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Cancer, Research, Sleep, Stanford News, Stem Cells, Transplants

Sleep deprivation affects stem cell function, say Stanford scientists

Sleep deprivation affects stem cell function, say Stanford scientists

sleepy mouseWe all know that sleep is important for many biological functions. But I’m still surprised at the breadth of its influence. Today, a former postdoctoral scholar at Stanford, Asya Rolls, PhD, published a fascinating study in Nature Communications showing that blood-forming stem cells from drowsy mice perform more poorly when transplanted into recipient animals. In particular, they are less able to home to the bone marrow, and they generate a smaller proportion of a type of immune cell called a myeloid cell than do stem cells from well-rested mice.

Although the researchers studied only laboratory mice, the possible implications for human transplant recipients (in humans, these procedures are called hematopoietic stem cell transplants, or sometimes bone marrow transplants) are intriguing. As Rolls, who is now an assistant professor at the Israel Institute of Technology, said in our release, “Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling. We go to all this trouble to find a matching donor, but this research suggests that if the donor is not well-rested it can impact the outcome of the transplantation.”

At Stanford, Rolls worked in the laboratory of psychiatrist and sleep medicine specialist Luis de Lecea, PhD, and she collaborated with Wendy Pang, MD, PhD, and Irving Weissman, MD, director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine, to conduct the research.

Despite the fact that sleep deprivation in the donor reduced the efficacy of their stem cells by about 50 percent, all is not lost. From our release:

Although the effect of sleep deprivation was stark in this study, Rolls and her colleagues found that it could be reversed by letting the drowsy mice catch up on their ZZZs. Even just two hours of recovery sleep restored the ability of the animals’ stem cells to function normally in the transplantation tests.

“Everyone has these stem cells, and they continuously replenish our blood and immune system,” said Rolls. “We still don’t know how sleep deprivation affects us all, not just bone marrow donors. The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.”

Previously: In mice, at least, uninterrupted sleep is critical for memory and Bone marrow transplantation: The ultimate exercise in matchmaking
Photo by Eddy Van 3000

Cancer, Public Health

Why are so many lives affected by cancer?

rope bridgeI’m a regular reader of The New York Times obituaries. I don’t read them because I’m a morbid person; rather, the obituaries offer me a window into history reflected through the lives of accomplished individuals.

One day in August, I was struck by the photos accompanying obituaries of three women, who all appeared to be relatively young. The 59-year old was co-founder of a nonprofit, Common Sense Media, committed to helping families navigate through entertainment, media and technology arenas. The 64-year old was an Olympic Equestrian medalist winning the U.S. title of rider of the year three times. And the 56-year old was a Harvard scholar and artist whose work explored myth, mystery and identity.

Each shared another characteristic besides a relatively early death: cancer.

These losses of life – far too early – brought back memories of the opening words of a story set more than 300 years ago: “On Friday noon, July twentieth, 1714, the finest bridge in all Peru broke and precipitated five travelers into the gulf below.” That was from Thornton Wilder’s 1927 novel, The Bridge of San Luis Rey. In this story, a friar, who observed the collapse of the rope bridge, wanted to know about the events that led up to each person being on the bridge at that time. Through extensive interviews, he was determined to understand the circumstances that led to their deaths.

A similar question haunts us in 2015: Why will one of every two of us, on average, “fall off the bridge” – that is, have our lives impacted by cancer? Over the past few decades, we’ve gained knowledge that allows for a safer life journey. We know that one half of cancers can be prevented by measures such as not smoking, protecting against excessive sun exposure, getting regular prostate check-ups, lowering obesity, reducing alcohol consumption and engaging in regular exercise.

We appear to be making progress. A recent report revealed that fewer people in the greater San Francisco Bay Area are getting cancer, and fewer are dying from it. More specifically, in the most recent 25-year period for which data are available, the occurrence of all new cancers combined declined by 13.2 percent.

Such news is encouraging. Yet, while advances in cancer treatment may allow more of us to cross our bridges safely and to help us heal if we fall, we must do better. We haven’t yet unlocked the mysteries of cancer. Indeed, the task is more daunting than we ever imagined; we now know that there are more than 200 diseases that we call cancer. We need to look for answers with large-scale genomics (looking at the structure and mapping of genes), bioinformatics (analyzing complex data, such as genetic codes) and computational biology (using data to study relationships in the biological system). We need to develop a better understanding of health disparities (across socially disadvantaged populations) and to drill down to an individual’s unique molecular and genetic characteristics.

