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Winship Cancer Institute

Without intent, yet malignant

Brain cancer doesn’t have a purpose or intent. It’s just a derangement of molecular biology, cells that keep growing when they’re not supposed to.

But it’s difficult not to think in terms of purpose or intent when looking at what cancers do.  For example, Winship Cancer Institute scientists Abdessamad (Samad) Zerrouqi, Beata Pyrzynska, Dan Brat and Erwin Van Meir have a recent paper in Cancer Research examining how glioblastoma cells regulate the process of blood clotting.*

Blood clots, often in the legs, are a frequent occurrence in patients fighting glioblastoma, the most common and the most aggressive form of brain cancer. Zerrouqi and http://www.gooakley.com/ Van Meir show that a tumor suppressor gene (p14ARF) that is often mutated in glioblastoma stops them from activating blood clotting. Take away the gene and glioblastoma cells activate the clotting process more.

At first glance, a puzzle emerges: why would a cancer “want” to induce blood clots? Cancer cells often send out growth factors that stimulate the growth of new blood vessels (angiogenesis). The cells are growing fast, thus they need their own blood supply. Activating clotting seems contradictory: why build a new highway and then induce a traffic jam?

Thrombosis-necrosis

The two left arrows indicate clots causing necrosis around the vessels. Cells at the edge of the necrotic zone (right arrow) tend to be more proliferative and invasive. Image courtesy of Zerrouqi.

In a way, tumor cells are acting somewhat Nietzschean, blindly managing their own cheap oakley evolution according to the principle “Whatever doesn’t kill me makes me stronger.”

Blood clots lead to both destruction of the healthy and tumor tissue and hypoxia, a shortage of oxygen that drives more aggressiveness in the tumor. The clots create “micro-necroses” at the leading edge of the tumor that over time probably fuse and create a big central necrosis.

“The paradox is that the tumor kills itself and the normal brain, yet the capacity of doing this is the hallmark of the most malignant form of this tumor,” Van Meir says.

“The advantage of tumoral thrombosis will be selection of cells to progress to higher aggressiveness: infiltrative,  resistant to death with conventional Oakley Sunglasses cheap therapies, metabolically adapted to low levels of oxygen and nutrients,” Zerrouqi says. “At this stage, the tumor seems to have a clear deadly intent.”

A fragment of one of the proteins that cancer cells use to exert the clotting effect, called TFPI2, could be used to antagonize blood clotting  therapeutically, they write in Cancer Research. The findings could also have implications for understanding the effects of current medications, such as the angiogenesis inhibitor bevacizumab, also known as Avastin.

*A paper by Van Meir and Dan Brat from 2005 is the top Google link under the search term “glioblastoma clotting.”

Posted on by Quinn Eastman in Cancer Leave a comment

Stop the blob!

For your viewing pleasure, we have two videos, courtesy of Winship Cancer Institute’s Adam Marcus. He and his colleagues are investigating whether Withania somnifera, a root used in Indian traditional medicine, could be a source for drugs that inhibit breast cancer invasion and metastasis. Metastasis occurs when cells from a primary tumor migrate to a new location and invade the tissues at the new location.

The first video, the blob that grows, shows MCF10a mammary Ray Ban outlet epithelial cells undergoing epithelial-mesenchymal transition (EMT) in response to TGF-beta. This is a laboratory model for understanding breast cancer invasion and metastasis.

The second shows what happens when the same cells are treated with an extract from Withania somnifera. The blob doesn’t expand in such a threatening way anymore! The results were recently published in PLOS One.

 

Posted on by Quinn Eastman in Cancer Leave a comment

When cells fix DNA the wrong way

Cells sometimes “fix” DNA the wrong way, creating an extra mutation, Emory scientists have revealed.

