Tag: Dermatology

The study, published in Nature Communications, highlights an innate sensing of bacteria by immune cells in the formation of skin tumours. This molecular process could tip the balance between normal wound repair and tumour formation in some patients, according to researchers. Although an association between tissue damage, chronic inflammation and cancer is well established, little is known about the underlying cause. Epidermolysis Bullosa (EB), for instance, is one of several rare inherited skin conditions associated with chronic wounding and increased risk of tumours. However, this study — funded primarily by the Medical Research Council (MRC) and the Wellcome Trust — is the first to demonstrate that bacteria present on the skin can contribute to the development of skin tumours. Researchers found that when mice with chronic skin inflammation are wounded they develop tumours at the wound site, with cells of the immune system required for this process to take place. They discovered that the underlying signalling mechanism involves a bacterial protein, flagellin, which is recognised by a receptor (Toll-like receptor 5) on the surface of the immune cells. Although the direct relevance to human tumours is yet to be tested, researchers have shown that a protein called HMGB1 — found to be highly expressed in mice with chronic skin inflammation — is increased in human patients with Epidermolysis Bullosa (EB). The study found a reduction in HMGB1 levels in mice when the TLR-5 receptor was removed from immune cells. This raises the possibility of future treatments aimed at reducing levels of the flagellin bacterial protein on the skin surface, or targeting the TLR-5 receptor. Professor Fiona Watt, lead author and Director of the Centre for Stem Cells and Regenerative Medicine at King’s College London, said: ‘These findings have broad implications for various types of cancers and in particular for the treatment of tumours that arise in patients suffering from chronic ulcers or skin blistering diseases. ‘In the context of chronic skin inflammation, the activity of a particular receptor in white blood cells, TLR-5, could tip the balance between normal wound repair and tumour formation.’ Professor Watt added: ‘Our findings raise the possibility that the use of specific antibiotics targeting bacteria in wound-induced malignancies might present an interesting clinical avenue.’

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/01/150109084723.htm Original web page at  Science Daily

Brief, acute psychological stress promoted healing in mouse models of three different types of skin irritations, in a study led by UC San Francisco researchers. The scientists found that healing was brought about by the anti-inflammatory effects of glucocorticoids — steroid hormones — produced by the adrenal glands in response to stress. “Under chronic stress, these same naturally-occurring steroids damage the protective functions of normal skin and inhibit wound healing, but during shorter intervals of stress, they are beneficial for inflammatory disorders and acute injury in both mice and humans,” said senior investigator Peter Elias, MD, a UCSF professor of dermatology based at the San Francisco VA Medical Center (SFVAMC). “We believe that our findings explain why this otherwise harmful component of the stress response has been preserved during human evolution,” he said. The study was published online in the Journal of Investigative Dermatology on August 7, 2014, in advance of print publication in the journal. The scientists studied mouse models of three types of common skin irritations: irritant contact dermatitis, caused by exposure to an irritant such as a soap or solvent; acute allergic contact dermatitis, of the sort caused by poison ivy or poison oak; and atopic dermatitis, or eczema. After exposure to irritants on a small patch of skin on one ear, one group of mice was returned to its regular cages, while another group was put in a stressful situation — being placed in very small enclosures for 18 hours a day over the course of four days. The researchers found that the stressed mice showed significantly reduced inflammation and faster healing in all three types of skin irritation. When stressed mice were simultaneously given mifepristone, which blocks steroid action, all of the healing benefits of stress disappeared. “This demonstrated the central role of internal steroids in providing these benefits,” said Elias. He noted that other researchers have recently proposed that psychological stress has a potential role in promoting healing, “but that work has focused on the immune system rather than glucocorticoids as the responsible, beneficial mediator.” According to Elias, the study provides a clue to an evolutionary puzzle: why, over millions of years, humans have preserved the tendency to produce steroids under stress. Previous research by Elias’s laboratory and others has demonstrated that prolonged exposure to steroids harms both the structure and function of skin and other organs.

