Topical gel made from oral blood pressure drugs shown effective in healing chronic wounds

An international team of researchers led by Johns Hopkins has shown that a topical gel made from a class of common blood pressure pills that block inflammation pathways speeds the healing of chronic skin wounds in mice and pigs.

A report of the findings, published Oct. 16 in the Journal of Investigative Dermatology, marks efforts to seek approval from the U.S. Food and Drug Administration (FDA) to use the gel application in treatment-resistant skin wounds among diabetics and others, particularly older adults.

“The FDA has not issued any new drug approval for wound healing in the past 10 years,” says Peter Abadir, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine and the paper’s first author. “Using medicines that have been available for more than two decades, we think we have shown that this class of medicines holds great promise in effectively healing chronic wounds that are prevalent in diabetic and aged patients.”

Chronic wounds, defined as skin injuries that fail to heal in a timely manner and increase the risk of infection and tissue breakdown, accounted for more than 100 million hospital visits in United States hospitals in 2008, according to Abadir.

In recent years, attention has turned to the skin’s renin-angiotensin system (RAS), which is involved in the skin’s inflammatory response, collagen deposition and signaling necessary for wound healing. Studies show that the RAS system is abnormally regulated in diabetic and older adults.

Abadir and colleagues experimented with gel formulations of angiotensin II receptor antagonists, or blockers, a long-standing class of drugs that includes losartan and valsartan, prescribed to treat hypertension. The drugs block RAS and increase wound blood flow, and the goal was to apply the gels directly to wounds, increasing wound tissue level of the drugs that promote faster healing.

Abadir and colleagues first tested 5 percent topical losartan on mice in three different phases of wound healing: group 1 treatment, for up to three days post-wound infliction to target the inflammatory phase; group 2 treatment, starting on day seven after wound infliction to target the proliferative/remodeling (later) phase of tissue healing; and group 3 treatment, starting the first day of wound infliction until closure to treat all wound healing phases. A fourth group was kept back as a control and given standard care and a placebo. Mice in group 2 experienced the most accelerated wound healing rate.

Next, Abadir and colleagues compared the effects of different concentrations of losartan and valsartan on young diabetic and aged mice during the proliferation/remodeling phase of wound healing, which involves the regrowth of normal tissue.

The results showed that valsartan was more effective in accelerating wound healing than losartan, without any significant difference in healing time between valsartan doses. Overall, 1 percent valsartan had the greatest impact on total closure compared with the other agents, and 10 percent losartan led to the worst wound healing, which Abadir says may be attributed to toxicity.

Final results showed that half of all mice that received 1 percent valsartan achieved complete wound healing, while only 10 percent of the mice given the placebo did.

Driven by 1 percent valsartan’s promising results in mice, the researchers tested its effects on wounds among aged, diabetic pigs, as pig skin has more similar properties to human skin.

Compared with pigs in the placebo group, wounds that received 1 percent valsartan healed much more quickly, and all 12 wounds were closed by day 50, compared with none of the placebo-treated wounds, the researchers say.

Of note, Abadir says, a low concentration (1 to 50 nanomoles) of valsartan was detected in the pigs’ blood near the beginning of treatment, and none was detected later in the treatment course, suggesting that the drug acts locally on the tissues where it’s absorbed, rather than affecting the entire body.

For comparison, oral ingestion of valsartan generally yields 4,000 to 5,000 nanomoles in the blood level for a human. This suggests that topical application of valsartan will not be absorbed into the bloodstream and could have unintended physiological effects, such as those that affected blood pressure, body weight or kidney function.

Finally, to determine the quality of 1 percent valsartan’s biological effects on wound repair–not just rate of repair–Abadir and colleagues examined collagen content and tensile strength in the pigs’ skin. Pigs treated with valsartan had a thicker epidermal layer (the outermost layer of the skin) and dermal collagen layer, as well as a more organized collagen fiber arrangement, all of which indicate 1 percent valsartan application leads to stronger healing skin, Abadir says.

“Our strategy for specifically targeting the biology that underlies chronic wounds in diabetics and older adults differs greatly from other approaches to wound care thus far. The topical gel likely enables a cascade of positive biological effects that facilitates and accelerates chronic wound healing,” says Jeremy Walston, M.D., professor of medicine and the paper’s senior author.

“Now that we’ve proven efficacy in animals, we’re moving on to the next stage of FDA-required testing in humans. Hopefully, this medication will be available for public use in a few years, if further research bears out our results,” adds Walston. Walston and colleagues envision that the medication could one day also be used to treat scars, wrinkles and other skin problems.

Twenty-nine million Americans have diabetes and 1.7 million are newly diagnosed each year. Of this group, approximately 900,000 will develop diabetic foot ulcers annually. With an aging population and incidence of diabetes increasing rapidly across the globe. Abadir estimates the total number of diabetic foot ulcers to be more than 20 million per year, with an estimated total cost of $25 billion annually in the U.S. alone.

Cancer Immunotherapy May Get a Boost by Disabling Specific T Cells

Cancer immunotherapy drugs only work for a minority of patients, but a generic drug now used to increase blood flow may be able to improve those odds, a study by Columbia University Medical Center (CUMC) researchers suggests.

In mice with melanoma, the researchers found that the drug – called pentoxifylline – boosts the effectiveness of immune-checkpoint inhibitors, a type of immunotherapy now commonly used in the treatment of melanoma and other cancers.

The study was published today in the online edition of Cell.

Checkpoint-blockade immunotherapy drugs – the first drugs were approved in 2011 – target proteins on tumor cells or cells of the immune system that prevent “killer” T cells from attacking cancer. These drugs have revolutionized cancer care, but do not work for all patients. “In advanced melanoma, for example, the cure rate is only about 20 percent. That’s a remarkable improvement over previous therapies,” says study leader Sankar Ghosh, PhD, Chair and Silverstein and Hutt Family Professor of Microbiology & Immunology. “But why doesn’t it work for the other 80 percent? There must be another mechanism that contributes to the suppression of the immune response.”

Dr. Ghosh and other cancer biologists suspected that a different type of T cell, known as regulatory T cells, or Tregs, may also suppress the immune system’s attack on cancer. Large numbers of these cells are found within several types of tumors. “One possible therapy would be to get rid of Tregs,” he said. “But Tregs are also needed to keep the immune system in check, and shutting down Tregs completely would unleash an attack against the body’s healthy cells and organs.”

This point is underscored by a related study, published today in Immunity, in which Dr. Ghosh and colleagues found that removing NF-kB from Tregs caused widespread and lethal autoimmunity in mice. However, a partial inhibition of NF-kB, achieved by removing only one, specific, NF-kB protein, called c-Rel, changed Treg function without causing widespread autoimmunity.  In the Cell study Ghosh and colleagues showed that these c-Rel deficient Tregs were specifically crippled in their ability to protect cancer cells. As a result, when c-Rel is blocked, killer T cells mounted a more robust attack on cancer cells without causing autoimmunity.