Biologist Gray Crouse, PhD, and radiation oncologist Yoke Wah Kow, PhD, recently published a paper in Proceedings of the National Academy of Sciences that shows how mismatch repair can introduce mutations in nondividing cells. Their paper was recognized by the National Institute of Environmental Health Sciences as an extramural paper of the month. The first author is lead research specialist Gina Rodriguez.

In DNA, a mismatch is when the bases on the two DNA strands do not conform to Watson-Crick rules, such as G with T or A with C. Mismatches can be introduced into DNA through copying errors as well as some kinds of DNA damage.

If the cell “fixes” the wrong side, that will introduce a mutation (see diagram). So how does the cell know which side of the mismatch needs to be repaired? Usually mismatch repair is tied to DNA replication. Replication enzymes appear to somehow mark the recently copied strand as being the one to replace — exactly how cells accomplish this is an active area of research.

In some situations, mismatch repair could introduce mutations into DNA.

Overall, mismatch repair is a good thing, from the point of view of preventing cancer. Inherited deficiencies in mismatch repair enzymes lead to an accumulation of mutations and an increased risk of colon cancer and other types of cancer.

But many of the cells in our bodies, such as muscle cells and neurons, have stopped dividing more or less permanently (in contrast with the colon). That means they no longer need to replicate their DNA. Other cells, such as resting white blood cells, have stopped dividing temporarily. Mutations in nondividing cells may have implications for aging and cancer formation in some tissues.

Through clever experimental design, Crouse’s team was able to isolate examples of when mismatch repair occurred in the absence of DNA replication.

As the NIEHS Newsletter notes:

“The researchers introduced specific mispairs into the DNA of yeast cells in a way that let them observe the very rare event of non-strand dependent DNA repair. They found that mispairs, not repaired during replication, sometimes underwent mismatch repair later when the cells were no longer dividing. This repair was not strand dependent and sometimes introduced mutations into the DNA sequence that allowed cells to resume growth. In one case, they observed such mutations arising in cells that had been in a non-dividing state for several days.”

Although the Emory team’s research was performed on yeast, the mechanisms of mismatch repair are highly conserved in mammalian cells. Their results could also shed light on a process that takes place in the immune system called somatic hypermutation, in which mutations fine-tune antibody genes to make the most potent antibodies.

Posted on by Quinn Eastman in Cancer 2 Comments

The challenges of graduate school

Biochemist Paul Doetsch’s recent appearance in a Science magazine feature on laboratory leadership led to a conversation with him about the challenges of graduate school.

He emphasized that scientific research is a team sport, and brilliance on the part of the lab head may not yield fruit without a productive relationship with the people in the lab. Doetsch suggested talking with Lydia Morris, a graduate student in the Genetics and Molecular Biology graduate program. Morris has been working in Doetsch’s lab for several years and is about to complete her degree. She has been examining the in vivo distribution of DNA repair proteins.

In this video, Morris and Doetsch talk about the differences between turn-the-crank and blue-sky projects, and the importance of backup projects, communications, high expectations and perseverance.

Posted on by Quinn Eastman in Cancer Leave a comment

Lab management: leading by example

Paul Doetsch, PhD

Cancer researcher Paul Doetsch is a prominent voice in a recent feature in Science magazine’s Careers section. The article gives scientists who are setting up their laboratories advice on how to manage their laboratories and lead by example.

Doetsch holds a distinguished chair of cancer research and is associate director for basic research at Winship Cancer Institute. His research on how cells handle DNA damage has provided insights into mechanisms of tumor formation and antibiotic resistance. His lab includes five graduate students, two senior postdocs and one technical specialist.

From the article:

Doetsch says that he tries to maintain a lab culture that provides technicians, students, postdocs, and research faculty a sense of “ownership” of their projects and to give the message everyone is making a significant contribution to the research enterprise, regardless of their specific title or role.
“I make it a point to walk around my lab several times a day to chat with my group and hold individual weekly research meetings with each member to get an update of their progress and provide them with direct, constructive feedback on their activities,” he says. “I always strongly encourage everyone to discuss their results and other issues affecting their project with their lab colleagues and to not hesitate to disagree with me when necessary.”

