Alternative antibody architecture

The complex genomic apparatus for making lampreys' antibody-like receptors

The age of blood

Investigating how long blood can be stored before the benefit of transfusion is compromised

PTH for stroke: stem cells lite

Spur the body's regenerative agents to emerge from the bone marrow

Winship Cancer Institute

Pilot human trial for image-guided cancer surgery tool

The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.

Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One. A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.

To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.

As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.

ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.

[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]

In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Valproate: epigenetic solvent

Oncologist Johann Brandes and colleagues from Winship Cancer Institute have a recent study on the preventive effects of valproate, now prescribed for epilepsy and bipolar disorder, against head and neck cancer.

Published in Cancer, it was a clever example of number crunching, using data from the Veterans’ Administration. If you want to know about the anticancer effects of a widely used drug, check who’s already taking it for another reason (25,000 veterans were taking it). The results suggest that valproate – OR a drug that works with a similar mechanism – might be used to prevent head and neck cancer in patients who are at high risk. Also see this related paper from Brandes and colleagues on chemoprevention in lung cancer.

However, any examination of valproate should take into account neurologist Kim Meador’s work on antiepileptic drugs taken by pregnant women — he was at Emory for several years but recently moved to Stanford. His work with the NEAD study definitively showed that valproate, taken during pregnancy, increases the risk of birth defects and intellectual disability in children.

There’s even more about valproate: it might help tone-deaf adults learn to differentiate musical tones, according to one study. It has been used to enhance the reprogramming of somatic cells into induced pluripotent stem cells. It seems that valproate just shakes things up, turning on genes that have been off, erasing decisions that cells have already made.

Valproate is a tricky drug, with several modes of action: it blocks sodium channels, enhances the effects of the inhibitory neurotransmitter GABA, and inhibits histone deacetylases. Although the first two may be contributing to the antiepileptic effects, the last one may be contributing to longer-lasting changes. Histone deacetylases are a way a cell keeps genes turned off; inhibit them and you loosen things up, allowing the remodeling of chromatin and unearthing genes that were silenced.

In tumors, genes that prevent runaway growth are silenced. It may be that valproate is loosening chromatin enough to allow the growth control machinery to reemerge, although the effects observed in the Brandes paper are specific for head and neck cancer, and not other forms of cancer. The data suggest that valproate has a preventive effect with respect to smoking-related cancers and not viral-related cancers.

With adults at high risk of cancer recurrence, side effects from valproate may be more acceptable than in other situations. Even so, with follow-up research, it may be possible to isolate where the anticancer effects of valproate come from – that is, which histone deacetylase in particular is responsible – find a more specific drug, and avoid potential broad side effects.

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment

Shoutout to Not a Mad Scientist

Cheers to microscopist and Winship Cancer Institute researcher Adam Marcus, who has started his own blog called “Not a Mad Scientist.” His first post talks about his educational outreach activities:

I have a super huge, somewhat tattered, and quite ugly suitcase that sits in my office.  This suitcase is not packed with clothes or extra large toiletries, but contains a pretty cool microscope, computer, and some shipping foam. Every few weeks I wheel it into the hallway, then into the elevator, and eventually into my car. The suitcase and I end up in Kindergarten-12th grade classrooms where I try to teach children something about science that they would not normally see.  I try to give them something different, something real, something scientific. I have seen over 3,000 children in about 200 classrooms in rural and urban schools, from pre-K to 12th grade…

We had a post in October about his lab’s research investigating Withania somnifera, a root used in Indian traditional medicine that contains potential tools for stopping breast cancer invasion and metastasis. Marcus’ blog has a collection of microscope movies, which we hope he will keep current.

Posted on by Quinn Eastman in Cancer Leave a comment

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 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 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 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 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 resistanceHis 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
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