A recent study by UK researchers shows a new way tobacco smoke may cause lung cancer: stopping a DNA repair process called nucleotide excision repair (NER).

UK researchers find a new way tobacco smoke can cause cancer

A recent study led by UK researchers illuminates a new way that tobacco smoke may promote the development of lung cancer: inhibiting a DNA repair process called nucleotide excision repair (NER). The results of the study were published in the journal PLoS ONE.

Tobacco smoke damages our DNA

Many components of tobacco smoke are carcinogens that can damage DNA. This damage must be removed by DNA repair processes to prevent the development of genetic mutations. In this way, DNA repair processes such as NER are crucial for blocking the accumulation of the DNA mutations that ultimately drive lung cancer development.

“It is well established that the carcinogens in tobacco smoke can produce mutations,” said Isabel Mellon, an associate professor in the Department of Toxicology and Cancer Biology at UK and the principal investigator of the study. “But relatively few researchers have investigated the effects of tobacco smoke on DNA repair pathways.”

Smoking also stops DNA from fixing itself

Mellon and her research team examined the effects of cigarette smoke condensate (CSC) – a commonly-used surrogate for tobacco smoke – on the function of the NER process in cultured human lung cells. They found that exposure of these cells to CSC significantly reduces NER efficiency. Additionally, the researchers showed that CSC exposure stimulates the destruction of a key NER protein known as XPC. The reduced abundance of XPC that follows might explain how CSC suppresses NER.

The study’s results point to a twofold effect of tobacco smoke on DNA integrity: it not only damages DNA, but it also suppresses a key process that repairs DNA damage.

“Inhibition of NER would likely increase the production of mutations and cancer incidence, particularly in cases of chronic DNA damage induction, as occurs in the lung issue of smokers,” Mellon explained.

Research that points toward the future

If this is the case, then the capacity of cells within the lung of a given person to repair damaged DNA could be used to predict that person’s risk of developing lung cancer as a result of tobacco smoke exposure.

“In the future, we hope to determine how the efficiency of the NER pathway differs among different people,” said Mellon. “We are also continuing to evaluate how the efficiency of DNA repair in people is negatively impacted by exposure to environmental agents. Whether due to genetic or environmental factors, reduced DNA repair could increase a person’s risk for developing cancer.”


Next Steps

The implantable WATCHMAN device may help reduce risk of stroke for those with atrial fibrillation.

New device may reduce risk of stroke for Afib patients

Written by Dr. John C. Gurley, director of the Structural Heart Program at UK HealthCare’s Gill Heart Institute.

Dr. John Gurley

Dr. John Gurley

A new implant device may be a breakthrough for reducing the stroke risk for atrial fibrillation (Afib) patients. The WATCHMAN Left Atrial Appendage Closure (LAAC) provides a new option for patients with non-valvular Afib, who may require an alternative to long-term use of blood thinners.

UK HealthCare was among the first centers in the world to implant the WATCHMAN as an investigational device through a clinical trial in 2005. The device is now FDA-approved in the U.S. and more widely available.

Those with Afib are at a higher risk for stroke

Currently, about 5 million Americans are diagnosed with atrial fibrillation, the most common cardiac arrhythmia, where the upper chambers of the heart (atrium) beat too fast and with irregular rhythm (fibrillation). But having an irregular heartbeat is not the only challenge facing these patients. The condition causes them to be at a higher risk of experiencing a stroke – in fact, five times more likely compared to those without atrial fibrillation.

Because the heart does not beat properly in atrial fibrillation patients, blood may not fully pump out of the heart, causing it to pool and then clot in a pouch in the heart’s left atrial appendage. In some cases, the blood clots can break loose and travel in the bloodstream to the brain, resulting in a stroke.

Along with putting patients at a greater risk of experiencing a stroke, these types of strokes caused by atrial fibrillation often are fatal or very disabling.

Finding a new way to treat Afib

In the past, the most common treatment to reduce the risk of stroke in these patients has been to have them take a blood-thinning medication called warfarin. However, despite their effectiveness, taking blood thinners for long periods of time can be difficult for patients because it isn’t always well-tolerated and it presents a significant risk for bleeding complications. Overall, about half of atrial fibrillation patients appropriate for warfarin go untreated because of their inability to tolerate or adhere to the medication.

