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Self-effacing and funny, Sharpless can discuss his research with anyone and make it interesting. But those attributes aren't what earned him his new job as director of the UNC Lineberger Comprehensive Cancer Center. A first-class researcher with exceptional leadership skills and a penchant to think well beyond the next grant or paper, Sharpless is an innovator and entrepreneur whose research inspired the creation of two companies aimed at helping people in his home state of North Carolina and around the world.
We sat down with Dr. Sharpless two weeks before he took the helm at UNC Lineberger on January 1 to ask him about his journey from UNC as an undergraduate to UNC as a professor and now director of a research organization with 300 scientists from 25 departments across campus. What follows is the story of how Dr. Sharpless landed at the helm of one of the nation's oldest and largest cancer centers.
Why did you pursue math as an undergraduate and then go to medical school, both at UNC, and then choose to become a cancer researcher?
My undergrad and early med school careers were characterized by a strong lack of planning. I was a bit immature for my age. Many people have a plan, and they're on a mission to get something done. I wasn't really like that, though I did like college. I was initially an English and math major but that became unworkable. At some point, it became easier to fulfill my major requirements for math.
I remember in some upper level math classes, they gave us two problems and a week to do them. That was really fun. No one could help you; there was no internet back then. You really had to figure it out yourself. But I also loved physics, English, and political science. I just had a great, well-rounded education at UNC, and I still believe in that. I think that writing essays on Shakespeare as an English major has helped me to write crisp, clear, terse explanations of my science, and that's really good for grants and scientific papers.
As for medical school, well, I was a pretty good undergraduate student but I didn't work in a lab, or shadow a physician, or volunteer in the hospital. I wasn't 100 percent sold on the idea of being a doctor, though deep down I think I knew I'd always become a doctor. My parents were physicians and I knew what that life was like.
During my senior year, I applied to the Peace Corps but didn't quite fill out the application correctly. Also—this was the 80's—I applied to work at investment banks, which back then were looking for mathematicians. They paid these absurdly high salaries, but they worked you to the bone and most people quit in despair. That also didn't work out. So I had two choices: take a gap year or go to medical school. I had applied to a couple of medical schools and only got into one of them: thank goodness for UNC.
When it comes to research, the really formative year was when I took a year off from med school to work at the National Institutes of Health as part of the Howard Hughes Medical Institute NIH Research Scholars Program. Within two weeks, I was telling people that science was what I was going to do. This was the first time I ever did any biomedical research. It was almost like being an artist, but at the same time it was data driven and you got to use math and talk to people. You could work at 3 a.m. if you wanted. I had total control of my life. The experience just appealed to everything about me.
I worked on AIDS and HIV. I was first author on two papers as a medical school student. Six months in at NIH, I was telling people that this was the best year of my life. There were about 30 of us in that program; these were clearly my people. Some of them are still my closest friends.
My third year back at medical school after the NIH, that's when you really learn how to be a doctor. I enjoyed it and I think I got pretty good at being a doctor, but for the rest of my training, I was one those residents who would sneak off to the library to read the journal Cell. I really had the research bug.
You were in Boston for ten years as an intern, resident, instructor, physician, and a research fellow. What was the most rewarding part of your time there, and did you always plan to or want to return to UNC?
The best part of my 10 years in Boston was when I ended up in Ron DePinho's lab. He's now the president at MD Anderson Cancer Center in Houston. Back then he had just started his lab at Dana-Farber Cancer Institute at Harvard Medical School. This is when I learned how to become an independent scientist and that's because Ron was a great boss. He not only trained us how to be scientists and get our experiments to work, but how to manage people, write grants, write papers, how to handle editors—real world skills at which he particularly excelled.
It was exhilarating but scary. I remember waking up at 3 a.m. terrified that I was out of my depth. I would go run in the snow—in Boston, in February—and when I returned home my wife would say, "What are you doing? You're crazy" And I'd say, "I just couldn't sleep." Running has always been how I decompress.
As for UNC, no, I didn't plan on coming back. I was in Ron's lab, productive and happy and learning from great scientists at Harvard. When I got a job offer after I published some papers, Ron wasn't fully supportive at first because he thought I should stay in the lab a few more years. But to his credit, he said, "Well if you're going to look at one job, you better look at five. Because if you look at one, you'll get a crummy offer and you'll take it and it will be a career-ender."
So he made some calls and put me on a plane. My first interview was at a prestigious school of medicine in the Midwest. Before I went, I told Ron I was just testing the waters, but I wasn't serious about leaving his lab. That was on a Thursday. On Monday, I marched back into his office and told him, "I'm out of here." Once I saw what sort of lab resources I could have and what life would be like as an independent scientist, it was hard to refuse.
Ron and my clinical mentor Bob Mayer (now Dean of Harvard Medical School Admission) recommended several schools as a good place for me to start as junior faculty, and the only one on both of their lists was UNC.
Ron knew that UNC had a terrific history of mouse cancer genetics with people like Oliver Smithies, Terry Van Dyke, and Terry Magnuson. And Bob knew that UNC Lineberger was a really special place. He was on the advisory board for a while and knew that this place was on a great trajectory. And I probably wouldn't have considered UNC had Ron and Bob not recommended it because when I left here in 1993, it was kind of sleepy in terms of cancer research. A couple doctors were putting people in clinical trials, but UNC wasn't the research juggernaut that it became throughout the decade I was gone.
While I had been away, they built all these research buildings and really began funding basic science. I hadn't been aware of that. So when I came back for a job interview, I was impressed. I hadn't realized the depth and size of things here. And that great trend has continued: when I returned in 2002, UNC had climbed to 14th nationally in total NIH funding. Now we're 7th.
You've said, previously, that some colleagues advised against pursuing aging as a topic of research when you came here as an assistant professor in 2002. Why did they say that and why didn't you take their advice?
That's standard advice given to young faculty, and I've given it to young faculty myself: when you start a lab you have to pick something at which you'll be competitive, and focus on that topic. So people said I should focus on melanoma—melanoma biology, melanoma mouse models—and they said I should be a melanoma doctor. And I did that to a degree. I worked on cancers, like melanoma, that are deficient in the p16 tumor suppressor protein, which was my research interest. But I also wanted to look into this other thing I thought the p16 gene might do—I thought it might contribute to a decline in the cellular capacity to replicate during aging. Only a few of us believed it played a big role at the time. So people thought I was crazy to pursue this odd topic. I didn't have training in gerontological research. Colleagues thought I'd be perceived as a dilettante.
So, now I modify that advice; I tell young scientists to work on something in which they're really interested, and that they think could turn out to be important. If it's a boring topic, it won't matter how plausible it is or how good you are at the science because you won't get funded and you won't stay passionate about the work.
The reason I didn't take that advice is because of an odd result I got while still at Harvard. P16 is supposed to be important in pancreatic cancer, so we studied the pancreatic tissue from mice I had generated lacking p16. There, we noted that expression of p16 seemed to modify beta cell function of the pancreatic islet, which produces insulin. We later showed in my group that p16 is highly expressed in beta cells in an age-dependent way. In young mice, there's no p16 and the beta cells can divide. When mice get old, there's lots of p16 and the beta cells stop dividing. We believe this explained why beta cells "got old" and why type II diabetes became so much more common with aging. We published that in Nature in 2006. It was one of the first big papers out of my lab.
The diabetes doctors I knew were polite at the time. They were focused on how the liver and muscle used glucose, and didn't think our findings were really that important. They said our results were interesting but probably not relevant in humans; they said, "It is probably a rodent-specific result, silly oncologist."
But we got the last laugh because when the genome-wide association studies happened and researchers determined the alleles [alternate forms of genes] that caused susceptibility to common human diseases, type II diabetes was one of the first diseases studied. And the second strongest hit out of those unbiased genetic screens was p16. The importance of the locus in determining diabetes in large populations of normal people has been really unexpected, even to us.
And we've since learned that p16 does another good thing besides preventing cancer – its expression also appears to prevent atherosclerosis, an association my lab first discovered. The lower the production of p16 and related genes, the more atherosclerosis people get. This suggests to me that one aspect of atherosclerosis is like cancer: it's a disease of too much cell division. In atherosclerosis, we believe it's the macrophages that divide too much inside arterial plaques. These macrophages don't divide very fast, but there's plenty of replication to cause a disease over 20 years. So, p16 has become a hot topic outside of cancer, also in diabetes and heart disease.
It's been really exciting. I'm glad I didn't listen to those people who told me not to work in this area.
You are a co-founder of two start-up companies. What are the goals of each and what progress have they made toward their goals?
The first company is called G1 Therapeutics. We're trying to use small molecule kinase inhibitors in a pill or IV medicine to prevent the toxic effects of chemotherapy on normal cells. We have evidence that by making cells stop dividing by inhibiting the enzyme CDK 4, we can make cells resistant to DNA damage. In simple terms, if you put cells to sleep – cells in bone marrow – then chemo won't be so toxic to them.
G1 has been successful. We have received a lot of government funding and two rounds of venture capital. And we expect to use the drug in clinical trials in 2014.
The other company is called HealthSpan Diagnostics. It's a harder road, but the science works. We can measure p16 in people and it goes up as we age. And if you have toxic events – such as years of smoking – your p16 level goes up even more. And we believe that your level of p16 can predict your 'molecular age' and risk of bad, age-related things happening. We've gotten to the stage where we have to make the assay [the experimental procedure] perfect. And that's not something we can do in my lab; the assay needs to work better than it does, and that's what the company is working on.
