research

Curators Versus Cancer

By Kim Krieger | Illustrations by Kailey Whitman

illustration of scientist look over hundreds of books

A special team of medical literature experts are on the hunt for cancer’s kryptonite, one mutation at a time.


If the genetic code is like a book, then a mutation is like a typo. Some typos are meaningless. Others have such dramatic consequences for a book, or a life, that the error alone could have an entire novel written about it.

Cancer mutations are like that. As oncology moves toward precision medicine — the idea that if we knew exactly which genetic mutations make a particular cancer tick, we could pick exactly the right treatments — oncologists have to keep up with an ever-expanding library of mutations and the drugs that might foil them. The number of cancer research papers published increases every year; there were about 35,000 published in 2015 just in the U.S. It’s far more than any one person can keep up with.

In the same way that a university has research librarians who keep up with the literature in specific fields, JAX has experts who keep up with cancer gene and drug research, even studies that are ongoing and not yet published.

A new collaboration between UConn Health and The Jackson Laboratory (JAX) hopes to help oncologists find the right treatments by keeping up with research for them — and using the institutions’ combined expertise in cancer treatment, molecular biology, and genetics to improve patient outcomes for cancers that currently don’t have good treatments. In the same way that a university has research librarians who keep up with the literature in specific fields, JAX has experts who keep up with cancer gene and drug research, even studies that are ongoing and not yet published. JAX already successfully connects these experts with doctors in the Maine Cancer Genomics Initiative, a philanthropy-funded statewide precision medicine program. UConn Health and JAX hope to expand the concept and demonstrate its feasibility more widely.

A UConn Health researcher holds a tumor sample.

A UConn Health researcher holds a tumor sample. Kristin Wallace

Bull’s Eye Treatment

Imagine that a patient has surgery or a needle biopsy to diagnose a tumor. It’s a particularly ugly tumor, the surgeon, oncologist, and pathologist all agree. Invasive, spreading, and perhaps this isn’t the first time this patient has had to come in for cancer surgery. The tumor is sampled and sent for genetic testing. In about two weeks, the results come back: there are three genetic variants in the tumor that might be drug targets.

At UConn Health, oncologists can send portions of particularly malignant tumors to a team at the JAX Clinical Laboratory. JAX sends back a report with information the oncologist can use to pick a drug regimen with the best chance to shrink that ugly tumor. “The goal is to define the optimal treatment regimen for each individual patient” who may not have good options otherwise, says Dr. Ketan R. Bulsara, chief of neurosurgery at UConn Health and one of the principal investigators on the project.

At UConn Health, oncologists can send portions of particularly malignant tumors to a team at the JAX Clinical Laboratory. JAX sends back a report with information the oncologist can use to pick a drug regimen with the best chance to shrink that ugly tumor.

The report is intended to be a standalone reference an oncologist can use to inform a treatment plan. But if the oncologist is unfamiliar with one of the mutations identified in the report or just wants more information, they can request that a genomic tumor board be convened. The board is composed of surgeons, pathologists, and molecular oncologists who act as external advisors, sharing their opinions with the oncologist. In just 15 minutes, the oncologist can get a wealth of expert opinion to combine with their own expertise and judgment. In the end, the oncologist and patient decide on the best treatment, based on all the available information.

“In a multidisciplinary fashion, doctors and scientists work hand in hand in this with one common goal: identify the best treatment regimen for that particular patient’s pathology,” Bulsara says.
The focus is always on the patient. But behind the scenes, there’s an entire team of researchers whose work goes into the genetic tumor report. Scientists at JAX Clinical Laboratory sequence the tumor’s genetic code and report information on more than 200 cancer-related genes. The genes were picked because they are associated with both malignancy and potential drug treatments. Any mutations or variants in these genes might be a clue to the cancer’s weakness. Or a red herring.

“A typical tumor might have 2,000 mutations. Not all of them really matter,” says Andrey Antov, the program director for the Maine Cancer Genome Initiative at JAX. Finding the key mutations that matter, the two or ten or twenty that could possibly inform treatment and a better outcome for the patient, is the job of the clinical genomic curators.

