#uc san diego
Neuroimaging study reveals potential brain mechanism underlying chronic neuropathic pain in individuals with HIV
As medical advances help individuals with HIV survive longer, there is an increasing need to treat their chronic symptoms. One of the most common is neuropathic pain, or pain caused by damage to the nervous system.
Distal sensory polyneuropathy (DSP) is the most prevalent neurological problem in HIV infection, affecting 50 percent of all HIV patients. Most persons with DSP describe sensations of numbness, tingling, burning and stinging in their hands or feet, which impair daily functioning and can lead to unemployment and depression.
Previous research on DSP has mostly focused on the peripheral nervous system, but nerve injury cannot fully explain the wide variability in DSP symptoms. Researchers at University of California San Diego School of Medicine and University of California San Francisco instead looked at the brain to see how it may be contributing to patients’ pain.
In a new study, published online October 29, 2021 in Brain Communications, the team observed unique patterns of brain activity in HIV-DSP patients when they experienced a painful stimulus. Compared to other patients with HIV, those with DSP showed increased activity in the anterior insula, a brain area involved in predicting and emotionally processing pain.
“The anterior insula is trying to predict the future for you,” said senior author Alan Simmons, PhD, professor of psychiatry at UC San Diego School of Medicine and research scientist at the Veterans Affairs San Diego Healthcare System. “It’s forming expectations about what is about to happen to you and how you’re going to feel. These expectations of pain play an important role in determining how much pain you then actually experience.”
Pictured: HIV patients with and without chronic neuropathic pain received short or long heat stimuli on their hands (control site) or feet (neuropathic site).
“Not So Great Expectations: Pain in HIV Related to Brain’s Expectations of Relief”
[The] UC San Diego-led team will receive a $9 million grant from the Aligning Science Across Parkinson’s (ASAP) initiative to help advance this research and position it for the next phases of drug development. ASAP is a coordinated research initiative to advance targeted basic research for Parkinson’s disease. Its mission is to accelerate the pace of discovery and inform the path to a cure through collaboration, research-enabling resources and data-sharing. The Michael J. Fox Foundation for Parkinson’s Research is the implementation partner for ASAP and issuer of the grant, which contributes to the Campaign for UC San Diego.
“This grant is supporting some of the most incredible progress being made in the Parkinson’s sphere. It’s a game-changing strategy that we hope will improve how Parkinson’s is treated,” said David Brenner, MD, vice chancellor of Health Sciences. “We are grateful to ASAP for making these advancements possible.”
Discovery of new metabolic pathway for stored sugars helps explain how cellular energy is produced and expended in obesity, advancing therapeutic potential
Humans carry around with them, often abundantly so, at least two kinds of fat tissue: white and brown. White fat cells are essentially inert containers for energy stored in the form of a single large, oily droplet. Brown fat cells are more complex, containing multiple, smaller droplets intermixed with dark-colored mitochondria — cellular organelles that give them their color and are the “engines” that convert the lipid droplets into heat and energy.
Some people also have “beige” fat cells, brown-like cells residing within white fat that can be activated to burn energy.
In recent years, there has been much effort to find ways to increase brown or beige fat cell activity, to induce fat cells, known as adipocytes, to burn energy and generate heat in a process called thermogenesis as a means to treat obesity, type 2 diabetes and other conditions.
But the therapeutic potential of brown fat — and perhaps beige fat cells —has been stymied by the complexity of the processes involved. It wasn’t until 2009 that the existence of active brown fat cells in healthy adults was confirmed; previously it was believed they were common only in newborns.
In a new study, published online October 27, 2021 in Nature, an international team of researchers led by senior author Alan Saltiel, PhD, director of the Institute for Diabetes and Metabolic Health at University of California San Diego School of Medicine, describe how energy expenditure and heat production are regulated in obesity through a previously unknown cellular pathway.
Image: Artistic rendering of a brown fat cell with nucleus in pink, mitochondria in purple and yellow lipid droplets scattered throughout. Image courtesy of Scientific Animations.
“Sweet! How Glycogen is Linked to Heat Generation in Fat Cells”
Researchers look at the use of intravenous immunoglobulin for treatment of Kawasaki disease and multisystem inflammatory syndrome in children, a rare reaction to SARS-CoV-2
Kawasaki disease (KD) is rare, with fewer than 6,000 diagnosed cases per year in the United States. It is most common in infants and young children and causes inflammation in the walls of some blood vessels in the body. KD is a common cause of acquired heart disease in children around the world, causing coronary artery aneurysms in a quarter of untreated children.
