Statins inhibit spread of some cancers

Cholesterol-lowering drugs appear to be a promising, cost-effective way to reduce the risk of metastases in some cancers, according to research led by the School of Medicine. Metastases, rather than the original tumor, are what usually kill people with cancer.

The discovery, published in Scientific Reports, reveals the mechanism by which statins may impede the process that cancerous tumor cells need in order to split off from the primary tumor and cause cancer elsewhere in the body.

Said senior author Zoltán Oltvai, pathology faculty member: “We didn’t plan to discover this — we were actually modeling metabolism of tumor cells and looking at the response of various tumor cells to existing drugs, including statins.

But, sure enough, we were able to show that these cholesterol-lowering drugs interrupt the growth of some cancer cell lines that are very similar to those cancer cells that leave the primary tumor and eventually colonize other organs.”

When a tumor metastasizes, it spreads cancer cells through the body using the blood stream. The cells then come to rest at another site in the body, eventually forming new tumors. Sometimes these cells lie dormant, and a person can appear cancer-free after the primary tumor is removed, only to have his or her cancer reappear years later in another organ.

Scientists have known for several years that statins sometimes seem to fight cancer; however, the mechanism wasn’t clear, and previous clinical trials have yielded mixed results regarding statins as anti-cancer drugs.

Cancer cells require the synthesis of cholesterol and cholesterol precursor molecules to reprogram themselves from an adherent, or “epithelial” state, to a mobile, or “mesenchymal” state, in order to leave the primary tumor and recolonize elsewhere in the body. Statins, which are used routinely to lower lipid levels, potentially could block cancer cell spread by inhibiting an enzyme that catalyzes a key step in the cholesterol synthesis process, Oltvai said.

His team found that slower-growing, mesenchymal-like cancer cell lines that contain the protein vimentin inside the cell, but do not display the protein E-cadherin on their surface, are particularly sensitive to statins. Knowing this, doctors eventually may be able to test biopsies from cancerous tumors for these markers to determine if statins may be effective.

“While statins probably aren’t going to be effective against a patient’s primary tumor, they could work to block the tumor’s ability to metastasize,” said Oltvai. “And that is very important because most cancer patients die because of the metastases.”

Oltvai noted that coupling treatment of the primary tumor — which can involve chemotherapy, surgical removal of the tumor and radiation — with statins might be a way to prevent the primary tumor from shedding cells, and also prevent those cells from surviving their journey through the body or reactivating elsewhere in the body later on.

These are preliminary results, and people should not start taking statins as an anti-cancer drug, Oltvai stressed.

His team tested the cancer cells’ reaction to statins in the laboratory, and the process could be different in the human body. The researchers are pursuing funding for additional studies on exactly how statins can interfere with the process that leads to metastases and whether combining statins with other drugs may be even more potent than using statins alone.

Additional researchers on this study were Katsuhiko Warita, Tomoko Warita, Colin Beckwitt, Mark Schurdak and Alan Wells, all from Pitt, and a colleague from Rutgers Cancer Institute of New Jersey.

This research was supported by the Department of Veterans Affairs, the National Center for Advancing Translational Sciences and the National Science Foundation.

Biomarkers linked to kidney damage in critically ill patients

High levels of two novel urinary biomarkers early in critical illness are associated with adverse long-term outcomes in patients with acute kidney injury (AKI), according to an international, multi-center study led by School of Medicine researchers. AKI is a condition that often affects those in intensive care and can occur hours to days after serious infections, surgery or taking certain medications.

The results, available online in the Journal of the American Society of Nephrology, show that the combination of tissue inhibitor metalloproteinase-2 (TIMP-2) and IGF-binding protein-7 (IGFBP7) can identify patients with AKI who are at increased risk for death or requiring renal replacement therapy, such as dialysis or kidney transplant, over the next nine months. The two biomarkers are indicators of cell stress and injury, key components in the development of AKI.

AKI is largely asymptomatic, particularly in the early stages when intervention is most beneficial. The incidence of AKI is high among critically ill patients, with up to 50 percent developing some degree of AKI during their illness, increasing the risk of death due to kidney failure.

Said senior investigator John Kellum, director of the Center for Critical Care Nephrology and a critical care physician at UPMC: “We found that not only do these biomarkers predict the development of AKI but, at high levels, they also tell us about long-term prognosis. This should greatly aid clinicians and researchers attempting to address this too-common complication.”

Investigators enrolled 692 critically ill patients at 35 medical centers in North America and Europe. The primary analysis assessed the outcomes of patients using an FDA-approved biomarker test, known as NephroCheck, within the first day of arrival in the intensive care unit. The team found strong associations between the biomarker combination and the risk of renal replacement therapy or death.

