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Aging, Cancer, Research, Stanford News

Stanford researchers deliver double punch to blood cancer

Stanford researchers deliver double punch to blood cancer

Acute myeloid leukemia is an aggressive and deadly cancer affecting cells that turn into our blood. Now, a study published in Nature Medicine shows that a drug known to cause cell death might be effective for a particular subtype of this lethal disease.

To get an idea of just how aggressive and deadly acute myeloid leukemia is, consider the survival rates for the 13-14,000 American adults who are sickened each year. The overall survival rate is 30-40 percent, according to Stanford cancer researcher Ravindra Majeti, MD, PhD, but if patients are over 65 years old, the survival rate dips to just 5 percent. The majority of acute myeloid leukemia patients are elderly.

Apoptosis, or cell death, of tumors is the goal in cancer treatments. There are multiple pathways leading to cell death, and identifying ways to nudge cancer cells towards dying is the focus of much cancer research.

But sometimes the path to cell death is nonlinear and hard to find.

In this work, a team of Stanford cancer researchers led by Majeti and Steven Chan, MD, identified a two-pronged attack for acute myeloid leukemia cancer cells. The researchers first focused on mutated proteins called isocitrate dehydrogenase 1 and 2 (known as IDH1/2 for short). Cancer cells containing mutated IDH1/2 proteins often survive traditional chemotherapy treatments, contributing to relapse, and they exist in 15 percent of acute myeloid leukemia patients. The second focus of the Stanford researchers was the BCL-2 gene, which is known to enable cancerous growth by putting the brakes on cell death in acute myeloid leukemia and other cancer cells. Simply stopping BCL-2 activity in acute myeloid leukemia patients is not very effective, as indicated by low survival rates for the disease.

The Stanford scientists found that giving a drug that inhibits BCL-2 successfully lifted the blockade on cell death, but only in cells with mutated IDH1/2 proteins. Majeti said the drug that promotes cancer cell death by inhibiting BCL-2 is now in clinical trials.

Kimberlee D’Ardenne is a writing intern in the medical school’s Office of Communication and Public Affairs.

Previously: The latest on stem-cell therapies for leukemia, Blood cancers shown to arise from mutations that accumulate in stem cells and Leukemia prognosis and cancer stem cells

Global Health, Haiti, Research, Stanford News

Health care in Haiti: “At risk of regressing”

Health care in Haiti: "At risk of regressing"

streets of Haiti - smallAs an undergraduate at Duke University, Maxwell Kligerman stumbled into an amazing scientific opportunity. He spent the summer of 2009 collecting data on the availability of health-care facilities in Leogane, Haiti, a coastal city with a population of about 50,000 to support the work of Family Health Ministries, a non-profit founded by Duke reproductive endocrinologist David Walmer, MD.

With a guide, Kligerman walked every street in Leogane, tabulating the location and characteristics of even the most modest doctors’ offices.

His tally was important for local residents and some global health scholars, but certainly not anything with worldwide relevance.

We still need to keep Haiti on our radar. It’s been five years since the earthquake, but now is really the tipping point.

Then, on Jan. 12, 2010, the magnitude 7.0 Haitian earthquake struck, its epicenter just five miles from Leogane. Kligerman had unique, pre-earthquake data that could show the effects of the quake on local health-care opportunities. He could see what happened when the city experienced an influx of foreign aid and how the quake affected the trajectory of its development.

Taking advantage of his rare opportunity, Kligerman returned to Leogane in both 2011 and 2013, collecting information about the availability of health-care facilities.

Now, Kligerman is a third-year medical student at Stanford and recently published his findings in The American Journal of Tropical Medicine and Hygiene, in collaboration with Walmer and Stanford’s Michele Barry, MD, senior associate dean for global health, and Eran Bendavid, MD, assistant professor of medicine.

He has a critical message for those interested in global health: “We still need to keep Leogane and Haiti on our radar. It’s been five years since the earthquake, but now is really the tipping point.”