Multisystem inflammatory syndrome in children (MIS-C) is also rare, a life-threatening illness that follows exposure to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). MIS-C is characterized by the acute onset of fever and variable symptoms, including rash, cardiovascular complications, shock and gastrointestinal symptoms, including abdominal pain, diarrhea and vomiting.
KD and MIS-C share several clinical features and immune responses. Both conditions are treated with intravenous immunoglobulin (IVIG), a therapeutic containing antibodies purified from blood products. Antibodies in the blood protect us from a number of viral, bacterial and fungal pathogens, but when administered as IVIG, can also suppress excessive inflammation. How it does this is an ongoing area of research worldwide.
In a pair of new studies, published online October 26 and August 31, 2021, two collaborating teams of researchers at University of California San Diego School of Medicine examined the use of IVIG in two groups; one group used a second dose of IVIG in children with KD who do not respond to the first dose of the drug, and the other group used IVIG as an effective treatment for MIS-C.
“Our research teams looked further into KD to improve treatment, and then used what we know about that disease to advance science in another illness,” said senior author Jane C. Burns, MD, professor and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego.
“Same Treatment Tested for Kids with Kawasaki Disease and Rare COVID-19 Reaction”
A stained histological slide, magnified 100 times, depicts cancer cells expansively spread through normal breast tissues, including a duct completely filled with tumor cells. Credit: Dr. Cecil Fox, National Cancer Institute
Researchers describe how malignancies leverage evolution and basic cellular functions to promote immune dysfunction and a better future for themselves
Writing in EMBO reports, researchers at University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health describe how a pair of fundamental genetic and cellular processes are exploited by cancer cells to promote tumor survival and growth.
Cancer is driven by multiple types of genetic alterations, including DNA mutations and copy number alterations ranging in scale from small insertions and deletions to whole genome duplication events.
Collectively, somatic copy number alterations in tumors frequently result in an abnormal number of chromosomes, termed aneuploidy, which has been shown to promote tumor development by increasing genetic diversity, instability and evolution. Approximately 90 percent of solid tumors and half of blood cancers present some form of aneuploidy, which is associated with tumor progression and poor prognoses.
In recent years, it has become apparent that cells cohabiting within a tumor microenvironment are subject not only to external stressors (mainly of metabolic origin, such as lack of nutrients), but also to the internal stressor aneuploidy. Both activate a stress response mechanism called the unfolded protein response (UPR), which leads to an accumulation of misfolded proteins in the endoplasmic reticulum (ER) of cells — an organelle that synthesizes proteins and transports them outside the cell.
When this primary transport/export system is disrupted, UPR attempts to restore normal function by halting the accumulation of misfolded proteins, degrading and removing them and activating signaling pathways to promote proper protein folding.
If homeostasis or equilibrium is not re-established quickly, non-tumor cells undergo cell death. Conversely, cancer cells thrive in this chaos, establishing a higher tolerance threshold that favors their survival.
“In these circumstances, they also co-opt neighboring cells in a spiral of deceit that progressively impairs local immune cells,” said co-senior author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and a tumor immunologist at Moores Cancer Center with Hannah Carter, PhD, associate professor of medicine and a computational biologist. Zanetti had previously introduced the hypothesis in a Sciencecommentary.
The researchers hypothesized that aneuploidy, UPR and immune cell dysregulation could be linked together in a deadly triangle. In the new study, Zanetti, Carter and colleagues analyzed 9,375 human tumor samples and found that cancer cell aneuploidy intersects preferentially with certain branches of the signaling response to stress and that this finding correlates with the damaging effects of aneuploidy on T lymphocytes, a type of immune cell.
“This was an ambitious goal not attempted before,” said Zanetti. “It was like interrogating three chief systems together — chromosomal abnormalities in toto, signaling mechanisms in response to endogenous stress and dysregulation of neighboring immune cells — just to prove a bold hypothesis.
“We knew the task would be challenging,” added Carter, “and that we would need to create and refine new analytical tools to test our hypotheses in heterogeneous human tumor data, but it was a worthwhile risk to take.”
The findings, they said, show that the stress response in cancer cells serves as an unpredicted link between aneuploidy and immune cells to “diminish immune competence and anti-tumor effects.” It also demonstrates that molecules released by aneuploid cells affect another type of immune cells — macrophages — by subverting their normal function to turn them into tumor-promoting actors.
“Tumor Reasons Why Cancers Thrive in Chromosomal Chaos”
A new trial by UC San Diego Health infectious disease specialist Maile Young Karris, MD, will use longitudinal questionnaires and qualitative interviews to assess the impact of living in an interconnected virtual village on the loneliness known to afflict older people with HIV.