What excites you most about the future of cancer care and research that will hopefully lead to better treatments?
As new director of the UNC Lineberger Comprehensive Cancer Center, I am excited about several areas of rapid progress. Cancer doctors have a number of promising new therapies for a wide variety of diseases that I once thought were very hard, such as metastatic colon or lung cancer. These now have new effective therapies, and we're seeing patients respond well. I am especially excited about the Cancer Center's new commitment to tumor immunotherapy, an approach to make the immune system fight the cancer. I'm also very excited about surprising work in cancer epidemiology – what causes certain types of cancer, what are the risks of getting certain types of cancer? Also survivorship issues – how can we give patients a better quality of life after treatments? These latter two are areas in which UNC particularly excels, and where we benefit from the great work at UNC Gillings School of Global Public Health.
I'm particularly interested in the translation of basic science into clinical care at a much more rapid pace. UNC has really bought into this idea. So now, if a scientist at UNC Lineberger has a great idea, we know how to make that into a treatment. Instead of just publishing the Cell paper and moving on, we know how to turn that finding into a device, or diagnostic test, or treatment that can help people. And this is an area of great interest for our pharmaceutical and industry partners.
And the last thing that I'm particularly interested in is the intersection between cancer and aging. That's becoming real. A number of UNC oncologists like Hy Muss have looked at this and said, well, most patients that get cancer are over 65. And they have a special set of issues that don't happen in younger people. How will a better understanding of the biology of aging allow us to take better care of people with cancer? That's one of the great research questions left in cancer biology. And that's what my lab will continue to work on.
Norman E. "Ned" Sharpless, MD, is the Wellcome Distinguished Professor of Cancer Research and professor of medicine and genetics in the UNC School of Medicine. He has been a member of the UNC Lineberger Comprehensive Cancer Center, including his most recent position as deputy director, since 2002.
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For his work, he earned a Jefferson-Pilot Fellowship from the UNC School of Medicine. We sat down with Dr. Wan to discuss the role of T cells in cancer and autoimmunity and what his research has revealed.
Why did you decide to become a scientist and why did you decide to study biochemistry and then microbiology and immunology at the University of Colorado?
I'm a curious person. When I was a child, I liked to tinker with complicated systems. Well, the human body is a complicated system. I decided to go into biological science so I could see how the human body works, while at the same time trying to potentially help people in need.
When I was an undergraduate, we compared gene expression in tumor cells to gene expression in healthy cells. This led me to study something called signaling transduction pathways – how cells communicate and respond to each other and the environment. My philosophy is that we have to understand signaling transduction and gene regulation under normal circumstances so we can understand what goes wrong in diseases.
For graduate school, I came to the United States from China because there's no doubt this is the best place to get PhD training, especially for biological research. That was the driving force to come here. And the more I learned in grad school about T cells the more fascinated I became, because any kind of disease has an immune implication.
What is the overarching goal of your research?
My overarching goal is to figure out precisely how T cell function is regulated. Equipped with that knowledge, we could identify targets for therapies against inflammatory diseases and tumors. Until we can really manipulate T cell function or immune cell-function, we cannot sufficiently tip the balance against diseases.
Recently, immune-function-based therapy for tumors has gotten a lot of attention. That's when we enhance the natural immune response to eliminate cancerous cells – or even precancerous cells – before they cause damage. Two drugs that could be on the market soon are really effective at targeting T cells, which is important because certain T cells play a major role in the onset and development of diseases. And we really need to understand how T cell function is regulated during different stages if we want to target those pathways to create better therapies.
What sorts of roles do T cells play in the development of disease?
Basically, there are subsets of T cells. One subset is conventional T cells – they promote immune function; they help us fight infection. But another subset is called suppressor or regulator T cells. These suppress the immune function; they can prevent autoimmunity and inflammation. We're interested in this because these suppressor T cells are also enriched in tumor tissue. That is, they prevent immune surveillance against a tumor.
Our lab identified a kind of protein that's important for the regulation of FOXp3, a bio-molecule involved in the function of suppressor T cells.
We also study TGF-beta – or transforming growth factor beta – that can be produced by tumor cells. TGF-beta has two functions: it suppresses the activation of the immune response from conventional T cells. At the same time, TGF-beta promotes the function of suppressor T cells. So you can imagine that tumors make a lot of this TGF-beta, which means that tumors can suppress whatever conventional T cells might try to kill it.
Therefore, we're trying to study the TGF-beta signaling pathway with the overall goal of shutting it down in suppressor T cells to treat disease. If we can block this suppressor T cell-function in tumor tissue, then we would enhance an immune response against the tumor.
You also study the role of specific enzymes called MAPKs. Why are they important?
We found that a MAP kinase is important for the generation, activation, and proliferation of T cells. We need to learn about how it works so we can manipulate it to dampen the function of T cells. And that could be beneficial for autoimmune diseases and inflammation.
This molecule is so important for T cell survival and proliferation. Right now, we and others are studying how this molecule might be important in leukemia. In normal T cells, MAPKs are tightly regulated. In T cell leukemia, something goes wrong with them.
We're thinking that this MAP kinase might be a good drug target to help restore normal T cell-function in leukemia patients.
What's the most rewarding part of your work?
Translating our findings into the clinic would be the most rewarding thing, although our studies haven't reached that stage yet. But for now, the most rewarding part is to have unexpected findings. We perform research based on certain hypotheses and we're happy when our hypotheses are correct. But we often find things that are unexpected. For me, that is the most rewarding part in basic research, because these findings will correct, direct, and further our understanding of how nature works.
Yisong Wan, PhD, is an assistant professor of in the Department of Microbiology and Immunology in the UNC School of Medicine and a member of the Lineberger Comprehensive Cancer Center. The Jefferson-Pilot Fellowship is a four-year, $20,000 award to support the research mission of junior faculty.
The original article from UNC Health Care can be found here.]]>
For Salie Babilonia, "the look" gets her every time.
"You know the one I'm talking about," said Salie, a wife and mother of three from Buxton, N.C. "You tell someone you have cancer, and you get that look of pity because it is scary and people don't know what to say.
"But you don't want people to pity you because it doesn't really help them or you. Instead, pray for fast healing."
It's that spunky spirit that has seen the 5'1" dynamo breeze through surgery and radioactive iodine therapy for the treatment of papillary thyroid carcinoma at UNC Hospitals.
Salie, a real estate sales associate and "forever 25," felt the knots in her neck as she and Carlos, 38, her husband of 16 years, were preparing for a two-week family vacation to their native Puerto Rico. Testing and scans, which included a biopsy, confirmed cancer.
She was referred to UNC Hospitals, and in June Salie had her thyroid gland and the lymph nodes on the left side of her neck removed by Carol G. Shores, MD, PhD, professor of otolaryngology/head and neck surgery in the UNC School of Medicine and a member of UNC Lineberger Comprehensive Cancer Center.
"My care at UNC Hospitals was incredible," said Salie, ever the organizer who has kept everything related to her cancer journey neatly ordered in a binder. "I was never a number. Dr. Shores herself called to tell me the biopsy confirmed cancer. It was sucky that she had to share that news, and I felt bad for her."
"Salie is very strong, very positive, and her surgery was uncomplicated," Dr. Shores said. "She was hospitalized for six days because the parathyroid glands, which control calcium levels in the blood, get moved around during the surgery and their function can be temporarily impaired. Her parathyroid function recovered, and Salie has recovered."
Papillary thyroid cancer is the only cancer staged by age, and women under age 45 are considered Stage 1 disease regardless of how much cancer in present and whether lymph nodes are involved, Dr. Shores said. "This cancer is not unusual in young women, and women under 45 have a good cure rate. They tend to do well in the long term, but the cancer can recur even 20 years after treatment, which is why life-time monitoring is required."
Salie will take thyroid hormones for the rest of her life and will be monitored by Julie Sharpless, MD, assistant professor of endocrinology and metabolism.
In July, under the care of Arif Sheikh, MD, assistant professor and director of the targeted radionuclide therapy and a member of Lineberger, Salie received radioactive iodine treatment in pill form as a standard of care to destroy any remaining cancerous thyroid tissue that could have remained after surgery.
In preparation, her thyroid hormones were not replaced for about six weeks and Salie had to adhere to a strict diet, low in iodine which equates to a no-preservatives no-salt diet as most prepared foods contain iodized salt.
And that's where the kitchen at SECU Family House came to the rescue. Carlos and Salie had already discovered the safe, supportive environment offered by the 40-room hospital hospitality house minutes from UNC Hospitals. Family House offers the home-away-from-home comfort needed by seriously ill patients and their families who come to UNC Hospitals for care.
"Essentially for those six weeks we had to prepare everything she ate from fresh, preferably organic ingredients and from scratch," said Carlos. "We could do that easily enough at home, but to be here in Chapel Hill a few days before that therapy began, we couldn't have done it without this kitchen. And the local resources for fresh, unprocessed ingredients were just what we needed."
The radioactive iodine therapy required Salie to be hospitalized for monitoring the iodine uptake and because her body was radioactive, she needed to be isolated, especially from children.
