A Better Way to Track Emerging Cell Therapies Using MRIs
Cellular therapeutics – using intact cells to treat and cure disease – is a hugely promising new approach in medicine but it is hindered by the inability of doctors and scientists to effectively track the movements, destination and persistence of these cells in patients without resorting to invasive procedures, like tissue sampling.
In a paper published September 17 in the online journal Magnetic Resonance in Medicine, researchers at the University of California, San Diego School of Medicine, University of Pittsburgh and elsewhere describe the first human tests of using a perfluorocarbon (PFC) tracer in combination with non-invasive magnetic resonance imaging (MRI) to track therapeutic immune cells injected into patients with colorectal cancer.
“Initially, we see this technique used for clinical trials that involve tests of new cell therapies,” said first author Eric T. Ahrens, PhD, professor in the Department of Radiology at UC San Diego. “Clinical development of cell therapies can be accelerated by providing feedback regarding cell motility, optimal delivery routes, individual therapeutic doses and engraftment success.”
Currently, there is no accepted way to image cells in the human body that covers a broad range of cell types and diseases. Earlier techniques have used metal ion-based vascular MRI contrast agents and radioisotopes. The former have proven difficult to differentiate in vivo; the latter raise concerns about radiation toxicity and do not provide the anatomical detail available with MRIs.
“This is the first human PFC cell tracking agent, which is a new way to do MRI cell tracking,” said Ahrens. “It’s the first example of a clinical MRI agent designed specifically for cell tracking.”
Researchers used a PFC tracer agent and an MRI technique that directly detects fluorine atoms in labeled cells. Fluorine atoms naturally occur in extremely low concentrations in the body, making it easier to observe cells labeled with fluorine using MRI. In this case, the modified and labeled dendritic cells – potent stimulators of the immune system – were first prepared from white blood cells extracted from the patient. The cells were then injected into patients with stage 4 metastatic colorectal cancer to stimulate an anti-cancer T-cell immune response.
The published study did not assess the efficacy of the cell therapy, but rather the ability of researchers to detect the labeled cells and monitor what happened to them. Ahrens said the technique worked as expected, with the surprising finding that only half of the delivered cell vaccine remained at the inoculation site after 24 hours.
“The imaging agent technology has been to shown to be able to tag any cell type that is of interest,” Ahrens said. “It is a platform imaging technology for a wide range of diseases and applications,” which might also speed development of relevant therapies.
“Non-invasive cell tracking may help lower regulatory barriers,” Ahrens explained. “For example, new stem cell therapies can be slow to obtain regulatory approvals in part because it is difficult, if not impossible, with current approaches to verify survival and location of transplanted cells. And cell therapy trials generally have a high cost per patient. Tools that allow the investigator to gain a ‘richer’ data set from individual patients mean it may be possible to reduce patient numbers enrolled in a trial, thus reducing total trial cost.”
Pictured: Artistic rendering of surface of human dendritic cell. Image courtesy of Sriram Subramaniam, National Cancer Institute.
Not Skipping a Beat: Sulpizio Cardiovascular Center Again Among Nation’s Best -
Becker’s Hospital Review Names SCVC among “100 Hospitals with Great Heart Programs”
UC San Diego Sulpizio Cardiovascular Center (SCVC) has been named among “100 Hospitals with Great Heart Programs” by Becker’s Hospital Review, a business and legal news publication for hospital and health system leadership.
According to Becker’s editorial team, the hospitals chosen for this list lead the nation in cardiovascular and thoracic healthcare, have pioneered groundbreaking procedures and have received top recognition for the highest quality of patient care.
“Since the doors opened in 2011, SCVC has become nationally recognized for the comprehensive and extraordinary care provided to patients. The facility combines all heart and vascular-related programs, research and technology under one roof,” said Paul Viviano, CEO, UC San Diego Health System. “It is an honor for the cardiovascular team to be recognized for its tireless dedication to superb clinical care and delivery of life-saving therapies every day.”