“Our ancestors did not have an arsenal of pharmaceutical steroids available to treat acute illnesses or injuries,” Elias observed. “This safe, effective internal anti-inflammatory system provides just the correct amount of steroids to promote healing, over a time interval that is too short to cause harm.” Elias emphasized that the study did not look at the implications for human medical treatments. However, he contrasted the “substantial benefits” seen from modest increases in glucocorticoid levels brought on by short-term stress with the “adverse effects that we see all too commonly” with steroid therapy. Elias speculated that those negative effects could be the result of “overly aggressive treatment — too high doses, and perhaps for unnecessarily prolonged treatment intervals.” He said that while his research team did not study other kinds of inflammatory disorders, “the same benefits of psychological stress should accrue in any acute illness or injury.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/08/140807104309.htm  Original web page at Science Daily

A cure for type 1 diabetes has long eluded even the top experts. Not because they do not know what must be done — but because the tools did not exist to do it. But now scientists at the Gladstone Institutes, harnessing the power of regenerative medicine, have developed a technique in animal models that could replenish the very cells destroyed by the disease. The team’s findings, published online in the journal Cell Stem Cell, are an important step towards freeing an entire generation of patients from the life-long injections that characterize this devastating disease. Type 1 diabetes, which usually manifests during childhood, is caused by the destruction of ß-cells, a type of cell that normally resides in the pancreas and produces a hormone called insulin. Without insulin, the body’s organs have difficulty absorbing sugars, such as glucose, from the blood. Once a death sentence, the disease can now be managed with regular glucose monitoring and insulin injections. A more permanent solution, however, would be to replace the missing ß-cells. But these cells are hard to come by, so researchers have looked towards stem cell technology as a way to make them. “The power of regenerative medicine is that it can potentially provide an unlimited source of functional, insulin-producing ß-cells that can then be transplanted into the patient,” said Dr. Ding, who is also a professor at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. “But previous attempts to produce large quantities of healthy ß-cells — and to develop a workable delivery system — have not been entirely successful. So we took a somewhat different approach.”

One of the major challenges to generating large quantities of ß-cells is that these cells have limited regenerative ability; once they mature it’s difficult to make more. So the team decided to go one step backwards in the life cycle of the cell. The team first collected skin cells, called fibroblasts, from laboratory mice. Then, by treating the fibroblasts with a unique ‘cocktail’ of molecules and reprogramming factors, they transformed the cells into endoderm-like cells. Endoderm cells are a type of cell found in the early embryo, and which eventually mature into the body’s major organs — including the pancreas. “Using another chemical cocktail, we then transformed these endoderm-like cells into cells that mimicked early pancreas-like cells, which we called PPLC’s,” said Gladstone Postdoctoral Scholar Ke Li, PhD, the paper’s lead author. “Our initial goal was to see whether we could coax these PPLC’s to mature into cells that, like ß-cells, respond to the correct chemical signals and — most importantly — secrete insulin. And our initial experiments, performed in a petri dish, revealed that they did.” The research team then wanted to see whether the same would occur in live animal models. So they transplanted PPLC’s into mice modified to have hyperglycemia (high glucose levels), a key indicator of diabetes.

“Importantly, just one week post-transplant, the animals’ glucose levels started to decrease gradually approaching normal levels,” continued Dr. Li. “And when we removed the transplanted cells, we saw an immediate glucose spike, revealing a direct link between the transplantation of the PPLC’s and reduced hyperglycemia.” But it was when the team tested the mice eight weeks post-transplant that they saw more dramatic changes: the PPLC’s had given rise to fully functional, insulin-secreting ß-cells. “These results not only highlight the power of small molecules in cellular reprogramming, they are proof-of-principle that could one day be used as a personalized therapeutic approach in patients,” explained Dr. Ding. “I am particularly excited about the prospect of translating these findings to the human system,” said Matthias Hebrok, PhD, one of the study’s authors and director of the UCSFDiabetesCenter. “Most immediately, this technology in human cells could significantly advance our understanding of how inherent defects in ß-cells result in diabetes, bringing us notably closer to a much-needed cure.”

http://www.sciencedaily.com/  Science Daily March 4, 2014

http://www.sciencedaily.com/releases/2014/02/140206133640.htm  Original web page at Science Daily

Researchers from the University of Southern Denmark have discovered that the skin is capable of communicating with the liver. The discovery has surprised the scientists, and they say that it may help our understanding of how skin diseases can affect the rest of the body. Professor Susanne Mandrup and her research group in collaboration with Nils Færgeman’s research group at the Department of Biochemistry and Molecular Biology at the University of Southern Denmark was actually studying something completely different when they made the groundbreaking discovery: That the skin, which is the body’s largest organ, can “talk” to the liver. “We have showed that the skin affects the metabolism in the liver, and that is quite a surprise,” say Susanne Mandrup and Ditte Neess, a former student in the Mandrup research group and now laboratory manager in Professor Nils Færgeman’s group. The phenomenon was observed in the researcher’s laboratory mice. The Mandrup and Færgeman groups work with so-called knock-out mice, in which a specific fat binding protein called acyl CoA binding protein has been removed (knocked out). Some knock-out mice produced by the researchers had a strange greasy fur, and they had difficulties being weaned from their mother. In the weaning period they gained less weight and showed a failure to thrive. Analyses also showed that the mice accumulated fat in the liver at weaning.