By August, Salie and Carlos were back home settling back into their daily routines and time with their children Carlos Jr.,15; Enrique,13; and Calia,10.
"North Carolina is home," said Carlos, who moved the family to Hatteras in 2009 with a career U.S. Coast Guard assignment. "We have a nice house, fruit trees in the backyard and a great network of friends who have helped us with the kids while Salie was being diagnosed and treated. The kids love it here, and even when I retire, we're staying."
"Family has always been first for us," Salie said. "We only take vacations as family, and our kids tell us they want us to be their best friends. About the only time I'm not happy is if our kids aren't happy. We've always been there for each other, putting the priorities where they need to be, learning the difference between needs and wants."
"We grew up together and have always been each other's go-to person," said Carlos who knew from first time he saw Salie in college that he would marry her. "We've been together through the happy, the sad and the in-between. We're still on the same page, but you have to work at it every day."
And just as "the look" of pity too often given to cancer patients gets to Salie, there is another look that gets to her every time.
"She's still the one, and this is forever," said Carlos, holding Salie's hand and meeting her eyes as if they were the only two in the room.
The original article from UNC Health Care can be found here.]]>
For his work he earned a Jefferson-Pilot Fellowship from the UNC School of Medicine to further his research mission. We sat down with Dr. Wang to discuss the science behind gene regulation and his most recent research findings.
What was the driving force behind your majoring in biochemistry at Fudan University and then pursuing a doctorate in biomedical sciences at UC San Diego?
I liked science all the way back to when I was young, especially physics and chemistry. I love science. It's very rigorous but logical, and I like logic. In college I realized that there's a molecular basis for human disease, and I wanted to contribute to our understanding of that.
I entered my undergraduate study at a time when people thought molecular medicine would be the science of the next century. I majored in biochemistry, learning the molecular basis for genes and cells. My thesis project was to study p53, a tumor suppressor gene that's commonly mutated in human cancers. Mutations are one of the driving forces of cancer. I felt like molecular biology was the field for me. So, I got admitted into the Ph.D. program in Biomedical Sciences at UC San Diego to learn how to use modern molecular biological approaches to study human disease.
I just felt that we haven't been able to understand the molecular biology of diseases including cancer as much as we need to.
In 2012, you published a paper about a unique class of proteins that bridge the gap between a gene's "on" and "off" stages. What role do these proteins have in cell differentiation and cancer biology?
Your cells – in your heart, muscles, blood, brain – all of them are different. How stem cells differentiate into all those kinds of cell types is due to a "switch" on our genes. We call this "on" or "off." But what this really means is that when a gene is "off" then that gene's function is closed down; it doesn't transcribe a protein to do something. Or, if the gene opens up and is "on" then that means a lot of RNA is produced and proteins are translated. So, there's a fundamental molecular biology question: how are these "on" and "off" switches being regulated when stem cells develop into differentiated cells?
In that 2013 paper, we studied the "off" mechanism related to a protein complex called PRC2. We found a protein sequence or structure that partially explains how this protein complex finds and locates the genes that are on and then work to turn them off. Then, we realized that the factor related to this mechanism is overexpressed in cancer cells – notably lymphoma and some solid carcinoma subtypes. So we're now studying how this overexpression factors into other cellular relationships in the development of cancer cell types.
The study could lead to a target for better anti-cancer therapies.
A focus of your lab is chromatin. What is it and why is it important in the study of cancer biology?
Chromatin is a combination of nucleic acids and types of proteins called histones that package DNA inside cells. A lot of gene regulation occurs on chromatin; it controls whether DNA is available or not – whether genes are "on" or "off" in specific cells. Basically, chromatin is a platform for how genes regulate their own function.
This relates to cancer biology. There's recently been a lot of sequencing efforts, and what people have seen is that a significant amount of the new recurrent mutations found in cancer cells are actually affecting the pathways that we know are involved in chromatin regulation. In turn, these new mutations may lead to a drastic change in gene expression and cause cancer development. This is why we study chromatin.
How might your work translate into treatments for disease, especially various cancer types?
This is a very exciting field because there are a lot of proteins – often enzymes –involved in regulating chromatin. These enzymes either add tiny chemical modifications onto chromatin, or they act as motors that slide onto chromatin to open or close down a gene's expression.
Often, enzymes are good drug targets because you can design a compound to inhibit their activity. So many of these chromatin regulators are actually what drug-discovery scientists can target. We also know that many of these enzymes are perturbed in human disease. For example, in one cancer type we see hyperactivity of a certain chromatin-regulatory enzyme, and theoretically you could design a drug to target that enzyme. Also, we're learning that some mutated enzymes are unique to cancer cells. That is, we don't find them in normal cells. That's an Achilles heel of cancer, because that it allows us to target just the cancer cells, not normal cells. The current front-line chemotherapies affect cancer cells and normal cells equally, which is one of the downsides to current cancer therapies.
There have been a couple of good examples of deregulated enzymes that specifically perturb chromatin regulation in cancer cells. I think in the next few years we'll see more and more of such examples that may serve as excellent drug targets. We're all very excited about that.
What is the most rewarding part of your job as a researcher?
The most rewarding part of science is to promote our understanding of human disease, which can have a contribution, eventually, to cures. Also, I feel very fortunate to be working on this very exciting and active research area, which nicely connects the basic mechanism of gene regulation to cancer and disease. There's a lot of opportunity to translate our basic understanding of genes and cells into medicine and into clinics.
With a lot of questions to be answered, you just have to ask yourself: what is the most critical question and how can we take the best path toward understanding and treatment? Then we set up a plan, execute, and try to achieve the goal. Getting all of it done and making things happen – that's the most exciting part. We want our research to have a benefit for patients down the road.
Greg Wang, PhD, is an assistant professor of in the Department of Biochemistry and Biophysics in the UNC School of Medicine and Lineberger Comprehensive Cancer Center. The Jefferson-Pilot Fellowship is a four-year, $20,000 award to support the research mission of junior faculty.
This article was originally published by UNC Health Care. To access the original article, click here.]]>
O'Brien and Sondek were two of eight GSK awardees out of 142 candidates in the United States and Canada. Without the award or collaboration with a drug company in general, the researchers would have access to just a small fraction of the millions of compounds that could be screened to identify leads for drug development.
O'Brien, a professor in the Department of Cell Biology and Physiology in the UNC School of Medicine and member of UNC Lineberger Comprehensive Cancer Center, studies the regulation of sperm production and function. Her lab found that a sperm-specific enzyme called GAPDHS is essential for the production of ATP – the energy of the cell that allows sperm to move. But other cells throughout the body have a similar, but not identical, enzyme called GAPDH. The trick for O'Brien is to find a compound that selectively modulates the GAPDHS pathway so that only the metabolism of sperm is inhibited or activated. Otherwise, many cells throughout the body could be affected.
Through collaborations with BRITE's drug discovery center at NC Central University and the UNC Center for Integrative Chemical Biology and Drug Discovery in the UNC School of Pharmacy, O'Brien screened about 90,000 compounds. She identified compounds that inhibit GAPDHS activity and sperm motility but do not have sufficient strength or selectivity for drug development.
"Finding a compound that can become a drug requires a partnership with a pharmaceutical company," O'Brien said. A typical high-throughput screen at GSK involves about 1.8 million compounds. "But they have new technology that we will use," O'Brien said, "and that will allow screening of several billion compounds." GSK's screen will allow O'Brien to see results by the middle of 2014.
To earn his GSK fast track award, John Sondek, a professor in the Department of Pharmacology in the UNC School of Medicine and member of UNC Lineberger Comprehensive Cancer Center, created an assay to find compounds that inhibit a protein called Rac1, which is the third most-frequently mutated active protein in melanoma, a kind of skin cancer. Of the two other commonly activated proteins, one of them – Ras – has failed as a drug target.
"But Rac1 mutations are fundamentally different and involve totally different mechanistic aspects of the protein's regulation," Sondek said. "What's interesting is that several different Ras-driven cancers need Rac1. So if we knock down the expression of Rac1, then we could interfere with tumor growth."
His assay could help GSK find compounds to treat lung, prostate, breast, and skin cancers.
Prior to winning a Drug Discovery Fast Track award, Sondek also worked with BRITE to screen about 80,000 compounds.
"We got hits," he said. "Getting hits isn't the problem. The problem is figuring out if the hits – the compounds that seem to inhibit Rac1 – are any good. But the hits from this compound library weren't good enough." For instance, the BRITE screen found compounds that altered Rac1 but didn't stop it in its tracks, which is a prerequisite for a drug company to spend time and resources creating a drug for clinical trials.
"Without the GSK award, that would've been the end of the line for our screen of Rac1," Sondek said. "Now we'll be able to screen 1.7 million compounds at one time."
He should find out what the GSK screen reveals by the middle of 2014.
GSK's inaugural Discovery Fast Track competition, designed to translate academic research into starting points for new potential medicines, attracted 142 entries across 17 therapeutic areas from 70 universities, academic research institutions, clinics, and hospitals in the United States and Canada. Read the GSK press release.
The selected scientists will collaborate with GSK's Discovery Partnerships with Academia (DPAc) team. The winning investigators could be offered a DPAc partnership to further refine molecules and assess their potential as new medicines. Since its inception in 2010, Glaxo's DPAc team has initiated nine collaborations with academic researchers in Great Britain, France, the U.S., and Canada.
