Category: Cancer Page 4 of 6

Students Brief Senate, FDA, & Personalized Medicine Coalition

On April 13, 2015

In Biology, Cancer, Genetics/Genomics, Students

By Nonie Arora

Duke students and faculty brief Senate staffers, Pictured left to right: Allison Dorogi, Nonie Arora, Robert Cook-Deegan, Samantha Phillips, Jenny Zhao, Elisa Berson. Credit: Robert Cook-Deegan

The week of April 13, at the height of cherry blossom season, Duke students traveled to Washington, D.C. to brief senior staff members of the Senate, Food and Drug Administration (FDA), and the Personalized Medicine Coalition (PMC). Over the spring semester, five students in the Genome Sciences & Policy Capstone course (including myself) studied the regulatory framework of laboratory developed tests (LDTs).

LDTs are tests developed for use in a single laboratory. The clinical laboratories that develop LDTs are considered to be medical device manufacturers and are therefore subject to FDA jurisdiction. The FDA exercises “enforcement discretion” over LDTs, which means they choose when to regulate these tests.

Duke students in Washington, D.C. Credit: Robert Cook-Deegan

Under the supervision of Duke professor Robert Cook-Deegan, we dove into five case studies regarding different types of LDT tests.

The case study that I focused on was the differential regulation of two tests used for breast cancer patients. The two tests, MammaPrint and Oncotype Dx are regulated differently even though both aim to help doctors understand when patients should have follow-up chemotherapy after surgery. The company that markets MammaPrint, Agendia, chose to obtain FDA clearance for their test, but the company behind Oncotype Dx, Genomic Health, chose against it. Surprisingly, this decision did not substantially increase the number of patients who receive Oncotype Dx relative to MammaPrint.

Furthermore, the two tests do not always produce the same result, according to a research study. Several key question remain, such as:

Is the FDA-regulated test more accurate?
Does the more accurate test get more market share? Does FDA approval make a difference?
How should these tests, and ones like them, be regulated to reduce harm to patients?

The students hope that their case studies will serve as illuminating examples for stakeholders and help guide the conversation regarding federal regulation of LDTs.

When Bad Viruses Do Good

By Karl Bates

On March 31, 2015

In Biomedical Engineering, Cancer, Medicine, Neuroscience, Students

Guest post by Ted Stanek, Graduate Student in Neurobiology

Poliovirus binding to a receptor, the first stage in infection.

The polio vaccine was a medical triumph, single-handedly decreasing the number of polio cases in the world from more than 350,000 in 1988 to only 416 in 2013. Now, surgeons at Duke University are using the once universally feared virus to target another disease – cancer.

One of the big problems with cancer is that your body doesn’t know it’s dangerous. For most infections, your immune system learns to recognize what a dangerous or infected cell looks like. Cells infected by a virus will display protein markers which alert your immune system that they are infected. Invading bacteria also display similar markers, aiding the immune system in finding and targeting them.

But in cancer, your own cells appear just like they always do, even while they are multiplying uncontrollably. Your immune system has no way to distinguish these multiplying cells from healthy cells, and so it doesn’t know to attack the tumor.

In Fan Wang’s lab at Duke, we use the rabies virus and special dyes to trace the paths of individual neurons in a mouse’s brain.

A team at the Preston Robert Tisch Brain Tumor Center at Duke is looking to viruses to help the immune system find and kill tumor cells. If a virus could be made to only attack tumor cells, then infecting tumors with such a virus could help your immune system clear away tumors – whether benign or malignant.

It turns out the polio virus can do this. Because tumor cells are growing and multiplying rapidly, they look a lot like muscle cells in a healthy, growing child – polio’s prime target. Infection of these cells results in muscle loss seen in some children with the disease. From here polio can infect neurons that activate these muscles, causing paralysis. In that sense, it uses the same process of entry into the nervous system as the rabies virus, which I and others in the lab of Fan Wang here at Duke use to trace circuits in the brain.

Matthias Gromeier engineered a poliovirus to attack brain tumors.

Like the rabies virus, most of the machinery in the polio virus is made to target and reproduce in these growing cells, while only one gene causes the actual disease. To get around this, associate professor of neurosurgery Dr. Matthias Gromeier deleted this polio disease gene and replaced it with one for the common cold. When tested in monkeys, the virus was found to be effective in targeting and helping to clear out brain tumors without affecting the nearby healthy neurons.