Co-authors of the study were from the University of Chicago, Vanderbilt, the Veterans Affairs Medical Center in Washington, D.C., the University of Florida, the Mayo Clinic, Otto von Guericke University and Walker Biosciences.

The study was sponsored by Astute Medical.

Flower pigmentation evolves as it did in animals, study shows

In 1833, Constantin Wilhelm Lambert Gloger published his key observation that warm-blooded animals tend to be more heavily pigmented or darker the closer they live to the equator, but he probably didn’t realize the degree to which the climate would change in the next 200 years or so.

This month, Matthew Koski and Tia-Lynn Ashman proved that the same phenomenon described by Gloger, a German zoologist, exists among flowers. Their paper, “Floral pigmentation patterns provide an example of Gloger’s rule in plants,” was published in the first issue of Nature’s new journal, Nature Plants. The finding expands our understanding of biological responses to global climate change, Koski and Ashman say.

Koski, the lead author, is pursuing his PhD in Ashman’s lab in the Department of Biological Sciences within the Dietrich School of Arts and Sciences. Ashman, the senior author, is a faculty member and associate chair of the department.

One of the reasons investigators have not pursued proof of Gloger’s rule in flowers is that pollinators, such as bees, don’t see what humans see when they look at a flower. Pollinators see in the ultraviolet as well as visible ranges. What appears bright yellow to a person can appear dark or patterned to a bee.

Koski and Ashman studied the flowers of Argentina anserina, a plant in the rose family, across four lines of latitude — three in the Northern Hemisphere and one in the Southern Hemisphere.

Using ultraviolet imaging, the pair examined the “bull’s-eye” centers of the flowers (which look dark to pollinators) and discovered that they were larger the nearer to the equator the flowers grew. Larger bull’s-eyes, Koski explained, are associated with higher levels of ultraviolet light, which is more intense near the equator.

Koski and Ashman then hypothesized that bigger bull’s-eyes absorb more ultraviolet light, functioning as a protective trait because high ultraviolet light levels are known to damage DNA. In their study, they confirmed that extreme ultraviolet light reduces the viability of pollen (gametes) in Argentina anserina.

One might predict then that as the Earth receives more ultraviolet light at extreme northern and southern climes due to depletion of the ozone layer, flowers farther from the equator are likely to begin to evolve traits, such as larger ultraviolet light-absorbing bull’s-eyes, that are beneficial to their survival. However, this may come at a cost as bigger bull’s-eyes obscure the “sweet center” of the flower where pollen and nectar rewards are found, thus making poorer targets for pollinators.

Noted Ashman: “Spring is coming earlier, and plants and pollinators are no longer in sync. Increased ultraviolet radiation is causing the same sort of disruption.”

Smoking, alcohol, gene interact for pancreatitis risk

Genetic mutations may link smoking and alcohol consumption to destruction of the pancreas observed in chronic pancreatitis, according to a 12-year study led by researchers at the School of Medicine.

The findings, published in Clinical and Translational Gastroenterology, provide insight into why some people develop this painful and debilitating inflammatory condition while most heavy smokers or drinkers do not appear to suffer any problems with it.

The process appears to begin with acute pancreatitis, which is the sudden onset of inflammation, causing nausea, vomiting and severe pain in the upper abdomen that may radiate to the back, and typically is triggered by excessive drinking or gallbladder problems, explained senior investigator David Whitcomb, chief of gastroenterology, hepatology and nutrition in the school. Up to one-third of those patients will have recurrent episodes of acute pancreatitis, and up to one-third of that group develops chronic disease, in which the organ becomes scarred from inflammation.

Said Whitcomb: “Smoking and drinking are known to be strong risk factors for chronic pancreatitis, but not everyone who smokes or drinks damages their pancreas. Our new study identifies gene variants that when combined with these lifestyle factors make people susceptible to chronic pancreatitis and may be useful to prevent patients from developing it.”

In the North American Pancreatitis Study II Consortium, researchers evaluated gene profiles and alcohol and smoking habits of more than 1,000 people with either chronic pancreatitis or recurrent acute pancreatitis and an equivalent number of healthy volunteers.

The researchers took a closer look at a gene called CTRC, which can protect pancreatic cells from injury caused by premature activation of trypsin, a digestive enzyme inside the pancreas instead of the intestine, a problem that already has been associated with pancreatitis.

They found that a certain variant of the CTRC gene, which is thought to be carried by about 10 percent of Caucasians, was a strong risk factor for alcohol- or smoking-associated chronic pancreatitis. It’s possible that the variant fails to protect the pancreas from trypsin, leaving the carrier vulnerable to ongoing pancreatic inflammation and scarring.

“This finding presents us with a window of opportunity to intervene in the disease’s process,” Whitcomb said. “When people come to the hospital with acute pancreatitis, we could screen for this gene variant and do everything possible to help those who have it quit smoking and drinking alcohol, as well as test new treatments, because they have the greatest risk of progressing to end-stage chronic pancreatitis.”