“At first we thought that the fat accumulation in the liver was linked with the fact that the gene was missing in the liver of the knock-out mice. But this was ruled out by a series of studies, and we had to find another explanation,” says Ditte Neess. She and her colleagues took another look at the rumpled and weak knock-out mice. Their fur was greasy, and they had a leaky skin from which they lost more water than normal mice. “When they lose water, they also lose heat. We therefore asked ourselves whether this water and heat loss could be the reason why the mice accumulated fat in the liver and became weak when weaned from their mother,” says Ditte Neess. To clarify this, the researchers made some mice that lacked the fat binding protein only in the skin. Similar to the full knockouts these mice had difficulties after weaning and accumulated fat in the liver. So this showed that the lack of the fat-binding protein in the skin was sufficient to induce accumulation of fat in the liver. To get to the bottom of how a defect in the skin “talks” to the liver, the researchers decided to cover the mice with Vaseline. This would prevent water evaporating from the skin and thus stopping the heat loss. As a result the fat accumulation in the liver disappeared. But as Vaseline contains fat, that could theoretically be absorbed by the skin or ingested by the mice, the researchers were a little unsure if there were side effects from the Vaseline. A student proposed to cover the mice with liquid latex, which she found in a local sex shop. Having covered the mice in blue latex the researchers saw that fat accumulation in the liver again disappeared. “We believe that the leaking of water from the skin makes the mice feel cold, and that this leads to breaking down of fat in their adipose (fat) tissue. The broken down fat is then moved to the liver. The mice move energy from the tissues to the liver,” Susanne Mandrup and Ditte Neess explain.

Science Daily
January 7, 2014

Original web page at Science Daily

The c-Fos oncogene has traditionally been linked to cellular activities related to cancer, such as cell division, differentiation — conversion from one cell type to another — or survival. Any alteration of these activities can set off the development of tumours, which has made c-Fos an important target for the understanding and treatment of cancer. A study led by Erwin Wagner, head of the F-BBVA-CNIO Cancer Cell Biology Programme and of the Genes, Development and Disease Group, has revealed a novel mechanism in which c-Fos is able to promote skin cancer: an increase in c-Fos expression in the skin stimulates the immune system, which induces the appearance of squamous cell carcinomas (SCCs), one of the most aggressive skin cancers. Another important result from this study is the observation in mice of a decrease in the progression of SCCs by using anti-inflammatory drugs, which block the immune response induced by c-Fos. The conclusions are published in the latest issue of the journal Genes and Development, and are featured on its cover. The classic way of looking at inflammatory immune response, which is more than 100 years old, asserts that defence mechanisms protect the organism when faced with neoplasms. This vision has given way over the last few years to new evidence that suggests chronic inflammation favours the proliferation and survival of tumour cells, thus increasing susceptibility to cancer.

“We know that there are cancers, like pancreatic, liver or colon cancer, in which the inflammatory component plays a very important role in the development of the disease,” says Juan Guinea-Viniegra, a researcher from Wagner’s team. Furthermore, inflammatory skin diseases, such as lupus or chronic ulcers, predispose patients to develop tumours, although for now the mechanisms responsible for this phenomenon had not been discovered. The research sheds light on this question for the first time. Eva Briso, first author of the study says: “We have discovered that mice that have higher c-Fos expression in the skin promote the recruitment of immune cells, known as CD4+T, leading to the development of skin lesions and carcinogenesis.” Briso adds that when mice were treated with anti-inflammatory drugs that specifically blocked CD4+T cell-mediated immune response, tumours decreased. Furthermore, the researchers analysed samples from nearly a hundred patients with SCCs, in which they found that up to 75% of the tumours displayed increased c-Fos expression, as well as an increase in inflammatory activity. These results open up the possibility of using anti-inflammatory drugs as a means of treating patients with this pathology. “If we find molecules that in patients are able to block this immune response, we could think about a new specific therapy for this disease,” says Wagner. Squamous cell carcinoma is a very aggressive type of skin cancer that can invade other tissues and form metastasis. It affects 16 out of every 100,000 people in Europe and is the type of skin cancer most related to sun exposure. Due to the few biological and molecular data available on the disease, the standard treatment is reduced to surgery and radiotherapy.

