Cory Dobson, Author at Sanford Burnham Prebys - Page 25 of 41

Author: Cory Dobson

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Rebooting the immune system after a bone marrow transplant

AuthorJessica Moore
Date

August 30, 2016

illustration of femur highlighting bone marrow

After a bone marrow transplant, it can take months for the number of T cells to reach healthy levels. Because T cells are crucial for launching an effective immune response, this leaves patients—usually cancer survivors whose immune systems were knocked out by chemotherapy—vulnerable to infections for longer. However, new research, to which Carl Ware, PhD, professor and director of the Infectious and Inflammatory Disease Center, contributed, identifies a novel target for immunotherapeutics to shorten this recovery time.

“This study shows that the lymphotoxin β receptor controls the entry of T cell progenitors into the thymus, the organ where T cells mature,” said Ware. “Future compounds that activate this receptor may help transplants give rise to functional T cells faster.”

Within the overall immune response against invading bacteria, viruses, and other pathogens, T cells are the field officers and special forces. Helper T cells send chemical signals to get other parts of the immune system involved, and cytotoxic T cells recognize and kill infected cells directly. They’re ‘trained’ to distinguish threats from the cells of the body in the thymus, where T cell progenitors that react to normal, uninfected cells are eliminated.

Publishing in the Journal of Immunology, the team, led by William Jenkinson, PhD, and Graham Anderson, PhD, of the University of Birmingham, looked at the importance of various receptors in letting T cell progenitors into the thymus, and found that only the lymphotoxin β receptor was required.

Significantly, the researchers also showed that stimulating the lymphotoxin β receptor boosted the number of transplant-derived T cells.

“Post-transplantation, T cell progenitors can struggle to enter the thymus, as if the doorway to the thymus is closed,” said Anderson. “Our work points to a way to ‘prop open’ the door and allow these cells to enter and mature.”

Ware and his lab have made many contributions to understanding how the lymphotoxin β receptor, as well as other related receptors, affect immunity and inflammation.

“The lymphotoxin β receptor is important not only in the thymus, but also at sites of inflammation and infection,” Ware added. “Further investigation of the effects of activating it throughout the body will determine whether this treatment approach is feasible, or perhaps should be targeted to the thymus.”

The paper is available online here.

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Remembering Eric

AuthorFrom the San Diego Union-Tribune obituatry
Date

August 30, 2016

Eric Dudl

Eric Preston Dudl

October 22, 1972 – August 30, 2006

The Eric Dudl Scholarship was established at Sanford Burnham Prebys to remember a very special young man that dedicated his life to helping others.

 

Eric passed away peacefully in his father’s arms succumbing to a cancer that could not be stopped by any known medical treatments. He was caring to the end; the last thoughts were unselfishly for his work, family and dear girlfriend Lilia. Eric was a loveable child with a quick wit and incredible intellect. He grew up in La Jolla, graduating from La Jolla High School in 1990. He went on to earn a degree in biochemistry from the University of Illinois in 1994. He chose to continue his education at the University of Southern California where he was awarded a PhD in biochemistry and immunology in 2005.

He had just begun a Postdoctoral Fellowship at Sanford Burnham Prebys following his passion for cancer research. Eric published several research papers focusing on cancer at the cellular level. It was his wish that he could contribute lasting research that would save lives. Cancer did not stop Eric from going to work every day when he was out of the hospital. His courage in the face of pain was a source of wonder to his family and friends. Eric set his goals and standards high and achieved them in spite of great difficulties. He had a love of things intellectual, humorous, philosophical and political. The last few months of his life were filled with love, family, laughter and soccer. Our family was able to travel to the 2006 World Cup in Germany in June where he attended a match. He said it was the best trip of his life.

Eric is survived by his father and mother, Robert James and Barbara Dudl; his brother, Bret; the Jasso, Gonzalas, and Diaz families, and the love of his life Lilia Castro. He will be missed by many more family members, collogues and friends. Eric was, is, and always will be our wonderful, brave, intelligent, fun, funny, loving, caring, big-hearted, son who loved and cared about all of you and us. We will miss him dearly and he will live on in our thoughts forever.

Love, 
The Dudl Family

 

Courage is the power to confront a world that is not always fair.
It is the refusal to beg for what will never be given again.
It is loving life even in the face of death.
It is embracing family and friends even when we fear to lose them.
It is opening ourselves to love, even for the last time.
Courage is Self-Esteem.
It prefers quiet determination to whining.
It prefers doing to waiting.
It affirms that exits, like entrances, have their own dignity.

 

Donate to make a gift to the Eric Dudl Scholarship Fund. Eric’s family will be notified of your generosity, but the amount of your gift will not be shared.