Author Emma Hitt was herself a graduate student at Emory.

Posted on by Quinn Eastman in Uncategorized Leave a comment

Esophageal lesions meet their match

Field Willingham, MD, MPH

Once esophageal tumors establish themselves, a patient’s prognosis is grim and morbidity vast. But when lesions are caught early and removed, especially in the premalignant stage, the odds of survival markedly improve.

When a case calls for it, Emory gastroenterologist Field F. Willingham, MD, MPH, uses a hybrid approach to ousting superficial esophageal lesions. Superficial esophageal lesions are commonly caused by acid reflux disease, or GERD. GERD occurs when stomach acid flows into the esophagus and can lead to a condition known as Barrett’s esophagus, where the cells in the lower esophagus become damaged. This in turn can lead to dysplasia, or pre-cancerous cells.

But for superficial cancers, it is now possible to remove a portion of the lining layer of the GI tract, containing the tumor, with an endoscope.  This can help carefully selected patients avoid a major surgery. The technique, known as an EMR, allows the removal of superficial esophageal tumors and pre-cancer with an endoscope, a slender tube-like instrument.

Detecting and removing esophageal tumors early is essential for a favorable outcome. Once tumors firmly establish themselves in esophageal tissue, the prognosis is grim and morbidity vast. In the past, a diagnosis of an esophageal tumor meant the removal of the esophagus and often the stomach. But now EMR can be used in tandem with radio frequency ablation.

In surgical situations in which radio frequency ablation is not feasible, Willingham and his colleagues are beginning to use an alternate technique, known as cryotherpay, in tandem with EMR. Cryotherapy involves freezing superficial cells to rid the esophagus of suspect cells.

“So, if the end of the esophagus is twisted, or if we can’t touch it with this balloon device, then we can use cryotherapy,” says Willingham. “We’re trying to kill the lining layer with the tumor cells without killing the deeper layer.”

Willingham and his colleagues are seeing evidence that using these very three very different, technologies in tandem or alone will provide patients with a better way to rid them of esophageal lesions while preserving their quality of life.

Posted on by Robin Tricoles in Uncategorized Leave a comment

Smoking’s reach – and risk – even broader than we thought

Smoking’s link to lung cancer has been well-known for decades, but we are still learning about its cancer-causing effects on other organs.

An article in the Journal of the American Medical Association (JAMA) provides solid epidemiological evidence that smoking’s link to bladder cancer is even higher than previously believed. And, the elevated risk factor appears to be the same for men and women.

Viraj Master, MD, PhD

“This is something I see in my practice every day,” says Viraj Master, associate professor of urology, Emory School of Medicine and director of urology clinical research at the Winship Cancer Institute of Emory University. “The dangers of smoking are pervasive. Patients are often surprised to hear of the link between smoking and bladder cancer, but it’s there, and it’s a very real risk.”

The bladder may not be the first organ you think about when you think about the harmful effects of cigarette smoking. After all, when a person inhales cigarette smoke, the mouth, throat and lungs are the primary destination. But, a lethal change in the composition of cigarettes makes the bladder a target for cancer.

Written by researchers at the National Cancer Institute, the study explains that while there is less tar and nicotine in cigarettes now that in years passed, there also has been “an apparent increase in the concentration of specific carcinogens,” including a known bladder cancer carcinogen and tobacco-specific nitrosamines. The study authors also note that epidemiological studies have observed higher relative risk rates associated with cigarette smoking for lung cancer.

“The take-home message, of course, is the same as it long has been – don’t start smoking, and if you do smoke, stop,” says Master. “We need to do everything in our power to both stop people from starting to smoke and to help those already addicted to stop.”

