$5 million grant targets TB with new vaccine component

Researchers at the School of Medicine have received a $5 million federal grant to develop a vaccine ingredient that can generate the type of immune response needed to protect against tuberculosis (TB) infection.

Vaccines are made primarily of antigens, which are pieces of proteins from specific bacteria or viruses, and another component called the adjuvant, which stimulates the immune system’s production of antibodies against the vaccine antigen.

Said principal investigator JoAnne L. Flynn, faculty in microbiology and molecular genetics and a member of the Center for Vaccine Research: “Nearly all of the vaccines administered today use similar adjuvants derived from alum salts. That works well when an antibody response to an invading germ is needed, but it is not very effective against the bacteria that cause TB.”

An adjuvant can program the correct T-cells of the immune system so they can respond when TB exposure occurs, which could make vaccines against the infection more effective, Flynn said.

In the project, she and her team will collaborate with scientists from Copenhagen’s Statens Serum Institut, who are developing a new adjuvant that induced CD4 and CD8 T-cell responses in animal studies. They will devise several vaccine formulations with input from Flynn’s team, who then will test them in animal models of TB.

“One way we can now monitor infection is using an imaging technique called PET/CT scanning,” she said. “We can track whether vaccinated animals develop pockets of infection called granulomas in their lungs after they’ve been exposed to TB, and that could speed identification of a vaccine that could be tested in human trials.”

The five-year study is funded by the National Institutes of Health.

Minimally invasive urological surgery successful

Blockage between the kidney and the ureter in infants can be repaired with minimally invasive surgical approaches, according to a new study led by senior investigator Michael Ost, vice chair of the urology department in the School of Medicine.

Ureteropelvic junction (UPJ) obstruction is the most common obstructive urinary system disease in infants. The problem typically has been repaired with a procedure called pyeloplasty, in which an incision is made in the infant’s side to reach and remove scar tissue where the kidney meets the ureter, the tube that carries urine to the bladder.

The minimally invasive approach — called transperitoneal laparoscopic pyeloplasty, which can also be done with robot assistance — has emerged as a safe, effective alternative to the standard open pyeloplasty. Both laparoscopic and open pyeloplasty have comparable effectiveness in pediatric patients, but the role in infants is less well defined.

Said Ost: “This population can be challenging to treat laparascopically because of the small size of the abdomen and caliber of the ureter.”

His team reviewed records of 29 children younger than 12 months old treated with transperitoneal laparoscopic pyeloplasty for UPJ obstruction from May 2005 to February 2012. Of the 24 patients for whom follow-up data were available, 22 (92 percent) had successful repairs. Two patients required a second, open procedure to correct the obstruction.

“Our results show the laparoscopic approach is a safe and effective option for the surgical management of UPJ obstruction in the infant population,” said Ost. “Our early experience reveals a developing success rate comparable to that of other treatment modalities with minimal morbidity.”

The findings were published in the April issue of The Journal of Urology.

Cancer studies presented at AACR

• Yuan Chang, pathology faculty member in the School of Medicine, presented her findings on Merkel cell polyomavirus and the potential to target it with therapies to destroy Merkel cell carcinoma, an uncommon but aggressive skin cancer.

Said Chang: “Viruses are an important model for cancer research. We’ve found that it may be possible to kill cancerous tumors by targeting the pathways these viruses use. That’s significant when you consider that 20 percent of all cancers are related to infectious diseases.”

Merkel cell polyomavirus was discovered at Pitt in 2008 in the Chang-Moore laboratory in the cancer virology program at the University of Pittsburgh Cancer Institute (UPCI). Chang and her colleagues at Pitt have applied to translate their basic research into human clinical trials.

• Donald P. Taylor, a graduate student researcher in the laboratory of pathology faculty member Alan Wells in the School of Medicine, presented his research aimed at uncovering the mechanisms that some breast cancer cells use to survive several years without emerging as detectable nodules.

Nearly half of breast cancer metastases are not detectable in patients until five or more years after the cancer appears to be destroyed, meaning that the cancer seems to be surviving in the patient but lying dormant. Understanding the function of a protein called E-cadherin that seems to be a hallmark of tumor dormancy should provide insight into the cancer cells’ survival.

Said Taylor: “Identifying these mechanisms could lead to new diagnostic methods and therapeutic treatments that could potentially help millions of breast cancer patients worldwide.”

