2014 Pilot Awardees
John Bilimek, PhD
The EMPATHy Toolkit: A prototype software application to help low-income diabetes patients overcome barriers to medication adherence
Although dozens of effective diabetes medications exist, their impact in real practice is limited by the fact that half of patients do not take their medications as prescribed. Patients who are nonadherent to their medication regimens are 80% more likely to die or suffer severe complications (myocardial infarction, stroke, etc.) than those who take their medications reliably. Many patients stop taking their medications because they cost too much, but many others deviate from their regimens for reasons such as concerns about side effects, doubts about the benefit of the medication, or confusion from having a regimen that is too complicated. Interventions led by community health workers (CHWs) have been developed to help overcome the patient-provider communication gap. CHW’s, also called promotores, are non-professional community members who are trained to work with patients to improve engagement and communication during the medical visit. CHW interventions have had mixed success in improving outcomes. Although CHWs possess excellent cultural competency and are very effective at establishing rapport with patients, they often lack a sophisticated understanding of all the potential challenges that can come with following a regimen. The proposed project will be the first to address this gap by translating well-developed behavioral economics methods (value clarification exercises) into a novel application: a software toolkit that a CHW can administer to help patients identify and articulate the most important barriers to adherence that they face. The primary objective of this project is to develop and pilot test “EMPATHy” a prototype software-based toolkit in an on-going, small scale CHW intervention. The toolkit will consist of 3 modules: an Educational Module (EM), a Preference Assessment Module (PA) and a Tailored Help Module (TH). All of this functionality can be delivered using commercially available software, so no custom software development is required for this pilot study. The specific aims for the current proposal are: Aim 1: Develop a prototype toolkit to enhance CHW-led interventions: EMPATHy develop an Educational Module (EM): using vignettes to communicate the real-world implications of experiencing different types of benefits and burdens associated with each regimen, develop a Preference Assessment (PA) module: adapting commercially available software for a value clarification exercise tailored to medication issues with diabetes, develop the Tailored Help (TH) module: a simple algorithm for the CHW to use to deliver the intervention Aim 2: Collect pilot data to show trends supporting the following hypothesis: Integrating EMPATHy into an established CHW-led intervention improves medication adherence. We will present pilot data comparing self-reported adherence for a “CHW +EMPATHy” group versus a “CHW with no software” group. Aim 3: Assess the feasibility and usability of EMPATHy. This aim will be achieved through interviews of the patients and CHWs in the intervention groups and audiotaping a small sample of patient/physician visits.
Bernard Choi, PhD
"Objective Measure of Anastomotic Blood Flow After Gastrointestinal Surgery Using Laser Speckle Imaging"
An esophagectomy involves removal of a cancerous portion of the esophagus, followed by attachment of the shortened esophagus to the stomach to reform the gastrointestinal (GI) tract. After an esophagectomy, approximately 10% of patients experience anastomotic leakage, in which the new bowel connection fails to maintain a water-tight seal and potentially fatal complications ensue. Similarly after colectomy, anastomotic leakage leads to significant patient morbidity and mortality. There is a critical need to identify the presence of poor perfusion at the site of anastomosis, both early and late in the postoperative period, which itself is a significant contributor to anastomotic leakage. The long-term goal is to develop a simple device that enables longitudinal, endoscopic monitoring of the state of anastomotic perfusion in patients post-esophagectomy and/or colectomy. The objective of our pilot projectis to design, build, and test a first-generation endoscope that is sensitive to tissue perfusion. The central hypothesis is that the method of Laser Speckle Imaging (LSI) provides accurate measurements of anastomotic perfusion. This hypothesis is based on our previous work , documented in the peer-reviewed literature, that describes the ability of LSI to measure blood flow and perfusion in a variety of other organs (brain, skin, etc.). To date, our published work involved LSI measurements in open-air configurations. We expect that LSI in an endoscopic configuration, will introduce additional challenges and constraints to imaging in confined spaces such as the esophagus or rectum. Hence, the rationale for the proposed research is to address the challenges associated with LSI in an endoscopic configuration. We anticipate that the preliminary data collected with the proposed research, are critical to the future success of a full application for extramural funds. Thus, the proposed research is relevant to that part of the ICTS’s mission that pertains to accelerate discoveries from the lab and to translate them into life-altering medical care. Guided by strong preliminary data collected in related research studies, our hypothesis will be tested by pursuing two Specific Aims: 1) Design and build a first-generation endoscope based on LSI methods; and 2) Test the endoscope in preliminary in-vitro and in-vivo studies using a porcine model. Under the first aim, we will evaluate two options: A) integration of LSI with a commercially-available endoscope, with minimal modification to the endoscope; and B) design of a custom probe that fits into the working channel of the clinical endoscope. We will assess both options with use of an in-vitro tissue construct designed to mimic a perfused esophagus. Under the second aim, we will test both options in a pig model at UCIMC (Building 54, basement), first post mortem and then in vivo.
