neurological disorders, beginning with stroke.”

Of course, success is neither guaranteed nor looming, but if it happens, astrocytes will have a starring role.

These photomicrographs depict comparative stained sections of a healthy brain (top) and of patient EP, in which significant structures in the medial temporal lobe are heavily damaged or missing. The letters identify specific brain structures, such as EC and PRC for entorhinal cortex and perirhinal cortex, respectively, both important to memory formation and function.
Gone, But Not ForgottenUC San Diego scientists recall EP, perhaps the world’s second-most famous amnesiac
An international team of neuroscientists has described for the first time in exhaustive detail the underlying neurobiology of an amnesiac who suffered from profound memory loss after damage to key portions of his brain.
Writing in this week’s Online Early Edition of PNAS, principal investigator Larry R. Squire, PhD, professor in the departments of Neurosciences, Psychiatry and Psychology at the University of California, San Diego School of Medicine and Veteran Affairs San Diego Healthcare System (VASDHS) – with colleagues at UC Davis and the University of Castilla-La Mancha in Spain – recount the case of EP, a man who suffered radical memory loss and dysfunction following a bout of viral encephalitis.
EP’s story is strikingly similar to the more famous case of HM, who also suffered permanent, dramatic memory loss after small portions of his medial temporal lobes were removed by doctors in 1953 to relieve severe epileptic seizures. The surgery was successful, but left HM unable to form new memories or recall people, places or events post-operation.
HM (later identified as Henry Gustav Molaison) was the subject of intense scientific scrutiny and study for the remainder of his life. When he died in 2008 at the age of 82, he was popularized as “the world’s most famous amnesiac.” His brain was removed and digitally preserved at The Brain Observatory, a UC San Diego-based lab headed by Jacopo Annese, PhD, an assistant adjunct professor in the Department of Radiology and a co-author of the PNAS paper.
Like Molaison, EP was also something of a scientific celebrity, albeit purposefully anonymous. In 1992, at the age of 70, he was diagnosed with viral encephalitis. He recovered, but the illness resulted in devastating neurological loss, both physiologically and psychologically.
Not only did he also lose the ability to form new memories, EP suffered a modest impairment in his semantic knowledge – the knowledge of things like words and the names of objects. Between 1994, when he moved to San Diego County, and his death 14 years later, EP was a subject of continued study, which included hundreds of different assessments of cognitive function.
“The work was long-term,” said Squire, a Career Research Scientist at the VASDHS. “We probably visited his house 200 times. We knew his family.” In a 2000 paper, Squire and colleagues described EP as a 6-foot-2, 192-pound affable fellow with a fascination for the computers used in his testing. He was always agreeable and pleasant. “He had a sense of humor,” said Squire.
More here

These photomicrographs depict comparative stained sections of a healthy brain (top) and of patient EP, in which significant structures in the medial temporal lobe are heavily damaged or missing. The letters identify specific brain structures, such as EC and PRC for entorhinal cortex and perirhinal cortex, respectively, both important to memory formation and function.

Gone, But Not Forgotten
UC San Diego scientists recall EP, perhaps the world’s second-most famous amnesiac

An international team of neuroscientists has described for the first time in exhaustive detail the underlying neurobiology of an amnesiac who suffered from profound memory loss after damage to key portions of his brain.

Writing in this week’s Online Early Edition of PNAS, principal investigator Larry R. Squire, PhD, professor in the departments of Neurosciences, Psychiatry and Psychology at the University of California, San Diego School of Medicine and Veteran Affairs San Diego Healthcare System (VASDHS) – with colleagues at UC Davis and the University of Castilla-La Mancha in Spain – recount the case of EP, a man who suffered radical memory loss and dysfunction following a bout of viral encephalitis.

EP’s story is strikingly similar to the more famous case of HM, who also suffered permanent, dramatic memory loss after small portions of his medial temporal lobes were removed by doctors in 1953 to relieve severe epileptic seizures. The surgery was successful, but left HM unable to form new memories or recall people, places or events post-operation.

HM (later identified as Henry Gustav Molaison) was the subject of intense scientific scrutiny and study for the remainder of his life. When he died in 2008 at the age of 82, he was popularized as “the world’s most famous amnesiac.” His brain was removed and digitally preserved at The Brain Observatory, a UC San Diego-based lab headed by Jacopo Annese, PhD, an assistant adjunct professor in the Department of Radiology and a co-author of the PNAS paper.