For asking troubling questions which threatened authority, the friar in The Bridge of San Luis Rey was tried by the Inquisition and burned at stake. I would only hope that those of us who are probing deeply to prevent the scourge of cancer will be treated more kindly by society (and, especially, by funding agencies).

Donna Randall, PhD, is chief executive officer of the Cancer Prevention Institute of California, a partner of the Stanford Cancer Institute.

Bioengineering, Cancer, Infectious Disease, Precision health, Research, Stanford News

Stanford scientists co-opt viral machinery to create medical delivery system

Stanford scientists co-opt viral machinery to create medical delivery system

James Swartz

Stanford engineering researcher James Swartz, PhD, and his colleagues have remodeled a hepatitis B virus to turn it into a microscopic taxi for medical therapies. The team stripped the virus of its pathogenic DNA and modified an outer shell so that they could “hang” molecular tags on the outside to help deliver vaccines or other therapies to specific cells. The researchers reported their findings in a paper in the scientific journal Proceedings of the National Academy this week.

They call the engineered product a virus-like particle (as opposed to a real virus with infectious material) or a smart particle. “We make it smart by adding molecular tags that act like addresses to send the therapeutic payload where we want it to go,” Swartz said in a Stanford News story.

The smart particle is a novel way to deliver vaccines or cancer therapies by teaching the body’s immune cells to recognize pathogens or cancer cells. Alternatively, the smart particle can deliver medicine specifically to the cells that need it.

Swartz and his colleagues’ effort is part of a larger field of targeted therapies that aims to precisely deliver therapies to the cells that need them and avoid damaging nearby healthy cells. Current cancer therapies, for example, are effective at fighting malignant cells, but also kill off healthy cells. That’s why cancer therapies often have such devastating side effects. But previous attempts to create virus-sized delivery systems have not been successful. In fact, Swartz’s team had a hard time getting funding for the early stages of this project because of previous failed efforts by other scientists.

So far, Swartz and colleagues have created the self-assembling shell that is invisible to the body’s natural immune defenses and strong enough to weather conditions in the blood stream and get its packaged contents to its destination inside the body. Next, they’ll work on putting specific cancer-fighting tags on the shell.

The most challenging task will be to pack the shell with a tiny dose of medicine. But Swartz sounded optimistic about his team’s goals. “I believe we can use this smart particle to deliver cancer-fighting immunotherapies that will have minimal side effects,” he said.

Previously: A less toxic, targeted therapy for childhood brain cancerIs cancer too complex for targeted therapies? and Working to create a universal flu vaccine
Photo, of Swartz holding an enlarged replica of a virus-like particle, by Linda Rice

Cancer, Genetics, Research, Science, Stanford News

Combination therapy could fight pancreatic cancer, say Stanford researchers

Combination therapy could fight pancreatic cancer, say Stanford researchers

I’ve mentioned here before my personal connection to pancreatic cancer, which claimed the life of my grandmother. So I was excited to hear from Stanford cancer researcher Julien Sage, PhD, about some developments on the research front. Sage and postdoctoral scholar Pawal Mazur, PhD, collaborated with Alexander Herner, MD and Jens Svieke, MD, at the Technical University Munich to conduct the work, which was published today in Nature Medicine.

In our release on the study, which was done in animal models, Sage explained:

Pancreatic cancer is one of the most deadly of all human cancers, and its incidence is increasing. Nearly always the cause of the disease seems to be a mutation in a gene called KRAS, which makes a protein that is essential for many cellular functions. Although this protein, and others that work with it in the Ras pathway, would appear to be a perfect target for therapy, drugs that block their effect often have severe side effects that limit their effectiveness. So we decided to investigate drugs that affect the DNA rather than the proteins.

Mazur and Herner worked together to test whether drugs that affect the epigenetic status of a cancer cell (that is, the dynamic arrangement of chemical tags on the DNA and its associated proteins that control how and when genes are expressed) could rein in its growth without serious side effects. Many of these tags are what’s called acetyl groups, and they are added to protein complexes called histones that keep the DNA tightly wound in the cell’s nucleus. As I explained in our release:

They started by investigating the effect of a small molecule they called JQ1 on the growth of human pancreatic tumor cells in a laboratory dish. JQ1 inhibits a family of proteins responsible for sensing acetyl groups on histones. The researchers found that the cells treated with JQ1 grew more slowly and displayed fewer cancerous traits. The molecule was also able to significantly shrink established pancreatic tumors in mice with the disease. However, it did not significantly affect the animals’ overall likelihood of survival.

