A Possible Cure for Baldness, in 3D.


 
Set the ball rolling. Human skin cells grown on a flat culture remain dispersed and unable to induce the formation of hair follicles (left). But in a 3D culture, the cells form spheres that can coax new hair follicle growth (right).

Christiano lab, Columbia University

Set the ball rolling. Human skin cells grown on a flat culture remain dispersed and unable to induce the formation of hair follicles (left). But in a 3D culture, the cells form spheres that can coax new hair follicle growth (right).

Scientists have successfully grown new hair follicles from the skin cells of balding men. While the research team hasn’t yet shown whether the structures, which produce strands of hair on our bodies, are fully functional and usable for transplants onto a scalp, experts say the discovery is a significant step toward finding new treatments for hair loss.

“Their work is very elegant and extremely rigorous,” says Radhika Atit, a skin biologist at Case Western Reserve University in Cleveland, Ohio, who was not involved in the new study. “This is a big technical advance.”

Balding occurs when hair follicles stop producing new strands of hair in any area of the body. Now, taking drugs that prevent or slow the hair loss or transplanting hair follicles from one area of the body to another are the only viable treatments. Producing new hair follicles in the lab has not been an option—at least for human patients. In mice, researchers have shown that if they isolate dermal papilla cells, which surround hair follicles in the skin, grow them in petri dishes to produce new cells, and then put the cells back in the mouse, new hair follicles will develop. But when dermal papilla cells from humans are put into dishes in the lab, they lose their ability to induce the formation of new follicles.

Angela Christiano, a skin researcher at Columbia University who has discovered genes related to hair loss, recently brainstormed potential solutions to the problem with her colleagues. They noticed that while the dermal papilla cells from mice naturally formed large clumps in culture, the human cells didn’t. “We began thinking that maybe if we could get the human cells to aggregate like the mouse cells, that might be a step toward getting them to form new follicles,” Christiano says.

Her team decided to try a cell-growing approach, called 3D cultures, that’s been successful for other types of cells that need to form complex structures as they grow. The researchers collected dermal papilla cells from seven volunteers who had been diagnosed with male-pattern baldness. Rather than stick the isolated cells on a flat culture dish, they mixed the cells with liquid, then let the mixture hang in tiny droplets from a plastic lid, like condensation on the roof of a container. Because the cells inside the droplets are free-floating, the technique allows them to contact each other in every direction, as they would in the human body, rather than only touch side to side as they do in a flat dish. In the droplets, the cells behaved differently; as they divided to form new cells, they clumped into what the researchers call “spheroids”—balls of about 3000 cells.

To test whether the new spheroids were a better mimic for functional dermal papilla cells than those that had been grown in typical dishes, Christiano and her team determined what genes were turned on and off in different sets of dermal papilla cells. In cells grown on flat culture dishes, the expression of thousands of genes didn’t match up with their normal patterns, explaining why the cells from those dishes had been unable to generate new hair follicles. But in the 3D cultures, 22% of those genes had been restored to their correct on or off state.

The researchers then took 10 to 15 of the spheroids that had formed from each donor and sandwiched them between two layers of human skin that were grafted onto mice. Six weeks later,spheroids from five of the seven donors had coaxed the skin cells around them to start rearranging, forming the telltale shape of a hair follicle, the team reports online today in the Proceedings of the National Academy of Sciences. In two cases, hairs were even seen beginning to extend from the follicles, though the researchers didn’t continue the initial experiment for long enough to test whether the hairs were fully normal in terms of their ability to regrow.

Using one’s own cells to generate new follicles is useful because hair color and thickness will match perfectly with the rest of someone’s head of hair, Christiano notes. And with the new tissue culture technique, clinicians would be able to take just a few dermal papilla cells from a balding patient and expand the number of hair follicles available for transplant, rather than only be able to move follicles around. “Using this technique could change the number of people who would be eligible for hair transplants,” Christiano says.

The success of the approach is exciting, but the real breakthrough for other researchers in the field is the new data on gene expression in dermal papilla cells, says George Cotsarelis, a dermatologist at the University of Pennsylvania. The full readout of what genes are on and off in dermal papilla cells has never been collected before, so researchers now have a new list of thousands of genes to study further that may play key roles in hair follicle development. “It could have implications for not just hair, but treating wounds and scarring,” he says.

