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UH researcher looks to the ocean to find a treatment for sepsis

Kills more people annually than HIV/AIDS, Breast or Prostate Cancer Combined

University of Hawaiʻi at Mānoa
Contact: Tina M Shelton, (808) 554-2586
Dir of Communications, Office of Dean of Medicine

Posted: Dec 22, 2014

It's likely that you wouldn't have to ask too many of your acquaintances to learn that some they loved died of sepsis. Sepsis, a complication of infection, is one of the leading causes of death in the world. Of the more than one million people diagnosed with sepsis each year in the United States, between 28 percent and 50 percent of them die. It is the tenth leading cause of death among elderly people, and it kills 30% of cancer patients.

Sepsis shock can deprive the organs of blood, triggering widespread organ failure and death. There is little medical personnel can do to help these patients. Currently the only treatment for sepsis is merely supportive in nature, including giving fluids and antibiotics.

Dr. Felix Ikuomola, a PhD candidate in Clinical Research at the John A. Burns School of Medicine (JABSOM) and a Graduate Research Assistant at the University of Hawai`i Cancer Center, has received a $104,477 grant from the National Institutes of Health to fund research he hopes will put natural products from Hawai'i's oceans to work blocking sepsis. He is working in the lab of his mentor, UH Cancer Center Assistant Professor Michelle Matter who

has an NIH R01 (considered the "gold standard" of research grants) funding. Ikuomola's diversity grant is a supplement to Dr. Matter's research.

"My work in Dr. Matter's lab involves screening small molecules, Fungi and Hawaiian marine natural products for potential inhibitory function in endothelial cell permeability," he explains.

An endothelial cell is a thin layer of structural and functional cells that cover the innermost part of blood and lymphatic vessels. Endothelial cells are responsible for many tissue responses including selective permeability of liquids & small chemicals, host-defense reactions to bacteria, repairs to injured cells, signaling between cells, cell proliferation, vascular smooth muscle tone, and cell migration to injured areas. Injury or damage to endothelial cells result in breakdown in barrier function, causing widened pores in the vascular lining that allow cancer to spread, as well as sepsis, edema, and other vascular life-threatening conditions.

Motivated by deaths close to him

Dr. Ikuomola, a U.S. citizen originally from Nigeria, is inspired to save lives because he has seen so many people lose their own struggle with disease, including members of his family.

"While in Africa, I felt frustrated to see my patients–especially the surgical patients with sepsis– without any treatment options. If there had been a pro-endothelial cell barrier enhancing therapeutics, my patient's lives could have been prolonged," said Dr. Ikuomola.

Dr. Ikuomola points out that the same molecular endothelial permeability mechanism also has been implicated in Diabetes Mellitus and Hypertension, the two major leading causes of disease and death in Africans, African-Americans, and Afro-Caribbeans.

"For me, to be involved in vascular biology research is very personal, because when I was seven years old, I lost my beloved father to Hypertension-induced hemorrhagic stroke and cousins to diabetic coma. My patients and family have been the driving force for me to be involved in sepsis research," said Ikuomola.

Why natural marine products?

His special interest is to understand, at the molecular level, how endothelial cells activate endothelial cell permeability to promote leakiness, and how these cells can also activate different pathways to promote endothelial cell barrier integrity and block leakiness. His work in Matter's lab involves screening small molecules, Fungi and Hawaiian marine natural products to potentially inhibit function in endothelial cell permeability.

The complex structure and diversity of natural products plays major role in target-binding selectivity, protein interactions, specificity, and other bio-molecular activities. "We are very hopeful that these Hawaiian marine natural products will work in sepsis because the marine natural products are able to survive the harsh and salty conditions of the ocean and able to control and regulate their internal conditions," said Ikuomola. These marine natural products regulate their cells in such a way that they do not suffer from a hyper-permeability condition which could have led to the uncontrollable influx of ocean water or efflux of cellular contents. "So, this property that maintains the cell integrity of th natural products is encouraging."

More about Dr. Ikuomola

Dr. Ikuomola is quick to thank those who have inspired and supported his work, and helped him receive the new grant. "I am very grateful to God; my wife Wendy; my mother; Dr. Rosanne Harrigan (JABSOM Director of Faculty Development); Dr. Michelle Matter; Dr. Joe Ramos; my colleagues at the UH Cancer Center Matter Lab; and The National Institutes of Health National Institute of General Medical Science for this diversity supplement grant," he said.

References

Centers for Disease Prevention and Control. (2014b). Sepsis questions and answers. Retrieved from http://www.cdc.gov

Danai, P. A., Moss, M., Mannino, D. M., & Martin, G. S. (2006). The epidemiology of sepsis in patients with malignancy. Chest, 129(6), 1432- 1440.

Griffiths, G. S., Grundl, M., Allen, III, J. S., & Matter, M. (2011). R-ras interacts with filamin A to maintain endothelial barrier function. J. Cell. Physiol., 226, 2287- 2296.

World-Sepsis-Day.org. (2014). Sepsis fact. Retrieved from http://www.world-sepsis-day.org

Recommended website: http://www.nigms.nih.gov/education/pages/factsheet_sepsis.aspx

For more information, visit: http://jabsom.hawaii.edu

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News Highlights

November 18, 2014

Friends of the Cancer Center Offers Quarterly Award for Winning Publication

by Chantal Jackson

Friends of the Cancer Center awards $4,500.00 quarterly, for a research item they deem worthy. A minimum of 80% of this monetary value is allocated to the research described in the winning publication. The award is based upon how well the research advances the field in terms of diagnosis, how the research supports the overall mission of the UH Cancer Center, and the impact factor of the journal in which the paper was published.