Personal Librarians

The clinical genomic curators are specialists in fields such as molecular oncology and oncological pharmacology. They’re dedicated to keeping up with the literature on cancer genes and the drugs that target them. More and more of these drug-gene connections are being discovered every day. It’s exciting, but the sheer volume of papers can be overwhelming. Navigating that ocean of scientific papers is the medical curators’ full-time job. They’re like librarians curating a Boston Public Library–size collection of genes and drugs with no cross references in the card catalog and only an imperfect search function. The hope is that just as a good librarian’s knowledge of the subject matter can unearth texts a researcher would never otherwise find, a medical curator’s grasp of oncological genetics and pharmacology can identify potential treatments that would otherwise remain obscure.

Each mutation identified by the genetic panel might require 10 to 20 scientific publications to understand. Once the curators have a handle on the variants’ significance, the clinical laboratory decides which two or three should be described in the report to the oncologist.

illustration of books in a library cart

Sifting the information down to something relevant and digestible is the ultimate goal.

“Today, all this information is disorganized and may not all be in the oncologist’s head. We’re trying to bring it together,” says Jens Rueter, medical director for the Maine Cancer Genome Initiative.

The ideal outcome of a tumor genetic analysis would be to identify a mutation such as the HER2 gene that is turned on in the most aggressive breast cancers. HER2 is responsible for the cancer’s malignancy. But it’s also the cancer’s Achilles’ heel. Once drugs were developed to block the HER2 protein, survival rates climbed sharply.

The goal of the Maine Cancer Genomics Initiative is to enable oncologists to identify other drug-gene connections as potent as the ones found for HER2. Although more and more of these drug-gene connections are being discovered, it remains difficult to provide a patient with access to these drugs. Many of them are only available if a patient participates in a clinical trial. And often, there are barriers to accessing clinical trials, and getting drugs off-label is the only way to get patients to treatments. That’s another benefit that Antov, Bulsara, and Rueter hope UConn Health’s collaboration with JAX will bring.

Positive Outcomes

Ultimately, the researchers hope to demonstrate that this approach leads to better outcomes for patients. During the past year more than 350 patients and 70 oncology practitioners (more than 80 percent of the Maine oncology community) enrolled in the Maine Cancer Genomics Initiative study protocol. A few patients have already been offered a targeted treatment through a trial or a compassionate drug access program as a result of enrollment in the program. And Maine health care professionals have logged more than 1,200 certified education hours through 35 genomic tumor boards, online modules, and annual forums held by JAX.

So far, five patients have done this at UConn Health within the last two months. Generous donors have given enough to fund 20 more.

The hope is that just as a good librarian’s knowledge of the subject matter can unearth texts a researcher would never otherwise find, a medical curator’s grasp of oncological genetics and pharmacology can identify potential treatments that would otherwise remain obscure.

“We hope to get funding for at least 100 patients to show the feasibility of this approach,” Bulsara says. “We want to show we can do this reliably, and that it reliably improves patient care.”

UConn Health already has the infrastructure to do this, in particular a biorepository for tumors set up by Neag Cancer Center Director Dr. Pramod Srivastava and pathologist Dr. Melinda Sanders. With that foundation and support from UConn medical school Dean Dr. Bruce Liang and UConn Health CEO Dr. Andrew Agwunobi, the program was piloted in the Department of Surgery by Bulsara, its chief of neurosurgery, with support from Department of Surgery Chairman Dr. David McFadden, hematology and oncology chief Dr. Susan Tannenbaum, anatomical pathology chief Dr. Qian Wu, and JAX Clinical Laboratory Director Honey Reddi.

If the UConn Health–JAX initiative does prove its feasibility, the approach will continue to spread and become a standard of care.

More oncologists could have access to the library of knowledge and advice of a genetic tumor board, and more cancer patients could benefit from longer, healthier lives.

Tumor samples are housed in UConn Health's research biorepository.

Tumor samples are housed in UConn Health’s research biorepository. Kristin Wallace

Better Ways to Heal Bones

Julie Bartucca

illustration of engineers going over blueprint of human skeleton with engineering notes on the hip bones

UConn Health is engineering innovative solutions for bone and joint problems, promoting faster recovery and less trauma to the body.


We’ve all signed a child’s colorful cast on their broken arm, gotten a call to inform us an elderly relative fell and broke a hip, or been laid up with back spasms ourselves. Maybe you’ve had a knee replacement or dealt with joint pain from years of athletic activity. It’s practically inescapable — 1 in 2 American adults suffers from a musculoskeletal disorder or injury such as arthritis, chronic back pain, fractures, or osteoporosis, according to 2016 data from the United States Bone and Joint Initiative (USBJI).