This article was originally published by UNC Health Care on November 6, 2013. To access the original article, click here.]]>
Osteoarthritis, or OA as it is commonly called, is the most common joint disease affecting middle-age and older people. It is characterized by progressive damage to the joint cartilage — the cushioning material at the end of long bones — and causes changes in the structures around the joint. These changes can include fluid accumulation, bony overgrowth, and loosening and weakness of muscles and tendons, all of which may limit movement and cause pain and swelling.
Knee osteoarthritis is a common form of osteoarthritis and is caused by cartilage breakdown in the knee joint. Factors that increase the risk of knee osteoarthritis — including being overweight, age, injury or stress to the joints, and family history — can increase the risk of knee osteoarthritis.
Postmenopausal female breast cancer patients whose adjuvant treatment generally includes an aromatase inhibitor, or AI, often experience joint pain or stiffness known as AI-associated arthralgia. An estimated 20 to 32 percent of these women stop taking their AI due to this side effect. Researchers at UNC conducted a pilot study to assess the potential positive effects of physical activity on joint pain and stiffness in these patients, as a potential alternative or adjunctive approach to arthralgia management that would enable them to continue their cancer therapy while living as pain-free as possible.
"We were interested in seeing if a physical activity program that is evidence-based for reducing joint pain, stiffness and fatigue in adults with arthritis might have similar benefits for women experiencing AI-associated arthralgia," said Kirsten A. Nyrop, PhD, principal investigator for the pilot study and a member of UNC's Thurston Arthritis Research Center. "We were particularly interested in testing the feasibility and benefits of this program among older breast cancer survivors, because cancer is a disease of aging and physical activity may pose a special challenge for this age group."
Nyrop and colleagues at UNC, including Hyman B. Muss, MD, professor of medicine and the Director of the Geriatric Oncology Program at UNC Lineberger Comprehensive Cancer Center, tested the Arthritis Foundation's Walk With Ease self-directed walking program, which they adapted for breast cancer patients. Twenty women participated in the study. All were age 65 and older, had Stage I-III breast cancer, were on AI therapy, and reported joint pain or stiffness. The women followed the walking program for six weeks.
At the end of six weeks, 100 percent of the study participants said they would recommend the program to other breast cancer survivors experiencing joint pain or stiffness. All the participants also reported that they learned how physical activity could lessen their joint pain and stiffness, and that the program taught them how to safely engage in physical activity. In addition, 90 percent thought the program motivated them to be more physically active, explained how to overcome physical and mental barriers to exercise, and reported were extremely confident that they would continue walking in the future. After six weeks of walking, the mean joint pain scores among the participants decreased by 10 percent, fatigue decreased by 19 percent, and joint stiffness decreased by 32 percent.
A moderate-intensity self-directed walking program is feasible for elderly breast cancer patients on AI therapy and increase their engagement in regular walking or similarly safe physical activity, the researchers concluded.
"Physical activity is recommended for breast cancer patients – as it is for all adults – for both physical and mental health reasons," Nyrop said. "It is important to offer breast cancer survivors physical activity options that are safe, enjoyable, easy to do at home and on their own, with the promise of joint symptom relief that will encourage them to remain physically active in the long run."
Co-authors of the study, all from UNC, are Hyman B. Muss, MD; Rebecca Cleveland, PhD; Betsy Hackney; Mary Altpeter, PhD and Leigh F. Callahan, PhD.
This article was originally published by UNC Health Care on October 28, 2013. To access the original article, click here.]]>
Doctors need to know about those roles, but the scientific data on many variations are scattered throughout the medical literature and in some cases the data are hard to make sense of.
Enter Jonathan Berg and James Evans, clinical geneticists at the UNC School of Medicine. They received a four-year, $8.4-million grant from the National Institutes of Health to help create a detailed database of all genetic variants thought to be related to human disease.
"The expectation with this grant is that we'll only begin to scratch the surface of the end goal: to have a freely available, public resource that has clinical annotations of the variants in genes that cause or increase the risk of disease."
This grant is part of a consortium assembled by the National Human Genome Research Institute, called the "Clinical Genomics Resource" or "ClinGen" that consists of two U01 awards, a U41 award, and the National Center for Biotechnology Information (NCBI).
"The expectation with this grant," Berg said, "is that we'll only begin to scratch the surface of the end goal: to have a freely available, public resource that has clinical annotations of the variants in genes that cause or increase the risk of disease."
Berg and Evans are part of an effort to recruit dozens of researchers, clinicians, and gene-sequencing labs around the country to collect variant data, curate the variants for clinical significance, and develop novel ways to figure out the disease-producing capacity of these variants. Once they have all the right people and computer infrastructure in place, the team will begin to build the data set.
Berg said, "We need to be able to say for each variant: what do we know about it? How many times has it been seen in medical cases and in controls? What do our prediction algorithms say about it? What is its predicted effect on the structure of a protein? Is it in an important functional domain?" The list goes on and on. Answering such questions will help Berg's team score each variant's pathogenicity.
The UNC group is also very interested in determining the "actionability" of gene-phenotype pairs. This feature may help patients and physicians decide how to handle a broad array of possible genomic findings. For instance, when a patient undergoes clinical genomic testing for a suspected genetic disorder, a clinical geneticist will expect to find only one or two variants that explain the patient's diagnosis. But the genomic test will also find many other variants that may or may not be associated with other unrelated health issues. The doctor has to make a decision about what to do with the information, and therefore knowing a variant's "actionability" would be crucial.
Also, Berg said, "When an organization, such as the American College of Medical Genetics and Genomics or the American Academy of Pediatrics, wants to set guidelines about the types of findings that should be reported to patients, this database would be an unbiased and evidence-based metric they could use."
Once Berg and his colleagues have evaluated the clinical validity and clinical actionability of each variant, they'll plug the data into a database, a resource that doctors and patients will be able to access.
Berg's team will first focus on genes and variants implicated in single-gene diseases. After that, the focus will turn to more complex, multi-gene conditions.
"So far, we know that about a quarter of our genes are related to disease," Berg said. "But as new information and genes are discovered, we want this database to be a resource that continues to grow when we have new findings."
Jonathan Berg, MD, PhD, is an assistant professor in the Department of Genetics and James Evans, MD, PhD, is the Bryson Distinguished Professor of Genetics and Medicine, both in the UNC School of Medicine. David Ledbetter, of Geisinger Health System, and Michael Watson, of the American College of Medical Genetics and Genomics, are also co-principal investigators on the grant. Both are members of the UNC Lineberger Comprehensive Cancer Center.
This article was originally published by UNC Health Care on October 15, 2013. To access the original article, click here.]]>
We sat down with Dr. Chen to discuss his motivation and his research, which has shed light on the differences between three main types of radiation therapy for prostate cancer. He's also conducted research on why there are disparities in the care of black and white prostate cancer patients.
What was the driving force behind your decision to become a doctor and a researcher?
I went to the University of Kansas, and I was very involved in promoting volunteerism during college. At one of the national conferences, I heard about a hospice program, and I talked with the people who ran it. At that time, I was a chemical engineering major. But partway through college I realized that chemical engineering wasn't what I wanted to do. I actually left school for a year and volunteered full-time at the hospice, which was run completely by volunteers. All of us lived in the hospice, and we served as the primary caretakers for dying patients.
That was a life-changing experience. I decided I wanted to be a doctor. I went back to school and changed my major to pre-med.
I went to medical school at Harvard knowing I wanted to be a cancer doctor. During my training as a radiation oncologist, I realized that I wanted to not only take care of cancer patients but also to advance the care of patients. So during my residency at the Harvard Radiation Oncology Program, I had the opportunity to get a master's degree in public health at Harvard – a one-year program. I did that to learn how to become a good researcher.
Now, I specialize in prostate cancer in the clinic, and my research is also focused on prostate cancer. I feel, as an academic physician, that having my clinic patients and experiences drive my research and then having that research feed back into improving patient care is a very nice synergistic way to do things.
In 2012, you researched the differences among three types of radiation therapy; what were the key findings and implications?
Radiation technologies have developed over time to help improve the cure rates for prostate cancer patients and also to help reduce side effects of radiation.
But there's a phenomenon in this country where we tend to adopt the latest treatment – usually the most expensive treatment – before research proves that the latest technology is better than the prior one.
In this particular study, we first looked at an older radiation technology. We found that that 3-D conformal radiation, which had been used for many years to treat prostate cancer, led to more side effects compared to intensity-modulated radiation therapy, or IMRT. Currently, across the country, almost everyone uses IMRT for prostate cancer. We found indeed that IMRT led to fewer side effects. It's a newer technology than 3-D conformal radiation.
Then we studied another radiation therapy technology – proton therapy. It's in the media a lot because of how expensive it is – about $150 million dollars to build one machine. There's a debate about whether it's better than IMRT, but very few studies have looked at that. Our study was one of the first. We weren't able to find any reduction in patient side effects with the use of proton therapy compared with IMRT.
Since our study, a couple of other studies have found that proton therapy might slightly reduce short-term side effects compared to IMRT, which disappear over time. Those studies found no benefits with regard to long-term side effects. And there's been no evidence that protons are more effective in treating the cancer.
There are about 10 proton radiation centers across the country currently, and about 20 more are being built right now.
