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April 28, 2016

Research Notes

Drug overdose deaths increase here

Areas in the U.S. with the highest drug-overdose death rates are not always places with high drug trafficking, according to a new Graduate School of Public Health analysis published in Preventive Medicine.

Drug-overdose mortality rates have increased an average of 6.7 percent per year since 1979 but held relatively steady in most U.S. border counties, indicating that drugs appear to pass through these counties without affecting the death rates of their residents.

Said lead author Jeanine Buchanich, deputy director of Pitt’s Center for Occupational Biostatistics and Epidemiology: “Our research reveals several potential new drug overdose problem regions that warrant careful attention as they may not correspond to areas covered by federal resources to combat drug trafficking. Western Pennsylvania is one such area that is not considered to have high drug trafficking, but yet has one of the fastest growing drug overdose rates nationwide.”

Using the Mortality and Population Data System, a unique repository and retrieval system for detailed death data from the National Center for Health Statistics, housed at Pitt, Buchanich and her team examined overdose deaths in the U.S. from 1979 to 2014. They started with 1979 because changes in reporting cause of death make it impossible to make comparisons with previous years. 2014 is the most recent year for which data are available.

The counties with the largest increases in overdose death rates were clustered in southern Michigan; eastern Ohio and western Pennsylvania; eastern Pennsylvania, New Jersey and much of southeastern New York; and coastal New England.

Counties in the Midwest, California and Texas have seen little to no increase in overdose death rates.

The mortality data was cross-referenced with counties in the high intensity drug trafficking areas program, which was created by Congress in 1988 to provide 31 high drug-trafficking areas of the U.S. with coordinated law enforcement resources dedicated to reducing trafficking and production.

High intensity drug trafficking areas with high overdose death rates mostly were concentrated in Appalachia and the Southwest U.S., whereas such areas with lower death rates were near the borders in California, Texas and southern Florida.

“While resources are justifiably being targeted to the high intensity drug trafficking areas, they must also be allocated to counties outside those areas with rapidly increasing and currently high drug overdose rates,” said Buchanich, also a faculty member in the Department of Biostatistics.

The Mortality and Population Data System also unveiled several demographic insights that could be used to guide prevention and drug intervention efforts, including that:
• Since 1979, death rates increased for all age groups, with the smallest rate of growth in those older than 65 and the largest in 45-54 year olds.
• In 1979, overdose deaths occurred most frequently among 25-34 year olds and blacks; in 2014, rates were highest among 45-54 year olds and whites.
• Mortality rates were slightly higher in urban counties than rural counties.
• Deaths due to overdose in women began increasing in the mid-1990s and increased dramatically in 2002; for men, the rates began climbing in the mid-1980s with a more rapid increase also beginning in 2002.
Buchanich will continue to build on her drug overdose research with funding from public health’s opioid pilot grant program. These one-year pilot grant projects explore different areas of the opioid overdose epidemic with the goal of providing research-based information to guide public health interventions.
Additional public health researchers on this study are Lauren C. Balmert, Dean Donald S. Burke and Gary M. Marsh. Janice L. Pringle of the School of Pharmacy and Karl E. Williams of the Office of the Medical Examiner of Allegheny County also contributed.
This research was supported by Pitt.

“Cura Zika” to
accelerate research

The public health school is launching Cura Zika, an international alliance to perform research addressing the Zika epidemic, with a symposium and live webinar featuring Pitt biomedical scientists and their Brazilian collaborators.

Zika is a mosquito-borne and sexually transmitted virus that causes microcephaly in infants born to mothers infected with it while pregnant. It also is associated with increased risk of Guillain-Barre syndrome and other neurological disorders in people who contract it. The virus is widespread in South and Central America and has a likelihood of gaining sustained transmission in the southern U.S. this summer.

Cura Zika builds on the public health school’s long-standing collaboration with FIOCRUZ, the most prominent science and technology health institution in Latin America.

Cura Zika — which means “Cure Zika” in Portuguese and Spanish — will provide quick-access funding to scientists performing time-sensitive research on the virus. This support is designed to move early stage innovative research ideas into larger studies in an accelerated manner.

Pitt faculty involved in the effort include Dean Donald S. Burke, UPMC-Jonas Salk Chair in Global Health and director, Pitt Center for Vaccine Research; Jennifer Adibi, faculty member in epidemiology and the School of Medicine Department of Obstetrics, Gynecology and Reproductive Sciences; Yoel Sadovsky, Elsie Hilliard Hillman Professor of Women’s and Infants’ Health Research in the School of Medicine and scientific director of the Magee-Womens Research Institute; and Ernesto Marques, faculty member in infectious diseases and microbiology.
The symposium is 1-3 p.m. May 5 in the public health auditorium (G23). Register at

UPJ, Concurrent
start research

Pitt-Johnstown and Johnstown-based Concurrent Technologies Corp. have created an academic-industry partnership to provide more hands-on research opportunities for faculty and students, particularly those in civil, chemical, computer, electrical and mechanical engineering.