This is compounded by the fact that the U.S. has a rapidly aging population and, as people age, they lose bone density and the risks increase. Experts say the incidence of and costs to treat such issues are in danger of spiraling out of control.

But researchers at UConn and UConn Health are using a host of materials and technologies — from stem cells to spider-spun silk fibers to hydrogel to ultrasound waves — to strengthen bones and joints and accelerate recovery from musculoskeletal diseases and injuries.

“Musculoskeletal injuries are among the most common reasons to see a doctor. If we can take care of those faster and more effectively, patients can get back to their activities and work faster.”

“Musculoskeletal injuries are among the most common reasons to see a doctor. If we can take care of those faster and more effectively, patients can get back to their activities and work faster, which helps everybody,” says Dr. Augustus D. Mazzocca, director of the UConn Musculoskeletal Institute (MSI) and chair of the Department of Orthopaedic Surgery at UConn Health.

“There’s the economic impact of having people out of work, and the emotional problems of people who lose mobility and are isolated,” he says. “We’re trying to bring you back into society and get you back to what you like to do.”

To that end, UConn Health doctors also are developing ways to get you home faster after any musculoskeletal procedure, including spearheading same-day joint replacements.

Faster, Safer Recovery

UConn Health hip and knee replacement patients don’t have to wait for our clinical innovations to come to market. They can benefit from new approaches to the surgeries right now — and “right now” might also describe when they can go home post-op.

“Nearly 100 percent of my patients go home within 24 hours, and some now the same day,” says Dr. Mo Halawi, a new UConn Health orthopaedic surgeon who specializes in joint reconstruction and is spearheading an effort to minimize the time these patients spend in the hospital recuperating.

“The criteria for discharge are identical whether a patient leaves on the day of surgery or several days later. But with minimally invasive techniques, regional anesthesia, blood-conserving strategies, opioid-sparing analgesia, and immediate mobilization, patients are now achieving recovery milestones a lot quicker than before,” he says.

According to Halawi, the ideal candidate for same-day total joint replacement is one who is independent, motivated, has a good support system, and has no major risk factors for surgical complications. Much of the work is done in advance to optimize patients’ health and prepare them for surgery, allowing for the
speedy discharge.

After surgery, Halawi takes a less-is-more approach. Patients get on their feet right away and have no IV medications, drains, catheters, dressing changes, braces, or laboratory tests. Very rarely do his patients get discharged to nursing homes or rehabilitation facilities. Studies have shown that “patients recover better and have fewer complications in the comfort
of their homes,” he says.

“Hip- and knee-replacement surgery is constantly evolving, and we need to always deliver safe, effective, efficient, and evidence-based medicine to our patients. Soon, more surgeons and patients will realize that long hospital stays and recovery times are outdated,” Halawi says.

Engineering Cartilage

Though it is in the very early stages of development, UConn Health tissue engineer Syam Nukavarapu and his team have created a hybrid hydrogel system that they hope is the first step toward forming a hypertrophic cartilage template with all the right ingredients to initiate bone tissue formation, vascularization, remodeling, and ultimately the establishment of functional bone marrow to repair long bone defects.

How the more than 200 bones in an adult human skeleton form and how they are repaired if injured varies and has posed a challenge for many researchers in the field of regenerative medicine.

The cartilage template Nukavarapu and his team created appears to overcome hurdles that make it difficult for regenerative scientists to help the body’s long bones regenerate.

Two processes involved with human skeletal development help all the bones in our body form and grow. These processes are called intramembranous and endochondral ossification: IO and EO respectively.

While they are both critical, IO is the process responsible for the formation of flat bones, and EO is the process that forms long bones like femurs and humeri.

For both processes, generic mesenchymal stem cells (MSCs) are needed to trigger the growth of new bone. Despite this similarity, IO is significantly easier to re-create in the lab since MSCs can directly differentiate, or become specialized, into bone-forming cells without any additional steps.

However, this relative simplicity comes with limitations. To circumvent the issues associated with IO, Nukavarapu’s team set out to develop an engineered extracellular matrix that uses hydrogels to guide and support the formation of bone through EO.

“Thus far, very few studies have been focused on matrix designs for endochondral ossification to regenerate and repair long bone,” says Nukavarapu, who holds joint appointments in the departments of Biomedical Engineering and Materials Science and Engineering. “By developing a hybrid hydrogel combination, we were able to form an engineered extracellular matrix that could support cartilage-template formation.”