• Thomas Kensler, a pharmacology and chemical biology faculty member in the School of Medicine, chaired the AACR session titled “Clinical Trials with Functional Foods.” Kensler joined three other professors from schools nationwide to share challenges and successes in optimizing the use of food in clinical trials.

Said Kensler prior to the AACR meeting: “Our presentations will give people with an interest in clinical trials using foods insight into the many issues that researchers must take into account to get meaningful scientific results. Where the food is grown, how it is harvested, stored, transported and processed are among the important factors researchers must consider to assure consistency and quality within and between studies.”

Kensler spoke about his decade of experience with clinical trials examining the bioactive molecules in broccoli and how they may help people in China detoxify air pollutants, among other findings.

• Vivian Lui, School of Medicine faculty member in otolaryngology and UPCI, led a national team of researchers presenting their serendipitous discovery of a head and neck cancer patient whose tumor disappeared after two weeks of being treated with the common lung cancer drug erlotinib as part of a randomized clinical trial.

Said otolaryngology faculty member Jennifer Rubin Grandis, in charge of the head and neck cancer program at UPCI: “The patient had an advanced cancer at diagnosis, but when the surgeon went in to remove it, he called to report that no tumor was found. That was very unusual. We think we’ve identified a genetic mutation that appears to be responsible for exquisite sensitivity to the drug.”

Grandis, Lui and their team have been doing follow-up experiments in the laboratory that support the hypothesis. In addition to head and neck cancers, the mutation is found in some cervical cancers.

• Julien Fourcade, instructor in the laboratory of fellow medicine faculty Hassane Zarour, presented the findings from their clinical trial testing different immunization strategies for melanoma.

In this phase I trial, patients with metastatic melanoma were immunized with a novel vaccine that included an adjuvant to increase the immunogenicity of the vaccine in combination with small portions of a tumor protein that induce either cytotoxic CD8+ T cells alone or CD8+ T cells and CD4+ helper T cells to stimulate the body to destroy tumor cells.

Said Fourcade: “Although this phase I trial was not designed to evaluate the clinical efficacy of the vaccines, we did observe that only patients with advanced melanoma who received the vaccine that stimulated both CD8+ and CD4+ T cells had evidence of prolonged stable disease. More clinical trials will be needed, but we anticipate that such vaccines may prove useful for patients with advanced melanoma.”

Fourcade was selected by AACR for an AACR-Bristol-Myers Squibb Oncology Scholar-in-Training Award to fund his participation in the annual meeting. The award is presented to fewer than 10 percent of applicants.

NASA honors geology & planetary science prof

Mike Ramsey, a geology and planetary science faculty member in the Dietrich School of Arts and Sciences, was honored by NASA as one of 22 researchers across the nation featured on its web site for April’s Earth Month. The educational project, “Know Your Earth 3.0, Local Connections,” is a partnership among 22 of NASA’s Earth-observing missions, and each mission has nominated a scientist/engineer to be featured on NASA web sites throughout April. Ramsey, who is involved with NASA’s Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER), was featured on the web site April 8.

Ramsey’s primary area of study is physical volcanology. The image-analysis center that he directs includes infrared spectroscopy and GPS technologies. His studies focus primarily on eruptions, volcanic processes and monitoring using thermal infrared remote sensing.

Researchers propose cheaper way to analyze fracking water

Research led by Radisav D. Vidic, William Kepler Whiteford Professor and chair of the Department of Civil and Environmental Engineering in the Swanson School of Engineering, is proposing simplified and less expensive methods to analyze potential flowback water from hydraulic fracturing, based on the level of chloride in geographic areas throughout Pennsylvania.

While additional geological studies are warranted, Vidic noted, the research indicates that the correlation between the drilling location (spatial) and when the wastewater is extracted (temporal) developed in this study can predict wastewater quality and guide the selection of management alternatives prior to extraction.

According to Vidic, composition of flowback and produced water from hydraulic fracturing varies both over time and by location in areas throughout Pennsylvania, with the most pronounced differences between the southwest and northeast regions. Vidic’s team also elucidated the role of chemical reactions that are governed by the fracking fluid quality and solid-water interactions on the quality of water recovered in the early stages of well operation (flowback period) when the majority of wastewater is collected.

