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A new study, done in part at the UK Markey Cancer Center, shed light on why lung cancer cells can resist therapeutic cancer treatment.

Markey research sheds light on lung cancer formation and treatment

A new study co-authored by a researcher starting her laboratory at the UK Markey Cancer Center shows that in certain genetic situations, one non-small cell lung cancer subtype can change into another subtype.

This lung cancer “lineage switching” could explain why some cancers are resistant to therapeutics, and this research examines exactly how the lineage switch can happen. The work was a collaborative effort between laboratories in Kentucky, New York and Boston.

“Now that we have a glimpse into the molecular mechanism of lineage switching, we can begin to learn how to manipulate this phenomenon for better therapeutic outcomes,” said study co-author Christine Fillmore Brainson, assistant professor in the UK Toxicology and Cancer Biology department.

Previously, it was unclear which cells in the adult lung can be the “cells-of-origin” of the two major subtypes of non-small cell lung cancer, namely adenocarcinoma and squamous cell carcinoma. Likewise, it was unclear what differences in DNA organization define the two distinct lung cancer subtypes. The existence of adenosquamous lung tumors, clinically defined by the presence of both glandular adenocarcinoma lesions and fully stratified squamous lesions within the same tumor, suggested that both adenocarcinomas and squamous cell carcinomas could come from the same cells in the lung, but clear evidence for this theory was lacking.

Published in Nature Communications, the study showed that adenocarcinoma cells can change to squamous cells due to reorganization of their DNA in specific ways. Beginning with a mouse model of adenosquamous lung tumors, researchers validated the genetics by comparing it to human adenosquamous lung tumor – the genetics are often the same, including activation of the oncogene KRAS and the deletion of the tumor suppressor Lkb1. The team then used transplant assays to demonstrate that established adenocarcinoma tumors could transition to squamous cell carcinomas in the mouse lung.

Lastly, the group isolated different lung cells, and demonstrated that only certain lung cells could give rise to tumors capable of undergoing the lineage switch.

“This data is exciting because it shows which cells in the lung can give rise to adenosquamous tumors,” Brainson said.  “And the technique we used to transform the isolated cells can be applied to many lung cancer models.”

Oncologists have observed this “lineage switching” after the failure of EGFR tyrosine kinase inhibitor treatment, when it is clinically justifiable to take a second biopsy. However, second biopsies are not normally done after chemotherapy, a practice that Brainson thinks could be revised to understand the exact mechanisms of therapy resistance.

In addition to Brainson, the manuscript was co-authored by Haikuo Zhang of the Dana-Farber Cancer Institute in Boston. The research was a collaborative effort between the laboratories of Carla Kim at Boston Children’s Hospital, where Brainson was based for her post-doctoral studies; Hideo Watanabe at Icahn School of Medicine in New York; and Dr. Kwok-Kin Wong at Pearlmutter Cancer Center in New York.

This work was funded in part by the American Cancer Society, the Lung Cancer Research Foundation, the V Foundation for Cancer Research, the March of Dimes, the National Cancer Institute, the Gross-Loh Family Fund for Lung Cancer Research and Susan Spooner Family Lung Cancer Research Fund at the Dana-Farber Cancer Institute


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UK researcher Hefei Wen has authored a study showing state drug-monitoring programs can reduce the number of opioids prescribed to Medicaid recipients.

Monitoring programs can help address opioid epidemic, UK research shows

New research from the UK College of Public Health suggests state drug-monitoring programs are effective in reducing the number of opioids prescribed to Medicaid recipients.

Led by researcher Hefei Wen, the study shows that state requirements for healthcare providers to participate in prescription-drug monitoring programs, or PDMPs, have influenced safer prescribing practices for Medicaid patients. Published in the April edition of Health Affairs, the research suggests state PDMP mandates are linked with reduced opioid prescriptions received by Medicaid patients as well as Medicaid spending on opioid prescriptions by as much as 10 percent.

The analysis done by Wen and her team showed state mandatory registration or use of a PDMP reduced Schedule II opioid prescriptions and spending by 9 to 10 percent between 2011 and 2014. The results suggest programs like these are effective in promoting safer and more contained prescribing of opioids with high potential for abuse and dependence. These implications support PDMP mandates as effective in addressing the opioid epidemic.

Forty-nine states and the District of Columbia have PDMPs in place to help providers identify patients at high risk of misusing or abusing controlled substances. However, the average registration rate across the states is low, and most registered prescribers do not use PDMPs on a consistent basis.

