Clinical Trial Evaluates Safety of Stem Cell Transplantation in Spine

Researchers at the University of California, San Diego School of Medicine have launched a clinical trial to investigate the safety of neural stem cell transplantation in patients with chronic spinal cord injuries. This Phase I clinical trial is recruiting eight patients for the 5-year study.

“The goal of this study is to evaluate the safety of transplanting neural stem cells into the spine for what one day could be a treatment for spinal cord injuries,” said Joseph Ciacci, MD, principal investigator and neurosurgeon at UC San Diego Health System. “The study’s immediate goal, however, is to determine whether  injecting these neural stem cells into the spine of patients with spinal cord injury is safe.”

Related goals of the clinical trial include evaluating the stem cell graft’s survival and the effectiveness of immunosuppression drugs to prevent rejection. The researchers will also look for possible therapeutic benefits such as changes in motor and sensory function, bowel and bladder function, and pain levels.

Patients who are accepted for the study will have spinal cord injury to the T7-T12 level of the spine’s vertebrae and will have incurred their injury between one and two years ago.

All participants will receive the stem cell injection. The scientists will use a line of human stem cells approved by the U.S. FDA for human trials in patients with chronic traumatic spinal injuries.  These cells were previously tested for safety in patients with amyotrophic lateral sclerosis (ALS).

Since stem cell transplantation for spinal cord injury is just beginning clinical tests, unforeseen risks, complications or unpredictable outcomes are possible. Careful clinical testing is essential to ensure that this type of therapy is developed responsibly with appropriate management of the risks that all medical therapies may present.

Pre-clinical studies of these cells by Ciacci and Martin Marsala, MD, at the UC San Diego School of Medicine, showed that these grafted neural stem cells improved motor function in spinal cord injured rats with minimal side effects indicating that human clinical trials are now warranted.

This clinical trial at UC San Diego Health System is funded by Neuralstem, Inc. and was launched and supported by the UC San Diego Sanford Stem Cell Clinical Center. The Center was recently created to advance leading-edge stem cell medicine and science, protect and counsel patients, and accelerate innovative stem cell research into patient diagnostics and therapy.

To learn more about eligibility for this clinical trial, please call Amber Faulise at 858-657-5175 or email her at rfaulise@ucsd.edu

How Breast Cancer Usurps the Powers of Mammary Stem Cells
During pregnancy, certain hormones trigger specialized mammary stem cells to create milk-producing cells essential to lactation. Scientists at the University of California, San Diego School of Medicine and Moores Cancer Center have found that mammary stem cells associated with the pregnant mammary gland are related to stem cells found in breast cancer. 
Writing in the August 11, 2014 issue of Developmental Cell, David A. Cheresh, PhD, Distinguished Professor of Pathology and vice-chair for research and development, Jay Desgrosellier, PhD, assistant professor of pathology and colleagues specifically identified a key molecular pathway associated with aggressive breast cancers that is also required for mammary stem cells to promote lactation development during pregnancy. 
“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated,” said Cheresh. “This pathway can be exploited. Certain drugs are known to disrupt this pathway and may interfere with the process of breast cancer progression.”
During pregnancy, a new mammary stem cell population arises, distinct from those involved in development and maintenance of the non-pregnant gland. These stem cells remodel the breasts and lactating glands in preparation for feeding the newborn child. Normally, these stem cells contribute only to early remodeling events and are switched off by the time milk production begins.
The researchers found, however, that signals regulating stem cell activation during pregnancy appear to be hijacked by cancer cells to produce faster-growing, more aggressive tumors. “This normal pathway ends up contributing to the progression of cancer,” said Desgrosellier, first author of the study.
A connection between pregnancy and breast cancer has long been known. But the association between pregnancy and breast cancer risk is complex. While having a child reduces a woman’s risk of developing breast cancer later in life, there is also an increased short-term risk for the development of a highly aggressive form of breast cancer following each pregnancy. The current study suggests that molecules important for stem cell behavior during pregnancy may contribute to these more aggressive pregnancy-associated breast cancers, a possibility the researchers plan to investigate further.
The authors are quick to point out that their findings should not be interpreted as a reason to avoid pregnancy. The signaling pathway usurped by cancer cells is not the cause of breast cancer. Rather, they said, it may worsen or accelerate a cancer caused by other factors, such as an underlying mutation or genetic predisposition.
“Our work doesn’t speak to the actual cause of cancer. Rather, it explains what can happen once cancer has been initiated,” said Cheresh. “Here’s an analogy: To get cancer, you first have to start with an oncogene, a gene that carries a mutation and has the potential to initiate cancer. Think of the oncogene as turning on a car’s ignition. The signaling pathway exploited by cancer cells is like applying gas. It gets the car moving, but it means nothing if the oncogene hasn’t first started the process.”
The researchers focused on a family of cell surface receptor proteins called integrins that act as key communications conduits, ultimately zeroing in on the role of one member of this family called beta-3 integrin. Also known as CD61, it was already linked to metastasis and resistance to cancer drugs.
Cheresh noted that CD61 represents a good marker for the incriminated signaling pathway involved in both mammary development during pregnancy and cancer. It’s easily detected and could be used to both diagnose and treat breast cancer cases. “Detecting CD61 might help doctors determine what kind of therapeutic approach to use, knowing that they might be dealing with a more aggressive yet treatable form of breast cancer. For example, there are existing drugs that block CD61 signaling, which might be another potential aspect of treatment.”