In October, Dr. Wei Jia was the recipient of this quarterly prize, for his collaborative paper, "A distinct glucose metabolism signature of acute myeloid leukemia with prognostic value" published in the September 4, 2014 issue of Blood. Dr. Wei Jia was the corresponding author in this paper describing a panel of markers used in the identification of intermediate group prognosis (the anticipated course of the disease) in individuals with acute myeloid leukemia (AML), a type of blood cancer.

AML is a group of blood cancers that can be divided into those associated with variable health outcomes: favorable, intermediate, and unfavorable. While the favorable and unfavorable groups demonstrate clear prognoses, the outcome of the intermediate group is not as straightforward.

In collaboration with Dr. Sai-Juan Chen and Dr. Zhu Chen in Shanghai, China, Dr. Jia and his team used serum metabolic profiling as a measure, and subsequently determined that the profiles of AML patients were markedly different from those of healthy individuals. Metabolite markers were differently expressed in serum which contributed to these different profiles.

Dr. Wei Jia explains: "Physicians can identify patients with AML who have favorable, intermediate, or unfavorable characteristics and their respective associated prognostic outcomes. It would be valuable to patients in the intermediate group for their physicians to be able to use these molecular biomarkers to determine prognosis".

In this paper, the authors identify serum metabolites and metabolic pathways as novel prognostic markers and potential therapeutic targets. By incorporating these markers, intermediate group prognoses can be determined, and a better targeted treatment plan can be established.

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December 4, 2014

Dr. Lana Garmire and team win University of Hawai'i Cancer Center's Publication of the Month

by Chantal Jackson

HONOLULU, HI - Dr. Lana Garmire won University of Hawai'i Cancer Center's November Publication of the Month award for her collaborative paper, "mirMark: a site-level and UTR-level classifier for miRNA target prediction," printed on October 25th 2014 in Genome Biology. Dr. Lana Garmire is a tenure-track assistant professor in the Cancer and Epidemiology Program at University of Hawai'i Cancer Center.

Micro RNA (miRNA) is a type of small RNA that regulates genes; markedly, miRNA plays an important role in cancer, and other diseases. Specifically, miRNAs regulate gene expression by binding to untranslated regions (UTRs) of mRNA.

Currently, other computational methods to predict miRNA targets are inadequate. In their study, three PhD students Mark Menor, Travers Ching, Xun Zhu, together with collaborator Dr. David Garmire, and senior corresponding author Dr. Lana Garmire employed machine learning methods and most comprehensive databases determine miRNA binding; in particular, if a specified gene is a miRNA target or not. This method is capable of miRNA target prediction at the site-level and gene-level. It achieves significantly better prediction than other tools, including TargetScan the most popular tool developed by David Bartel's group at MIT.

Dr. Lana Garmire explains, "The present goal is to determine if a gene sequence is a target of miRNA, which can be done at two levels: a coarse level (UTR-level), or a fine level (Site-level)." Dr. Garmire further highlights the general application for this miRNA target prediction approach, "We want to improve the inconsistency and overlap associated with different predictive tools, and this will help us better understand miRNA's functions in cancer. In this manner, knowledge-based guidance will be provided to molecular biologists for their experiments."

miRNAs are indicated as good biomarkers and therapeutic candidates for various cancers including breast, prostate and liver. The method discussed in this report will theoretically improve experimental research of such diseases, and ultimately serve to improve the lives of individuals enduring them.

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News Highlights

November 7, 2014

Mesothelioma Patients with Germline BAP1 Mutations have Improved Long-Term Survival

by Chantal Jackson

HONOLULU, HI - Dr. Francine Baumann, assistant professor in the Cancer Epidemiology Program at University of Hawai'i Cancer Center, has provided evidence for enhanced long-term mesothelioma survival linked to a specific germline mutation, BAP1. Her paper: "Mesothelioma Patients with Germline BAP1 Mutations have Seven-Fold Improved Long-Term Survival" was published in Carcinogenesis on November 7, 2014.

Malignant mesothelioma (MM) is a form of cancer associated with exposure to mineral fibers. There is a long latency period between exposure and diagnosis, with a generally poor prognosis. Dr. Baumann and her team used data from the United States Surveillance, Epidemiology, and End Results (SEER) program from 1973-2010 as a population based comparison group, noting that the median survival for MM patients was less than 1 year.

Dr. Baumann's group tested the hypothesis that MM associated with germline BAP1 mutations has a better prognosis compared to sporadic MM; indeed, they determined that the actuarial median survival for MM patients with germline BAP1 mutations was five years. Dr. Baumann explains, "Malignant mesothelioma is a high fatality disease, usually these individuals live less than one year after diagnosis. There is currently no treatment available to increase survival in this group. The current research demonstrates that in cases where the individuals have this BAP1 germline mutation, there is a longer period of survival."

Dr. Baumann highlights the clinical value in this finding, "The information shows a seven-fold increased survival in MM patients with the BAP1 germline mutation. If a clinician observes a high incidence of cancer within a particular family, it is important to test for this mutation and offer treatment based upon prognosis". For example, in sporadic MM, a survival prediction of approximately one year might be approached differently than a prognosis of five years, as seen in the case of BAP1 germline mutations associated with MM. By testing for this mutation, different therapeutic options could be recommended that might ultimately improve the patient's quality of life.

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