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Dermatology, Research, Science, Stanford News, Stem Cells

The politics of destruction: Short-lived RNA helps stem cells turn on a dime

The politics of destruction: Short-lived RNA helps stem cells turn on a dime

Many stem cells live a life of monotony, biding their time until they’re needed to repair tissue damage or propel the growth of a developing embryo. But when the time is right, they must spring into action without hesitation. Like Clark Kent in a phone booth, they fling aside their former identity to become the needed skin, muscle, bone or other cell types.

Now researchers at Stanford, Harvard and the University of California-Los Angeles have learned that embryonic stem cells in mice and humans chemically tag RNA messages encoding key stem-cell genes. The tags tell the cell not to let the messages linger, but to degrade them quickly. Getting rid of those messages allows the cells to respond more nimbly to their new marching orders. As dermatology professor Howard Chang, MD, PhD, explained to me in an email:

Until now, we’ve not fully understood how RNA messages within the cell dissipate. In many cases, it was thought to be somewhat random. This research shows that embryonic stem cells actively tag RNA messages that they may later need to forget. In the absence of this mechanism, the stem cells are never able to forget they are stem cells. They are stuck and cannot become brain, heart or gut, for example.

Chang, who is a Howard Hughes Medical Institute investigator and a member of the Stanford Cancer Institute, is a co-senior author of a paper describing the research, which was published today in Cell Stem Cell. He shares senior authorship with Yi Xing, PhD, an associate professor of microbiology, immunology and molecular genetics at UCLA, and Cosmas Giallourakis, MD, an assistant professor of medicine at Harvard. Lead authorship is shared by postdoctoral scholars Pedro Batista, PhD, of Stanford, and Jinkai Wang, PhD, of UCLA; and by senior research fellow Benoit Molinie, PhD, of Harvard.

Messenger RNAs are used to convey information from the genes in a cell’s nucleus to protein-making factories in the cytoplasm. They carry the instructions necessary to assemble the hundreds of thousands of individual proteins that do the work of the cell. When, where and how long each protein is made is a carefully orchestrated process that controls the fate of the cell. For example, embryonic stem cells, which can become any cell in the body, maintain their “stemness” through the ongoing production of proteins known to confer pluripotency, a term used to describe how these cells can become any cell in the body.

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Dermatology, Stanford News

From the newsstands to exam rooms: My chat with Stanford dermatologist Laurel Geraghty

From the newsstands to exam rooms: My chat with Stanford dermatologist Laurel Geraghty

Laurel G

First thing to know about Laurel Geraghty, MD: She can geek out with the best of them. Don’t be fooled by her fashionable clothes or her graceful manner: Geraghty can riff on mole types and describe the symptoms of psoriasis with passion. Geraghty had to suppress her science savvy as an editor at Glamour magazine, although there were plenty of other perks – including weekend jaunts to Las Vegas or the Caribbean and “working” celebrity-packed Manhattan fashion shows.

Now, she’s a second-year dermatology resident at Stanford, married and the mother of a 3-year-old and a 5-year-old. In a recent interview, I chatted with Geraghty about her career change, future plans, skin cancer, acne, and even tattoos. About the latter, she told me:

Tattoos can be safe if done by a reputable professional using new and sterilized equipment. There is a risk of transmitting communicable diseases, including hepatitis, if needles are re-used or are not sterilized. There are a variety of different itchy, red, skin reactions that people can get from tattoo ink, especially red ink, which contains mercury sulfide, and that can be hard to deal with when it happens.

But tattoos don’t have to be forever. Skin lasers can break down tattoo ink within the skin, though the treatments can be painful and expensive. Some say the laser removal is more painful than getting the tattoo. Red tattoo ink is by far the most difficult color to remove and has the highest risk of causing a skin reaction, so avoiding red may be a good choice

And for Geraghty herself? No tattoos. “When I went away to college, my mother told me she would not pay my tuition if I ever came home with a tattoo. So I never did.”

