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Cancer, Immunology, Research, Stem Cells

How cancer stem cells dodge the immune system

How cancer stem cells dodge the immune system

Hidden cat

Cancer stem cells are tricky beasts. They are often resistant to common treatments and can hide out in the body long after the bulk of tumor cells have been eliminated. Over time, they’re thought to contribute to the recurrence of disease in seemingly successfully treated people.

Stanford head and neck surgeon John Sunwoo, MD, and graduate student Yunqin Lee have been investigating how stem cells in head and neck cancers manage to evade the body’s immune system. Although it’s been known that a type of head and neck cancer cells — CD44+ cells — are particularly resilient to treatment, it’s not been known exactly how they accomplish this feat.

Now, Sunwoo and Lee published today in Clinical Cancer Research a study that sheds some light on the issue. They found that a protein called PD-L1 is expressed at higher levels on the surface membrane of CD44+ cells than on other cancer cells. PD-L1  is believed to play a role in suppressing the immune system during pregnancy and in diseases like hepatitis. It does so by binding to a protein called PD-1 on a subset of immune cells (T cells) and dampening their response to signals calling for growth and activation.

As Sunwoo described to me in an email:

We believe that our work provides very important insight into how cancer stem cells, in general, contribute to tumor cell dormancy and minimally residual disease that may recur years later. Our findings also provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of head and neck cancer following surgical resection.

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Global Health, Infectious Disease, Microbiology, Research, Stanford News

If you gum up a malaria parasite’s protein-chewing machine, it can’t do the things it used to do

If you gum up a malaria parasite's protein-chewing machine, it can't do the things it used to do

chewing gum“Life in the tropics” evokes images of rain forests, palm trees, tamarinds and toucans. It also has a downside. To wit: One-third of the Earth’s population – 2.3 billion people – is at risk for infection with the mosquito-borne parasite that causes malaria.

Thankfully, mortality rates are dropping because of large-scale global intervention efforts. But malaria remains stubbornly prevalent in sub-Saharan Africa and Southeast Asia, where hundreds of millions of people become infected each year and more than 400,000 of them – mostly children younger than 5 – still die from it.

The parasite has the knack of evolving rapidly to develop resistance to each new generation of drugs used to fend it off. Lately, resistance to the current front-line antimalarial drug, artemisinin, is spreading and has now been spotted in a half-dozen Southeast Asian countries.

So it’s encouraging to learn that Stanford drug-development pioneer Matt Bogyo, PhD, and his colleagues have designed a new compound that can effectively kill artemisinin-resistant malaria parasites. Better, exposure to low doses of this substances re-sensitizes them to artemisinin.

By exploiting tiny structural differences between the parasitic and human versions of an intercellular protein-recycling machine called the proteasome, the compound Bogyo’s team has created attacks the malaria parasite while sparing human cells.

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Patient Care, Pediatrics, Stanford News

Send a Valentine to a Packard Children’s Hospital patient

Send a Valentine to a Packard Children's Hospital patient

Screen Shot 2016-02-09 at 10.15.55 PMLast night I saw a post on Twitter that made my heart melt. The message was simple: Send a Lucile Packard Children’s Hospital Stanford patient a Valentine to let them know that someone is thinking of them and cheering them on.

Their goal is to collect at least 1000 cards by this Friday to distribute to children and their families this Valentine’s Day. Well-wishers can show their support by going to Packard Children’s virtual Valentine site to choose an electronic card, write a message and send some love.

Here on Scope we’ve written numerous stories about the positive health benefits that people derive from being compassionate towards others. So if you’re hemming and hawing about how to celebrate Valentine’s Day, here’s a great way to show someone special you care.

Previously: A Super Bowl surprise at Packard Children’sGirls’ Day Out event helps unite — and nurture — teens battling cancer and Image of the Week: Lucile Packard Children’s Hospital Holiday Art Contest

Neuroscience, Research

Successful replacement of eye cells hints at future glaucoma treatment

Successful replacement of eye cells hints at future glaucoma treatment

2553516471_2dbf6fbb2f_oFor the first time, a team has successfully transplanted retinal ganglion cells into living animals. The new cells mimicked existing cells in the eye and responded to light.

The work, which was co-led by Jeffrey Goldberg, MD, PhD, professor and chair of ophthalmology at Stanford, is an effort to improve therapies for retinal and optic nerve diseases including glaucoma, which is the leading cause of irreversible blindness. Glaucoma is caused by a variety of conditions, but it leads to the loss of retinal ganglion cells, nerve cells that transmit information from photoreceptors in the eye to the visual centers in the brain.