Nukavarapu’s team’s findings could be the first step to initiating the proper healing of long bones with biomedical help.

Using the Wisdom of Spider Webs

When someone breaks a load-bearing bone — the femur, for instance — doctors might install a metal plate to support the bone as it fuses and heals. But the metal can cause inflammation and irritation, and since metals are very stiff, the new bone may grow back weaker and more vulnerable to fracture.

UConn materials scientist and biomedical engineer Mei Wei and her team have developed an alternative to metal: a composite made with silk fibroin, a protein found in the silk fibers spun by spiders and moths and a common component in medical sutures and tissue engineering because of its strength and biodegradability.

Wei’s study found that the high-performance biodegradable composite showed strength and flexibility characteristics that are among the highest ever recorded for similar bioresorbable materials.

Working with UConn mechanical engineer Dianyun Zhang, Wei’s lab created a mix of silk and polylactic acid fibers coated in bioceramic particles. The new composite lasts about a year — large, adult leg bones can take many months to heal — and then starts to degrade. No surgery is required for removal.


Tissue engineer Syam Nukavarapu (left) examines a specimen of his hybrid hydrogel in his UConn Health lab.


Capturing the Power of Ultrasound

In the Department of Orthopaedic Surgery and the Institute for Regenerative Engineering at the UConn School of Medicine, researchers Yusuf Khan, Bryan Huey, and Lakshmi Nair are studying the combined power of gel-encapsulated bone cells and ultrasound waves to help fractured bones heal.

Physical force has been shown to stimulate bone cell regeneration for full healing, but immobilizing the fracture with a cast doesn’t allow for any movement. Khan believes that adding cells to the fracture site early on, and then directing a transdermal physical force toward the cells via low-intensity ultrasound, could accelerate fracture repair. In cases where a fracture can’t heal on its own, the therapy could provide the necessary stimulus to complete the healing process.

The team’s lab has already demonstrated the successful placement of bone cell hydrogels in mice and is working with the Department of Materials Science and Engineering to optimize the gel capsules for human use.

Harnessing Stem and Amniotic Cell Strength

Dr. Cato T. Laurencin, the Albert and Wilda Van Dusen Distinguished Professor of Orthopaedic Surgery and the director of the Institute for Regenerative Engineering at UConn Health, is developing clinical therapies to treat — and potentially reverse the effects of — osteoarthritis using human amniotic tissue, stem cells, and new combinations of the two.

An estimated 20 percent of Americans suffer from osteoarthritis, the most common degenerative joint disease and the leading cause of disability worldwide. Although current surgical and non-surgical therapies can provide some relief, none treat the root cause of the disease.

Stem cells have been proven to reduce pain and improve function in osteoarthritis patients. New studies suggest that the use of stem cells may heal cartilage, but results vary. Thanks to the host of powerful cytokines contained in amniotic tissue, many of which have been shown to decrease inflammation, Laurencin believes human amniotic tissue may overcome the limitations of current stem cell therapies, providing an ideal delivery system with added benefits.

“Soon, more surgeons and patients will realize that long hospital stays and recovery times are outdated.”

In its initial studies, Laurencin’s team has found its amnion-based delivery system can support stem cell survival, growth, and proliferation, and that the combination of amnion matrices and stem cells have immunosuppressive and anti-inflammatory effects on knee tissue cells.

“We believe amniotic tissue growth factors help drive human development and regeneration,” says Laurencin. “We are hopeful that harnessing this powerful new cell combination will help us further advance regenerative engineering for patients, especially those with arthritis or sports injuries, who want to avoid steroid treatments or are interested in next-generation therapies.”

Although it is not yet covered by insurance, amnion tissue treatment is available now to Laurencin’s patients. Laurencin’s team hopes to make the combination amnion¬stem cell therapy available within the next three years.

From the advanced research that’s changing the care of the future to the clinical changes happening now, Musculoskeletal Institute head Mazzocca says the Institute is uniquely positioned to provide the best possible care to patients.

“We try to take all the clinical people that treat musculoskeletal disease — rheumatology, osteoporosis, comprehensive spine, orthopaedics — and put it in one place, and combine them with all the researchers so they can cross-pollinate and make care better for the people of the state of Connecticut,” he says. “And there’s nobody else in the state of Connecticut that does what we do.”

Jessica McBride, Colin Poitras, and Lauren Woods contributed to this story.