Pentoxifylline is a drug that is used in patients to increase blood flow in the hands and feet of people with poor circulation, but it’s also known to inhibit the c-Rel protein. In the Cell study, the researchers demonstrated that pentoxifylline blocked Treg function and boosted the effectiveness of standard checkpoint-blockade immunotherapies.  As a result, mice treated with both drugs showed significantly reduced melanoma tumor burden, compared to animals that received the standard therapy alone.

“The next step is to test this drug combination in human clinical trials,” Dr. Ghosh says. “If trials are successful, the use of c-Rel inhibitors could become a standard addition to immune checkpoint therapy for many types of cancer.”

Genetic modifier for Huntington’s disease progression identified

A team led by UCL and Cardiff University researchers has developed a novel measure of disease progression for Huntington’s disease, which enabled them to identify a genetic modifier associated with how rapidly the disease progresses.

“We’ve identified a gene that could be a target for treating Huntington’s disease. While there’s currently no cure for the disease, we’re hopeful that our finding could be a step towards life-extending treatments,” said Dr Davina Hensman Moss (UCL Huntington’s Disease Centre, UCL Institute of Neurology), one of the lead authors of the Lancet Neurology study.

Huntington’s disease (HD) is a fatal neurological disease caused by a genetic mutation. Larger mutations are linked to rapidly progressing disease, but that does not account for all aspects of disease progression. Understanding factors which change the rate of disease progression can help direct drug development and therapies.

The research team used the high quality phenotypic data from the intensively studied TRACK-HD cohort of people with the HD gene mutation. They established that different symptoms of disease progress in parallel, so they were able to combine the data from 24 cognitive, motor and MRI brain imaging variables to generate their progression score for genetic analysis.

They then looked for areas of the genome associated with their progression measure, and found a significant result in their sample of 216 people, which they then validated in a larger sample of 1773 people from a separate cohort, the European Huntington’s Disease Network (EHDN) REGISTRY study.

The genetic signal is likely to be driven by the gene MSH3, a DNA repair gene which has been linked to changes in size of the HD mutation. The researchers identified that a variation in MSH3 encodes an amino acid change in the gene. MSH3 has previously been extensively implicated in the pathogenesis of HD in both mouse and cell studies. The group’s findings may also be relevant to other diseases caused by repeats in the DNA, including some spinocerebellar ataxias.

Dr Hensman Moss said: “The gene variant we pinpointed is a common variant that doesn’t cause problems in people without HD, so hopefully it could be targeted for HD treatments without causing other problems.”

Professor Lesley Jones (Cardiff University), who co-led the study, said: “The strength of our finding implies that the variant we identified has a very large effect on HD, or that the new progression measure we developed is a much better measure of the relevant aspects of the disease, or most likely, both.”

The researchers say their study demonstrates the value of getting high quality data about the people with a disease when doing genetic studies.

Professor Sarah Tabrizi (UCL Huntington’s Disease Centre), who co-led the study said: “This is an example of reverse translation: these novel findings we observed in people with HD support many years of basic laboratory work in cells and mice. Now we know that MSH3 is critical in the progression of HD in patients, we can focus our attention on it and how this finding may be harnessed to develop new therapies that slow disease progression.”

International study identifies new genetic risk factors for testicular cancer

Testicular cancer is relatively rare with only 8,850 cases expected this year in the United States. A majority of testicular cancer, 95 percent of all cases, begins in testicular germ cells, which are the cells responsible for producing sperm. Testicular germ cell tumors (TGCT) are the most common cancer in men aged 20 to 39 years in the U.S. and Europe. Peter Kanetsky, Ph.D., M.P.H., chair of the Cancer Epidemiology Department at Moffitt Cancer Center, and colleagues from the International TEsticular CAncer Consortium (TECAC), launched a large analysis of five major testicular cancer studies to investigate genetic risk factors linked to TGCT. Their results, which uncovered eight new genetic markers associated with TGCT, were published in the June 12 issue of Nature Genetics.

The incidence of TGCT has been increasing around the world throughout the past 50 years. Between 1973 and 2003, the number of men diagnosed with TGCT rose by 54 percent. TGCT is also more prevalent in certain populations. Men who are of Northern European ancestry have the highest incidence of TGCT, while men of African decent have the lowest incidence.

Scientists are unsure why the incidence of TGCT has been increasing or why it is more prevalent in certain populations. Their goal is to identify risk factors for TGCT to increase their understanding of how it arises and to identify those patients who may develop TGCT to prevent progression and treat the disease earlier.

It is believed that some TGCT risk factors may be inherited. Men who have a father with TGCT are four times more likely to develop it, and the risk increases eight-fold if they have a brother with TGCT. Approximately 30 genetic risk factors have been identified so far, but these do not completely account for all of the potential heritable risks.

TECAC combined data from five previous genome-wide association studies, providing researchers with more than 3,500 TGCT cases internationally to review. Their analysis identified eight new genetic markers that are associated with an increased risk of developing TGCT and refined four previously reported susceptibility regions.

“Our findings substantially increase the number of known susceptibility genes associated with TGCT. This moves the field closer to a comprehensive understanding of the underlying genetic architecture and development of the disease,” Kanetsky said.

Altered virus may expand patient recruitment in human gene therapy trials

For many patients, participating in gene therapy clinical trials isn’t an option because their immune system recognizes and fights the helpful virus used for treatment. Now, University of Florida Health and University of North Carolina researchers have found a solution that may allow it to evade the body’s normal immune response.

The discovery, published May 29 in the Proceedings of the National Academy of Sciences, is a crucial step in averting the immune response that prevents many people from taking part in clinical trials for various disorders, said Mavis Agbandje-McKenna, Ph.D., a professor in the University of Florida College of Medicine department of biochemistry and molecular biology and director of the Center for Structural Biology.

During gene therapy, engineered viruses are used to deliver new genes to a patient’s cells. While the recombinant adeno-associated virus, or AAV, is effective at delivering its genetic cargo, prior natural exposure to AAV results in antibodies in some people. As many as 70 percent of patients have pre-existing immunity that makes them ineligible for gene therapy clinical trials, Agbandje-McKenna said.

The findings provide a road map for designing virus strains that can evade neutralizing antibodies, said Aravind Asokan, Ph.D., an associate professor in the department of genetics at the University of North Carolina, who led the study. At UF Health, the structural “footprints” where pre-existing antibodies interact with the virus were identified using cryo-electron microscope resources provided by the UF College of Medicine and the UF Office of Research’s Division of Sponsored Programs. The UNC researchers then evolved new viral protein shells. Using serum from mice, rhesus monkeys and humans, the researchers showed that the redesigned virus can slip past the immune system.

“This is the blueprint for producing AAV strains that could help more patients become eligible for human gene therapy. Now we know how to do it,” Agbandje-McKenna said.

While the findings prove that one variation of AAV can be evolved, further study in preclinical models is needed before the approach can be tested in humans. Next, the immune profile of one particularly promising virus variant will need to be evaluated in a larger number of human serum samples, and dose-finding studies are needed in certain animal models. Researchers may also need to study whether the same virus-manipulating technique can be used in a broader range of gene therapy viruses, Agbandje-McKenna said.

Although human gene therapy remains an emerging field and has yet to reach patients on a wide scale, researchers elsewhere have used AAV therapy to successfully treat hemophilia, a blood-clotting disorder, in a small trial. It has also been or is now being studied as a way to treat hereditary blindness, certain immune deficiencies, neurological and metabolic disorders, and certain cancers.

The latest findings are the result of more than 10 years of studying the interactions between viruses and antibodies and a long-standing collaboration with Asokan, who heads the synthetic virology group at the UNC Gene Therapy Center, according to Agbandje-McKenna.

Alectinib halts lung cancer growth more than a year longer than crizotinib

Findings from a phase III clinical trial point to a more effective initial treatment for patients with ALK-positive non-small cell lung cancer (NSCLC). Compared to the current standard of care crizotinib (Xalkori), the newer ALK inhibitor alectinib (Alecensa) halted cancer growth for a median of 15 months longer and caused fewer severe side effects.

The study was featured in a press briefing today and presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

“This is the first global study to compare alectinib with crizotinib in ALK-positive lung cancer and establishes alectinib as the new standard of care for initial treatment in this setting,” said lead study author Alice T. Shaw, MD, PhD, Director of Thoracic Oncology at Massachusetts General Hospital Cancer Center in Boston, MA. “Alectinib was especially beneficial in controlling and preventing brain metastases, which can have a major impact on patients’ quality of life.”

About 5% of NSCLCs are ALK-positive, meaning they have a genetic rearrangement where the ALK gene is fused with another gene. In the United States, about 12,500 people are diagnosed with ALK-positive NSCLC each year.

Crizotinib, the first medicine to specifically target ALK, was approved by the FDA in 2011. Although the majority of patients initially benefit from crizotinib, the cancer typically starts growing again within a year. Alectinib is a more potent, next-generation inhibitor of ALK. It was initially approved in 2015 for use in patients with advanced NSCLC that worsens despite crizotinib.

“The fact that this second-generation targeted treatment halted advanced lung cancer growth for more than two years while preventing brain metastases is a remarkable result in this difficult disease,” said ASCO Expert John Heymach, MD, PhD. “Thanks to this advance, we are on the road to helping these patients live longer and better.”

About the Study

In this open label clinical trial (ALEX), researchers randomly assigned 303 patients with stage IIIB or IV, ALK-positive NSCLC to receive alectinib or crizotinib. The patients had not received prior systemic therapy for advanced NSCLC.

Key Findings

Alectinib reduced the risk of cancer progression or death by 53% compared with crizotinib. Based on independent review, alectinib extended the median time to progression by about 15 months (median progression-free survival was 25.7 months with alectinib and 10.4 months with crizotinib).

“Nobody imagined it would be possible to delay advanced lung cancer progression by this much. Most targeted therapies for lung cancer are associated with a median progression-free survival of roughly 12 months,” said Dr. Shaw.

While both treatments cross the blood-brain barrier, alectinib was more effective in preventing brain metastases than crizotinib, because it can better penetrate into the brain. At 12 months, the incidence of brain metastases was much lower with alectinib than with crizotinib (9% vs. 41%).

Overall, severe side effects were less common with alectinib than with crizotinib, occurring in 41% vs. 50% of patients. The most common side effects of alectinib were fatigue, constipation, muscle aches, and swelling, whereas crizotinib caused gastrointestinal problems and liver enzyme abnormalities.

Next Steps

The researchers will continue to follow patients on this study to see if those treated with alectinib live longer than those treated with crizotinib. Meanwhile, several ongoing clinical trials are comparing other next-generation ALK inhibitors to crizotinib in the first-line setting.

Engineers design a new weapon against bacteria

Over the past few decades, many bacteria have become resistant to existing antibiotics, and few new drugs have emerged. A recent study from a U.K. commission on antimicrobial resistance estimated that by 2050, antibiotic-resistant bacterial infections will kill 10 million people per year, if no new drugs are developed.

To help rebuild the arsenal against infectious diseases, many scientists are turning toward naturally occurring proteins known as antimicrobial peptides, which can kill not only bacteria but other microbes such as viruses and fungi. A team of researchers at MIT, the University of Brasilia, and the University of British Columbia has now engineered an antimicrobial peptide that can destroy many types of bacteria, including some that are resistant to most antibiotics.

“One of our main goals is to provide solutions to try to combat antibiotic resistance,” says MIT postdoc Cesar de la Fuente. “This peptide is exciting in the sense that it provides a new alternative for treating these infections, which are predicted to kill more people annually than any other cause of death in our society, including cancer.”

De la Fuente is the corresponding author of the new study, and one of its lead authors along with Osmar Silva, a postdoc at the University of Brasilia, and Evan Haney, a postdoc at the University of British Columbia. Timothy Lu, an MIT associate professor of electrical engineering and computer science, and of biological engineering, is also an author of the paper, which appears in the Nov. 2 issue of Scientific Reports.

Improving on nature

Antimicrobial peptides, produced by all living organisms as part of their immune defenses, kill microbes in several different ways. First, they poke holes in the invaders’ cell membranes. Once inside, they can disrupt several cellular targets, including DNA, RNA, and proteins.

These peptides also have another critical ability that sets them apart from traditional antibiotics: They can recruit the host’s immune system, summoning cells called leukocytes that secrete chemicals that help kill the invading microbes.

Scientists have been working for several years to try to adapt these peptides as alternatives to antibiotics, as bacteria become resistant to existing drugs. Naturally occurring peptides can be composed of 20 different amino acids, so there is a great deal of possible variation in their sequences.

“You can tailor their sequences in such a way that you can tune them for specific functions,” de la Fuente says. “We have the computational power to try to generate therapeutics that can make it to the clinic and have an impact on society.”

In this study, the researchers began with a naturally occurring antimicrobial peptide called clavanin-A, which was originally isolated from a marine animal known as a tunicate. The original form of the peptide kills many types of bacteria, but the researchers decided to try to engineer it to make it even more effective.

Antimicrobial peptides have a positively charged region that allows them to poke through bacterial cell membranes, and a hydrophobic stretch that enables interaction with and translocation into membranes. The researchers decided to add a sequence of five amino acids that would make the peptides even more hydrophobic, in hopes that it would improve their killing ability.

This new peptide, which they called clavanin-MO, was very potent against many bacterial strains. In tests in mice, the researchers found that it could kill strains of Escherichia coli and Staphylococcus aureus that are resistant to most antibiotics.

Suppressing sepsis

Another key advantage of these peptides is that while they recruit immune cells to combat the infection, they also suppress the overactive inflammatory response that can cause sepsis, a life threatening condition.

“In this single molecule, you have a synthetic peptide that can kill microbes — both susceptible and drug-resistant — and at the same time can act as an anti-inflammatory mediator and enhance protective immunity,” de la Fuente says.

The researchers also found that these peptides can destroy certain biofilms, which are thin layers of bacterial cells that form on surfaces. That raises the possibility of using them to treat infections caused by biofilms, such as the Pseudomonas aeruginosa infections that often affect the lungs of cystic fibrosis patients. Or, they could be embedded into surfaces such as tabletops to make them resistant to microbial growth.

Other possible applications for these peptides include antimicrobial coatings for catheters, or ointments that could be used to treat skin infections caused by Staphylococcus aureus or other bacteria.

If these peptides are developed for therapeutic use, the researchers anticipate that they could be used either in stand-alone therapy or together with traditional antibiotics, which would make it more difficult for bacteria to evolve drug resistance. The researchers are now investigating what makes the engineered peptides more effective than the naturally occurring ones, with hopes of making them even better.

The calling card of aggressive thyroid cancer

A new discovery from University of Alberta scientists represents an important milestone in the fight against thyroid cancer. In a study published in EBioMedicine and recently presented at the American Thyroid Association annual meeting, the team has identified a marker of aggressive disease for papillary thyroid cancer, which comprises about 90 per cent of all thyroid cancers. The marker–a protein known as Platelet Derived Growth Factor Receptor Alpha, or PDGFRA–could also be used as a therapeutic target for future treatments.

Todd McMullen, senior author and associate professor of surgery with the U of A‘s Faculty of Medicine & Dentistry, believes the findings will have a significant clinical impact.

“The big problem for individual patients and physicians is knowing if the patient has the disease that is easy to treat or if they have a more aggressive variant. A lot of patients get over-treated simply because we don’t want to miss the one case in five that may spread to other sites,” says McMullen.

“The only way to be sure it doesn’t spread is to undertake a larger surgery which can have lifelong consequences. Most of these patients are young. They have children. The majority tend to opt for the surgery because until now we haven’t had another tool to help them know when it is needed.”

Each year approximately 6,300 Canadians will be diagnosed with thyroid cancer. More than three quarters of those patients are women. Treatments for the disease include radioactive iodine therapy and surgery. Those who opt for aggressive surgery can see their speech affected, have trouble eating, swallowing and even breathing as a result.

“We came up with a tool to identify aggressive tumours so that people can have just the right amount of surgery. No more, no less,” says McMullen. “What we’re really excited about is that this is both a diagnostic tool and a therapy. It can be used to do both. We’ve identified the mechanism of how this protein actually drives metastasis in thyroid cancer. And not only that, we found out that it also makes the cancer resistant to radioactive iodine therapy.”

McMullen says that by identifying the mechanism, the team is able to predict which people will have recurrent disease and which patients will respond to radioactive iodine therapy–both tools that are currently lacking in the medical community.

The foundation of the work stems from previous efforts in which McMullen’s team examined thyroid cancer patient specimens. In a study published in 2012 they looked at genetic signatures showing which patients experienced metastasis and which patients did not. Through their efforts at that time they discovered PDGFRA was linked to metastatic disease. According to McMullen, this latest research significantly advances that work.

In the very near future the team hopes to begin two separate clinical trials. The first will investigate a new way to treat thyroid cancers using a cancer drug that specifically targets PDGFRA. The second will work on a new diagnostic tool to give patients an early indicator of whether their thyroid cancer will be aggressive or not.

“We hope within the next 18 months that we can prove the utility of this approach and change the way thyroid cancers are managed for those patients that have the worst disease,” says McMullen. “We were lucky enough to find something that we think is important for thyroid cancer. It will be put to the test now.”

Heart disease, leukemia linked to dysfunction in nucleus

We put things into a container to keep them organized and safe. In cells, the nucleus has a similar role: keeping DNA protected and intact within an enveloping membrane. But a new study by Salk Institute scientists, detailed in the November 2 issue of Genes & Development, reveals that this cellular container acts on its contents to influence gene expression.

“Our research shows that, far from being a passive enclosure as many biologists have thought, the nuclear membrane is an active regulatory structure,” says Salk Professor Martin Hetzer, who is also holder of the Jesse and Caryl Philips Foundation chair. “Not only does it interact with portions of the genome to drive gene expression, but it can also contribute to disease processes when components are faulty.”

Using a suite of molecular biology technologies, the Salk team discovered that two proteins, which sit in the nuclear envelope, together with the membrane-spanning complexes they form, actively associate with stretches of DNA to trigger expression of key genes. Better understanding these higher-level functions could provide insight into diseases that appear to be related to dysfunctional nuclear membrane components, such as leukemia, heart disease and aging disorders.

Historically, the nuclear membrane’s main purpose was thought to be keeping the contents of the nucleus physically separated from the rest of the cell. Complexes of at least thirty different proteins, called nucleoporins, form gateways (pores) in the membrane, controlling what goes in or out. But as the Hetzer lab’s work on nucleoporins shows, these nuclear pore complexes (NPCs), beyond being mere gateways into the nucleus, have surprising regulatory effects on the DNA inside.

“Discovering that key regulatory regions of the genome are actually positioned at nuclear pores was very unexpected,” says Arkaitz Ibarra, a Salk staff scientist and first author of the paper. “And even more importantly, nuclear pore proteins are critical for the function of those genomic sites.”

Curious about all the regions of DNA with which nucleoporins potentially interact, the team turned to a human bone cancer cell line. The scientists used a molecular biology technique called DamID to pinpoint where two nucleoporins, Nup153 and Nup93, came into contact with the genome. Then they used several other sequencing techniques to understand which genes were being affected in those regions, and how.

The Salk team discovered that Nup153 and Nup93 interacted with stretches of the genome called super-enhancers, which are known to help determine cell identity. Since every cell in our body has the same DNA, what makes a muscle cell different from a liver cell or a nerve cell is which particular genes are turned on, or expressed, within that cell. In the Salk study, the presence of Nup153 and Nup93 was found to regulate expression of super-enhancer driven genes and experiments that silenced either protein resulted in abnormal gene expression from these regions. Further experiments in a lung cancer cell line validated the bone cancer line results: Nucleoporins in the NPC were found to interact with multiple super-enhancer regions to drive gene expression, while experiments that altered the NPC proteins made related gene expression faulty, even though the proteins still performed their primary role as gatekeepers in the cell membrane.

“It was incredible to find that we could perturb the proteins without affecting their gateway role, but still have nearby gene expression go awry,” says Ibarra.

The results bolster other work indicating that problems with the nuclear membrane play a role in heart disease, leukemia and progeria, a rare premature aging syndrome.

“People have thought the nuclear membrane is just a protective barrier, which is maybe the reason why it evolved in the first place. But there are many more regulatory levels that we don’t understand. And it’s such an important area because so far, every membrane protein that has been studied and found to be mutated or mis-localized, seems to cause a human disease,” says Hetzer.

Ginger And Chili Peppers Could Work Together To Lower Cancer Risk

For many people, there’s nothing more satisfying than a hot, spicy meal. But some research has suggested that capsaicin, the compound that gives chili peppers their kick, might cause cancer. Now researchers show in mouse studies that the pungent compound in ginger, 6-ginergol, could counteract capsaicin’s potentially harmful effects. In combination with the capsaicin, 6-gingerol could lower the risk of cancer, they say. The study appears in ACSJournal of Agricultural and Food Chemistry.

Both chili peppers and ginger are widely used spices in certain cuisines, particularly in Asia, and have been studied for potential health effects. Although some studies have shown that peppers can have benefits, others suggest that diets rich in capsaicin might be associated with stomach cancer. Ginger, however, has shown promise as a health-promoting ingredient. Oddly enough, capsaicin and 6-gingerol both bind to the same cellular receptor — one that is related to tumor growth. Jiahuan Li, Gangjun Du and colleagues wanted to further investigate this apparent contradiction.

Over several weeks, the researchers fed mice prone to lung cancer either capsaicin or 6-gingerol alone, or a combination of both. During the study period, all of the mice that received only capsaicin developed lung carcinomas while only half of the mice fed 6-gingerol did. Surprisingly, an even lower percentage — only 20 percent — of the mice given both compounds developed cancer. The researchers also dug into the potential molecular underpinnings of how the compounds interact to lead to this effect.

Parkinson’s disease biomarker found in patient urine samples

For more than five years, urine and cerebral-spinal fluid samples from patients with Parkinson’s disease have been locked in freezers in the NINDS National Repository, stored with the expectation they might someday help unravel the still-hidden course of this slow-acting neurodegenerative disease.

Now, research by Andrew West, Ph.D., and colleagues at the University of Alabama at Birmingham has revealed that the tubes hold a brand-new type of biomarker — a phosphorylated protein that correlates with the presence and severity of Parkinson’s disease. West and colleagues, with support from the National Institutes of Health, the Michael J. Fox Foundation for Parkinson’s Disease Research and the Parkinson’s Disease Foundation, are digging deeper into these biobanked samples, to validate the biomarker as a possible guide for future clinical treatments and a monitor of the efficacy of potential new Parkinson’s drugs in real time during treatment.

“Nobody thought we’d be able to measure the activity of this huge protein called LRRK2 (pronounced lark two) in biofluids since it is usually found inside neurons in the brain,” said West, co-director of the Center for Neurodegeneration and Experimental Therapeutics, and the John A. and Ruth R. Jurenko Professor of Neurology at UAB. “New biochemical markers like the one we’ve discovered together with new neuroimaging approaches are going to be the key to successfully stopping Parkinson’s disease in its tracks. I think the days of blindly testing new therapies for complex diseases like Parkinson’s without having active feedback both for ‘on-target’ drug effects and for effectiveness in patients are thankfully coming to an end.”

A biomarker helps physicians predict, diagnose or monitor disease, because the biomarker corresponds to the presence or risk of disease, and its levels may change as the disease progresses. Validated biomarkers can aid both preclinical trial work in the laboratory and future clinical trials of drugs to treat Parkinson’s. West and others are paving the way for an inhibitor drug that prevented neuroinflammation and neurodegeneration in an animal model of the disease, as reported last year by West and colleagues.

The new biomarker findings were published in Neurology in March and Movement Disorders in June. The biomarker, LRRK2, has been shown to play a role in hereditary Parkinson’s, and the most common of these mutations — called G2019S — causes the LRRK2 kinase to add too many phosphates to itself and other proteins. Why this leads to Parkinson’s disease is not yet clear.

The key to West’s biomarker approach was the recognition that LRRK2 can be purified from a new type of vesicle called exosomes found in all human biofluids, like urine and saliva. Cells in the body continually release exosomes that contain a mixture of proteins, RNA and DNA derived from different kinds of cells. West and colleagues were able to purify exosomes from 3- or 4-ounce urine samples donated by patients, and then measure phosphorylated LRRK2 in those exosomes.

The findings

In the Neurology study, they found that elevated phosphorylated LRRK2 predicted the risk for onset of Parkinson’s disease for people carrying a mutation in LRRK2, which is about 2-3 percent of all Parkinson’s disease patients. These findings were first tested with a preliminary, 14-person cohort of urine samples from the Columbia University Movement Disorders Center. That was followed by a larger replication study of 72 biobanked urine samples from the Michael J. Fox Foundation LRRK2 Cohort Consortium. All samples were provided to UAB in a blinded fashion to ensure the approach was rigorous.

The follow-up Movement Disorders paper — the first study of its type — expanded the scope to people without LRRK2 mutations, which is most Parkinson’s disease patients. Using 158 urine samples from Parkinson’s disease patients and healthy controls enrolled in the UAB Movement Disorder Clinic as part of the NIH Parkinson’s Disease Biomarker Program, West and colleagues found that approximately 20 percent of people without LRRK2 mutations but with Parkinson’s disease also showed highly elevated phosphorylated LRRK2 similar to people with LRRK2 mutations, and this was not present in healthy controls. The study speculates that people with elevated phosphorylated LRRK2 may be particularly good candidates for future drugs that reduce phosphorylated LRRK2.

Next steps

Questions remain for this evidence of biochemical changes in LRRK2 in idiopathic Parkinson’s disease. One is finding out where the urinary exosomes come from. Given a suspected role for inflammation in Parkinson’s disease, it is interesting that LRRK2 is highly expressed in cells of the innate immune system. A possible explanation for the phosphorylated LRRK2 in patients with more severe disease may be an increased inflammation in those patients who have aggressive progression of disease.

In May, West was awarded a new U01 collaborative grant from the National Institute of Neurological Disorders and Stroke to further explore urinary exosomes and extend the observations to cerebral-spinal fluid as a marker for disease prediction and prognosis.

New anti-cancer strategy mobilizes both innate and adaptive immune response

Though a variety of immunotherapy-based strategies are being used against cancer, they are often hindered by the inability of the immune response to enter the immunosuppressive tumor microenvironment and to effectively mount a response to cancer cells. Now, scientists from the RIKEN Center for Integrative Medical Sciences have developed a new vaccine that involves injecting cells that have been modified so that they can stimulate both an innate immune response and the more specific adaptive response, which allows the body to keep memories and attack new tumor cells as they form. In the study published in Cancer Research, they found that the vaccine made it possible for killer CD8+T-cells–important players in the immune response against cancer–to enter the tumor microenvironment and target cancerous cells.

According to Shin-ichiro Fujii, leader of the Laboratory for Immunotherapy, who led the study, “Cancer cells have different sensitivities to the innate or adaptive response, so it important to target both in order to eradicate it. We have developed a special type of modified cell, called aAVC, which we found can do this.”

The aAVC cells are not taken from the subject’s own body but are foreign cells. The cells are modified by adding a natural killer t-cell ligand, which permits them to stimulate natural killer T-cells, along with an antigen associated with a cancer. The group found that when these cells are activated, they in turn promote the maturation of dendritic cells, which act as coordinators of the innate and acquired response. Dendritic cells are key because they allow the activation of immune memory, where the body remembers and responds to a threat even years later.

To find whether it worked in actual bodies, they conducted experiments in mice with a virulent form of melanoma that also expresses a model antigen called OVA. Tests in mice showed, moreover, that aggressive tumors could be shrunken by vaccinating the animals with aAVC cells that were programmed to display OVA antigen. Following the treatment, the tumors in the treated animals were smaller and necrotic in the interior–a sign that the tumor was being attacked by the killer CD8+T-cells.

Fujii continues, “We were interesting in finding a mechanism, and were able to understand that the aAVC treatment led to the development of blood vessels in the tumors that expressed a pair of important adhesion molecules, ICAM-1 and VCAM-1, that are not normally expressed in tumors. This allowed the killer CD8+T cells to penetrate into the tumor.”

They also found that in animals that had undergone the treatment, cancer cells injected even a year later were eliminated. “This indicates,” says Fujii, “that we have successfully created an immune memory that remembers the tumor and attacks it even later.”

Looking to the future, Fujii says, “Our therapy with aAVC is promising because typical immunotherapies have to be tailor-made with the patient’s own cells. In our case we use foreign cells, so they can be made with a stable quality. Because we found that our treatment can lead to the maturation of dendritic cells, immunotherapy can move to local treatment to more systemic treatment based on immune memory.”

Penn Team Identifies Amino Acid Associated with Poor Performance Under Sleep Restriction

The amino acid acetylcarnitine may help predict an individual’s neurobehavioral performance during chronic sleep restriction, according to results of a new study (abstract 0251) from researchers at the Perelman School of Medicine at the University of Pennsylvania that will be presented at SLEEP 2016, the 30th annual meeting of the Associated Professional Sleep Societies LLC.

Previous studies have shown that sleep loss degrades behavioral attention, cognitive processing and memory, but this study offers the first experimental evidence that acetylcarnitine — which transports fatty acids into the mitochondria where they are broken down and oxidized and formed into energy — may predict neurobehavioral vulnerability to sleep loss in healthy adults.

In the study at the sleep lab at the Hospital of the University of Pennsylvania, participants’ blood samples were taken after 10-12 hours of fasting following one night of baseline sleep (10 hours time in bed), chronic sleep restriction (5 consecutive nights of 4 hours time in bed), and one night of recovery sleep (12 hours time in bed).

The Psychomotor Vigilance Test (PVT), the Digit Symbol Substitution Task (DSST), the Digit Span Task (DS), the Karolinska Sleepiness Scale (KSS) and the Profile of Mood States (POMS) tests were administered every two hours while participants were awake.

The preliminary data associated acetylcarnitine with six neurobehavioral variables during sleep loss, including PVT lapses (longer than 500 millisecond responses) and errors, PVT response speed, DSST total correct, DS total correct, KSS scores, and POMS vigor scores — but not at baseline or recovery. Higher levels of this molecule predicted poorer behavioral attention, slower ability to process information, and poorer memory and increased sleepiness.

“We know that there are robust differences in how individuals respond to sleep loss,” said Namni Goel, PhD, a research associate professor of psychology in Psychiatry in the division of Sleep and Chronobiology, and lead author on the study. “Some people are very vulnerable, while others are more resistant to these effects. Identifying this marker is an important step in identifying measures to mitigate the disruptive effects of sleep loss in those who are more affected.”

The findings have implications for government agencies and other institutions interested in predicting who may be vulnerable to sleep loss and finding ways to offset the negative effects of sleep loss when they occur.

Narcotic painkillers prolong pain in rats, says CU-Boulder study

The dark side of painkillers – their dramatic increase in use and ability to trigger abuse, addiction and thousands of fatal overdoses annually in the United States is in the news virtually every day.

Brace for another shot across the bow: Opioids like morphine have now been shown to paradoxically cause an increase in chronic pain in lab rats, findings that could have far-reaching implications for humans, says a new study led by the University of Colorado Boulder.

Led by CU-Boulder Assistant Research Professor Peter Grace and Distinguished Professor Linda Watkins, the study showed that just a few days of morphine treatment caused chronic pain that went on for several months by exacerbating the release of pain signals from specific immune cells in the spinal cord. The results suggest that the recent escalation of opioid prescriptions in humans may be a contributor to chronic pain, said Grace.

“We are showing for the first time that even a brief exposure to opioids can have long-term negative effects on pain,” said Grace, who is a faculty member along with Watkins in CU-Boulder’s Department of Psychology and Neuroscience. “We found the treatment was contributing to the problem.”

A paper on the study was published May 30 in the Proceedings of the National Academy of Sciences.

The study showed that a peripheral nerve injury in rats sends a message from damaged nerve cells to spinal cord immune cells known as glial cells, which normally act as “housekeepers” to clear out unwanted debris and microorganisms. The first signal of pain sends glial cells into an alert mode, priming them for further action.

“I look at it like turning up a dimmer switch on the spinal cord,” said Grace.

When the injury was treated with just five days of opioids the glial cells went into overdrive, triggering a cascade of actions, including spinal cord inflammation. Watkins said the initial pain signals to the spinal cord and the subsequent morphine-induced treatment is a two-hit process, which she likened to slapping a person’s face.

“You might get away with the first slap, but not the second,” she said. “This one-two hit causes the glial cells to explode into action, making pain neurons go wild.”

The team discovered that the pain signals from a peripheral injury combined with subsequent morphine treatment worked together to cause a glial cell signaling cascade. The cascade produces a cell signal from a protein called interleukin-1beta (IL-1b), which increases the activity of pain-responsive nerve cells in the spinal cord and brain. That can cause increases in pain duration lasting several months.

“The implications for people taking opioids like morphine, oxycodone and methadone are great, since we show the short-term decision to take such opioids can have devastating consequences of making pain worse and longer lasting,” said Watkins. “This is a very ugly side to opioids that had not been recognized before.”

Roughly 20,000 Americans died in 2015 from overdoses of prescription opioid pain relievers, according to the National Institute on Drug Abuse.

On the up side, the researchers have found ways to block specific receptors on glial cells that recognize opioids. This could allow for some pain relief while potentially preventing chronic pain. The team used a designer drug technology known as DREADD to selectively turn off targeted glial cells, something that has not been done before, said Grace.

Hunting for the brain’s opioid addiction switch

New research by Steven Laviolette’s research team at Western University is contributing to a better understanding of the ways opiate-class drugs modify brain circuits to drive the addiction cycle. Using rodent models of opiate addiction, Dr. Laviolette’s research has shown that opiates affect pathways of associative memory formation in multiple ways, both at the level of anatomy (connections between neurons) and at the molecular levels (how molecules inside the brain affect these connections). The identification of these opiate-induced changes offers the best hope for developing more effective pharmacological targets and therapies to prevent or reverse the effect of opiate exposure and addiction. These results were presented at the 10th Annual Canadian Neuroscience Meeting, that took place  in Toronto, Canada.

“Developing more effective opiate addiction treatments will require a change in the way we view the effects of opiates on the brain. Instead of addiction being a chronic, permanent disease, recent evidence is showing that addiction is controlled by molecular switching mechanisms in the brain, that can be turned on or off with the right interventions” says Dr. Steven Laviolette.

Addiction to opiates is spreading and increasing exponentially, and is currently estimated to affect 15.5 million people worldwide. Opiate drugs’ addictive properties are largely due to the ability of this class of drugs to produce powerful memories associated with the intense experience of pleasure and euphoria they cause. Environmental reminders triggering the recall of these memories can cause a relapse, and these memories can be considered the primary driver of the addiction cycle, from chronic use, to withdrawal and then memory-triggered relapse. For decades, clinical and pre-clinical research considered that opiate consumption caused permanent changes in the brain’s reward circuits, resulting in a persistent vulnerability to relapse. However, more recent investigations have shown that opiates induce changes in multiple brain circuits, including reward and memory circuits, and that these changes are not static, but rather that many drug-induced adaptations could be reversed.

“A critical challenge for addiction research is identifying the precise molecular brain changes caused by addictive drugs like heroin or prescription narcotics”, says Dr. Laviolette. “Once we understand this process, we can develop more effective pharmacological interventions to prevent or reverse them”

Among the targets identified by Dr. Laviolette are receptors and other proteins involved in signalling of a neurotransmitter called dopamine. More specifically, his work has shown that dopamine signalling in two connected brain regions involved in opiate-related memory processing, called the Basolateral Amygdala (BLA), a region deep within the brain, and the medial prefrontal cortex (mPFC), located near the surface of the brain, is switched by opiate exposure. His research shows that in animals that are opiate naïve, never previously exposed to opiates, the reward memory associated with opiates requires a dopamine receptor called D1R in the BLA, and a signalling molecule called extracellular signal-related kinase 1/2 (ERK1/2). Following chronic opiate exposure, however, opiate reward memory formation becomes independent of D1R, and rather depends on a second dopamine receptor, called D2r, and a protein called CaMKII. As CaMKII expression has been associated with consolidation and permanence of memories in other brain regions, this switch may reflect the formation of a stronger and more stable opiate reward memory.

Interestingly, when Dr. Laviolette’s team looked at dopamine signaling inside another brain region also involved in opiate related memory procession, and located closer to the surface of the brain, the mPFC, they found that this signaling was also switched by opiate exposure, but opposite to what was observed in the BLA. In the mPFC, opiate naïve signaling requires CaMKII, while it did not in opiate habituated animals.

Taken together, these results highlight the precise changes and adaptations that occur in the brain following opiate exposure and development of addiction. New pharmacological approaches to target these changes will provide much needed and more effective treatments to reduce the power of drug-related associative memories that drive opiate addiction.

Researchers find new signs of stress damage in the brain, plus hope for prevention

Chronic stress can make us worn-out, anxious, depressed–in fact, it can change the architecture of the brain. New research at The Rockefeller University shows that when mice experience prolonged stress, structural changes occur within a little-studied region of their amygdala, a part of the brain that regulates basic emotions, such as fear and anxiety. These changes are linked to behaviors associated with anxiety and depressive disorders

There is good news, too: an experimental new drug might prevent these changes.

“There have been hints that the amygdala displays a complex response to stress,” says lead author Carla Nasca, a postdoc in Bruce S. McEwen’s lab. “When we took a closer look at three regions within it, we found that neurons within one, the medial amygdala, retract as a result of chronic stress.

“While this rewiring can contribute to disorders such as anxiety and depression, our experiments with mice showed that the neurological and behavioral effects of stress can be prevented with treatment by a promising potential antidepressant that acts rapidly,” Nasca says.

In the research, published May 31 in Molecular Psychiatry, her team found this protective approach increased resilience among mice most at risk for developing anxiety or depression-like behaviors.

A close look at the amygdala

The brain’s limbic system controls emotions and memory, and it comprises a number of structures, including the amygdala, which is found deep in the brain. Scientists interested in the neurological effects of stress have focused on several structures in the limbic system, but the medial amygdala has thus far received little attention in stress studies.

To see what was going on in this area, as well as two other parts of the amygdala, Nasca and her team first subjected mice to 21 days of periodic confinement within a small space–an unpleasant experience for mice. Afterward, they tested the mice to see if their behaviors had changed–for instance, if they had begun to avoid social interaction and showed other signs of depression. They also analyzed the neurons of these mice within the three regions of the amygdala.

One area saw no change with stress. In another, the basolateral amygdala, they saw that neurons’ branches became longer and more complex–a healthy sign of flexibility and adaptation, and something that had been shown up in previous work. But in the medial amygdala, they neuronal branches, which form crucial connections to other parts of the brain, appeared to shrink. The loss of connections like these can harm the brain, distorting its ability to adapt to new experiences, leaving it trapped in a state of anxiety or depression.

Protecting neurons

This effect could be prevented. The scientists repeated the stress experiment, and this time they treated mice nearing the end of their 21 days of chronic stress with acetyl carnitine, a molecule Nasca is studying for its potential as a rapid-acting antidepressant. These mice fared better than their untreated counterparts; not only were they more sociable, the neurons of their medial amygdalas also showed more branching.

Stress does not affect everyone the same way. This is true for both humans and mice–some individuals are just more vulnerable. Nasca and her colleagues’ experiments included mice at high risk of developing anxiety- and depression-like behaviors in response to stress. Treatment with acetyl carnitine also appeared to protect these mice, suggesting that a similar preventative approach might work for depression-prone people.

Both humans and rodents naturally produce acetyl carnitine under normal conditions and several depression-prone animal models are deficient in acetyl carnitine. In a separate study, Nasca and colleagues are examining whether people with depression have abnormally low levels of the molecule.

“Chronic stress is linked to a number of psychiatric conditions, and this research may offer some new insights on their pathology,” McEwen says. “It seems possible that the contrasting responses we see within the amygdala, and the limbic system in general, may contribute to these disorders’ differing symptoms, which can range from avoiding social contact to experiencing vivid flashbacks.”

Fighting hospital germs with sugar

A vaccine against one of the most dangerous hospital germs may soon be available. Scientists from the Max Planck Institute of Colloids and Interfaces in Potsdam and the Freie Universität Berlin have developed a substance that elicits an immune response against the gut bacterium Clostridium difficile. The potential vaccine resembles the sugar structures presented on the surface of the bacterium and therefore primes the immune system to recognize the pathogen itself. C. difficile infects a large proportion of patients in hospitals and kills around 15,000 people a year in the USA alone. Doctors could treat the infection with antibiotics, but the bacterium mutates constantly, allowing it to escape the effects of the drugs. The discovery by the Max Planck researchers may pave the way for developing inexpensive and effective vaccines and drugs against C. difficile.

Around 40 percent of patients in hospitals and nursing homes carry the gut bacterium C. difficile. Such patients are easy prey for the pathogen. Because the patients’ intestinal flora is often damaged by antibiotic treatments, the bacteria are able to spread unhindered. Moreover, treatment of the infection becomes increasingly difficult, as the bacteria tend to develop resistance to antibiotics.

Researchers at the Max Planck Institute of Colloids and Interfaces have now constructed a molecule that could protect patients against C. difficile. It resembles the characteristic sugar coating on the surface of bacteria and, as such, is able to elicit a similar immune response as the bacterium itself. The molecule could thus be used as a vaccine, because once the immune system has produced antibodies against a pathogen, it is prepared to fend off the invaders in the event of a later infection.

Synthetic molecule as a cost-effective alternative for immunization

The researchers first investigated which parts of the sugar coating are actually necessary to trigger an immune response. They then constructed an artificial molecule with those properties by attaching the essential sugar structures to an amino acid backbone. Coupled with an immunostimulating peptide, the molecule stimulated the immune system in mice to produce antibodies that were effective against the similarly constructed surface sugars of C. difficile. The mice are therefore protected against a subsequent infection with the bacterium. Moreover, it may be possible to use the molecule to produce therapeutic antibodies that can be administered to sick patients to boost their immune system and combat infections.

Many bacteria bear characteristic carbohydrates on their surface, and it is known that these surface sugars are suitable for immunization purposes. However, the surface sugars usually have to be detached from specially bred microbes – an expensive and complicated process. By synthesizing artificial molecules for immunization, the researchers have now come up with a cost-effective alternative. “Our findings are a very good example of how basic research into the human immune response to sugars can lead to new candidates in the fight against dangerous hospital germs,” says Peter H. Seeberger, Director at the Max Planck Institute of Colloids and Interfaces and Professor at Freie Universität Berlin. As early as 2011, he and his team synthesized a molecule for immunizing against C. difficile; at the time, however, they used a different surface sugar molecule as a template.

In order to progress from research results to actual use in patients, the scientists at the Max Planck Institute of Colloids and Interfaces in Potsdam are working with Vaxxilon AG (Reinach, Switzerland) to develop novel carbohydrate-based vaccines. Vaxxilon has licensed a portfolio of vaccine candidates against a number of pathogens, including C. difficile.

Breast cancer drug found to reduce seizures

A class of drug that inhibits estrogen production and is used to treat breast cancer has been found to quickly and effectively suppress dangerous brain seizures, according to a new Northwestern University study.

“The effect was profound and very clear,” said Catherine S. Woolley, senior author of the study, which was conducted in a rat model of status epilepticus, a condition characterized by a prolonged episode of seizure activity. “This shows that clinically available drugs could be effective therapies for suppressing seizures in humans.”

Woolley and postdoctoral fellow Satoru M. Sato also discovered, to their surprise, that seizures stimulate the production of estrogens in the brain of both males and females and that this plays a previously unknown role in the escalation of seizure activity. Estrogen synthesis during a seizure fuels the seizure, making it worse.

The findings suggest a new approach to treating seizures in humans: shut down the brain’s production of estrogen when a seizure first begins. Current seizure treatments are not targeted; they work by dampening neural activity generally and come with many side effects, such as drowsiness, dizziness or difficulty concentrating.

“Status epilepticus is a neurological emergency,” Woolley said. “This occurs when large groups of connected neurons fire excessively and in synchrony for a prolonged time. Recognizing that estrogen synthesis during seizures fuels seizure activity gives researchers a specific target for therapeutically breaking the dangerous escalation cycle.”

Woolley is the William Deering Chair in Biological Sciences, professor of neurobiology in the Weinberg College of Arts and Sciences and a member of the Women’s Health Research Institute at Northwestern University Feinberg School of Medicine.

The study, published this week as a Research Article by the online life sciences and biomedicine journal eLife, builds on past work showing estrogen increases neuronal activity via a number of mechanisms.

In their study, Woolley and Sato found inhibiting estrogen synthesis just after seizure onset strongly suppressed seizures in both sexes, without anti-seizure drugs or other interventions. The effect was seen both in the animal’s behavior and in hippocampal electroencephalogram (EEG) recordings.

The scientists injected male and female animals with either an inert substance or an aromatase inhibitor, either letrozole or fadrozole, just after the start of a chemically induced seizure. (An aromatase inhibitor inhibits estrogen synthesis; letrozole, or Femera®, is used clinically to treat breast cancer in postmenopausal women.) They studied the animals for up to six hours and found both fadrozole and letrozole strongly suppressed seizures in both sexes.

The hippocampus is a critically important part of the brain in the initiation and propagation of seizure activity. In another part of their study, Woolley and Sato found the impact of seizures on estrogen production in the hippocampus was surprisingly large in both sexes, showing a two- to three-fold increase during seizures.

Woolley said it is important to distinguish between seizures and epilepsy, which are not synonymous. Epilepsy, which affects about 1 percent of the population, is a condition in which a person has spontaneous recurrent seizures, often lasting only a few minutes. Status epilepticus is a more severe seizure episode, affecting about 40 people per 100,000 per year.

The overall mortality rate of status epilepticus is estimated at 20 percent, and patients who recover have an increased likelihood of subsequent unprovoked seizures, the researchers say. New approaches to acute seizure control are needed.

“Given the unacceptably high mortality rate of status epilepticus in humans, these data from the Northwestern study are likely to elicit great interest by physicians in the field,” said Dr. Stephen M. Smith, director of medical critical care at the VA Portland Health Care System. He was not involved in the study but is familiar with Woolley’s research.

“Hopefully, this new study will trigger clinical trials to determine the efficacy and safety of currently available aromatase inhibitors in patients with status epilepticus,” said Smith, professor of medicine at Oregon Health & Science University.