Before the earthquake, Leogane had 25 health-care facilities, ranging from a small doctors’ offices to large hospitals. Eleven of those buildings collapsed during the earthquake.

But soon, the international community swooped in, upping the number to 28. By 2013, Leogane had 34 healthcare facilities, many offering free care. Yet although the numbers look rosy, change is on the horizon.

Doctors without Borders, which operates the only full-service hospital, has announced plans to close the facility in 2015. That alone will dramatically reduce the availability of health care to Leogane residents, Kligerman said.

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Clinical Trials, Patient Care, Public Health, Research, Stanford News

Screening for diseases doesn’t necessarily save lives, study shows

Screening for diseases doesn't necessarily save lives, study shows

6143531948_a9bdfe6fb5_zIt seems like it should work: If everyone was tested for every disease, lives would be saved, right? These conditions would be spotted quickly, treated and voilà – the deadly disorder would go away.

Not necessarily, according to a new study from a team led by Stanford epidemiologist John Ioannidis, MD, DSc, published this week in the International Journal of  Epidemiology. Here’s Ioannidis:

Screening for diseases that can lead to death typically does not prolong life substantially; a few screening tests may avert some deaths caused by the disease being screened, but even then it is difficult to document an improvement in overall survival.

Ioannidis and his team examined whether screening prevents death in 19 diseases with 39 screening tests, looking at evidence from randomized controlled trials and from meta-analyses combining the results of the trials. Patients were asymptomatic when tested.

In their meta-analysis, the researchers found that mortality from the disease dropped in these cases: ultrasound for abdominal aortic aneurysm in men, mammographyfor breast cancer, and fecal occult blood test and flexible sigmoidoscopy for colorectal cancer. But no other tests reduced the number of deaths caused by the disease in meta-analyses.

What gives?

The test might not be able to detect accurately enough early stages of the disease, or there might not be life-saving treatments available, Ioannidis and colleagues write.

Ioannidis acknowledges that screening might ward off other ill-effects of disease aside from death. But in general, few screening tests among the many new ones being proposed are subjected to a randomized controlled trial before they are introduced, Ioannidis said.

“This is unfortunate. All screening tests should be evaluated with rigorous randomized controlled trials. I see no alternative to prove that they are worth being adopted in large populations,” he told me.

This work follows another recently published paper, in which Ioannidis and colleagues argue that screening all baby boomers for hepatitis C isn’t necessarily beneficial.

Previously: To screen or not to screen for hepatitis C, Bad news for pill poppers? Little clear evidence for Vitamin D efficiency, says Stanford’s John Ioannidis, John Ioannidis, MD: Research’s researcher and Screening could slash number of breast cancer cases
Photo by david_jones

Aging, Genetics, Immunology, Infectious Disease, Research, Stanford News

In human defenses against disease, environment beats heredity, study of twins shows

In human defenses against disease, environment beats heredity, study of twins shows

Pfc. Lane Higson and Pfc. Casey Higson, identical twins serving in Iraq with the Enhanced Combat Aviation Brigade, 1st Infantry Division. The twins, natives of Myrtle Beach, S.C., joined the Army together and have not separated since.I’m one of those people who’ve paid to have their genomes analyzed for the purpose of getting a handle on susceptibility to this or that disease as time goes by. So it was with great interest that I came across a new study of twins conducted by immunologist Mark Davis, PhD, and fellow Stanford investigators. The study, published in CELL, shows that our environment, more than our heredity, plays the starring role in determining the state of our immune system, the body’s primary defense against disease. This is especially true as we age.

Improving gene-sequencing technologies have focused attention on the role of genes in diseases. But the finding that the environment is an even greater factor in shaping our immune response should give pause to anyone who thinks a whole-genome test is going to predict the course of their health status over a lifetime.

“The idea in some circles has been that if you sequence someone’s genome, you can tell what diseases they’re going to have 50 years later,” Davis told me when I interviewed him for a news release I wrote on the study. But, he noted, the immune system has to be tremendously adaptable in order to cope with unpredictable episodes of infection, injury and tumor formation.