Read more here
Scientists Discover “Dimmer Switch” For Mood Disorders
Researchers at University of California, San Diego School of Medicine have identified a control mechanism for an area of the brain that processes sensory and emotive information that humans experience as “disappointment.”
The discovery of what may effectively be a neurochemical antidote for feeling let-down is reported Sept. 18 in the online edition of Science.
“The idea that some people see the world as a glass half empty has a chemical basis in the brain,” said senior author Roberto Malinow, MD, PhD, professor in the Department of Neurosciences and neurobiology section of the Division of Biological Sciences. “What we have found is a process that may dampen the brain’s sensitivity to negative life events.”
Because people struggling with depression are believed to register negative experiences more strongly than others, the study’s findings have implications for understanding not just why some people have a brain chemistry that predisposes them to depression but also how to treat it.
Specifically, in experiments with rodents, UC San Diego researchers discovered that neurons feeding into a small region above the thalamus known as the lateral habenula (LHb) secrete both a common excitatory neurotransmitter, glutamate, and its opposite, the inhibitory neurotransmitter GABA.
Excitatory neurotransmitters promote neuronal firing while inhibitory ones suppress it, and although glutamate and GABA are among two of the most common neurotransmitters in the mammalian brain, neurons are usually specialists, producing one but not both kinds of chemical messengers.
Indeed, prior to the study, there were only two other systems in the brain where neurons had been observed to co-release excitatory and inhibitory neurotransmitters – in a particular connection in the hippocampus and in the brainstem during development of the brain’s auditory map.
“Our study is one of the first to rigorously document that inhibition can co-exist with excitation in a brain pathway,” said lead author Steven Shabel, a postdoctoral researcher with Department of Neurosciences and neurobiology section of the Division of Biological Sciences. “In our case, that pathway is believed to signal disappointment.”
The LHb is a small node-like structure in the epithalamus region of the brain that is critical for processing a variety of inputs from the basal ganglia, hypothalamus and cerebral cortex and transmitting encoded responses (output) to the brainstem, an ancient part of the brain that mammals share with reptiles.
Experiments with primates have shown that activity in the LHb increases markedly when monkeys are expecting but don’t get a sip of fruit juice or other reward, hence the idea that this region is part of a so-called disappointment pathway.
Proper functioning of the LHb, however, is believed to be important in much more than just disappointment and has been implicated in regulating pain responses and a variety of motivational behaviors. It has also been linked to psychosis.
Depression, in particular, has been linked to hyperactivity of the LHb, but until this study, researchers had little empirical evidence as to how this overstimulation is prevented in healthy individuals given the apparent lack of inhibitory neurons in this region of the brain.
"The take-home of this study is that inhibition in this pathway is coming from an unusual co-release of neurotransmitters into the habenula," Shabel said. Researchers do not know why this region of the brain is controlled in this manner, but one hypothesis is that it allows for a more subtle control of signaling than having two neurons directly counter-acting each other.
Researchers were also able to show that neurons of rodents with aspects of human depression produced less GABA, relative to glutamate. When these animals were given an antidepressant to raise their brain’s serotonin levels, their relative GABA levels increased.
"Our study suggests that one of the ways in which serotonin alleviates depression is by rebalancing the brain’s processing of negative life events vis-à-vis the balance of glutamate and GABA in the habenula," Shabel said. "We may now have a precise neurochemical explanation for why antidepressants make some people more resilient to negative experiences."
Pictured: Basal ganglia neurons (green) feed into the brain and release glutamate (red) and GABA (blue) and sometimes a mix of both neurotransmitters (white).
Novel Drug Targeting Leukemia Cells Enters Clinical Trial -
Researchers at the University of California, San Diego School of Medicine have launched a phase 1 human clinical trial to assess the safety and efficacy of a new monoclonal antibody for patients with chronic lymphocytic leukemia (CLL), the most common form of blood cancer in adults.