You've also studied racial disparities in cancer care. What are your key findings and implications?
A lot of my research looks at how we can improve care and benefit our own patients in North Carolina. Many researchers here at UNC, including my mentor Dr. Paul Godley, have done research on racial disparities in prostate cancer care. We know from prior studies that African American men tend to be diagnosed later, they tend to receive less aggressive treatment, and they tend to more commonly die from prostate cancer than do Caucasian men.
We studied why. We looked at whether there's a longer delay between diagnosis and treatment in African American patients -- you could imagine that a longer delay could lead to a higher chance of reoccurrence of cancer. In this study, we looked at Medicare patients, and we found that – on average – African American men took a week longer between diagnosis and starting treatment compared to Caucasian men. And the delay was even longer for patients who were diagnosed with aggressive, high-risk prostate cancer.
Why that is we don't really know. But, our study urges the research community to conduct more studies – so we can potentially make that better.
You are the director of the UNC CyberKnife Radiosurgery Program. What is that, why is it necessary, and what sorts of results have the program seen since 2007?
Essentially CyberKnife is a small radiation machine attached to a robot. The patient lies on a table and the robot moves to where the tumor is to deliver radiation to the tumor. The benefit is that it's an extremely accurate way to deliver radiation targeted to a tumor. It helps us minimize radiating normal tissue so that we reduce side effects as much as possible.
The other thing that's really important about CyberKnife is that the machine and the radiation it delivers can follow a moving target. For prostate cancer treatment, this is important because the prostate is a moving target. So are lung tumors -- CyberKnife can move to follow the lung tumor as the patient breathes.
To be clear, CyberKnife is not appropriate for every tumor. But it is commonly used for prostate, lung and brain tumors. There's good evidence that it's effective and safe in certain types of tumors – especially small tumors – and has allowed us to be very accurate.
Another advantage of CyberKnife is that we've been able to dramatically reduce treatment time. For example, standard prostate cancer radiation generally is every day for eight weeks. That's a long time for patients. But with CyberKnife, we're able to reduce treatment to four or five days total. Our research has shown that this is an effective treatment for early prostate cancer and patients have good quality of life outcomes afterwards.
A lot of research is currently being done to use Cyberknife radiation in additional situations. There's currently a clinical trial being conducted here at UNC for patients with liver tumors and spine tumors – and continued research will help us learn more about the effectiveness of CyberKnife radiation in these settings.
What is the most rewarding part of your job?
I would say my job involves three different parts. I think of myself as physician first, because I want to help cancer patients live better lives. I think my research compliments that and allows me to be a better doctor and potentially advance treatments that help us get better outcomes for patients. Also, I teach medical students and residents. I think of that as complementary to my patient-centered mission, as well.
I think the most important and rewarding part of my job is interacting with patients and following them after treatment to make sure they're doing well.
Ronald Chen, MD, MPH, is an assistant professor in the department of radiation oncology at the UNC School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center. The James W. Wood Junior Faculty Award, which comes with a $3,000 stipend, supports promising young members of the School of Medicine's clinical faculty. Chen has also been awarded the school's 2012 Medical Student Research Mentor Award.
This article was originally published by UNC Health Care. To access the original article, click here.]]>
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Two University of North Carolina School of Medicine researchers who lead an effort to sequence the entire genome of 400 infants as part of an NIH-funded study will answer your questions in a live Facebook chat at noon (12 p.m.) Eastern time on Thursday, Sept. 26.
The chat with Dr. Cynthia Powell and Dr. Jonathan Berg will take place on UNC Health Care's Facebook page at http://www.facebook.com/unchealthcare. You can sign up to have an email reminder sent to you here.
Researchers at UNC plan to sequence the entire genome of 400 infants to determine what useful clinical data can be acquired through the tests. In conjunction with the testing, the UNC team has partnered with Research Triangle Park-based RTI International to develop educational and consent tools to determine how best to educate parents and physicians about the test and its results.
The tests will examine the genomic data from a healthy group of children and a cohort of children with suspected or diagnosed genetic disorders such as phenylketonuria, cystic fibrosis and other disorders involving metabolism. The ultimate goal is to determine whether genomic testing can be an effective tool for pediatricians to incorporate alongside existing tests.
The study is funded by a 5-year, $5 million grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.]]>
You can never quite anticipate what words are going to come out of Bill Clanton's mouth, but you better pay attention.
The humorous, direct turns of phrase carry life lessons that endear this bear of a man to his family, his health-care team and complete strangers.
"I like to think that these little shooting pains are the cancer cells leaving my body," said Clanton, wincing and squeezing his blue eyes tight when the sensation gets his attention without warning. "I have lived in this body for 82 years, so I know when things are changing.
"And I've never had anything that Vick's [Vapo-Rub] salve wouldn't cure until this," he said, pointing to his bulbous nose, red and blistered from radiation to treat the skin cancer inside his columella, the little column of tissue that divides his nostrils.
"But you see how pink and alive my skin looks," said a seemingly unfazed Clanton of Aurora, N.C., (pop. 520) in Beaufort County. "That means there is blood circulation, and that is good."
Clanton, retired from the U.S. Air Force and the construction industry but not from a life-long love of gardening and quail-hunting, received the radiation at UNC Hospitals over 25 days. He was referred to UNC by Dwight Grady, MD, an ear, nose and throat specialist in New Bern, after inflammation inside his nose refused to heal.
"It was a pretty sneaky tumor," said William W. Shockley, MD, division chief of facial plastic and reconstructive surgery and W. Paul Biggers Distinguished Professor, to whom Clanton was referred. "It had grown up under the tissues in the tip of his nose. Surgery would have left him with less than half his nose."
Dr. Shockley believed radiation was an equally viable option, and he called on colleague Bhisham S. Chera, MD, assistant professor in the Department of Radiation Oncology.
"Bill's treatment was multidisciplinary for which we are known," Dr. Chera said. "A lot of surgeons don't have the understanding that surgery is not always the best thing. Dr. Shockley gets that."
"That's the beauty of working at UNC," Dr. Shockley said. "We have specialists and super-specialists who can mobilize quickly. When I realized the surgery for which Bill was referred wasn't his best option, Dr. Chera was able to see him that same day. We did the CT scans later that day, too, trying to accomplish as much as we could, being aware that Bill lives at least three hours away. It was a long first day, but he and his son-in-law, Jeff Fleming, left with a plan."
The radiation treatment was complicated, but personalized. Clanton was fitted with a customized lead mask to protect his eyes and facial features as the radiation fields were changed during treatment to get at the pesky cells.
"The set-up and techniques were laborious, for him to sit through and for us to give," Dr. Chera said. "But he has shown tremendous fortitude, plus he's been so positive and jovial, characteristics we don't always see in a patient."
All of which comes as no surprise to Clanton's children, ages 52 to 59, four of whom traveled from Texas and three towns in Georgia to take turns being with him during his treatment.
His daughter, Carla, and her family, stayed on their 15-acre farm in Aurora, caring for their mother, Gladys. "The best way I can help take care of Dad, is to take good care of Mom," Carla said.
"He's always been about family, faith and self-sufficiency," said Chuck, 54, superintendent of city properties in Hapeville, Ga. "We never lacked for support, a kind word or advice. It's about morals and integrity. He has always been there for us regardless. We wouldn't be here if not for him."
While in Chapel Hill, the Clantons stayed at SECU Family House, the 40-bedroom hospital hospitality house that is the ideal home-away-from-home for patients who may have daily appointments at the hospital or need immediate medical attention.
"Being at Family House is like going to a homecoming," Chuck said. "You are able to be yourself and share yourself with others."
"It's like these big arms reach out and pull you in," said Terry, 59, chief building official for Rockdale County in Conyers, Ga.
"There's a warmth you can't get at a hotel. You feel it regardless of how many times you go out and come back in."
"There is a quiet understanding here," said Rebecca, 52, of Houston, Texas. "Everyone here is hurting in some way, but yet we are supportive of each other. Being here is my chance to dote on my Daddy, but I know if I had to leave for some emergency at home, the people we've met just this week would take care of him."
The Family House kitchen gave Rebecca and Bill the opportunity to nourish bodies, too.
Rebecca, winner of the Food Networks 2012 Cupcake Wars, made delectably decadent cupcakes for fellow house guests and staff — twice — to keep in practice for two upcoming cooking shows in the Lone Star State.
Bill turned out a few banana puddings and apple cobblers so an over-abundance of fresh fruit donated by local grocers wasn't wasted. But his signature dish — sausage gravy and biscuits — converted more than one non-breakfast eater.
"And you know you have to use a wooden spoon to make the gravy," Bill said. "It's science. You will burn your fingers if you use a metal one."
It's talk that makes a difference for Bill. Always has, but especially during his care at UNC Hospitals.
"My doctors talk to each other," Bill said, tears welling. "I have an invalid wife and a dead daughter because doctors in another state and in another time did not. I don't know how to say it any stronger."
(Bill and Gladys, his wife of 60 years, live with daughter, Carla, and husband, Jeff, a retired Master Gunnery Sergeant, USMC, who are primary caregivers. The Clantons' oldest daughter, Debbie Clanton McLaurin, died in 2009 at age 53. An infant son, Michael Paul, died at two days old in 1962. Sons Barry, 59, and Jim, 55, live in Duluth, Ga., and Cincinnati, Ohio, respectively.)