Whitcomb’s team has been implementing more personalized approaches to pancreatic diseases in the Pancreas Center of Excellence within the Digestive Disorders Center at UPMC and hopes to learn whether use of genetic information can, in fact, reduce the chances of chronic disease in high-risk patients.

Other members of the Pitt study team were Jessica La-Rusch, Antonio Lozano-Leon, Kimberly Stello, Amanda Moore, Venkata Muddana, Michael O’Connell, Brenda Diergaarde and Dhiraj Yadav.

The project was funded by the National Institutes of Health (NIH) and the Conselleria de Industria e Innovación, Xunta de Galicia, Spain.

Grants focus on improving patient care at bedside

With a focus on improving patient care at the bedside, the Beckwith Institute recently awarded 11 grants to UPMC clinicians and staff worth nearly $89,000.

Incorporating both high-tech and “high touch” ideas, the projects cover a multitude of departments and hospitals and range from improving the notification system for incoming trauma patients to providing the first-ever mobile pediatric concussion testing platform.

Supported by UPMC chairman G. Nicholas Beckwith and his wife, Dotty, with matching funds from UPMC, the Beckwith Institute annually provides grants to improve clinical outcomes by empowering both clinicians and patients to explore innovative ways of transforming health care.

The grants are administered through the frontline innovation program, which focuses on improving the patient bedside experience, and the clinical transformation program, which supports comprehensive redesign of processes to put the involvement of the patient and their family members at the core.

The projects awarded 2014-15 grants include:

• a notification system for incoming trauma patients that will send detailed yet confidential patient information to TV monitors outside the trauma bay at UPMC Presbyterian.

• the incorporation of ultrasound-guidance for small biopsies to provide rapid and effective evaluation for patients at the bedside.

• a system for customizing music therapy for oncology patients to improve symptoms such as anxiety and fatigue.

• a plan for purchasing 18 iPads to provide the first-ever mobile concussion-testing platform for pediatric patients, aiming to improve the management and treatment of concussion.

• development of a training program that will improve the handoff of open-heart surgery patients from the operating room to the cardiovascular intensive care unit at UPMC Passavant.

Early blood glucose control in Type 1 diabetes yields longer lifespan

People with Type 1 diabetes who intensively control their blood glucose soon after diagnosis are likely to live longer than those who do not, a recent report led by a Graduate School of Public Health investigator revealed.

Data from a long-running trial and follow-up observational study funded by NIH, with participants from 27 academic medical centers in the U.S. and Canada, showed a 33 percent reduction in deaths over the past several decades among participants who had early, good control of their blood glucose. The findings were detailed in the Journal of the American Medical Association.

Said lead author Trevor Orchard, epidemiology faculty member in public health: “We can now confidently tell doctors and patients that good, early control of blood glucose greatly reduces any risk for early mortality in people with Type 1 diabetes, usually diagnosed in children and young adults. These results also remove any lingering concern that intensive therapy may lead to increased mortality.”

The Diabetes Control and Complications Trial (DCCT) and the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) observational study have significantly changed treatment protocols for Type 1 diabetes and improved the outlook for people with the condition over the past several decades.

Type 1 diabetes happens when the body does not produce insulin, a hormone that is needed to convert sugar into energy. By regularly monitoring their blood glucose levels and adjusting doses of insulin accordingly, patients can work to keep their blood glucose in a normal range.

Beginning in 1983, the DCCT enrolled 1,441 volunteers ages 13-39 with recent-onset Type 1 diabetes. Half were assigned randomly to intensive efforts to keep blood glucose as close to normal levels as possible. The other half were assigned to the conventional treatment at the time, which simply sought to keep blood glucose levels from getting so high or low that patients would show symptoms, such as blurred vision or shortness of breath.

The trial ended in 1993 when the intensive group was found to have less eye, nerve and kidney disease. All participants then were taught the intensive blood glucose control techniques and early, good control of blood glucose was recommended for all people with Type 1 diabetes. The EDIC study then was launched to continue tracking the health of all the participants.

Since 1983, 107 trial participants have died, with 64 in the group that originally received standard treatment, compared with 43 in the intensive treatment group.

The most common causes of death were cardiovascular disease (22 percent), cancer (20 percent) and acute diabetes complications (18 percent), all of which were more common in the group that originally received conventional treatment. Accidents or suicide were the fourth most-common cause of death (17 percent), with nominally more deaths in the people assigned to the early intensive treatment.

Higher average glucose levels and increased protein in the urine — a marker of diabetic kidney disease — were the major risk factors for death.

