The University of Pittsburgh School of Dental Medicine Center for Craniofacial and Dental Genetics (CCDG) has received a $4 million grant that will expand its ongoing Factors Contributing to Oral Health Disparities in Appalachia project, part of the Center for Oral Health Research in Appalachia (COHRA).
The new grant will be dedicated to enrolling pregnant African-American women in the COHRA project, which was previously limited to Caucasian women and their children. COHRA’s long-term goal is to design and implement preventive interventions for oral disease, particularly childhood caries, a bacterial infection that causes corrosion of a child’s teeth due to bacteria that is passed from his or her mother.
Both increased sugar intake and frequency of exposure can trigger a disease process that leads to caries. Additional factors associated with caries in children include genetic risk, household socioeconomic status, maternal caregiving behavior and stress, access to care and ethnicity.
“Through the ongoing work of the existing COHRA study, progress has been made in understanding many of these factors that lead to caries,” said Dr. Mary Marazita, CCDG director and principal investigator of the COHRA study. “However, much remains to be done to further characterize individual risk factors, and, just as importantly, to determine how interactions among them lead to oral health disparities.”
Protocols from the original grant will be followed in the new African-American cohort, adding a large, high-quality data set from an underrepresented population to the study’s existing data. The important influence of race as a factor in oral health disparities can then be added to the genetic, dietary, behavioral, microbiological, medical, and demographic factors already assessed in the study.
In addition to Marazita, investigators from Pitt’s School of Dental Medicine include Dr. Robert Weyant, Dr. Katherine Dr. Neiswanger, Dr. Deborah Polk, Dr. Alexandre Vieira, and Dr. Seth Weinberg. The team also includes Dr. John Shaffer and Dr. Lisa Bodnar from Pitt’s Graduate School of Public Health, and Dr. Debra Bogan from Children’s Hospital of Pittsburgh of UPMC. As with the parent project, the extension of the COHRA grant is a collaboration with West Virginia University and the University of Michigan.
Jill Cicirelli is a member of the University of Pittsburgh’s Center for Craniofacial and Dental Genetics.
The chance that a person will develop cancer is determined by a mix of hard-wired genetic factors that are inherited and environmental changes that affect how genes are expressed. However, some of these environmental factors such as smoking or alcohol abuse are known to have “epigenetic” effects on genes that may also be inherited. Such epigenetic alterations don’t change the letters of the DNA code itself, but involve either placing or removing chemical tags on proteins that control whether these genes are turned on or off.
Since alcohol use disorder is known to increase the risk of cancer, Dr. Shirley Hill, professor of psychiatry at the University of Pittsburgh School of Medicine, wondered whether this increase in risk could be passed on to subsequent generations by an epigenetic change in cancer-causing genes.
Her recent findings, published in the journal Epigenomics, provide some preliminary evidence to suggest that this may indeed be the case.
“Establishing a connection between epigenetic changes and the risk of developing cancer is not easy,” Hill said. “It requires an in-depth history of alcohol use not only in study participants, but also their relatives across multiple generations. It also requires data to be collected on mothers’ alcohol use during pregnancy as this can help rule out any direct effects of alcohol on the fetus during pregnancy.”
Hill and her team had this exact information, along with DNA samples, as part of a long-running study on the psychiatric impacts of multi-generational alcohol use disorder in families.
“Because we had the foresight to store DNA for third generation offspring when they were still children, we could be fairly confident that any epigenetic changes we observed would have been inherited from either the parents or grandparents,” she said. “It was a one of a kind opportunity, and we had to take advantage of that.”
The researchers analyzed DNA from 62 first and second-generation individuals and 441 third-generation offspring, looking for the presence or absence of a chemical “methyl” tag on two genes – HRAS, an “oncogene” known to promote tumor growth, and TP53, a “tumor-suppressor” gene that as the name suggests, plays a role in inhibiting the growth of cancer cells.
Their analysis showed that having a parent or grandparent with alcohol dependence was associated with increased levels of the chemical tag (methylation) on the TP53 gene, which in turn could lead to lower levels of the tumor protective protein. (more…)
As the opioid epidemic continues to devastate the United States, the country is also battling the entwined epidemic of chronic pain, which affects more than 100 million Americans. Half of those individuals suffer from lower back pain, making it the most common type of chronic pain nationwide.
Since opioids are currently a go-to therapy for this condition, three UPMC physicians are looking for a solution to help patients manage their lower back pain while also decreasing the risk of addiction and maximizing the role of non-opioid therapies.
Dr. Howard Gutstein, professor of anesthesiology at the University of Pittsburgh School of Medicine, Dr. Gwen Sowa, director of the UPMC Rehabilitation Institute, and Dr. Ajay Wasan, vice chair for pain medicine in the UPMC Department of Anesthesiology are using existing data from multiple sources across the UPMC system to develop models to predict how patients with lower back pain will respond to treatment while also identifying which patients are most susceptible to opioid addiction.
“If we are able to understand which patients would respond to various lower back pain therapies and which patients are susceptible to addiction before considering opioids, we could guide their treatments to maximize pain relief while minimizing the risk of opioid dependency,” Wasan said.
Existing research also showed an association between protein biomarkers found in the blood, recurring genetic variations and a patient’s response to spinal injections for lower back pain. UPMC then conducted additional research that classified patient responses to those spinal injections into 10 categories based on their genetics.
Funded by a Bench at the Bedside grant from The Beckwith Institute, Gutstein, Sowa and Wasan are combining their expertise to analyze UPMC’s abundance of existing data and build new predictive models based on this research.
