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Clinical Trials, Immunology, Research, Transplants

Transplant without lifelong drugs gives patient another chance

Transplant without lifelong drugs gives patient another chance

"DCIM100GOPRO"Imagine learning you have an illness. It’s the same illness that killed your mother. You watched her fade, the last years of her life dreadful to watch, unimaginably tough to endure. The same fate awaits you. Until… it doesn’t. Now there’s a therapy that just might save you.

That’s the story of San Francisco Bay Area resident Cynthia Alcaraz-Jew, featured in the fall issue of Stanford Medicine Magazine. Now in her late 40s, Alcaraz-Jew, like her mother, suffers from a rare genetic condition called Alport Syndrome. The ailment leads to kidney, ear and eye problems.

Alcaraz-Jew didn’t immediately luck out. Her kidneys failed first and her younger brother, Xavier, a perfect immunologic match, offered to donate his kidney. Great news, of course, but a transplant usually means years of immunosuppressive drugs, which leave bones brittle and can lead to infections, heart disease, or even, ironically kidney failure.

Thanks to her perfectly matched kidney, Alcaraz-Jew was able to enroll in a trial led by Stanford immunologist Samuel Strober, MD, that aims to wean transplant patients off immunosuppressive drugs. From the article:

Of the 24 kidney transplant patients with perfectly matched donors who enrolled in the trial beginning in 2000, 16, including Alcaraz-Jew, are living drug free, and three others are working to get off the medications, Strober says. The team is planning to publish a paper summarizing the research results in the near future.

And the photo? That’s Alcaraz-Jew and her husband swimming with whale sharks in Mexico earlier this year.

Previously: Stanford Medicine magazine traverses the immune system, Kidney-transplant recipients party without drugs — immune-suppressing anti-rejection drugs, that is, Might kidney-transplant recipients be able to toss their pills?  and Marked improvement in transplant success on the way, says Stanford immunologist
Photo courtesy of Cynthia Alcaraz-Jew

Bioengineering, Cardiovascular Medicine, Clinical Trials, Research, Science, Stanford News

Using “nanobullets” for good – not evil

Using "nanobullets" for good - not evil

14858598815_b572bddbf9_zMy husband, a big science fiction fan, perked up the other day when I told him I was writing a medical science story about nanotechnology. Apparently, nanotechnology – the study and application of extremely small things – has long been big in the world of science fiction. There, authors have used it to create lots of cool-sounding phantasmagorical stuff like the “nanoprobes” used by the Borg in the movie Star Trek: The Next Generation to assimilate individuals into their collective.

I’m not sure how the fictional nanoprobe was supposedly built, but in my real-life story on the modern day use of nanotechnology to design better methods for heart disease treatment, I do describe the creation of “nanobullets” by Stanford researchers. And it’s pretty cool.

Jayakumar Rajadas, PhD and his colleagues detailed their work in a scientific paper published this month in the journal Biomaterials. Their idea was to create a new and improved delivery system for the delicate peptide apelin into the heart as a treatment for hypertrophic heart disease, which I discuss in the piece:

In a treatment model similar to giving insulin to diabetes patients, physicians have attempted to treat these heart conditions with doses of apelin. The therapeutic agent is delivered intravenously through to the cardiovascular tissue, but due to its short half-life — the drug is quickly eliminated from the blood plasma — the success of this treatment has been limited.

Rajadas considered the possibility for improving the delivery system of the peptide using nanotechnoloy because it has been used for the past 10 years to stabilize therapeutic agents in the body and target them to specific tissues, he said. In this case, the idea was to protect the quickly degrading apelin peptides with large, stable molecules to help transport them to their target organ - the heart:

The research team developed a novel technique to increase the stability of the fragile apelin peptides by protecting them with a lipid cover that Rajadas calls the ‘Trojan Horse’ method of delivery. The liposome ‘nanocarriers’ encapsulates the apelin and sneaks it through the blood to the heart tissue.

The resulting apelin “nanobullets,” as the researchers refer to them, were then delivered through the blood system to the cardiovascular tissue of mice with induced hypertrophic heart conditions. The theory was that the apelin would not be released until it was near the heart tissue.