For patients seeking an alternative to warfarin, the WATCHMAN implant offers a treatment option that could free them from the challenges of long-term blood-thinning therapy. The catheter-delivered heart implant is a one-time procedure that usually takes about an hour.

During the procedure, the implant is designed to close off the left atrial appendage to prevent blood clots from entering the bloodstream that potentially could cause a stroke for higher risk patients with non-valvular Afib.

Once the left atrial appendage is closed off, patients may, over time, be able to stop taking warfarin.


Next Steps

A new study led by UK Markey Cancer researchers and published in the Journal of Cell Science establishes a novel link between cell polarity and cancer-associated inflammation.

Proposed clinical trial could change the game for triple-negative breast cancer

This is the first post in a two-part series about UK Markey Cancer Center researchers’ efforts to improve treatment for triple-negative breast cancer, a deadly form of the disease. Check out Part Two here.

UK Markey Cancer Center Oncologist Dr. Edward Romond spent his career at UK treating and studying breast cancer, even leading major Phase 3 clinical trials on the breast cancer drug trastuzumab in the early 2000s. Commonly known as Herceptin, this drug became a standard of care for patients with HER2-positive breast cancer.

Though he retired from practice last year, Romond continues to work part-time with the research team at Markey, this time pushing toward a cure for a different, more deadly, type of breast cancer.

“Breast cancer, we now recognize, is at least five different diseases that are completely different from each other,” Romond said. “And the hardest nut to crack is this one called triple-negative breast cancer.”

Treating triple-negative breast cancer

Triple-negative breast cancer is a moniker given to a particularly aggressive group of breast cancers that often affect younger women. Unlike the receptor-positive types of breast cancer, which have biomarkers that tell oncologists which treatment the patient should respond to, triple negative breast cancers have no definitive biomarkers. If the patient does not respond well to the current standard of care, it’s up to the oncologist to make an educated guess about which chemotherapy will do the job.

The good news is that triple-negative breast cancers do generally respond well to chemotherapy. However, because triple-negative breast cancers are not the same, and every single patient responds differently to various chemotherapies, it’s difficult to predict which chemotherapy will best treat each patient’s cancer.

But the researchers at Markey are working to change that paradox. Markey’s Breast Translational Group is currently developing a proposed clinical trial that could create a major shift in the way triple-negative breast cancers are treated.

Currently, after a patient is diagnosed with triple-negative breast cancer, she usually receives chemotherapy first to try and shrink the tumor (known as neoadjuvant therapy), followed by surgery to remove as much of the mass as possible. The patients are then monitored for signs of recurrence. If a patient has residual cancer despite getting neoadjuvant chemotherapy, they are at a high risk for recurrence.

Proposed clinical trial

There are currently at least six different types of chemotherapy that can be used as a possible therapy for patients, and each one may affect each individual patient in a different way. To tailor the treatment to each distinct patient, the investigators aim to test the tumors in a set of animal model “avatars” with these different therapies to gauge the response.

Here’s how the proposed trial would work: after the patient’s biopsy, her cancerous tissue would be transferred into a mouse that is bred to grow human tumors, then subsequently into three dozen mice: her “avatars.” While the patient undergoes neoadjuvant chemotherapy and then surgery – a process that can take up to six months – the avatars will be divided into groups, with each group receiving one of the six available chemotherapies.

When the researchers see which avatar group has the best result, they’ll know which chemotherapy should work best for that patient. Knowing this would provide additional options for women who have residual cancer after neoadjuvant chemotherapy, and may reduce their risk for disease recurrence.

“It would prevent us from having to experiment with each individual patient, and end up finding that they didn’t respond to that therapy,” said Kathleen O’Connor, director of Markey’s Breast Translational Group. “If we can do this, then the oncologists will no longer have to guess.”

Disrupting the standard of care

Dr. Aju Mathew, a medical oncologist who treats triple-negative breast cancer patients at Markey, compares his team’s game-changing proposition to the way Uber has altered the use of public and personal transportation.