Blood Test Can Alert Doctors to Delirium Risk

artsy photo depicting two nurses walking down hospital corridor in the view point of someone experiencing the effects of confusion or delirium


Researchers at UConn Health and Beth Israel Deaconess Medical Center have found that a blood test could make it easier to identify patients at risk for delirium, the sudden, acute state of confusion that most often affects older adults and incurs $6.9 billion in medical costs each year in the U.S. Their study, published online in The Journal of Gerontology: Medical Sciences, reports that elevated blood levels of specific proteins called cytokines can hint that a patient will develop delirium during a hospital stay.

If you do things such as improve a patient’s vision and hearing, reorient them to where they are regularly, promote restful sleep, increase mobility, and stop medications that could be making the delirium worse, all that can help.

Dr. George Kuchel, director of the UConn Center on Aging and one of the authors of the study, says the suspected blood signature for delirium shows two cytokines at higher-than-normal levels in patients who develop delirium. Both cytokines are associated with inflammation.

Researchers don’t yet know exactly how inflammation and delirium are linked. The two cytokines the researchers saw in the blood signature, interleukin-6 and interleukin-2, can cause swelling of the membrane around the brain. Chronic stress from low-level illness can also elevate both cytokines and stress hormones such as cortisol, which over the long term can shrink part of the brain and perhaps increase an elderly person’s susceptibility to delirium.

Kuchel and his colleagues worked with patients who participated in the Successful Aging after Elective Surgery (SAGES) study to get a better handle on the relationship between inflammation and delirium. This large study, sponsored by the National Institute on Aging, has been following 566 surgical patients over the age of 70 for the past five years, with the goal of finding new approaches to prevent delirium and its long-term consequences in older adults.

The UConn study found that patients who developed delirium had higher levels of interleukin-2 than non-delirium patients at all times they were tested: before surgery, in the first two days afterward, and one month later.

This is the first study to look at cytokine levels in older surgical patients at several points in time, both before and after surgery. The results need to be replicated in other studies, but if they prove to be generally true, the blood signature could provide a quick way to alert doctors and nurses to seniors at higher risk of delirium. They can then take extra precautions to keep the patients oriented.

“If you do things such as improve a patient’s vision and hearing, reorient them to where they are regularly, promote restful sleep, increase mobility, and stop medications that could be making the delirium worse, all that can help,” says Kuchel.

New Epilepsy Drug May Be Safer, More Effective

A PET scan of human brain

A PET (positron emission tomography) scan shows blood flow and metabolic activity, used to diagnose the cause of epilepsy and for surgical planning.


A new drug that selectively affects potassium channels in the brain may offer effective treatment for epilepsy and prevent tinnitus, UConn neurophysiologist Anastasios Tzingounis and colleagues reported in a recent issue of The Journal of Neuroscience.

The existing drugs to treat epilepsy don’t always work, and can have serious side effects. One of the more effective, called retigabine, helps open KCNQ potassium channels, which shut down the signaling of overly excited nerves. Unfortunately, retigabine has significant adverse side effects, including sleepiness, dizziness, problems with urination and hearing, and an unnerving tendency to turn people’s skin and eyes blue. Because of this, it’s usually only given to adults who don’t get relief from other epilepsy drugs.

This drug gives me a better tool to dissect the function of these channels. We need to find solutions for kids – and adults – with [epilepsy].

There are five different kinds of KCNQ potassium channels in the body, but only two are important in epilepsy and tinnitus: KCNQ2 and KCNQ3. The problem with retigabine is that it acts on other KCNQ potassium channels as well, and that’s why it has so many unwanted side effects.

Tzingounis’ research has found that a new drug – SF0034, which is chemically identical to retigabine, except with an extra fluorine atom – seems to open only KCNQ2 and KCNQ3 potassium channels, not affecting KCNQ4 or 5. It was more effective than retigabine at preventing seizures in animals, and it was also less toxic.

The drug company that developed SF0034, SciFluor, now plans to start FDA trials to see whether the drug is safe and effective in people. Treating epilepsy is the primary goal, but tinnitus can be similarly debilitating, and sufferers would welcome a decent treatment.

“This drug gives me another tool, and a better tool, to dissect the function of these channels,” Tzingounis says. “We need to find solutions for kids – and adults – with this problem.”

‘Talk to Your Mother’ Proves to be Healthy Advice

Daughter has serious conversation with mother outdoors


Bringing out the proverbial “skeleton in the closet” can provide health benefits, but the degree of benefit depends on who you confide in, says a new UConn study.