Researchers then tried it out, shooting the nanobullets into the hearts of mice with hypertrophic heart disease. They delivered two shots over a 14-day period. Results showed that symptoms dramatically improved in the mice that received the shots with the apelin nanobullets when compared to mice shot with saline treatments or even treatments of apelin not protected with the liposome covering.

“Apelin in this form could eventually be used as treatment for humans delivered as a shot rather than intravenously as in the past,” Rajadas told me. “The idea is that regular monthly or bimonthly shots could lesson symptoms.”

Previously: Stanford team develops nanotech-based microchip to diagnose Type 1 diabetes
Photo by NMK Photography

Aging, Chronic Disease, Clinical Trials, Immunology, Research, Stanford News

Is osteoarthritis an inflammatory disorder? New thinking gets clinical test

Is osteoarthritis an inflammatory disorder? New thinking gets clinical test

SM arthritis imageOsteoarthritis sort of comes with the territory of aging. If you live long enough, you’ll probably get it.

For those fortunate enough not to have a working acquaintance with the disease, I describe its onset in a just-published Stanford Medicine article, “When Bones Collide”:

You start to feel some combination of pain, stiffness and tenderness in a thumb, a knee, a hip, a toe or perhaps your back or neck. It takes root, settles in and, probably, gets worse. And once you’ve got it, it never goes away. Eventually, it can get tough to twist off a bottle cap or to get around, depending on the joint or joints affected.

All too many of us, of course, are perfectly familiar with the symptoms of osteoarthritis. An estimated 27 million people in the United States have been diagnosed with it. By 2030, due mainly to the aging of the population, the number will be more like 50 million. Anything so common is all too easy to look at as inevitable: basically, the result of the same kind of wear and tear on your joints that causes the treads on a commuter car’s set of tires to disappear eventually.

But Stanford rheumatologists Bill Robinson, MD, PhD, and Mark Genovese, MD, think that just may not be the way it works. Almost four years ago I wrote about Robinson’s discovery that osteoarthritis is propelled by a sequence of inflammatory events similar to ones associated with Alzheimer’s disease, cardiovascular disease, and type-2 diabetes. That discovery and a steady stream of follow-up work in his lab have spawned a clinical trial, now underway and led by Genovese, to see if a regimen of anti-inflammatory medicines that’s been shown to roll back osteoarthritis’s progression in mice can do the same thing in people.

That’s the kind of progress most of us could live without.

Previously: New thinking about osteoarthritis, older people’s nemesis and Inflammation, not just wear and tear, spawn arthritis
Illustration by Jeffrey Decoster

Clinical Trials, Health Policy, NIH, Women's Health

A look at NIH’s new rules for gender balance in biomedical studies

A look at NIH’s new rules for gender balance in biomedical studies

In May, Francis Collins, MD, PhD, director of the National Institutes of Health, co-authored a Comment piece in Nature, outlining new requirements for biomedical researchers that made balancing the sex of animals and cell lines in studies much more important than they have been in the past. The first changes were set to be implemented this month. But, as Scientific American reported earlier this week,  the NIH isn’t likely to implement the changes as quickly as previously thought:

Funding rules, however, have yet to change, with only one week left in the month. Instead, the agency is gathering comments from researchers about which research areas need sex balance the most and the challenges scientists face in including male and female subjects in their studies. Officials have set aside $10.1 million in grants for scientists who want to add animals of the opposite sex to their existing experiments. The NIH is also making videos and online tutorials to teach scientists who are new to studying both sexes how to design such studies. Meanwhile, [Janine A. Clayton, director of the NIH’s Office of Research on Women’s Health] “can’t say” when new funding rules will take effect. “Details about the policy and implementation plans will roll out during the next year,” she says.

Scientists rely heavily on male animals, rarely using females, and the changes would require some drastic changes for researchers seeking funds from NIH. More from Scientific American:

Once in place and codified, the requirement would be a major shift for the nation’s biomedical labs, many of which study mostly or exclusively male animals. One estimate found that pharmacology studies include five times as many male animals as female ones, while neuroscience studies are skewed 5.5:1 male-to-female.

