Genetic Mutations Tested In Zebrafish

The zebrafish is a potential tool for testing one class of unique individual genetic differences found in humans, and may yield information helpful for the emerging field of personalized medicine, according to a team led by Penn State College of Medicine scientists. The differences, or mutations, in question create minor changes in amino acids -- the building blocks of DNA -- from person to person. Zebrafish can be used as a model to understand what biological effects result from these genetic mutations.

Personalized medicine uses modern technology and tools to find biological and genetic differences in individuals so that treatment is more effectively delivered.

"A major challenge of personalized medicine is the lack of a standard way to define the importance of each of the many unique mutations found in an individual's genetic code," said Keith Cheng, M.D., Ph.D., professor of pathology and lead researcher. "Approaches are particularly needed to experimentally determine what differences these mutations make. It is difficult to distinguish the effects of a single amino acid change caused by those changes in our DNA."

The zebrafish is a good choice because of its similarity to humans as a vertebrate, its transparency as an embryo and the powerful genetic tools available in this model organism.

The Cheng lab's approach is like testing small damages in car parts, one at a time. For example, a "mutant" car headlight is known not to work when a certain connector is missing. Taking a normally functioning connector out of a working headlight and replacing it with a connector damaged in a specific way -- a cracked wire casing or a corroded wire connector, for example -- can show whether the damage matters. If the light works, then that mutation makes no difference on the function of the headlight. If the light does not work, the mutation has an effect.

Postdoctoral fellow Zurab Tsetskhladze, who performed the zebrafish experiments, tested this method with two genes that affect skin color. He started with an equivalent of the broken car part: mutant zebrafish with lighter pigment cells. First, Tsetskhladze confirmed that by injecting normal messenger RNA (ribonucleic acid) into the mutant zebrafish, the lighter pigment cells become "cured" -- or darker -- like those of a normal zebrafish. Messenger RNA makes the cells produce the protein the scientists want to study.

Tsetskhladze was then able to test RNA with only one "human" mutation to see if cure was still possible. Cure suggests that the mutation does not matter. If cure is prevented by the mutation, the conclusion is that the protein's function is affected by the amino acid difference being tested.

Cheng's lab works with zebrafish to study genetic differences that contribute to human skin color. Scientists want to determine the role these differences play in the development of skin cancer, and to find ways to better protect people from cancer.

In the current study, two of the amino acid differences that Cheng has shown in prior studies to contribute to light skin color in humans prevented the zebrafish color from darkening. A third amino acid difference that is common in Eastern Asians was of unknown effect. The researchers found that the change made no difference in function in zebrafish. This finding matched the findings of K.C. Ang, postdoctoral fellow, who found no effect of the tested change on the skin color of East Asians.

To see if this approach might be used in other ways, Stephen Wentzel, graduate student, Penn State College of Medicine, looked at mutations in the four genes known to contribute to albinism, which lightens the color of skin, eyes and hair, and is associated with any one of more than 250 known single amino acid differences. He found that at least 210 of these are theoretically testable in the zebrafish. This new test may help scientists to determine which mutations can be ignored and which may need action - such as a change in life habit.

"This approach may potentially be extended to other biological functions and may therefore be useful in personalized medicine," Cheng said.

Fighting Melanoma's Resistance To Chemotherapy

Blocking the action of a particular protein in our skin could improve the treatment of skin cancers, according to a study published in Oncogene by Philippe Roux, a researcher at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC). "Our findings reveal part of the mechanisms responsible for the resistance of melanoma to anti-cancer treatments, and suggest that a particular protein in our bodies called RSK may be targeted in combination therapies to overcome drug resistance," Roux explained.

Although melanoma accounts for only 4% of all skin cancers, it is responsible for 80% of skin cancer-related deaths worldwide as it is highly invasive and resistant to conventional chemotherapies. Melanoma originates from pigment-producing cells, called melanocytes, located in the skin. The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy to treat it. Approximately 160,000 new cases of the disease are diagnosed each year.

Roux and his team focused their research on a signaling pathway called Ras/MAPK, which is often deregulated in melanoma, but also in lung, colon and pancreatic cancers. A signaling pathway is a chemical chain reaction that causes the cells in our bodies to act in a certain way. In this study, Roux and his team found that a protein in the Ras/MAPK pathway, RSK, contributes to chemoresistance by altering the response of cancer cells to chemotherapeutic agents.

This is the second Oncogene publication for Philippe Roux this year. In a paper published in July, Roux and his colleagues, IRIC Principal Investigators Katherine Borden and Sylvain Meloche, demonstrated that the same protein involved in chemoresistance contributes to melanoma growth, making the protein RSK a promising therapeutic target for treating the disease.

How Patterns, Timing Of Sunlight Exposure Contribute To Skin Cancers

Researchers at Moffitt Cancer Center, the University of South Florida and the International Agency for Research on Cancer in France have studied the patterns and timing of sunlight exposure and how each is related to two nonmelanoma skin cancers - basal cell carcinoma and squamous cell carcinoma.