The spheroids capable of producing hair follicles could also be used as a new way to test drugs for their ability to restore follicle function, Atit says. “This is a better model system to use for drug testing than a two-dimensional plate.”

New Therapies Bring Progress Against Multiple Myeloma.


The 21st century has seen great strides in treatment for multiple myeloma, a cancer of the bone marrow once considered a death sentence. In fact, thanks to research by Dana-Farber scientists, this blood cancer that took the lives ofGeraldine Ferraro and Leonard P. Zakim has become a chronic disease for many patients.

Ken Anderson, MD, and his colleagues have helped transform multiple myeloma into a more manageable illness by shepherding many novel drugs from the laboratory to the patient bedside.

Over a decade ago, median survival in multiple myeloma was just 2 to 3 years. Today, James (Jim) Bond of Cleveland, Ohio, who bicycles across his home state every year to raise money for cancer research, has been living with multiple myeloma for 20 years. Bond credits Dana-Farber’s clinical trials for his longevity.

Multiple myeloma is estimated to strike 22,350 people in the U.S. in 2013. Although there is still no cure, Dana-Farber researchers have contributed to the following advances.

  • Velcade. In 2003, the FDA approved a drug called bortezomib (Velcade), which today is standard treatment for newly diagnosed myeloma, thanks to research conducted by Anderson,Paul Richardson, MD, and their colleagues at Harvard Medical School and elsewhere.
  • Studying the tumor’s “neighborhood.” Around the time that Velcade was approved, Anderson and his team were also investigating the drug thalidomide (Thalomid) as a treatment for myeloma. They explored the effect of medications not just on the tumor cells but also on those surrounding the tumor, including non-cancerous immune and other cells.
  • Thalidomide, Revlimid and Pomalidomide. Anderson and his team discovered that thalidomide and its close cousin lenalidomide (Revlimid) actively recruit immune cells to fight cancer. Clinical trials led by Richardson and colleagues set the stage for the approval of lenalidomide to treat advanced myeloma in 2006. The most potent immunomodulator studied by both the laboratory and clinical team to date, called pomalidomide (Pomalyst), was approved in February 2013.
  • Combination drugs. Because many genetic mutations drive a single tumor, cancer is often best treated with combinations of therapies. Dana-Farber researchers hope to personalize multiple myeloma treatment by categorizing patients based on the molecular pathways that drive their cancer, and prescribe the appropriate combinations of drugs.
  • Stem cell transplant. This procedure is still a key component of treatment for multiple myeloma.  DF/BWCC is a leading provider of stem cell transplantation, which involves giving the patient healthy bone marrow harvested from his or her own stem cells, or sometimes those of a donor.

Source: dana-farber.org

Studies Cast Doubt on Cancer Drug as Alzheimer’s Treatment.


studies-cast-doubt-cancer-drug-alzheimers_1

Four labs can’t replicate finding that showed large-scale clearance of disease-related plaques. Some hope remains for improving memory

Bexarotene, a cancer drug touted as a potential treatment for Alzheimer’s disease, may not be the blockbuster remedy scientists were hoping for, according to several analyses published in Science on 24 May. Four independent research groups report that they failed to fully replicate striking results published in the journal last year by Gary Landreth, a neuroscientist at Case Western Reserve University School of Medicine in Cleveland, Ohio, and his colleagues.

Landreth’s team reported that the drug bexarotene could lower brain concentrations of the β-amyloid protein that has long been suspected as a key contributor to Alzheimer’s disease, and could even reverse cognitive impairments in diseased mice. But the study garnered particular attention for its claim that the drug could clear 50% of amyloid plaques — sticky clumps of the protein thought to interfere with brain function — in as little as 72 hours.

“That attracted a lot of folks to try to replicate these studies,” says Philip Wong, a neuroscientist at Johns Hopkins University in Baltimore, Maryland. “No drug at the present moment can do things like that.”

None of the follow-up studies published this week replicated the effects of bexarotene on plaques. Two groups did, however, confirm Landreth’s finding that the drug reduced levels of a soluble, free-floating form of β-amyloid, which can aggregate in plaques.

Not all of the papers examined memory in mice, but one group led by Radosveta Koldamova, a neuroscientist at the University of Pittsburgh in Pennsylvania, found that bexarotene treatment led to cognitive improvements.

Sticking points
“It was our expectation other people would be able to repeat this,” says Landreth about the results of the studies. “Turns out that wasn’t the case, and we fundamentally don’t understand that.” He suggests that the other groups might have used different drug preparations that altered the concentration of bexarotene in the brain or even changed its biological activity.