Gromeier and Duke neurosurgeons are injecting a form of the polio vaccine directly into human brain tumors in a Phase I trial they hope will lead to approval as a cancer treatment – and so far they have had some encouraging successes.

The beauty of this treatment is that it might not be limited to brain tumors. Gromeier is planning to test the virus in future clinical trials against prostate cancer, lung cancer, colon cancer, and many others.

(CBS 60 Minutes just aired a special two-part segment on these experiments with polio virus. View them here.)

His Lab Work Makes Organic Chem More than a "Weed-Out"

By Lyndsey Garcia

On November 17, 2014

In Biology, Cancer, Medicine, Students

By Lyndsey Garcia

“Hey, I ran one of those tests in my lab!” Zach whispered to me during biology lecture. I give him a sideways look, because I definitely didn’t recall running a Southern blot in our assigned lab section. But then I realized that he was referring to the lab that he works in on campus.

Zachary Visco presenting research at the Duke Cancer Institute Annual Retreat

Zachary Visco is a sophomore biomedical engineering major on the pre-health track. After hours of hunting through job listings and emailing lab managers, he finally landed a position of working in an ovarian cancer research lab on campus led by Dr. Susan Murphy and Dr. Andrew Berchuck this past summer.

Having only a year of undergraduate education under his belt, he found some of the concepts and techniques in his new job over his head.

“I had no idea what I was doing. I didn’t have any lab experience, but my boss, Dr. Zhiqing Huang, was very patient and walked me through everything,” Zach explained.

As Zach gained more experience in the lab, he started performing more experiments and gaining more responsibility. He would typically perform experiments that ranged from Western Blots, to cDNA preps, to real-time PCR. He was started to gain knowledge of how the pieces worked, but didn’t understand everything behind the science. However, Zach found in his class lectures, he was actually learning about concepts that pertained to his lab.

“Biology has helped explain some of the terminology and processes performed in lab, and organic chemistry has helped explain how and why some of the reactions occur,” he said.

For instance, he learned about the significance of cDNA and the information that can be determined from it. In his lab, he learned that running cDNA preps involved transcribing cDNA from mature RNA in order to perform a real-time PCR. In biology lecture, he learned why his lab would use cDNA instead of normal template DNA because mature RNA only expresses the exon, or the actual genes in our DNA, therefore the cDNA would only express the genes as well.

“I had hoped that I would eventually gain an understanding of the lab work during my undergrad, but when I first started, it all seemed very overwhelming,” Zach said. “I was pleasantly surprised when I found that I could actually apply knowledge from my classes to my work. It made it seem like I was finally learning material that could pertain to my career, not just trying to pass a weed-out class.”

Zach has found that working in the lab and the material taught in his classes has influenced his career path more than he realized. He had previously only imagined himself working in clinic-based research, but is now considering a path in lab-based research.

“I find lab research very interesting because it’s like a puzzle and you are trying to figure out the pieces as you go.”

A scientist’s unlikely path, with Duke Provost Sally Kornbluth

By Robin Smith

On October 31, 2014

In Biology, Cancer, Faculty, Lecture

By Robin Smith

Many scientists have an inkling of their path at an early age, having spent their childhoods breeding hamsters for fun, or conducting backyard experiments on earthworms.

Not so for Duke Provost and cell biologist Sally Kornbluth.

Provost Sally Kornbluth delivers her lecture, “What Makes Me a Scientist,” at Love Auditorium.

“Science wasn’t a part of my upbringing at all,” said Kornbluth, who grew up in Fair Lawn, New Jersey, a small suburb 25 miles outside of New York City. Her mother was an opera singer.

“My mother once played Queen Elizabeth at the Metropolitan Opera. I can tell you she certainly wouldn’t have let us bring something like a worm or a hamster into the house.”

In an October 30 talk hosted by the Duke BioCoRE program, Kornbluth shared this story and the unlikely path she took to becoming a scientist and the lessons she learned along the way.

As an undergraduate at Williams College, Kornbluth majored in political science. She remembers leading a tour group through the science quad as a freshman tour guide and thinking, “I’ll never take a class here.”

“The only reason I signed up for my first science course — a class on human biology and social issues taught by a professor named Bill DeWitt — was I thought it would be a relatively painless way to satisfy the graduation requirements,” she said.