An increasing number of states that have implemented mandates that require providers to register with the monitoring programs and to use program data when prescribing opioids and other controlled substances. For instance, in 2012, legislators in Kentucky passed one of the most comprehensive mandates.

The Kentucky mandate requires prescribers to register with the Kentucky All Schedule Prescription Electronic Reporting System (KASPER). Then, they must query the KASPER system for all first-time prescriptions and a minimum of every 12 months after the first prescription. Similarly strong mandates can help improve participation in PDMPs and fulfill their potential in addressing the opioid epidemic.

Wen is an assistant professor in health management and policy in the UK College of Public Health. Her research leverages economic thinking to inform health care and public safety, with a concentration on behavioral health and drug control policy.


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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.”


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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.


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Former UK nurse Kristin Ashford has dedicated her life to researching ways to prevent pre-term birth and promote healthy pregnancies.

UK nurse, researcher helps prevent pre-term birth

Working as a labor and delivery nurse for a decade, Kristin Ashford was surrounded by happy beginnings. She helped women and families welcome healthy babies into the world. But Ashford also helped mothers and their families deal with the stressful and heart-wrenching experience of pre-term birth.

As a first-hand witness of the negative outcomes associated with pre-term birth, Ashford was motivated to make a difference. She transitioned from nursing into a researcher, studying risk factors of pre-term birth and creating strategies to prevent them through pregnancy interventions.

“It really got me interested in how to help these women more,” Ashford said of her nursing experience in labor and delivery. “Not only to reduce their risk, but also to help them emotionally cope with pre-term birth.”

Risk factors for pre-term birth

Pre-term birth is defined as delivery prior to 37 weeks gestation. Several risk factors, including smoking, substance abuse, poor socioeconomic conditions and obesity, increase a woman’s chance of experiencing pre-term birth. The consequences for the baby include respiratory illness, gastrointestinal disorders, immune deficiency, hearing and vision problems, and a prolonged hospital sta. There can also be longer-term motor, cognitive, visual, hearing, behavioral, social-emotional, health, and growth problems.

Now, as the assistant dean of research in the UK College of Nursing, Ashford oversees multiple research projects and interventions driven by the common goal of prolonging pregnancy.

“I think that any time that you can prolong a pregnancy, it is a rewarding experience,” she said. “If you can prevent the child from being sick, prevent that family’s stress and prevent life-long complications associated with that risk, that’s extremely rewarding.”

Research and interventions

Ashford’s research covers the issues relevant to pre-natal care, as there are many things that can be changed in order to prevent pre-term birth, like tobacco use. Her interventions aim to prevent tobacco and illicit drug use, manage chronic conditions such as diabetes and obesity, and reduce emotional distress in expectant mothers.

Ashford’s interventions are founded on the CenteringPregnancy model, which prepares women for pregnancy, labor and delivery, and motherhood through a peer support groups led by nursing and other health professionals. Ashford has designed CenteringPregnancy interventions to help pregnant women in high-risk categories like diabetes, tobacco use, substance abuse, or other socioeconomic or ethnic risk factors.

“Our UK program actually wants to put women together that have more in common with one another,” Ashford said. “So, in addition to being put in the group about the same time that they’re pregnant, they also are put in (a group) based on their most high-risk factor for pre-term birth.”

One intervention effort led by Ashford effort seeks to inform pregnant women about the dangers of using tobacco products while pregnant and give them resources to quit. Despite the known risks of using tobacco products during pregnancy, many pregnant women in Kentucky still smoke. Ashford is troubled by the rising popularity of e-cigarettes among women of childbearing age. Her research studies indicate that women are using both e-cigarettes and traditional tobacco products during pregnancy.

“Tobacco causes birth defects in pregnancy — that’s known,” Ashford said. “And so, it’s very clear that electronic cigarettes contain tobacco. Certainly, there’s risks associated with electronic cigarette use in pregnancy.”

Ashford is expanding CenteringPregnancy programs to areas in Eastern and Western Kentucky. She is working with local health departments to provide a Centering support network for pregnant women in high-risk groups.

She said her position in the UK College of Nursing allows her to research and circulate interventions, teach future nurses and nursing researchers, and serve communities by improving the quality of health care.

UK assistant professor has been awarded a $65,000 grant to support new UK research on coloboma, a leading cause of blindness in children.