The Clantons' devotion to family does not go unnoticed.
"I typically have a long talk with the patient about what to expect," Dr. Shockley said. "It's a very detailed discussion because it's important to understand the commitment it is going to take.
"For Bill and his children, they have a lot on their plates and have been thrown a lot of curve balls in life already. But they were unwaveringly united in their commitment to being there for Bill. When you see that, you know that things are going to go the way you want them to go, and you have the best shot at taking care of the patient."
Bill completed treatment Aug. 27 and returned to Aurora to rest and heal, activities he believes are best achieved sitting on the 64-foot-long front porch where two swings and six rocking chairs only begin to accommodate his 14 grandchildren and 11 great-grandchildren.
"The sweet potatoes and peanuts aren't quite ready to harvest, but the tomatoes and cucumbers are done," Bill said, showing pictures of the bounty from the family garden he canned on weekends at home during treatment.
"For now, it's looking at all the zinnias and the thousands of butterflies we've had this season. If that's not enough entertainment, a black bear comes thought the yard now and then."
The original article from UNC Health Care can be found here.]]>
Also amazing is Oliver Smithies' career as a scientist. He won the Nobel Prize for his research in gene modification. What you may not know is that since he was a child, he's been enthralled with flying.
Of particular interest is the glider plan, where the idea is not to reach a certain destination but to enjoy floating on currents and taking in the view from above.
Not without a set of risks and rewards, Smithies draws an interesting comparison between flying a glider and scientific research, particularly the work that led to his 2007 Nobel Prize.
So in the vein of floating and taking in your surroundings, sit back and enjoy this month's episode of real doctors, real people.
And if you're interested in hearing more about his early years, education and the influences along the way, see the outtakes video as well.]]>
The researchers believe that understanding this process could lead to more effective interventions for illnesses that are characterized by cellular stress, such as diabetes, stroke, heart attack, trauma, and cancer.
"Proteins that sense a change in pH are rare and hard to find, but they are likely to be important in protecting the cell from pretty dramatic effects. It was a big surprise to find that G-proteins could play this completely new role, because this protein family is already so well understood," said senior study author Henrik Dohlman, PhD, professor, vice chair of the Department of Biochemistry and Biophysics and member of UNC Lineberger. The results of the research appear online Aug. 15, 2013, in the journal Molecular Cell.
G protein-coupled receptors serve as middlemen in the constant and essential communication between cells and their environment. They can detect chemical and sensory cues -- familiar hormones and neurotransmitters like dopamine, histamine, and adrenaline and environmental signals like odors, taste and light -- and then activate responses to those stimuli within the cell. In this study, Dohlman and his collaborator Dan Isom, PhD, decided to investigate whether G protein-coupled receptor pathways could also sense a change in pH.
Isom began by designing a computer program, which he called pHinder, to examine large numbers of protein structures for hints that they might be able to detect pH. Specifically, the program looked for patterns or spatial networks of protein building blocks that could go from a neutral to a charged status with a change in the environment.
When Isom used this computer program to screen a database of 11,890 different protein structures, he found that only 10 percent of proteins contained potential pH-sensing patterns. However, among this fraction were Ga subunits, structures that had been shown to be key in transmitting signals from G protein-coupled receptors.
The researchers then conducted a series of biochemical and biophysical experiments to confirm the pH-sensing properties of this specialized subunit. By changing the pH inside the cell, they were able to drive a change in the actual shape of the Ga subunit that mimicked the changes seen when the G protein-coupled receptor itself is turned on.
"This pH sensor appears to be part of a signaling network that can tell when the cell is in trouble," said lead study author Dan G. Isom, research assistant professor in Dohlman's laboratory. "When a cell is starved, the pH drops, and these sensors alert the cell to go into a mode of protection. It gets reprogrammed to only do what is absolutely necessary and to start looking for alternative resources."
By further understanding this pH sensor and uncovering others like it, researchers may be able to develop new ways of treating common illnesses like heart disease and cancer. For example, a shared characteristic of nearly all cancers is a slightly elevated pH inside the cell. By identifying the pH sensors within cancer cells, researchers may be able to develop a universal strategy that could work for many different types of cancer.
The research was supported in part by the National Institutes of Health, the UNC University Research Council, and the National Science Foundation.
Study co-authors from UNC were Vishwajith Sridharan; Rachael Baker; Sarah T. Clement; and David M. Smalley.]]>
"Philosophers have long distinguished two basic forms of well-being: a 'hedonic' [hee-DON-ic] form representing an individual's pleasurable experiences, and a deeper 'eudaimonic,' [u-DY-moh-nick] form that results from striving toward meaning and a noble purpose beyond simple self-gratification," wrote Fredrickson and her colleagues.
It's the difference, for example, between enjoying a good meal and feeling connected to a larger community through a service project, she said. Both give us a sense of happiness, but each is experienced very differently in the body's cells.
"We know from many studies that both forms of well-being are associated with improved physical and mental health, beyond the effects of reduced stress and depression," Fredrickson said. "But we have had less information on the biological bases for these relationships."
Collaborating with a team from the University of California at Los Angeles led by Steven W. Cole, professor of medicine, psychiatry and behavioral sciences, Fredrickson and her colleagues looked at the biological influence of hedonic and eudaimonic well-being through the human genome. They were interested in the pattern of gene expression within people's immune cells.
Past work by Cole and colleagues had discovered a systematic shift in gene expression associated with chronic stress, a shift "characterized by increased expression of genes involved in inflammation" that are implicated in a wide variety of human ills, including arthritis and heart disease, and "decreased expression of genes involved in … antiviral responses," the study noted. Cole and colleagues coined the phrase "conserved transcriptional response to adversity" or CTRA to describe this shift. In short, the functional genomic fingerprint of chronic stress sets us up for illness, Fredrickson said.
But if all happiness is created equal, and equally opposite to ill-being, then patterns of gene expression should be the same regardless of hedonic or eudaimonic well-being. Not so, found the researchers.
Eudaimonic well-being was, indeed, associated with a significant decrease in the stress-related CTRA gene expression profile. In contrast, hedonic well-being was associated with a significant increase in the CTRA profile. Their genomics-based analyses, the authors reported, reveal the hidden costs of purely hedonic well-being.
Fredrickson found the results initially surprising, because study participants themselves reported overall feelings of well-being. One possibility, she suggested, is that people who experience more hedonic than eudaimonic well-being consume the emotional equivalent of empty calories. "Their daily activities provide short-term happiness yet result in negative physical consequences long-term," she said.
"We can make ourselves happy through simple pleasures, but those 'empty calories' don't help us broaden our awareness or build our capacity in ways that benefit us physically," she said. "At the cellular level, our bodies appear to respond better to a different kind of well-being, one based on a sense of connectedness and purpose."
The results bolster Fredrickson's previous work on the effects of positive emotions, as well as research linking a sense of connectedness with longevity. "Understanding the cascade to gene expression will help inform further work in these areas," she added.
Fredrickson collaborated with Karen M. Grewen, associate professor of psychiatry in UNC's School of Medicine; and Kimberly A. Coffey, research assistant professor, and Sara B. Algoe, assistant professor, both of psychology, in UNC's College of Arts and Sciences.
Date: July 29, 2013]]>
Under the mentorship of Dr. Lisa Carey, Mohiuddin developed a Breast Cancer Risk Calculator, an online tool in which a user can answer a simple four-part questionnaire to determine a patient's risk of breast cancer relapse. Mohiuddin wanted to provide physicians and patients with a model that was reliable and peer-reviewed. He believes it fills an "information gap" for patients.
"I think everyone knows someone who has or has had breast cancer," said Mohiuddin. "The disease has such a big impact, which makes it very exciting to get involved with breast cancer research. I'm going to continue researching it in the future."
When asked about the potential to exacerbate patients' fears by assigning a numerical value to their risk of relapse, Mohiuddin is optimistic that the potential benefits will outweigh the costs.
"The feedback I valued the most at ASCO was from a patient advocate," he said. "She is a breast cancer survivor herself, and works for a research foundation.…She was very excited about the website; she thought it filled a void, and when I brought up [the emotional aspect] with her, she didn't think that it would be a major issue."
In fact, during the conversation with the patient advocate, Mohiuddin discussed the potential for researching how patients use the tool and how it affects their emotional state.
"As with anything, you can see upsides and downsides," he said. "But I think the benefits of having a peer-reviewed tool are very helpful."
Watch the video for Mohiuddin's explanation of the Breast Cancer Risk Calculator.
For more information on the Breast Cancer Risk Calculator visit: www.neoadjuvantrelapse.info.
Date: July 18, 2013]]>


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DNA match leads to search for suspect in Dallas sexual assaults
(CNN) — Dallas police Saturday said DNA evidence has provided a breakthrough in an investigation of nine sexual assaults in South Dallas this summer.
Police asked for the public's help in locating Van Dralan Dixson, 38, who is named in an arrest warrant for aggravated sexual assault. His DNA matched evidence gathered in one case, a police statement said. Samples for other cases are awaiting analysis.
Dallas police had said officers were "saturating" the area of the attacks and that a task force had been created to investigate the crimes.
Police have said a single suspect was believed responsible for attacks on nine victims from June 22 through September 1.