Things changed once she started the course. “That’s when I realized, wow, science is about asking interesting questions and solving puzzles and finding out how things work. Having a set of facts was only the starting point.”

She describes DeWitt as the best teacher she’s ever had. “The impact of teachers who influenced me along the way was really profound,” she said.

After graduating from college in 1982 she considered applying to medical school. But then she received a scholarship to go to Cambridge University in England for two years, where she earned a second bachelor’s degree in genetics.

“One of the formative things about that time was we were forced to read a lot of journal articles. The science textbooks I’d read gave the impression that experiments always work so cleanly and beautifully. But reading scientific papers helped me realize that things aren’t as neat, and not everyone agrees with each other.”

She also learned a lesson about remembering the big picture.

“Especially if you’re doing experiments that are long and involved, you have to be motivated by the idea behind the experiment, not by the actual physical things you’re doing every day, because often they’re pretty mundane. When you’re doing lab work in molecular biology it’s hard to get excited about doing one hundred mini-preps.”

Kornbluth took these lessons with her to graduate school. She earned a Ph.D. in molecular oncology from Rockefeller University in 1989, and did postdoctoral training at the University of California, San Diego.

She joined the Duke faculty in 1994, along with her husband, Daniel Lew, Ph.D., both as professors of pharmacology and cancer biology at Duke Medicine.

“We got lucky because we both worked on aspects of the cell cycle, which was a super hot field at the time,” she said.

Her recent research aims to identify the molecular signals that tell tumor cells to divide or die, which may help explain why some cancers fail to respond to chemotherapy. The work could point to new ways of overcoming drug resistance in breast, pancreatic and other cancers.

For Kornbluth, one of the biggest joys of being a scientist is the camaraderie and the collaborative nature of the work. “Maybe that’s why I went into administration,” she says.

Kornbluth served as vice dean for basic science at Duke Medicine from 2006 to 2014.

This June, she succeeded 15-year-veteran Peter Lange as provost, the chief academic officer at Duke. She is the first woman to hold the post.

An Intersection of Math and Medicine: Modeling Cancerous Tumor Kinetics

By Olivia Zhu

On September 24, 2014

In Biology, Cancer, Mathematics, Students

Anne Talkington with the MAMS function

By Olivia Zhu

Anne Talkington, an undergraduate Mathematics student under the auspices of Richard Durrett, attempts to gain a quantitative grasp on cancer through mathematical modeling. Historically, tumor growth has only been measured in vitro (in a laboratory setting); however, Talkington looks at clinical data from MRIs and mammograms to study how tumors grow in vivo (in the human body).

Talkington is primarily interested in how fast tumors grow and if growth is limited. To analyze these trends, Talkington extracted two time-point measurements of tumor size — one at diagnosis and one immediately before treatment — and compared their change to a variety of mathematical functions. She studied unlimited functions, including the exponential, the power law, and the 2/3 power law, which represents growth limited by surface area, as well as limited functions, including the generalized logistic, which has an upper growth limit, and the Gompertz. Her favorite function is an unlimited function that she created called the Modified Alternating Maclaurin Series, or MAMS, which she originally intended to model microbial growth.

Talkington also examined various types of cancer: breast cancer, liver cancer, tumors of the nerve that connect the ear to the brain, and meningioma, or tumors of the membranes that surround the brain and spinal cord. She expected growth rates among clinical groups to be constant, but she did not generalize between the groups due to demographic bias and other confounding factors.

Ultimately, Talkington found that breast cancer and liver cancer grew exponentially, while tumors of the meninges or vestibulocochlear nerve grew according to the 2/3 power law. Talkington’s work in model-fitting cancer growth will facilitate the administration of effective treatment, which is often growth-stage dependent.

A Quiet but Fundamental Case in the Flame Retardant Debate

By Olivia Zhu

On September 4, 2014

In Cancer, Chemistry, Environment/Sustainability

By Olivia Zhu

The dangers of flame retardants have long been the source of public health debate, thrust into the public eye by legislators, non-profit organizations, and special interest groups.

Often missing, though, is the story of the extensive scientific background necessary to ground these arguments: Heather Stapleton, the Dan and Bunny Gabel Associate Professor of Environmental Ethics and Sustainable Environmental Management, and research scientist Ellen Cooper and their teams fill this role at the Nicholas School of the Environment.