Mazur, who began the work in Siveke’s lab and continued it when he moved to Sage’s lab, next tested whether using JQ1 in combination with any other medications could be more effective:

“It happened that the drug that worked best was another epigenetic drug called vorinostat,” said Sage. “On its own, vorinostat didn’t work very well, but when combined with JQ1 it showed a very strong synergistic effect in both the laboratory mice with pancreatic cancer and in pancreatic cancer cells from people with the disease.”

Vorinostat works by inhibiting a family of proteins that remove the acetyl groups from histones. It has been approved by the FDA for use in people with recurrent or difficult-to-treat cutaneous T cell lymphoma. When human pancreatic cancer cells were treated simultaneously with JQ1 and vorinostat, the cells grew more slowly and were more likely to die.

Mice with established pancreatic cancers treated with both of the drugs showed a marked reduction in tumor size and a significant increase in overall survival time. Their tumors showed no signs of developing a resistance to the treatment, and the mice did not develop any noticeable side effects.

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Bioengineering, Cancer, Genetics, Stanford News

Cancer drug produced in common plant

Cancer drug produced in common plant

I knew that many of the drugs we use today were first identified in plants. What I didn’t know was in how many cases those plants are still the only source of the drug because scientists haven’t figured out how to make them in the lab.

If the only source of an effective drug is a plant that is rare, endangered, or hard to grow in the lab, that’s obviously a problem.

Elizabeth Sattely, PhD, a Stanford chemical engineer, recently tackled this problem for a popular cancer drug that comes from a Himalayan plant called the Mayapple. She managed to identify the ten drug-making enzymes in the Mayapple and insert those genes into a much easier-to-grow plant. In a story about the work, which appears today in the journal Science, I wrote:

[It] could lead to new ways of modifying the natural pathways to produce derivative drugs that are safer or more effective than the natural source.

“A big promise of synthetic biology is to be able to engineer pathways that occur in nature, but if we don’t know what the proteins are, then we can’t even start on that endeavor,” said Sattely, who is also a member of the interdisciplinary institutes Stanford Bio-X and Stanford ChEM-H.

Sattely said this is really a first step. Ultimately she’d like to get those same enzymes into yeast, which can produce high volumes of drugs in big laboratory vats.

Video by Amy Adams

Cancer, Genetics, Imaging, Precision health, Research, Science, Stanford News

You know it when you see it: A precision health approach to diagnosing brain cancer

You know it when you see it: A precision health approach to diagnosing brain cancer

BurlIf you know which virus has made a person ill, as well as whether your patient responds better to drug A or drug B, you’re in a much better position to treat them. In the world of oncology, it’s often the genetic personality of the tumor itself that determines the best treatment protocol. A tumor with one set of gene variants may be susceptible to only one of several treatments. To decide which drug to prescribe, you’ve got to know your tumor.

In some cancers, such as skin cancer, it’s easy to physically examine the tumor and easy to take a biopsy to root out the tumor’s genetic secrets. But for cancers deep in the brain, a biopsy is problematic. And without knowing more about a brain tumor, it’s harder to guess the right treatment.

Now a team of researchers, led by Stanford’s Haruka Itakura, MD, and Olivier Gevaert, PhD, have distinguished three types of brain tumors. Each type is identifiable by their appearance in MRIs and predictably associated with specific molecular characteristics. Itakura and Gevaert report their work in today’s Science Translational Medicine.

Magnetic resonance imaging revealed three distinct kinds of glioblastoma brain tumors, each of which could be associated with a different probability of patient survival and a unique set of molecular signaling pathways. The work paves the way for more precise diagnosis, better targeted therapies and personalized treatment of GBM brain tumors.

Previously: Brain imaging, and the “image management” cells that make it possibleA century of brain imaging and When it comes to brain imaging, there’s nothing simple about it
Photo by Travis

Cancer, Patient Care, Stanford News, Transplants, Videos

Immunosuppression brings higher risk for skin cancer – and need for specialized care

Immunosuppression brings higher risk for skin cancer – and need for specialized care

An estimated 50 million Americans must take immunosuppressants to treat more than 80 autoimmune disorders, according to the National Institutes of Health. These medications are particularly vital to the survival of people who have undergone organ transplants to prevent their bodies from rejecting their donor organ.