Scientists assumed biology findings that held in males would apply just as well to females, but a growing body of research has discovered this is not always true. Female and male mice’s bodies make different amounts of many proteins, for example. Men and women have differing risks for many health conditions that are not obviously sex-based, including anxiety, depression, hypertension and strokes. Yet those diseases are still predominantly studied in male animals. Scientists who study sex differences think the mismatch might be the reason women suffer more side effects than men do from drugs approved by the U.S. Food and Drug Administration. Pharmaceuticals that researchers test mainly on male animals may work better for men than for women.

When the NIH does begin to implement these changes, the first steps will be training staff and grantees on what these changes mean for experimental design. And it should be noted that this isn’t the first time that NIH has encouraged sex balance. In 2013, its Office of Research on Women’s Health started a program of supplemental grants for currently funded researchers to add enough animals for gender-balanced study results.

Previously: Why it’s critical to study the impact of gender differences on diseases and treatments, Large federal analysis: Hormone therapy shouldn’t be used for chronic-disease prevention and A call to advance research on women’s health issues
Photo by Mycroyance

Cancer, Clinical Trials, Research, Science, Stanford News, Stem Cells

Drug may prevent bladder cancer progression, say Stanford researchers

Drug may prevent bladder cancer progression, say Stanford researchers

Bladder cancer is an insidious foe. About 70 percent of the time the condition is diagnosed while still confined to the bladder lining (in these cases, it’s known as a “carcinoma in situ,” or CIS). However, a subset of these localized cancers will go on to invade tissue surrounding the bladder and become much more deadly.

Now, developmental biologist Philip Beachy, PhD, a Howard Hughes Medical Institute investigator, and his colleagues have found that low doses of a drug called FK506 currently used to prevent the rejection of transplanted organs can prevent the progression of CIS into invasive bladder cancer in mice. Beachy collaborated with collaborated with urologist Joseph Liao, MD, and pulmonary specialist Edda Spiekerkoetter, MD, to conduct the research, which was published today in Cancer Cell. As Beachy explains in our release:

This could be a boon to the management of bladder cancer patients. Bladder cancer is the most expensive cancer to treat per patient because most patients require continual monitoring. The effective prevention of progression to invasive carcinoma would be a major advance in the treatment of this disease.

Beachy and Liao are members of the Stanford Cancer Institute. Together they’re hoping to initiate clinical trials of FK506 in people with CIS to learn whether the drug can also prevent progression to invasive cancer in humans.

The findings of the current study build upon previous research into the disease in Beachy’s laboratory and a long-time interest by Beachy in a molecular signaling pathway governed by a protein called sonic hedgehog. Beachy identified the first hedgehog protein in 1992; the protein (and the hedgehog pathway) have since been shown to play a vital role in embryonic developments and many types of cancers. Sonic hedgehog, Beachy has found, is produced by specialized stem cells in the bladder as a way to communicate with neighboring cells. They learned it’s required for the formation of CIS, but that it must also be lost in order for the cancer cells to invade other tissues. As Beachy explained in our release:

This was a very provocative finding. It was clear that these [sonic-hedgehog-expressing] bladder stem cells were the source of the intermediate cancers, or carcinomas in situ, that remain confined to the bladder lining. However, it was equally clear that sonic hedgehog expression must then be lost in order for those cancer cells to be able to invade surrounding tissue. We wondered whether the loss of this expression leads to increased tumor cell growth.

The researchers found that sonic hedgehog expression works in a loop with another class of proteins called BMPs. (You can read more about this in our release.) FK506 works by activating the BMP portion of the pathway in the absence of sonic hedgehog. Ten out of ten mice with CIS who received a low dose of the drug (low enough not to cause immunosuppression) were protected from developing invasive bladder cancer after five months of exposure to the carcinogen. In contrast, seven of nine mice receiving a placebo did develop the invasive form of the disease within the same time period.

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Clinical Trials, Ethics, Genetics, NIH, Pediatrics

The promise and peril of genome sequencing newborns

NICUEven though doctors and researchers have made great strides in caring for patients in the past few decades, there are still many illnesses that are difficult to diagnose, let alone treat. Among the most heartbreaking cases are those newborns who come down with mysterious illnesses that defy medical expertise. But in recent years, doctors have turned to genetic sequencing in some of these cases to identify the culprit causes of the illnesses.