Previously: Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers, Ask Stanford Med: A focus on on scleroderma, New study: Genes may affect skin youthfulness
Photo by Norbert von der Groeben

Cancer, Dermatology, Research, Science, Stanford News

Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers

Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers

sunbathingA link between the UV rays in sunshine and the development of skin cancer is nothing new. We’ve all (hopefully) known about the damage sun exposure can wreak on the DNA of unprotected cells. But it’s not been known exactly how it causes cancers like squamous cell carcinoma or melanoma. Now, Stanford dermatologists Paul Khavari, MD, PhD and Carolyn Lee, MD, PhD have identified a UV-induced mutation in a protein active during cell division as the likely driver in tens of thousands of cases of skin cancer. Although the protein hasn’t been previously associated with cancer, the work of Khavari and Lee suggests it may actually be the most-commonly mutated oncogene in humans.

Their work was published yesterday in Nature Genetics. As we describe in our release:

Lee and Khavari made the discovery while investigating the genetic causes of cutaneous squamous cell carcinoma. They compared the DNA sequences of genes from the tumor cells with those of normal skin and looked for mutations that occurred only in the tumors. They found 336 candidate genes for further study, including some familiar culprits. The top two most commonly mutated genes were CDKN2A and TP53, which were already known to be associated with squamous cell carcinoma.

The third most commonly mutated gene, KNSTRN, was a surprise. It encodes a protein that helps to form the kinetochore — a structure that serves as a kind of handle used to pull pairs of newly replicated chromosomes to either end of the cell during cell division. Sequestering the DNA at either end of the cell allows the cell to split along the middle to form two daughter cells, each with the proper complement of chromosomes.

If the chromosomes don’t separate correctly, the daughter cells will have abnormal amounts of DNA. These cells with extra or missing chromosomes are known as aneuploid, and they are often severely dysfunctional. They tend to misread cellular cues and to behave erratically. Aneuploidy is a critical early step toward the development of many types of cancer.

The mutation in KNSTRN is a type known to be specifically associated with exposure to UV light. Khavari and Lee found the mutation in pre-cancerous skin samples from patients, but not in any samples of normal skin. This suggests the mutation occurs early, and may be the driving force, in the development of skin cancers. As Khavari, chair of the Department of Dermatology and dermatology service chief at the Veterans Affairs Palo Alto Health Care System, explained in the release:

Mutations at this UV hotspot are not found in any of the other cancers we investigated. They occur only in skin cancers… Essentially, one ultraviolet-mediated mutation in this region promotes aneuploidy and subsequent tumorigenesis. It is critical to protect the skin from the sun.

Previously: Master regulator for skin development identified by Stanford researchers and My pet tumor – Stanford researchers grow 3D tumor in lab from normal cells
Photo by Michael Coghlin

Cancer, Dermatology, In the News, Public Safety, Research, Stanford News

A closer look at new research showing disproportionate rates of melanoma in Marin County

Last week, Cancer Prevention Institute of California/Stanford Cancer Institute researcher Christine Clarke, PhD, shared results of a new report (.pdf) showing that a county in California has higher numbers of melanoma skin cancer than the rest of the state. On this morning’s Forum Clarke joined two other guests, including Stanford dermatologist Susan Swetter, MD, director of the Pigmented Lesion and Melanoma Program at the Stanford Cancer Institute, to discuss the research and to offer skin safety and screening tips for the summer.

It’s worth a listen – especially if you live in the county just north of San Francisco.

Previously: Melanoma rates exceed rates of lung cancer in some areasWorking to protect athletes from sun dangers, As summer heats up take steps to protect your skin, Stanford study: Young men more likely to succumb to melanoma, New research shows aspirin may cut melanoma risk and Working to prevent melanoma

Cancer, Dermatology, Public Health, Research, Stanford News

Melanoma rates exceed rates of lung cancer in some areas

Melanoma rates exceed rates of lung cancer in some areas

stinson_beach

Californians, step away from the beach and grab a hat and sunscreen. Our team of researchers from the Cancer Prevention Institute of California/Stanford Cancer Institute released a new report (.pdf) this week documenting the rapidly growing burden of melanoma in Marin County, California. This small, homogenous (and wealthy) county just over the Golden Gate Bridge from San Francisco has been the focus of cancer studies before, as high rates of breast cancer were first reported there in the late 1990’s (rates declined there as in the rest of the country in 2003 when women stopped taking hormone therapy).