Posted on by Kerry Ludlam in Uncategorized Leave a comment

Sunscreen: Looking Beyond the Numbers

Carl Washington, MD

Seems pretty obvious – if a sunscreen with an SPF of 30 is good, then an SPF of 100 should be at least three times as good.

Unfortunately, that is not the case.  There are other important details to consider when you are purchasing a sunscreen.

“People have become much more educated about the importance of using sunscreen, and manufacturers have responded with an abundance of products,” says Carl Washington, MD, associate professor of Dermatology at Emory University School of Medicine. “Unfortunately, the labeling can be confusing and many of the current sunscreens only contain the ingredients necessary to offer protection against sunburn, but not skin cancer or aging.”

Recently, the Food and Drug Administration created new regulations to establish standards for sunscreen manufacturers to follow before they label their products.

Under the new regulations, which will go into effect in 2012, sunscreen products that protect against all types of sun-induced skin damage will be labeled “broad spectrum” and “SPF 15” or higher on the container. Only products that have been tested to ensure they protect against both UVA (ultraviolet radiation A) and UVB (ultraviolet radiation B) radiation will be allowed to use this labeling.  Broad-spectrum sunscreens of SPF 15 and higher can also be labeled as protective against skin cancer and premature aging. The maximum SPF value is set at 50-plus because the FDA says anything higher doesn’t provide a significant amount of additional protection.

Manufacturers will have to include warning labels on products that are not broad spectrum. Products that claim to be water resistant must indicate how long the consumer should expect to be protected in the water, and using such language as “waterproof” or “sweat proof” will not be allowed.

“Skin cancer is the most common form of cancer in the United States, and the number of people affected keeps rising. Simply getting into the habit of using a sunscreen every day – with the appropriate levels of protection – can make a significant difference in preventing many skin cancers, as well as premature aging,” says Washington.

“These new regulations will help consumers understand the difference in degrees of sun protection, and choose carefully.”

Washington also suggests staying out of direct sunlight between 10 am and 2 pm, seeking shade when you are outdoors, remembering to reapply sunscreen every two hours and wearing protective clothing.

Posted on by Kathi Baker in Uncategorized Leave a comment

Emory University Hospital Set to Be Launch Site for EPIC

Can it really be possible to transform a person’s own cells into a weapon against various forms of disease? And what if those very cells could be retrained to attack cancer cells or to prevent autoimmune diseases?

Answers to these questions and many more are about to soon be realized, as Emory University Hospital will serve as the launch site for the very appropriately-named EPIC (Emory Personalized Immunotherapy Center).

The new Center, which is the creation of Dr. Jacques Galipeau, MD, professor of hematology and medical oncology & pediatrics of Emory University, will soon be operational after final touches have been put on construction of the lab. This cell processing facility will foster development of novel personalized cellular therapies for Emory patients facing catastrophic ailments and unmet medical needs.

According to Galipeau, the premise of EPIC and its overlying mission will focus on cellular and biological therapies that use a patient’s own cells as a weapon to seek and destroy cells that actually make a person sick. In partnership with the Winship Cancer Institute of Emory University, Children’s Healthcare of Atlanta, Aflac Cancer & Blood Disorders Center and the Emory School of Medicine, EPIC seeks to improve the health of children and adults afflicted with cancer and immune disease.

“First and foremost, we seek to bring a level of care and discovery that is first in Georgia, first in human and first in child. Blood and marrow derived cells have been used for more than a quarter century to treat life threatening hematological conditions and are now established therapies worldwide. More recently, the use of specific adult somatic cells from marrow, blood and other tissues are being studied in cellular medicine of a wide array of ailments including heart, lung, neurological and immune diseases,” says Galipeau. “The use of blood borne immune cells can also be exploited for treatment of cancer, autoimmune disease, organ transplantation and chronic viral illnesses such as HIV.”