“These results build on earlier studies that suggested that increased protein in the urine largely accounts for shorter lifespans for people with Type 1 diabetes,” said Orchard. “Our findings further emphasize the importance of good, early glucose control, as this reduces the risk for increased protein in the urine in general, as well as for diabetic kidney disease itself.”

While this study found an association between intensive blood glucose control and decreased mortality in people with Type 1 diabetes, Orchard and his colleagues noted that the results cannot be extended to people with Type 2 diabetes. Previous, unrelated studies have shown conflicting results for Type 2 diabetes.

Additional authors were from George Washington University, Harvard, the University of Toronto and Cornell.

Primary funding came from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the general clinical research centers program and clinical translational science center program.

Head, neck, lung cancer screenings should be concurrent

Adding head and neck cancer screenings to recommended lung cancer screenings likely would improve early detection and survival, according to a multidisciplinary team led by scientists affiliated with the University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter.

In an analysis published in the journal Cancer and funded by NIH, the team provided a rationale for a national clinical trial to assess the effectiveness of adding examination of the head and neck to lung cancer screening programs. People most at risk for lung cancer also are those most at risk for head and neck cancer.

Said senior author Brenda Diergaarde, epidemiology faculty member in public health and member of UPCI: “When caught early, the five-year survival rate for head and neck cancer is over 83 percent. However, the majority of cases are diagnosed later when survival rates generally shrink below 50 percent. There is a strong need to develop strategies that will result in identification of the cancer when it can still be successfully treated.”

Head and neck cancer is the world’s sixth-most common type of cancer. Worldwide, every year 600,000 people are diagnosed with it and about 350,000 die. Tobacco use and alcohol consumption are the major risk factors for developing the cancer.

The early symptoms are typically a lump or sore in the mouth or throat, trouble swallowing or a voice change, which are often brushed off as a cold or something that will heal. Treatment, particularly in later stages, can be disfiguring and can change the way a person talks or eats.

Diergaarde and her team analyzed the records of 3,587 people enrolled in the Pittsburgh Lung Screening Study (PLuSS), which consists of current and ex-smokers aged 50 and older, to see if they had a higher chance of developing head and neck cancer.

In the general U.S. population, fewer than 43 per 100,000 people would be expected to develop head and neck cancer annually among those 50 and older. Among the PLuSS participants, the rate was 71.4 cases annually per 100,000 people.

Recently, the U.S. Preventive Services Task Force, as well as the American Cancer Society and other organizations, recommended annual screening for lung cancer with low-dose computed tomography in people 55-74 years old with a smoking history averaging at least a pack a day for a total of 30 years. The recommendation came after a national clinical trial showed that such screening reduces lung cancer mortality.

Said co-author David O. Wilson, associate director of UPMC’s Lung Cancer Center: “Head and neck cancer is relatively rare, and screening the general population would be impractical. However, the patients at risk for lung cancer whom we would refer for the newly recommended annual screening are the same patients that our study shows also likely would benefit from regular head and neck cancer screenings. If such screening reduces mortality in these at-risk patients, that would be a convenient way to increase early detection and save lives.”

Diergaarde’s team is collaborating with otolaryngologists to design a national trial that would determine if regular head and neck cancer screenings for people referred for lung cancer screenings would indeed reduce mortality.

Additional Pitt researchers on this study were Ronak Dixit, Joel L. Weissfeld, Paula Balogh, Pamela Sufka and Jennifer R. Grandis. A researcher from the University of Minnesota also contributed to the study.

Genetic mutations could explain early ovarian failure

Two newly identified genetic mutations could increase understanding of the causes behind premature ovarian failure, which is one cause of infertility, and potentially guide options for treating women with the condition, according to research from Magee-Womens Research Institute (MWRI) published online in the Journal of Clinical Investigation and the American Journal of Human Genetics.

The mutations, which occurred in women with premature ovarian failure, a condition that causes a woman’s ovaries to stop working prior to 40 years of age, were found in genes that repair damaged DNA in the cells of the ovary that eventually become egg cells.

In the United States, premature ovarian failure affects about 1 percent of women during their reproductive years, some as early as their teenage years. Apart from compromising fertility, the condition also puts women at high risk for osteoporosis and heart disease.

Researchers from MWRI, in collaboration with international colleagues, performed genome sequencing on blood and skin samples from three families. Each family had at least one woman with premature ovarian failure.

Said senior author Aleksandar Rajkovic, Marcus Allen Hogge Chair in Reproductive Sciences: “Most women with premature ovarian failure don’t know why they can’t reproduce, and it can be devastating for them. Our findings indicate that genetics may play a strong role in this condition and raise the prospect of one day developing therapies to delay the early onset of menopause.”

According to Rajkovic, this research shows the power of whole-genome sequencing. “Now that we understand some of the contributors to premature ovarian failure, we can work toward correcting the condition,” he said.

—Compiled by Marty Levine

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The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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