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Research News

In cancer's aftermath, helping survivors confront "late effects"
In cancer's aftermath, helping survivors confront
Smita Bhatia, M.D., M.P.H., director of UAB's new Institute for Cancer Outcomes and Survivorship, explains how cancer treatments can lead to chronic health conditions in later life — and how "survivorship clinics" will help.

Written by Matt Windsor

This article is adapted from a video interview with Dr. Bhatia on UAB’s MD Learning Channel.

Smita BhatiaEven after cancer is defeated, it can cast a lifelong shadow. “Cancer survivorship represents a very critical phase,” said Smita Bhatia, M.D., M.P.H., a pediatric oncologist and director of the new Institute for Cancer Outcomes and Survivorship in the UAB School of Medicine and associate director for cancer outcomes research at theUAB Comprehensive Cancer Center. “We and others have shown in our research studies that our cancer survivors are a vulnerable population,” she said. “When you follow them long-term, you find that they have a very high burden of chronic health conditions.”

Often, these health problems can be linked back to cancer treatments, including chemotherapy, radiation and even surgeries, Bhatia said. Because these complications can occur “many years after the completion of treatment,” they are called “late effects.” One example involves a particular class of chemotherapy drug known as anthracyclines. “We use these agents often because they are highly effective in a large variety of cancers,” Bhatia said. But research shows that patients who take these drugs have a high risk of developing congestive heart failure many years later.

Girls who have “received radiation to the chest around puberty for lymphoma,” have “an increased risk of breast cancer,” Bhatia added. And this breast cancer “occurs at a much younger age than would be anticipated in the general population. So these girls are developing breast cancer at age 30 and 40, whereas in the general population you’d be anticipating breast cancer at age 60.”

Results from a survey have shown that only a third of patients realize they are at risk for these late effects, and because the family practitioners and internists who are seeing these patients do not encounter cancer survivors very often, “it is not in the forefront in terms of their understanding, in terms of their knowledge base and in terms of their experience of what they should anticipate,” Bhatia said. Addressing this situation becomes even more urgent as the number of survivors grows, she adds. “The number of cancer survivors is growing at the rate of about 2 percent every year,” Bhatia said. “We will, by about 2022, have 18 million cancer survivors.”

“In order to provide the most comprehensive long-term care to our survivors, we need care plans. These “are essentially a summary of all the treatment that the patients received for their particular cancer, along with recommendations for long-term follow-up in order to detect complications.”

That is why UAB is establishing special survivorship clinics. “In order to provide the most comprehensive long-term care to our survivors, we need care plans,” Bhatia said. These “are essentially a summary of all the treatment that the patients received for their particular cancer, along with recommendations for long-term follow-up in order to detect complications.”

The idea, Bhatia said, is to lay out “a roadmap for our cancer survivors for life. That’s what I would like to do for all our cancer survivors who are coming to UAB, no matter what diagnosis they have, no matter what their age is, from here on.”

Survivorship clinics are staffed by physicians, nurse practitioners, social workers, psychologists, and dietitians, “who provide absolutely comprehensive but very tailored care to the survivors,” Bhatia said. “So we would, for example, do heart tests in order to detect heart failure at an earlier stage only amongst patients who’ve received treatments that are toxic to the heart. Mammograms would be recommended for patients who’ve received radiation to the chest at a young age, and who are at risk for breast cancer.”

This “very tailored but anticipatory screening” is designed “to detect these complications at an earlier stage,” said Bhatia.

The same survivorship model can now be extended to care for patients with many different chronic health conditions, Bhatia says. These include patients with sickle cell disease, HIV, congenital heart disease — “any chronic condition where the health care providers can really coordinate the care of the patient as a whole, the entirety of their health, and provide complete and comprehensive care long-term.”

On the front lines of the heroin epidemic, offering a lifesaving treatment
On the front lines of the heroin epidemic, offering a lifesaving treatment
Naloxone kits have prevented more than 10,000 deaths from opioid overdose since local distribution programs began in 1996. Now, as deaths from opioid overdose reach an all-time high in the United States, a crowdfunded project from UAB researchers aims to put naloxone in the hands of those at highest risk.

Written by Matt Windsor

Deaths from opioid overdose are at an all-time high across the United States, and Birmingham has been hit particularly hard. In the past four years, heroin overdose deaths in Jefferson County and surrounding areas rose from 12 individuals to 137. But a team of UAB researchers is taking action to respond.