Hye-Won Shin, PhD
A Novel Noninvasive Approach for Inhaled Corticosteroids Compliance: Quantification of Aerosol Hydrofluoroalkane Elimination Kinetics in the Exhaled Breath of Asthmatics
Inhaled corticosteroids (ICS) are the first line of asthma treatment. However, one of the most vexing problems facing clinicians and researchers has been the lack of technologies to measure treatment compliance. Patient self-report of ICS use is notoriously inaccurate. The clinician’s inability to quantify compliance can confound treatment of both acute and chronic asthma. This proof-of-concept research will explore a novel, noninvasive way to gauge inhaler use by measuring in the exhaled breath the biologically inactive aerosol propellant used in asthma medications. Hydrofluoroalkane (HFA) is the most commonly used aerosol propellant. We hypothesize (based on preliminary healthy subjects’ data) that HFA can be detected in the exhaled human breath for at least 48 hours with washout patterns that are amenable to pharmacokinetic analysis. Our team of biomedical engineers, chemists, and pulmonologists has experience in generating novel information about breath biomarkers relevant to diseases (nitric oxide for asthma). In addition, these studies are possible because of our collaboration with the Atmospheric Volatile Organic Chemistry lab, established by the late Nobel Laureate F. Sherwood Rowland at our institution; in which parts-per billion (ppb) and parts-per-trillion (ppt) detection range is uniquely achievable.
Specific Aims. Our goal is to measure HFA concentration in the exhaled breath following ICS administration in order to establish for the first time in asthmatic individuals a reliable estimate of HFA elimination kinetics in the lung. The Specific Aims are:
1. To quantify the elimination kinetics of HFA in the exhaled breath following an inhaled dose in participants with non-symptomatic mild-moderate asthma and with symptomatic asthma on ICS treatment.
2. To compare breath HFA levels with biomarkers of clinical assessments such as lung function (PFTs) and inflammation (exhaled nitric oxide).
The proposed research begins to test an innovative noninvasive approach utilizing HFA in the exhaled breath toward monitoring ICS compliance. If breath HFA can be reproducibly detected and quantified following inhaler usage, the proposed methodology could open new fields of asthma managements. We anticipate that proposed Specific Aims 1 and 2 will be completed in one year under the Pilot grant support from UCI ICTS. Then, future study Aims will be: A) To relate breath HFA concentrations with circulating levels of i) HFA and ii) active asthma medication (i.e., Fluticasone); and B) To search for as yet undiscovered exhaled breath biomarkers of drug metabolism. We foresee that the proposed research will eventually contribute to the development of a device for bedside, field, or other clinical venues for rapid and accurate monitoring of ICS adherence based on this novel approach.
Alan Widgerow, MBBCh, FCS, MMed, FACS
Signaling Profile of Thermal Trauma (SPoTT) - Exudate (Fluid) Analysis in Acute Burn Patients - A Diagnostic Test and Device with Therapeutic Potential
The purpose of this Research is to assess the extent and nature of the outpouring of signalmediators in burn wound exudate in the first 48 hours of the burn injury, examining the relationship betweenthese levels and the depth of burn, with the ultimate goal of controlling the extent of the signal elaboration withinteractive dressings / devices. This control may well influence the consequent tissue damage, systemiccomplications (SIRS) and final outcome of the burn injury. Additionally blood levels and exudate levels ofmediators will be compared to assess a correlation or lack there-of. Aim 1: Compare and contrast the levels of selected inflammatory mediators within the first 48hrs of a burn injury in the blood stream versus the wound exudate. Define a diagnostic (SPoTT) test anddevelop a unique SPoTT fluid collection device. Aim 2: Select two separate areas of measurement within the same burn patient corresponding to asuperficial burn and a deeper burn and measure both burn wound exudates to establish if there is arelationship to depth of burn and healing outcome with the level of inflammatory mediators. Aim 3 : Use nanocrystalline silver dressing that has strong anti-inflammatory component (Ag°) and assess theeffect on the SPoTT mediator profile in the exudate and correlate with the healing outcome;Once the diagnostic test is defined, a number of other dressing or mediator antagonist options canbe explored and tested for therapeutic efficacy. Isolation of signaling profiles and analyzing their consequences has important therapeuticimplications. In this regard new publications have highlighted accelerated healing including re-epithelialization,collagen deposition, and wound contraction by modulating the cytokine profile. Irrespective of thepathophysiologic hypotheses detailed above, it is apparent that a standardized diagnostic measuring thesignaling profile in acute burn wound exudates is sorely needed. This would allow objective measurement oftissue damage and potential therapeutic interventions in the form of medical device/ dressings to counteract orbalance these mediators with a possible effect on the healing outcome and complications. Furthermore thefluid collection device, based on microfluidic technology, is marketable, particularly when the later extensions(therapeutic instillation capacity and thermographic sensor for assessing perfusion and depth of burn) aredeveloped.