How Breast Cancer Usurps the Powers of Mammary Stem Cells

During pregnancy, certain hormones trigger specialized mammary stem cells to create milk-producing cells essential to lactation. Scientists at the University of California, San Diego School of Medicine and Moores Cancer Center have found that mammary stem cells associated with the pregnant mammary gland are related to stem cells found in breast cancer. 

Writing in the August 11, 2014 issue of Developmental Cell, David A. Cheresh, PhD, Distinguished Professor of Pathology and vice-chair for research and development, Jay Desgrosellier, PhD, assistant professor of pathology and colleagues specifically identified a key molecular pathway associated with aggressive breast cancers that is also required for mammary stem cells to promote lactation development during pregnancy. 

“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated,” said Cheresh. “This pathway can be exploited. Certain drugs are known to disrupt this pathway and may interfere with the process of breast cancer progression.”

During pregnancy, a new mammary stem cell population arises, distinct from those involved in development and maintenance of the non-pregnant gland. These stem cells remodel the breasts and lactating glands in preparation for feeding the newborn child. Normally, these stem cells contribute only to early remodeling events and are switched off by the time milk production begins.

The researchers found, however, that signals regulating stem cell activation during pregnancy appear to be hijacked by cancer cells to produce faster-growing, more aggressive tumors. “This normal pathway ends up contributing to the progression of cancer,” said Desgrosellier, first author of the study.

A connection between pregnancy and breast cancer has long been known. But the association between pregnancy and breast cancer risk is complex. While having a child reduces a woman’s risk of developing breast cancer later in life, there is also an increased short-term risk for the development of a highly aggressive form of breast cancer following each pregnancy. The current study suggests that molecules important for stem cell behavior during pregnancy may contribute to these more aggressive pregnancy-associated breast cancers, a possibility the researchers plan to investigate further.

The authors are quick to point out that their findings should not be interpreted as a reason to avoid pregnancy. The signaling pathway usurped by cancer cells is not the cause of breast cancer. Rather, they said, it may worsen or accelerate a cancer caused by other factors, such as an underlying mutation or genetic predisposition.

“Our work doesn’t speak to the actual cause of cancer. Rather, it explains what can happen once cancer has been initiated,” said Cheresh. “Here’s an analogy: To get cancer, you first have to start with an oncogene, a gene that carries a mutation and has the potential to initiate cancer. Think of the oncogene as turning on a car’s ignition. The signaling pathway exploited by cancer cells is like applying gas. It gets the car moving, but it means nothing if the oncogene hasn’t first started the process.”