Last year, the National Institutes of Health funded four pilot projects looking into the efficacy and ethics of genetic screening for otherwise inexplicable illnesses in newborns. The first of the trials will begin next week at Children’s Mercy Hospital in Kansas City, Missouri, as reported in a recent story from Nature. The trial at Children’s Mercy Hospital will focus on rapid genome sequencing with a 24-hour turn-around. Genetic sequencing normally takes weeks, but some of these infants don’t survive that long. Doctors have used similar rapid genome sequencing to diagnose an infant with cardiac defects at Lucile Packard Children’s Hospital Stanford.

Earlier this year, I had the opportunity to report on a rare genetic mutation that leads young infants to develop inflammatory bowel disease. I spoke with some parents of children with the mutation, which was identified by sequencing the children’s exome – just the protein-producing part of the genome – as part of a new project (separate from the NIH trials) at the University of Toronto in Canada. As I explain in the piece, getting a bone marrow transplant early enough can help alleviate symptoms and save the child’s life.

The parents were uniformly grateful for the sequencing technology that made it possible to understand what was causing their baby’s illness, even in cases where the child didn’t survive long after diagnosis. One mother mentioned that realizing some of the best doctors in the country didn’t know what was ailing her daughter made the experience even more frightening. After months of worried confusion about their young children’s deteriorating health, for these parents to have an answer was a relief.

But because the technique is so new, several ethical details still need clarification – which the NIH study hopes to answer. From the Nature news story:

Misha Angrist, a genomic-policy expert at Duke University in Durham, North Carolina, says that although the 24-hour genome process is impressive, it is not clear whether genomic sequencing of newborns will soon become standard practice. Many questions remain about who will pay for sequencing, who should have access to the data and how far clinicians should go in extracting genome information that is unrelated to the disease at hand. Then there is the question of how informative the process is. “I think it’s really important that we do these experiments so that we start to see what that yield is,” Angrist says.

All four teams will include an ethicist who will be responsible for dealing with questions like the ones Angrist raises. The other three trials at Boston Children’s Hospital, the University of North Carolina in Chapel Hill, and at the University of California, San Francisco are still awaiting approval from the Federal Drug Adminstration.

Previously: Stanford patient on having her genome sequenced: “This is the right thing to do for our family” When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside Whole genome sequencing: The known knowns and the unknown unknowns
Photo by kqedquest

Clinical Trials, History, Immunology, Infectious Disease, Research

Stanford scientists strive to solve centuries-old puzzle: Why are young children so vulnerable to disease?

Stanford scientists strive to solve centuries-old puzzle: Why are young children so vulnerable to disease?

512px-Gabriël_Metsu_-_The_Sick_Child_-_WGA15091

Several months ago, Stanford immunologist Mark Davis, PhD, went for a stroll in Union Cemetery in Redwood City, Calif. (not far from the Stanford campus). Graves there date from the Civil War-era and Davis, who’s currently immersed in a study of childhood immunity, was intrigued.

“In the early years, you see entire families — mom, dad, and then a whole bunch of children’s headstones,” Davis told me. “It really brought home to me how differently we live now that we just take for granted a kid will survive and grow up.”

Vaccines arrived and childhood survival rates soared. Yet young children remain much more vulnerable to infectious diseases than adults. Why?

Davis and his team think vaccines trigger a set of changes that strengthens children’s immune systems — allowing them to ward off diseases they haven’t even heard of before. That’s why the researchers are conducting a group of studies, all focused on revealing new details about the immune system’s response to the flu vaccine. They need participants, particularly young children who have never received a flu vaccine before. They also need older children and twins. All participants will receive a licensed flu vaccine that will help protect from influenza this coming winter.

Davis and colleagues plan to investigate the children’s development of two types of immune cells — memory T and B cells — that are specialized to recognize certain foreign invaders. Interestingly, adults have T cells that spot diseases they’ve never been exposed to, such as HIV, Davis said. Yet newborns lack these specialized cells, leaving them vulnerable to infection.

“Somewhere between birth and adulthood we see the appearance of these memory T cells without having the particular disease,” Davis said. “It’s a real puzzle.”