While immunosuppressants can be life-saving, their very action of reducing the body’s innate defense systems can have negative side-effects. One particularly dangerous concern is an increased risk for skin cancer, particularly for those individuals with fair skin or an inherited tendency to develop skin cancers. (My colleague Tracie White told the story of one transplant patient’s struggle here earlier this summer.)

To address the specialized needs of patients taking immunosuppressants or with compromised immune function, Stanford dermatologists recently launched the High-Risk Skin Cancer Clinic.

In this Stanford Health Care video, the clinic’s Carolyn Lee, MD, PhD, explains the particular vulnerabilities of transplant patients to aggressive skin cancer and the importance of a dedicated clinic to meet their needs. “What we hate to see — and it’s easily preventable — is someone who’s been waiting for a transplant to finally get it, only to be felled by skin cancer,” she says.


Previously: Rebuilding Cassie’s smile: A lung transplant patient’s struggle with skin cancer and This summer’s Stanford Medicine magazine shows some skin

Cancer, Research, Science, Stanford News, Stem Cells

A stem cell “kill switch” may make therapies safer, say Stanford researchers

A stem cell "kill switch" may make therapies safer, say Stanford researchers

3225255407_596aa5bdff_zStem cell biologist Hiromitsu Nakauchi, MD, PhD, and his colleagues published an interesting article today about how to use stem cell technology to boost our body’s own immune cells to fight cancer or chronic viral infections like HIV or Epstein Barr virus. Because there’s a possible cancer risk with the use of induced pluripotent stem cells, or iPS cells, in humans, he and his colleagues have devised an innovative way to specifically eliminate these cells within the body if they start to cause problems. Their research appears today in Stem Cell Reports.

As Nakauchi explained to me in an email:

The discovery of induced pluripotent stem cells created promising new avenues for therapies. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern that must be addressed before iPS cell-based therapies can be routinely used in the clinic.

The researchers studied a type of immune cell called a cytotoxic T cell. These cells recognize specific sequences, or antigens, on the surface of other cells. Some antigens indicate that the cell is infected with a virus; others are found on cells that have become cancerous. When a cytotoxic T cells sees these antigens, it moves in to kill the cell and remove the threat.

In order to ensure that our immune systems recognize the widest variety of antigens, developing T cells randomly shuffle their genes to create unique antigen receptors. Researchers have found that it’s possible to identify, and isolate, T cell populations that specifically recognize cancer cells. By growing those cells in the laboratory, and then injecting them back into a patient, clinicians can give a boost to the immune response that can help kill tumor cells. The technique is known as adoptive immunotherapy, and it’s shown promise in treating melanoma. However, these cytotoxic T cells can become exhausted as they fight the cancer and become less effective over time.

Recently researchers in Nakauchi’s lab showed that it’s possible to create induced pluripotent stem cells from cytotoxic T cells. These iPS cells are then induced to again become cytotoxic T cells. These rejuvenated T cells, or rejT cells, recognize the same antigen they did before their brief dip in the pluripotency pool, but they are far more sprightly than the cells from which they were derived – they can divide many more times and have longer telomeres (an indicator of youthfulness).

So far, so good. But, as Nakauchi mentioned above, iPS cells carry their own set of risks. Because they are by definition pluripotent (they can become any cell in the body), they can easily grow out of control. In fact, one way of proving a cell’s pluripotency is to inject it into an animal and see if it forms a type of tumor called a teratoma, which is made up of multiple cell types.

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Big data, Cancer, Research, Stanford News

A recipe for disaster: Stanford researchers identify mutations that contribute to rare blood cancers

A recipe for disaster: Stanford researchers identify mutations that contribute to rare blood cancers

recipe box“One thing we’ve learned about cancers is that each has its own unique recipe for malignancy. Some use the same ingredients and some a have a wide palate of ingredients.”

This is the analogy Paul Khavari, MD, PhD, professor and chair of dermatology at Stanford, used to describe the mutated genes that turn our own cells against us. The abnormal proteins derived from these genes disrupt the cellular machinery that keeps cell growth under control and monitors the DNA for mistakes. Fast-multiplying, unmonitored cells acquire more mutations in their DNA and the cycle continues.