The group is led by Karen Cropsey, Psy.D., an associate professor in theUAB School of MedicineDepartment of Psychiatry and Behavioral Neurobiology. Cropsey specializes in substance abuse treatment in vulnerable populations; some of her current research programs involve treatment of individuals in the criminal justice system and people living with HIV/AIDS. She regularly witnesses the devastation of prescription opioid and heroin overdose in Birmingham. “I felt like there was something we could do about that,” she said.

To combat the rising rates of death from overdose, Cropsey and her team are exploring the distribution of naloxone kits directly to individuals with opioid addictions, or their caregivers. Using naloxone isn't a new idea. It's been the standard of care for opioid overdose in emergency rooms, including at UAB, since the early 1970s. The kits offer a last resort option to reverse an opioid overdose and prevent death. Several states, including California, New Mexico and Massachusetts, have successful local distribution programs for naloxone. In 2010 the CDC reported that since the first local distribution programs began in 1996, naloxone kits have prevented more than 10,000 deaths from opioid overdose.

Nalonoxe Hydrochloride 2

Naloxone to the people

Cropsey and her colleagues want to bring a naloxone program to Birmingham as well. But “our program is different,” Cropsey said. Instead of distributing naloxone kits to first responders and law enforcement officers — the typical model — the UAB team wants to try a new approach: prescribing kits to individuals.

By taking advantage of the new Crowdfunding at UAB site, Cropsey’s team raised grassroots financial support for a unique study. In 30 days, the team collected $11,500 in pledges — enough to purchase more than 200 naloxone kits. Now they’re working to get the kits into the hands of the people who need them most: active opioid and heroin users.

The researchers are now hanging flyers around Birmingham and screening individuals interested in participating. They will be collecting information on how many kits are used, how many deaths they prevented and if participants follow up with treatment options after using naloxone. “I want to demonstrate that these kits can save lives,” Cropsey said. 

Participants in the study are receiving training “on how to recognize signs of opioid overdose and how to administer the naloxone,” Cropsey said. They are instructed to then call 911 and go to the emergency room. Training is also being offered to friends or family members. It’s analogous to an EpiPen for someone with allergies, or insulin for someone with diabetes, Cropsey says the person who is prescribed the treatment may not be able to use it when it’s needed.

How naloxone works

When a person overdoses on an opioid, their breathing starts to slow down. After about one to two hours — or as short as a few minutes — breathing slows to a stop. This leaves a narrow but vital window to intervene. Opioids such as heroin or prescription drugs, including hydrocodone and oxycodone, work by latching on to receptors in the brain that produce their powerful effects. Naloxone rapidly displaces these drugs and then occupies the receptors so the opioid cannot return. Within minutes, the opioid is completely removed and the person who overdosed begins to breathe again.

But that success comes at a price. With complete removal of the opioid’s effects on the brain, naloxone puts the user into immediate, severe withdrawal. Imagine a sudden onset of the worst flu-like symptoms you’ve ever had, Cropsey explained. It’s “the nuclear option for people who would otherwise die.”

Make a gift to support the naloxone crowdsourcing project

“They need to be alive to get treatment”

Working with such a stigmatized group of people brings challenges, Cropsey says. She often hears that people addicted to drugs should just quit — that they choose to be addicted in the first place and need to choose to stop. But while addiction does start as a choice, Cropsey explains, it doesn’t take long for a user’s system to get hijacked by the drugs.

Besides, many of us are dealing with the consequences of choices that negatively affect our health, she adds. Whether it’s Type 2 diabetes or obesity from our eating habits, or lung cancer from smoking, a majority of the leading causes of death result from behavioral choices we make, Cropsey said. “Addiction is a medical disease just as much as heart disease or diabetes.”

In an ideal world, no one would use drugs, Cropsey said. “Unfortunately that’s not the case here. We don’t live in an ideal world.” More than 2.5 million people in the United States abuse prescription opioids or heroin. Addiction finds its way into the lives of our families, friends and coworkers, Cropsey said. “What would you do if this was your friend or family member?”

Cropsey acknowledges the argument that distributing kits is simply enabling addiction. Naloxone kits reduce harm of overdose by preventing death, she says, but they aren’t the complete picture. “The goal is to get people substance abuse treatment to help them stop using opioids,” Cropsey said. “But they need to be alive to get treatment.”

If you are actively using a prescription opioid or heroin, or are the friend or family member of an active user, and are interested in learning more about the program, call 205-975-4528 and ask about the naloxone study.

