New More Effective Antimicrobials Might Rise From Old

Findings could have major impact in struggle against evolving drug resistance

By tinkering with their chemical structures, researchers at the University of California, San Diego School of Medicine have essentially re-invented a class of popular antimicrobial drugs, restoring and in some cases, expanding or improving, their effectiveness against drug-resistant pathogens in animal models.

Writing in the October 7 Early Edition of PNAS, Lars Eckmann, MD, professor of medicine, and colleagues … Read the full story from the UCSD Newsroom

Dr. Lars EckmannLars Eckmann, MD, professor of medicine and a researcher in the Division of Gastroenterology, is senior investigator in the study.

Eckmann directs the UCSD Center for Tissue Repair, Epithelial Biology and Inflammation, and Transformation (C-TREAT), a National Institutes of Health Digestive Disease Research Development Center.

In his research laboratory, he addresses the mechanisms governing infection-related intestinal disease and the host defenses against them; and the pathophysiology of intestinal inflammation.

Other Department of Medicine coauthors of the PNAS report are project scientist Yukiko Miyamoto, Dae Young Cheung, Ricardo Lozano, Eduardo R. Cobo and professor Douglas E. Berg.

Citation for the study report:

Yukiko Miyamoto, Jarosław Kalisiak, Keith Korthals, Tineke Lauwaet, Dae Young Cheung, Ricardo Lozano, Eduardo R. Cobo, Peter Upcroft, Jacqueline A. Upcroft, Douglas E. Berg, Frances D. Gillin, Valery V. Fokin, K. Barry Sharpless, and Lars Eckmann. Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity. PNAS 2013; published ahead of print October 7, 2013, doi:10.1073/pnas.1302664110  |  Full text PDF (UCSD only)

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Drug Targets Hard-to-Reach Leukemia Stem Cells Responsible for Relapses

Researchers at the University of California, San Diego School of Medicine have discovered that hard-to-reach, drug-resistant leukemia stem cells (LSCs) that overexpress multiple pro-survival protein forms are sensitive – and thus vulnerable – to a novel cancer stem cell-targeting drug currently under development. … Read the full story from the UCSD Newsroom

Catriona H. M. Jamieson, MD, PhDPrincipal investigator of the study is Catriona H. M. Jamieson, MD, PhD, associate professor of medicine in the Division of Hematology-Oncology and director of stem cell research at the UC San Diego Moores Cancer Center.

Dr. Jamieson is on the steering committee for the Moores Cancer Center’s My Answer to Cancer initiative for personalized cancer therapy. She is a member of the faculty in the UCSD Biomedical Sciences Graduate Program.

Citation for the report: Goff DJ, Recart AC, Sadarangani A, Chun H-J, Barrett CL, Krajewska M, Leu H, Low-Marchelli J, Ma W, Shih AY, Wei J, Zhai D, Geron I, Pu M, Bao L, Chuang R, Balaian L, Gotlib J, Minden M, Martinelli G, Rusert J, Dao K-H, Shazand K, Wentworth P, Smith KM, Jamieson CAM, Morris SR, Messer K, S.B. Goldstein LSB, Hudson TJ, Marra M, Frazer KA, Pellecchia M, Reed JC, and Jamieson CHM. (2013) A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition. Cell Stem Cell 10.1016/j.stem.2012.12.011, online January 17, 2013.

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Researchers Block Pathway to Cancer Stem Cell Self-Renewal

NOTCH1 Signaling Promotes T-Cell Acute Lymphoblastic Leukemia-Initiating Cell Regeneration

Research suggests that patients with leukemia sometimes relapse because standard chemotherapy fails to kill the self-renewing leukemia initiating cells, often referred to as cancer stem cells … A team of researchers – led by Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at the University of California, San Diego School of Medicine and director of Stem Cell Research at UC San Diego Moores Cancer Center – studied these cells in mouse models that had been transplanted with human leukemia cells. They discovered … Read the full story from the UCSD Newsroom

Dr. Catriona JamiesonThe senior investigator of the study described in the press release is Catriona H. M. Jamieson, MD, PhD, associate professor of medicine in the Division of Hematology-Oncology and director of stem cell research at the UC San Diego Moores Cancer Center.

In the study, the investigators successfully block leukemia stem cell self-renewal. Their work was funded in part by a California Institute for Regenerative Medicine (CIRM) Development of Highly Active Anti-Leukemia Stem Cell Therapy (HALT) Leukemia Disease Team Research grant for which Dr. Jamieson serves as co-principal investigator with Dennis A. Carson, MD, former director of the Moores Cancer Center.

The overall goal of the HALT project is to develop six drugs – three monoclonal antibodies and three small molecules – to destroy leukemia stem cells.

Funding also came from the Ratner Family Foundation and the Leichtag Family Foundation. Antibody development was performed by Pfizer.

In her research, Dr. Jamieson focuses on translational studies to develop new treatments for myeloproliferative disorders and leukemia. In 2010, she received a $3.34 million grant from CIRM to support her efforts to develop treatments that reduce the risk of relapse in leukemia.  More about this funded project

Dr. Jamieson was named to the “San Diego’s Top Doctors” list for 2010 and 2011.