The study of 400 people, published in the Journal of Health Psychology, found that people who are living with issues such as mental illness, substance abuse, domestic violence, rape, or childhood abuse reap considerable health benefits from discussing those issues.

But they experience more health benefits – both psychological and physical – from disclosing the issue to mom, a romantic partner, or a best friend than from disclosing it to dad, siblings, or a close colleague, says Diane Quinn, UConn psychology professor and study author.

People have unseen scars and they may be reluctant to talk about their stigmatized identity or experience … but if they do choose to talk about it, then they will gain even more benefit from their social interactions than if they remain silent.

“It seems that people expect their mothers to love them unconditionally, and they just assume that she will handle letting the rest of the family – including the father –know about a problem,” says Quinn.

Researchers studied a group of people who averaged 32 years old and who had at least one past experience that they kept hidden from others.

Participants were asked to rate their social networks according to differing degrees of support. Those ranged from a basic level of support, such as an offer to go to lunch, to more substantial support, such as an offer of a place to stay during an emergency. They were also asked to rate their own physical health, both in terms of actual symptoms of illness and how they perceived their health in general. Finally, they were asked to quantify how “out” they were about their issue within their social network.

Results showed that people who characterized themselves as being the most “out” derived the greatest health benefits, especially when their confidantes included mom, a romantic partner, or a close friend.

“People have unseen scars and they may be reluctant to talk about their stigmatized identity or experience,” says co-author Bradley Weisz, a doctoral student in psychology, “but if they do choose to talk about it, then they will gain even more benefit from their social interactions than if they remain silent.”

But while being “out” about a stigmatized identity or a traumatic experience can be helpful in the long run, Quinn says that not everyone has to follow the same path. “It’s a matter of your personal comfort zone,” she says.

Funded by the National Institutes of Health (NIH), the study was also co-authored by UConn psychology professor Michelle Williams.

Getting to the Heart of the Matter

Why do some patients with high ‘good’ cholesterol also show signs of heart disease? UConn research has found the common gene mutation that may be to blame.

By Kim Krieger

Scientific image of kidney cells dyed colors to show mutated cells

UConn Health endocrinologist Dr. Annabelle Rodriguez-Oquendo’s lab used color stains to figure out where the kidney cells were expressing a mutant gene: those areas glow yellow in this picture. Most of the yellow is in the endoplasmic reticulum, the cell’s transportation network. Photograph provided by Annabelle Rodriquez-Oquendo


Guidelines about cholesterol used to be straightforward: high-density lipoprotein (HDL) cholesterol is healthy, and low-density lipoprotein (LDL) cholesterol is not. Relatively high levels of HDL were no cause for concern, as long as LDL was low.

But recent discoveries show that may be an oversimplification. A common variant in a gene that regulates cholesterol levels may raise the risk of heart disease in carriers with high HDL, according to a new UConn Health study.

Researchers examined a variant called missense rs4238001, which alters the type of protein made by the gene SCARB1. The variant form of SCARB1 changes a liver receptor protein from a glycine to a serine. The change occurs in the liver receptor that grabs HDL out of the blood and breaks it down for disposal. The variant protein makes the receptor more fragile and not as effective at latching onto HDL, leading to higher levels of HDL in the bloodstream.

The study, led by Dr. Annabelle Rodriguez-Oquendo, an endocrinologist at UConn Health, was based on information about more than 5,000 people who participated in the Multi-Ethnic Study of Atherosclerosis in major American cities from 2000 to 2002.

The risk of heart disease among those with the variant was up to 49 percent greater than in the general population.

Rodriguez-Oquendo and her colleagues charted the genotypes of the participants and tracked episodes of heart disease over a period of seven years.

They found that the variant was associated with an increased risk of heart disease, particularly among men and African Americans, findings that were published in the May 20 issue of PLOS ONE.

The risk of heart disease among participants with the rs4238001 variant was up to 49 percent greater than the risk in the general population. Overall, men with the variant had a 29 percent higher risk of heart disease than men without it. African American males with the variant fared the worst, with a 49 percent increased risk. For white males with the variant, the risk was 24 percent higher.

The gene mutation itself is not rare, according to Rodriguez-Oquendo. It occurs in less than 3 percent of Chinese Americans, about 8 percent of African Americans, and 10 to 12 percent of Latinos and Caucasians in the U.S. A genetic test for the rs4238001 variant is already available to help clinicians identify patients who are carriers, so that they can offer counseling about heart risk prevention.