Davis suspects that routine vaccines and infections may spur the development in children of a broad spectrum of memory T cells, ones that recognize all sorts of diseases. One study plans to follow children for several years, perhaps revealing how, and when, the children develop a full compliment of these memory T cells, Davis told me.

The studies are possible thanks to the development of new analytical techniques, according to virologist and immunologist Harry Greenberg, MD, who is working with Davis on the influenza studies.

“We’ve been studying influenza for half a century, but these new assays developed in the last five years offer hope we can develop better ways of protecting more people,” Greenberg told me.

More information about the flu vaccine studies and the Stanford-LPCH Vaccine Program is available here or (650) 498-7284.

Becky Bach is a proud graduate of the UC Santa Cruz Science Communication Program (go Banana Slugs!) and a science-writing intern at the Office of Communications and Public Affairs.

Previously: Q&A about enterovirus-D68 with Stanford/Packard infectious disease expert, Gut bacteria may influence effectiveness of flu vaccine and Side effects of childhood vaccines are extremely rare, new study finds
Photo by Gabriel Metsu

Cancer, Clinical Trials, In the News, NIH, Patient Care, Research

National Cancer Institute looking for “Exceptional Responders”

OLYMPUS DIGITAL CAMERAHope is a powerful force in cancer treatment. For patients and their families, the hope is that, no matter how unlikely, the treatment plan will cure the patient and eradicate the disease. Sadly, this is sometimes a long shot. But sometimes, against all odds, the therapy is unusually successful. Now the National Cancer Institute is trying to learn why.

This week the institute launched a study into the phenomena of “Exceptional Responders” – that is, cancer patients who have a unique response to treatments (primarily chemotherapy) that have not been effective for most other patients. As they describe in a Q&A about the effort:

For this initiative, exceptional responders will be identified among patients enrolled in early-phase clinical trials in which fewer than 10 percent of the patients responded to the treatments being studied; patients who were treated with drugs not found to be generally effective for their disease; patients who were treated in later-phase clinical trials of single agents or combinations; and even patients who were treated with established therapies. In this pilot study, malignant tissue (and normal tissue, when possible) and clinical data will be obtained from a group of exceptional responders and analyzed in detail. The goal is to determine whether certain molecular features of the malignant tissue can predict responses to the same or similar drugs.

The researchers would like to obtain tumor samples, as well as normal tissue, from about 100 exceptional responders. They’ll compare DNA sequences and RNA transcript levels and other molecular measurements to try to understand why these patients were such outliers in their response to treatment. In at least one previous case, an exceptional responder with bladder cancer led researchers to discover a new molecular pathway involved in the development of the disease, and suggested new therapeutic approaches for other similar patients.

Do you know someone who might qualify for the study? More from the Q&A:

Patients who believe they may be exceptional responders should contact their physicians or clinical trialists to see if they can assist in submitting tissue for consideration. [...] Investigators who have tissue from a potential exceptional responder should send an email to NCIExceptionalResponders@mail.nih.gov. The email should include a short description of the case, without patient identifiers; information about whether tissue collected before the exceptional response is available; whether informed consent was given to use tissue for research; and the patient’s vital status.

Photo by pol sifter

Clinical Trials, Immunology, Pain, Research, Stanford News, Surgery, Technology

Discovery may help predict how many days it will take for individual surgery patients to bounce back

Discovery may help predict how many days it will take for individual surgery patients to bounce back

pandaPost-surgery recovery rates, even from identical procedures, vary widely from patient to patient. Some feel better in a week. Others take a month to get back on their feet. And – until now, anyway – nobody has been able to accurately predict how quickly a given surgical patient will start feeling better. Docs don’t know what to tell the patient, and the patient doesn’t know what to tell loved ones or the boss.

Worldwide, hundreds of millions of surgeries are performed every year. Of those, tens of millions are major ones that trigger massive inflammatory reactions in patients’ bodies. As far as your immune system is concerned, there isn’t any difference between a surgical incision and a saber-tooth tiger attack.

In fact, that inflammatory response is a good thing whether the cut came from a surgical scalpel or a tiger’s tooth, because post-wound inflammation is an early component of the healing process. But when that inflammation hangs on for too long, it impedes rather than speeds healing. Timing is everything.