All of the victims were walking between midnight and 6 a.m. when an armed man forced them to nearby secluded areas. The victims were robbed and sexually assaulted.
Victims said the attacker covered his face with a mask or bandanna, CNN affiliate WFAA-TV reported.
WFAA said a sexual assault was reported near an abandoned store in the same area early Saturday. Police did not immediately say whether that attack was similar to the previous nine.

subset: commoncrawl


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Sprinkler break had little impact on restaurant
Friday, February 1, 2013
ROCHESTER — After an end cap burst in Restaurant 103's sprinkler system Tuesday morning, owner Steve Moody says the restaurant is back up and running with little impact to the Mexican smokehouse establishment.
Regarding Tuesday's incident, Moody said he couldn't thank the Rochester Fire Department enough for their help.
"They were incredible. Without their help there we would have had so much more damage. I could not thank them enough," he said. "…We want to let everyone know we are open and we're going 100 percent."


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Hampton Pound Bumper Plates - Durability is the hallmark of these double-flanged Pound Bumper Training Plates. The iron plate is actually grooved around the rim so that the smooth rubber encasement remains more securely in place. High schools and universities all over the country feature these plates in their gyms. Plus they're available in pounds (5, 10, 25, 35, and 45).
Note: 5 lb. and 10 lb. PBP plates are constructed from solid virgin rubber and are meant to be used as TRAINING PLATES ONLY and NOT bumpers when used by themselves. If intended for bumper plate usage then they should always be accompanied by other sizes of larger diameter plates while in use to prevent damage to lighter plates. Also note that 5 lb. PBP are smaller in diameter than larger increment plates.
View the Bumper Plate brochure
Shipping Included
Shipping cost included within the lower 48 states only
Ships via UPS


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When the government of the magic world and authorities at Hogwarts School of Witchcraft and Wizardry refuse to believe in the growing threat of a freshly revived Lord Voldemort, fifteen-year-old Harry Potter finds support from his loyal friends in facingthe evil wizard and other new terrors.
Being a Harry Potter fan, this was a great addition to my collection
The only problem with the book was that it had a couple of small barely noticeable stains on the hard cover underneath the artwork sleeve. Other than that its great and im enjoying the book!!!
As with all the other Potter books, I couldn't seem to put it down. I can't wait for the next book.
shipping took forever but the over all product was worth the wait
Book arrived in new condition and proper packaging. It arrived promptly. The price is better than Borders or other bookstore. My child loved reading this book! Thanks!
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Home • Coaxial Cable • F Type Connectors • Part Number 200-279
F-pin Coaxial Grounding Block, 2.5 GHz, Dual F-pin Female
Product Details
- Warranty: Lifetime
- Connection: 2 F-Pin Female Jacks
- Connection: 2 F-Pin Female Jacks
- Weight: 0.50 lbs
Part Number - 200-279
In stock - Usually ships same day
Price: $1.78
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- Lifetime Warranty
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Dual F-pin Coaxial Grounding Block, 2.5 GHz, F-pin FemaleThis grounding block can be used to prevent a buildup of static electricity at the point an F-pin coax cable enters the home. This is great for cable and satellite feeds.
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7th International Congress on 3D Dental Imaging: From Scan to Plan to Treat
Posted on November 21, 2013
Hatfield, PA (November 19, 2013) i-CAT and Henry Schein Dental held the fall session of the 7th International Congress on 3D Dental Imaging in Boston on October 25-26, 2013. This session informed, inspired, and educated general dentists and specialists on the benefits of cone beam imaging for the modern-day dental practice. During these two information-packed days, experienced professionals delved into the many applications of 3D dentistry for implants, orthodontics, TMD and airway diagnosis, oral and maxillofacial surgery, and periodontics.
3D technology has already become a valuable tool for facilitating efficiency and accuracy of treatment planning for a more precise implementation by the doctor. This educational opportunity allowed dental practitioners to experience real-world utilization of this technology.
Lectures ranged from basic information sessions to detailed clinical use and hands-on training with 3D planning software programs. Attendees heard from knowledgeable industry experts and colleagues who shared their perspectives on real 3D imaging applications during main podium lectures and breakout sessions. To maximize the learning opportunities at the conference, small group sessions allowed attendees to meet, socialize, and exchange insights with the experts in cone beam 3D imaging.
Clinicians also benefited from networking opportunities with colleagues from around the world. Partners and vendors demonstrated 3D imaging tools and options, supporting 3D products for imaging, implant, restorative systems, orthodontics, and 3D treatment-planning software.
Speaker Dr. Scott Ganz noted, "It is clear that we are all very passionate about our involvement with CBCT imaging as evidenced by the exceptional presentations representing the state-of-the-art modalities combined with the positive interactions and feedback from participants who attended the Boston 3D Congress."
One attendee was delighted to discover that he was the winner of the $50,000 off of an i-CAT® FLX Sweepstakes. Dr. Stephen Dunn of Ocala, Florida is a firm believer in educating his patients, allowing them to make the best treatment decisions for their oral health. His new i-CAT® FLX will be instrumental in providing him with the detailed information needed for such procedures as implants and sleep dentistry. Dr. Dunn noted, "My passion for dentistry has encouraged me to pursue knowledge so that I can look at each patient from many different perspectives and allow the patient many avenues of treatment in order to achieve excellent oral health and function." The i-CAT FLX offers the treatment tools and flexible imaging options to help him attain his goal while delivering 3D imaging at lower radiation dose than a typical 2D panoramic X-ray.*
"When a clinician can operate more effectively and efficiently, both the dentist and the patient benefit," states Matt Garrett, VP of Marketing for i-CAT. "Education on 3D technology can help to achieve this goal. To that end, we are proud that this well-respected educational event has completed its seventh year."
The International Congress on 3D Dental Imaging can help expand the dental landscape for those at any stage in learning about 3D dentistry — from those researching the technology all the way to advanced users. The next International Congress will be held April 11-12, 2014 in Scottsdale, Arizona. For more information, call 267-954-0330 or visit www.i-cat.com/events/congress.
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Westgate Mfg. Outdoor Wall Lights
Westside Wholesale offers a product line of high quality outdoor lighting devices from Westgate Manufacturing, which is one of the lighting industry leaders. The manufacturer has over 35 years of experience in developing outdoor lighting solutions aimed to satisfy the needs of both homeowners and businesses. The Westgate Manufacturing outdoor lighting devices offered for sale by Westside Wholesale are made of premium materials to ensure long service life and available at attractive prices. The fixtures' design will bring a special appeal to any exterior no matter whether it is an industrial facility or a house.
To narrow your search, Westside Wholesale offers Westgate Mfg. outdoor lighting fixtures in two categories according to the bulb type used: metal halide and high-pressure sodium. In addition, the fixtures are categorized given the voltage supported: 120V and multi-voltage devices. A wide range of lighting products from Westgate Manufacturing available on Westside Wholesale makes it possible to find a certain fixture that suits your needs and expectations. The time-tested quality and thoughtful design of Westgate Manufacturing outdoor lighting fixtures make the range of their applications wide: sidewalks, building perimeter, entrance to the house lighting, etc.
The wall packs available on Westside Wholesale have durable bronze powder coated finish resistant to scratches and mechanical damages. The rugged housing perfectly does its job protecting internal components from any weather conditions (moisture, dust, water). Thus, the fixtures can be used both indoors and outdoors.
Westgate's outdoor lighting fixtures are equipped with borotitanate durable glass to ensure long service life and uncompromising safety. Aluminum reflector used in the product line devices amplifies luminous intensity. Westside Wholesale makes the high quality outdoor lighting fixtures with outstanding technical characteristics available to everyone at the most attractive prices.
Westgate Mfg. Outdoor Light, Multi-Voltage Metal Halide Wall Pack Light, 250W - Bronze
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Westgate Mfg. Outdoor Light, High Pressure Sodium Wall Pack Light, 150W, 120V - Bronze
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How to Select
How to select Outdoor Wall Lights
There's no doubt about it, outdoor lights are what gives visitors and passerby's a first impression of your house from the street. Needless to say, equipping your home or office with proper illumination also plays a very important role when it comes to your comfort level. The following guide will help you learn about the most valuable factors so that you can select the perfect outdoor wall lights for your needs.
The first factor that you should consider is the size of the wall light. If you are replacing your old fixtures, new lights don't necessary have to have the same size or hold the same power capacity. Calculate the amount of light that the area requires and then look for wall lights that will match the requirements. If you have a hard time deciding what lamp to select, always go with the larger one. In addition to that, remember that the front door is the most important door of any building, which means it should have the largest, fanciest wall light fixture.
The next factors to consider when selecting wall lights are color and style. Remember to choose a fixture that will complement the style of the building. Outdoor wall lights are usually made from bronze, stainless steel, satin nickel and similar materials that look great with both traditional and contemporary constructions. In addition to style, pay attention to the durability of the fixture and its resistance to weather changes.
The installation location and mounting height are other details to consider. All of the outdoor wall lights that you select should be installed above eye level. This will ensure that you can see the light from a distance and it won't come directly in the eyes of people approaching the building.
How much wattage should outdoor lights consume? Most decorative outdoor wall lights should not use more than 60 watts for incandescent fixtures and 20-30 watt for CFL ones. Before you select any wall lights, calculate their operating cost and look for the most efficient options.