“We often hear about disruptive technology — Uber being one, for example,” he said. “It disrupted the current paradigm of everyone driving a car on their own or hiring a cab. This trial is our way of disrupting the current standard of care, the current technology, and the current practice of medicine, to try to change the paradigm of ‘one size fits all’ approach for triple-negative breast cancer patients.”

Though the avatar model of research isn’t new, O’Connor notes that not many researchers are using them specifically for the treatment of an individual patient. Using a trial protocol to get the tissues directly from the patient’s biopsy is a key factor in making the research work.

“The important thing is that we need to get the tumor tissue before they’ve been exposed to chemotherapy,” O’Connor said. “This is one of the things that makes our trial unique.”

With the trial design in place, the team just needs to provide ample data showing that growing a patient’s tumor in the avatar from biopsy will work. But to gather that data, they need more funding. Initial pilot funds stemming from Markey’s National Cancer Institute (NCI) designation grant have enabled the team to establish their first set of avatars with tissues taken from patients’ surgeries. But a boost in funding would help them establish the preliminary data for the trial and allow the team to then apply for major federal funding.

“We have a large group of people who have freely given their time up to this point,” O’Connor said. “But we need to have money to protect the time of the researchers doing this work, and we need enough money to get the mice in order to do this.”

Check out the video below to see Markey researchers talk about their triple-negative breast cancer research.


Next steps:

Triple-negative breast cancer can be difficult to treat, but a new clinical trial currently in development at the University of Kentucky Markey Cancer Center could potentially change the standard of care for this deadly disease.

Mom continues daughter’s fight to raise breast cancer awareness

This is the second post in a two-part series about UK Markey Cancer Center researchers’ efforts to improve treatment for triple-negative breast cancer, a deadly form of the disease. Check out Part One here.

Funding for triple-negative breast cancer has been a major focus for Lexington resident Cindy Praska, whose daughter Whitney was diagnosed with the disease in 2007 at age 24. After undergoing a double mastectomy, chemotherapy and radiation at another hospital, Whitney was deemed cancer-free.

In the years following her diagnosis, Whitney became an advocate for breast cancer awareness and fundraising, becoming actively involved in the Frankfort Country Club’s Rally for the Cure, which has raised money for the Susan G. Komen Foundation and the UK Markey Cancer Center for nearly 20 years.

Though her initial treatment for triple-negative breast cancer was successful, Whitney then developed bone cancer, or osteosarcoma, in 2012. This time, she elected to have her surgery out of state and came to Markey for her chemotherapy. Genetic testing revealed she carried a P53 genetic mutation, which was the cause of her original cancer, and combined with the radiation she had received prior, also caused her osteosarcoma. Despite Whitney’s and her doctors’ best efforts, her cancer metastasized and she succumbed to the disease in November of that year.

Carrying the torch for her daughter, Cindy continues to push for education, awareness and research toward triple-negative breast cancer and is still heavily involved in fundraising.

This Saturday, Oct. 15, Cindy and the team behind the Frankfort Country Club Rally for the Cure have planned a “party with a purpose” called Bourbon & Jazz for the Cure to celebrate the organization’s 20th anniversary. Held at the Frankfort Country Club on Saturday at 6:30 p.m., this special fundraising gala includes a silent and live auction featuring limited-edition Buffalo Trace bourbon bottles, and the funds raised from the gala will directly benefit the research team behind Markey’s proposed triple-negative breast cancer clinical trial.

“Whitney helped bring awareness to this disease, and it is so rewarding to me that work is progressing so that more young women her age will live to marry, have a family, and be able to see their young children grow up,” Cindy said. “It has given me a purpose to be an advocate for these causes and it’s an honor to be supporting Markey, who we called family and home the last year of her life.”


Next steps:

Meet Dr. Aju Mathew, breast cancer specialist and history buff

Making the RoundsDr. Aju Mathew, a medical oncologist at the UK Markey Cancer Center, is featured in this week’s Making the Rounds. Making the Rounds is a Q&A series where you’ll get to know the providers at UK HealthCare and what they’re like outside the lab and clinic.

Dr. Mathew studied medicine in the United Kingdom and later in India, his home country. At the UK Markey Cancer Center, he works as part of the care team specializing in breast cancer treatment.

How would your friends and family describe you?

I think they would describe me as a very passionate person who has no hesitation voicing his opinions. I’m very passionate.