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Insulin Resistance, Inflammation and a Muscle-Saving Protein

In the online May 2 issue of the journal Cell Metabolism, researchers at the University of California, San Diego School of Medicine publish three distinct articles exploring:

  • the complex interactions of lipids and inflammation in insulin resistance
  • the roles of omega 3 fatty acids and a particular gene in fighting inflammation
  • how elevated levels of a particular protein might delay the muscle-destroying effects of amyotrophic lateral sclerosis.

Type 2 diabetes has reached epidemic proportions around the world … Read the full story from the UCSD Newsroom

Dr. Jerrold Olefsky
Dr. Jerrold Olefsky coauthored two of the three articles published:

  • Perspective article: Inflammation and Lipid Signaling in the Etiology of Insulin Resistance – Free full text
  • Omega 3 Fatty Acids and GPR120 – Article summary

Dr. Olefsky is Associate Dean for Scientific Affairs, UC San Diego Health Sciences; and Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism.

Dr. Joseph Vinetz Awarded $9.2 Million for International Malaria Project

Dr. Joseph Vinetz is principal investigator of the new 7-year, $9.2 million malaria research project described in the UCSD Newsroom story, “UC San Diego To Lead New Malaria Research Center in South America.”

Joseph M. Vinetz, M.D., is Professor of Medicine in the Division of Infectious Diseases.

Read the abstract of the project.

Dr. Antonino Catanzaro Wins Funding for 5-Year Study of Extensively Drug Resistant TB

Dr. Antonino CatanzaroAntonino Catanzaro, M.D., has received nearly $2.5 million in funding from the National Institute of Allergy and Infectious Diseases (NIAID) for a 5-year international collaborative study of extensively drug resistant tuberculosis.Dr. Catanzaro, Professor of Medicine in the Division of Pulmonary and Critical Care Medicine, specializes in chronic pulmonary diseases, particularly tuberculosis.

Extensively drug resistant tuberculosis, which has a high fatality rate, is considered a global threat to tuberculosis control. Rapid detection and treatment are crucial, but current detection methods can take as long as three months.

Dr. Catanzaro and his multidisciplinary team of investigators will develop and evaluate three rapid new testing methods. In addition, they will analyze samples to correlate genetic variations with resistance to anti-tuberculosis drugs in populations in India, South Africa, Moldova, and the Philippines.

The project is “Rapid Tests for Drug Resistance to Detect Extensively Drug-Resistant Tuberculosis.”   I  Read the abstract of Dr. Catanzaro’s grant

Endocrinology Researchers Uncover New Hope for Treating Type 2 Diabetes

Dr. Jerrold OlefskyDr. Jerrold M. Olefsky and colleagues have reported a discovery that suggests a new way to treat obesity-related insulin resistance and Type 2 diabetes.

In a laboratory study, they found that insulin resistance could be reversed by lowering the amount of adipose tissue macrophages (ATMs) in tissue.

ATMs normally help fight infection, but in obesity they accumulate in fat tissue and can become triggers for inflammation. The inflammation is a factor in the development of insulin resistance and Type 2 diabetes.

Jerrold M. Olefsky, M.D., is Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism and Associate Dean for Scientific Affairs. Co-leader of the study is Jaap Neels, Ph.D., a former UCSD colleague.

Read the full story
from UC San Diego
Health Sciences Communications

Their Division of Endocrinology and Metabolism coauthors are researchers David Patsouris, Ph.D., Ping-Ping Li, and Divya Thapar.

The report is published in the October 8 issue of the journal Cell Metabolism. The full citation:

Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008 Oct;8(4):301-309. Read the article abstract

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Drs. Wang and Kolodner Find a Key to Cisplatin Resistance

Why are some patients resistant to cisplatin chemotherapy for cancer?

A clue has come from a study released this month by Drs. Jean Wang, Richard Kolodner, and colleagues.

In patients who receive cisplatin therapy, their own DNA mismatch protein PMS2 normally plays a key role in helping the drug destroy the cancer cells.

There are a dozen variations of human PMS2, and Drs. Wang and Kolodner have found that cisplatin’s antitumor effects are blocked when one particular PMS2 variant is active.

Read the full story
from UC San Diego
Health Sciences Communications

Read the scientific
report in PNAS

The findings pave the way for further studies to confirm this discovery and apply it to the challenge of selecting the best chemotherapy regimen for each patient.

Jean Y. J. Wang, Ph.D., is Distinguished Professor of Medicine and Associate Director of Basic Research at the Moores UCSD Cancer Center.

Richard Kolodner, Ph.D., is Distinguished Professor of Medicine, Leader of the Cancer Genetics Program at the Moores UC San Diego Cancer Center, and Executive Director for Laboratory Science and Technology at the Ludwig Institute for Cancer Research.

Earlier this year, Dr. Kolodner was honored with election to the American Academy of Arts & Sciences (AAAS).

Drs. Wang and Kolodner are faculty members in the Division of Hematology-Oncology.

Their report was published online September 3, and in print in the September 16 issue of the Proceedings of the National Academy of Sciences:

Marinovic-Terzic I, Yoshioka-Yamashita A, Shimodaira H, Avdievich E, Hunton IC, Kolodner RD, Edelmann W, and Wang JYJ. Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q. Proc. Natl. Acad. Sci. USA. 2008; 105:13993-13998.  |  Read the report (PDF)

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