VOLUME 13 • 2020 • SUPPLEMENT 2

WHAT’S INSIDE: FRONTIERS RESEARCH DAY 2020 ABSTRACTS •ORIGINAL RESEARCH • COMMENTARY • LETTER TO THE EDITORTA BL E OF CON T EN TS
PREFACEORIGINAL RESEARCH
2
A Randomized, Double-Blinded, Placebo-Controlled, Cross Over Study Evaluating the Efficacy and Safety of
Timolol Ophthalmic Solution as an Acute Treatment of Migraine
Dipika Aggarwal, M.D., Andrew J. Heim, CCRP, Brennen Bittel, D.O., Deetra Ford, M.D., Richard Dubinsky, M.D.,
Gary Gronseth, M.D., Vernita Hairston, M.D., Patrick Landazuri, M.D., Fred Sachen, M.D., Laura Herbelin, CCRP,
Richard J. Barohn, M.D.
6

Development of Silica-Immobilized Vaccines for Improving Thermo-Tolerance and Shelf-Life
Nicole Montoya, B.S., Ch.E., Kaylee Barr, Brian Kirchhoff, Edward Reyes, Jorge Umana, Kalena Nichol,
Eric Hartman, William Picking, Ph.D., Fei Phillip Gao, Ph.D., David R. Corbin, Ph.D., Mark B. Shiflett, Ph.D.

10

Methotrexate Polyglutamation in a Myasthenia Gravis Clinical Trial
Mamatha Pasnoor, M.D., Andrew J. Heim, CCRP, Laura Herbelin, CCRP, Jeffrey Statland, M.D.,
Mazen M. Dimachkie, M.D., Mara Becker, M.D., Richard J. Barohn, M.D., Methotrexate in MG Investigators of
the Muscle Group StudyCOMMENTARY
14 Development of GCRC and CTSA Programs at the University of Kansas Medical Center: A Personal 10-year
Perspective
Richard J. Barohn, M.D.
20 Navigating the NIH Public Access Policy for Peer-Reviewed Manuscripts: Why and How to get a PMCID 		
NumberRobin Liston, MPH, Richard J. Barohn, M.D.
24

Step-by-Step Guide for Setting up a Company in Kansas and Missouri
James W. Mitchell, Ph.D., Steve O’Connor, Ph.D., Maria Meyers, Rajiv Kulkarni, Richard J. Barohn, M.D.

26

Dedicated to the Pipeline: KU Frontiers’ Pursuit of Maintaining and Cultivating the Careers of Current andFuture Physician-Scientists
Amy M. Smith, M.S., MBA, Won S. Choi, Ph.D.

LETTER TO THE EDITOR
29 Letter to the Editor: A Randomized, Double-Blinded, Placebo-Controlled, Cross Over Study Evaluating the
Efficacy and Safety of Timolol Ophthalmic Solution as an Acute Treatment of Migraine
John C. Hagan III, M.D., FACS, FAAOFRONTIERS RESEARCH DAY ABSTRACTSKANSAS JOURNAL of M E D I C I N E

PREFACE
Frontiers Edition
February 2020
This is the first year that Frontiers: University of Kansas Clinical and Translational Science Institute has had the privilege of having anentire edition of the Kansas Journal of Medicine – a terrific academic, open-access publication – dedicated solely to Frontiers research. We
are also excited to have this Frontiers-focused issue published to coincide with our annual Frontiers Research Day, which aims to highlight thetranslational research being done throughout the region and to facilitate interdisciplinary collaborations.
Every abstract, commentary and paper in this volume was facilitated by Frontiers and truly showcases the breadth of support the CTSI
provides across the translational research spectrum. Contributors in this issue range from pre-doctoral TL1 trainee scholars to administrative
staff to senior investigators from not only the University of Kansas Medical Center, but also from the University of Kansas – Lawrence, theUniversity of Kansas School of Medicine – Wichita, the University of Missouri – Kansas City and Children’s Mercy - Kansas City.
Frontiers is part of a national network of medical research institutions working together to speed the research process from scientific discovery to patient care. We are supported by a five-year, $25 million grant from the National Center for Advancing Translational Sciences (NCATS)of the National Institutes of Health (NIH). Frontiers provides support to investigators and their teams across the spectrum of translational
research, from animal health studies to community-based and population health outcomes research. We would like to express our appreciation
to Dr. James Kallail for making this Frontiers’ issue of the Kansas Journal of Medicine possible.

Guest Editors:
Richard J. Barohn, M.D.
Director, Frontiers: University of Kansas Clinical and Translational Science InstituteVice Chancellor for Research
Gertrude and Dewey Ziegler Professor
University Distinguished Professor, Department of Neurology
University of Kansas Medical Center
William M. Brooks, Ph.D.
Associate Director, Frontiers: University of Kansas Clinical and Translational Science Institute
Co-Director of Team Science, Frontiers: University of Kansas Clinical and Translational Science Institute
Director, Hoglund Biomedical Imaging Center
Professor, Department of Neurology
University of Kansas Medical Center
Kim S. Kimminau, Ph.D.
Associate Director, Frontiers: University of Kansas Clinical and Translational Science Institute
Co-Director of Team Science, Frontiers: University of Kansas Clinical and Translational Science Institute
Professor, Family Medicine Research
University of Kansas Medical Center
Marion During, M.A.
Communication Specialist, Frontiers: University of Kansas Clinical and Translational Science Institute
University of Kansas Medical Center1

A Randomized, Double-Blinded, PlaceboControlled, Cross Over Study Evaluating the
Efficacy and Safety of Timolol Ophthalmic
Solution as an Acute Treatment of Migraine
Dipika Aggarwal, M.D., Andrew J. Heim, CCRP,
Brennen Bittel, D.O., Deetra Ford, M.D.,
Richard Dubinsky, M.D., Gary Gronseth, M.D.,
Vernita Hairston, M.D., Patrick Landazuri, M.D.,
Fred Sachen, M.D., Laura Herbelin, CCRP,
Richard J. Barohn, M.D.
University of Kansas Medical Center, Kansas City, KS
Department of Neurology

Received Feb. 10, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction. Daily oral beta-adrenoreceptor antagonist has beenshown to be effective in preventing migraine headaches. Timolol 0.5%
ophthalmic solution is a non-selective beta-adrenoreceptor antagonist, where the primary use is for glaucoma. There have been casereports that timolol is effective in aborting or improving an acutemigraine headache. The objective of this study was to assess theefficacy (decrease of ≥ 50% in pain scale at 120 minutes) of timolol
0.5% ophthalmic solution compared to placebo in acute treatment of
migraine headache.
Methods.xWe performed a randomized, double-blind, crossover,placebo-controlled, study. Study entry criteria required subjects tohave one to eight migraine episodes per month. The primary outcome
was comparison of the change in a visual analog pain scale (VAS) at
120 minutes after taking the study medication. Study subjects were
given a pain scale with a range of 1 (no pain) to 10 (most severe pain)
to complete after onset of migraine but before administration of study
drops and 120 minutes after administration of study drops. Improvement was defined as a ≥ 50% decrease in pain scale.
Results. Nineteen subjects completed the study and were used foranalysis. The primary outcome changes in pain scale, 120 minutes
after dose, showed a similar decrease for placebo and drug with aslightly wider 95% CI for placebo. Six subjects in each arm experienced a ≥ 50% decrease in pain scale.
Conclusion. These results support that timolol 0.5% ophthalmic
solution is not an efficacious treatment for acute migraine headache.
Kans J Med 2020;13(Suppl 2):2-5.
INTRODUCTION
Migraine is a common, disabling neurological disorder, affecting 10– 12% of the U.S. population; 18% women and 6% men.1 The treatmentof migraine headache includes preventive therapies and abortive therapies. There are several preventive therapies available with the goal todecrease the overall frequency and intensity of migraine attacks. The
abortive medications are used during acute migraine episode. There
are several methods that are used for migraine abortive therapy, suchas triptans and NSAIDs.
Despite the various migraine abortive therapies available, there isan ongoing need for novel therapies. Beta-blocker medications have