UK researcher uses zebrafish to study eye disorder

UK Assistant Professor of Biology Jakub Famulski has been awarded a Career Starter Grant by the Knights Templar Eye Foundation, a charity sponsored by the Grand Encampment of Knights Templar. The $65,000 grant will support Famulski’s new UK research on coloboma, a leading cause of blindness in children. The eye abnormality occurs before birth and involves missing tissue in or around the eye.

Famulski and his collaborators recently discovered a new type of coloboma, superior coloboma, which occurs in the top of the eye. But the underlying cause of most coloboma cases remains unknown.

To better understand the disorder, Famulski and UK graduate students Kristyn Van Der Meulen and Nicholas Carrara will use zebrafish as a model to study how coloboma occurs in the eye’s early development. With zebrafish, the team can easily and efficiently observe, manage and change cells in the laboratory.

“For a junior faculty member like myself, this grant is not only great financial help, but also confirmation that scientists in the community value this work, which I hope will help patients suffering from this disorder,” Famulski said.

The Knights Templar Eye Foundation, incorporated in 1956, works to improve vision through research, education and supporting access to care. Since its beginning, the foundation has awarded more than $23 million in grants to pediatric ophthalmology research. Thanks to this most recent grant, new UK research can help Famulski make a difference through the power of advanced medicine.

UK HealthCare looks to improve research and help infertility heartbreak.

Knowing risks, options can aid those with infertility

Written by Patrick Hannon, post-doctoral researcher in the UK Department of Obstetrics and Gynecology.

About 15 percent of couples in the United States experience infertility, which is when a couple has tried to become pregnant for a year without success. Infertility comes as a shock to many couples who have spent years preventing pregnancy.

The inability to become pregnant leads to long-lasting and detrimental effects on a woman’s physical and emotional wellbeing. These detrimental effects include a decreased quality of life as indicated by increased levels of stress, impairments in physical and mental health, and diminished social functioning when compared to fertile women. Research has shown that being diagnosed with infertility has similar emotional and life-altering impacts as being diagnosed with cancer or a heart attack.

Infertility is a major public health concern as the diagnosis and treatment of infertility is estimated to cost society over $5 billion annually. For many couples, equally devastating is the realization that their health insurance does not cover infertility treatment, and all their medical costs must be paid out-of-pocket. It is critically important for UK infertility research to understand the causes of infertility in order to refine treatments, decrease the costs associated with infertility, and benefit the overall wellbeing of those suffering from infertility

Risk factors

The most prominent underlying causes of female infertility are defects in ovulation, or release of the egg from the ovary. The exact cause for defects in the woman’s reproductive tract is not entirely understood, but several risk factors are associated with infertility, including:

  • Untreated sexually transmitted infections
  • Pelvic inflammatory disease
  • Certain cancer treatment regimens
  • Endometriosis
  • Polycystic ovarian syndrome
  • Exposure to environmental toxicants
  • Lifestyle factors such as smoking, drug use, excessive alcohol use, abnormally high levels of stress, and extreme weight gain or loss

Age and female infertility

However, the single most significant contributing factor to female infertility is age. Fertility greatly declines with age due to the natural depletion of eggs within the ovary and decreased quality of the remaining eggs, leading to increased chances of miscarriage. Further, the potential health of the child can be impacted by a woman’s age due to genetic abnormalities in the eggs of older women. As women in today’s society are delaying child birth for personal, professional and financial reasons, age becomes an important factor contributing to infertility.

Combating infertility

To combat infertility, women can undergo treatment from a trained infertility specialist, which includes infertility testing, drug treatment to aid in ovulation, surgery to repair abnormalities in the reproductive tract and assisted reproductive technologies (ART), which includes the commonly used in vitro fertilization (IVF) procedure. In ART, the egg is fertilized outside the body before being placed back into the woman’s uterus. Unfortunately, the challenges of infertility treatments, specifically ART, are that success rates are low (approximately 56 percent) and decline with age.

UK infertility research

Scientists are continuing to refine and improve ART methods, such as working to optimize dosing regimens of the drugs that aid in ovulation, refining the conditions in which fertilization takes place outside the body, enhancing the procedures used to evaluate embryo quality prior to placing the embryo back into the woman, and investigating ways to preserve the fertility of cancer patients by using ovarian cryopreservation.

In our laboratories here at the University of Kentucky, we are determining precisely how ovulation is controlled in women and are identifying novel factors that drive ovulation. Each of these advancements aims to improve effectiveness, while decreasing the time and cost of infertility treatments.