As a former intern at the Center for Environmental Health, where I advocated against legislation that promotes the use of flame retardant chemicals, I was fascinated to learn the technical side of the conversation from Cooper.

Flame retardants have been present in furniture and other foam-based items largely due to fire safety regulations like California’s TB117, which requires home furniture to resist bursting into flame for a certain amount of time. Historically, manufacturers have met this standard by using flame retardant chemicals that may impact brain development in children or even cause cancer. Consequently, foam producers have added flame retardants to all their foam, even foam meant for products not covered under TB117. Evidently, the resulting flame retardant-laden selection of furniture poses a threat to the health of consumers, who effectively have little choice in protecting themselves against potentially dangerous chemicals.

Nicholas school environmental chemist Heather Stapleton in the lab. (Duke Photography)

Unsurprisingly, scientifically studying flame retardants requires rigorous chemical analysis. Ellen Cooper, along with the Analytical Chemistry Core, specializes in preparing foam samples and running them through mass spectrometers to identify the flame retardants. The Chemistry Core collaborates with the Stapleton Lab to ensure accurate analysis of often-fragile flame retardants. Both are a part of Duke’s Superfund Research Center.

Cooper’s work has been instrumental in the Stapleton lab’s creation of a foam testing service for consumers. In January, the Stapleton lab started the first foam testing service ever open to the public! Now, consumers can send in up to five samples from their furniture to receive complimentary results which are provided by the Analytical Chemistry Core. On the foam testing website, consumers can also find statistics on common sources of flame retardants and information on how to avoid exposure to flame retardants. Through these efforts, the Stapleton lab is allowing consumers to take back their autonomy.

Additionally, Cooper is working to create a database of all collected samples. Currently, there exists no definite data on which manufacturers’ products contain which flame retardants, or how levels of flame retardants in furniture have changed over time. With enough data points, Cooper and her team hope to create such heat maps or time analyses, making for a more informed debate, and ultimately a more well-protected public.

Lab develops cheaper, faster cancer vaccine

By Karl Bates

On July 30, 2014

In Biomedical Engineering, Cancer, Faculty, Guest Post, Medicine

Sarah Avery, Duke Medicine News and Communications

In the 20 years since a group of Duke University researchers pioneered the use of RNA-loaded dendritic cells as cancer vaccines, they and many others have shown that this is a safe and effective way to induce tumor-specific immune responses.

Florescence microscopy image of mouse dendritic cells with mRNA-loaded blood cells.

But the approach has had drawbacks – primarily in the amount of time and money it takes to develop the cells.

Now the researchers, led by Smita K. Nair, Ph.D., associate professor in the Department of Surgery, are moving the science forward with new findings that could significantly improve the utility of this promising therapy.

Appearing in the June 2014, issue of the Journal Advanced Healthcare Materials, Nair and colleagues demonstrate that a tumor vaccine can be formulated by loading RNA into whole blood cells directly after a blood draw without the need for any form of cell culture.

This overcomes the major impediments. The original approach required harvesting cells from the patient via leukapheresis – a step that relies on special equipment and highly trained technicians – to generate dendritic cells from the cellular population. Then the cells were loaded with RNA and injected back into the patient. The process took up to nine days.

Using the new method, the team can create vaccines in less than two hours.

“The therapeutic benefit in mice immunized with mRNA-loaded whole blood cells and those immunized with mRNA-loaded dendritic cells (the gold-standard for cell-based vaccines) was comparable,” Nair said. “This new approach has the potential to be an effective substitute to existing cell-based vaccinations. It could also cut costs for treatment and speed clinical translation of cell-based mRNA tumor vaccines.”

Nair said pre-clinical studies using human blood cells are continuing, with clinical trials on the near horizon.

Keely Glass, the Omni-Chemist

By Karl Bates

On January 13, 2014

In Cancer, Chemistry, Guest Post, Physics, Students

Guest post by Addie Jackson, North Carolina School of Science and Mathematics

Keely’s picture from Linked-In

Ask Keely Glass how she would describe her research to a third grader, and she laughs while thinking of the best way to explain.

“So, say you’re sitting next to your friends. One has really black hair and one has red hair. They have different hair colors, because their hair colors come from the different pigments. Your friend with black hair has more eumelanin, while your friend with red hair has pheomelanin.”