By the time the cancer is detected, the DNA can be so riddled with mutations and rearrangements that even the power of next generation sequencing to read the DNA of the chromosomes might not be enough to identify the key ingredients – the mutated genes that drive the cancer.

The two T-cell cancers Khavari studies, mycosis fungoides and Sezary syndrome, come from particularly eclectic genetic cookbooks lacking a single obvious cancer-causing mutation. This makes identifying drugs that would fight these cancers extremely difficult.

By turning to clinical and biological data, Khavari’s team selected about 500 genes for deeper investigation. An identical point mutation in a single gene seen in only 5 percent of the examined tumor led them to identify a cell-survival mechanism that had not previously been implicated in any cancer.

In a paper published today in Nature Genetics the researchers reported that almost 40 percent of patients had a genetic abnormality in at least one gene involved in this mechanism. In our press release on the paper, I wrote about how these mutations turn the cells cancerous:

Khavari… likens skin T cells to patrolling sentries, rotating on and off duty. At the end of their shift, the cell-survival mechanism shuts down, and, with no signal, the T cells leave or die. The mutations Khavari’s team found prevent the pathway from turning off, causing T cells to pile up in the skin or circulate through the blood stream. “More and more sentries keep showing up for duty,” said Khavari. “It’s out of control.”

With the mutated genes identified, Khavari plans to introduce them into mice models. By studying their biological effects he hopes to suss out the mutations that are the cancers’ critical ingredients.

To read more about a stem cell treatment for these cancers being developed at Stanford, check out this article in the most recent Stanford Medicine magazine.

Kim Smuga-Otto is a student in UC Santa Cruz’s science communication program and a writing intern in the medical school’s Office of Communication and Public Affairs.

Previously: Smoking gun or hit-and-run? How oncogenes make good cells go bad, When a rash just isn’t a rash: A patient’s battle with mycosis fungoides and Linking cancer gene expression with survival rates, Stanford researchers bring “big data” into the clinic
Photo by April Griffus

Cancer, Events, Patient Care, Pediatrics

Girls’ Day Out event helps unite — and nurture — teens battling cancer

Untitled designThere are many treatments, therapies and drugs for cancer, but sometimes a day of pampering with friends is just what the doctor ordered.

That’s why nine teenage girls being treated for cancer at Lucile Packard Children’s Hospital Stanford  were lavished with a bit of tender loving care — and some quality bonding time — at the seventh annual Girls’ Day Out.

The festivities began at 8:30 on Wednesday night with a limo ride from the hospital to TOVA Day Spa in the Fairmont Hotel in downtown San Jose. At TOVA, teens that had attended Girls’ Day Out events from years before had the opportunity to reconnect, chat and welcome newcomers as they received massages, pedicures, manicures, hairstyling and a gourmet lunch. This story in the San Jose Mercury News explains:

“It’s really fun and a great getaway; it’s really nice to be with people who won’t keep asking ‘what happened to your arm,’ ” said incoming Saratoga High School freshman Simran Mallik, 14. She was left with a scar on her arm after undergoing treatment for Ewing Sarcoma, a type of bone cancer. “I feel like I connect with them more; it’s just easier to communicate.”

Tova Yaron, the owner of TOVA Day Spa, has sponsored this event for the past seven years with support from the Children Having Exceptional Educational and Recreational Support (CHEERS) program that’s a part of the 19 for Life Foundation. At the event, Yaron and her staff donate their time and expertise to create a day of fun, and free spa treatments, for the girls.

TOVA’s spa treatments are a refreshing break from the kind of treatments and therapies the teens are used to receiving as cancer patients, but perhaps the most important gift the girls receive is the opportunity to relax and be themselves among friends who understand what it’s like to be a teenager battling cancer.

“It’s interesting to see how other people are after they’ve gone through (cancer treatment),” said Vivian Lou 15, a student at James Logan High School in Union City who was diagnosed with Wilms Tumor, a type of kidney cancer, five years ago. “It’s nice because I don’t have to feel weird about it because they’ve also been through it.”

“I wish I could do more,” said Yaron. “I am honored, they are lovely girls, they have amazing attitudes, they are brave beyond belief, they are amazing. They are inspiring us with their bravery.”

Previously: Not just for kids: A discussion of play and why we all need to do itHow social connection can improve physical and mental health and The scientific importance of social connections for your health
Photo by Lucile Packard Children’s Hospital Stanford

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