Science Daily
October 15, 2013

Original web page at Science Daily

For deer mice living in the Nebraska Sandhills, color can be the difference between life and death. When the dark-coated mice first colonized the region, they stood out starkly against the light-colored, sandy soil, making them easy prey for predators. Over the next 8,000 years, however, the mice evolved a system of camouflage, with lighter coats, changes in the stripe on their tails, and changes in body pigment that allowed them to blend into their habitat. Now Harvard researchers are using their example to answer one of the fundamental questions about evolution. Is it a process marked by large leaps — single mutations that result in dramatic changes in an organism — or is it the result of many smaller changes that accumulate over time? As described in a March 15 paper in the journal Science, a team of researchers, including former Harvard postdoctoral fellow Catherine Linnen, now an assistant professor at the University of Kentucky, and led by Hopi Hoekstra, Harvard professor of organismic and evolutionary biology and molecular and cellular biology, were able to show that the changes in mouse coat color were the result not of a single mutation but of at least nine mutations within a single gene.

“The findings demonstrate how the cumulative effect of natural selection, acting on many small genetic changes, can produce rapid and dramatic change,” said Linnen, the first author of the paper. “This helps us to understand, from a genetic perspective, the uncanny fit between so many organisms and their environments. By acting on many small changes, rather than a handful of large ones, natural selection can produce very finely honed adaptations.” Surprisingly, Hoekstra said, that honing occurred in a single gene. The role of this gene, called agouti, in camouflage was first discovered by Linnen, Hoekstra, and colleagues in 2009, and it is responsible for changes in pigmentation in the coats of many animals. Every domesticated black cat, for example, has a DNA deletion in the gene. What surprised Hoekstra and her team, however, wasn’t that the gene was involved, but that each of the nine mutations were tied to a unique change in the animal’s coats, that all the new mutations led to more camouflaging color, and that the mutations occurred in a relatively short, 8,000-year timeframe. “Essentially, it seems as though these mutations — each of which makes the mouse a little lighter and more camouflaged — have accumulated over time,” Hoekstra said. Focusing on these mutations, researchers then examined the DNA of natural populations of the mice to determine whether the mutations are actually beneficial.

“For each of the mutations associated with color change, we also find a signal that’s consistent with positive selection,” Hoekstra said. “That implies that each of the specific changes to pigmentation is beneficial. This is consistent with the story we are telling, about how these mutations are fine-tuning this trait.” While the findings offer valuable insight into the way that natural selection operates, Hoekstra said they also highlight the importance of following research questions to their ultimate end. “The question has always been whether evolution is dominated by these big leaps or smaller steps,” she said. “When we first implicated the agouti gene, we could have stopped there and concluded that evolution takes these big steps as only one major gene was involved, but that would have been wrong. When we looked more closely, within this gene, we found that even within this single locus, there are, in fact, many small steps.” Going forward, Hoekstra said, her team hopes to understand the order in which the mutations happened, which would allow it to reconstruct how the mice changed over time. “For evolutionary biologists, this is exciting because we want to learn about the past, but we only have data from the present to study it,” she said. “This ability to go back in time and reconstruct an evolutionary path is very exciting, and I think this data set is uniquely suited for this type of time travel.” Taking the time to understand not only which genes are involved but which specific mutations may be driving natural selection, Hoekstra said, can give researchers a much fuller picture of not only the molecular mechanisms by which mutations alter traits, but also the evolutionary history of an organism. “By doing this, we’ve discovered all kinds of new things,” she said. “While we often think about changes happening in the entire genome, our results suggest that even within a very basic unit — the gene — we can see evidence for evolutionary fine-tuning.”