“These data provide a hint that replacing these cells and restoring these connections is one step closer to possible,” Goldberg told me.

The team, including first author Praseeda Venugopalan, PhD, a former graduate student in neuroscience at the University of Miami, injected labeled retinal ganglion cells into 152 adult rats. Although the new cells integrated into only about one of six animals, that success rate was surprisingly high, Goldberg said.

Goldberg said they are not sure why their procedure worked when other attempts have failed. They used fully differentiated retinal ganglion cells, rather than undifferentiated stem cells, which could be an important factor, he said.

In this study, the team implanted the cells in healthy eyes, but they’re planning future studies to determine if the procedure is equally successful in eyes already suffering from glaucoma, Goldberg said.

The study appeared recently in Nature Communications. Kenneth Muller, PhD, professor of neuroscience at the University of Miami, is also a senior author.

Previously: Stanford-developed eye implant could work with smartphone to improve glaucoma treatments, What I did this summer: Stanford medical student investigates early detection methods for glaucoma and The retina: One researcher’s window into the brain
Photo by Rachel Collins

Education, Stanford Medicine Unplugged

Ten surprising things that Stanford med students do

Ten surprising things that Stanford med students do

Stanford Medicine Unplugged (formerly SMS Unplugged) is a forum for students to chronicle their experiences in medical school. The student-penned entries appear on Scope once a week during the academic year; the entire blog series can be found in the Stanford Medicine Unplugged category.

Megan Deakins-RocheMy family keeps asking me why I want to write novels. After all, I’m in medical school. Isn’t that enough? No, I tell them. That’s just it. That’s why I have to write. I haven’t even started my clinical rotations, yet I’ve already seen some patients at their most vulnerable moments. I have seen myself and my classmates struggle to balance impossible expectations and inspiring dreams with the reality of our very human limitations. And so I argue back, what’s wrong with me letting my brain imagine a world in which I get to choose the outcomes? What’s wrong with letting myself create villains I like and protagonists who surprise me?

That is my way to process medicine, my way of being myself in a career path that is highly defined by my superiors. And I’m lucky to be surrounded by classmates who have their own unique, thrilling ways of living their individuality while in medical school. Stanford attracts some of the most creative, productive students in the world, and I’d like to share a small glimpse of the incredible people who inspire me with what they do outside of their careers.

Here, then, are ten of my fellow medical students and their surprising hobbies:

gourmet salad

  1. Sarah Cheng has her own gourmet food blog. The first year of medical school, she made coffee Oreo cupcakes for my birthday, and I nearly died.
  2. James Pan is a photography enthusiast. One of his photos is my profile pic. #instagood
  3. Brian Hsueh is a ballroom dancer who competed in the national USA Dance circuit for the first four years of his MD/PhD. He trained three days a week and teaches introductory classes.
  4. Cesar Lopez and (former Scope contributor) Jennifer DeCoste-Lopez came to Stanford’s medical school already married. I met them when I was an undergrad and was inspired by how grounded they were. I met them again on my interview day and they were having a baby as third year students, a testament to their ability to balance life in medical school.
  5. Megan Deakins-Roche is on the U.S. Mountain Running Team. She and her husband are sponsored by Nike and are a part of the Nike Trail Elite team.
  6. Justin Norden is a professional Ultimate Frisbee player. He’s a member of the San Jose Spiders and was a part of the team that won the 2015 championship.
  7. Austin Cook is a national champion in Judo. He now trains for fun… so I wouldn’t recommend taking a shot at him in a bar Friday night.
  8. Sheun Aleuko is a certified yoga instructor. It’s not trivial to meditate away stress… but if anything can help, it’s yoga.
  9. Ben Robison is a violinist, composer and producer who has performed around the world. He was won international prizes and has collaborated with luminaries such as David Finckel, Ani Kavafian and Luciano Pavarotti.
  10. Steven Sloan grows brains in a petri dish. He is an MD/PhD student in the neurosciences. During one of our recent conversations, he excused himself to go check on the neurons that were self-assembling into mini-brains. Just a side project, yo.

Natalia Birgisson is between her second and third year of medical school. She is half Icelandic, half Venezuelan and grew up moving internationally before coming to Stanford for college. 

Photo of Megan Deakins-Roche courtesy of Deakins-Roche; photo at lower left courtesy of Sarah Cheng

Cancer, Mental Health, Pain, Patient Care, Public Health

Coping with depression: A free online resource for cancer patients and their families

Coping with depression: A free online resource for cancer patients and their families

4523771529_0431b725aa_z-2If you or someone you know has cancer you’ve probably discovered that the disease can affect more than your physical health: It can alter your mood, your relationships with others and your relationship with yourself.