Describe your ideal weekend.

A nice sunny day where I can go out with my wife for a nice hike. I love nature and the outdoors.

What website do you visit most often?

I’m a news buff so I visit news websites a lot, but I like Facebook, too.

What’s the last movie you saw?

I saw Race. It’s a fascinating movie about Jesse Owens, an African American sprinter, and how he crossed several racial barriers and basically embarrassed the Nazis in their home territory at the Olympics. He won four gold medals.

What’s the last book you read?

I just finished a book on the history of Japan. It’s an amazing tale. Right now I’m reading a book on Eric Liddell. It’s called For the Glory. He’s an athlete – he inspired the movie Chariots of Fire, and he won the Olympic gold.

I love history.

Do you have a hobby or interest outside of medicine?

Going to the antique mall and checking out old, old newspapers. I have 1940s newspapers of the D-Day landing, and I spend time reading through them and it’s fascinating! It’s my latest hobby.

What historical or fictional character do you most identify with?

Dietrich Bonhoeffer, a Lutheran pastor and anti-Nazi dissident. He went against the stream of the times and made a tough decision, which is even controversial now, by opposing the Nazi regime. He sensed what is right and he did it, even in the fact of what was happening during those times.

Fictional character? Batman.


Check out our video interview below with Dr. Mathew, where he discusses the breast cancer treatment at Markey and his patient care philosophy.


Next steps:

Flu season in Kentucky

Flu season in Kentucky has started. Here’s what you need to know.

Several cases of influenza have already been confirmed across the Commonwealth, marking the early arrival of flu season in Kentucky.

Here’s what you need to know about the flu this year.

Vaccines are necessary every year

Getting a flu shot every year is the single most effective way to prevent the flu. It’s safe and recommended for anyone 6 months or older.

Influenza viruses are constantly changing, which is why it’s important to get a shot at the start of every flu season. This year’s vaccine is updated to better protect against the flu viruses experts expect to circulate this season.

FluMist is no longer an option

Studies showed the nasal spray flu vaccine, or FluMist, was not effective in protecting against the flu last year, and it is no longer being produced. Although FluMist was often the preferred choice for children or those averse to needles, all individuals who can receive a flu shot should do so.

Help protect those around you

Receiving a flu vaccination helps keep those around you protected, too. If you live or care for infants too young to receive a vaccination, getting a flu shot will help protect them from the virus.

Encourage your loved ones to get vaccinated, and be conscious of those in your life who are more susceptible to the virus. They include people older than 65, those with chronic medical conditions like asthma or diabetes, and pregnant women.


Next steps:

  • Shots are available from primary care doctors and many pharmacies. Check out the CDC’s Flu Vaccine Finder to find a flu vaccine clinic near you.
  • Members of the UK community can get a flu shot as part of University Health Service’s Big Flu Madness. See the student and campus employee flu shot schedule here and the UK HealthCare employee schedule here.
Clearing up confusion about breast cancer screening.

Confused about when to get a mammogram?

Dr. Margaret Szabunio

Dr. Margaret Szabunio

When should you have your first mammogram? How often should you be screened?

There are a lot of different answers out there, and the result is confusion and frustration for many women. In honor of Breast Cancer Awareness Month, we sat down with Dr. Margaret Szabunio, associate medical director of the UK Comprehensive Breast Care Center, to discuss why mammograms are so important and what she recommends.

How common is breast cancer?

Szabunio: One in eight women will develop breast cancer in her lifetime. Of these women, three in four will have no family history of breast cancer.

Why should women have mammograms?

Szabunio: Despite varying recommendations about timing and frequency, mammography remains the best method we have for finding breast cancer early at a curable stage. Since mammography screening became widespread in the 1990s, the U.S. breast cancer death rate has decreased by 30 percent.

When should women have their first mammogram?

Szabunio: You should have your first mammogram at age 40 and an annual screening every year after that. Why? Because it results in the greatest mortality reduction, the most lives saved and the most life years gained.

Your chances of getting breast cancer increase substantially around age 40. In fact, women ages 40-44 are twice as likely to develop the disease as women ages 35-39. One in six breast cancers occur in women age 40-49.