Where to install outdoor wall lights? Usually, locations that have doors or tracks around the house require illumination during the darker time of the day. Garage doors, for instance, should have a proper light to help you find your way in the dark. If your budget is limited and you can't spend much money on decorative lights for the entire building, equipping the doors with energy-efficient wall lights should be enough.
What is the best wall light type to install outdoors? The best wall light to install both indoors and out is the one that uses less energy while providing you with great lighting options. Today, LED is the technology that saves your money and at the same time has minimum impact on the environment.


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Suraj Sharma landed the lead part in Life of Pi by accident. Accompanying his brother to Dehli, India for an audition, casting agents asked Sharma to read for the part as well. He was there, why not? Sharma's natural, emotional presence (and a dash of Pi-appropriate fate) made him director Ang Lee's choice for the role, and now the unknown actor is headlining this holiday weekend's thrilling blockbuster.
Tasked with leading a film that relies heavily on his abilities — a majority of the movie is Pi stranded at sea in a life boat with only a Bengel tiger for company — Sharma collaborated with the Crouching Tiger, Hidden Dragon and Brokeback Mountain director to find the core of Pi, and in turn, Lee pushed him harder then he had ever been pushed before, physically or mentally.
Hollywood.com caught up with Sharma after Life of Pi's New York Film Festival premiere. The blockbuster debut marked a number of firsts for the actor, who couldn't have been happier to finally see his laborious role pay off on the big screen:
The movie played for the first time in front of an enormous crowd. What was the experience like for you?
Suraj Sharma: I saw the movie for the first time then. I had not seen any bit of any of it.
Some actors don't like watching themselves.
Sharma: It's strange seeing yourself at first, but I got involved in the movie! There's so much going on in the movie that you forget about yourself.
It's impressive you were able to lose yourself in your own movie.
Sharma: Well when we made the movie, everything was blue [laughs]. Now there are so many colors, so much going on on screen... I mean, I was reliving bits and pieces of what was going on behind-the-scenes, how things were at that point. But at the same time, I had never seen anything like this. I watched the entire thing and I couldn't move from my seat. I didn't know what to say.
How much acting had you done before?
Sharma: Nothing.
So how did Ang guide you through this experience? I imagine walking on to set on Day 1 was terrifying.
Sharma: Three months before shooting he trained me. In a million different fields. Basically, everyday in every way, he'd build a little bit of Pi in my head. Little by little there were blocks and blocks and blocks. By the end of it, I felt Pi was part of me.
What is the Ang Lee boot camp regiment?
Sharma: He never really tells you anything directly. He'll just get it in you. You'll understand without him really saying anything ever. It's really [imitates sound of a drum] — you gotta go with him. It's hard. He knows what he wants and he will get it out of you. So you don't really need to "act" you just need to listen to him. And it'll happen on its own.
I had all this training: yoga, meditation, weight loss, weight gain, learn how to swim, learn how to hold your breath, sea skills, fish, cut fish....
Who trained you to do all this stuff?
Sharma: All these people on the crew! We had a crew that was like a family to me. Everybody — be it the stunt people, Ang, the producers, the camera guys — everybody taught me something. I was there for 10 months and every day I learned something.
Was there a particular skill that was hard for you to master?
Sharma: Everything was extremely hard, but you get trained by some of the best people. The best at what they do. And because so many people are trusting you, you want to give it everything. There's no space for not learning.
It was a big risk putting me in the movie. I had never acted. I didn't understand why they were trusting me with it. But because they were trusting me... it gave me some serious drive.
How did you discuss Pi's faith with Ang, which is complex, but always present on the journey?
Sharma: There was never one conversation. He talked about religion, he talked about spirituality, he would talk about how religions are, he would talk about the central theme to everything. Looking for truth, faith or hope or whatever you anybody want to call it. It's common to all religions basically. There's the exterior shell, but inside it's all the same thing.
Did he have a method to explaining the character?
Sharma: There are a million ways he did it. He made me watch all these movies, which gave me an idea of what was going on at that point. 1960s, '70s. My favorite among them was The Bicycle Thief, which is just...wow. But he would also make me watch films like It's a Mad Mad Mad Mad World or Young Frankenstein. Anything to get an idea of what it was like at that time. We'd also do meditation every morning. It centers you.
You and Ang would actually meditate together?
Sharma: Oh, every morning. He was better at yoga than me! Ang as a director wants to be involved with everything. He wants to undergo the same thing to understand what he wants.
How did Ang help you understand what the world was going to be like when you were performing on the all-blue set?
Sharma: So over the months as we were building, by the end of it I too knew how Pi was going to react. The other thing about Ang is he will make you feel however he wants you to feel and it won't be hard for him. You just have to look him in the eye and listen to him.
What types of things is he saying to you while directing?
Sharma: It's less about what he says than how he says it. I used to walk to the place he watched on set and I'd literally walk in with no feeling, no emotion whatsoever. He just explained the shot to me and looked me in the eye. There was a technique he taught me in the beginning where you get an idea of what emotion you want to portray and then you go, go, go, go, go back until you find something with a similar emotion. And then you live them again. You keep playing it and playing it until it's in font of you and you feel it. You do that, and you talk to Ang and you look him in the eye and even though you walked in completely numb, you walk out overflowing with emotion. Then you don't need to do anything. You go on camera and do what he says.
Then you see a tiger.
Sharma: [Laughs] Tigers, whales, everything.
Were you ever playing opposite a real tiger? Or even a guy in a tiger suit?
Sharma: Unless the tiger had to whack something from my hand, then there would be a string pulling it away. But mostly, it was an empty boat.
We had four tigers on set, being trained. They wanted it to be as real as possible so they needed reference. There were four different tigers of different sizes. I used to watch these tigers for long periods of time just to get an idea of how they react to things, move on the boat. Ang made me watch videos of tigers in different scenarios, different moods. Angry tigers, sad tigers, happy tigers, friendly tigers, tigers killing things... you get an idea, but you can never have an idea of what a tiger is really thinking [laughs]. But you get a sense and deal with it.
Even though it uses a lot of special effects, were the stunts you performed real?
Sharma: Oh yeah. Lots. That was my favorite part. This movie was extremely physical and I didn't know how to swim when I came into Taiwan. They tossed me in the ocean. I learned somehow [laughs]. I came in really skinny with no muscle. I had gain weight and become stronger. You can deal with most things after you've done that.
Charlie and Cameron who were the main stunt guys, they became very close to me. Cameron was my aid. We would work every day for three hours. Swim underwater training. There would be weights tied to me and I'd have to go across swimming. All day. I'd sink to the bottom of the pool and I'd pull a rope to get to the other side. Then I'd have to lunch during the time I had to lose weight. We'd work out, but I'd eat tuna and lettuce after that. But I became strong and I could swim forever. I felt like a fish — nothing could sink me.
We just went and did the stunts. I'd be hanging upside down on a boat and there would be waves and I'd be submerged and then come back and submerged. Then the boat would flip — BOOM! — and I'd be holding on to it — BAM! — and then I'd jump off the ship.
Have you kept up the training?
Sharma: [Laughs] I will never be as strong as I was back then. It was awesome. I used to feel like Superman.
[Photo Credit: 20th Century Fox]
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Located in the left field corner of the Excelsior Level, the Acela Club features a fine-dining and hospitality experience inspired by winner of the James Beard Outstanding Restaurateur award Drew Nieporent and his world renowned Myriad Group of Tribeca Grill and Nobu fame.
The restaurant and bar is complete with indoor and outdoor tiered seating overlooking the playing field and a large dining room with views of the New York City skyline and the World's Fair Marina.
Come visit for a glass of wine or a cocktail at the bar or sit down and enjoy the exquisite prix fixe menu.
Guests in the following seating areas are eligible to access the Acela Club:
*All Season & 40-Game Plan seat holders also have access.Reservations:
Contact Metropolitan Hospitality to book Bar/Bat Mitzvahs, trade shows, dinners, luncheon events, and large receptions in the Acela Club on non-gamedays.


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Wine-tasting at Lagos Mare Hotel
Connecting with the true identity of the Cyclades
Last Sunday, at Lagos Mare, we "raised our glasses" to the future of the Greek wineries, during a gracious evening dedicated to contemporary wine production in the Cyclades. Three important producers honed us with their presence; Mr. Dimopoulos from Santorini, Mr. Moraitis from Paros and Mr. Asimomitis from Mykonos, and talked about the thing they love so: how do they make great wine.
The wine-tasting that was organized by the Travel Center for the members of The Culinary Historians of Boston, took place by the lighted swimming pool of our hotel. The most interesting conversations emerged around the quality of local grape varieties, organic vineyards and the special characteristics of each island's soil… Our guests tasted wines from the varieties of Assyrtico, Athiri and Aidani from Santorini; Monemvasia, Assyrtico, Malagouzia, Mantilaria and red Aidani from Paros; Ai-giannitis and Mantilaria from Mykonos.
The event evolved into a complete gourmet experience, thanks to the creativity of Mr. Nikos Petrakis, Chef of Lagos Mare Hotel. Mr. Petrakis composed a menu based on a combination of local cheeses and naxian products suitable to bring out the flavors of the selected bottles.
It was a warm spring evening, where the ancient aromas of local grape varieties made us connect with the true identity of the Cyclades and with its deep-rooted history.
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