The new antibody targets ROR1, a protein used by embryonic cells during early development and exploited by cancer cells to promote tumor growth and metastasis, the latter responsible for 90 percent of all cancer-related deaths.
Because ROR1 is not expressed by normal adult cells, scientists believe it is a biomarker of cancer cells in general and cancer stem cells in particular. Because it appears to drive tumor growth and disease spread, they believe it also presents an excellent target for anti-cancer therapy.
Developed at UC San Diego Moores Cancer Center by Thomas Kipps, MD, PhD, who holds the Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues, the antibody is called cirmtuzumab (also known as UC-961). In previous animal studies, Kipps’ team reported that ROR1 is singularly expressed on CLL and also on a variety of different cancers, including cancers of the breast, pancreas, colon, lung and ovary. In mouse models of CLL, ROR1 acts as an accelerant when combined with another oncogene to produce a faster-growing, more aggressive cancer.
Cirmtuzumab was developed under the auspices of the California Institute for Regenerative Medicine’s HALT leukemia grant awarded to Dennis Carson, MD, principal investigator, and Catriona Jamieson, MD, PhD, co-principal investigator to develop six distinct therapies against cancer stem cells. Kipps led one of the six projects and generated antibodies against ROR1, leading to the cirmtuzumab trial in patients with CLL.
“The primary goal of this phase I clinical trial is to evaluate whether cirmtuzumab is a safe and well-tolerated cancer stem cell-targeted agent in patients with CLL,” said Jamieson, chief of the Division of Regenerative Medicine, associate professor of medicine, director of stem cell research at UC San Diego Moores Cancer Center, deputy director of the Sanford Stem Cell Clinical Center and a principal investigator of the cirmtuzumab clinical trial.
Michael Choi, MD, assistant clinical professor of medicine and co-principal investigator of the clinical trial said, “The trial will involve patients with relapsed or refractory CLL, who will receive an intravenous infusion every 14 days at Moores, followed by regular monitoring and clinic visits to assess efficacy and identify and manage any adverse effects. Initial treatment is planned for two months.”
To learn more about eligibility for this clinical trial, call Reilly L. Kidwell at 858-534-4801 or Samuel Zhang at 858-534-8127.
The current, on-going Ebola crisis is just the latest reminder that we live in a world dominated by microbes, many of them harmful to our health and lives.
The Ebola virus is indisputably frightening, with outbreaks that have a case fatality rate of up to 90 percent. Fortunately, its mode of transmission appears limited: Close contact with the blood, secretions, organs and other bodily fluids of infected animals. So far, its spread has been limited to defined regions of Africa where healthcare services and disease prevention efforts have proved minimal to non-existent.
For the time being, at least, Ebola seems a bit exotic. But there are plenty of menacing microbes closer at hand. They may not possess the same nasty ability to kill but they are often easier to transmit and more prone to infect.
Among them is Escherichia coli, more commonly called E. coli. It is an abundant bacterium. Most strains, which reside in the lower intestine of warm-blooded organisms (including humans) are harmless, but some strains are not. When the latter taint foods, perhaps through unseen and unknown fecal contamination, the result can be severe food poisoning or worse.
E. coli outbreaks are not uncommon. They can – and do – kill too.
That’s worth remembering, along with these rules.
Pictured: Electron micrograph of E. coli bacteria courtesy of Thomas Deerinck, National Center for Microscopy and Imaging Research at UC San Diego.
Cancer and the Immune System: A Double-Edged Sword -
Cell surface sugars can promote or inhibit cancer depending upon stage
During cancer development, tumor cells decorate their surfaces with sugar compounds called glycans that are different from those found on normal, healthy cells. In the Sept. 15 online Early Edition of the Proceedings of the National Academy of Sciences (PNAS), researchers at the University of California, San Diego School of Medicine report that sialic acids at the tips of these cancer cell glycans are capable of engaging with immune system cells and changing the latter’s response to the tumor – for good and bad.
“These cell surface glycans can promote or inhibit cancer progression, depending upon the stage of the disease,” said principal investigator Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine. “Our findings underscore the complexity of cancer and the consequent challenges in conquering it. The immune system may be a double-edged sword in cancer, tumor-promoting or tumor-inhibiting, depending upon circumstances.”
Specifically, the researchers found that receptors called siglecs on subsets of neutrophils and macrophages (two types of immune cell) can bind to sialic acids on the surface of tumor cells. Depending upon the stage of cancer and the tumor model used, the scientists reported that interaction between immune cell siglecs and tumor cell sialic acids produced opposite outcomes.
“During initial stages of growth, cancer cells appear to protect themselves from extermination by neutrophils by engaging siglecs via sialic acid-capped glycans,” said Varki, who is also a faculty member of the UC San Diego Moores Cancer Center. “But once the tumor was established, further growth was inhibited by engagement of siglecs on macrophages.”
The findings follow upon research by Varki and colleagues published earlier this year in PNAS that showed anti-tumor antibodies also behave contrarily. Low concentrations of antibodies can support cancer growth, but higher concentrations may inhibit it.
“The fact that the immune system can exert a promoting or inhibiting effect on cancer progression, depending on the situation and stage of disease, has importance for designing clinical trials with drugs that target the immune system,” said first author Heinz Läubli, MD, PhD.
For example, siglecs might prove viable drug targets for preventing early cancer progression. Study co-author Ann Schwartz, PhD, MPH, of the Karmanos Cancer Institute at Wayne State University School of Medicine in Detroit investigated 332 patients with lung cancer to assess whether they had a natural siglec variant that reduced binding to tumor cell surface sialic acids. Such patients have a greater chance for survival after two years, but the effect diminishes and disappears later.
“We need more studies to understand the mechanisms in siglecs mediating the switch between tumor-promoting and tumor-inhibiting before possible therapies can be developed,” Varki said.
In Rats and Men, Nicotine Withdrawal Casts Similar Pall
Reduced reward response in brains helps explain why it’s so hard to quit smoking
Efforts to quit smoking tend to end in failure. Almost half of smokers attempt to quit each year, but only 4 to 7 percent succeed on any given attempt without medicines or assistance, according to the American Cancer Society, and less than 25 percent of smokers who use medicines remain smoke-free for more than six months. Relapse is especially common within 48 hours of quitting when nicotine withdrawal symptoms are most acute.
In a set of novel experiments involving both humans and rats, researchers at the University of California, San Diego School of Medicine, Florida Atlantic University (FAU), University of Pittsburgh, Washington University and Harvard Medical School report that the brain’s response to reward – its ability to recognize and derive pleasure from natural stimuli such as food, money or sex – is measurably reduced after nicotine withdrawal.
The findings, published this week online in JAMA Psychiatry, suggest that nicotine withdrawal significantly impacts the ability to modulate behavioral choices based on the expectancy of reward. This deficit is seen often in people who suffer from depression.
“What we saw in both humans and rats was decreased responsiveness to reward,” said Athina Markou, PhD, professor and vice-chair of research in the Department of Psychiatry at UC San Diego. “During acute nicotine withdrawal, both people and animals attended less to positive rewards. That’s a hallmark of depression. And there is evidence that people who already express depressive symptoms and quit smoking are more likely to become clinically depressed and stay that way. These findings have an obvious bearing on how we approach cessation treatment.”
The study authors say the breadth of the findings involving similar results in two different species offer a strong translational framework for future studies that will allow development of clinical treatments focusing on reward responsiveness during early nicotine withdrawal.
“The fact that the effect was similar across species using this translational task not only provides us with a ready framework to proceed with additional research to better understand the mechanisms underlying withdrawal of nicotine, and potentially new treatment development, but it also makes us feel more confident that we are actually studying the same behavior in humans and rats as the studies move forward,” said Michele Pergadia, PhD, associate professor of clinical biomedical science in the Charles E. Schmidt College of Medicine at FAU.