“It’s about changing the culture back to how it used to be,” Karris said, “where neighbors actually knew each other and helped each other and you didn’t have to worry so much about your poor dad who lives by himself, far away from you, because you knew that his neighbors would call you if anything happened or would make sure that he was eating.”
Electroconvulsive therapy has long been used to treat severe, persistent depression, but not without unwelcome side effects; researchers looked at whether magnets might be better over the long-term
Treatment-resistant depression or TRD is exactly what it sounds like: a form of mental illness that defies effective therapy. It is not rare, with an estimated 3 million persons in the United States suffering from TRD.
In a novel study, published in the October 19, 2021 online issue of The Journal of Clinical Psychiatry, an international team of scientists led by senior author Zafiris J. Daskalakis, MD, PhD, professor of psychiatry and chair of the Department of Psychiatry at University of San Diego School of Medicine, investigated whether continued magnetic seizure therapy (MST) might effectively prevent the relapse of TRD, particularly in comparison to what is known about electroconvulsive therapy (ECT), the current standard of care but a method with mixed results and a controversial history.
ECT often works when other treatments are unsuccessful, but it does not work for everyone, and some side effects may still occur, such as confusion and memory loss. These concerns, and a lingering public stigma, have limited its widespread use.
MST is a different form of electrical brain stimulation, debuting in the late-1990s. It induces a seizure in the brain by delivering high intensity magnetic field impulses through a magnetic coil. Stimulation can be tightly focused to a region of the brain, with minimal effect on surrounding tissues and fewer cognitive side effects. Like ECT, MST is being studied for treating depression, psychosis and obsessive-compulsive disorder.
An international team researchers, including University of California San Diego School of Medicine, has broadened and deepened understanding of how inherited retinal dystrophies (IRDs) affect different populations of people and, in the process, have identified new gene variants that may cause the diseases.
Researchers identify a bacteria on healthy cats that produces antibiotics against severe skin infections; the findings may lead to new bacteriotherapies for humans and their pets
Researchers at University of California San Diego School of Medicine used bacteria found on healthy cats to successfully treat a skin infection on mice. These bacteria may serve as the basis for new therapeutics against severe skin infections in humans, dogs and cats.
The study, published in eLife on October 19, 2021, was led by Richard L. Gallo, MD, PhD, Distinguished Professor and chair of the Department of Dermatology at UC San Diego School of Medicine, whose team specializes in using bacteria and their products to treat illnesses — an approach known as “bacteriotherapy.”
Skin is colonized by hundreds of bacterial species that play important roles in skin health, immunity and fighting infection. All species need to maintain a diverse balance of healthy skin bacteria to fight potential pathogens.
“Our health absolutely depends on these ‘good’ bacteria,” said Gallo. “They rely on our healthy skin to live, and in return some of them protect us from ‘bad’ bacteria. But if we get sick, ‘bad’ bacteria can take advantage of our weakened defenses and cause infection.”
This is the case with methicillin-resistant Staphylococcus pseudintermedius (MRSP), a bacterium commonly found on domesticated animals that becomes infectious when the animals are sick or injured. MRSP is an emerging pathogen that can jump between species and cause severe atopic dermatitis, or eczema. These infections are common in dogs and cats, and can also occur in humans, though rates of human infection vary around the world. As its name suggests, MRSP is resistant to common antibiotics and has been difficult to treat in clinical and veterinary settings.
To address this, researchers first screened a library of bacteria that normally live on dogs and cats and grew them in the presence of MRSP. From this, they identified a strain of cat bacteria called Staphylococcus felis(S. felis) that was especially good at inhibiting MRSP growth. They found that this special strain of S. felis naturally produces multiple antibiotics that kill MRSP by disrupting its cell wall and increasing the production of toxic free radicals.
“The potency of this species is extreme,” said Gallo. “It is strongly capable of killing pathogens, in part because it attacks them from many sides — a strategy known as ‘polypharmacy.’ This makes it particularly attractive as a therapeutic.”
Bacteria can easily develop resistance to a single antibiotic. To get around this, S. felis has four genes that code for four distinct antimicrobial peptides. Each of these antibiotics is capable of killing MRSP on their own, but by working together, they make it more difficult for the bacteria to fight back.
Having established how S. felis kills the MRSP, the next step was to see whether it could work as a therapy on a live animal. The team exposed mice to the most common form of the pathogen and then added either S. felis bacteria or bacterial extract to the same site. The skin showed a reduction in scaling and redness after either treatment, compared with animals that had no treatment. There were also fewer viable MRSP bacteria left on the skin after treatment with S. felis.
Next steps include plans for a clinical trial to confirm whether S. felis can be used to treat MRSP infections in dogs. Bacteriotherapies like this one can be delivered via topical sprays, creams or gels that contain either live bacteria or purified extract of the antimicrobial peptides.
Pictured above: To identify candidates for a new bacteriotherapy against skin infection, researchers first screened various bacteria from dogs and cats and co-cultured them with S. pseudintermedius in liquid and agar antimicrobial assays.
“Cat Bacteria Treats Mouse Skin Infection, May Help You and Your Pets As Well”
Left: JoAnn Trejo, PhD, is professor in the Department of Pharmacology at UC San Diego School of Medicine and assistant vice chancellor for UC San Diego Health Sciences Faculty Affairs. Right: Elizabeth Winzeler, PhD, is professor in the Division of Host Microbe Systems and Therapeutics in the Department of Pediatrics at UC San Diego School of Medicine and adjunct professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego.
Leaders in cell biology and anti-malarial drug development respectively, JoAnn Trejo and Elizabeth Winzeler were recognized by their peers with one of the highest honors in health and medicine.
Trejo is known for discovering how cellular responses are regulated by molecules known as G protein-coupled receptors, particularly in the context of vascular inflammation and cancer. Her findings have advanced the fundamental knowledge of cell biology and helped identify new targets for drug development. Trejo’s research has been continuously funded by the National Institutes of Health (NIH), including a recent NIH R35 Outstanding Investigator Award.
Winzeler is known for her early contribution to the field of functional genomics, where she worked primarily in the model yeast, Saccharomyces cerevisiae. Concerned about global health disparities and the alarming rise in the number of worldwide malaria cases in the early 2000s, she shifted her research focus to malaria, beginning with functional genomics and then moving to drug discovery.
“Two UC San Diego Scientists Elected to National Academy of Medicine”
The National Institutes of Health (NIH) has awarded researchers at University of California San Diego approximately $30 million over five years to expand and deepen longitudinal studies of the developing brain in children.
“This is a groundbreaking study of normal and atypical brain developmental trajectories from day 0 to 10 years of age in a large sample of about 8,000 families,” Christina Chambers, PhD, MPH, professor of pediatrics at UC San Diego School of Medicine and professor in the Herbert Wertheim School of Public Health and Human Longevity Science at UC San Diego.
Molecular profiling is more often used after standard cancer treatments have failed, but a new study suggests that it could effectively guide first-line treatment, especially for poor-prognosis cancers
In treating cancer, personalized medicine means recognizing that the same disease can behave differently from one patient to another, and precision medicine means that diagnosis and treatment should involve understanding the specific genetic makeup of each patient’s tumor and disease.
In a recent study, published October 4, 2021 in Genome Medicine, researchers at University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health, with colleagues elsewhere, report that conducting genomic evaluations of advanced malignancies can be effective in guiding first-line-of-treatment, rather than waiting until standard-of-care therapies have failed.
By their nature, cancers are molecularly complex, each with a heterogeneous combination of genetic mutations that, more often than not, defy easy treatment. With every stage and line of therapy, tumor cells adapt to become more resistant to remedy.
The study authors hypothesized that developing matched, individualized combination therapies for patients with advanced cancers who had not been previously treated might be feasible and effective.
Just under 150 adults with newly diagnosed cases of advance malignancies were enrolled in the prospective study at two sites: Moores Cancer Center and Avera Cancer Institute in Sioux Falls, South Dakota. The patients had either incurable, lethal cancers (at least a 50 percent cancer-associated mortality rate within two years) or they had a rare tumor with no approved therapies.
Researchers performed extensive genomic profiling of all patients, identifying and documenting all detectable gene mutations to create a molecular profile of each patient’s tumor that would guide their precision cancer therapy.
“Each patient received a personalized N-of-1 treatment plan that optimally matched therapeutic agents to their tumor’s distinct biology, while also taking into account other variables, such as underlying conditions or co-morbidities unique to that patient,” said first author Jason Sicklick, MD, professor of surgery at UC San Diego School of Medicine and surgical oncologist at Moores Cancer Center.
Pictured: Cancer cells ( Thomas Deerinck)
“At Initial Cancer Diagnosis, a Deeply Personalized Assessment”
In recent years, hallucinogens ranging from LSD and ecstasy (MDMA/Molly) to salvia divinorum and ketamine have garnered renewed interest as potential as therapeutics for a variety of psychiatric conditions. Both LSD and ketamine, for example, are being widely studied as a treatment for major depression.
In a study published online April 28, 2022 in the journal Addictive Behaviors, researchers at UC San Diego School of Medicine and New York University investigated how use of these substances outside of medical settings relates to subsequent psychological distress, depression and suicidality.