Said UPJ President Jem Spectar: “Engineering students and faculty will benefit from the combined synergies of our two organizations … focusing on mutually aligned technology areas such as additive manufacturing, energy storage, big data, immersive environments, water sustainability and others.”

Added Edward J. Sheehan Jr., president and chief executive officer of Concurrent: “Our engineers and scientists will collaborate with professors and students from Pitt-Johnstown through research and development projects that can lead to technology-based economic development. Academic industry partnerships such as this can result in exciting new commercialization pathways, technical community projects and entrepreneurship that benefit regional economies.”
According to the agreement, each organization will:
• Identify opportunities for technical information exchanges.
• Host collaborative sessions concerning each other’s capabilities and core competencies.
• Hold academic-industry ideation sessions to develop research concepts.
• Jointly pursue external research funding and develop proposals in response to grants, broad agency announcements and other solicitations.
• Increase visibility through joint technical publications.

4 researchers from same lab honored

Four investigators from the same laboratory at the University of Pittsburgh Cancer Institute, partner with UPMC CancerCenter, have been recognized with American Association for Cancer Research (AACR) scholar-in-training awards.

Shivendra Singh, faculty member in pharmacology and chemical biology in the School of Medicine and UPMC Chair in Cancer Prevention Research, leads the lab. It focuses on examining enzymes that play a role in drug metabolism and cellular defenses against environmental toxins, as well as exploring the anti-carcinogenic effects of certain natural agents found in edible plants.

All of the investigations were supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

Three of the researchers received scholar-in training awards for high-quality papers relating to cancer prevention research:

• Su Hyeong Kim, for “Role of c-Myc in Prostate Cancer Stem-Like Cell Inhibition by Sulforaphane.” In this project, Kim showed that sulforaphane, which naturally occurs in broccoli and other cruciferous vegetables, can inhibit prostate cancer in lab tests because it blocks the effects of c-Myc, a gene that regulates cancer growth.

• Subrata K. Pore, for “Benzyl Isothiocyanate Inhibits Breast Cancer-Induced Osteoclastogenesis.” Pore and colleagues built on previous work showing that benzyl isothiocyanate (BITC), found in edible cruciferous vegetables such as garden cress, inhibits breast cancer in a mouse model of the disease. In advanced breast cancer, bone loss can occur, which can be deadly with the spreading disease. In this project, the team showed that BITC can limit bone breakdown by reducing the production of bone-resorbing cells called osteoclasts.

• Krishna Beer Singh, for “c-Myc Is a Novel Target of Prostate Cancer Cell Growth Inhibition by Honokiol.” Singh led a project that showed honokiol, a naturally occurring agent derived from magnolia trees, suppressed activity of c-Myc and other genes that play key roles in prostate cancer growth.

The fourth researcher received a $1,500 AACR-Triple Negative Breast Cancer Foundation scholar-in-training award:

• Ruchi Roy for “Benzyl Isothiocyanate Mediates Glucose Uptake Through AKT Activation in Breast Cancer Cells.” Roy showed in animal models that BITC’s effects in suppressing Her-2-driven breast tumors could be enhanced with the addition of an agent that inhibits the protein AKT.

Watercress extract detoxifies smoking carcinogens

Watercress extract taken multiple times a day significantly inhibits the activation of a tobacco-derived carcinogen in cigarette smokers, researchers at UPCI/UPMC CancerCenter demonstrated in a phase II clinical trial presented at the AACR annual meeting.

The trial also showed that the extract detoxifies environmental carcinogens and toxicants found in cigarette smoke, and that the effect is stronger in people who lack certain genes involved in processing carcinogens. This trial was supported by the NCI.

Said Jian-Min Yuan, associate director of the UPCI’s Division of Cancer Control and Population Science and an epidemiology faculty member in public h ealth: “Cigarette smokers are at far greater risk than the general public for developing lung cancer, and helping smokers quit should be our top cancer prevention priority in these people. But nicotine is very addictive, and quitting can take time and multiple relapses. Having a tolerable, nontoxic treatment, like watercress extract, that can protect smokers against cancer would be an incredibly valuable tool in our cancer-fighting arsenal.”