Molecular study points to possible therapy for autoimmune disease
Molecular study points to possible therapy for autoimmune disease
The challenge is to stifle the binding of inhibitory antibodies but retain activity of a blood enzyme.

Long ZhengLong ZhengA rare autoimmune disease creates sudden pain in the abdomen or the head, sending a patient to the emergency room with a potentially fatal condition. The pain comes from a multitude of blockages of tiny blood vessels, formed after the patient’s own immune system somehow inhibits an enzyme that is vital to control clotting.

The syndrome is called thrombotic thrombocytopenic purpura, or TTP, and treatment involves exchanging three to seven liters of plasma each day, at a cost of $10,000 a day. This costly care may continue for several weeks or months.

Long Zheng, M.D., Ph.D., the Robert B. Adams Endowed professor and director of the Division of Laboratory Medicine at the University of Alabama at BirminghamDepartment of Pathology, wants to create a faster and more effective treatment for these patients. This has led Zheng and colleagues to molecular-level studies of the antibody that inactivates a blood enzyme, called ADAMTS13. ADAMTS13 recognizes and cuts a blood adhesion protein called von Willebrand factor. The inhibition of ADAMTS13 activity by the antibody in TTP patients allows ultra-large von Willebrand factor to form disseminated microvascular clots.

The ability of ADAMTS13 to recognize von Willibrand factor is exquisitely sensitive, somewhat like a fan who goes to a football game with 50,000 people and yet recognizes his cousin out of all the faces in the crowd. Similarly, the ability of the autoimmune antibodies in a TTP patient to recognize and bind to the patient’s own ADAMTS13 enzyme is also exquisitely sensitive, picking only ADAMTS13 out of all the other possible “self” proteins in the body.

Learning the molecular details of these two recognition abilities will help Zheng subtly alter ADAMTS13, to produce a therapeutic enzyme that can elude recognition by the autoimmune antibodies, yet still retains its activity to cleave von Willebrand factor. Such an engineered enzyme could be given to TTP patients in the hospital to speed recovery and slash the cost of treatment.

In a paper published in the Proceedings of the National Academy of Sciences, “High Resolution Epitope Mapping by HX MS Reveals the Pathogenic Mechanism and a Possible Therapy for Autoimmune TTP Disease,” senior author Zheng and colleagues report on those molecular details. The results reveal, for the first time, the mechanism of the inhibition of ADAMTS13 by autoantibodies and suggest an avenue for therapeutic intervention.

“This was really surprising. It’s like a table with five legs. If you take one away, it should still stand, but somehow it collapsed. This suggests that you need the coordinated activity of all five.”

The researchers found that five small loops in the protein’s amino acid sequence are necessary for the autoantibodies to bind to ADAMTS13. Cutting or substituting several amino acids out of any single one of the five loops prevented binding; furthermore, those small deletions in any single one of the five small loops also left the enzyme unable to cut von Willebrand factor.

“This was really surprising,” Zheng said. “It’s like a table with five legs. If you take one away, it should still stand, but somehow it collapsed. This suggests that you need the coordinated activity of all five.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor. More importantly, analysis of autoantibodies from 23 more TTP patients found that most use the same binding site, suggesting that a modified ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

The five years of research for this paper included the labs of Don L. Siegel, M.D., Ph.D., an expert in phage display, and S. Walter Englander, Ph.D., father of hydrogen exchange/mass spectrometry analysis to measure the protein-protein interaction regions of large proteins. Both Siegel and Englander are at the Perelman School of Medicine at the University of Pennsylvania, where Zheng used to work before moving to Birmingham.

The researchers first isolated messenger RNAs that code single chains of variable region of the monoclonal antibodies from B cells of patients with acquired TTP. They used a technique called phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies are then expressed in E. coli cells, purified, and biochemically characterized.

Of these, three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen (in H2O) exchange with deuterium (D2O) on each amino acid residue except proline. After reaction was stopped, the protein was then cut into small pieces (or peptide fragments) and run through HPLC for separation and mass spectrometry for identification. Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the three high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients. The results demonstrate that this particular binding epitope is common among patients with acquired autoimmune TTP.