A PhD candidate in the chemistry department at Duke, Glass currently does research on analytical methods to analyze these pigments in biological and historical samples. She’s also using those skills to provide direct chemical evidence for the presence and preservation of eumelanin in the fossil record.

Trust us, that’s a fossil squid. (Courtesy of Willsquish on Wikimedia Commons.)

Glass elaborates by describing a common fascination with squids, also known as cephalopods, who release pure black eumelanin when faced with a predator. Two kinds of melanin are present in nature: eumelanin (brown to black in color) and pheomelanin (yellow to red). Through her work, she and her team have verified that eumelanin is preserved in the fossil record, and showed that it can be identified directly using its known chemical signature. They have also found that the eumelanin identified in the fossil record is not significantly different from the modern eumelanin, meaning it hasn’t evolved in the more than 160 million years since.

Another lab at Duke, run by Professor Warren S. Warren, uses a pump-probe microscopy system to characterize melanins to attempt to find statistically significant variations between melanomas (skin cancers) that do not develop metastases. The hope for this project is to improve diagnostic accuracy for these metastatic melanomas, through analyzing the melanin distribution in “old” archived (stored for >10 years) tissue samples. Glass says, “The paper I wrote with them essentially says if melanin resists degradation (stays intact and doesn’t alter) over more than 160 million years, it’s fairly clear that it will resist degradation in storage for 10 years. In other words, it’s pretty clear that these archived tissue samples are still viable for melanin analysis.”

Fourteen months in the life of one man’s nodular melanoma. (Courtesy of 0x6adb015 via Wikimedia Commons.)

Working with the Warren group, Glass also found that the pump-probe system was sensitive to the higher iron-concentration fossilized squid melanin as compared with modern cephalopod melanin. They were able to mirror the iron-independent signal by adding iron to modern cephalopod melanin. This proved to be interesting because metastatic melanomas have increased iron levels, which may or may not be responsible for signature variations.

The classical fields of chemistry (analytical, organic, physical, theoretical, inorganic, and biological) have become more integrated over time, making the labels themselves increasingly obsolete. To better label themselves, most chemists mix and match: “I’ve called myself at various times a ‘Bioanalytical Chemist,’ ‘Biophysical Organic Chemist,’ ‘Analytical Biochemist,’ ‘Organic Geochemist’ etc. to emphasize that the systems I’ve worked on, the techniques I’ve used, and the skills I’ve obtained are diverse and dependent on the project I’m defining.”

Glass says, “When I think that the names have gone a little haywire, I jokingly call myself an omni-chemist. Like most chemists I work on diverse array of projects that require techniques and knowledge from many fields.”

Addie Jackson interviewed Keely Glass and wrote this post as part of a Science Communication seminar led by NCSSM Dean of Science Amy Sheck.

Humans, Whales and Taylor Swift

By Ashley Mooney

On October 25, 2013

In Animals, Biology, Cancer, Climate/Global Change, Field Research, Lecture

by Ashley Mooney

The similarities between chromium workers and whales are greater than one might think.

Environmental toxicology researcher John Wise has been studying the connection between exposure to pollutants and the onset of cancer in humans. To understand the link, he said one must take into account all species, especially whales. Wise spoke at Duke Oct. 25 at the Inaugural Duke Distinguished Lecture in Cancer and the Environment.

Chromium crystals. Courtesy of Wikimedia Commons.

“For environmental health for me, [the Earth] is the big picture,” Wise said. “This is home and we only have one, so we have to think pretty hard about environmental health.”

Wise studies the effect of pollutants—specifically forms of chromium—on genetic material in humans, marine mammals, and birds and other marine species. While the standard approach to environmental toxicology research is to conduct epidemiology studies on highly exposed populations and then expose animals to high doses of the toxin, Wise has adopted a new method of study.

“We don’t really know what high-dose exposures mean on a day-to-day basis,” he said.

To understand the relationship between chromium exposure and the onset of cancer, Wise looks at the personal factors that affect one’s health, such as an individual’s body and genome, lifestyle, daily exposures and what kind of environment one lives in.

“We need to know mechanism: how does a normal cell become a tumor cell?” he said. “For a long time that is where the field has been hung up, trying to identify the ultimate carcinogen.”