The experiments reported in JAMA Psychiatry assessed reward responsiveness based upon the propensity to modulate behavior according to prior experience. In human testing, conducted at Washington University, participants were asked to repeat a computer task, with “correct” responses earning a modest financial reward. In testing at UC San Diego, rats were trained to press a lever upon hearing a specific tone to earn a food reward.
Results were similar. Human participants who were smokers but who had abstained from smoking for 24 hours prior to testing and rats chronically exposed to nicotine but deprived for 24 hours also prior to testing both performed less effectively than non-smokers and rats with no nicotine experience. That is, both humans and rats withdrawing from nicotine failed to display a bias toward maximizing their rewards.
Markou’s team, which included co-authors Andre Der-Avakian, PhD, and Manoranjan D’Souza, MD, PhD, subsequently re-exposed rats to nicotine and re-tested them. This time, the animals showed a heightened reward response, stronger than before.
“This finding indicates that after the initial withdrawal, if a relapse occurs, it will produce a more pleasurable effect. That’s why smokers who have a single cigarette after quitting often find it triggers a full relapse and they’re soon back to smoking as much as before.”
Markou and Pergadia say the findings open up two avenues of future research: Studying the neurobiology of the reward response phenomenon to pinpoint where in the brain it occurs and which circuits or neurons are involved; and assessing potential medications on rats during reward response testing. Promising drugs, if approved by the FDA for human administration, could then be tested on humans in similar experiments – an approach that could provide both new insights and speed the drug development process.
Scientists Discover Neurochemical Imbalance in Schizophrenia
Using human induced pluripotent stem cells (hiPSCs), researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California, San Diego have discovered that neurons from patients with schizophrenia secrete higher amounts of three neurotransmitters broadly implicated in a range of psychiatric disorders.
The findings, reported online Sept. 11 in Stem Cell Reports, represent an important step toward understanding the chemical basis for schizophrenia, a chronic, severe and disabling brain disorder that affects an estimated one in 100 persons at some point in their lives. Currently, schizophrenia has no known definitive cause or cure and leaves no tell-tale physical marks in brain tissue.
"The study provides new insights into neurotransmitter mechanisms in schizophrenia that can lead to new drug targets and therapeutics,” said senior author Vivian Hook, PhD, a professor with Skaggs School of Pharmacy and UC San Diego School of Medicine.
In the study, UC San Diego researchers with colleagues at The Salk Institute for Biological Studies and the Icahn School of Medicine at Mount Sinai, N.Y., created functioning neurons derived from hiPSCs, themselves reprogrammed from skin cells of schizophrenia patients. The approach allowed scientists to observe and stimulate human neurons in ways impossible in animal models or human subjects.
Researchers activated these neurons so that they would secrete neurotransmitters – chemicals that excite or inhibit the transmission of electrical signals through the brain. The process was replicated on stem cell lines from healthy adults.
A comparison of neurotransmitters produced by the cultured “brain in a dish” neurons showed that the neurons derived from schizophrenia patients secreted significantly greater amounts of the catecholamine neurotransmitters dopamine, norepinephrine and epinephrine.
Catecholamine neurotransmitters are synthesized from the amino acid tyrosine and the regulation of these neurotransmitters is known to be altered in a variety of psychiatric diseases. Several psychotropic drugs selectively target the activity of these neurotransmitters in the brain.
In addition to documenting aberrant neurotransmitter secretion from neurons derived from patients with schizophrenia, researchers also observed that more neurons were dedicated to the production of tyrosine hydroxylase, the first enzyme in the biosynthetic pathway for the synthesis of dopamine, from which both norepinephrine and epinephrine are made.
This discovery is significant because it offers a reason for why schizophrenia patients have altered catecholamine neurotransmitter levels: They are preprogrammed to have more of the neurons that make these neurotransmitters.
“All behavior has a neurochemical basis in the brain,” Hook said. “This study shows that it is possible to look at precise chemical changes in neurons of people with schizophrenia.”