Besides Zheng, co-authors are Veronica Casina, Wenbing Hu, Jianhua Mao, Rui-Nan Lu, Hayley Hanby, Brandy Pickens, Zhongyuan Kan, Woon Lim, Leland Mayne, Eric Ostertag, Stephen Kacir, Don Siegel and S. Walter Englander, all of the University of Pennsylvania. Zheng was recruited to UAB from the University of Pennsylvania in February and is the inaugural holder of the Robert B. Adams Endowed Professorship in Pathology in the UAB School of Medicine.

Ocean acidification to lead the way for food chain changes
Ocean acidification to lead the way for food chain changes
UAB research shows that phytoplankton, the foundation of all marine life, will experience varied growth rates due to ocean acidification levels during the next century.

Phytoplankton 2Thermal image of the Earth highlighting phytoplankton communities in purpleNew research published by University of Alabama at Birmingham researcher Jeffrey Morris, Ph.D., in Nature Climate Change, proposes the ocean’s food chain might operate differently in the future, based on the effects climate change will have on phytoplankton communities.

Phytoplankton’s role in the marine food chain is particularly significant. Phytoplankton, which are microscopic marine plants, form the foundation of the marine food web and regulate key biogeochemical processes. In a balanced ecosystem, phytoplankton provide food for a wide range of sea creatures, including whales, shrimp, snails and jellyfish.

“Because phytoplankton types are not physiologically interchangeable, changing which species are most common in a community can impact the cycling of elements, the flow of nutrients and energy through the marine food web,” Morris, assistant professor in UAB’s College of Arts and Sciences Department of Biology, said. “The implications could be substantial.”

While phytoplankton are extremely crucial to the marine ecosystem, these organisms face multiple environmental changes, including the decline in ocean pH, also known as ocean acidification, caused by rising atmospheric pCO2.

The world’s oceans have absorbed about 30 percent of fossil fuel carbon emissions caused by human activity, resulting in a significant decrease in surface ocean pH. Concerns over the impacts of ocean acidification on marine life have led to a number of laboratory and field experiments examining the response of marine life to acidification.

“One of the striking things about this work is it shows that all phytoplankton groups will be affected by ocean acidification — not just the groups that make calcium carbonate shells, like those you see on corals, which is what researchers have traditionally assumed."

Morris’ research analyzed published experimental data that assessed growth rates of different phytoplankton populations under typical and elevated pCO2 levels. The data showed a wide variety of responses. Morris, along with collaborators at MIT and Columbia University, then took the effect of ocean acidification on the different populations and studied it within the context of a global marine ecosystem to explore how marine phytoplankton communities might be impacted over the course of a hypothetical 21st century, from 2000 to 2100.

The model ocean changes through the 21st century included warming waters, decreased macronutrient supply, altered light environments, lower pH and increased pCO2 — approximately 0.3 pH units lower and thus twice as acidic. By 2100, temperatures and nutrient conditions were shifted latitudinally relative to 2000, but pCO2 was substantially altered everywhere in the open ocean. Morris’ research focused on global changes to phytoplankton community structure and biogeography as a result of the ocean alterations.

The research found that different types of phytoplankton responded to the alterations in different ways — some populations grew faster in the future and others grew slower, but all phytoplankton groups were altered in some manner.

“One of the striking things about this work is it shows that all phytoplankton groups will be affected by ocean acidification — not just the groups that make calcium carbonate shells, like those you see on corals, which is what researchers have traditionally assumed,” Morris said.

In all, the results emphasized that the differing responses to elevated pCO2 caused sufficient changes in competitive fitness between phytoplankton types to significantly alter community structure. Acidification specifically had a greater impact on the populations than warming or reduced nutrient supply did.

Morris’ research shows that the phytoplankton community will look different by 2100, which in turn will impact the structure of the marine ecosystem as a whole.

“We now know that the structure of phytoplankton populations will morph in the future,” Morris said. “Further research will help us determine how that shift will alter other marine life that depend on phytoplankton for survival, and the marine ecosystem in its entirety.”

“Holy guanine, Batman!” Superheroes and genetic genius at the frontiers of science
“Holy guanine, Batman!” Superheroes and genetic genius at the frontiers of science
Gene mastermind Shawn Levy, Ph.D., and his team at the HudsonAlpha Genomic Services Laboratory are helping UAB investigators — and researchers from around the world — crack the mysteries of life.

shawn levyWritten by Matt Windsor

In a chilly room at Huntsville’s HudsonAlpha Institute for Biotechnology, a multi-million dollar band of superheroes is solving genetic puzzles from around the globe. In the hands of Shawn Levy, Ph.D., and his crack team of sequencing experts, these next-generation machines are a centerpiece of the UAB-HudsonAlpha Center for Genomic Medicine, which is tackling cancer, Parkinson’s disease and other top health threats. They have also helped make Alabama a global leader in genetic discovery.