Most forms of naturally occurring chromium are not toxic. Man-made hexavalent chromium, however, has been shown to cause lung cancer in those who are regularly or heavily exposed to it. Prolonged exposure induces an altered chromosome number and structure, as well as DNA double strand breaks.

Chronic exposure to chromium also causes a shift from more a protective form of DNA repair called homologous recombination to a less stable and error-prone pathway called non-homologous end joining. This means that cells will have permanently deficient repair mechanisms.

Wise applies his research in the context of ocean health, namely how chromium exposure might harm whale DNA.

Most ocean pollutants, including the toxic form of chromium, are in the ocean sediment. As the ocean becomes increasingly more acidic, the sediment breaks off and poses a growing threat to marine species.

Wise measured chromium levels in baleen whale skin, and found that Atlantic seaboard species—the northern right whale, fin whale and humpback whale—have 16- to 41-fold higher levels than other baleen whales. Toothed whales living in the Gulf of Mexico exhibited levels that resembled those found in chromium workers who died of lung cancer.

A humpback whale surfacing for air. Courtesy of: Protected Resouces Division, Southwest Fisheries Science Center, La Jolla, California. swfsc.nmfs.noaa.gov/PRD/.

In whales, chromium can lead to DNA damage and reproductive suppression.

“There’s only 400 [northern right whales] left in existence,” Wise said. “If you only have 400 animals, you need every single one of them [to be able to reproduce].”

Wise said he hopes his research will encourage people to think more about habitat degradation and climate change, and how they affect all species.

taylor-conor-sailing-team, courtesy of popdust.com

Wise (back right) photographed with his lab and Conor Kennedy (back left). Courtesy of popdust.com.

His lab, however, has recently gained publicity not for its research, but for the public figures that have worked with it. Conor Kennedy, a member of the influential Kennedy family, worked with Wise’s team and Ocean Alliance last year. At the time he was dating pop-star Taylor Swift.

“[He was], like any other high school student, constantly texting on his phone and I would do what I did with my kids and the other students, and say ‘put the girl down, we have to go to work,’ not knowing the girl was Taylor Swift,” Wise said. “It really hit home that we were traveling in very different circles.”

Basic Science Day Should be Every Day

By Karl Bates

On October 15, 2013

In Cancer, Medicine, Neuroscience

By Karl Leif Bates

The Med School’s fourth celebration of basic science was held in and around the Great Hall of the gorgeous new Mary Duke Biddle Trent Semans Center on Monday, Oct. 14. Basic science hero and Nobel laureate Bob Lefkowitz of biochemistry packed the room for his keynote, “A funny thing happened on the way to Stockholm,” and attendance was steady throughout the day for a series of half-hour talks by Duke faculty from the six basic science departments of the Med School.

Immunology professor Yuan Zhuang closed his Basic Science Day talk on the lineage of T-Cells from infancy to adulthood with a powerful metaphor.

Immunology professor Yuan Zhuang closed his Basic Science Day talk on the lineage of T-Cells from infancy to adulthood with a very timely political metaphor.

“Duke’s scientists are invited to speak all over the world, but they often don’t have the chance to hear about the great science going on in the labs of their own colleagues here at Duke,” said Sally Kornbluth, vice dean for basic science and master of ceremonies for the day.

Anne West of neurobiology said “there’s still a gigantic gulf,” between what she’s investigating and patient care as she seeks to understand gene expression patterns in the brain that might leave one person more susceptible to high stress responses than another. “We’d like to be able to guess who’s going to respond adaptively and who’s going to respond maladaptively,” she said as she updated colleagues on her group’s progress.

But everything doctors can do for you in the clinic had to start somewhere. “New disease treatments don’t spring from nowhere,” said Kornbluth, who’s home department is pharmacology and cancer biology. “To advance clinical treatments, you need fundamental basic science to provide a pipeline of translatable discoveries. We saw several examples of this kind of work today, from Mariano Garcia-Blanco working on ways to eradicate Dengue and Yellow Fever viruses, to Donald McDonnell establishing important links between obesity and cancer via cholesterol metabolism.”

Speaking of progress, three dozen posters out in the lobby offered updates on Duke’s basic understanding of breast cancer and brain cancer; salmonella, chlamydia and fungal pathogens; DNA repair, RNA interference, neuronal circuitry and Alzheimer’s, schizophrenia and obsessive-compulsive disorder.