Karl Klose, director of the South Texas Center for Emerging Infectious Diseases (STCEID) at The University of Texas at San Antonio (UTSA), says his lab collaborated with researchers at the Burnham Institute for Medical Research, The University of Texas Southwestern Medical Center at Dallas and Thomas Jefferson University in a study that discovered that Francisella tularensis makes an essential metabolic molecule, nicotinamide adenine dinucleotide (NAD), using a different process and different enzyme from all other living organisms.
F. tularensis is a highly infectious organism that causes morbidity and mortality in humans. Very little is known about its molecular mechanisms of pathogenesis, and no vaccine is available for protection against tularemia, the disease it causes. Consequently, there is great concern about its role as a potential bioweapon.
However, the researchers' findings are promising. Because F. tularensis makes NAD using a unique pathway that is not used by humans, that pathway can be targeted to destroy the tularemia organism without doing damage to the human host.
"There is a 'conventional' way to make NAD, nicotinamide adenine dinucleotide, in all living organisms studied thus far, ranging from bacteria to humans," said Klose, whose lab studies the genetics behind the virulence of F. tularensis . "Our study uncovered that Francisella makes NAD in a very unique way, using the enzyme nicotinamide mononucleotide synthetase, or NMS. The findings offer us a possible target for the development of therapeutics against tularemia."
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To achieve this task, Drs Farmer, Mauro Delorenzi, and Pratyaksha Wirapati from the Swiss Institute of Bioinformatics developed new computational methods to extract relevant gene patterns from the vast quantity of data generated by the microarray experiment. "In this study, we have mined the gene expression data in order to find a particular gene activity pattern, or gene signature, that would be associated with how patients respond to chemotherapy," Dr Farmer said.
Results showed that a signature measuring the biological activity of tumor's microenvironment, also known as reactive stroma, predicted how patients would respond to the treatment.
Researchers found that it is precisely the magnitude of this stroma reaction that was predictive of a response to chemotherapy. "It was a surprise to us to find that it was not the tumor itself but rather how surrounding non-tumorous tissue reacts to the presence of the tumor that was our best clue in predicting resistance to treatment," Dr Farmer continued. "Patients who had a strong stroma reaction characterized by an increased quantity of fibroblasts surrounding the tumor were more likely to have a bad response to this particular chemotherapy."
"What this means is that success in treatment, having tumors shrink or disappear altogether, is in part due to molecular differences in tumors and their immediate surroundings," Dr Farmer continued.
Researchers hope that one day this discovery will contribute to changing how breast cancer patients are treated. Indeed, in the future, if a clinician learns with a simplified test that a particular woman has a high probability of not responding to an anthracyclin-based therapy, this clinician may consider prescribing an alternative chemotherapeutic regimen. Moreover, this study suggests that predicting how individual patients might respond to chemotherapy could be possible, which raises hopes that one day, personalized medicine in the treatment of breast cancer may become a reality.
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