Research Spotlight

Posted June 15th 2016

Love of angiotensin-converting enzyme inhibitors in the time of cholera.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2016). “Love of angiotensin-converting enzyme inhibitors in the time of cholera.” JACC Heart Fail: April 2016 [Epub ahead of print].

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The highly acclaimed novel Love in the Time of Cholera by the Nobel Prize-winning Colombian author Gabriel García Márquez is a brilliant exploration of the complexity of love, specifically the struggle between our attraction to the ideal and depraved dimensions of love and the importance of passion and societal expectations in defining the attributes and personal rewards of love (1). Lovesickness is viewed as an illness, just as cholera is defined (from an intriguing Spanish perspective) as a passion, separate from its conventional consideration as a disease. The flow of the story (which evolves over decades) can be viewed simplistically, but that would be a mistake. The author himself has warned readers “you have to be careful not to fall into my trap” (1).


Posted June 15th 2016

A 380-gene meta-signature of active tuberculosis compared with healthy controls.

Virginia Pascual M.D.

Virginia Pascual M.D.

Blankley, S., C. M. Graham, J. Levin, J. Turner, M. P. Berry, C. I. Bloom, Z. Xu, V. Pascual, J. Banchereau, D. Chaussabel, R. Breen, G. Santis, D. M. Blankenship, M. Lipman and A. O’Garra (2016). “A 380-gene meta-signature of active tuberculosis compared with healthy controls.” Eur Respir J 47(6): 1873-1876.

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Mycobacterium tuberculosis is estimated to have infected one third of the world’s population and continues to be a significant cause of mortality and morbidity [1]. There is a need for new and improved diagnostics or treatment-monitoring tools and blood-based mRNA diagnostics are a potential solution [2]. Gene expression microarray analysis of human blood has been widely used to profile the host transcriptional response in active tuberculosis (TB) to identify potential biomarkers and better understand the host immune response [2]. So far, there has been a relative lack of concordance in the actual genes being identified from the published studies [2, 3], although there has been agreement in some of the pathways identified. Interferon (IFN) signalling has been identified as a dominant signature in many of the individual studies [2, 4]; however, when significant gene lists were combined from eight publicly available TB datasets, TREM1 (triggering receptor expressed on myeloid cells 1) signalling became the most significant pathway [5].


Posted June 15th 2016

Impact of donor age on cardiac transplantation outcomes and on cardiac function.

Brian Lima M.D.

Brian Lima M.D.

Chamogeorgakis, T., S. Joseph, S. Hall, G. V. Gonzalez-Stawinski, G. Saracino, A. Rafael, J. MacHannaford, I. Toumpoulis, J. Mendez and B. Lima (2016). “Impact of donor age on cardiac transplantation outcomes and on cardiac function.” Interact Cardiovasc Thorac Surg: May 2016 [Epub ahead of print].

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OBJECTIVES: Although the impact of older donors on heart transplant outcomes has been previously published, the survival results are conflicting. We herein analyse the impact of older donors on transplant survival and myocardial function. METHODS: The records of the patients who underwent heart transplant at Baylor University Medical Center at Dallas from November 2012 until March 2015 were reviewed and the data were extracted. The heart recipients were divided into two groups based on donors age; 50 years of age was the division point. The two groups were compared with regard to the following transplant outcomes: in-hospital and 1-year survival, severe (3R) rejection, primary graft dysfunction, myocardial performance as reflected by the inotropic score, left ventricular ejection fraction, intensive care unit and overall length of stay. RESULTS: Anoxia was more common cause of death in younger donors (43.9%), whereas intracranial bleeding was more frequent in older donors (48.1%, P = 0.016). The in-hospital survival and 1-year survival were the same between the two groups. Additionally, cardiac transplantation from older donors was not associated with higher incidence of graft dysfunction, higher inotropic support score, longer intensive care unit and total hospital length of stay or more frequent severe rejection episodes. The left ventricular ejection fraction was similar between the two groups. CONCLUSIONS: Heart transplant from older donors is not associated with lower in-hospital and mid-term survival if donors are carefully selected; furthermore, the graft function is comparable. The use of hearts from donors older than 50 years of age can be expanded beyond critically ill recipients in carefully selected recipients.


Posted June 15th 2016

A phase 1 clinical trial of ASG-5ME, a novel drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and gastric cancers.

Carlos Becerra M.D.

Carlos Becerra M.D.

Coveler, A. L., A. H. Ko, D. V. Catenacci, D. Von Hoff, C. Becerra, N. C. Whiting, J. Yang and B. Wolpin (2016). “A phase 1 clinical trial of asg-5me, a novel drug-antibody conjugate targeting slc44a4, in patients with advanced pancreatic and gastric cancers.” Invest New Drugs 34(3): 319-328.

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ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.


Posted June 15th 2016

Objective assessment of activity in inpatients with traumatic brain injury: Initial findings.

Simon Driver Ph.D.

Simon Driver Ph.D.

Driver, S., L. Rachal, C. Swank and R. Dubiel (2016). “Objective assessment of activity in inpatients with traumatic brain injury: Initial findings.” Brain Impairment 17(1): 55-63.

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Purpose: Use accelerometers to examine the physical activity behaviours of individuals following TBI undergoing inpatient rehabilitation. Method: Twenty-one individuals with Traumatic brain injury (TBI) undergoing inpatient rehabilitation (9 females, 12 males; M age = 43.8 14.7 years; M GCS = 9.1 4.3; M time since injury = 40.8 +/- 22.1 days; M length of stay (LOS) = 30 +/- 14 days) wore accelerometers for an average of 8.4 +/- 2.0 consecutive days (1440 minutes/day). Activity counts (AC) were collected at 1 minute epochs and descriptive statistics were calculated to assess intensity of activity and time spent being active and sedentary. Results: During scheduled therapy, time individuals completed an average of 161.4 +/- 65.5 AC/minute, which decreased to 114.5 +/- 51.3 during non-therapy time and 22.2 +/- 10 when sleeping. Using population level cut points, individuals were on average considered inactive during therapy, inactive or sedentary during non-therapy time, and only one participant spent >1 minute in moderate intensity activity. The mean length of active and sedentary bouts was 9 minutes. Discussion: Findings indicate that the amount and intensity of activity completed is low amongst individuals completing inpatient rehabilitation after TBI, with the majority considered sedentary or inactive. While the sample is small, it is important to develop and implement safe and effective strategies to increase activity levels during rehabilitation.