Said Vidic: “By analyzing well sites around the state, we found trends that indicated what total dissolved solids would be found in a particular well. Even though there are various dissolved solids in different amounts in each well, we could correlate these amounts based simply on the amount of chloride in the wastewater, which was the dominant ion regardless of location.”

The researchers found that concentrations of calcium, magnesium and bromide are higher in southwestern Pennsylvania, while concentrations of barium and strontium are higher in the northeast. They hypothesize that this may be the result of the geologic history of these deposits.

“We can then analyze general trends in the geochemistry of the produced water,” said Vidic, “and provide more comprehensive information to develop more sustainable water management plans. By knowing what waste will be generated at a given site over time, we can more effectively treat and reuse the wastewater, rather than utilizing new sources of freshwater that must be harvested and transported to the site.”

In addition to Vidic, the research group included Elise Barbot and Natasa S. Vidic, faculty in engineering, and a researcher at Carnegie Mellon University. The research was the cover story in the March 19 issue of the journal Environmental Science and Technology.

Support was provided by the U.S. Department of Energy National Energy Technology Laboratory.

Metals in flowers may play role in bee decline

A study led by Tia-Lynn Ashman, faculty member in the Department of Biological Sciences in the Dietrich School of Arts and Sciences, points toward another potential reason why a powerful new class of pesticides may be killing off bumblebees.

The study finds that bumblebees are at risk of ingesting toxic amounts of metals like aluminum and nickel found in flowers growing in soil that has been contaminated by exhaust from vehicles, industrial machinery and farming equipment. It finds that bumblebees have the ability to taste — and later ignore — certain metals such as nickel, but can do so only after they visit a contaminated flower. Therefore, the insects are exposed to toxins before they even sense the presence of metals.

Said Ashman: “Although many metals are required by living organisms in small amounts, they can be toxic to both plants and animals when found in moderate to high concentrations. Beyond leading to mortality, these metals can interfere with insect taste perception, agility and working memory — all necessary attributes for busy bumblebee workers.”

Ashman and co-author George Meindl, a PhD candidate in Ashman’s lab, studied bumblebee behavior using impatiens capensis, a North American flower that blooms in summer. Its flowers are large, producing a high volume of sugar-rich nectar each day — an ideal place for bumblebees to forage. The blooms were collected from the field each morning of the two-week study and were of a similar age, color and size.

To determine whether nickel and aluminum in the flowers’ nectar influenced bumblebee behavior, Ashman and Meindl used two groups of uncontaminated flowers, one group of flowers contaminated by nickel and another contaminated by aluminum, at Powdermill Nature Reserve near Rector, Pa., during August and September 2012.

When a bumblebee visited a flower in an array, the entire visitation was recorded as well as the number of seconds spent foraging on each individual flower. This included monitoring whether the bee moved from a contaminated to a non-contaminated flower, whether the bee moved within the same group it had just sampled, or whether the bee left the flower group without visiting other individual blooms. Following each observed visit, all flowers in the array were replaced with new flowers, to ensure accurate results.

“We found that the bees still visited those flowers contaminated by metal, indicating that they can’t detect metal from afar,” said Ashman. “However, once bumblebees arrive at flowers and sample the nectar, they are able to discriminate against certain metals.”

In the study, the bees were able to taste, discriminate against and leave flowers containing nickel. However, this was not the case for the aluminum-treated flowers, as the bees foraged on the contaminated flowers for time periods equal to those of the noncontaminated flowers.

“It’s unclear why the bees didn’t sense the aluminum,” said Meindl. “However, past studies show that the concentrations of aluminum found throughout blooms tend to be higher than concentrations of nickel. This suggests that the bees may be more tolerant or immune to its presence.”

These results have implications for environmentally friendly efforts to decontaminate soil, in particular a method called phytoremediation — a promising approach that involves growing metal-accumulating plants on polluted soil to remove such contaminates. Ashman says this approach should be considered with caution because the bees observed in the study foraged on metal-rich flowers. She states that further research is needed to identify plants that are ecologically safe and won’t pose threats to local animals that pollinate.

The research first appeared online March 6 in Environmental Pollution.

Funding was provided by the Carnegie Museum of Natural History’s Powdermill Nature Reserve, a Botany-in-Action Fellowship from the Phipps Botanical Garden and Conservatory, an Ivey McManus Predoctoral Fellowship to Meindl and a National Science Foundation grant to Ashman.

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