Our most recent cancer registry data show that rates of malignant melanomas in Marin County are 43 percent higher than the rest of the San Francisco Bay Area and 60 percent higher than other parts of California among non-Hispanic whites, who because of their fairer skin tones are diagnosed with melanoma at 20-30 times the rate of other ethnic groups. Also of concern is that the death rate due to melanoma is 18 percent higher in Marin whites than whites in other regions, a significant difference not seen before. Most of the elevated rates are limited to persons over age 65, especially men.

The Bay Area news media reported our findings as front-page news. Most coverage centered on the question of why the rates are so much higher in Marin County. Our best guess is that the higher average socioeconomic status of its residents corresponds to a higher proportion of people with the known risk factors for melanoma: fair complexion (pale skin, blonde or red hair, blue or green eyes) and a history of “intense intermittent” sun exposure over their lifetimes (exposure in big doses like you might get on a beach vacation in the winter).

However, it is also likely that better access to health care and skin screening has resulted in earlier diagnosis, a notion confirmed by the higher proportion of melanomas in Marin County caught when thin and more curable. Local dermatologists reacted to the statistics with some surprise, but didn’t change their standing advice regarding skin cancer prevention: talk to your doctor about skin screening and stay sun safe by wearing hats, long-sleeves and broad-spectrum sunscreen during outdoor activities.

One statistic mostly overlooked by the media was our finding that melanoma is now the second most common cancer diagnosed in men living in Marin County, as rates have surpassed those for lung cancer. This pattern is very different than that observed for whites in the US and world, for whom prostate or lung are first, and melanoma is ranked much lower. With one of the most successful public tobacco control efforts in the world, most populations in California have seen rapid declines in the incidence of smoking-related cancers of the lung and respiratory system.

Unfortunately, it seems for older white persons in Marin County (as well as parts of Utah and Hawaii, where smoking rates have also declined), melanoma and skin cancers represent a major—and relentlessly growing—cancer threat. Perhaps putting down the cigarettes was accompanied by more time at the pool or beach without adequate sun protection. Although California was the first state to ban tanning bed use by minors, we should look to Australia and other countries also battling rising skin cancer rates for innovative new policies and strategies for encouraging safe sun exposure in our at-risk communities.

Christina A. Clarke, PhD, is a Research Scientist and Scientific Communications Advisor for the Cancer Prevention Institute of California, and a member of the Stanford Cancer Institute.

Previously: Beat the heat – and protect your skin from the sun, Working to protect athletes from sun dangers, As summer heats up take steps to protect your skin, Stanford study: Young men more likely to succumb to melanoma and How ultraviolet radiation changes the protective functions of human skin
Photo by stefan klocek

Dermatology, In the News, Public Health

Don’t feed the bedbugs: Tips for travelers

hotel bedHere’s something to think about before heading out for a summer weekend adventure: bedbugs. They still exist. And a new article from Wired offers a few practical tips to spot and avoid bringing home unwelcome guests.

From the piece (weigh the pros and cons of viewing “itch-inducing photos” before clicking the link below):

Tools you will need: A flashlight, or the flashlight feature of your phone. Use your phone to take photos of anything suspicious.

What you are looking for: Bedbugs hang out near their food source–you. After feeding, bed bugs poop, creating tell-tale brown stains of your clotted blood. You typically won’t see bugs — they are fairly tiny and can scurry quickly — but you will see these stains. You can find many itch-inducing photos here to help you know what to look for.

Author Gwen Pearson reminds readers that luggage is a popular mode of transportation for bedbugs, so stow your bags in the hotel room bathtub until the coast is clear. Check everything in sight. Sleep tight! And if you’ve made it through the night, check your sheets in the morning.