Galipeau said that once operational, EPIC will begin by working with Crohn’s disease in pediatric and adult patients, an inflammatory bowel disease. Symptoms of Crohn’s disease include severe abdominal pain, diarrhea, fever, weight loss, and the inability for a child to properly grow. Resulting bouts of inflammation may also affect the entire digestive tract, including the mouth, esophagus and stomach.  In some cases, a radical surgery involving the removal of part of the lower intestinal tract is required.

“There is no current answer for what specifically causes Crohn’s disease, nor is there a cure. But we hope that through our research and efforts, we will be able to first target the inflammatory mechanisms in these patients through immunotherapy, and in turn reduce the amount of flare-ups and limit  the damage that occurs from this disease,” says Galipeau.

Galipeau says the EPIC program could represent a powerful cornerstone to the launch and the development of an entirely new, Emory-based initiative which bundles the strengths of the School of Medicine, Emory University Hospital, Children’s Healthcare of Atlanta, and many Woodruff Health Sciences Center centers of excellence,” says Galipeau.

“My ultimate goal is to elevate the biomedical scientific and scholarly enterprise to a higher level – making a difference in the lives of people. The EPIC program and multi-levels of support could be a fundamental underpinning to our success.”

Posted on by Lance Skelly in Immunology Leave a comment

Proton Therapy and Its Importance to Georgia

From Clinic to You

By Walter J. Curran, Jr., MD
Executive Director, Winship Cancer Institute
Chair, Department of Radiation Oncology, Emory University School of Medicine

Walter J. Curran, Jr., MD

Walter J. Curran, Jr., MD

Emory Healthcare is a key player in plans to bring the world’s most advanced radiation treatment for cancer patients to Georgia.  Emory Healthcare has signed a letter of intent with Advanced Particle Therapy, LLC, of Minden, Nevada, opening the door to a final exploratory phase for development of The Georgia Proton Treatment Center – Georgia’s first proton therapy facility.

For certain cancers, proton therapy offers a more precise and aggressive approach to destroying cancerous and non-cancerous tumors, as compared to conventional X-ray radiation. Proton therapy involves the use of a controlled beam of protons to target tumors with precision unavailable in other radiation therapies. According to The National Association for Proton Therapy, the precise delivery of proton energy may limit damage to healthy surrounding tissue, potentially resulting in lower side effects to the patient. This precision also allows for a more effective dose of radiation to be used.

Proton therapy is frequently used in the care of children diagnosed with cancer, as well as in adults who have small, well-defined tumors in organs such as the prostate, brain, head, neck, bladder, lungs, or the spine.  And research is continuing into its efficacy in other cancers.

The gantry, or supporting structure, of a proton therapy machine.

The gantry, or supporting structure, of a proton therapy machine.

The closest proton therapy facility to Georgia is the University of Florida Proton Therapy Institute in Jacksonville.  Currently there are only nine proton therapy centers in the United States, including centers at Massachusetts General Hospital, MD Anderson Cancer Center in Houston and the University of Pennsylvania.

This is an exciting development in our ability to offer not only patients throughout Georgia and the Southeast the widest possible array of treatment options but patients from around the world who can come to Atlanta via the world’s busiest airport, Hartsfield-Jackson International. In addition, we will work to expand its utility and access for patients through collaborative research projects with Georgia Tech and other institutions. Winship physicians will also be able to reach out to their international colleagues and provide direction in how best to study and implement this technology in the care of cancer patients.

Under the letter of intent, Emory Healthcare faculty and staff will provide physician services, medical direction, and other administrative services to the center. Advanced Particle Therapy, through a Special Purpose Company, Georgia Proton Treatment Center, LLC, (GPTC) will design, build, equip and own the center.  The facility, which will be funded by GPTC, will be approximately 100,000 square feet and is expected to cost approximately $200 million.  Site selection for the facility is underway, and pending various approvals, groundbreaking is expected in the Spring of 2012.

Video

The follow video presents a 3D simulation of proton therapy technology.

Additional Information:

Posted on by Vince Dollard in Uncategorized 1 Comment