This study, published in the open-access journal BioMed Central, is the first case-control study to simultaneously evaluate identical patterns and timing of sunlight exposure as they are related to basal cell and squamous cell carcinomas in the same U.S. population with high annual ultraviolet radiation exposure. Patterns of sunlight exposure are continuous or intermittent, and timing refers to exposure during childhood, adulthood or both. It included 703 Florida residents - 218 with basal cell carcinoma, 169 with squamous cell carcinoma and 316 without skin cancer. The research goal was to identify potential differences or similarities in sunlight exposure responses for basal cell and squamous cell carcinomas.

"There are more than a million new cases of basal cell and squamous cell carcinomas diagnosed in the United States each year," said senior study author Dana E. Rollison, Ph.D., associate member of the Cancer Epidemiology Program, and vice president and chief health information officer at Moffitt. "While mortality associated with nonmelanoma skin cancers, such as basal cell and squamous cell carcinomas, is low, patients may experience substantial morbidity and treatment costs are high."

It is estimated that 25 percent of lifetime sunlight exposure occurs before age 18. Youth is a time of greater toxic sunlight exposure and also a time when the chances of receiving blistering sunburns are higher.

"Blistering sunburn is believed to result from high doses of intense ultraviolet radiation exposure in short increments of time and is considered to be a measure of intermittent exposure," said study co-author Michelle Iannacone, Marie Curie postdoctoral fellow at the International Agency for Research on Cancer.

The researchers surveyed those with basal cell and squamous cell carcinomas, as well as those with no history of skin cancer, to determine the effects of intermittent versus continuous sunlight exposure, as well as the timing of the exposure and age. They noted that although the relationship between both cancers and sunlight exposure is complex, researchers began to identify cumulative outdoor sunlight exposure as a risk factor for nonmelanoma skin cancer beginning in the 1950s.

Being exposed to ultraviolet radiation intermittently, perhaps while on summer vacation in high ultraviolet radiation regions, and continuous exposure through working at a job outside in the sunlight were patterns the researchers wanted to identify and correlate to basal cell and squamous cell carcinomas.

Study subjects were surveyed on their recollections of their history of sun exposure.

Survey results reveal that a history of blistering sunburn was associated with both basal cell and squamous cell carcinomas. Having a job in the sunlight was also associated with basal cell and squamous cell carcinomas. Measures of younger age at sunlight exposure "tended to be associated with squamous cell carcinoma, but not basal cell carcinoma, risk," researchers concluded.

"Sunlight exposure, regardless of the exposure pattern, is associated with both basal cell and squamous cell carcinomas," Iannacone said. "Understanding how sunlight exposure response may differ by nonmelanoma skin cancer type is important for educating the public on safe sunlight behaviors. Applying sunscreen while on vacation may decrease basal cell carcinoma risk with intermittent sunlight exposure, but may not impact the risk of squamous cell carcinoma, which may be more strongly related to continuous sunlight exposure."

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Advanced Melanoma Tumors Eradicated In Mouse Model

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Cancers arise in the body all the time. Most are nipped in the bud by the immune response, not least by its T cells, which detect telltale molecular markers - or antigens - on cancer cells and destroy them before they grow into tumors. Cancer cells, for their part, evolve constantly to evade such assassination. Those that succeed become full-blown malignancies. Yet, given the right sort of help, the immune system can destroy even these entrenched tumors.

In the Journal of Experimental Medicine, researchers led by Jedd Wolchok, MD, PhD, of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York describe one way in which that might be achieved. The paper relates how the cancer drug cyclophosphamide (CTX) and OX86 - an antibody that activates a molecule named OX40 on T cells - were combined with a cutting-edge therapy known as adoptive T cell transfer to eradicate advanced melanoma tumors in mice.

Wolchok and his colleagues had previously shown that CTX and OX86 treatment caused the regression of such tumors. Now they wanted to see if adding T cell transfer to the mix would further improve outcomes. T cell transfer is an investigative immunotherapy in which T cells that target tumors are isolated from patients, manipulated, expanded and then transfused back into those patients.

A variety of T cells are of relevance to this approach. One is the CD8

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Genetic Mutations Tested In Zebrafish

The zebrafish is a potential tool for testing one class of unique individual genetic differences found in humans, and may yield information helpful for the emerging field of personalized medicine, according to a team led by Penn State College of Medicine scientists. The differences, or mutations, in question create minor changes in amino acids -- the building blocks of DNA -- from person to person. Zebrafish can be used as a model to understand what biological effects result from these genetic mutations.

Personalized medicine uses modern technology and tools to find biological and genetic differences in individuals so that treatment is more effectively delivered.

"A major challenge of personalized medicine is the lack of a standard way to define the importance of each of the many unique mutations found in an individual's genetic code," said Keith Cheng, M.D., Ph.D., professor of pathology and lead researcher. "Approaches are particularly needed to experimentally determine what differences these mutations make. It is difficult to distinguish the effects of a single amino acid change caused by those changes in our DNA."

The zebrafish is a good choice because of its similarity to humans as a vertebrate, its transparency as an embryo and the powerful genetic tools available in this model organism.