Dr. Annabelle Rodriguez- Oquendo and team

UConn Health endocrinologist Dr. Annabelle Rodriguez-Oquendo looks at DNA data with researchers in her lab. Peter Morenus – UConn Photo

UConn Health endocrinologist Dr. Carl Malchoff uses the test to help patients who aren’t sure whether or how they should treat their high cholesterol. For example, Malchoff had one patient with high HDL and a family history of longevity. But she had suffered a stroke at a young age, and wanted more information before deciding on a treatment.

This particular patient tested negative for the variant. But those who test positive would be advised to use a more aggressive type and dose of cholesterol medication. Patients with the variant could also inform their children that they might also have it.

“Usually if patients don’t have the variant, we assume their high HDL is protective,” Malchoff says.

Sometimes, however, a treatment decision might be more ambiguous, and could require further information before the best therapy is chosen. Another patient of Malchoff’s had high levels of both HDL and LDL cholesterol. She was taking a statin to lower her cholesterol, but was experiencing terrible muscle pain as a side effect. She wondered if there was a way to tell whether her high HDL protected her from the heart disease risk associated with high LDL. If so, could she stop taking the statin?

This patient could be tested for the same variant. If her test was negative, she could assume that her high HDL cholesterol was helping protect her against heart attack, even with high levels of LDL cholesterol. If the test was positive, she would know that her high HDL cholesterol would not protect her. She could then take another type of cholesterol-lowering medication, just not one classified as a statin.

Malchoff and his colleagues at UConn Health are working with Rodriguez-Oquendo to determine when testing for the variant is most helpful.

Read the full research article at the PLOS ONE website.

“My approach to patient care in an academic center is that we should look for things our colleagues in practice can’t do and do those things, so we can help them and be their partners,” Malchoff says of his role in the research.

Now that the UConn study has made the connection between the mutation in SCARB1 and heart disease, the researchers want to figure out a way to fix it.

“We want to go deep in the cell, and figure out how to repair it,” Rodriguez-Oquendo says. The researchers don’t know exactly why changing the protein in a liver receptor from a glycine to a serine makes it more fragile. “We’re really interested in understanding more about how this protein gets chewed up and degraded faster.”

The answers may impact the current standard of care for heart disease prevention and treatment for patients who are carriers of this genetic variant. That could happen through indirect means, such as adjusting hormone levels to alter cholesterol metabolism, or in the future through direct means such as genetic therapy.

Breaking the Cycle: How Anxious Parents Can Protect Their Kids from Becoming Anxious Adults

By Kim Krieger

Infographic showcasing logical and illogical fears oppressing a nervous child figure


A woman who won’t drive long distances because she has panic attacks in the car. A man who has contamination fears so intense he cannot bring himself to use public bathrooms. A woman who can’t go to church because she fears enclosed spaces. All of these people have two things in common: they have an anxiety disorder, and they happen to be parents.

These parents sought help because they struggle with anxiety, and want to prevent their children from suffering the same way. Anxiety tends to run in families, with 30 to 50 percent of children of anxious parents growing up to be anxious themselves. But that does not have to be the case, according to new research by UConn Health child psychologist Golda S. Ginsburg.

Ginsburg and colleagues at Johns Hopkins University tested a one-year therapy intervention as part of a study of 136 families where at least one parent had anxiety and at least one child was between the ages of 6 and 13.

The study, published in the August issue of The American Journal of Psychiatry, found that therapy-based intervention works. Only 9 percent of children who participated in a therapist-directed intervention developed anxiety after one year, compared to 21 percent in a group that received written instruction, and 31 percent in the group that did not receive any therapy or written instruction.

Children of anxious parents have up to a 50 percent chance of growing up to be anxious themselves. But that does not have to be the case.

Both inborn temperament and life experiences play a role in whether an adult has anxiety. The more negative experiences a person has growing up, the greater the likelihood he or she will struggle with anxiety as an adult. But there is also a component of anxiety that is learned, taught inadvertently by parents who model the behavior. It’s these learned behaviors and thought patterns that interventions can help change, according to Ginsburg.

“The finding underscores the vulnerability of offspring of anxious parents,” says Ginsburg. She wants to do something about that vulnerability. “If we can identify kids at risk, let’s try and prevent this.”