KANSAS JOURNAL of M E D I C I N E
been used for migraine prevention for decades. However, their use for
migraine abortion has not been well-identified.
Oral beta-blockers are a class of medications frequently used tocontrol blood pressure, angina, and heart irregularities. Certain oral
beta-blockers, such as propranolol, are used on a daily basis to prevent
migraines. Both topical and oral timolol can be used daily prophylactically to decrease the frequency of migraine.2-5 However, propranolol
and timolol tablets have not been shown to be effective as an acutetreatment to stop attacks of migraine because of their longer onsetof action.
In this study, we tested the use of topical beta-blocker eye drops
for acute treatment of migraine headache. It was proposed that betablocker eye drops, since they are quickly absorbed unlike tablets, canbe beneficial and efficacious in the treatment of headache abortion. A
prior case series of seven cases reported a substantial benefit of beta
blocker eye drops in acute migraine in all patients.6 The case series
was published with four editorials in the same journal recommendingthat further studies be done in the form of randomized-controlled
trials.7-10 We now report a randomized, placebo-controlled, blindedcontrolled trial to test the use of timolol for acute migraine headache.
METHODS
Trial Design. We performed a randomized, double-blind,crossover, placebo-controlled, study containing a screening visit, adouble-blind treatment phase, and an end-of-study visit. The University of Kansas Medical Center was the only site as part of the study
that enrolled patients from April 2017 to February 2018.
Standard Protocol Approvals, Registrations, and Patient Consents. The trial was approved by the Institutional Review Board at the
University of Kansas Medical Center. Written informed consent was
obtained by all participants, in accordance with the Declaration of
Helsinki and the principles of Good Clinical Practice. This study was
registered at clinicaltrials.gov (NCT03836664).
A total of 26 subjects were enrolled in a randomized, double-blindfashion. Participants ranged in age from 22 - 64 years; 25 female
and one male. Subjects enrolled had a diagnosis of migraine with orwithout aura according to ICHD-2 criteria for at least one year prior
to informed consent. Frequency of migraine episode was between
one to eight migraines per month for inclusion. Women of childbearing potential had to complete a negative pregnancy test and practiceeffective birth control methods throughout the duration of the study.
Patients were excluded if they were not able to distinguish between
migraines and headaches; had headaches at a frequency greater than
15 days per month; used chronic opioid therapy for headaches; hada history or signs and symptoms of ischemic cardiac syndromes; ahistory of glaucoma and/or current treatment with prescription eye
drops; history of naso-lacrimal duct obstruction or surgery; treatment
for any severe ophthalmic disease; physical problems or coordination difficulty or eye avoidance sensitivity that would preclude proper

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

2

KANSAS JOURNAL of M E D I C I N E
OPTHAMOLIC TIMOLOL FOR MIGRAINE
continued.
installation of eye drops; history of uncontrolled asthma, COPD, diabetes mellitus, hyperthyroidism, or reversible airway disease; historyof clinically symptomatic bradycardia, congestive heart failure, or
hypotension; and a history of drug or alcohol abuse as defined by
DSM-IV criteria.
Baseline characteristics include the location, symptom, and character of migraines experienced by enrolled subjects. Frontal was themost common location migraines were experienced at 42% of study
population. The different characters associated with migraines experienced by the study population were throbbing, pulsating, sharp,
stabbing, and pressure. Symptoms associated with migraines werealso recorded. Symptoms recorded were photophobia, nausea, phonophobia, and visual.
Outcomes and Measures. Baseline characteristics included
gender, age, and ethnicity. Migraine history was also collected
including frequency, location, character, and associated symptoms.
Subject-reported pain scales, satisfaction questionnaires, adverse
events, and concomitant medications were assessed at visit two andvisit three.
The primary end point of the study is to compare differences inheadache severity at 120 minutes between study medication andplacebo. Study subjects were given a visual analog pain scale (VAS)
with a range of 0 (no pain) to 10 (most severe pain) to complete at
two different time points: at onset of migraine and before administration of study drops, and at 120 minutes after administration of
study drops. To account for the crossover design, the mean differencein the change in headache severity following placebo compared totimolol for each patient along with its 95% confidence interval was
calculated.
The secondary end points were to assess subject satisfaction withtreatment, proportion of subjects with at least a 50% decreased inpain severity at two hours, and safety. Patients were given a Treatment
Satisfaction Scale to be completed 120 minutes after administration of study drops. The Treatment Satisfaction Scale contained fiveitems: not satisfied at all, somewhat not satisfied, neutral, somewhat
satisfied, and very satisfied. Adverse events were recorded at two
timepoints throughout the study for safety.
Randomization and Blinding. Patients were randomly assigned
to timolol 0.5% solution or placebo based on their subject number atthe baseline visit. Subjects were assigned study IDs in the numerical order they were enrolled. Consistent with the design of thecrossover study, patients that did not receive timolol 0.5% solution
at the baseline visit were given timolol at visit two and vice versa.
The investigator, study staff, and subjects were blinded to treatment
assignment.
Sample Size and Calculation. A total of 26 subjects were enrolled
in the study. Twenty subjects were needed to have an 80% chance ofdetecting a one-point difference in the change in pain scores between
the two arms, at an alpha of 0.05.

3

RESULTS
Twenty-eight patients were screened for eligibility; 26 wereenrolled. Reasons for screen failure included headache frequency
greater than 15 episodes per month and not experiencing a migraine
within a month after being enrolled. One patient dropped out of thestudy and six patients did not complete the study. Nineteen total participants completed the study and were used for analysis.
Out of the 26 subjects enrolled, participants were nearly exclusively female (96%) and an average age of 41 years (range 21 - 63).
Participants averaged three migraine episodes per month with arange of one to eight episodes per month. The most common character of migraines was throbbing (96%) and nausea (77%) was the mostcommon symptom (Table 1).
Table 1. Baseline characteristics of migraines.
Symptom

Number%Photophobia

25

96

Nausea20

77

Phonophobia

1350

Visual2

8Location

Number%

Frontal11

42

Occipital

8

31

Holocephalic

831

Temporal

4

15

Character

Number%Throbbing25

96

Pulsating

6

23

Sharp

4

15

Stabbing

3

12

Pressure

1

4

Table 2 shows the raw data. Pain reductions were not significantly
different following placebo or timolol treatment. Table 3 shows themean difference of differences in change in pain, 0.1 (SD 2.6) VAS
points favoring placebo, 95% CI -1.1 to 1.3. Similarly, there were no
significant differences in the number of patients reporting 50% ormore reduction in pain severity (six for each treatment) or for satisfaction with treatment (timolol = 3, placebo = 6).
One adverse event was experienced throughout the study, which
was a mild stinging/burning sensation in the eye shortly after administration of eye drops. Each was graded mild, related, and all subjects
recovered. Four of 19 study completers experienced this adverse
event.

			KANSAS JOURNAL of M E D I C I N E																	OPTHAMOLIC TIMOLOL FOR MIGRAINE
continued.

Table 2. Summary of subject responses while using timolol and placebo.
Drug
Subject number

Pain scale before drug

Pain scale 120 min. after drug

Delta

Percent decrease≥ 50%aSatisfieda

M001

7

3

4

57

1

0

M003

3

0

3

100

1

1

M004

9

8

1

11

0

0

M006

8

6

2

25

0

0

M007

8

8

0

0

0

0

M009

8

8

0

0

0

0

M010

4

6

-2

-50

0

0

M011

6

6

0

0

0

0

M012

8

3

5

63

1

0

M013

9

4

5

56

1

0

M014

10

4

6

60

1

1

M016

9

7

2

22

0

0

M017

7

7

0

0

0

0

M019

7

6

1

14

0

0

M021

8

5

3

38

0

0

M022

5

4

1

20

0

0

M023

8

4

4

50

1

1

M024

7

5

2

29

0

0

M025

7

6

1

14

0

0

M001

7

3

4

57

1

1

M003

2

2

0

0

0

0

M004

7

4

3

43

0

0

M006

9

3

6

67

1

1

M007

7

4

3

43

0

1

M009

8

8

0

0

0

0

M010

5

7

-2

-40

0

0

M011

5

4

1

20

0

0

M012

7

1

6

86

1

1

M013

9

5

4

44

0

0

Placebo

a

M014

8

9

-1

-13

0

0

M016

9

4

5

56

1

1

M017

6

7

-1

-17

0

0

M019

6

7

-1

-17

0

0

M021

7

5

2

29

0

0

M022

6

6

0

0

0

0

M023

4

2

2

50

1

0

M024

7

2

5

71

1

1

M025

7

7

0

0

0

0

≥ 50% decrease and satisfaction coded 0 = no, 1 = yes.

Table 3. Change in VAS.*
Timolol

PlaceboOnset

Two hours

Delta

Onset

Two hours

Delta

7.3 (1.7)

5.3 (2.0)

2 (2.1)

6.63 (1.7)

4.7 (2.2)

1.9 (2.5)*Mean (SD)4

KANSAS JOURNAL of M E D I C I N E
OPTHAMOLIC TIMOLOL FOR MIGRAINE
continued.

5

DISCUSSION
Migraine and other benign recurrent headache disorders are amajor public health problem, particularly among reproductive-aged
women. They are associated with substantial personal suffering, disability, and societal expense. The impact of migraine is substantial
because of its high prevalence, accompanying significant disability,
and risk for other comorbidities. Data from the National Ambulatory
Medical Care Survey (NAMCS), and the National Hospital Ambulatory Medical Care Survey (NHAMCS) indicate that headache isamong the top 20 reasons for outpatient medical visits and among the
top five reasons for emergency department visits. Several preventive
and abortive medications are available for the treatment of migraine
headaches. Despite of various treatments available, there seem to be
an ongoing need for novel therapies.
Certain beta-blockers medications like propranolol and timolol
have been used as a preventive therapy for migraine headaches. Theirsafety and efficacy in the prevention of migraines has been well established. In this study we used topical beta-blocker eye drops for acutetreatment of migraine attack. Topical and local application betablocker eye drops are directly absorbed through the ophthalmic andnasolacrimal mucosa and enters the blood stream within minutes.
Timolol is a non-selective beta-adrenoreceptor antagonist. Oraltimolol (20 - 30 mg daily) has been studied in three randomized controlled trials and have been found to reduce headache frequency bymore than 50% when compared to placebo.3-5 It has been approvedby FDA for prophylactic use in migraine patients and had Level A
evidence to support this indication. The prophylactic benefit of betablockers in migraine treatment is not completely understood. It may
be related to the effect of beta-blockers on central autonomic vasculartone center, which in turn modulate the cerebrovascular reactivity tosensory stimulation.11-12 Propranolol, a beta-adrenergic blocker modulates serotoninergic transmission, regulates periaqueductal pathway
activation and prevents central sensitization, normalizes neuronal
excitability in the CNS, and blocks cortical spreading depression.
Topical ocular beta blockers when used daily have been reported toprevent migraine attacks.13-14
The specific aims in this study were to 1) assess the efficacy (headache freedom at 120 minutes) of timolol 0.5% ophthalmic solution
compared to placebo in acute treatment of migraine headache; and 2)
assess the safety and tolerability of timolol 0.5% ophthalmic solution
in treatment of acute migraine headache.
The results of this randomized-controlled trial support that timolol
0.5% ophthalmic solution is not an efficacious treatment for acutemigraine headache in this group of patients.
Our results are similar to a recent report by Cossack et al.15 They
reported a randomized-controlled study of timolol in acute migraine.
Ten patients participated that reported one to eight migraine attacks
per month. In this series, the average percentage of headaches with aseverity of none or mild at 120 minutes was 57% with placebo compared with 78% with timolol. This was not statistically significant (p= 0.26). In an exit survey, four patients found timolol highly effective
compared to placebo and one patient reported placebo highly effective compared to timolol. The other five subjects did not report majordifferences between the two.
Therefore, while there is a good rationale for the use of topicalophthalmic beta-blocker medication for acute migraine, and priorcase reports suggested such a benefit, we now have two randomizedcontrolled trials that did not demonstrate a marked effect of the drug
compared to placebo. This is not to say that physicians may encounter individual patients who could report a beneficial effect of beta
blocker eyedrops for acute migraine headaches. However, we could
not demonstrate in a randomized-controlled trial the superiority ofbeta blocker eyedrops over placebo. Also, perhaps other formulations of beta blocker medications might be effective for treating acutemigraine such as sublingual or intranasal. Finally, perhaps trials witha larger number of subjects with more power to detect a difference
might show different results. Such a trial would require an externalsponsor, either a pharmaceutical industry or the NIH.
FUNDING SUPPORTThis work was supported by a Ziegler Junior Investigator Grant
from the Department of Neurology and a CTSA grant from NCATS
awarded to the University of Kansas for Frontiers: University of Kansas
Clinical and Translational Science Institute (# UL1TR002366). The
contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS.
REFERENCES

Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine
prevalence, disease burden, and the need for preventive therapy. Neurology 2007;
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Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2
and beta3 adrenoceptors. Br J Pharmacol 2005; 144(3):317-322. PMID: 15655528.
3.
Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen H, Olesen J. Timolol vspropranolol vs placebo in common migraine prophylaxis: A double-blind multicenter
trial. Acta Neurol Scand 1984; 69(1):1-8. PMID: 6367336.
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Standnes B. The prophylactic effect of timolol versus propranolol and placebo incommon migraine: Beta-blockers in migraine. Cephalalgia 1982; 2(3):165-170. PMID:
6758949.
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Stellar S, Ahrens SP, Meibohm AR, Reines SA. Migraine prevention with timolol.
A double-blind crossover study. JAMA 1984; 252(18):2576-2580. PMID: 6387197.
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Migliazzo CV, Hagan JC. Beta blocker eye drops for treatment of acute migraine. Mo
Med 2014; 111(4):283-288. PMID: 25211851.
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Hagan JC. Are drops the solution? A eureka moment? Beta blocker eye drops for
acute migraines. Mo Med 2014; 111(4): 280-281. PMID: 25211850.
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French BR, Singh NN. Beta blocking eyedrops in acute migraine: A novel use of anold drug. Mo Med 2014; 111(4):289-291. PMID: 25211852.
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Dexter JK, Cady RK. Ophthalmic beta blockers: Treatment for acute migraine? Mo
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Chung SM. Can topical beta blockers be successful for acute migraine management?
Mo Med 2014; 111(4):294-296. PMID: 25211854.
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Min JH, Kwon HM, Nam H. The effect of propranolol on cerebrovascular reactivity to visual stimulation in migraine. J Neurol Sci 2011; 305(1-2):136-138. PMID:
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Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR. Neurobiology of
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Bhagey J, James B. Topical timolol prevented migraine attacks. Eye (Lond) 2004;
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Chiam PJ. Topical beta-blocker treatment for migraine. Int Ophthalmol 2012;32(1):85-88. PMID: 22278763.
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Cossack M, Nabrinsky E, Turner H, Abraham A, Gratton S. Timolol eyedrops in
the treatment of acute migraine attacks: A randomized crossover study. JAMA Neurol
2018; 75(8):1024-1025. PMID: 29799915.
1.

Keywords: migraine, headache, beta-blocker, opthamolicDevelopment of Silica-Immobilized
Vaccines for Improving Thermo-Tolerance
and Shelf-Life

Nicole Montoya, B.S., Ch.E.1, Kaylee Barr1, Brian Kirchhoff1,
Edward Reyes1, Jorge Umana1, Kalena Nichol1, Eric Hartman1,
William Picking, Ph.D.2, Fei Phillip Gao, Ph.D.3,
David R. Corbin, Ph.D.4, Mark B. Shiflett, Ph.D.1,4
University of Kansas, Lawrence, KS
1
Department of Chemical and Petroleum Engineering
2
Pharmaceutical Chemistry3
Shankel Structural Biology Center
4
Center for Environmentally Beneficial Catalysis
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction. It is estimated that 50% of vaccines produced annually are wasted because effectivity is dependent on protein structureand heat exposure disrupts the intermolecular interactions thatmaintain this structure. Since 90% of vaccines require a temperaturecontrolled supply chain, it is necessary to create a cold chain system
to minimize vaccine waste. We have developed a more sustainable
technology via the adsorption of Invasion Plasmid Antigen D (IpaD)
onto mesoporous silica gels, improving the thermal stability of protein-based therapeutics.
Methods.xThe solution depletion method using UV-Vis was utilized to study the adsorption of IpaD onto silica gels. The silica-IpaDcomplex is heated above the denaturing temperature of the protein
and then the IpaD is removed using N,N-Dimethyldodecylamine
N-oxide (LDAO) and their secondary structure is tested using circular dichroism (CD).
Results. Pore diameter, pore volume and surface area were characterized for seven different silica gels. Silica gels designated as 6389,
6378, and 6375 had an adsorption percentage above 95% at porevolumes of 2.2, 2.8 and 3.8 cm3 mg-1, respectively. CD analyses confirmed that the adsorbed IpaD after the heat treatment displayed asimilar “W” shape CD signal as the native IpaD, indicating the conservation of α-helices. In contrast, the unprotected IpaD after being
exposed to high temperature shows a flat CD signal, demonstrating
the loss of secondary structure.
Conclusion. We have successfully increased the thermo-tolerance
for IpaD using mesoporous silica and continue to further optimize
mesoporous silica’s physiochemical properties to improve adsorption
and desorption yields. Kans J Med 2020;13(Suppl 2):6-9.
INTRODUCTION
Temperature-sensitive substances composed of proteins, enzymes,
and antibodies are inherently unstable at ambient temperature
because they lose their secondary structure and their activity overtime. This is a particularly sensitive issue for protein-based medications, such as vaccines, as their storage and handling usually requires
continuous cold chain transportation (2 to 8°C) to maintain theirfunctional properties. Cold chain logistics are expensive and prone
to disruptions, which often leads to rapid loss of protein potency
and deactivation, creating serious concerns for global public health.1

KANSAS JOURNAL of M E D I C I N E
Although there have been several efforts to develop successful
approaches for enhancing the long-term thermal-stability of proteins and vaccines, including pegylation,2 addition of excipients,3,4
biomineralization5 and nanopatches.6 These methods are unable toprovide satisfactory thermal stability, while ensuring the delivery ina biologically active form at the point of care, particularly in developing countries. Thus, the development of innovative and cost-effective
strategies capable of protecting thermo-sensitive substances would
eliminate the need for an uninterruptible cold chain and help to solve
one of the most important issues associated with vaccine wastage.
Such advancement can help to ensure that proper treatment is delivered safely and efficiently to the patient, from vaccine production to
the patient bedside.
Silica gels have demonstrated the ability to retain protein structureand functionality.7,8 Some of the most relevant advantages of silicas
in protein adsorption include: high thermal stability, useful porosity
range for proteins, simple chemistry, mild pH, tunable surface chemistry, and encapsulated biomolecular samples that retain high activity.
Shigellosis is a gastrointestinal disease that causes over a million
deaths annually,9 especially in developing countries and among children.10 Shigella flexneri, the bacteria that is responsible for causing
Shigellosis, is spread through the fecal-oral route and only a very low
dose is needed for causing an infection.11 S. flexneri is acid-tolerant,
and once it reaches the large intestines, it is transcytosed throughM cells.9,12 At this point, the bacteria induces apoptosis in macrophages and invades epithelial cells using a type-III secretion system(TTSS).13 Invasion plasmid antigen D (IpaD) has a crucial role in
TTSS, as it controls the secretion of IpaB and IpaC. All three Ipa
proteins must be released for epithelial cell invasion.14
Currently, there is no existing vaccine for shigellosis15 despiteextensive attempts to formulate a vaccine against this bacteria.16,17,18
This is because previously developed vaccines have shown high reactogenicity in human trials.19 IpaD is a promising target for shigellosis
vaccine development since it has already been demonstrated that
IpaD antibodies are present in serum from infected patients.20,21
Circular dichroism (CD) and Fourier transform infrared (FTIR)
have proven that IpaD is predominantly an alpha-helical protein.13,22
IpaD has a high thermal stability with denaturing occurring above
80°C. Approximately 13% of IpaD is made up of serine amino acids,23
which are able to form hydrogen bonds at the surface of the silica asshown in Figure 1. Therefore, it is possible to encapsulate IpaD withinmesoporous silica and prevent protein denaturation.
METHODS
Adsorption. Silica gel particles were crushed and sifted to a particle size of 90 - 150 μm. Then 0.7 mL of IpaD in 1xPBS buffer at
1.5 mg/mL was added to 30 mg of silica. The solution was mixed on
the ThermoMixer at 950 rpm and 25°C for 20 hours. The samples
were centrifuged at 14,800 rpm for four minutes at ambient temperature to separate the silica-IpaD complex from the supernatant.

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6

KANSAS JOURNAL of M E D I C I N E
SILICA-IMMOBILIZED VACCINES
continued.

The solution depletion method was utilized to determine the amountof IpaD transferred from the solution into the silica, such that thesupernatant concentration indirectly determined the proteins
adsorbed. The concentration of the supernatant was measured at
280 nm with an IpaD extinction coefficient of 9.48 M-1cm-1 using the
Nanodrop 2000 UV-Vis spectrophotometer. The supernatant concentration was used along with the original concentration of IpaD toquantify the adsorption process in Equation 1:
Percent adsorption = (1-(Supernatant IpaD concentration)/(Inital IpaD concentration))*100

Figure 1. Hydrogen bonds between IpaD and mesoporous silica.

Washing. The unbound proteins in the supernatant were extracted by removing the supernatant from the silica-IpaD particles. A
sample containing 0.6 mL of 1xPBS was added to the silica to remove
any unattached IpaD trapped within the silica particles. The vials
were mixed briefly to loosen the unbound proteins then centrifuged
at 14,800 rpm for four minutes, and the wash supernatant was
extracted. The washing method was repeated twice, with the exception that 1xPBS was not added back to the sample vial on the third
wash. The supernatant of each wash was combined into a single vial,
and the concentration was measured.
Heating. The samples were then placed on the ThermoMixer at
95°C for two hours at 950 rpm. The samples were allowed to cool
down to room temperature for at least 30 minutes.
Desorption. To detach the proteins from the silica gel, 0.7 mLof 10% LDAO was added to each sample. The samples were thenmixed at 950 rpm and 25°C for 20 hours. Finally, the samples were
centrifuged at 14,800 rpm for four minutes and the percent IpaD
desorption was calculated using the equation:
Percent desorption= ((Mass of desorbed IpaD)/(Mass of IpaD
on silica after wash))*100
Circular Dichroism. A Jasco J-1500 Circular Dichroism Spectrophotometer instrument was used to evaluate the secondary
structure of chiral protein samples at a temperature of 15°C over a
wavelength range of 190 - 260 nm. Before CD measurements were
performed, the samples were diluted to 0.4 mg/mL in 10% LDAO
which is within the required concentration range of 0.2 - 0.5 mg/mL.
The nitrogen flowrate was set at 30 SCFH. A 1 cm pathlength quartz
cuvettes was cleaned using 2% Hellmanex II solution to remove any

7remaining biological specimen from previous runs. Then the cuvettes
were thoroughly washed with milliQ water before purging with nitrogen to remove remaining moisture. The cuvettes were filled with 250
μL of sample and placed in the cuvette holder in the instrument. The
raw data from CD was reported in Q (mdeg). This was converted tomolar ellipticity to account for the concentration of the sample andproperties of IpaD using the equation:
θ=(Q∙100∙MW)/(C∙l∙n∙1000)
MW represents the molecular weight of the protein sample and n
represents the number of amino acids. For IpaD, these values are
38825.29 Da and 352, respectively. C is the concentration of thesample in mg/mL, and it is found at 280 nm using UV-Vis absorbance
spectrophotometry. The length (l) of the quartz cuvette is 1 cm for the
J-1500 instrument.
RESULTS
Physiochemical Characterization. The physicochemical properties of seven mesoporous silica gel materials were characterized togenerate a “tool box” with a range of physicochemical properties. The
material selection criteria for the immobilization of IpaD were correlated between the physico-chemical properties of the support (poresizes, volumes and shapes, and surface functional groups) and withthose of the protein. The physico-chemical properties of selected
mesoporous silica gel materials used as supports for the protein thermal-stabilization studies are provided in Table 1. The identificationof the specific silica gels (6360, 6369, 6765, 6389, 6378 and 6395)
are confidential and a patent application is being prepared for filing.
Table 1. Physicochemical characterization of selected mesoporous silica gel materials.
CEBC code

Average pore Accessible pore
diameter (nm) volume (cm3/g)
1.41

Accessible surface
area (m2/g)

6339

17.7

319.3

6360

3.9

0.07

39.0

6369

8.1

0.30

125.6

6378

36.3

2.87

286.1

6389

24.2

2.18

370.7

6395

30.2

3.78

300.0

6765

15.0

1.28

332.0

Effect of silica pore volume on IpaD percent adsorption. After
improving the protocol to adsorb IpaD onto various silica gel materials, the material properties with the most impact on the adsorption
efficiency of IpaD were investigated. Our results show that the successful adsorption of IpaD protein is strongly influenced by the porevolume of the silica gel material (Figure 2). We define accessible porevolumes as the pores with diameters ≥ 5 nm.
IpaD secondary structure. To assess whether the adsorption
into silica-based supports protects the protein against high temperatures, the IpaD adsorbed onto the silica gels was heated to 95ºC for
2.5 h, desorbed from the support, and then analyzed by CD. Nonadsorbed (native) IpaD which was not heated was used as control.
The CD analyses demonstrate that the adsorbed IpaD after the heat
treatment (and desorption step) displays a similar “W” shape CD
signal as the native unheated IpaD.

KANSAS JOURNAL of M E D I C I N E
SILICA-IMMOBILIZED VACCINES
continued.

Figure 2. Average percent of IpaD adsorbed to mesoporous silica gel materials
as a function of accessible pore volumes (cm3/g).

DISCUSSION
Effect of silica pore volume on IpaD adsorption. The adsorption of IpaD onto various mesoporous silicas has been hypothesized
to have similar surface chemistry for all silicas tested. The adsorption process is governed by electrostatic interactions and hydrogenbonding between the hydroxyls on the silica surface and the properties of the amino acid side chains on IpaD.23 The most abundantamino acid in IpaD is serine, which makes up 13% of the structure.
This creates the potential for a high level of hydrogen bonding
between serine residues and the silica surface. As shown in Figure
2, there is a strong correlation between the pore volume of the silica
gel to the percent of IpaD adsorbed. For example, silica gel 6765 has
a pore volume of 1.29 cm3/g and adsorbs an average of 92.2% IpaD,
while silica gel 6360 has a pore volume of 0.20 cm3/g and adsorbs
an average of 9.7% IpaD. According to Figure 2, silicas with a porevolume greater than 1 cm3/g are expected to adsorb more than 90%
IpaD. The pore diameter of the silica gels followed a similar trend
to the pore volume. Therefore, silicas with larger pore volumes andpore diameters tend to adsorb more IpaD. This indicates that theproteins are not only attaching to the surface of the silica, but also
being adsorbed into the interior of the larger silica pores. IpaD’s thermostability while attached to silica during heating further supports
the idea that IpaD is confined within the pores during adsorption.
IpaD secondary structure. The purpose of this study was todemonstrate that silica gels improve the thermostability of IpaD. It
is evident from Figure 3 that the presence of silica during heating
enables IpaD to maintain its α-helical structure as shown by thecharacteristic “W” curve. The IpaD in solution completely denaturesduring heating, and the IpaD heated on silica has a small decrease inmolar ellipticity from that of the native IpaD. We hypothesize that
this decrease in molar ellipticity will not reduce IpaD’s efficacy in a
vaccine.
The source of the loss in structure for the IpaD heated on silica ismost likely due to variables other than heating. It has been commonly
reported that proteins lose some of their conformational structure
upon adsorption to a solid surface.24,25,26,27 Another possible alternative for this loss in structure is the effects of LDAO on IpaD. This
zwitterionic detergent is used at a high concentration to remove IpaD
from the silica in these studies. One problem is that LDAO increases
the high tension (HT) voltage due to the high concentration (10%LDAO). During CD experimentation, it has been observed that the

HT voltage is above the recommended value of 600 V at wavelengths
below 200 nm. This indicates that the sample is absorbing too muchlight, which means it is overly concentrated. This effect creates noisein the CD wavelength range of 190 - 200 nm, which eliminates the
expected Cotton effect peak at 195 nm that is seen in the native IpaD
sample. Furthermore, the drop in molar ellipticity in Figure 3 ispotentially due to the buffer concentration interference with the CD
signal for the protein. While it is difficult to isolate the effect of LDAO
on the CD signal from the physical effect of LDAO interactions with
IpaD, further studies have indicated that LDAO is partially denaturing IpaD during the desorption process.

Figure 3. CD spectra for IpaD heated to 95°C for 150 minutes attached to silica
gel 6339, native unheated IpaD, and IpaD denatured in PBS solution at 95°C
for two hours. The blue curve is the average of 10 samples, and the green curveis the average of two samples.

CONCLUSION
This study has successfully characterized the physiochemical
properties of different silica gels using the BJH method. With these
physiochemical properties, it was possible to determine the relationship between pore volume and percent adsorption. In general, as porevolume increases, percent adsorption also increases. The most significant result is that IpaD adsorbed in mesoporous silica has a higher
thermal stability than unadsorbed IpaD. This was confirmed by thecharacteristic W shape observed by CD, indicating the presence ofalpha helices even after heat treatment.
Future research will explore alternative desorbing agents that are
not as harsh as LDAO to reduce the small loss of protein conformational structure during desorption. The next steps will include thedesign of a device where a vaccine encapsulated in silica can be mixed
with the desorbing agent for removing the bound protein and madeready for administration to a patient.
ACKNOWLEDGEMENTS
The authors would like to thank Dr. Ana Rita C. Morais, Dr. David
Minnick, Dr. Bill Gilbert, Katie Baugess, Simon Velasquez Morales,
Channary Ny and Lily Higgins who each worked on and contributed
to the success of this project.
I

8

KANSAS JOURNAL of M E D I C I N E
SILICA-IMMOBILIZED VACCINES
continued.

FUNDING SUPPORTThis work was supported by a CTSA grant from NCATS awarded
to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (#UL1TR002366). The
contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS.
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Epler CR, Dickenson NE, Olive AJ, Picking WL, Picking WD. Liposomes
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Cohen D, Ashkenazi S, Green M, et al. Safety and immunogenicity ofinvestigational Shigella conjugate vaccines in Israeli volunteers. InfectImmun 1996; 64(10):4074-4077. PMID: 8926071.
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Keywords: mesoporous silica, shigellosis, IpaD protein, vaccinesMethotrexate Polyglutamation in a
Myasthenia Gravis Clinical Trial

Mamatha Pasnoor, M.D.1, Andrew J. Heim, CCRP1,
Laura Herbelin, CCRP1, Jeffrey Statland, M.D.1,
Mazen M. Dimachkie, M.D.1, Mara Becker, M.D.2,
Richard J. Barohn, M.D.1, Methotrexate in MG Investigators of
the Muscle Group Study*
1
University of Kansas Medical Center, Department of
Neurology, Kansas City, KS
2Duke University School of Medicine, Division ofRheumatology, Durham, NC
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction. Methotrexate (MTX) is an immunosuppressive andanti-inflammatory drug used to treat rheumatoid arthritis (RA) andother autoimmune conditions. MTX is transported into cells, where
glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported thatthe degree of polyglutamation correlates with the anti-inflammatory
effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome
measures. The objective of this study was to assess the correlation
between methotrexate (MTX) polyglutamates (MTXPGs) with
Myasthenia Gravis (MG) outcome measures.
Methods.xAn analysis was done of blood drawn from patientsenrolled in the 12-month randomized, placebo-controlled study of
MTX in MG study. Red blood cell MTXPGs were measured via ultraperformance liquid chromatography and tandem mass spectrometry.
MTXPG was correlated to MG outcome measures using Spearman
Correlation Coefficient. A two-group t-test was used to determine
the difference in MTXPG based on clinical outcome responder definitions.
Results. Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects onplacebo. Pentaglutamate had the strongest correlation with the
MG-ADL (0.99), while tetraglutamate had the strongest correlation
with the QMG (0.54). Triglutamate had the strongest correlation
with MGC (0.76).
Conclusion. There were variable correlations between MTXPG1-5
and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long
chain methotrexate polyglutamates correlate better with MG outcomes. Kans J Med 2020;13(Suppl 2):10-13.
INTRODUCTION
Methotrexate (MTX) is a disease-modifying antirheumatic drug
(DMARD) used in the management of rheumatoid arthritis (RA).
Methotrexate is a folate analogue, used in treatment of cancers andautoimmune diseases. Given orally or subcutaneously, MTX is transported into cells, where additional glutamate moieties are added
and is retained as methotrexate polyglutamates (MTXPGs). Prior
studies suggest the degree of polyglutamation correlates with the

KANSAS JOURNAL of M E D I C I N E
anti-inflammatory effect of MTX in RA. There are no prior studies
evaluating the relationship between MTXPGs and myasthenia gravis(MG) outcome measures.
Although the full molecular anti-inflammatory mechanism of
MTX is not clearly elucidated, it is known that MTX acts as a folate
antagonist. Once intracellular, MTX is bioactivated to the polyglutamated form of methotrexate (MTXglun) by folylpolyglutamyl
synthase (FPGS), which promotes cellular retention and inhibition of several enzymes.1 No or low glutamation leads to the effluxof MTX by the ATP-binding cassette (ABC) family of transporters.
FPGS and ABCG2 are of particular interest as folate deprivation has
been associated with increased expression of FPGS and decreased
expression of ABCG2,2 suggesting a cellular response to low folatewith an increase in polyglutamation and decrease in folate export topromote retention of folate within the cell. Additionally, upregulation of ABCG2 protein expression has been associated with MTX
resistance in cancer cells. Therefore, allelic variation in these genes
resulting in increased or decreased activity may be associated witheither increased or decreased MTXglun. This entire process is also
likely dependent upon the folate status of the patient, reflected by thepolyglutamation of folate itself, and the relative concentrations of thetwo groups of mutually antagonistic compounds.
As serum MTX concentrations have been notoriously unreliably
associated with MTX clinical outcomes,3-5 the search for more stablebiomarkers of diseases response to MTX have been ongoing. An
association between RBC MTXglun and effectiveness of MTX in RA
has been reported.6-7 Higher levels of “long chain MTXglun” (definedas MTXglu3 or greater) were associated with improved effectivenessof MTX in RA. There has also been reported variability of MTXglun
concentrations and patterns associated with MTX dosing routeand dose of administration in Juvenile Idiopathic Arthritis patientsprescribed this medication.8 Since RBC folate concentrations are
established during erythropoiesis and represent the average folate
status over the preceding 120 days,9 by extension, MTX concentrations in RBCs are a surrogate biomarker of average drug exposure
over a similar period of time. Furthermore, methotrexate polyglutamates in RBCs are considered to be representative of intracellular
MTX levels in target tissues, are more stable than serum levels of
MTX, and may potentially predict response to the drug.6-7, 10-11
Methotrexate may also cause hepatotoxicity,12 probably as aresult of accumulation in the liver as polyglutamates13 and can cause
increases in serum alaninine aminotransferace (ALT) and aspartate
aminotranseferase (AST).14 Renal impairment is a significant contributing factor to the occurrence of toxicities in other organ system,
particularly hematopoietic and gastrointestinal systems. Whether
methotrexate produces some degree of renal insufficiency has notbeen clearly established. Headache, dizziness, vertigo, mood changes,
seizures, ataxia and cognitive impairment have been infrequently
described.15

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

10

KANSAS JOURNAL of M E D I C I N E
METHOTREXATE POLYGLUTAMATION IN MG
continued.
We performed a randomized-controlled trial of oral methotrexate
in myasthenia gravis involving 50 subjects at 19 sites.16 Myasthenia
gravis is an autoimmune disease with antibodies derived against theacetylcholine receptor in muscle at the neuromuscular junction.17
Prednisone is the first line immunosuppressive therapy for MG.18
We studied if methotrexate would be of benefit to MG patients on
prednisone. In this study, we failed to show MTX subjects were ona lower prednisone dose at the end of twelve months, which was
our primary endpoint. Secondary endpoints such as the Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis - Activities
of Daily Living (MG-ADL) showed trends toward greater improvement in MTX subjects but did not meet statistical significance in the
pre-determined intent-to-treat analysis. When alternative intentto-treat analyses were done post-hoc, QMG and MG-ADL did meetsignificance. We also performed polyglutamation blood studies onparticipants at the conclusion of the 12-month study.
METHODS
Trial Design. Analysis was done on blood drawn from patientsenrolled in the 12-month randomized, placebo-controlled study of
MTX in MG. Red blood cell MTXPGs were measured via ultra-performance liquid chromatography and tandem mass spectrometry.19
MTXPG was correlated to MG outcome measures using Spearman
Correlation Coefficient.
Standard Protocol Approvals, Registrations, and Patient Consents. The trial was approved by the Institutional Review Board at
the University of Kansas Medical Center. Written informed consent
was obtained by all participants, in accordance with the Declarationof Helsinki and the principles of Good Clinical Practice.
Outcomes and Measures. Monoglutamate (1), diglutamate (2),triglutamate (3), tetraglutamate (4), and pentaglutamate (5) wereanalyzed for correlation to the MG-ADL scale, the QMG scale, andthe Myasthenia Gravis Composite (QMC) scale, all standard MG
research outcome measures.
Statistics. A total of 33 polyglutamate samples were collected in
the study and 21 samples were used from subjects who were on active
MTX for analysis. The differences of the outcome measures between
the baseline and end of study visit was calculated. A two-group t-test
was used to determine the difference in MTXPG based on clinicaloutcome responder definitions. We correlated MTXPG1-5 to MG
outcome measures using Spearman Correlation Coefficient.
RESULTSA total of 33 polyglutamate samples were collected in the study.
Twenty-five samples were from subjects on MTX and eight samples
were from subjects on placebo. Twenty-one samples were used foranalysis (Figure 1). The median age of subjects was 64 ± 11.3 and themale/female ratio was 16:5.

11

Figure 1. Study design.

The results of the degree of polyglutamation for each sample
are shown in Figure 2. There were variable correlations between
MTXPG1-5 and MG outcomes with a rho range: 0.08 to 0.99 (Table
1). Strong correlations were seen between MTXPG2,4,5 and MGADL,MTXPG4,5 with QMG and MTXPG3 with MGC. Both coefficients lie
between -1 and +1. The more the correlation coefficient comes closer
to -1 or 1, the more there is a correlation between two variables. Ourinterpretation of strength of correlation in this study is as follows: <0.15 = very weak, 0.15 – 0.25 = weak, 0.25 – 0.40 = moderate, 0.40 –0.75 = strong, >0.75 = very strong (Table 1).

Figure 2. Degree of methotrexate polyglutamation in MG subjects.

Table 1. Correlation of methotrexate polyglutamation and MG.
Polyglutamates*

Correlation with MG outcomes (rho)MG-ADL

QMG

MGC

Prednisone dose

Monoglutamates

0.20

0.08

0.08

0.17

Diglutamates

0.60

0.02

0.39

0.14

Triglutamates

0.38

0.19

0.76

0.36

Tetraglutamates

0.71

0.54

0.30

0.30

Pentaglutamates

0.99

0.53

0.15

-0.18

MG-ADL = Myasthenia Gravis Activities of Daily Living; QMG = Quantitative
Myasthenia Gravis; MGC = Myasthenia Gravis Composite*Bolded are strong and very strong correlations.

DISCUSSION
We found that the therapeutic effect of MTXPGs correlates with
MG clinical outcome measures used in our prospective randomized
trial. The therapeutic effects of MTX in RA depend on its conversion
to MTXPGs, so measuring intracellular MTXPGs has been proposed
as an objective method to guide MTX therapy in various disease
conditions. Most of the information on MTXPG is from rheumatoid
arthritis literature. Methotrexate helps stabilize rheumatoid arthritis
conditions. Long chain MTXPGs stay in the cell longer than shortchain MTXPG; therefore, long chain MTXPG keeps MTX in active
form longer inside the cell, hence possibly allowing MTX to work
longer. Rheumatoid arthritis literature showed higher concentrations of RBC long chain MTXPGs were associated with increased
therapeutic response to MTX. However, literature is limited in otherconditions.
This is the first study studying MTXPGs in Myasthenia Gravis
and correlating it with outcomes in a randomized-controlled trial.
We showed a wide inter-patient variability of RBC MTXPG concentrations in patients receiving similar dose of MTX therapy, which
is similar to the rheumatoid arthritis literature. Also similar to therheumatoid literature, the long chain polyglutamates (tetra andpenta) correlated well with outcomes. In this case outcomes usedwere QMG, MG-ADL, and MGC. Prior studies showed no statisticalsignificance of the MTXPGs levels with side effects; however, thisanalysis was not performed in our study. Of note, none of the subjects
who were part of this sub-study developed liver toxicity.
Although the phase II Methotrexate in MG trial was negative(did not show significant reduction in the prednisone dose under the
curve), the polyglutamate analysis showed strong correlations with
MG outcome measures. This supported our other findings that secondary outcomes showed trends in improvement when patients wereon methotrexate versus placebo.
As a result of this analysis, we believe that polyglutamation may be
a useful personalized medicine biomarker to predict clinical improvement in MG when patients are on methotrexate. However, further
studies should be done using this tool in myasthenia gravis.
FUNDING SUPPORTThe Methotrexate in MG trial was funded by the FDA Orphan
Products Division, Grant # R01FA003538. This work was also supported by a CTSA grant from NCATS awarded to the University of
Kansas for Frontiers: University of Kansas Clinical and Translational
Science Institute (# UL1TR002366). The contents are solely the
responsibility of the authors and do not necessarily represent theofficial views of the NIH or NCATS.

KANSAS JOURNAL of M E D I C I N E
METHOTREXATE POLYGLUTAMATION IN MG
continued.
*Coinvestigators: The Methotrexate in MG Investigators of the Muscle StudyGroup

University of Kansas Medical Center: Richard J. Barohn, M.D. (PI);
Mamatha Pasnoor, M.D. (co-PI); Mazen M. Dimachkie, M.D. (co-I); April
L. McVey, M.D. (co-I); Jeff Statland, M.D. ( co-I); Laura Herbelin (project
manager); J. Miller (regulatory project manager)
University of Texas Southwestern Medical Center: Sharon Nations, M.D.
(PI); Nina Gorham; Rhonda McLin, PTA
University of Texas Health Science Center San Antonio:
Carlayne Jackson, M.D. (PI); Pam Kittrell, MSN, RN; Deborah Myers, PT
University of Virginia: Ted M. Burns, M.D. (PI); Kristen Keller; Amruta
Joshi
University of Miami: Michael Benatar, M.D. (PI); Alexandra Waltz
Ohio State University: Bakri Elsheikh, M.D. (PI); John T. Kissel, M.D. (coI); Amy Bartlett; Colleen Pineda; Wendy King, PT
University of California, Irvine: Annabel K. Wang, M.D. (PI); Tahseen
Mozaffar, M.D. (co-I), Veronica Martin, Brian Minton
University of San Francisco–Fresno: Jeffrey Rosenfeld, M.D. (PI);
Christine Banda, Kim Voelz
Indiana University: Robert Pascuzzi, M.D. (PI); Sandra Guingrich
University of North Carolina: James F. Howard, Jr., M.D. (PI); Manisha
ChopraMassachusetts General Hospital: Namita Goyal, M.D. (PI); William
David, M.D. (PI); Owen O’Connor
University of Iowa Hospitals and Clinics: Andrea Swenson, M.D. (PI); Jeri
SierenNerve and Muscle Center in Texas: Aziz Shaibani, M.D. (PI); Chia Arif,
M.D.
The Methodist Hospital System: Ericka Simpson, M.D. (PI); Sharon
Halton, Luis Lay Jr.
Penn State Hershey Medical Center: Matthew Wicklund, M.D. (PI); Heidi
M. Runk, CCRC
Phoenix Neurological Associates: David Saperstein, M.D. (PI); Nicole
Hank
University of Florida-Jacksonville: Michael Pulley, M.D. (PI); Lisa Smith
University of Toronto: Vera Bril, M.D. (PI); Patti Nwe, Mehran Soltani,
Eduardo Ng
McGill University: Angela Genge, M.D. (PI); Austin Zaloum, Kristiana
SalmonChildren’s Mercy Hospital and Clinics (for polyglutamation assays): Mara
Becker, M.D.
Muscle Study Group (MSG) Steering Committee: Annabel K. Wang,
M.D.; Ted M. Burns, M.D.; Richard J. Barohn, M.D.; Mamatha Pasnoor,
M.D.; Laura Herbelin; Jianghua (Wendy) He, Ph.D.
Safety Monitoring Committee: Kevin Latinis, M.D. (chair; University of
Kansas Medical Center); Anthony Amato, M.D. (Brigham and Women’s
Hospital); Erik Ensrud, M.D. (Boston VA Health Care System); and Jonathan Goldstein, M.D. (Yale University School of Medicine)

12

KANSAS JOURNAL of M E D I C I N E
METHOTREXATE POLYGLUTAMATION IN MG
continued.
REFERENCES

Chabner BA, Allegra CJ, Curt GA, et al. Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest 1985; 76(3):907-912. PMID:
2413074.
2.
Ifergan I, Shafran A, Jansen G, Hooijberg JH, Scheffer GL, Assaraf YG.
Folate deprivation results in the loss of breast cancer resistance protein(BCRP/ABCG2) expression. A role for BCRP in cellular folate homeostasis.
J Biol Chem 2004; 279(24):25527-25534. PMID: 15047700.
3.
Lafforgue P, Monjanel-Mouterde S, Durand A, Catalin J, Acquaviva PC.
Lack of correlation between pharmacokinetics and efficacy of low dose
methotrexate in patients with rheumatoid arthritis. J Rheumatol 1995;
22(5):844-849. PMID: 8587070.
4.
Ravelli A, Di Fuccia G, Molinaro M, et al. Plasma levels after oral methotrexate in children with juvenile rheumatoid arthritis. J Rheumatol 1993;
20(9):1573-1577. PMID: 8164218.
5.
Wallace CA, Bleyer WA, Sherry DD, Salmonson KL, Wedgwood RJ. Toxicity and serum levels of methotrexate in children with juvenile rheumatoid
arthritis. Arthritis Rheum 1989; 32(6):677-681. PMID: 2735961.
6.
Dervieux T, Furst D, Lein DO, et al. Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid
arthritis treated with methotrexate: Results of a multicentred cross sectional observational study. Ann Rheum Dis 2005; 64(8):1180-1185. PMID:
15677700.
7.
Dervieux T, Furst D, Lein DO, et al. Polyglutamation of methotrexate
with common polymorphisms in reduced folate carrier, aminoimidazolecarboxamide ribonucleotide transformylase, and thymidylate synthase
are associated with methotrexate effects in rheumatoid arthritis. Arthritis
Rheum 2004; 50(9):2766-2774. PMID: 15457444.
8.
Becker ML, van Haandel L, Gaedigk R, et al. Analysis of intracellularmethotrexate polyglutamates in patients with juvenile idiopathic arthritis:
Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations. Arthritis Rheum 2010; 62(6):1803-1812.
PMID: 20191581.
9.
Herbert V. Making sense of laboratory tests of folate status: Folate requirements to sustain normality. Am J Hematol 1987; 26(2):199-207. PMID:
3310615.
10.
Dalrymple JM, Stamp LK, O’Donnell JL, Chapman PT, Zhang M, Barclay
ML. Pharmacokinetics of oral methotrexate in patients with rheumatoid
arthritis. Arthritis Rheum 2008; 58(11):3299-3308. PMID: 18975321.
11.
Stamp LK, O’Donnell JL, Chapman PT, et al. Determinants of red blood
cell methotrexate polyglutamate concentrations in rheumatoid arthritis
patients receiving long-term methotrexate treatment. Arthritis Rheum
2009; 60(8):2248-2256. PMID: 19644853.
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Shergy WJ, Polisson RP, Caldwell DS, Rice JR, Pisetsky DS, Allen NB.
Methotrexate-associated hepatotoxicity: Retrospective analysis of 210
patients with rheumatoid arthritis. Am J Med 1988; 85(6):771-774. PMID:
3195601.
13.
Kremer JM, Galivan J, Streckfuss A, Kamen B. Methotrexate metabolism
analysis in blood and liver of rheumatoid arthritis patients. Association with
hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum
1986; 29(7):832-835. PMID: 2427090.
14.
Berkowitz RS, Goldstein DP, Bernstein MR. Ten year’s experience withmethotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 1986; 23(1):111-118. PMID: 3002916.
15.
Baker RI, Manoharan A. Cytopenias induced by methotrexate in inflammatory arthritis. Aust N Z J Med 1989; 19(6):747-748. PMID: 2631672.
16.
Pasnoor M, He J, Herbelin L, et al. A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology 2016;
87(1):57-64. PMID: 27306628.
17.
Pasnoor M, Dimachkie MM, Farmakidis C, Barohn RJ. Diagnosis of myasthenia gravis. Neurol Clin 2018; 36(2):261-274. PMID: 29655449.
18.
Farmakidis C, Pasnoor M, Dimachkie MM, Barohn RJ. Treatment of
myasthenia gravis. Neurol Clin 2018; 36(2):311-337. PMID: 29655452.
19.
van Haandel L, Becker ML, Williams TD, Stobaugh JF, Leeder JS.
Comprehensive quantitative measurement of folate polyglutamates inhuman erythrocytes by ion pairing ultra-performance liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2012;26(14):1617-1630. PMID: 22693118.
1.

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Keywords: myasthenia gravis, methotrexate, polyglutamate

Development of GCRC and CTSA Programs
at the University of Kansas Medical Center:
A Personal 10-year Perspective

KANSAS JOURNAL of M E D I C I N E

Richard J. Barohn, M.D.
University of Kansas Medical Center, Department of
Neurology, Kansas City, KS

Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

Early Beginnings
Drs. Thomas DuBose (Chair of Medicine) and Richard Barohn(Chair of Neurology) had arrived to KUMC in 2000 - 2001 fromthe University of Texas system where General Clinical ResearchCenter’s (GCRC) were an important infrastructure component for
researchers. Dr. DuBose had called one meeting in 2001 to discuss
the possibility of a GCRC at KUMC. Dr. Barohn and others attended
but there were no minutes recorded from that meeting. Dr. DuBose
left KUMC shortly thereafter (to be Chair of Medicine at Wake
Forest Medical Center). After several months Dr. Barohn asked theexecutive dean, Dr. Barbara Atkinson, if he could restart the initiative
and was given permission to form the GCRC planning committee. It
should be noted KUMC had a GCRC once before for one funding
cycle in the early 1970s. Drs. Jared Grantham and Areyh Hurwitz,
who were on the GCRC Planning Committee, were at KUMC duringthat time.
The Process Begins: Initial Goals. We began the process of initiating a GCRC for The University of Kansas Medical Center (KUMC)
campus in 2002. At that time we established four goals:• Provide clinical investigators from the School of Medicine,
School of Nursing and School of Allied Health (as it was thencalled) with a modern, state of the art facility in which clinicalresearch could be conducted.
• Enhance multidisciplinary research across departments andthe three schools.
• Enable and train junior faculty and trainees to become more
involved in clinical research.
• Apply for federal funding to support the GCRC.
GCRC Planning Committee. A GCRC planning committee wasformed in 2002 and Figure 1 shows the initial members and the commencement of the first official meeting.
This committee met for two years in order to develop the infrastructure needs for the GCRC. Minutes were taken by Dr. Barohn at
all committee meetings and prepared by Debbie Jursch, Dr. Barohn’s
administrative assistant in the Department of Neurology (Appendix
A, B, C, D, E, F, G, H, I; available at journals.ku.edu/kjm). As seen inthese minutes, Dr. Barohn added a number of additional members
quickly, including representation by the Schools of Allied Health(Dr. John Ferraro) and Nursing (Dr. Marge Bott). The committee
was active, collegial and lively, but there was some suspicion that wewould not be able to pull this off. As we made progress this skepticism
disappeared. As I was new to KUMC and had been focused primarilyon neurology issues, through this committee I developed close friendships with colleagues across the campus in all these schools including
Marge Bott, John Ferraro, Matt Mayo, and Jared Grantham.