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Feast or famine: the switch that helps your liver adapt

AuthorJessica Moore
Date

August 25, 2016

sign with arrows pointing to 'Feast' and 'Famine'

Scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a previously unknown way that stress hormones (glucocorticoids) control genes in the liver to help the body adapt to the fasting state. The study, published in Cell Metabolism, describes an obscure protein, SETDB2, that’s increased during times of fasting and alters the genome to help turn on genes needed to adjust to the absence of food.

“Our study provides evidence that SETDB2 may be a potential therapeutic target to modulate glucocorticoid activity in metabolic diseases with altered glucocorticoid sensitivity such as obesity and diabetes, or in patients undergoing chronic glucocorticoid treatment,” said Timothy Osborne, PhD, professor and director of the Integrative Metabolism Program at SBP, who directed the research. “These conditions are associated with liver dysfunction and can lead to nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), fibrosis or liver cancer.”

Glucocorticoids
Glucocorticoids are steroids secreted by the adrenal glands in response to stress signals from the brain. They help maintain normal concentrations of glucose in the blood and reduce inflammation, which can be beneficial in treating chronic autoimmune diseases and allergies.

“Synthetic glucocorticoids, such as prednisone, dexamethasone and hydrocortisone have been prescribed for decades to stop inflammation. However, there are major side effects associated with steroid treatment, including immunosuppression that leaves a patient vulnerable to infection, and the exacerbation of metabolic diseases,” added Osborne.

The yin and yang of metabolism

The new study, led by Manuel Roqueta-Rivera, a postdoctoral researcher in Osborne’s lab, sought to find the mechanism that the liver uses to transition between the fed and fasted states—two extreme metabolic conditions that require genes to switch “on and off” to promote either energy storage or energy use.

Roqueta-Rivera induced a fasting state in mice by depriving them of food for 24 hours. In the liver, one of the genes activated by fasting was SETDB2, an enzyme that modifies other proteins, including histones—the proteins whose association with DNA helps control whether genes can be read.

Restoring metabolic equilibrium

“These results suggest that inhibiting SETDB2 could lessen certain metabolic side effects such as weight gain and insulin resistance in patients taking steroids for inflammatory disease,” Osborne added. “Since SETDB2 only affects a subset of steroid hormone-regulated genes related to metabolism, we think this strategy would not interfere with steroids’ anti-inflammatory effects.

“Modulating SETDB2 activity might also benefit patients with other metabolic conditions, but it’s not clear yet whether it would be better to inhibit the enzyme or activate it. Blocking SETDB2 would likely lower blood glucose, which would be beneficial, but it might also enhance fat storage in the liver, which is damaging.”

“Future therapies targeting SETDB2 likely wouldn’t be one-size-fits-all,” commented Osborne. “Metabolic disease is complex—its presentation varies widely—so if these drugs are developed, they could be targeted to specific patients.”

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Zika virus may affect adult brain cells in those with immune deficiencies

AuthorJessica Moore
Date

August 19, 2016

mosquito sucking blood from a person

Concerns over the Zika virus have focused on pregnant women due to mounting evidence that it causes brain abnormalities in developing fetuses. However, new research to which Alexey Terskikh, PhD, associate professor in the Development, Aging, and Regeneration Program, contributed, provides tentative evidence that certain adult brain cells may be vulnerable to infection as well. These cells replace lost or damaged neurons throughout adulthood, and are critical to learning and memory.

 

“We examined whether the Zika virus can get into the adult brain by infecting mice. Since normal adult mice are resistant to Zika, we used special mice that lack a major antiviral response,” said Terskikh. “We found that in these mice the virus infects neural progenitor cells (NPCs). This suggests that people who have been infected with Zika might, in the long term, develop neurological symptoms such as memory or mood problems—and people with weakened immune systems would be especially vulnerable.”

The investigation, published in Cell Stem Cell, was co-led by Joseph Gleeson, MD, adjunct professor at Rockefeller University, and Sujan Shresta, PhD, professor at the La Jolla Institute of Allergy and Immunology. Terskikh’s lab performed the experiments, which he helped design, in parallel with the other teams.

In adults, NPCs are found in two small regions of the brain. Infection correlated with evidence of cell death and reduced generation of new neurons in these regions. Similar deficits have been linked to cognitive decline and depression.

Since Zika infections in healthy humans lead to much lower viral counts than those in the mice in the study, whether the virus enters the brain in typical cases remains unclear.

“The majority of adults who are infected with Zika rarely show detectable symptoms,” said Shresta. “Its effect on the adult brain may be subtle, and now we know what to look for.”