Most of the adults who participated in the study struggled in school and didn’t tell anyone. They didn’t raise their hands, or they got sick before exams. They might not have had any friends. As adults, their anxiety still limits their activities and sometimes those of their family members, and they are very motivated to help their children avoid the same.

Physicians can often identify children at risk before they develop an anxiety disorder. Such kids are often hyper-aware of aches and other bodily sensations, and are frequent flyers at the doctor’s office and emergency room. For example, such a child might think “my heart is racing — I’m having a heart attack!” when a less anxious individual would think “my heart is racing because I just ran up a hill.”

Other signs of children at risk for anxiety include avoidance of school, parties, and other social situations, as well as unusual worries.

“Anxiety and fear are protective and adaptive,” says Ginsburg. “But in anxious kids they may not be, because these children have thoughts about danger and threat when there really isn’t one.”

For such a child, meeting a new peer for the first time can be paralyzing. Trying an unfamiliar food might summon worries of being poisoned. To cope with this kind of debilitating anxiety, children start avoiding whatever provokes the anxious feelings. If they’re afraid of the dark they might insist on sleeping with all the lights on. If they’re afraid of failing they won’t try new things. In extreme cases, they may refuse even to leave the house.

I’d say we need to change our model of mental health to a checkup method. Like going to the dentist every six months.

One of the ways to reduce anxiety is to do a reality check. It’s a way to recognize when a fear is healthy and worth paying attention to (a growling dog) or unhealthy (a possibly poisoned birthday cake).

In the study, some of the families participated in eight, hour-long sessions with a trained therapist over a period of two months. Others were just given a pamphlet that contained general information about anxiety disorders and treatments. Still others received nothing at all.

The families who participated in therapy were taught to identify the signs of anxiety and how to reduce it. They practiced problem-solving skills, and exercised safe exposures to whatever made their child anxious.

“We taught the kids how to identify scary thoughts, and how to change them,” Ginsburg says.

If you are interested in collaborating on such a study or have patients who might benefit from a family intervention, contact Golda Ginsburg at Gginsburg@uchc.edu, or call her office at 860.523.3788.

For example, if a child is afraid of cats and encounters one in the street, the child can first identify the scary thought: “that cat is going to hurt me.” Then the child can test that thought — is it likely that cat will hurt me? No, the cat doesn’t look angry. It isn’t baring its teeth or hissing, it’s just sitting there. OK, I can walk past that cat and it won’t do anything.

In general, children who participated in the intervention had lower anxiety overall than children who did not participate in the intervention with their families.

Now the researchers have funding from the National Institutes of Health for a follow-up to see whether the effects are maintained over time. Ginsburg wonders whether there would be value in providing regular checkups for families on mental health issues. She is considering approaching insurers about offering this kind of service to families at risk, to see if it lowers their healthcare costs overall.

“I’d say we need to change our model of mental health to a checkup method,” says Ginsburg, “like going to the dentist every six months.”

When Getting Your Flu Shot, Timing is Everything

Elderly patient being tended to by a nurse


Pharmacies advertising flu vaccinations in August and September are doing their elderly clients a disservice, say UConn Center on Aging researchers. The immunity they gain from vaccine in late summer may wane by the time flu season hits hard in late winter.

As summer temperatures peaked this August, pharmacies were already advertising the influenza vaccine. But if you thought that was too early to be getting a flu shot — you were right.

If you’re interested in volunteering for the study, contact Lisa Kenyon at the UConn Center on Aging at 860.679.3956.

“When adults get the vaccine in September, the peak effect wears off by late December. But flu season peaks in January and February,” warns Laura Haynes, an immunologist and gerontologist at UConn Health.

October or November is a much better time to get the vaccine. That way, you’re still protected when virus season is at its worst.

This is especially important for the elderly, who are at particular risk from flu. People over 65 are much more likely than younger adults to have serious complications or even die from a bout with the virus.

One way to better stimulate the immune response is to administer a high-dose vaccine, which contains four times as much flu antigen as the regular version. But the high-dose vaccine has stronger side effects, is more expensive, and may not be best for everyone.

Haynes and her colleagues at UConn Health, funded by a Program Project Grant from the National Institute on Aging, will run two studies this autumn to better understand older people’s responses to the regular flu vaccine and the high-dose version. The studies will look at how the immune system reacts to the flu vaccine, as well as how to identify patients who would benefit from the high-dose version.