Previously: A (mostly bleak) bedbug updateWhy we worry about bedbugs and Image of the week: Bedbug
Photo by Simon Davison

Cancer, Dermatology, Events, Public Health, Stanford News

Free skin cancer screening being held Saturday

Free skin cancer screening being held Saturday

sunbatherScreening for skin cancer is advised for people with many moles or atypical moles, fair skin or a history of excessive sun exposure, a personal history of skin cancer or precancerous spots, or a parent or sibling who has had skin cancer. Each year, Stanford dermatologists offer a free screening for those in the local community, and this year’s event – being held tomorrow, May 31 – will offer more than the experienced eyes of skin clinicians.

Understanding that many people have concerns about one particular spot, the organizers are debuting a form of fast-track evaluation for just such concerns. During the Spot Check service, clinicians will use and study a new Stanford-developed smartphone-based device. As Justin Ko, MD, co-chief of medical dermatology at Stanford Hospital & Clinics, explained to me, “The device allows a user to capture clinical images of a skin lesion with their smartphone previously possible only with specialized, expensive devices typically used by dermatologists. We’ll be doing some studies to validate what we believe may well ‘democratize’ ability to capture and send medical-quality images of skin lesions by making this technology accessible and easy to use.”

The screening event (.pdf) will also include information on SUNSPORT, a collaboration of the Stanford Cancer Institute, the medical school’s Department of Dermatology, Stanford Athletics, and Stanford Hospital & Clinics, which provides student-athletes with information about their heightened risks for sun-related skin damage and works with the teams’ coaches and athletic trainers to reinforce skin-protection practices on a daily basis.

For local readers: The event runs from 8-11 AM at the Stanford Medicine Outpatient Center in Redwood City. Call (650) 723-6316 for more information.

Previously: Skin cancer images help people check skin more often and effectively, Working to protect athletes from sun dangersStanford clinic addresses cancer-related skin issuesAs summer heats up take steps to protect your skin and Man’s story shows how cancer screenings saves lives
Photo by Tom Godber

Dermatology, Health Costs, In the News, Research, Stanford News, Videos

Stanford dermatologist tackles free drug samples on NewsHour

Stanford dermatologist tackles free drug samples on NewsHour

Last week, my colleague reported on a new Stanford study showing that free drug samples lead to more expensive prescriptions. Over the weekend, dermatologist Al Lane, MD, senior author of the study, appeared on PBS NewsHour to discuss the implications of his findings. (He’s also quoted in a New York Times blog post on the research.) After mentioning that pharmaceutical companies spend more than $6 billion a year on sampling, he told NewsHour’s Hari Sreenivasan “that [this] cost eventually has to be paid by someone.” And he closes on a powerful note:

One of the focuses of our study was for the dermatologists to realize that although they think they’re helping the patients, they’re really being manipulated to write for more expensive medications with no proven benefit of those medications over the generic drugs.

Previously: Drug samples lead to more expensive prescriptions, Stanford study finds

Dermatology, Ethics, Health Costs, Research, Stanford News

Drug samples lead to more expensive prescriptions, Stanford study finds

Drug samples lead to more expensive prescriptions, Stanford study finds

drugs on money - big

It’s been years (fortunately) since I’ve needed a prescription for anything more than a simple antibiotic. But when I did, I remember I was always thankful on those occasions when my doctor offered a free sample of a medication to try before (or sometimes instead of) pulling out the prescription pad. I appreciated the chance to see if a medication would work for me, and I was happy for any opportunity to save myself (or, at times, my insurance company) a few dollars. The fact that the samples were invariably for drugs that were still on patent (known as brand name drugs or branded generics) to a particular company certainly escaped me.

Now, a study by Stanford dermatologist Al Lane, MD, highlights the dark side of such free samples, which are provided to doctors by the pharmaceutical companies who make the drugs. The research, along with an accompanying editorial, is published today in JAMA Dermatology. As Lane comments in my release on the work:

Physicians may not be aware of the cost difference between brand-name and generic drugs and patients may not realize that, by accepting samples, they could be unintentionally channeled into subsequently receiving a prescription for a more expensive medication.