The Cheng lab's approach is like testing small damages in car parts, one at a time. For example, a "mutant" car headlight is known not to work when a certain connector is missing. Taking a normally functioning connector out of a working headlight and replacing it with a connector damaged in a specific way -- a cracked wire casing or a corroded wire connector, for example -- can show whether the damage matters. If the light works, then that mutation makes no difference on the function of the headlight. If the light does not work, the mutation has an effect.

Postdoctoral fellow Zurab Tsetskhladze, who performed the zebrafish experiments, tested this method with two genes that affect skin color. He started with an equivalent of the broken car part: mutant zebrafish with lighter pigment cells. First, Tsetskhladze confirmed that by injecting normal messenger RNA (ribonucleic acid) into the mutant zebrafish, the lighter pigment cells become "cured" -- or darker -- like those of a normal zebrafish. Messenger RNA makes the cells produce the protein the scientists want to study.

Tsetskhladze was then able to test RNA with only one "human" mutation to see if cure was still possible. Cure suggests that the mutation does not matter. If cure is prevented by the mutation, the conclusion is that the protein's function is affected by the amino acid difference being tested.

Cheng's lab works with zebrafish to study genetic differences that contribute to human skin color. Scientists want to determine the role these differences play in the development of skin cancer, and to find ways to better protect people from cancer.

In the current study, two of the amino acid differences that Cheng has shown in prior studies to contribute to light skin color in humans prevented the zebrafish color from darkening. A third amino acid difference that is common in Eastern Asians was of unknown effect. The researchers found that the change made no difference in function in zebrafish. This finding matched the findings of K.C. Ang, postdoctoral fellow, who found no effect of the tested change on the skin color of East Asians.

To see if this approach might be used in other ways, Stephen Wentzel, graduate student, Penn State College of Medicine, looked at mutations in the four genes known to contribute to albinism, which lightens the color of skin, eyes and hair, and is associated with any one of more than 250 known single amino acid differences. He found that at least 210 of these are theoretically testable in the zebrafish. This new test may help scientists to determine which mutations can be ignored and which may need action - such as a change in life habit.

"This approach may potentially be extended to other biological functions and may therefore be useful in personalized medicine," Cheng said.

View the Original article

Fighting Melanoma's Resistance To Chemotherapy

Blocking the action of a particular protein in our skin could improve the treatment of skin cancers, according to a study published in Oncogene by Philippe Roux, a researcher at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC). "Our findings reveal part of the mechanisms responsible for the resistance of melanoma to anti-cancer treatments, and suggest that a particular protein in our bodies called RSK may be targeted in combination therapies to overcome drug resistance," Roux explained.

Although melanoma accounts for only 4% of all skin cancers, it is responsible for 80% of skin cancer-related deaths worldwide as it is highly invasive and resistant to conventional chemotherapies. Melanoma originates from pigment-producing cells, called melanocytes, located in the skin. The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy to treat it. Approximately 160,000 new cases of the disease are diagnosed each year.

Roux and his team focused their research on a signaling pathway called Ras/MAPK, which is often deregulated in melanoma, but also in lung, colon and pancreatic cancers. A signaling pathway is a chemical chain reaction that causes the cells in our bodies to act in a certain way. In this study, Roux and his team found that a protein in the Ras/MAPK pathway, RSK, contributes to chemoresistance by altering the response of cancer cells to chemotherapeutic agents.

This is the second Oncogene publication for Philippe Roux this year. In a paper published in July, Roux and his colleagues, IRIC Principal Investigators Katherine Borden and Sylvain Meloche, demonstrated that the same protein involved in chemoresistance contributes to melanoma growth, making the protein RSK a promising therapeutic target for treating the disease.

View the Original article

Michigan State announces epic 'Gran Fondo' cycling event for 2013 to fund skin cancer research

Bicyclists will want to start training big time for a monstrous new event starting next year, where a good cause will be worth feeling the burn.

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Top medical innovations address headache, diabetes, cancer

The best medical innovations for next year include an almond-size device that's implanted in the mouth to relieve severe headaches and a hand-held scanner resembling a blow dryer that detects skin cancer, the Cleveland Clinic said on Wednesday.

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Health Matters: New Drug for High Risk Basal Cell Skin Cancer

"They have found different spots, mostly on my arms and on my back, from being out in the sun when I was younger," says Bob Davies, who battles with basal cell carcinoma.

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Routine blood test predicts prognosis in aggressive skin cancer

A routine blood test may help predict survival in patients with an aggressive form of skin cancer known as Merkel cell carcinoma, according to new findings by Fox Chase Cancer Center researchers.

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Pigment find may help cancer fight

The type of skin pigment found in red-haired and fair-skinned people may contribute to the development of melanoma, a finding which could lead to new skin cancer prevention methods, a study has found.

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Trial Of Genetically Engineered Immune System To Fight Melanoma

Main Category: Melanoma / Skin Cancer
Also Included In: Genetics;  Immune System / Vaccines
Article Date: 04 Oct 2012 - 0:00 PDT



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