Like Molaison, EP was also something of a scientific celebrity, albeit purposefully anonymous. In 1992, at the age of 70, he was diagnosed with viral encephalitis. He recovered, but the illness resulted in devastating neurological loss, both physiologically and psychologically.

Not only did he also lose the ability to form new memories, EP suffered a modest impairment in his semantic knowledge – the knowledge of things like words and the names of objects. Between 1994, when he moved to San Diego County, and his death 14 years later, EP was a subject of continued study, which included hundreds of different assessments of cognitive function.

“The work was long-term,” said Squire, a Career Research Scientist at the VASDHS. “We probably visited his house 200 times. We knew his family.” In a 2000 paper, Squire and colleagues described EP as a 6-foot-2, 192-pound affable fellow with a fascination for the computers used in his testing. He was always agreeable and pleasant. “He had a sense of humor,” said Squire.

More here

How cancer hijacks healthy cell circuits to stay alive
Fundamentally, cancer is a disease of cell growth and function run amok. Frequently, the culprit is mutations in the proteins that regulate growth, such as epidermal growth factor receptor or EGFR, which has been implicated in a variety of cancers.
Among these is glioblastoma multiforme (GBM), a highly malignant brain cancer that has thus far defied satisfactory remedy. More than 9,000 new cases of GBM are diagnosed each year in the United States and effective treatments are limited. GBM tumors are aggressive and resistant to current therapies, such as surgery, radiation and chemotherapy. The median survival rate for newly diagnosed GBM patients is just 14 months.
Drugs devised to block mutant growth signals in GBM have so far proven only temporarily effective. Eventually, cancer cells adapt and overcome. Most current research has focused on how mutations in other proteins in cancer cells allow them to become drug resistant.
In a new paper, published in Cancer Discovery, a team of scientists co-led by Paul Mischel, MD, a principal investigator at the Ludwig Institute for Cancer at the University of California, San Diego and a professor of pathology in the UC San Diego School of Medicine, identify a unique mechanism that allows GBM cells to develop resistance to drugs targeting EGFR signaling.
The feat, according to Mischel and co-leader Steven Bensinger, VMD, PhD, at UCLA, is accomplished not through mutation, but by hijacking the signaling of a normal cell surface protein called platelet-derived growth factor receptor-beta or PDGFR-beta.
“It’s almost like a game of whack-a-mole,” said Mischel. “You use a drug to suppress a choice target and something else pops up to take its place and keep the cells alive—in this case a growth factor receptor that is perfectly normal in physiological terms.”
When scientists targeted both EGFR and PDGFR-beta in GBM tumors in animal models, the tumors were suppressed and drug resistance prevented. The next step is to develop clinical trials of treatments that target both involved proteins. And while this study focused on glioblastomas, Mischel and Bensinger believe the findings are relevant to other forms of cancer.
You can read the full Ludwig news release here.

How cancer hijacks healthy cell circuits to stay alive

Fundamentally, cancer is a disease of cell growth and function run amok. Frequently, the culprit is mutations in the proteins that regulate growth, such as epidermal growth factor receptor or EGFR, which has been implicated in a variety of cancers.

Among these is glioblastoma multiforme (GBM), a highly malignant brain cancer that has thus far defied satisfactory remedy. More than 9,000 new cases of GBM are diagnosed each year in the United States and effective treatments are limited. GBM tumors are aggressive and resistant to current therapies, such as surgery, radiation and chemotherapy. The median survival rate for newly diagnosed GBM patients is just 14 months.

Drugs devised to block mutant growth signals in GBM have so far proven only temporarily effective. Eventually, cancer cells adapt and overcome. Most current research has focused on how mutations in other proteins in cancer cells allow them to become drug resistant.

In a new paper, published in Cancer Discovery, a team of scientists co-led by Paul Mischel, MD, a principal investigator at the Ludwig Institute for Cancer at the University of California, San Diego and a professor of pathology in the UC San Diego School of Medicine, identify a unique mechanism that allows GBM cells to develop resistance to drugs targeting EGFR signaling.

The feat, according to Mischel and co-leader Steven Bensinger, VMD, PhD, at UCLA, is accomplished not through mutation, but by hijacking the signaling of a normal cell surface protein called platelet-derived growth factor receptor-beta or PDGFR-beta.

“It’s almost like a game of whack-a-mole,” said Mischel. “You use a drug to suppress a choice target and something else pops up to take its place and keep the cells alive—in this case a growth factor receptor that is perfectly normal in physiological terms.”