Specifically, Lane and medical student Michael Hurley found that dermatologists with access to free drug samples wrote prescriptions for medications with a retail price of about twice that of prescriptions written by dermatologists without access to samples. All of the patients had the same first-time diagnosis of adult acne. The difference is nothing to sniff at – $465 for docs who accepted samples and about $200 for docs who did not. What’s more, the overall prescribing patterns of the two groups of physicians showed almost no overlap. Physicians without access to samples prescribed mainly generic drugs (83 percent of the time), whereas those with access to samples prescribed generics much less frequently (21 percent of the time). Only one drug of the top ten most commonly prescribed by physicians without access to samples even made it into the top ten list of physicians who did accept samples.

The distribution of free drug samples in this country is big business. It’s been estimated that pharmaceutical companies give away samples of medications with a retail value of about $16 billion every year. But many physicians feel the availability of samples doesn’t sway their prescribing choices, and instead feel the samples allow them more flexibility to treat their patients. Lane himself thought so, until Stanford Medicine prohibited physicians to accept samples or other industry gifts in 2006. As he explains in the release:

At one time, we at Stanford really felt that samples were a very important part of our practice. It seemed a good way to help poorer patients, who maybe couldn’t afford to pay for medications out-of-pocket, and we had the perception that this was very beneficial for patients. But the important question physicians should be asking themselves now is whether any potential, and as yet unproven, benefit in patient compliance, satisfaction or adherence is really worth the increased cost to patients and the health-care system.

Clearly Lane has had a change of heart, in part based on the data in the study. Now he’s hoping to get the word out to other physicians. He and Hurley conclude in the paper, “The negative consequences of free drug samples affect clinical practice on a national level, and policies should be in place to properly mitigate their inappropriate influence on prescribing patterns.”

Previously: Consumers’ behavior responsible for $163 billion in wasteful pharmacy-related costs and Stanford’s medical school expands its policy to limit industry access
Photo by StockMonkeys.com

Clinical Trials, Dermatology, Pediatrics, Research, Stanford News

Using Viagra to treat a rare childhood deformity: A research update

Using Viagra to treat a rare childhood deformity: A research update

Researchers at Lucile Packard Children’s Hospital Stanford are investigating a surprising treatment for a rare and potentially dangerous childhood deformity. As I’ve described previously, pediatric dermatologist Al Lane, MD, and his colleagues are studying the drug sildenafil – better known by its trade name, Viagra – as a treatment for lymphangioma. The condition, an overgrowth of the body’s lymph vessels, can cause disfigurement and even threaten children’s lives if the deformity impinges on essential body structures such as the airway.

“It can be lethal in 10 percent of people or more, and the problem is, we don’t know what’s the best treatment,” Lane told me.

Other treatments, such as surgery and sclerotherapy, are less effective than doctors would like: Afterward, the deformity often grows back.

A new publication from Lane’s team appeared this week in the Journal of the American Academy of Dermatology, reporting on the first seven patients to have their lymphangiomas treated with sildenafil. Though the idea of giving this drug to children might seem startling, it has a good safety profile and is already used in kids who have a form of high blood pressure in the lungs called pulmonary arterial hypertension. Lane realized that the medication might work for both PAH and lymphangioma when he treated a child with both conditions who was receiving the drug.

The new study shows mixed results. Six of the seven children responded to the medication, though not all responses were equally strong. One child’s deformity became worse while taking the drug. The team is now planning a larger, placebo-controlled, blinded study to investigate why they saw these differences.

“If we can identify which patients respond to sildenafil, we may get a better idea for the molecular mechanism of how it helps, and that could help us understand the disease more,” Lane said.

His team has applied for an orphan disease grant through the National Institutes of Health and the U.S. Food and Drug Administration and will find out in the fall if they’ve been funded.

Previously: Viagra may treat rare childhood deformity

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