By not getting annual mammograms starting at age 40, you increase your chances of dying from breast cancer and the likelihood that you will experience more extensive and expensive treatment for any cancers found.

If you have a family history of breast cancer or you are otherwise at increased risk, let your doctor know and discuss the best screening plan for you.

Besides talking with their doctor about mammograms, what else can women do to prevent breast cancer?

Szabunio: A healthy lifestyle decreases risk for cancer and many other diseases. Eat a healthy diet low in fat with plenty of fresh fruits and vegetables, and exercise regularly. Avoid alcohol and cigarettes, both of which increase the risk for breast and other cancers.

But remember, even women with a healthy lifestyle may develop breast cancer, and there is no substitute for screening mammography to find cancers early and reduce deaths from breast cancer.


Next steps:

Making the Rounds with Dr. Darren Johnson.

Dr. Darren Johnson, top-ranked knee surgeon, talks about his most important role

Making the RoundsDr. Darren Johnson, chairman of UK Orthopaedic Surgery & Sports Medicine, joined us for our third installment of Making the Rounds, a blog series where you’ll get to know what our providers are like away from the hospital.

Dr. Johnson has been seeing patients, including UK student-athletes, at UK HealthCare since 1993, and thanks to his exceptional care, recently he was named one of the 16 best knee surgeons in North America.

In his free time, Dr. Johnson enjoys spending time with his wife, Nancy, a registered nurse, and their three children, Lauren, Kelsey and BrandonAll three Johnson children are pursing careers in medicine.

Dr. Darren Johnson

Dr. Darren Johnson

What person, real or fictional, do you most admire?

That’s a tough one because for me, you’d have to think of mentors that I’ve had. And that goes back to medical school at UCLA, residency at USC and then my fellowship at the University of Pittsburgh. It’s probably just physician-mentors that I’ve had that I try to model myself after.

I’m a huge John Wayne fan, and I’m a Clint Eastwood fan, too. That’s probably it.

Do you have a favorite movie?

A favorite movie for me, personally? Probably “Braveheart.” Great movie, right? But yeah [my kids and I] go to movies a lot. I like to go to movies. Unfortunately, I don’t get to go enough.

Do you have a favorite meal or type of food you like to eat with your family?

Fortunately for my wife I’ll eat anything, but if I had to pick, growing up in Southern California, probably Mexican food.

From left to right: Dr. Johnson, Mrs. Nancy Johnson, daughters Lauren and Kelsey, and son Brandon.

From left to right: Dr. Johnson, wife Nancy, daughters Lauren and Kelsey, and son Brandon.

When you do get time off, where do you like to go?

Destin, Florida, because we’ve always gone there since our kids were little, and that’s the kids’ favorite spot. So if it’s your kids’ favorite spot, that’s your favorite spot. Pretty simple.

How would your kids describe you?

Hard worker. Expects a lot out of them. Sometimes too honest for a father – kids don’t like honesty. You know, hopefully as a great dad. That’s my most important role – being a dad.

We have a very close family.


We asked Dr. Johnson about his work with patients with sports injuries. Watch the video:


Next Steps

UK teams up with Mayo to study multiple chronic conditions.

UK teams up with Mayo Clinic to study chronic conditions

When a person has multiple health concerns that last a year or longer and require consistent medical attention, health care can quickly become a burden. Patients sacrifice their time, emotion and attention on their treatment, which takes away from their ability to complete and enjoy other tasks in life.

This scenario, known as multiple chronic conditions, or MCC, affects one in four Americans overall and about three in four Americans age 65 and older. To treat patients with MCC, a shift in health care is required: one that focuses on each patient’s health situation and on the limited capacity patients have to devote to their health, while still pursuing joyful lives. Using a new tool developed at Mayo Clinic, researchers at UK are assessing how to better treat patients with MCC.

The ICAN Discussion Aid, developed by the research team at Mayo Clinic’s Knowledge and Evaluation Research Unit, is an intervention to support a new practice for patients with MCC. ICAN helps health care providers better understand the relationship between the patient’s life circumstances, health care goals, the work patients are asked to do and their capacity to enact it. Informed with evidence about the patient’s life, health care teams are better able to co-create treatment plans that are considerate of each patient.