Many patients and their loved ones also experience feelings of depression and helplessness when faced with a cancer diagnosis, and this common and complex issue is addressed in an excerpt from Everyone’s Guide to Cancer Supportive Care found in the resource section of the Ernest and Isadora Rosenbaum Library at Stanford’s Center for Integrative Medicine.

The “Coping With Depression” piece, written by clinical psychologist Andrew Kneier, PhD, walks the reader through various aspects of the topic, touching on ways cancer and depression are related, what you can do to protect yourself from negative feelings, and how to overcome such feelings. Perhaps one of the most interesting and helpful parts of the piece is its examination of how depression linked to cancer differs from other forms of depression:

Cancer patients often get depressed simply because having cancer can be a depressing experience. However, there is usually more to it than that. Most cancer patients are not clinically depressed. To varying degrees, they are frightened and upset, but this is not depression. When cancer causes depression, there are psychological or biological reasons for it. These causes are understandable, and they are treatable.

Whether you have cancer or not, the piece is worth a read.

Previously: Ernest and Isadora Rosenbaum Library: A free, comprehensive guide to living with cancerLooking at cancer as a chronic illnessEmotional, social support crucial for cancer patients and Stanford psychiatrist David Spiegel’s path west
Photo by Fiona Cullinan

HIV/AIDS, Infectious Disease, Research, Science, Stanford News

“Unprecedented” approach for attempting to create an HIV vaccine

"Unprecedented" approach for attempting to create an HIV vaccine

Stanford’s 588732155_c05dda114e_zPeter S. Kim, PhD, was recently elected to the National Academy of Engineering, making him one of only 20 people who are members of all three National Academies (the other two are Medicine and Science). Stephen Quake, PhD, a bioengineer here, is also a member of all three academies.

This honor is particularly fitting for Kim, who joined Stanford in 2014 to be part of the new interdisciplinary institute Stanford ChEM-H, which bridges the schools of medicine, engineering and humanities & sciences for research in human health. Kim had spent a decade as president of Merck Research Laboratories and hopes that in his return to academic research his group will be able to help create a vaccine for HIV.

I talked to Kim recently about why he thinks he’ll succeed where so many have failed in their efforts to develop an HIV vaccine, and the importance of working across disciplines:

How is your approach to creating an HIV vaccine different from ones that haven’t been successful?

In over 30 years of intense work by many people to try and come up with a vaccine, none has succeeded. That’s in large part because the virus can mutate very quickly. It can change and therefore escape an antibody. The approach that we’re taking is to target a part of HIV that is normally buried but becomes exposed during the infection process. This region is highly conserved – it is 90 percent identical between all HIV strains.

If this region doesn’t mutate often why haven’t other people tried to target it?

It is unprecedented to make a vaccine against a region of a protein that is only exposed briefly. People are skeptical because the vaccine has to be there right at the moment that the virus is infecting the cell.

What gives you confidence the approach will work?

There’s an FDA-approved drug, called Fuzeon, that binds this same region and has been shown to be effective in people. That drug isn’t widely used because it has to be injected, but it validates our idea that targeting this transiently exposed part of the protein can be effective at fighting the virus in humans.

How far along are you?

We’ve shown that we can elicit antibodies in animals that are capable of inhibiting HIV in a lab dish. Thus, we know that our vaccine candidates can generate antibodies against the virus, and that those antibodies recognize and fight the virus. But, we still need to generate a much stronger inhibitory response before we test it in people.

You’re now a member of the three academies that also represent the academic interests of ChEM-H, which brought you to Stanford. Do you think spanning disciplines helps in your work?

The research that we do is greatly enhanced by having the proximity of engineering, medicine and science at Stanford. We study things as basic as the molecular structures of viral proteins. Ultimately, we need to understand how the human immune system creates antibodies against these proteins. This work is greatly facilitated by engineering methods to determine the DNA sequence of single immune cells. In the future, we would also love to see what is occurring at a single molecule level when a virus infects a cell. To do that will require bringing together world class engineering, science and medicine.

Previously: Research investment needed now, say top scientists and Stanford ChEM-H bridges chemistry, engineering and medicine
Image of an HIV particle by AJ Cann

Global Health, Health Policy, In the News, Public Health

Zika outbreak shares key traits with Ebola crisis, Stanford experts point out

Zika outbreak shares key traits with Ebola crisis, Stanford experts point out

An op-ed co-authored by global-health physician Michele Barry, MD, calls attention today to alarming parallels between the outbreaks of Ebola and Zika. In the Los Angeles Times, she and co-author Yanbai Andrea Wang, JD, PhD, write:

Both were detected late… Both disease outbreaks generated sluggish international responses… And in both outbreaks, the heaviest burden fell on vulnerable populations least able to bear it…

These mistakes will continue to repeat, they write, unless significant changes are made:

To build an effective global system for containing infectious diseases like Zika and Ebola, we need to make sure that countries around the world have the surveillance capacity to identify outbreaks before they spiral out of control. That means giving technical and financial assistance to developing countries and having external monitoring and incentives to make sure that capacity is built. We also need to make sure that WHO — the only organization with the representation and legitimacy to do so — is up to the task of leading outbreak response when local forces are overwhelmed.