Yuan, who also is the Arnold Palmer Endowed Chair in Cancer Prevention, and his colleagues enrolled 82 cigarette smokers in the randomized clinical trial. The participants took either 10 milligrams of watercress extract mixed in 1 milliliter of olive oil four times a day for a week or a placebo. Each group of participants then had one week without medication, then switched groups, so that those getting the placebo now received the extract. They all continued their regular smoking habits throughout the trial.

In one week, the watercress extract reduced activation of the carcinogen known as nicotine-derived nitrosamine ketone in the smokers by an average of 7.7 percent. It increased detoxification of benzene by 24.6 percent and acrolein by 15.1 percent, but had no effect on crotonaldehyde. All the substances are found in cigarette smoke.

Participants who lacked two genes involved in a genetic pathway that helps the antioxidant glutathione remove carcinogens and toxicants from the body saw an even bigger benefit to taking the watercress extract, which increased their detoxification of benzene by 95.4 percent, acrolein by 32.7 percent and crotonaldehyde by 29.8 percent.

A phase III clinical trial in hundreds of people must be performed before the treatment could be recommended for smokers. Yuan warned that while eating cruciferous vegetables, such as watercress and broccoli, is good for people, it is unlikely to have the same pronounced effect as the extract.
This project also involved researchers from the University of Minnesota.

Nursing faculty team secures patent

Cecelia C. Yates, faculty member in the School of Nursing, is part of a research team that successfully sought a patent for “Activators of CXCR3 for the Treatment of Angiopathies of the Eye.”

Angiopathy is any disease of the blood vessels. Such eye disorders may include macular degeneration, restenosis following glaucoma treatment or diabetic retinopathy. Yates and her team developed a compound – the IP-10 (peptide) – which is an activator of the C-X-C chemokine receptor 3 (CXCR3). CXCR3 provokes an anti-angiogenic mechanism (blocking new blood vessel growth), which would be beneficial in wound healing and treating angiogenic disorders of the eye.

In excess of 12 million older Americans suffer from vision loss caused by excessive ocular blood vessel growth. The new IP-10 peptide is designed as an injectable solution that will remove excess blood vessels to restore vision, not just halt vision loss.

Yates’ Pitt co-inventors were Joel S. Schuman, Ian Conner and Alan Wells.

Thyroid tumor
reclassified as

Led by researchers at the School of Medicine, an international panel of pathologists and clinicians has reclassified a type of thyroid cancer to reflect that it is noninvasive and has a low risk of recurrence. The name change, described in JAMA Oncology, is expected to reduce the psychological and medical consequences of a cancer diagnosis, potentially affecting thousands of people worldwide.

The incidence of thyroid cancer has been rising, partly due to early detection of tumors that are indolent or nonprogressing, despite the presence of certain cellular abnormalities that traditionally are considered cancerous.

Said senior investigator Yuri Nikiforov, faculty member in pathology and director of the Division of Molecular and Genomic Pathology: “This phenomenon is known as overdiagnosis. To my knowledge, this is the first time in the modern era a type of cancer is being reclassified as a noncancer. I hope that it will set an example for other expert groups to address nomenclature of various cancer types that have indolent behavior to prevent inappropriate and costly treatment.”

In particular, a tumor type known as encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) has increased in incidence by an estimated two- to three-fold over the past 20-30 years and makes up 10-20 percent of all thyroid cancers diagnosed in Europe and North America. Although studies have shown EFVPTC is not dangerous, it is typically treated as aggressively as other types of thyroid cancer. At the recommendation of the NCI, the Medicine-led panel sought to revise the terminology and to see if the word “cancer” could be dropped from its name.

Two dozen experienced pathologists from seven countries and four continents independently reviewed 268 tumor samples diagnosed as EFVPTC from 13 institutions. The experts established diagnostic criteria, including cellular features, tumor invasion and other factors. In a group of more than 100 noninvasive EFVPTCs, there were no recurrences or other manifestations of the disease at a median follow-up of 13 years, the panel found.

These experts decided to rename EFVPTC “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” or NIFTP. The new name cites key features to guide pathologists in diagnosis, but omits the word “cancer,” indicating that it need not be treated with radioiodine or other aggressive approaches.
“We determined that, if NIFTP is carefully diagnosed, the tumor’s recurrence rate is extremely low, likely less than 1 percent within the first 15 years,” Nikiforov said. “The cost of treating thyroid cancer in 2013 was estimated to exceed $1.6 billion in the U.S. Not only does the reclassification eliminate the psychological impact of the diagnosis of ‘cancer,’ it reduces the likelihood of complications of total thyroid removal, and the overall cost of health care.”

The team included researchers from the University of Bologna, Italy; the University of Pennsylvania; the University of Pisa, Italy; Harvard medical school; and others.

The project was funded in part by UPCI, UPMC and CBLPath.

—Compiled by Marty Levine



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