The researchers focused on a family of cell surface receptor proteins called integrins that act as key communications conduits, ultimately zeroing in on the role of one member of this family called beta-3 integrin. Also known as CD61, it was already linked to metastasis and resistance to cancer drugs.

Cheresh noted that CD61 represents a good marker for the incriminated signaling pathway involved in both mammary development during pregnancy and cancer. It’s easily detected and could be used to both diagnose and treat breast cancer cases. “Detecting CD61 might help doctors determine what kind of therapeutic approach to use, knowing that they might be dealing with a more aggressive yet treatable form of breast cancer. For example, there are existing drugs that block CD61 signaling, which might be another potential aspect of treatment.”

Dramatic Growth of Grafted Stem Cells in Rat Spinal Cord InjuriesReprogrammed human neurons extend axons almost entire length of central nervous system
Building upon previous research, scientists at the University of California, San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System report that neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.
Writing in the August 7 early online edition of Neuron, lead scientist Paul Lu, PhD, of the UC San Diego Department of Neurosciences and colleagues said the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses. 
The iPSCs used were developed from a healthy 86-year-old human male.
“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, MD, PhD, professor of Neurosciences and director of the UC San Diego Center for Neural Repair.
For several years, Tuszynski and colleagues have been steadily chipping away at the notion that a spinal cord injury necessarily results in permanent dysfunction and paralysis. Earlier work has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs. The new findings underscore the potential of iPSC-based therapy and suggest a host of new studies and questions to be asked, such as whether axons can be guided and how will they develop, function and mature over longer periods of time.
While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.
“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible harmful side effects if axons are mistargeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame – months to years – or more rapidly. If maturity is reached on a human time frame, it could take months to years to observe functional benefits or problems in human clinical trials.”
In the latest work, Lu, Tuszynski and colleagues converted skin cells from a healthy 86-year-old man into iPSCs, which possess the ability to become almost any kind of cell. The iPSCs were then reprogrammed to become neurons in collaboration with the laboratory of Larry Goldstein, PhD, director of the UC San Diego Sanford Stem Cell Clinical Center. The new human neurons were subsequently embedded in a matrix containing growth factors and grafted into two-week-old spinal cord injuries in rats.
Three months later, researchers examined the post-transplantation injury sites. They found biomarkers indicating the presence of mature neurons and extensive axonal growth across long distances in the rats’ spinal cords, even extending into the brain. The axons traversed wound tissues to penetrate and connect with existing rat neurons. Similarly, rat neurons extended axons into the grafted material and cells. The transplants produced no detectable tumors.
While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. However, Lu noted that tests assessed the rats’ skilled use of the hand. Simpler assays of leg movement could still show benefit. Also, several iPSC grafts contained scars that may have blocked beneficial effects of new connections. Continuing research seeks to optimize transplantation methods to eliminate scar formation.
Tuszynski said he and his team are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types.
“Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It’s easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”
Pictured: Image depicts extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury and transplantation of human induced pluripotent stem cell-derived neurons. Green fluorescent protein identifies human graft-derived axons, myelin (red) indicates host rat spinal cord white matter and blue marks host rat gray matter.

Dramatic Growth of Grafted Stem Cells in Rat Spinal Cord Injuries
Reprogrammed human neurons extend axons almost entire length of central nervous system

Building upon previous research, scientists at the University of California, San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System report that neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.

Writing in the August 7 early online edition of Neuron, lead scientist Paul Lu, PhD, of the UC San Diego Department of Neurosciences and colleagues said the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses. 

The iPSCs used were developed from a healthy 86-year-old human male.

“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, MD, PhD, professor of Neurosciences and director of the UC San Diego Center for Neural Repair.

For several years, Tuszynski and colleagues have been steadily chipping away at the notion that a spinal cord injury necessarily results in permanent dysfunction and paralysis. Earlier work has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs. The new findings underscore the potential of iPSC-based therapy and suggest a host of new studies and questions to be asked, such as whether axons can be guided and how will they develop, function and mature over longer periods of time.

While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.