The UK Center for Health Services Research strives for interdisciplinary collaborations locally and nationally and has established relationships with institutes such as Mayo Clinic and Kentucky Primary Care Association (KPCA). In collaboration with KPCA, UK is one of four sites in the nation that will assess the ways in which ICAN-supported primary care is feasible and successful. Researchers will look at patient and health care teams’ experience of care and communication and whether or not patients’ burden of treatment is reduced.

This innovative intervention is an application of Minimally Disruptive Medicine, declared by the British Medical Journal as one of the most important new ideas in medicine in the last 20 years. The My Life, My Healthcare study is funded by the Gordon & Betty Moore Foundation, and will use a mixed methods, cluster-randomized trial design to test ICAN’s feasibility and efficacy on a much larger scale.


Next steps:

UK College of Medicine Professor Stefan Stamm has identified how alternative splicing in RNA may point to new ways to treat obesity and cancer.

UK research could yield treatment for cancer, obesity

UK College of Medicine Professor Stefan Stamm has identified a previously-unknown function of small nucleolar RNAs (snoRNAs): regulating a fundamental cellular process called alternative splicing. His findings point to new ways to treat obesity and cancer.

“Alternative splicing allows cells to make multiple proteins out of a single gene,” Stamm explains.

What is alternative splicing?

In alternative splicing, the molecule being spliced – a form of RNA known as precursor messenger RNA (pre-mRNA) – is an intermediate species between the DNA template that contains the instructions to make a protein and the protein product that is ultimately generated by following those instructions. During this process, the cell’s splicing machinery cuts out segments of the pre-mRNA. It then splices the remaining pieces together to create the mature mRNA that will be used to make a protein. Many pre-mRNAs can be spliced in different ways, and the disparate mRNAs that result are used to produce unique variants of the corresponding proteins.

But most RNAs are not used to make proteins. Among these so-called non-coding RNAs are small nucleolar RNAs (snoRNAs), which guide certain RNA-modifying proteins to their job sites. Curiously, the absence of some snoRNAs is tied to diseases, including certain cancers and Prader-Willi syndrome, a genetic form of obesity. These links indicate that snoRNAs do more than direct RNA modification.

Collaboration leads to new insights

In collaboration with Professor Ruth Sperling of the Hebrew University of Jerusalem, Stamm’s laboratory found that some snoRNAs engage with newfound cellular partners to regulate alternative splicing. Since alternative splicing can regulate protein function, the researchers suspect that this role of snoRNAs might explain why the absence of certain snoRNAs is associated with disease.

If missing snoRNAs are a cause of some diseases, Stamm hypothesized, then replacing the missing snoRNAs with synthetic surrogates should be effective in treating those diseases. To test this hypothesis, Stamm collaborated with Professor Ronald Emeson of Vanderbilt University.

Stamm’s previous work had revealed that SNORD115, a snoRNA that is not produced in people with Prader-Willi syndrome, regulates the alternative splicing of serotonin 2C receptor’s pre-mRNA. Since this receptor is involved in controlling appetite and food consumption, Stamm’s observations suggested that alternative splicing-induced changes in its function may contribute to the drive of people with Prader-Willi syndrome to overeat. He collaborated with Emeson to determine whether a synthetic replacement for SNORD115 might be successful in treating this condition.

Alternative splicing shows promise for treatment

“In order to stop these patients from overeating, we looked for a way to substitute this snoRNA,” said Stamm. “We identified an oligonucleotide – a short strand of RNA – that could mimic the effect of the naturally-occurring snoRNA.”

When the researchers tested the oligonucleotide in animal models, they found that the group who received the oligonucleotide ate less food than did the control groups.

“This shows that food consumption is regulated at the level of alternative splicing,” said Stamm, “and that we can interfere with this system using an RNA oligonucleotide.”

While the missing snoRNA in Prader-Willi syndrome may have inspired the design of this new treatment strategy, the implications extend beyond the rare genetic disorder.

“What’s fascinating is that, because Prader-Willi syndrome is a genetic disease, it’s basically an exaggeration of normal obesity,” said Stamm. “From this, we can learn new ways to treat obesity in the general population.”


To see Stamm discuss his new findings,check out this video.


Next Steps