To better understand the effects of Zika on normal adult brains, Terskikh’s lab is now using a different mouse line with a dampened, rather than absent, antiviral response.

The paper is available online here.

This post is based in part on a press release from Rockefeller University and the La Jolla Institute for Allergy and Immunology.

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Boosting cells’ ability to recycle their parts to treat muscular dystrophy

AuthorJessica Moore
Date

August 15, 2016

Fluorescently stained skeletal muscle fibers showing striations

If a cell can’t efficiently recycle its machinery—energy generators, protein makers, and transport systems—it ends up using faulty equipment. Cell recycling, called autophagy, is necessary to keep cells functioning at full capacity. When autophagy doesn’t work well in muscle stem cells, which replace worn-out muscle cells, the ability to maintain healthy muscle tissue is compromised.

This is precisely what Pier Lorenzo Puri, MD, professor in the Development, Aging, and Regeneration Program, discovered in a study conducted in collaboration with Lucia Latella, PhD, at the Fondazione Santa Lucia in Rome.

Their work, published in Cell Death and Differentiation, showed that impaired autophagy in muscle stem cells of patients with advanced Duchenne muscular dystrophy (DMD) reduces their ability to support long-term regeneration. DMD is a childhood-onset genetic disorder, which mostly affects boys and causes progressive muscle weakness, invariably leading to loss of the ability to walk. As the heart and respiratory muscles also eventually deteriorate, DMD shortens lifespan, usually to less than 30 years.

They also demonstrate that boosting autophagy in a mouse model of DMD, at later stages when the recycling process slows down, improves muscle regeneration.

“These findings provide solid evidence that future drugs that increase rates of autophagy would help DMD patients,” said Puri. “In this study, mice were fed a low-protein diet to induce autophagy. The low-protein diet makes cells break down their own proteins to get the building blocks needed to make new muscle. But of course a low-protein diet isn’t a feasible approach in the long term, which is why we need drugs that specifically induce autophagy.

“Although there are several FDA-approved drugs to treat other conditions—such as high blood sugar and elevated cholesterol—they tend to have side effects that would rule them out for DMD patients. It may take a few years, but new drugs that activate autophagy in DMD patients could significantly improve their health.

Our next step will be to examine whether combining this approach with others, such as nitric oxide releasers or histone deacetylase inhibitors, which may also increase autophagy, would further promote muscle regeneration.”

The paper is available online here.

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The Epstein Family Foundation gives $1M for pancreatic and prostate cancer research

AuthorKristen Cusato
Date

August 10, 2016

Nicholas Cosford, PhD

Sanford Burnham Prebys Medical Discovery Institute (SBP) has received a $1M donation from The Epstein Family Foundation for scientists to study pancreatic and prostate cancer. The gift, contributed by SBP board member Dan Epstein and his wife Phyllis, will support the lab of Nicholas Cosford, PhD, associate director of Translational Research at the Institute’s NCI-designated Cancer Center.

“Nick Cosford is one of our leading scientists investigating new approaches to treat patients with pancreatic and prostate cancers,” said Perry Nisen, MD, PhD, chief executive officer of SBP. “This generous donation from The Epstein Family Foundation will help us realize our vision to translate fundamental research into clinically meaningful benefit for patients.”

Pancreatic cancer is one of the deadliest forms of cancer. There are no effective therapies and the five-year survival rate is only six percent. Prostate cancer is the second leading cause of cancer death in U.S. men. 180,000 men are diagnosed with prostate cancer every year in this country.

“I am pleased to be able to help advance research, especially in these two challenging types of cancer,” said Epstein, a long-time supporter of SBP who has been a member of the Institute’s board of trustees since 2011. “Nick Cosford is doing some exciting work in his lab and I look forward to hearing about discoveries that may improve the lives of patients diagnosed with these diseases.”

Cosford, who has spent more than 25 years assembling small molecules into disease-fighting chemical compounds, talked about his lab’s focus.

“Aggressive tumor cells, such as those found in pancreatic and advanced prostate cancer, are highly resistant to the normal mechanisms the body uses to eliminate abnormal cells. We are developing medicines that overcome this resistance by inhibiting the pathways tumor cells use to survive. By designing small molecules that act on apoptosis (programmed cell death) and autophagy (a cell survival mechanism), we hope to develop drugs that will destroy deadly tumor cells and improve patient outcomes,” Cosford said.