“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible harmful side effects if axons are mistargeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame – months to years – or more rapidly. If maturity is reached on a human time frame, it could take months to years to observe functional benefits or problems in human clinical trials.”

In the latest work, Lu, Tuszynski and colleagues converted skin cells from a healthy 86-year-old man into iPSCs, which possess the ability to become almost any kind of cell. The iPSCs were then reprogrammed to become neurons in collaboration with the laboratory of Larry Goldstein, PhD, director of the UC San Diego Sanford Stem Cell Clinical Center. The new human neurons were subsequently embedded in a matrix containing growth factors and grafted into two-week-old spinal cord injuries in rats.

Three months later, researchers examined the post-transplantation injury sites. They found biomarkers indicating the presence of mature neurons and extensive axonal growth across long distances in the rats’ spinal cords, even extending into the brain. The axons traversed wound tissues to penetrate and connect with existing rat neurons. Similarly, rat neurons extended axons into the grafted material and cells. The transplants produced no detectable tumors.

While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. However, Lu noted that tests assessed the rats’ skilled use of the hand. Simpler assays of leg movement could still show benefit. Also, several iPSC grafts contained scars that may have blocked beneficial effects of new connections. Continuing research seeks to optimize transplantation methods to eliminate scar formation.

Tuszynski said he and his team are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types.

“Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It’s easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”

Pictured: Image depicts extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury and transplantation of human induced pluripotent stem cell-derived neurons. Green fluorescent protein identifies human graft-derived axons, myelin (red) indicates host rat spinal cord white matter and blue marks host rat gray matter.

Hey, remember this post? Learn more about how a diet high in capsaicin may (or may not) lower your risk of colorectal cancer on our sister blog!
ucsdcancer:

Photo credit: “Chili (633442211)” by Randi Hausken from Bærum, Norway - Chili Uploaded by russavia. Licensed under Creative Commons Attribution-Share Alike 2.0 via Wikimedia Commons 

Food for thought: Chili peppers are more than spice in your diet
Attend one of our free Healing Foods Kitchen cooking classes and you’ll hear Susan Faerber tell you that capsaicin, the active ingredient that makes chili peppers hot, has protective benefits against cancer. In a study published in the Aug. 1 issue of The Journal of Clinical Investigation, UC San Diego Moores Cancer Center researchers say capsaicin triggers a reaction that reduces the risk of colorectal tumors.
But before you add a Carolina Reaper, the world’s hottest pepper, to one of Susan’s cancer fighting recipes or your own healthy meal, read about the science behind the study at our sister blog ucsdhealthsciences.
We asked the researchers to break down this spicy news for our own consumption and tell us what does it mean for you and me? Do countries with a traditionally high use of chili peppers in their diet see lower incidence of colorectal cancer?
The answer is a bit complicated and we must be cautious to infer any cause-and-effect relationships from epidemiological data, said Petrus de Jong, MD, first author of the study. Still, a 2009 study on colorectal cancer incidence shows there are benefits.
“Countries with a high dietary intake of capsaicinoids (e.g. India, Bangladesh, Thailand, Mexico) show a five to 10-fold lower incidence of colorectal cancer compared to Western countries,” said Dr. de Jong.
“Various factors may be associated with the reduced incidence of colorectal cancer in these countries, including dietary factors such as low consumption of red meats and high consumption of non-starch polysaccharides, vegetables and phytochemicals (i.e. capsaicin). Indeed, a shift from a traditional Mexican to a predominantly Western diet has been associated with an increased risk of this cancer as shown by a 2003 study.”
So there is a benefit! But, how much do we need to eat?
“A significant anti-tumor effect would require more than just ‘a spicy diet’,” said Dr. de Jong.
The amount of capsaicin used in the experiments is at least five times higher than what the average people in countries who eat lots chili pepper consume. Dr. de Jong says a good starting point to determine how much capsaicin we need to ingest would be a feasibility study that would target the active substance mainly to the large intestine. So until then, eat your habanero, jalapeño, piri piri or the pepper of choice depending on your heat level tolerance and know that it has some health benefits in addition to adding flavor to your meals.
Bon appétit. 

Hey, remember this post? Learn more about how a diet high in capsaicin may (or may not) lower your risk of colorectal cancer on our sister blog!

ucsdcancer:

Photo credit: “Chili (633442211)” by Randi Hausken from Bærum, Norway - Chili Uploaded by russavia. Licensed under Creative Commons Attribution-Share Alike 2.0 via Wikimedia Commons

Food for thought: Chili peppers are more than spice in your diet

Attend one of our free Healing Foods Kitchen cooking classes and you’ll hear Susan Faerber tell you that capsaicin, the active ingredient that makes chili peppers hot, has protective benefits against cancer. In a study published in the Aug. 1 issue of The Journal of Clinical Investigation, UC San Diego Moores Cancer Center researchers say capsaicin triggers a reaction that reduces the risk of colorectal tumors.

But before you add a Carolina Reaper, the world’s hottest pepper, to one of Susan’s cancer fighting recipes or your own healthy meal, read about the science behind the study at our sister blog ucsdhealthsciences.

We asked the researchers to break down this spicy news for our own consumption and tell us what does it mean for you and me? Do countries with a traditionally high use of chili peppers in their diet see lower incidence of colorectal cancer?

The answer is a bit complicated and we must be cautious to infer any cause-and-effect relationships from epidemiological data, said Petrus de Jong, MD, first author of the study. Still, a 2009 study on colorectal cancer incidence shows there are benefits.

“Countries with a high dietary intake of capsaicinoids (e.g. India, Bangladesh, Thailand, Mexico) show a five to 10-fold lower incidence of colorectal cancer compared to Western countries,” said Dr. de Jong.

“Various factors may be associated with the reduced incidence of colorectal cancer in these countries, including dietary factors such as low consumption of red meats and high consumption of non-starch polysaccharides, vegetables and phytochemicals (i.e. capsaicin). Indeed, a shift from a traditional Mexican to a predominantly Western diet has been associated with an increased risk of this cancer as shown by a 2003 study.”

So there is a benefit! But, how much do we need to eat?

“A significant anti-tumor effect would require more than just ‘a spicy diet’,” said Dr. de Jong.

The amount of capsaicin used in the experiments is at least five times higher than what the average people in countries who eat lots chili pepper consume. Dr. de Jong says a good starting point to determine how much capsaicin we need to ingest would be a feasibility study that would target the active substance mainly to the large intestine. So until then, eat your habanero, jalapeño, piri piri or the pepper of choice depending on your heat level tolerance and know that it has some health benefits in addition to adding flavor to your meals.

Bon appétit. 

News That’s Spit To Print
The North American moose (Alces alces), which can reach more than 1,500 pounds, is a voracious eater, mostly grasses, forbs and fresh shoots from trees like willow and birch. Many plants, of course, have developed defense mechanisms to dissuade consumption by predatory ungulates. Think thorns or a bitter taste.
Which brings us to red fescue grass (Festuca rubra), which harbors a toxic fungus called Epichloe festucae that can make grazing animals sick, sometimes to the point of actual death. But moose eat lots of red fescue grass without apparent harm, which piqued the curiosity of researchers at York University in Canada.
In this month’s Biology Letters, they provide a possible answer: The saliva of moose (and reindeer) contains an anti-fungal agent that counteracts the grass fungus.
Specifically, the moose saliva anti-fungal agent inhibited fungal growth in red fescue grass, making it safer to eat more of it. “We know that animals can remember if certain plants have made them feel ill, and they may avoid these plants in future,” said study author Dawn Bazely. “This study is the first evidence, to our knowledge, of herbivore saliva being shown to ‘fight back’ and slow down the growth of the fungus.”
While the York researchers’ work offers no immediately obvious clinical applications for humans, it does prove at least that a moose is nobody’s drool.

News That’s Spit To Print

The North American moose (Alces alces), which can reach more than 1,500 pounds, is a voracious eater, mostly grasses, forbs and fresh shoots from trees like willow and birch. Many plants, of course, have developed defense mechanisms to dissuade consumption by predatory ungulates. Think thorns or a bitter taste.