Science Daily
April 2, 2013

Original web page at Science Daily

To pierce your skin, a porcupine quill needs only about half the force of a hypodermic needle, according to a new study. The work, which also explains why the quills are so hard to remove, could improve the design of a variety of medical instruments, from devices that poke us to those that help keep wounds shut. Porcupines are famed for their quills, which are actually large, stiff hairs that help defend the animals against natural predators. Contrary to popular notions, the large rodents can’t throw their quills at an enemy, says Jeffrey Karp, a bioengineer at Harvard Medical School in Boston. However, the quills are readily shed and can become firmly embedded in an unfortunate victim. The North American porcupine has about 30,000 quills, each one adorned with between 700 and 800 barbs along the 4 millimeters or so nearest its tip. Although those barbs help the quills remain embedded in a victim’s skin, scientists haven’t studied the details of how they do so. To better understand the function of the barbs and to determine if they might be useful for medical devices, Karp and his colleagues conducted several lab tests—with, in some cases, unexpected results.

The researchers took barbed porcupine quills and plunged them into samples of pig skin, measuring how much force it took to pierce the flesh and then how much force was required to extricate the quill. The team then performed the same tests using quills whose barbs they had sanded off. They also tested an African porcupine’s quills (which naturally have no barbs) and an 18-gauge hypodermic needle, which is approximately the same diameter as a quill from the North American porcupine. To the scientists’ surprise, barbed quills required approximately half the penetration force of the barbless quills—either those naturally barbless or those sanded clean—and only 56% of the force needed for the hypodermic needle to breach the skin. The researchers report their findings online today in the Proceedings of the National Academy of Sciences. Computer models suggest that the barbs ease the quill’s penetration by concentrating force along the edges of the barbs, similar to how the serrations on a knife blade make cutting meat easier, Karp says. Barbs render a quill about four times harder to pull out once they’re embedded, the team found. The barbs at the tip of the quill were most effective at resisting removal. In fact, the barbs located within 1 millimeter of the tip contributed about half of the pull-out resistance—possibly because the flesh more tightly surrounded the tip than it did the rest of the quill, Karp says.

The team’s findings could be used to enhance various biomedical devices or to design new ones, Karp says. For instance, he notes, rather than use wound dressings that rely on a chemical adhesive, which can trigger allergies or cause other problems, dressings could use tiny barbed needles to pierce the skin and then hold tight. Also, the staples now used to hold some surgical incisions shut—which largely rely on friction along their length to remain in the flesh—could be replaced by barbed staples that are shorter and have a smaller diameter. Even though porcupine quills cause some damage to flesh when they’re pulled out, extricating smaller, quill-inspired staples would likely cause less overall damage than pulling out the staples currently in use, Karp suggests. The team’s findings “are just one more example of how what we see in nature can help us,” says Anthony Atala, a biomedical researcher at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina. Hollow versions of quill-inspired needles could help doctors better deliver drugs or chemicals through patches adhering to the skin, he notes. “Now that we know how these barbs work, we can modify them to make devices perform even better.”

ScienceNow
January 8, 2013

Original web page at ScienceNow

A research team at the National Institutes of Health has found that bacteria that normally live in the skin may help protect the body from infection. As the largest organ of the body, the skin represents a major site of interaction with microbes in the environment. Although immune cells in the skin protect against harmful organisms, until now, it has not been known if the millions of naturally occurring commensal bacteria in the skin — collectively known as the skin microbiota — also have a beneficial role. Using mouse models, the NIH team observed that commensals contribute to protective immunity by interacting with the immune cells in the skin. Their findings appear online on July 26 in Science. The investigators colonized germ-free mice (mice bred with no naturally occurring microbes in the gut or skin) with the human skin commensal Staphylococcus epidermidis. The team observed that colonizing the mice with this one species of good bacteria enabled an immune cell in the mouse skin to produce a cell-signaling molecule needed to protect against harmful microbes. The researchers subsequently infected both colonized and non-colonized germ-free mice with a parasite. Mice that were not colonized with the bacteria did not mount an effective immune response to the parasite; mice that were colonized did.

In separate experiments, the team sought to determine if the presence or absence of commensals in the gut played a role in skin immunity. They observed that adding or eliminating beneficial bacteria in the gut did not affect the immune response at the skin. These findings indicate that microbiota found in different tissues — skin, gut, lung — have unique roles at each site and that maintaining good health requires the presence of several different sets of commensal communities. This study provides new insights into the protective role of skin commensals and demonstrates that skin health relies on the interaction of commensals and immune cells. Further research is needed, say the authors, to determine whether skin disorders such as eczema and psoriasis may be caused or exacerbated by an imbalance of skin commensals and potentially harmful microbes that influence the skin and its immune cells.

Science Daily
August 7, 2012

Original web page at Science Daily