“Currently, our modeling accurately identifies the response of roughly 22 percent of all patients receiving spinal injections – those most likely to improve and those least likely to improve,” Sowa said. “This project focuses on finding more accurate data to predict how the rest of patients will respond to treatment while also addressing the question of opioid addiction.”
As the algorithms develops, the team is hopeful that the models can be utilized by physicians at UPMC and beyond to guide treatment decisions and reduce pain and opioid abuse.
“This project will help build the foundation for more personalized and precision medical care by selecting the most appropriate and effective pain treatments — and even help define more successful treatment strategies for individuals who have an existing opioid addiction,” said Gutstein.
Additional information about Bench at the Bedside grants and the projects they support is available on The Beckwith Institute website.
For more than two decades, Olivera Finn has tirelessly pursued one goal in her research: to develop a vaccine to prevent cancer. She has had this goal since 1989, when her research team discovered the first tumor antigen recognized by a type of immune cell that can kill cancer cells. That antigen—an abnormal version of a protein called MUC1—is produced by the cells of more than 80% of cancer types, including cancers of the breast, pancreas, colon, lung, and prostate.
Although she started her research career as an organ transplant immunologist, the discovery of MUC1 was a pivotal point in Olivera’s career trajectory. “Once we discovered tumor antigens,” she said, “I never looked back.” Olivera received her first NCI grant in 1991 and has been funded ever since to study the biology of tumor antigens and develop them as targets for cancer prevention.
Cancer can take many years—even decades—to develop. Some cancers arise from precursor growths that can be detected by current screening methods. For example, colorectal polyps called advanced adenomas, which can be detected by colonoscopy, can progress to colorectal cancer. These adenomas can be removed surgically, but in many patients, new ones continue to develop and some will become malignant. Olivera’s lab found that the cells of advanced adenomas and the precursors of pancreatic, lung, and many other types of cancer all produce abnormal MUC1 protein.
The presence of abnormal MUC1 on premalignant growths may make it a good target for a vaccine that would prevent their progression to cancer or the development of new precursors. To test this idea, Olivera’s group conducted the first ever clinical trial of a cancer prevention vaccine based on a tumor antigen in healthy people without cancer who were at increased risk of developing the disease.
In the NCI-funded trial, reported in 2013, individuals with a history of advanced adenomas were given an MUC1 vaccine. The vaccine was shown to be safe and to elicit a strong immune response and a long-lasting immune memory. NCI is currently sponsoring a phase II trial testing whether the vaccine will prevent the regrowth of colorectal polyps.
Looking forward, Olivera envisions, “If you are in your 60s and your doctor discovers you are at high risk for cancer, the idea would be to vaccinate to boost the immune system’s ability to keep any abnormal cells in check instead of waiting to see if cancer develops.”
Olivera says that funding from NCI is critical for her research and for cancer prevention research in general. Cancer prevention research is complex, and translating laboratory discoveries into new ways to prevent cancer requires sustained investments over many years—investments that the private sector is often reluctant to make. But “building the evidence that vaccines are an effective way of controlling cancer will go a long way toward getting companies interested,” she said.
The field of cancer immunology has expanded dramatically and has led to immunotherapies for the treatment of advanced cancers as well as vaccines against some viruses that cause cancer. Boosting the immune system to prevent cancers that are not caused by viruses may now be within reach. “The opportunities are amazing,” she added.
University of Pittsburgh and UPMC researcher Dr. Olivera Finn was featured in Stories of Impact by the National Cancer Institute. This story was originally published by the National Cancer Institute.
Every year, more than 44,000 Americans take their own lives, and suicide is the second-leading cause of death in adolescents between the ages of 15 to 24.
These alarming numbers beg for better identification of patients at risk for suicide to ensure they get the care they need, when they need it. That’s why two UPMC doctors – Dr. David Brent and Dr. Neal Ryan – and one University of Pittsburgh professor, Dr. Fuchiang (Rich) Tsui, are leading a project to better track patients at risk for suicide through the electronic health record (EHR).
“In many cases, the last clinical contact a suicide victim sees is a primary care physician or someone in the emergency room, not a mental health professional,” Brent said. “This project is working to change that.”
Using Brent’s background in child psychology, epidemiology and suicide prevention, Ryan’s experience in child psychology, and Tsui’s expertise in data science, the group set out to develop EHR algorithms to track patient patterns and flag those at high risk of suicide.
The algorithms combine diagnostic, machine learning and natural language processing information to analyze all relevant information about a patient, automating the process of analyzing records and searching for signs of suicide that often go undetected by humans. Patients at risk for suicide and suicidal behavior will be identified and their chart flagged so psychiatric professionals can provide the help patient needs.
“Our initial efforts will look just within the electronic medical records of the clinical sites involved in the study at UPMC,” Ryan said. “Once the algorithm is solidified at UPMC, we are hoping to expand it to other health systems and adapt the algorithms to fit their electronic health records.”
To help develop and expand the system, the research team was awarded a Bench to Bedside grant from The Beckwith Institute in June 2017. The program supports research that translates directly to patient care.
“As a data scientist, I am excited by this project that has developed a predictive system that automatically identifies relevant risk factors from potentially tens of thousands of clinical findings and computes a patient’s suicide risk accordingly,” Tsui said.
As the project expands across different health systems, the algorithms will need to be able to read all the data languages the various hospitals employ. After the system is up and running, it will need training every few years to update the algorithms.
“This project is a low-cost, low-risk method to yield better patient care,” Brent said. “This is an extra resource to guide physician decision making and referrals, which ultimately uses this predictive data approach to save lives.”