Xiaolin Zi, MD, PhD
A novel mechanism of targeting LEF1 for treatment of castration-resistant prostate cancer
Nearly 34,000 men are expected to die of castration resistant prostate cancer (CRPC) this year in the U.S. The options for treatment of CRPC are limited and not curative. Therefore, there is an urgent need to develop more effective and targeted novel therapies. The development of new therapies may be guided by considerations of the unique biological characteristics present in CRPC. An example of such a target may be the lymphoid enhancer binding factor-1 (LEF-1). LEF-1 acts in downstream of the canonical Wnt signaling, binding to Wnt response elements to regulate expression of multiple cancer genes (i.e. c-Met, survivin, cyclin D1). LEF-1 has been considered to be an oncogene. The interaction and competitive relationship between androgen receptor and β-catenin/LEF-1 (Li H, et al. J Biol Chem. 279:4212-20, 2004) suggest that castration (androgen deprivation) result in an enhanced Wnt signaling leading to castration resistance. Indeed, the mRNA levels of LEF-1 in LNCaP-AI (androgen-independent variant of LNCaP) cells was reported to be 100-fold higher than that in its parent LNCaP cells. In addition, LEF-1 was found to be overexpressed in metastatic prostate cancer (PCa) compared to benign prostate and primary PCa (Li Y et al. Cancer Res 69: 3332-8, 2009). Furthermore, in normal prostate development, LEF-1 was shown to be able to identify an androgen-independent population of prostate progenitors (Wu X, et al. Mol Endocrinol. 25:1018-26, 2011). In our preliminary studies, we have identified a novel small-molecule Wnt inhibitor with an IC50 value of about 20nM through a high throughput screen of inhibitors of LEF/TCF transcription reporter activity from 76,000 compounds. The Wnt inhibitor, named SULF-1, does not alter levels of β-catenin, nor inhibit proliferation, or promote differentiation of cardiogenic stem cells at concentrations that block TCF transcription activity. We have further shown that SULF-1 caused a slower mobility shift of LEF-1 in a Western blot analysis, suggesting that SULF-1 may affect post-translational modification of LEF-1 (e.g. phosphorylation, etc.). SULF-1 treatment led to the blockade of LEF-1 transcriptional activity; however, it did not affect cytoskeletal functions of β-catenin in the stabilizing adheren junctions in the cell membrane nor change the stem cell functions. Therefore, SULF-1 may have the potential to specifically target the transcriptional activity of LEF-1. In addition, we have demonstrated that SULF-1 selectively and potently inhibited the growth of CRPC cells at nM concentrations (IC50s are from 23 to 95 nM) with minimal effect on the growth of non-malignant prostate epithelial cells. SULF-1 also induced apoptosis in prostate cancer cell line PC3 by down-regulation of Wnt target gene survivin. Taken together, we suggest that SULF-1 is a cancer-specific and druggable Wnt inhibitor that deserves further preclinical investigation. We hypothesize that SULF-1 inhibits the Wnt pathway in CRPC via post-translational modification of LEF-1. Therefore, the goal of this pilot project is to generate preliminary data that would convince the NIH and DOD funding agencies that SULF-1 or its derivatives, through targeting LEF-1, as a novel compound for treatment of CRPC will lead to an Investigational New Drug (IND) application in the future.