Davis, who heads Stanford’s Institute for Immunity, Transplantation and Infection, is worth taking seriously. He’s made a number of major contributions to the field of immunology over the last 30 years or so.  (Not long ago, I wrote an article about one of those exploits for Stanford Medicine.)

To find out whether the tremendous differences observed between different people’s immune systems reflec tunderlying genetic differences or something else, Davis and his colleagues compared members of twin pairs to one another. Identical twins inherit the same genome, while fraternal twin pairs are no more alike genetically than regular siblings, on average sharing 50 percent of their genes. (Little-known fun factoid: The percentage can vary from 0 to 100, in principle, depending on the roll of the chromosomal dice. But it typically hovers pretty close to 50 percent, just as rolling real dice gives you a preponderance of 6s, 7s, and 8s. Think of a Bell curve.)

Because both types of twins share the same in utero environment and, usually, pretty close to the same childhood environment as well, they make great subjects for contrasting hereditary versus environmental influence. (If members of identical-twin pairs are found to be no more alike than members of fraternal-twin pairs with respect to the presence of some trait, that trait is considered to lack any genetic influence.)

In all, the researchers recruited 78 identical-twin pairs and 27 pairs of fraternal twins and drew blood from both members of each twin pair. That blood was hustled over to Stanford’s Human Monitoring Center, which houses the latest immune-sleuthing technology under a single roof. There, the Stanford team applied sophisticated laboratory methods to the blood samples to measure more than 200 distinct immune-system cell types, substances and activities.

Said Davis: “We found that in most cases – including your reaction to a standard influenza vaccine and other types of immune responsiveness – there is little or no genetic influence at work, and most likely the environment and your exposure to innumerable microbes is the major driver.”

It makes sense. A healthy human immune system has to continually adapt to its encounters with hostile pathogens, friendly gut microbes, nutritional components and more.

“The immune system has to think on its feet,” Davis said.

Previously: Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before and Immunology escapes from the mouse trap
Photo by DVIDSHUB

Biomed Bites, Cancer, Obesity, Research, Stanford News

Stanford researcher tackles tricky problem: How does a cell become a fat cell?

Stanford researcher tackles tricky problem: How does a cell become a fat cell?

Here’s this week’s Biomed Bites. Check each Thursday to meet more of Stanford’s most innovative biomedical researchers.

Mary Teruel had no intention of becoming a biology professor — after all, she was in a PhD program for aeronautical engineering. But the more she learned about cells, the more fascinated she became.

“I became very interested in the challenging problem of trying to understand the complex network in cells and trying to see if you could apply some of the principles from engineering to understand theses processes and make an insight into human disease,” Teruel says in the video above.

Teruel’s drive to investigate cells led her into her current role as an assistant professor of chemical and systems biology, where she’s striving to unravel a puzzle that underlies the obesity crisis in America: How do cells called pre-adipocytes (or pre-fat cells) become adipocytes (or adipocytes)?

By learning more about cell differentiation, Teruel’s research can also shed light on processes — and potential treatments — involved in cancer.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: Secrets of fat cells discovered, Fed Up: A documentary looks for answers about childhood obesity and How physicians address obesity may affect patients’ success in losing weight

Addiction, Pain, Public Health, Research

Medical marijuana and the risk of painkiller overdose

Medical marijuana and the risk of painkiller overdose

medical marijuanaAfter a study published this fall showed that that opioid overdoses (e.g., with painkillers such as Oxycontin) occur at lower rates in states with legalized medical marijuana, many people interpreted the results as proof that using medical marijuana lowers an individual’s risk of overdose. For example, some speculated that marijuana allows people in pain to forgo using opioids or at least use them in lower doses. Other suggested that medical marijuana reduces users’ consumption of alcohol and anti-anxiety medications, both of which make opioid use more likely to lead to overdose. Still others hypothesized that medical marijuana improves mental health, reducing the risk of intentional opioid overdose (i.e., suicide attempts),

However, all of this speculation was premature. Many things that are associated when geographic areas are compared are not associated in the lives of the individuals who reside in those areas. For example, geographic areas with higher rates of cigarette smoking and higher radon exposure have lower cancer rates, even though individuals who smoke and/or get exposed to radon have higher rather than lower risk of cancer.