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Preuss School interns dive deep into research

AuthorJessica Moore
Date

August 9, 2016

Eight high school interns with their certificates

Not many high schoolers get to do cancer research, but that’s exactly the opportunity extended by Sanford Burnham Prebys Medical Discovery Institute (SBP) to a small group of rising seniors from The Preuss School at UC San Diego each summer. In contrast to the two-week program for rising juniors, the senior intern program lets students spend six weeks in the lab full-time, during which they complete experiments using the same techniques that the graduate students who train them use in their projects. 

“I got so much more out of this than I expected,” said Victor Ruiz. “We didn’t just do experiments, we understood the scientific goals. The instructors explained the rationale, and how the results would fit into their overall project.”

Their comprehension was evident in the outstanding presentations the students gave at the end of the program—they were well prepared to answer their classmates’ questions.

Interns gained more than technical knowledge—they came away with a new appreciation of the many steps—sometimes ‘baby steps’—needed to advance cancer research and develop better therapies.

“I used to think that cancer was one disease, and that a cure was just around the corner,” said Gabriel Ramos. “Now I know that it’s really complicated. There are thousands of types of cancer, and tumors adapt to resist treatment.”

Some students were inspired to consider research careers. “I had been leaning toward engineering, but now I see the appeal of research—you get to ask questions and discover things no one knew before,” said Luis Vidal. “Also, it was really amazing when we transfected cells with a gene for fluorescent protein—I made cancer glow!”

Others saw how expertise in biology could benefit their planned careers. “I want to work in the medical field,” said Maricruz Gonzalez. “I look forward to being able to help patients understand their options and what their diagnosis means.”

And the interns weren’t the only ones who benefited—the young researchers in SBP’s PhD program who taught and supervised them grew as well.

“It’s so rewarding to watch the students’ perspective change,” said Monica Gonzalez Ramirez, lead instructor in the program and a graduate student in the laboratory of Guy Salvesen, PhD, dean of the Graduate School. “Being a mentor usually happens later in your career—I feel lucky that I get the chance to do it early on.”

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Scientists discover potential avenue to early treatment for type 2 diabetes

AuthorJessica Moore
Date

August 8, 2016

insulin pens

Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new potential target for drugs to prevent type 2 diabetes. A paper published in the Journal of Clinical Investigation shows that blocking a cellular glucose sensor in muscle improves insulin responsiveness.

“Our new study shows that a protein called MondoA may serve as a key link between insulin resistance and accumulation of fat in muscle, which occurs in obesity-related diabetes,” said Daniel P. Kelly, MD, professor and director of SBP’s Center for Metabolic Origins of Disease. “This study is the first step towards testing MondoA-targeted drugs to prevent type 2 diabetes in pre-clinical studies.”

About 8% of Americans have type 2 diabetes, and another 25% of the population is at risk because of obesity. Type 2 diabetes is a lifelong disease that represents an enormous public health burden, accounting for as much as 20% of all healthcare costs in the US. A significant proportion of those costs result from complications of diabetes, including damage to the kidneys, peripheral nerves, and retinas.

The precursor to type 2 diabetes is insulin resistance, in which insulin no longer causes the body’s cells to take up the glucose from a meal and use it for energy. This leads to diabetes because glucose continues to circulate in the blood, stimulating the pancreas to make more and more insulin, which eventually becomes so taxing that the insulin-producing cells die.

Kelly’s team focused on skeletal muscle because it’s the main insulin-responsive tissue in the body. An early marker of insulin resistance is the accumulation of fat in muscle, along with decreased import of glucose, so they examined whether these two processes are linked. To find a protein that regulates both, they screened thousands of molecules for their ability to block fat synthesis and enhance glucose uptake in muscle cells.

“Investigating the cellular effects of SBI-477, the best hit molecule from our screen, led us to MondoA,” added Kelly. “Our experiments showed that this protein regulates genes involved in synthesizing fats as well as inhibiting insulin signaling.”

“Until now, it wasn’t clear why people who are insulin resistant accumulate fat in their muscle,” he explained. “These results show that MondoA is one mechanism that ties these phenomena together, serving as a gatekeeper for fuel burning in muscle.”

The researchers went on to demonstrate that SBI-477 also enhances glucose uptake in liver cells, suggesting that a MondoA blocker may have this effect on multiple tissues. Further, it mitigates insulin resistance in mice fed a high-fat diet.

“We think that MondoA normally responds to oversupply of glucose by inhibiting transport of glucose into cells and enhancing its conversion to fat, but persistent activation promotes insulin resistance,” Kelly said.

Kelly and his collaborators next plan to develop better molecules that inhibit MondoA.

“Directly enhancing glucose uptake by muscle and other tissues is a very different strategy from those of other anti-diabetic drugs in development. Since this action would favor energy burning, it may also have beneficial effects on overall metabolism and body weight.”

The paper is available online here.