Which brings us to red fescue grass (Festuca rubra), which harbors a toxic fungus called Epichloe festucae that can make grazing animals sick, sometimes to the point of actual death. But moose eat lots of red fescue grass without apparent harm, which piqued the curiosity of researchers at York University in Canada.

In this month’s Biology Letters, they provide a possible answer: The saliva of moose (and reindeer) contains an anti-fungal agent that counteracts the grass fungus.

Specifically, the moose saliva anti-fungal agent inhibited fungal growth in red fescue grass, making it safer to eat more of it. “We know that animals can remember if certain plants have made them feel ill, and they may avoid these plants in future,” said study author Dawn Bazely. “This study is the first evidence, to our knowledge, of herbivore saliva being shown to ‘fight back’ and slow down the growth of the fungus.”

While the York researchers’ work offers no immediately obvious clinical applications for humans, it does prove at least that a moose is nobody’s drool.

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.

Pepper and Halt: Spicy Chemical May Inhibit Gut Tumors
Researchers at the University of California, San Diego School of Medicine report that dietary capsaicin – the active ingredient in chili peppers – produces chronic activation of a receptor on cells lining the intestines of mice, triggering a reaction that ultimately reduces the risk of colorectal tumors.
The findings are published in the August 1, 2014 issue of The Journal of Clinical Investigation.
The receptor or ion channel, called TRPV1, was originally discovered in sensory neurons, where it acts as a sentinel for heat, acidity and spicy chemicals in the environment. “These are all potentially harmful stimuli to cells,” said Eyal Raz, MD, professor of Medicine and senior author of the study. “Thus, TRPV1 was quickly described as a molecular ‘pain receptor.’ This can be considered to be its conventional function, which all takes place in the nervous system.”
But Raz and colleagues have found that TPRV1 is also expressed by epithelial cells of the intestines, where it is activated by epidermal growth factor receptor or EGFR. EGFR is an important driver of cell proliferation in the intestines, whose epithelial lining is replaced approximately every four to six days.
“A basic level of EGFR activity is required to maintain the normal cell turnover in the gut,” said Petrus de Jong, MD, first author of the study. “However, if EGFR signaling is left unrestrained, the risk of sporadic tumor development increases.”
The scientists discovered that TRPV1, once activated by the EGFR, initiates a direct negative feedback on the EGFR, dampening the latter to reduce the risk of unwanted growth and intestinal tumor development. They found that mice genetically modified to be TRPV1-deficient suffered higher-than-normal rates of intestinal tumor growths.
“These results showed us that epithelial TRPV1 normally works as a tumor suppressor in the intestines,” said de Jong. In addition, molecular studies of human colorectal cancer samples recently uncovered multiple mutations in the TRPV1 gene, though Raz noted that currently there is no direct evidence that TRPV1 deficiency is a risk factor for colorectal cancer in humans.
“A direct association between TRPV1 function and human colorectal cancer should be addressed in future clinical studies,” he said.
But if such proves to be the case, the current study suggests one potential remedy might be spicy capsaicin, which acts as an irritant in mammals, generating a burning sensation in contact with tissue. Capsaicin is already broadly used as an analgesic in topical ointments, where its properties as an irritant overwhelm nerves, rendering them unable to report pain for extended periods of time. It’s also the active ingredient in pepper spray.
The researchers fed capsaicin to mice genetically prone to developing multiple tumors in the gastrointestinal tract. The treatment resulted in a reduced tumor burden and extended the lifespans of the mice by more than 30 percent. The treatment was even more effective when combined with celecoxib, a COX-2 non-steroidal anti-inflammatory drug already approved for treating some forms of arthritis and pain.
“Our data suggest that individuals at high risk of developing recurrent intestinal tumors may benefit from chronic TRPV1 activation,” said Raz. “We have provided proof-of-principle.”

Pepper and Halt: Spicy Chemical May Inhibit Gut Tumors

Researchers at the University of California, San Diego School of Medicine report that dietary capsaicin – the active ingredient in chili peppers – produces chronic activation of a receptor on cells lining the intestines of mice, triggering a reaction that ultimately reduces the risk of colorectal tumors.