When scientists targeted both EGFR and PDGFR-beta in GBM tumors in animal models, the tumors were suppressed and drug resistance prevented. The next step is to develop clinical trials of treatments that target both involved proteins. And while this study focused on glioblastomas, Mischel and Bensinger believe the findings are relevant to other forms of cancer.

You can read the full Ludwig news release here.

UC San Diego Health System Listed among Nation’s Top Neurosurgery and Spine Programs
University of California, San Diego Health System has been named among “100 Hospitals with Great Neurosurgery and Spine Programs” by Becker’s Hospital Review, a news publication for hospital and health system leadership.
According to the Becker’s Hospital Review editorial team, these hospitals offer outstanding spine and neurosurgical care, and were selected based on nominations, clinical accolades, quality care and other spine and neurosurgical proficiencies.
“The UC San Diego Neurological Institute is proud to have its neurosurgery program recognized as a leading program in complex brain and spine care,” said Bob Carter, MD, PhD, professor of surgery at UC San Diego School of Medicine, and chief of neurosurgery at UC San Diego Health System. “We have been fortunate to attract an outstanding cadre of neurosurgeons to UC San Diego who specialize in every form of neurosurgery, from minimally invasive techniques to the most complex spine and brain surgery.”
More here

UC San Diego Health System Listed among Nation’s Top Neurosurgery and Spine Programs

University of California, San Diego Health System has been named among “100 Hospitals with Great Neurosurgery and Spine Programs” by Becker’s Hospital Review, a news publication for hospital and health system leadership.

According to the Becker’s Hospital Review editorial team, these hospitals offer outstanding spine and neurosurgical care, and were selected based on nominations, clinical accolades, quality care and other spine and neurosurgical proficiencies.

“The UC San Diego Neurological Institute is proud to have its neurosurgery program recognized as a leading program in complex brain and spine care,” said Bob Carter, MD, PhD, professor of surgery at UC San Diego School of Medicine, and chief of neurosurgery at UC San Diego Health System. “We have been fortunate to attract an outstanding cadre of neurosurgeons to UC San Diego who specialize in every form of neurosurgery, from minimally invasive techniques to the most complex spine and brain surgery.”

More here

Taking down a tumor
Glioblastoma multiforme(GBM) is the most common and aggressive form of malignant brain tumor in humans. It has steadfastly defied efforts to treat it. Patients with GBMs either have an upfront resistance to current therapies or quickly develop one to the existing drug-based inhibitors designed to disable a protein called epidermal growth factor receptor or EGFR that is critical to tumor growth and survival.
As a result, a GBM prognosis is not good.  Median survival time after diagnosis (usually made after the tumor is well-developed) is just 14 months.
In a paper published today in the Proceedings of the National Academy of Sciences, researchers from the Ludwig Institute for Cancer Research, UC San Diego, UCLA and the University of Sao Paolo in Brazil describe a mechanism in GBMs that defines its resistance to therapy. You can read the full news release here.
The work builds upon earlier research by Furnari and colleagues. Also, in 2011, UC San Diego scientists, in collaboration with colleagues in Boston and South Korea, identified a novel gene mutation that causes at least one form of GBM. Perhaps more importantly, the researchers found that two drugs already being used to treat other forms of cancer effectively prolonged the survival of mice modeling this particular form of the brain tumor.

Taking down a tumor

Glioblastoma multiforme(GBM) is the most common and aggressive form of malignant brain tumor in humans. It has steadfastly defied efforts to treat it. Patients with GBMs either have an upfront resistance to current therapies or quickly develop one to the existing drug-based inhibitors designed to disable a protein called epidermal growth factor receptor or EGFR that is critical to tumor growth and survival.

As a result, a GBM prognosis is not good.  Median survival time after diagnosis (usually made after the tumor is well-developed) is just 14 months.

In a paper published today in the Proceedings of the National Academy of Sciences, researchers from the Ludwig Institute for Cancer Research, UC San Diego, UCLA and the University of Sao Paolo in Brazil describe a mechanism in GBMs that defines its resistance to therapy. You can read the full news release here.

The work builds upon earlier research by Furnari and colleagues. Also, in 2011, UC San Diego scientists, in collaboration with colleagues in Boston and South Korea, identified a novel gene mutation that causes at least one form of GBM. Perhaps more importantly, the researchers found that two drugs already being used to treat other forms of cancer effectively prolonged the survival of mice modeling this particular form of the brain tumor.

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