The applications for future treatments include being able to evaluate the severity of an individual’s disease, identify different sub-types of the disease and pre-screen patients for drugs that would be most likely to help them. It also offers a way to test the efficacy of new drugs.
“It is very powerful to be able to see differences in neurons derived from individual patients and a big accomplishment in the field to develop a method that allows this,” Hook said.
Pictured: Enzymes that biosynthesize the neurotransmitters dopamine (left), norepinephrine (center) and epinephrine (right).
Ferrara Receives Champalimaud Award for Role in Eye Disease Therapy -
Napoleone Ferrara, MD, Distinguished Professor of Pathology and Distinguished Adjunct Professor of Ophthalmology 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 as one of seven recipients of the António Champalimaud Vision Award in Lisbon, Portugal.
Autism Early Detection Program Expands -
Developed at UC San Diego, effort seeks to identify at-risk toddlers by first birthday
Autism spectrum disorder (ASD) is now estimated to impact one in every 68 children born in the United States. Yet despite its rising prevalence and the known benefits of early detection and treatment, toddlers in much of the United States are routinely not identified as possibly having ASD until well after their third birthday.
“By that time, much precious brain development has already occurred,” said Karen Pierce, PhD, associate professor of neurosciences at the University of California, San Diego School of Medicine and assistant director of the UC San Diego Autism Center of Excellence.
A new 5-year, $5.1 million grant from the National Institute of Mental Health (NIMH) seeks to remedy that by expanding a program developed by Pierce and colleagues to reduce the mean age of ASD diagnosis in multiple cities across the U.S.
The program, called Get SET Early, is based upon a one-year well-baby check that Pierce first described in a paper published in 2011. In those findings, Pierce and colleagues reported that San Diego toddlers who were systematically assessed for ASD around their first birthday typically began receiving treatment within a few months, years before children in many other cities.
With NIMH funding, the Get SET Early program expands upon Pierce’s original model, adding new features and technologies, such as an iPad-based automatic referral system.
The improved model consists of three stages: In the Screening stage, a network of pediatricians conduct repeat evaluations of toddlers at multiple ages – 12, 18 and 24 months – using standardized testing and scoring. “Since the symptoms of autism can come on slowly between 12 and 24 months, if we screen three times we are almost guaranteed to detect the overwhelming majority of children with this disorder,” Pierce said.
In the second Evaluation stage, toddlers who may have ASD are immediately referred to local clinics that specialize in ASD for more detailed evaluation.
In the final stage, Treatment, toddlers showing clear signs of ASD are referred to an established network of healthcare specialists for rapid treatment. “There is evidence that early therapy can have a positive impact on the developing brain,” Pierce said. “The opportunity to diagnose and thus begin treatment for autism around a child’s first birthday has enormous potential to change outcomes for children affected with the disorder.”
The Get SET Early program will expand first to Phoenix, which has one of the oldest average ages of ASD detection in the country. A recent survey conducted by the U.S. Centers for Disease Control found that children with autism living in Phoenix were typically not identified until they were almost five years old.
In her 2011 study, published in the Journal of Pediatrics, Pierce and colleagues created a network of 137 pediatricians in the San Diego region and asked them to include a brief assessment at the toddlers’ traditional one-year health checkup. The assessment consisted of parents or caregivers answering a questionnaire called the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist that queried about a child’s use of eye contact, sounds, words, gestures, object recognition and other forms of age-appropriate communication. Any infant who failed the screening was referred to the UC San Diego Autism Center of Excellence for further testing and re-evaluation every six months until age three.
While the NIMH grant will initially test the feasibility of establishing the Get SET Early model in Phoenix, research and testing will also continue in San Diego to assess the efficacy of new improvements, such as repeat triple screenings and Internet-based tracking of referrals and treatment.
“By creating a simple screening, evaluation and treatment initiation and tracking model, we hope to establish national standards so that one day ASD detection and treatment between the first and second birthday will happen for all children,” said Pierce.