The only way to understand the influence of medical marijuana on individuals’ risk of opioid overdose is to actually research individuals, and that is what an Australian team has done. In a recently published study of more than 1,500 people who were on prescribed opioids for pain, they examined experiences with medical marijuana.

Seeking pain relief from medical marijuana was common in the sample, with 1 in 6 participants doing so and 1 in 4 saying they would do so if they had ready access to it. The results did not support the idea that medical marijuana users are at relatively low risk of opioid overdose. Indeed, on every dimension they appeared to be at higher risk than those individuals who did not use medical marijuana for pain.

Specifically, relative to individuals who only used opioids for pain, the medical marijuana users were on higher doses of opioids, were more likely to take opioids in ways not recommended by their doctor, were over twice as likely to have an alcohol use disorder and four times as likely to have a heroin use disorder. Medical marijuana users were also over 50 percent more likely to be taking anti-anxiety medications (benzodiazepines), which when combined with opioids are particularly likely to cause an overdose.

Neither did the medical marijuana users have better mental health. Almost two-thirds were depressed and about 30 percent had an anxiety disorder.   These rates were half again as high as those for non-medical marijuana users.

Medical marijuana thus appears to be commonly sought for pain relief among people who are taking prescribed opioids for pain. But in this population, it’s a marker for much higher rather than lower risk for opioid overdose.

Addiction expert Keith Humphreys, PhD, is a professor of psychiatry and behavioral sciences at Stanford and a career research scientist at the Palo Alto VA. He has served in the past as a senior advisor in the Office of National Drug Control Policy in Washington, DC. He can be followed on Twitter at @KeithNHumphreys.

Previously: Assessing the opioid overdose epidemicTo reduce use, educate teens on the risks of marijuana and prescription drugs and Study shows prescribing higher doses of pain meds may increase risk of overdose
Photo by David Trawin

Health Costs, Pain, Public Health, Research

Study examines trends in headache management among physicians

Study examines trends in headache management among physicians

4175034274_63cd0d4a7c_zAn estimated 12 percent, or 36 million Americans, suffer from migraines, resulting in an economic loss of $31 billion each year due to lost productivity, medical expenses and absenteeism.

Making lifestyle changes, such as exercising regularly, getting adequate sleep, reducing stress and cutting food triggers from your diet, have been shown (.pdf) to be effective ways to manage headache symptoms. But research recently published in the Journal of General Internal Medicine shows that physicians are increasingly ordering medical tests and providing referrals to specialists instead of offering counseling to patients on how changing their behavior could relieve their pain. Medical News Today reports:

The study, which analyzed an estimated 144 million patient visits, found a persistent overuse of low-value, high-cost services such as advanced imaging, as well as prescriptions of opioids and barbiturates. In contrast, the study found clinician counseling declined from 23.5 percent to 18.5 percent between 1999 and 2010.

The use of acetaminophen and non-steroidal anti-inflammatory drugs like ibuprofen for migraine remained stable at approximately 16 percent of the medications. Meanwhile, the use of anti-migraine medications such as triptans and ergot alkaloids rose from 9.8 percent to 15.4 percent. Encouragingly, guideline-recommended preventive therapies – including anti-convulsants, anti-depressants, beta blockers and calcium channel blockers – rose from 8.5 percent to 15.9 percent.

Unlike with the treatment of back pain, researchers found no increase in the use of opioids or barbiturates, whose usage should be discouraged, although they were used in 18 percent of the cases reviewed.

Researchers also found a significant increase in advanced imaging such as CT scans and MRIs, from 6.7 percent of visits in 1999 to 13.9 percent in 2010. The use of imaging appeared to rise more rapidly among patients with acute symptoms, compared to those with chronic headache.