Levy, the director of the HudsonAlpha Genomic Services Laboratory, and his team have worked with more than 500 principal investigators and samples from every continent, including Antarctica. Between September 2009 and February 2015, the GSL sequenced more than 5,000 whole genomes and processed more than 100,000 external samples. Those numbers are set to grow exponentially with the arrival of 10 Illumina HiSeq X Ten sequencers this spring. Per GSL’s custom, each of these units gets a nickname. The previous generation Illumina HiSeq 2500s, which are still in use, were named after Muppets. For the X Tens, the lab chose comic superhero characters, including Batman, Electra and Wonder Woman. The ultra-quick new machines generate so much heat that they required a customized new space at HudsonAlpha, cooled by industrial-strength chillers.

These machines never sleep

The GSL’s advanced gene-sequencing machines, and sterling reputation, attract plenty of business — apart from maintenance periods, they toil away around the clock. “Shawn does beautiful work,” says Haydeh Payami, Ph.D., who is using large-scale gene sequencing to find new ways to prevent and treat Parkinson’s disease. (See related article.) “The best sequencing comes out of HudsonAlpha. And HudsonAlpha is one of the few places in the country that has the X Ten and the expertise to use it effectively.”

Collaborative opportunities with HudsonAlpha, Levy and his team helped convince Payami to leave New York in 2014 and become the first faculty recruit to the UAB-HudsonAlpha Center for Genomic Medicine.

gsl batmanSubway series

Levy, who is also an adjunct associate professor in the Department of Epidemiology at the UAB School of Public Health, and his team of expert scientists did all the sequencing on a blockbuster study of the New York subway that made national headlines last year. Researchers from Weill Cornell Medical College collected nearly 1,500 samples at New York’s 466 subway stations and sent them to HudsonAlpha for shotgun sequencing. “This was the first city-scale metagenomic profile,” Levy said. The lab detected more than 15,000 life-forms in those samples, and “almost half of the organisms we identified were unknown.”

Researchers for the study, known as PathoMap, also found that DNA data “correlates nicely with Census data,” Levy said, when they overlaid genetic predictions of ethnicity from samples collected at each stop with the actual population data from Census reports at those stops. The study proved that you can detect “humans’ molecular echo,” Levy added.

Exponential growth

In a recent symposium for researchers interested in the Center for Genomic Medicine, Levy offered an overview of the remarkable advances in sequencing technology over the past decade. Ten years ago, he explained, the commercial gene-sequencing era arrived with the debut of the Genome Analyzer, which could sequence 1 gig abase of data per run. (That is, 1 billion base pairs; there are 3.2 billion base pairs in the human genome.) Today, the X Ten can sequence up to 1.8 terabase (1.8 trillion base pairs) per run. Only four other locations in the country have higher sequencing capacity than HudsonAlpha, Levy noted.

The massive amounts of data generated by next-generation sequencing machines “put a substantial challenge on infrastructure,” Levy said. Next-gen machines put such stress on the hard drives in their attendant computers that the drives have to be replaced three times per year. HudsonAlpha and UAB are subsequently investing heavily in increased data storage and processing capacity. “You can pretty quickly get to a calculation where it’s cheaper to resequence a sample later than to store its data long-term,” said Levy.

That’s just one aspect of the ever-changing sequencing landscape. “We do a lot of research and development on the tech side,” Levy said. The GSL team works closely with manufacturers such as Illumina to pioneer new hardware and techniques. “We’re always exploring the next thing,” he said. The lab is currently testing single-cell sequencing machines from multiple manufacturers. “Everything that has been done so far is based on averages” generated by sequencing genes from many different cells, Levy explained. For blood and other body systems, “the question is better answered that way.” But for the brain or immune system, for example, the ability to sequence cell by cell “has opened up new things,” Levy said. “We can tease apart what all the different cells involved are doing.”

American-Scandinavian Foundation Translation Prizes

The Translation Prize includes a $2000 award, publication of an excerpt in Scandinavian Review, and a commemorative bronze medallion.
The Leif and Inger Sjöberg Award, given to an individual whose literature translations have not previously been published, includes a $1,000 award, publication of an excerpt in Scandinavian Review, and a commemorative bronze medallion.

Information and eligibility requirements are available at: