A newly identified genetic disorder associated with degeneration of the central and peripheral nervous systems in humans, along with the genetic cause, is reported in the April 24, 2014 issue of Cell.
The findings were generated by two independent but collaborative scientific teams, one based primarily at Baylor College of Medicine and the Austrian Academy of Sciences, the other at the University of California, San Diego School of Medicine, the Academic Medical Center (AMC) in the Netherlands and the Yale University School of Medicine.
By performing DNA sequencing of more than 4,000 families affected by neurological problems, the two research teams independently discovered that a disease marked by reduced brain size and sensory and motor defects is caused by a mutation in a gene called CLP1, which is known to regulate tRNA metabolism in cells. Insights into this rare disorder, the researchers said, may have important implications for the future treatment of more common neurological conditions.
“What we found particularly striking, when considering the two studies together, is that this is not a condition that we would have been able to separate from other similar disorders based purely on patient symptoms or clinical features”, said Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children’s Hospital-San Diego, a research affiliate of UC San Diego. “Once we had the gene spotted in these total of seven families, then we could see the common features. It is the opposite way that doctors have defined diseases, but represents a transformation in the way that medicine is practiced.”
Each child tested was affected by undiagnosed neurological problems. All of the children were discovered to carry a mutation in the CLP1 gene and displayed the same symptoms, such as brain malformations, intellectual disabilities, seizures and sensory and motor defects. A similar pattern emerged in both studies, one led by Gleeson, with Murat Gunel, MD, of the Yale University School of Medicine and Frank Baas, PhD, of the Academic Medical Center in the Netherlands, and the other by Josef Penninger and Javier Martinez of the Austrian Academy of Sciences, teamed with James R. Lupski, MD, PhD, of the Baylor College of Medicine.
“Knowing fundamental pathways that regulate the degeneration of neurons should allow us to define new pathways that, when modulated, might help us to protect motor neurons from dying, such as in Lou Gehrig’s disease,” said Penninger, scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences.
The CLP1 protein plays an important role in generating mature, functional molecules called transfer RNAs (tRNAs), which shuttle amino acids to cellular subunits called ribosomes for assembly into proteins. Mutations affecting molecules involved in producing tRNAs have been implicated in human neurological disorders, such as pontocerebellar hypoplasia (PCH), a currently incurable neurodegenerative disease affecting children. Although CLP1 mutations have been linked to neuronal death and motor defects in mice, the role of CLP1 in human disease was not known until now.
These scientists performed DNA sequencing on children with neurological problems. Seven out of the more than 4,000 families studied shared an identical CLP1 mutation, which was associated with motor defects, speech impairments, seizures, brain atrophy and neuronal death.
Bass at the AMC said the neurological condition represents a new form of PCH. “Identification of yet another genetic cause for this neurodegenerative disorder will allow for better genetic testing and counseling to families with an affected child,” he said.
In a published paper last year, Gleeson and colleagues identified a different gene mutation for a particularly severe form of PCH, and reported early evidence that a nutritional supplement might one day be able to prevent or reverse the condition.
Majority of participants in randomized trial lost weight and reduced medication use
Weight loss and control of blood sugar can reduce the risk of complications in patients with diabetes but this is difficult for many to achieve. A University of California, San Diego School of Medicine randomized controlled trial of obese adults with type 2 diabetes suggests that participants enrolled in a community-based structured weight loss program are able to shed more pounds, improve blood sugar control and reduce or eliminate insulin use and other medications compared to a control group.
“Support and a tailored lifestyle intervention have been shown to reduce cardiovascular disease risk factors and adverse outcomes in people with diabetes,” said Cheryl L. Rock, PhD, RD, professor of Family and Preventive Medicine and principal investigator of the study. “However, most overweight individuals with type 2 diabetes do not receive this degree of support for changes in diet and physical activity to promote weight loss in their clinical care, due in part to constraints of time and training for most health care providers and clinicians.”