They examined data from a representative sampling of noninstitutionalized adults (2015-2020) who had reported specific drug use on the National Survey on Drug Use and Health, and whether that use was associated with any reported serious psychological distress, major depressive episode (MDE) or suicidality.
The researchers found that LSD was associated with an increased likelihood of MDE and suicidal thinking. Salvia divinorum, a plant species with psychoactive properties when its leaves are consumed by chewing, smoking or as a tea, was linked to increased suicidal thinking. The hallucinogens DMT, AMT and Foxy were associated with suicidal planning.
Sometimes called “Maria Pastora” or “Sally-D,” Salvia divinorum contains opioid-like compounds that induce hallucinations when the leaves are chewed, smoke or brewed in a tea. Researcher found the plant also induces an increased likelihood of suicidal thinking.
Conversely, ecstasy use was associated with a decreased likelihood of serious psychological distress, MDE and suicidal planning.
“The findings suggest there are differences among specific hallucinogens with respect to depression and suicidality,” wrote authors Kevin H. Yang, a fourth year medical student; Benjamin H. Han, MD, an assistant adjunct professor at UC San Diego School of Medicine; and Joseph J. Palamar of New York University. “More research is warranted to understand consequences of and risk factors for hallucinogen use outside of medical settings among adults experiencing depression or suicidality.”
— Scott LaFee
If you or someone you know may be considering suicide, contact the National Suicide Prevention Lifeline at 1-800-273-8255 (En Español: 1-888-628-9454; Deaf and Hard of Hearing: 1-800-799-4889) or the Crisis Text Line by texting HOME to 741741.
Brain organoids provide insight into the mechanism of a difficult-to-treat seizure disorder
Brain cells, or neurons, communicate through organized electrical bursts to control body processes like walking, talking and breathing. Sometimes, those electrical bursts can become disorganized and cause seizures, or epilepsy if the seizures are recurring. Focal cortical dysplasia — a brain disease characterized by abnormal balloon cells in the outer layer of the brain — is the leading cause of medication-resistant epilepsy. Some cases are caused by spontaneous genetic mutations, but the majority have an unknown cause. Treatment options are limited to invasive brain surgery, which may be ineffective.
In a new study, published online December 27, 2021 in Brain, an international collaboration between teams of researchers led by senior authors Alysson Muotri, PhD, director of the Stem Cell Program at the University of California San Diego School of Medicine and Iscia Lopes Cendes, PhD, professor in the Department of Translational Medicine at the University of Campinas, Brazil, describe a new laboratory model for focal cortical dysplasia using small floating balls of human brain cells called brain organoids.
Using a method called “reprogramming,” researchers are able to take skin cells from a skin biopsy and turn them into pluripotent stem cells. These stem cells can transform into any cell in the body — even tissues like brain organoids — and retain the same genetic material as the patient that received the skin biopsy, making it easier to personalize medicine.
The lead author of the study, Simoni Avancini, PhD, generated brain organoids from stem cells derived from patients with focal cortical dysplasia and compared them to brain organoids derived from healthy patients.
The researchers mimicked several aspects of the disease using the new model. They observed abnormal neurons, abnormal balloon cells, less actively dividing cells and more electrical bursts between the neurons. The results suggested that, at least in these patients, spontaneous genetic mutations do not cause focal cortical dysplasia, and it may be caused by unknown inherited mutations.
Inside brain organoids are sunflower-shaped areas called neural rosettes. where cells divide and mature into neurons. Precursor cells divide and fill the inner circle. Maturing neurons grow out of that circle like the petals of a sunflower. To investigate why brain organoids from patients with focal cortical dysplasia had less actively dividing cells, the researchers zoomed in on those neural rosettes and discovered differences in the expression of ZO-1 — a protein that helps cells stick together.
Unlike brain organoids from healthy patients where ZO-1 forms a smooth outline around the inner circle, brain organoids from patients with focal cortical dysplasia show ZO-1 as disorganized points within the inner circle. This led the researchers to investigate RHOA — a gene that regulates ZO-1 — in diseased brain organoids, and they discovered decreased expression of this gene compared to healthy brain organoids, suggesting that the decrease in actively dividing cells is caused by abnormal RHOA regulation.
Overall, these findings offer new insights into the mechanisms underlying focal cortical dysplasia, write the authors.
“We hope that this model will be useful to test and screen new theories and new ideas regarding focal cortical dysplasia, as well as finding novel treatments for this condition,” said Muotri.
— Gabriela Goldberg, graduate student
Brain organoids derived from a healthy person (left) compared to a person with focal cortical dysplasia (right).
Click to watch a video with Professor Lopes Cendes.