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Imaging, Neuroscience, Research, Science, Stanford News

New insights into how the brain stays bright

New insights into how the brain stays bright

Neon brainAxel Brunger, PhD, professor and chair of Stanford’s Department of Molecular and Cellular Physioogy , and a team composed of several Stanford colleagues and UCSF scientists including Yifan Cheng, PhD, have moved neuroscience a step forward with a close-up inspection of a brain-wide nano-recycling operation.

A healthy adult brain accounts for about 2 percent of a healthy person’s weight, and it consumes about 20 percent of all the energy that person’s body uses. That’s a lot of sugar getting burned up in your head, and here’s why: Incessant chit-chat throughout the brain’s staggeringly complex circuitry. A single nerve cell (of the brain’s estimated 100 billion) may communicate directly with as many as a million others, with the median in the vicinity of 10,000.

To transmit signals to one another, nerve cells release specialized chemicals called neurotransmitters into small gaps called synapses that separate one nerve cell in a circuit from the next. The firing patterns of our synapses underwrite our consciousness, emotions and behavior. The simple act of tasting a doughnut requires millions of simultaneous and precise synaptic firing events throughout the brain and, in turn, precisely coordinated timing of neurotransmitter release.

You’d better believe these chemicals don’t just ooze out of nerve cells at random. Prior to their release, they’re sequestered within membrane-bound packets, or vesicles, inside the cells. Every time a nerve cell transmits a signal to the next one – which can be more than 100 times a second – hundreds of tiny chemical-packed vesicles approach the edge of the first nerve cell and fuse with its outer membrane, like a small bubble merging with a larger one surrounding it. At just the right time, numerous vesicles’ stored contents spill out into the synapse, to be quickly taken up by receptors dotting the nearby edge of the nerve cell on the synapse’s far side, where, like little electronic ones and zeroes in a computer circuit, they may either trigger or impede the firing of an impulse along that next nerve cell.

Each instance of bubble-like fusion – and this happens not only in neurotransmitter release but in hormone secretion and other processes throughout the body – is carefully managed by a complex of interconnecting proteins, collectively known as the SNARE complex. The molecular equivalent of a clamp, the SNARE complex guides the vesicle ever nearer to the nerve-cell’s surface and then, at just the right moment, squishes it up against the cell’s outer membrane. The vesicle bursts, spilling its contents into the synapse.

Myriad repetitions of this process typify the average day in the life of the average nerve cell. This requires not only a ton of energy (which I guess is where the doughnut comes in) but ultra-efficient recycling. The entire SNARE complex must be constantly disassembled, then reassembled. In a new study in Nature, Brunger and his associates snagged a set of near-atomic-scale snapshots of the SNARE complex as well as the molecular machinery that recycles its components, allowing them to make sophisticated guesses about how the whole thing works. (See the Howard Hughes Medical Institute’s news release on the study here.)

This has been a long time coming. In fact, Brunger’s lab first determined the molecular structure of the SNARE complex, via X-ray crystallography, in 1998. The careful decades-long process of tracking down the SNARE complex’s components and their interactions won Stanford neuroscientist Tom Sudhof, MD, the 2013 Nobel Prize in Medicine. But despite its immense importance, you probably haven’t heard much about it. Studies of molecular structures are in general opaque to lay readers, complicated systems such as the SNARE complex all the more so. The popular press pays attention to the awarding of the Nobel, but seldom to the long, towering staircase of incremental discoveries that was climbed to earn it.

Previously: Revealed: The likely role of Parkinson’s protein in the healthy brain, Step by step, Sudhof stalked the devil in the details, snagged a Nobel and But is it news? How the Nobel prize transformed “noteworthy” into “newsworthy”
Photo by Carolyn Speranza

Aging, Ethics, Medicine and Society, Research, Science, Stanford News

Golden years? Researcher explores longevity research and the companies banking on its success

Golden years? Researcher explores longevity research and the companies banking on its success

Elderly Japanese woman for Scott blog postAlthough I haven’t had a birthday yet this year, the transition to writing 2015 on all my checks (whoops, did I just date myself there? ahem) has made me feel older. Coincidentally, I’ve also been working on an article for an upcoming issue of Stanford Medicine magazine about aging and longevity. So, yeah. I’ve been thinking a lot about the passage of time.