The findings are published in the August 1, 2014 issue of The Journal of Clinical Investigation.

The receptor or ion channel, called TRPV1, was originally discovered in sensory neurons, where it acts as a sentinel for heat, acidity and spicy chemicals in the environment. “These are all potentially harmful stimuli to cells,” said Eyal Raz, MD, professor of Medicine and senior author of the study. “Thus, TRPV1 was quickly described as a molecular ‘pain receptor.’ This can be considered to be its conventional function, which all takes place in the nervous system.”

But Raz and colleagues have found that TPRV1 is also expressed by epithelial cells of the intestines, where it is activated by epidermal growth factor receptor or EGFR. EGFR is an important driver of cell proliferation in the intestines, whose epithelial lining is replaced approximately every four to six days.

“A basic level of EGFR activity is required to maintain the normal cell turnover in the gut,” said Petrus de Jong, MD, first author of the study. “However, if EGFR signaling is left unrestrained, the risk of sporadic tumor development increases.”

The scientists discovered that TRPV1, once activated by the EGFR, initiates a direct negative feedback on the EGFR, dampening the latter to reduce the risk of unwanted growth and intestinal tumor development. They found that mice genetically modified to be TRPV1-deficient suffered higher-than-normal rates of intestinal tumor growths.

“These results showed us that epithelial TRPV1 normally works as a tumor suppressor in the intestines,” said de Jong. In addition, molecular studies of human colorectal cancer samples recently uncovered multiple mutations in the TRPV1 gene, though Raz noted that currently there is no direct evidence that TRPV1 deficiency is a risk factor for colorectal cancer in humans.

“A direct association between TRPV1 function and human colorectal cancer should be addressed in future clinical studies,” he said.

But if such proves to be the case, the current study suggests one potential remedy might be spicy capsaicin, which acts as an irritant in mammals, generating a burning sensation in contact with tissue. Capsaicin is already broadly used as an analgesic in topical ointments, where its properties as an irritant overwhelm nerves, rendering them unable to report pain for extended periods of time. It’s also the active ingredient in pepper spray.

The researchers fed capsaicin to mice genetically prone to developing multiple tumors in the gastrointestinal tract. The treatment resulted in a reduced tumor burden and extended the lifespans of the mice by more than 30 percent. The treatment was even more effective when combined with celecoxib, a COX-2 non-steroidal anti-inflammatory drug already approved for treating some forms of arthritis and pain.

“Our data suggest that individuals at high risk of developing recurrent intestinal tumors may benefit from chronic TRPV1 activation,” said Raz. “We have provided proof-of-principle.”