In a study just published in Science Translational Medicine, Stanford researchers under the direction of perioperative specialist Martin Angst, MD, and immunology techno-wizard Garry Nolan, PhD, have identified an “immune signature” common to all 32 patients they monitored before and after those patients had hip-replacement surgery. This may permit reasonable predictions of individual patients’ recovery rates.

In my news release on this study, I wrote:

The Stanford team observed what Angst called “a very well-orchestrated, cell-type- and time-specific pattern of immune response to surgery.” The pattern consisted of a sequence of coordinated rises and falls in numbers of diverse immune-cell types, along with various changes in activity within each cell type.

While this post-surgical signature showed up in every single patient, the magnitude of the various increases and decreases in cell numbers and activity varied from one patient to the next. One particular factor – changes, at one hour versus 24 hours post-surgery, in the activation states of key interacting proteins inside a small set of “first-responder” immune cells – accounted for 40-60 percent of the variation in the timing of these patients’ recovery.

That robust correlation dwarfs those observed in earlier studies of the immune-system/recovery connection – probably because such previous studies have tended to look at, for example, levels of one or another substance or cell type in a blood sample. The new method lets scientists simultaneously score dozens of identifying surface features and goings-on inside cells, one cell at a time.

The Stanford group is now hoping to identify a pre-operation immune signature that predicts the rate of recovery, according to Brice Gaudilierre, MD, PhD, the study’s lead author. That would let physicians and patients know who’d benefit from boosting their immune strength beforehand (there do appear to be some ways to do that), or from pre-surgery interventions such as physical therapy.

This discovery isn’t going to remain relevant only to planned operations. A better understanding, at the cellular and molecular level, of how immune response drives recovery from wounds may also help emergency clinicians tweak a victim’s immune system after an accident or a saber-tooth tiger attack.

Previously: Targeting stimulation of specific brain cells boosts stroke recovery in mice, A closer look at Stanford study on women and pain and New device identifies immune cells at an unprecedented level of detail, inside and out
Photo by yoppy

Clinical Trials, Ethics, Health Policy, Stanford News, Videos

Video explains why doctors don’t always know best

Video explains why doctors don’t always know best

“Over 85 percent of our major medical guideline recommendations are not based on high-quality evidence,” said Robert Califf, MD, director of the Duke Translational Medicine Institute, in an article I recently wrote for Inside Stanford Medicine.

This was the inconvenient truth that Stanford bioethicist David Magnus, PhD, had to explain to patients during focus groups, as he began developing policy recommendations for conducting ethical comparative-effectiveness research within physician practices.

“We had to dispel the myth that doctors always know which treatments are most effective for individual patients,” Magnus told me. “The truth is, in the absence of good evidence, these choices are often influenced by advertising, insurance coverage and local preferences.”

Gathering better treatment evidence is a key objective of the Affordable Care Act’s health-care reform mandate. It provides incentives for medical practices to continually evaluate the relative effectiveness of competing medical interventions as a way of delivering better, less costly care to more people. The widespread adoption of electronic medical records is enabling researchers to conduct these head-to-head comparisons in more automated ways, reducing the time and expense associated with the highly controlled clinical trials used to evaluate new drugs and devices.

A communications challenge with these new approaches, however, is how to explain the risks and rewards of participation to patients. In focus groups, Magnus found that no meaningful discussions could take place until his research team had educated patients on some fundamental concepts of medical research, such as standards-of-care, randomization and informed consent. To help with this process, his team produced three short, animated videos that would rapidly get everyone up to the same level of understanding. Magnus and his collaborators are making these videos available to all for educational purposes.

The first video, “Which Medication is Best?,” explores the influences and uncertainty associated with physicians’ prescribing preferences. “Research on Medical Practices” explains medical record reviews, study randomization and randomization of clinics and hospitals; and “Informing or Asking” describes ways to explain study participation to patients.

Magnus and his bioethicist collaborators from the Seattle Children’s Research Institute and University of Washington expect to publish their final ethics policy recommendations later this year.

Previously: Bioethicists say criticisms of preemie oxygen study could have “chilling effect” on clinical researchStanford biomedical ethicist discusses Choosing Wisely Initiative and Will new guidelines lead to massive statin use?
Videos by Booster Shot Media

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