Zika is a mosquito-borne virus that can cause fever and joint pain and, in some cases, severe birth defects such as microcephaly. Recent cases have been concentrated in South and Latin America, particularly northern Brazil, and on Feb. 1, the World Health Organization declared the outbreak an international public health emergency.

Photos of babies with tiny heads have captured global attention, Barry and Wang note. “Let’s remember the broader systemic shortcomings that got us here in the first place.”

Previously: Ebola: It’s not over, Ebola: This outbreak is different and Stanford team develops a method to prevent the viral infection that causes dengue fever
Photo courtesy of USDA

History, Research, Surgery

Ancient surgical technique still used to rebuild noses today

Ancient surgical technique still used to rebuild noses today

When facial surgeon Sam Most, MD, first contacted me about doing a story on one of his favorite procedures called the “forehead flap,” which he uses for major nose reconstructions, he sent along photos of what a patient looks like prior to surgery.

The photos make it clear real fast how unfortunate it is to lose your nose. The nose is the focal point of the face. It’s what people notice first. The numbers of people losing their noses due to skin cancer is on the rise, and many, are left wearing uncomfortable, unflattering prostheses for years.

Enter surgeons like Most, part artist, part scientist — a sculptor of noses. According to Most, it’s the most difficult facial plastic surgery procedure. And key among the many necessary tools needed to succeed is the “forehead flap” — a procedure that originated with cobblers in ancient India. My article tells the story of this fascinating surgery, which was first introduced into Western medicine in 1794:

Most is quick to recount the historical significance of the forehead flap, Most is quick to recount the historical significance of the forehead flap technique, which originated in India probably before the birth of Christ but wasn’t widely known to Western medicine until 1794 with the publication of a letter to the editor in Gentlemen’s Magazine of London. The letter provided the first account in English literature of the procedure.

At the time, India was a colony of the British. A sultan, angry at the occupation, offered bounties for the amputated ears, noses and hands of British sympathizers. The letter describes the nasal reconstruction of an Indian bullock driver who, having been imprisoned by the sultan, had his nose and one of his hands cut off for delivering supplies to British troops. It goes into detail how the driver’s nose was rebuilt 12 months later, after he joined the Bombay Army of the East India Company.

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Cancer, Global Health, Pediatrics, Stanford News

The “little angel” who helps young Latin American children with cancer

The “little angel” who helps young Latin American children with cancer

ZambranoEduardo Zambrano’s spare office in Stanford Hospital displays some of the essentials of his pathology practice: a large microscope which dominates his desktop and a cabinet overflowing with colorful, hand-painted wooden boxes, each one representing a Latin American child with cancer.

Over the last 12 years, Zambrano, MD, has received as many as 1,000 tumor samples from pediatric oncologists in Venezuela and other Latin American countries who treat desperately poor young patients with various forms of cancer. Each sample is carried on a glass slide or embedded in wax, then carefully wrapped in tissue paper and lovingly packaged in a wooden box painted by a patient’s mother or local artisan as a gesture of gratitude. The boxes are covered in suns, stars, flowers and other images of life and hope.

“To me, behind each one of these boxes is a child with cancer, and to know we’ve been able to help them is very special to me,” said Zambrano, chief of pathology at Lucile Packard Children’s Hospital Stanford. An expert in pediatric solid tumors, he volunteers his service on behalf of these youngsters.

A professor of pediatrics and of pathology who came to Stanford a year ago, he said he receives one or two of these boxes a week. He examines the samples under the microscope and then issues a diagnosis, some involving rare cancers. Clinicians ship the samples to him because in these low-resourced countries, they don’t have the means to accurately diagnose the problem.

“Very frequently the diagnosis (from the home country) is either incomplete because they don’t have the resources to perform confirmatory tests or it’s wrong because they don’t have expertise in pediatric tumors,” he said. “It’s frequent that I have to give them a significantly different diagnosis than what they sent.”

Among the most common tumors he sees are pediatric sarcomas, which can originate in various parts of the body; neuroblastomas; lymphomas; and brain tumors.

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