Birthday Matters for Wiring-Up the Brain’s Vision Centers
Researchers at the University of California, San Diego School of Medicine have evidence suggesting that neurons in the developing brains of mice are guided by a simple but elegant birth order rule that allows them to find and form their proper connections.
The study is published online July 31 in Cell Reports.
“Nothing about brain wiring is haphazard,” said senior author Andrew Huberman, PhD, assistant professor in the Department of Neurosciences, Division of Biological Sciences and Department of Ophthalmology, UC San Diego.
A mature, healthy brain has billions of precisely interconnected neurons. Yet the brain starts with just one neuron that divides and divides – up to 250,000 new neurons per minute at times during early development. The question for biologists has been how do these neurons decide which other neurons to connect to, a process neuroscientists call target selection.
The answer has both fundamental scientific value and clinical relevance. Some researchers believe that autism and other disorders linked to brain development may be caused, in part, by a failure of neurons to properly reposition their axons as needed when mistakes in target selection occur.
To better understand how a young brain gets wired, researchers focused on the development of retinal ganglion cells (RGCs) in mice. These cells connect the eyes and brain. Specifically, the main cell bodies of RGCs reside in the retina but their axons – slender projections along which electrical impulses travel – extend into the centers of the brain that process visual information and give rise to what we commonly think of as “sight,” as well as other light-influenced physiological processes, such as the effect of light on mood.
For the study, scientists tagged RGCs and watched where they directed their axons during development. The experiments revealed that specific types of RGCs target specific areas of the brain, allowing mice to do things such as sense direction of motion, move their eyes and detect changes in daily light cycles. It was also observed that some types of RGCs (such as those that detect brightness and control pupil constriction) are created early in development while others (such as those controlling eye movements) are created later.
The study’s main finding is that early RGCs (those created early in the sequence of brain division) make a lot of connections to other neurons and a lot of mistakes, which they then correct by repositioning or removing their axons. By contrast, later RGCs were observed to be highly accurate in their target selection skills and made almost no errors.
“The neurons are paying attention to when they were born and reading out which choices they should make based on their birthdate,” said Jessica Osterhout, a doctoral student in biology and the study’s lead author. “It seems to all boil down to birthdate.”
The idea that timing is important for cell differentiation is a classic principle of developmental biology, but this study is among the first to show that the timing of neuronal generation is linked to how neurons achieve specific brain wiring.
In addition to clarifying normal brain development, researchers plan to examine the role of time-dependent wiring mishaps in models of human disorders, such as autism and schizophrenia, as well as diseases specific to the visual system, such as congenital blindness.
“We want to know if in diseases such as autism neurons are made out of order and as a result get confused about which connections to make,” Huberman said.

Birthday Matters for Wiring-Up the Brain’s Vision Centers

Researchers at the University of California, San Diego School of Medicine have evidence suggesting that neurons in the developing brains of mice are guided by a simple but elegant birth order rule that allows them to find and form their proper connections.

The study is published online July 31 in Cell Reports.

“Nothing about brain wiring is haphazard,” said senior author Andrew Huberman, PhD, assistant professor in the Department of Neurosciences, Division of Biological Sciences and Department of Ophthalmology, UC San Diego.

A mature, healthy brain has billions of precisely interconnected neurons. Yet the brain starts with just one neuron that divides and divides – up to 250,000 new neurons per minute at times during early development. The question for biologists has been how do these neurons decide which other neurons to connect to, a process neuroscientists call target selection.

The answer has both fundamental scientific value and clinical relevance. Some researchers believe that autism and other disorders linked to brain development may be caused, in part, by a failure of neurons to properly reposition their axons as needed when mistakes in target selection occur.

To better understand how a young brain gets wired, researchers focused on the development of retinal ganglion cells (RGCs) in mice. These cells connect the eyes and brain. Specifically, the main cell bodies of RGCs reside in the retina but their axons – slender projections along which electrical impulses travel – extend into the centers of the brain that process visual information and give rise to what we commonly think of as “sight,” as well as other light-influenced physiological processes, such as the effect of light on mood.

For the study, scientists tagged RGCs and watched where they directed their axons during development. The experiments revealed that specific types of RGCs target specific areas of the brain, allowing mice to do things such as sense direction of motion, move their eyes and detect changes in daily light cycles. It was also observed that some types of RGCs (such as those that detect brightness and control pupil constriction) are created early in development while others (such as those controlling eye movements) are created later.

The study’s main finding is that early RGCs (those created early in the sequence of brain division) make a lot of connections to other neurons and a lot of mistakes, which they then correct by repositioning or removing their axons. By contrast, later RGCs were observed to be highly accurate in their target selection skills and made almost no errors.

“The neurons are paying attention to when they were born and reading out which choices they should make based on their birthdate,” said Jessica Osterhout, a doctoral student in biology and the study’s lead author. “It seems to all boil down to birthdate.”

The idea that timing is important for cell differentiation is a classic principle of developmental biology, but this study is among the first to show that the timing of neuronal generation is linked to how neurons achieve specific brain wiring.

In addition to clarifying normal brain development, researchers plan to examine the role of time-dependent wiring mishaps in models of human disorders, such as autism and schizophrenia, as well as diseases specific to the visual system, such as congenital blindness.

“We want to know if in diseases such as autism neurons are made out of order and as a result get confused about which connections to make,” Huberman said.

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