That’s why I was really interested to learn that Stanford bioethicist Christopher Scott, PhD, teamed up with Nature Biotechnology senior editor Laura DeFrancesco to c0-author a feature article examining the commercialization of longevity research. The article layers research advances with the rise and fall (and rise again) of companies and organizations that have tossed their hats into the anti-aging ring since the 1990s. With it, Scott and DeFrancesco paint a picture of a dynamic field on the brink of something big. As Scott explained in an email to me:

Aging research, as we knew it in the 1990s and 2000’s, is being abandoned in favor of something much more ambitious. The central features of longevity research include an embrace of big data, a pivot away from studies hoping to find aging genes, a recognition that aging is best thought of a collection of diseases, not just one disease.

I’m fascinated by how quickly this new direction has taken off, especially since classic aging research yielded so little, and became saddled with hype. Longevity research has that same feel to it, and from an ethics and policy perspective one question is whether the promise of healthy lifespans will outrun the reality of the science.

And there’s the rub. As Scott points out, it’s not enough to just live long. No one wants a prolonged, but unhealthy, old age. We need to live long and well. The concept that gained ground is “healthspan” rather than “lifespan.” And from Google’s Calico to Craig Venter’s Human Longevity, Inc , there are a lot of bright minds (and plenty of $) focused on this problem. But there’s a lot at stake.

As Scott explained:

These are highly consequential decisions (funding research, creating new companies, establishing new scientific disciplines), technological inventions, and social changes that are being pursued on the tacit assumption that such decisions, inventions, and changes do lead to a healthier, longer life and the promise of a better future. In ethics, I think these assumptions are largely unexplored and unacknowledged.

The article is a fascinating cross-section of a rapidly growing field, but, as Scott points out, there are still many questions that scientists haven’t addressed. It’s well worth the time to read, whether you’re a writer on a deadline or just a person trying to figure out how to gracefully change that “4” into a “5” on …all your paperwork.

Previously: Exploring the value of longevity with bioethicist Ezekiel Emanuel , Tick tock goes the clock – is aging the biggest illness of all? and Researchers aim to extend how long – and how well – we live
Photo by Maya Stone

Behavioral Science, Research, Science

Hormone similarity helps bird couples stay together

Hormone similarity helps bird couples stay together

GreatTit002My husband and I — total opposites. He’s neat, I’m messy. He’s early, I’m late. He dislikes socializing, I love to go out with friends. He digs meat and potatoes, I’m a veggie. And I could go on.

So if we were a type of European songbird called the great tit, I’m afraid we wouldn’t be together. Great tits choose mates quite similar to each other, with a recent study from the Netherlands Institute of Ecology showing they even have similar hormone levels. And those levels converge the longer the birds are together.

Researchers, who presented at the 2015 annual meeting of the Society for Integrative and Comparitive Biology, measured the levels of corticosterone, a stress hormone, in breeding pairs of great tits. Pairs with similar levels of hormones were also more likely to have more healthy babies. “For at least three years, the pairs that stay together increase their similarities year after year after year,” ecologist Jenny Ouyang, PhD, said in a release.

Pairs with dissimilar levels were more likely to “divorce” or break-up, a costly move in the avian world when being without a mate reduces your chances to reproduce. Some researchers have speculated that coordinating the feeding of the babies might lead the partners to have more similar hormone levels. But the exact mechanism remains unknown.

Thankfully, my husband and I can talk, hopefully avoiding the need to compare our hormone levels, which I’d bet are quite different, and growing more so every day.

Previously: “Love hormone” may mediate wider range of relationships than previously thought, Stress hormones moonlight as immune-system traffic cops and My couple’s match: Applying for medical residency as a duo
Photo by Shirley Clarke

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