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Breakthrough in understanding how stem cells become specialized

AuthorJessica Moore
Date

August 4, 2016

stem cells (pink) in the process of reprogramming to neurons (green)

Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have made a major advance in understanding how the cells of an organism, which all contain the same genetic information, come to be so diverse. A new study published in Molecular Cell shows that a protein called OCT4 narrows down the range of cell types that stem cells can become. The findings could impact efforts to produce specific types of cells for future therapies to treat a broad range of diseases, as well as aid the understanding of which cells are affected by drugs that influence cell specialization.

“We found that the stem cell-specific protein OCT4 primes certain genes that, when activated, cause the cell to differentiate, or become more specialized,” said Laszlo Nagy, MD, PhD, professor and director of the Genomic Control of Metabolism Program at SBP’s Lake Nona campus and senior author of the study. “This priming customizes stem cells’ responses to signals that induce differentiation and makes the underlying genetic process more efficient.”

Differentiation matters

As an organism—such as a human—develops from its simplest, earliest form into maturity, its cells transition from a highly flexible state—stem cells—to more specialized types that make up its tissues. Many labs are trying to recapitulate this process to generate specific types of cells that could be transplanted into patients to treat disease. For example, pancreatic beta cells could treat diabetes, and neurons that produce dopamine could treat Parkinson’s.

What OCT4 does

OCT4 is a transcription factor—a protein that regulates gene activity—that maintains stem cells’ ability to give rise to any tissue in the body. OCT4 works by sitting on DNA and recruiting factors that either help initiate or repress the reading of specific genes.

The new study shows that, at certain genes, OCT4 also collaborates with transcription factors that are activated by external signals, such as the retinoic acid (vitamin A) receptor (RAR) and beta-catenin, to turn on their respective genes. Vitamin A converts stem cells to neuronal precursors, and activation of beta-catenin by Wnt can either support pluripotency or promote non-neural differentiation, depending on what other signals are present. Recruitment of these factors ‘primes’ a subset of the genes that the signal-responsive factors can activate.

The big picture

“Our findings suggest a general principle for how the same differentiation signal induces distinct transitions in various types of cells,” added Nagy. “Whereas in stem cells, OCT4 recruits the RAR to neuronal genes, in bone marrow cells, another transcription factor would recruit RAR to genes for the granulocyte program. Which factors determine the effects of differentiation signals in bone marrow cells—and other cell types—remains to be determined.”

Next steps

“In a sense, we’ve found the code for stem cells that links the input—signals like vitamin A and Wnt—to the output—cell type,” said Nagy. “Now we plan to explore whether other transcription factors behave similarly to OCT4—that is, to find the code in more mature cell types.

“If other factors also have this dual function—both maintaining the current state and priming certain genes to respond to external signals—that would answer a key question in developmental biology and advance the field of stem cell research.”

The paper is available online here.

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Graduate student Marisa Sanchez shares her love of science with 3rd graders

AuthorJessica Moore
Date

August 3, 2016

Kids playing with balloons in school yard

Last school year, Marisa Sanchez, a graduate student in the laboratory of Dieter Wolf, MD, led weekly science lessons at Lafayette Elementary School through UC San Diego’s BioCircuits Institute’s outreach program. We recently spoke with her about the experience—here’s the interview:

What motivated you to participate?

I heard about it when the director of the program came to Sanford Burnham Prebys to recruit volunteers, and it seemed really fun. I like working with kids, and the lessons seemed like they’d get them excited about science. Plus, after the first week, I was hooked—I knew I’d be doing it as long as I have the opportunity. I’m volunteering next year as well, and I’ll get to work with the same teacher.

What was your favorite lesson?

The one on reflection and refraction of light was a big hit—it was basically a game where the kids tried to set up a bunch of mirrors in a way that would get a laser beam to hit a target. I could tell they understood the concepts because they were using them directly.

Were there any breakthrough moments?

When we did a lesson on how much gravity differs among the planets because of their different masses, one kid who’d been quiet all year suddenly got really talkative, sharing all these facts he’d learned from a documentary. Discussing one of his favorite subjects really helped him open up socially.

Were there any funny moments?

During a lesson about frequencies, I tried to explain what a pager was, and the kids had no idea what I was talking about. I switched to a different example—a VHS tape—but that didn’t come across any clearer!

What do you think the kids got out of the program?

It gives them the opportunity to grow with science. Since science is often considered to be so complicated, kids don’t always get to learn about fundamental concepts until they’re older. I could see some of the kids’ interest being sparked—even if they didn’t totally get every aspect, they know they’re interested, so next time it comes up in school they’ll get more out of it.