In a response published alongside the comment articles, Landreth emphasizes that some of the studies affirm two key conclusions of the original paper: the lowering of soluble β-amyloid levels and the reversal of cognitive deficits. He says that the interest in plaques may even be irrelevant to Alzheimer’s disease. In the past ten years, some neuroscientists have begun to question whether it is plaques or soluble β-amyloid proteins that are most dangerous to brain health.

As the debate over plaques continues, Koldamova says that the cognitive improvement she and Landreth observed suggests that bexarotene is still very promising. “Patients don’t go to the doctor because they have plaques. They go because they have memory decline,” she says.

Ethical dilemma
Other researchers say the contradictory results suggest that much more basic research is needed before bexarotene is used to treat Alzheimer’s. “The mechanism of action behind bexarotene has not been proven,” says Kevin Felsenstein, a neuroscientist at the University of Florida College of Medicine in Gainesville, and a co-author of one of the dissenting papers. Felsenstein’s group found no evidence that bexarotene lowered levels of soluble or plaque forms of β-amyloid protein.

Felsenstein worries that interest in Landreth’s original results could lead to misuse of the drug because, unlike many experimental treatments, it is already on the market. The US Food and Drug Administration has approved bexarotene to treat skin cancer.

In August 2012, The New England Journal of Medicine published an article anticipating growing demand for unauthorized prescriptions of bexarotene as an Alzheimer’s treatment and urging physicians to wait for evidence from human clinical trials.

Physicians and researchers may get some answers soon: Landreth’s group has begun an early clinical trial to test the drug in healthy participants.

Source: scientificamerican.com

 


Diabetes: Is It Now a Surgical Disease?

Hi. I’m Dr. Henry Black. I’m Clinical Professor of Internal Medicine at the New York University School of Medicine, a member of the Center for the Prevention of Cardiovascular Disease at that institution, and former President of the American Society of Hypertension. If I had said 10 years ago that diabetes was going to become a surgical disease, I think I would have been laughed off the stage; yet, increasing evidence shows that this may not be a completely far-out idea. Two very small but important studies were recently published in the New England Journal of Medicine, one from the Cleveland Clinic[1] and one from Italy.[2] Both of them looked at people with high body mass index (BMI). BMIs were somewhat lower in the Cleveland Clinic study, with an average of about 34; in the Italian study, the average BMI was 45 and the average weight was about 300 lb. The investigators compared intensive medical therapy given by experts with surgical approaches. The Cleveland study looked at sleeve gastrectomies and bypass, and the Italian study compared intensive medical therapy (including exercise, which wasn’t specifically done in the Cleveland Clinic study) with ileojejunostomy and bypass.

The results were strikingly similar. These were small studies; there were about 20 patients per group in the Italian study and about 50 per group in the Cleveland Clinic study. They both showed dramatic reductions in weight that were generally seen within 3 months. Patients were followed for 1 year in Cleveland and 2 years in the Italian study, and a significant improvement in all the metabolic parameters that we follow in diabetics — including lipids, hemoglobin A1c, and even blood pressure — happened before the weight loss was completely achieved. Patients with jejunostomy and bypass were able to be taken off diabetic medicines and, in some cases, lipid-lowering therapy, something that was never seen in patients who received only medical therapy.

This implies that we have to start thinking about using one of these techniques sooner until we can find a way to deliver behavioral therapy that people will follow. There is no question that some things in this study are not necessarily generalizable. The Cleveland Clinic study had a single surgeon and the Italian study had teams that were well trained. We don’t know whether this is going to translate into every surgeon in every community, but it is an important thing to bear in mind. We also have to do some assessment of outcomes.

These were very small studies. Reoperations were necessary in both studies, but there were no fatalities. BMIs went to under 30 in the Italian study and were similar in the Cleveland Clinic study. It’s time for those of us who see obese patients with diabetes to start talking about this as something that is getting close to being proven. An old Swedish study[3] showed outcome improvement with what was more complicated surgery than we are doing now. Also, how are we going to better deliver behavioral therapy? This is something the public needs to know and needs to know now. Thank you.

References

  1. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366:1567-1576. Abstract
  2. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577-1585. Abstract
  3. Sjostrom L, Lindroos AK, Peltonen M, et al; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351:2683-2693. Abstract

Source: Medscape.com