The results of the study, published in the April 23, 2014 online issue of Diabetes Care, found that 72 percent of participants on the weight loss program that included portion-controlled foods and personalized counseling were able to change their insulin use compared to eight percent of the control group. Similarly, other diabetes, cholesterol and blood pressure drugs were decreased or discontinued more often among the weight loss program enrollees.
According to the Centers for Disease Control and Prevention, 35 percent of adults in the United States are obese and eight percent of adults are affected by diabetes.
“Weight loss is a primary strategy for successful management of type 2 diabetes due to its impact on glycemic control and improvements in cardiovascular disease risk factors,” said Rock. “These study results suggest that patients not only lose weight on structured commercial weight loss programs that include behavioral modification and individual support, but that this weight loss translates to significant improvements in diabetes control and cardio-metabolic parameters.”
Igor Grant Named Chair of UC San Diego Department of Psychiatry
Igor Grant, MD, FRCP(C), an internationally recognized neuropsychiatrist, whose research interests have ranged from the neurobiology of HIV/AIDS and substance abuse, psychobiology of stress, to the therapeutic potential of medicinal cannabis, has been named the new Chair of the Department of Psychiatry at the University of California, San Diego School of Medicine.
“Dr. Grant embodies the extraordinary scope and depth of research in the Department of Psychiatry. Indeed, he has been fundamental to its rise and enduring excellence,” said David Brenner, MD, vice chancellor for Health Sciences and dean of the School of Medicine. “Dr. Grant has always been at the forefront of his science, pushing for answers to questions in new and sometimes controversial or difficult areas. I have no doubt that the Department of Psychiatry will continue to excel under his leadership.”
The difference between an immune response that kills cancer cells and one that conversely stimulates tumor growth can be as narrow as a “double-edged sword,” report researchers at the University of California, San Diego School of Medicine in the April 7, 2014 online issue of the Proceedings of the National Academy of Sciences.
“We have found that the intensity difference between an immune response that stimulates cancer and one that kills it may not be very much,” said principal investigator Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine. “This may come as a surprise to researchers exploring two areas typically considered distinct: the role of the immune system in preventing and killing cancers and the role of chronic inflammation in stimulating cancers. As always, it turns out that the immune system is a double-edged sword.”
The concept of naturally occurring “immunosurveillance” against malignancies is not new, and there is compelling evidence for it. But understanding this process is confounded by the fact that some types of immune reaction promote tumor development. Varki and colleagues looked specifically at a non-human sialic acid sugar molecule called Neu5Gc. Previous research has found that Neu5Gc accumulates in human tumors from dietary sources, despite an on-going antibody response against it.
The scientists deployed antibodies against Neu5Gc in a human-like mouse tumor model to determine whether and to what degree the antibodies altered tumor progression. They found that low antibody doses stimulated growth, but high doses inhibited it. The effect occurred over a “linear and remarkably narrow range,” said Varki, generating an immune response curve or “inverse hormesis.” Moreover, this curve could be shifted to the left or right simply by modifying the quality of the immune response.
Similar findings were made in experiments with two other mouse tumor models, and with a human tumor xenograft model using a monoclonal antibody currently in clinical use. The scientists concluded that the difference in intensity between an immune response stimulating tumors and one that kills them may be much less than previously imagined.
Varki said the results may have implications for all aspects of cancer science, from studying its causes to prevention and treatment. This is because the immune response can have multiple roles in the genesis of cancers, in altering the progress of established tumors and in anti-cancer therapies that use antibodies as drugs.
Researchers discover too much or too little of a single enzyme may promote cancer
Researchers at the University of California, San Diego School of Medicine have found that too little or too much of an enzyme called SRPK1 promotes cancer by disrupting a regulatory event critical for many fundamental cellular processes, including proliferation.
The findings are published in the current online issue of Molecular Cell.
The family of SRPK kinases was first discovered by Xiang-Dong Fu, PhD, professor in the Department of Cellular and Molecular Medicine at UC San Diego in 1994. In 2012, Fu and colleagues uncovered that SPRK1 was a key signal transducer devoted to regulating alternative pre-mRNA splicing, a process that allows a single gene to produce multiple mRNA isoforms, which in many cases encode functionally distinct proteins. In this pathway, SRPK1 was a downstream target of Akt, also known as protein kinase B. Akt- activated SRPK1 moves to the nucleus to induce its targeted splicing factors.
In their latest paper, Fu and colleagues report that SRPK1 was found to act as a tumor suppressor because when ablated or removed from mouse embryonic fibroblasts, unwanted cell transformation occurred. Unexpectedly, when SRPK1 was overexpressed in mouse cells, tumor development also happened.
“To my knowledge, this is the first time it has been shown that a signal kinase behaves as a tumor suppressor or a promoter, depending upon its abundance in the same cell” said Fu. “The point is that too much or too little are both bad.”
Such contrary phenomena are due to a surprising role of SRPK1 in regulating the activity of Akt via a specific Akt phosphatase discovered earlier by Alexandra C. Newton, PhD, professor of pharmacology at UC San Diego. The Akt phosphatase cannot find Akt when there is too little SRPK1 to assist, and the phosphatase is tied up when there is too much SRPK1. In both cases, the result is a dampening of Akt inactivation.
As Akt plays a key role in many cellular processes, such as glucose metabolism, apoptosis, proliferation and all key aspects of tumor development, the elucidated mechanism provides a critical insight into tumorigenesis in humans. Indeed, compared to normal cells, many tumors show SRPK1 overexpression while others display reduced expression.
The findings may have future therapeutic implications, but Fu said the challenges remain daunting. “Most tumors show SRPK1 overexpression, so it may be possible to treat certain cancers with a specific SRPK1 inhibitor. This has been already demonstrated by others. But suppressing a cancer not related to SRPK1 overexpression could actually stimulate that cancer.”
The University of California, San Diego Medical Center in Hillcrest has been named one of “100 Great Hospitals in America” by Becker’s Hospital Review, a publishing group that conducts hospital and healthcare news and analyses, which described the honorees as “some of the most prominent, forward-thinking and focused healthcare facilities in the nation.”
Honored for research leading to new therapies for cancer and wet macular degeneration
Napoleone Ferrara, MD, distinguished professor of pathology at the University of California, San Diego School of Medicine and senior deputy director for basic sciences at UC San Diego Moores Cancer Center, was named today among eight recipients of the Canada Gairdner Awards at a ceremony in Toronto.
The Gairdner awards are among the most esteemed honors in medical research, celebrating outstanding discoveries or contributions to medical and life sciences. This year’s awards showcase achievements in cardiovascular disease, cancer, immunotherapy and human parasitic diseases.
Ferrara was recognized for his work identifying the role of the human VEGF gene in promoting angiogenesis – the formation of new blood vessels that can feed tumor growth – and subsequent development of two major monoclonal antibody drugs: Bevacizumab (marketed as Avastin), which is used to treat multiple forms of cancer, including breast, brain and colorectal, and ranibizumab (marketed as Lucentis), which treats wet age-related macular degeneration, a leading cause of blindness in the elderly.
Other 2014 recipients are James P. Allison, PhD, of the University of Texas MD Anderson Cancer Center for developing immune system-based cancer therapies; Titia de Lange, PhD, of Rockefeller University for her discovery of the mechanisms protecting mammalian telomeres from damage; Sir Marc Feldman, FRS, and Sir Ravinder Nath Maini, FRS, of the University of Oxford for their discovery of a new rheumatoid arthritis treatment; Harold Fisher Dvorak, MD, of Harvard Medical School for his work describing how cancer tumors make VEGF; Satoshi Omura, PhD, of Kitasato University for identifying the causative microorganisms of river blindness and helping develop a successful treatment; and Salim Yusuf, MBBS, of David Braley Research Institute for his extensive epidemiological cardiovascular studies in more than 60 countries.
The Gairdner awards have been presented by the Gairdner Foundation since 1959, and are sometimes a precursor to later Nobel Prizes. Each award comes with a $100,000 stipend in Canadian dollars. The awards will be formally presented at a dinner in Toronto in late October.
In honor of Social Work Month, we would like to thank all social workers who dedicate themselves to improving the quality of life for people with cancer. In this post, Yuko Abbott, LCSW, shares with us the role a social worker plays through a cancer diagnosis.
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Our sister blog highlights the important role social workers can play in helping patients with cancer.
Findings point to potential biomarkers for early detection of at-risk youth
Researchers at the University of California, San Diego School of Medicine have discovered impaired neuronal activity in the parts of the brain associated with anticipatory functioning among occasional 18- to 24-year-old users of stimulant drugs, such as cocaine, amphetamines and prescription drugs such as Adderall.
The brain differences, detected using functional magnetic resonance imaging (fMRI), are believed to represent an internal hard wiring that may make some people more prone to drug addiction later in life.
Among the study’s main implications is the possibility of being able to use brain activity patterns as a means of identifying at-risk youth long before they have any obvious outward signs of addictive behaviors.
The study is published in the March 26 issue of the Journal of Neuroscience.
“If you show me 100 college students and tell me which ones have taken stimulants a dozen times, I can tell you those students’ brains are different,” said Martin Paulus, MD, professor of psychiatry and a co-senior author with Angela Yu, PhD, professor of cognitive science at UC San Diego. “Our study is telling us, it’s not ‘this is your brain on drugs,’ it’s ‘this is the brain that does drugs.’”
In the study, 18- to 24-year-old college students were shown either an X or an O on a screen and instructed to press, as quickly as possible, a left button if an X appeared or a right button if an O appeared. If a tone was heard, they were instructed not to press a button. Each participant’s reaction times and errors were measured for 288 trials, while their brain activity was recorded via fMRI.
Occasional users were characterized as having taken stimulants an average of 12 to 15 times. The “stimulant naïve” control group included students who had never taken stimulants. Both groups were screened for factors, such as alcohol dependency and mental health disorders, that might have confounded the study’s results.
The outcomes from the trials showed that occasional users have slightly faster reaction times, suggesting a tendency toward impulsivity. The most striking difference, however, occurred during the “stop” trials. Here, the occasional users made more mistakes, and their performance worsened, relative to the control group, as the task became harder (i.e., when the tone occurred later in the trial).
The brain images of the occasional users showed consistent patterns of diminished neuronal activity in the parts of the brain associated with anticipatory functioning and updating anticipation based on past trials.
“We used to think that drug addicts just did not hold themselves back but this work suggests that the root of this is an impaired ability to anticipate a situation and to detect trends in when they need to stop,” said Katia Harlé, PhD, a postdoctoral researcher in the Paulus laboratory and the study’s lead author.
The next step will be to examine the degree to which these brain activity patterns are permanent or can be re-calibrated. The researchers said it may be possible to “exercise” weak areas of the brain, where attenuated neuronal activity is associated with higher tendency to addiction.
“Right now there are no treatments for stimulant addiction and the relapse rate is upward of 50 percent,” Paulus said. “Early intervention is our best option.”
Scientists at University of California, San Diego School of Medicine and Sanford-Burnham Medical Research Institute have shown that by encapsulating immature pancreatic cells derived from human embryonic stem cells (hESC), and implanting them under the skin of diabetic mouse models, sufficient insulin is produced to maintain glucose levels without unwanted potential trade-offs of the technology.
The research, published online in Stem Cell Research, suggests that encapsulated hESC-derived insulin-producing cells may be an effective and safe cell replacement therapy for insulin dependent-diabetes.
“Our study critically evaluates some of the potential pitfalls of using stem cells to treat insulin dependent-diabetes,” said Pamela Itkin-Ansari, PhD, assistant project scientist in the UC San Diego Department of Pediatrics and adjunct assistant professor in Development, Aging and Regenerative program at Sanford-Burnham.
“We have shown that encapsulated hESC-derived insulin-producing cells are able to produce insulin in response to elevated glucose without an increase in the mass or their escape from the capsule,” said Itkin-Ansari. “These results are important because it means that the encapsulated cells are both fully functional and retrievable.”
Previous attempts to replace insulin producing cells, called beta cells, have met with significant challenges. For example, researchers have tried treating diabetics with mature beta cells, but because these cells are fragile and scarce, the method is fraught with problems. Moreover, since the cells come from organ donors, they may be recognized as foreign by the recipient’s immune system – requiring patients to take immunosuppressive drugs to prevent their immune system from attacking the donor’s cells, ultimately leaving patients vulnerable to infections, tumors and other adverse events.
Encapsulation technology was developed to protect donor cells from exposure to the immune system – and has proven extremely successful in preclinical studies.
Itkin-Ansari and her research team previously made an important contribution to the encapsulation approach by showing that pancreatic islet progenitor cells are an optimal cell type for encapsulation. They found that progenitor cells were more robust than mature beta cells to encapsulate, and while encapsulated, they matured into insulin-producing cells that secreted insulin only when needed.
In the study, Itkin-Ansari and her team used bioluminescent imaging to determine if encapsulated cells stay in the capsule after implantation.
“We were thrilled to see that the cells remained fully encapsulated for up to 150 days, the longest period tested,” said Itkin-Ansari. “Equally important is that we show that the progenitor cells develop glucose-responsiveness without a significant change in mass – meaning they don’t outgrow their capsule.”
Next steps for the development of the approach will be to figure out the size of the capsule required to house the number of progenitor beta cells needed to respond to glucose in humans.
“And of course we want to learn how long a capsule will function once implanted,” said Itkin-Ansari. “Given these goals and continued successful results, I expect to see the technology become a treatment option for patients with insulin dependent-diabetes.”
Published in the April issue of Gynecologic Oncology, the official publication of the Society of Gynecologic Oncology, the findings indicate obesity may be a modifiable risk factor for endometrial cancer, and bariatric surgery a viable option for eligible patients. They are based on a retrospective cohort study of 7,431,858 patients in the University HealthSystem Consortium database, which contains information from contributing academic medical centers in the United States and affiliated hospitals. Of this total, 103,797 patients had a history of bariatric surgery and 44,345 had a diagnosis of uterine malignancy.
Obesity is a widespread public health problem in the United States, with an estimated two-thirds of the U.S. adult population considered to be overweight or obese. The condition is strongly linked to a host of health risks, among them heart disease, diabetes and cancer, in particular endometrial cancer.
“Estimating from various studies that looked at increasing BMI and endometrial cancer risk, a woman with a Body Mass Index (BMI) of 40 would have approximately eight times greater risk of endometrial cancer than someone with a BMI of 25,” said first author Kristy Ward, MD, the senior gynecologic oncology fellow in the Department of Reproductive Medicine at UC San Diego School of Medicine. “This risk likely continues to go up as BMI goes up.”
Bariatric surgery is often the last resort for obese patients after all other non-surgical weight loss efforts have failed. To qualify, patients must be an acceptable surgical risk and be defined as either severely obese with a BMI of 40 or greater or have a BMI of 35 or greater with at least one related condition: diabetes, obstructive sleep apnea, obesity-related cardiomyopathy or heart muscle disease or severe joint disease.
Typically, bariatric surgery involves reducing the size of the stomach using a constrictive gastric band, removing a portion of the stomach or resecting and re-routing the small intestines to a small stomach pouch. In all cases, the surgery must be followed by lifestyle changes to ensure long-term weight loss success.
A number of biological mechanisms link obesity to endometrial cancer. Excessive adipose or fat tissue, for example, raises circulating levels of estrogen, which is associated with tumor creation and metastasis. Obesity also causes chronic inflammation, boosting insulin resistance and increased estrogen levels.
“The majority of endometrial cancers are estrogen-driven,” said Ward. “In a normal menstruating woman, two hormones control the endometrium (inner lining of the uterus). Estrogen builds up the endometrium and progesterone stabilizes it. A woman with excess adipose tissue has an increased level of estrogen because the fat tissue converts steroid hormones into a form of estrogen.
“So there is too much estrogen, causing the endometrium to build up, but not enough progesterone to stabilize it. The endometrium continues to grow and can undergo changes into abnormal tissue, leading to cancer.”
Bariatric surgery has been shown to reduce the impact of these factors: hormone levels become normal; inflammation decreases; insulin resistance drops; weight loss allows for increased physical activity and improved overall health.
“The obesity epidemic is a complicated problem,” she said. “Further work is needed to define the role of bariatric surgery in cancer care and prevention, but we know that women with endometrial cancer are more likely to die of cardiovascular causes than they are of endometrial cancer. It’s clear that patients who are overweight and obese should be counseled about weight loss, and referral to a bariatric program should be considered in patients who meet criteria.”
A team of scientists from the University of California, San Diego School of Medicine, the Medical University of South Carolina and San Diego-based American Life Science Pharmaceuticals, Inc., report that cathepsin B gene knockout or its reduction by an enzyme inhibitor blocks creation of key neurotoxic pGlu-Aβ peptides linked to Alzheimer’s disease (AD). Moreover, the candidate inhibitor drug has been shown to be safe in humans.
The findings, based on AD mouse models and published online in the Journal of Alzheimer’s Disease, support continued development of cysteine protease inhibitors as a new drug target class for AD. “No other therapeutic program is investigating cysteine protease inhibitors for treating AD,” said collaborator Vivian Hook, PhD, professor in the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and in the UC San Diego School of Medicine.
Current AD drugs treat some symptoms of the devastating neurological disorder, but none actually slow its progress, prevent or cure it. No new AD drug has been approved in more than a decade.
The researchers focused on cathepsin B production of N-truncated pGlu-Aβ, a peptide or short chain of amino acids, and the blockade of cathepsin B by E64d, a compound shown to inhibit cysteine proteases, a type of enzyme. AD is characterized by accumulation of a variety of Aβ peptides as oligomers and amyloid plaques in the brain, factors involved in neuronal loss and memory deficits over time. These neurotoxic Aβ peptides are created when enzymes cleave a large protein called amyloid precursor protein (APP) into smaller Aβ peptides of varying toxicity. N-truncated pGlu-Aβ has been shown to be among the most neurotoxic of multiple forms of Aβ peptides.
Much AD research has focused on the APP-cutting enzyme BACE1 β-secretase, but its role in producing pGlu-Aβ was unknown. Cathepsin B is an alternative β-secretase which cleaves the wild-type β-secretase site of APP, which is expressed in the major sporadic and many familial forms of AD. Hook and colleagues looked at what happened after gene knockout of BACE1 or cathepsin B. They found that cathepsin B, but not BACE1, produced the highly toxic pGlu-Aβ.
Perhaps most interestingly, the scientists found that E64d, an enzyme inhibitor of cathepsin B, reduced production of pGlu-Aβ and other AD-associated Aβ peptides. Key was the finding that E64d and cathepsin B gene knock out resulted in improved memory deficits in a mouse model of AD.
“This is an exciting finding,” said Hook. “It addresses a new target – cathepsin B – and an effective, safe small molecule, E64d, to reduce the pGlu-Aβ that initiates development of the disease’s neurotoxicity. No other work in the field has addressed protease inhibition for reducing pGlu-Aβ of AD.”
Hook noted that E64d has already been shown to be safe in clinical trials of patients with muscular dystrophy and would, therefore, likely prove safe for treating AD as well. She hopes to launch Phase 1 human clinical trials in the near future with a modified version of the drug candidate.
Researchers at the University of California, San Diego School of Medicine have discovered that FDA-approved anti-psychotic drugs possess tumor-killing activity against the most aggressive form of primary brain cancer, glioblastoma. The finding was published in this week’s online edition of Oncotarget.
The team of scientists, led by principal investigator, Clark C. Chen, MD, PhD, vice-chairman, UC San Diego, School of Medicine, division of neurosurgery, used a technology platform called shRNA to test how each gene in the human genome contributed to glioblastoma growth. The discovery that led to the shRNA technology won the Nobel Prize in Physiology/Medicine in 2006.
“ShRNAs are invaluable tools in the study of what genes do. They function like molecular erasers,” said Chen. “We can design these ‘erasers’ against every gene in the human genome. These shRNAs can then be packaged into viruses and introduced into cancer cells. If a gene is required for glioblastoma growth and the shRNA erases the function of that gene, then the cancer cell will either stop growing or die.”
Chen said that one surprising finding is that many genes required for glioblastoma growth are also required for dopamine receptor function. Dopamine is a small molecule that is released by nerve cells and binds to the dopamine receptor in surrounding nerve cells, enabling cell communication.
Abnormal dopamine regulation is associated with Parkinson’s disease, schizophrenia, and Attention Deficit Hyperactivity Disorder. Because of the importance of dopamine in these diseases, drugs have been developed to neutralize the effect of dopamine, called dopamine antagonists.
Following clues unveiled by their shRNA study, Chen and his team tested the effects of dopamine antagonists against glioblastoma and found that these drugs exert significant anti-tumor effects both in cultured cells and mouse models. These effects are synergistic when combined with other anti-glioblastoma drugs in terms of halting tumor growth.
“The anti-glioblastoma effects of these drugs are completely unexpected and were only uncovered because we carried out an unbiased genetic screen,” said Chen.
“On the clinical front, the finding is important for two reasons,” said Bob Carter, MD, PhD, chairman of UC San Diego, School of Medicine, division of neurosurgery. “First, these drugs are already FDA-cleared for human use in the treatment of other diseases, so it is possible these drugs may be re-purposed for glioblastoma treatment, thereby bypassing years of pre-clinical testing. Second, these drugs have been shown to cross the blood-brain barrier, a barrier that prevents more than 90 percent of drugs from entry into the brain.”
Chen is now working with the UC San Diego Moores Cancer Center Neuro-Oncology team to translate his findings into a clinical trial.
UC San Diego researchers say risks are manageable, provided doctors recognize them
In the first study of its type, researchers at the University of California, San Diego School of Medicine have looked at the health threat to pregnant women with a history of Kawasaki disease (KD), concluding that the risks are low with informed management and care.
The findings are published in the March 6, 2014 online edition of the British Journal of Obstetrics and Gynaecology.
KD is a childhood condition affecting the coronary arteries. It is the most common cause of acquired heart disease in children. First recognized in Japan following World War II, KD diagnoses are rising among children in Asia, the United States and Western Europe. Predictive models estimate that by 2020 one in every 1,600 American adults will be affected by KD.
“A growing number of women with a history of KD are reaching child-bearing age, but there is little information available to guide their obstetrical care,” said study author Jane C. Burns, MD, professor and director of the Kawasaki Disease Research Center at UC San Diego and Rady Children’s Hospital-San Diego. “By and large, KD is virtually unknown among working obstetricians.”
KD is currently diagnosed by a constellation of clinical signs, with supporting lab tests that indicate high levels of inflammation. These signs include abrupt onset of high fever, accompanied by four of five criteria, among them: widespread rash, cracked and fissured lips, “strawberry tongue,” bloodshot eyes, lymph node enlargement and red, swollen hands and feet.
Without treatment, 25 percent of children with KD develop coronary artery aneurysms – balloon-like bulges of heart vessels – that may eventually result in heart attacks, congestive heart failure or sudden death. The condition can be treated with a high-dose of intravenous immunoglobulin and aspirin, reducing the risk of aneurysms to 5 percent. The long-term risk for adults with a history of KD in childhood is not known.
Senior study author John Gordon, MD, and colleagues conducted the first KD study of non-Japanese patients, and the first to explore the health risks to women with a history of KD and their offspring. They found that the health risks for mothers with no KD-related coronary artery damage were similar to the general population. For women with aneurysms, the risks were low with appropriate management and care.
“The main message is positive,” said Burns. “Women who have had KD can successfully deliver to term without complications. C-sections are not necessarily indicated if they have aneurysms, they can labor normally, if their overall cardiovascular status is OK.”
There is a genetic component to KD. The study found that two of the 21 children born to the 10 women with a history of KD also developed the disease. “There is clearly an increased risk in offspring,” said Burns, “but the (study) numbers are small so we cannot really calculate a risk until there is a larger population of KD adults who have had children.”