Figure 1. Initial members and commencement of the first GCRC planning committee.

The space in Delp Pavilion was identified (G040 suite of rooms)
that had previously been space for the Parkinson’s program in the
Department of Neurology. The reason the Parkinson’s space became
available was because the Neurology department had relocated to
The Landon Center on Aging. An old driving simulation lab thatwas no longer used (also in Neurology) in Delp, across the hall from
G040, was closed, as was an adjacent ophthalmology office, andthese, plus the abandoned radiation therapy space in Delp (G037
suite of rooms), was to become the administrative and nursing offices
for GCRC staff. A state-of-the-art metabolic kitchen was installed in
one of the G037 rooms through funding by Dr. Joan Hunt, Vice Chancellor of Research. Dr. Deborah Sullivan, Department of Nutrition in
the School of Allied Health (as it was then called) directed the metabolic kitchen. There was a lot of discussion on how to organize theclinical GCRC space and we looked at many possible floor plans provided by KUMC architect Steve Smallwood. Originally, the GCRC
clinic space had only one bathroom. Dr. Aryeh Hurwitz lobbied theplanning committee successfully for two bathrooms, one for the staff
and one for patients providing specimen samples and his suggestion
was adopted. Many of us remember Dr. Hurwitz request fondly andof course he was correct. Dr. Hurwitz died too young from a cardiac
arrest in October 2005 but he did get to see the new GCRC open withtwo bathrooms. Remodeling began in June 2004 and was completedin October 2004. The GCRC officially opened its doors in January2005 (Figure 2). At the same time, we disbanded the GCRC planningcommittee as its function was completed.

14

KANSAS JOURNAL of M E D I C I N EGCRC AND CTSA PROGRAMS AT KUMC
continued.

from the GCRC at the University of Texas Southwestern in Dallas tobe the Chief Nurse of the GCRC. Dr. Barohn had worked in the GCRC
at UTSW and he was introduced to Ms. Otey as a potential candidate
to be the nurse and GCRC leader in Kansas. He and Ms. Otey hired
Suzie Schmidt to be the administrative director, Nicole Ladisech tobe the administrative assistant and Mary Reed, RN, to be a clinicalresearch nurse (Figure 3).

Figure 2. GCRC in 2005.

Foundation of the GCRC Advisory Committee
Drs. Barbara Atkinson and Richard Barohn announced the formation of the (GCRC Advisory Committee) GAC in the summerof 2004 and notice went out to all clinical investigators on the KU
Medical Center campus to indicate that research applications could
be submitted in order to use the new GCRC space and resources. Dr.
Barohn asked Dr. John Ferraro (Associate Dean of Research, Schoolof Health Professions) to chair the committee of approximately 20
faculty and GCRC staff (the GAC began reviewing protocols monthly
in September 2004). The GAC was a group that took their role seriously when they gave feedback to faculty applying to use the GCRC.
When Dr. Patricia Kluding (who was an assistant professor in Physical Therapy) applied to use the GCRC she received intense criticism
for her proposal. She rose to the occasion and fixed her protocol. We
immediately appointed her to be a member of the GAC so she could
be part of the process of reviewing future protocols in order to assist
those investigators. She has been a key leader in our clinical research
infrastructure ever since.
Initial Internal Funding, Staffing and Organization of the GCRC
Two primary sources provided the initial funding for the KU
Medical Center GCRC since its inception. The majority of the funds
were supplied through the Executive Vice Chancellor/Vice Chancellor of Research office at KUMC. Dr. Barbara Atkinson was the
Executive Vice Chancellor (EVC) in addition to the Executive Deanof the School of Medicine and Dr. Joan Hunt was the VCR. Funds
were provided for renovation of space, office supplies and computers, and most significantly nursing, administrative and biostatisticalpersonnel. In addition, the University of Kansas Hospital generously
provided all initial equipment and medical supplies in the clinicalresearch areas, including a metabolic cart, electrocardiogram, freezers, and centrifuges. All of this financial support was provided in
anticipation of an NIH grant submission. Mr. Jon Jackson, one of the
KU Hospital vice presidents, was the primary champion to develop
GCRC. In addition, some funds were obtained from the Kansas City
Area Life Sciences Institute that was used to hire research nurses.
Dr. Barohn received a planning grant from the Research Institute toprepare the GCRC application. Dr. Barohn invited Judy Otey, RN,

15

Figure 3. Initial GCRC leadership and staff (January 2005 Grand Opening).
Left to right: Nicole Ladisech, Suzie Schmidt, Richard J. Barohn, Judy Otey,
Mary Reed.

Shortly after construction in the initial Delp GCRC space began,
KU Hospital announced they would be closing the old mechanics
machine shop (located in Delp in the rear of the old radiation therapy
room, Delp G036). Dr. Barohn obtained this space from KU Hospital, and funds for remodeling, so that it would become the initial
exercise physiology laboratory in the GCRC. The exercise physiology
space was large and well equipped and used by all three schools. It
was a major factor in recruiting Dr. Jeffrey Burns to the Departmentof Neurology to begin the Alzheimer’s Disease program which was tohave an exercise and metabolic focus. The initial organization of the
GCRC is displayed in Figure 4. Dr. Barohn has recorded parts of thedevelopment of the GCRC KU study at the Merrill Retreat sponsored
by KU-Lawrence in 2016.1
GCRC NIH Grant
Simultaneous with the development of a functioning GCRC, agrant application was prepared. We notified the NIH/NCRR ofthe development of our GCRC at KU Medical Center and they hadscheduled us to submit our proposal in 2006. The KU Medical Center
GCRC NIH grant application was submitted on June 1, 2006 andwas funded in the spring of 2007 for three years at approximately $3
million dollars/year. It was the last new GCRC application funded by
the NIH. The NIH officials informed Dr. Barohn that the Clinical andTranslational Science Award (CTSA) was being initiated, and that
this would replace the GCRC program. They advised Dr. Barohn tosubmit the GCRC application, but said “if funded it would only be forthree years and after that time KUMC would have to obtain a CTSA
grant.” They also told Dr. Barohn that there would be an opportunity
to apply for a CTSA planning grant.

KANSAS JOURNAL of M E D I C I N EGCRC AND CTSA PROGRAMS AT KUMC
continued.

Figure 4. Initial organization of the GCRC.

Announcement of the Clinical and Translational Science Award
Program
In September 2005, the NIH released an RFA announcement for
institutional Clinical and Translational Science Awards (CTSA). The
stated purposed for the CTSA project was to forge a transformativeand integrative academic home for clinical and translational science.
Dr. Zerhouni, the NIH Director, stipulated that these new homes inacademic health centers would be a center, department, or institute.
These clinical research units were to encompass all components ofclinical research, including education, career development, and regulatory components for clinical research infrastructure.2 These newclinical research units were to promote multi-disciplinary researchteams, create an incubator for innovative research tools, and catalyze
the application of new knowledge to clinical practice. These clinicalresearch units were to also provide degree-granting capabilities inclinical research that will lead a trainee to either a masters or a doctorate degree.
The clinical research infrastructure provided by GCRCs were to
be incorporated into the larger CTSA awards. By doing so, this would
give academic health centers greater flexibility in modeling clinicalresearch infrastructure space for the future. In this new model, there
were potentially fewer restrictions on collaborations with industry
in developing clinical research programs at academic health centers.
There was no restriction on number of industry sponsored studies orin the amount of funds that a clinical research center can receive fromindustry. Under GCRC rules this was not the case.
Planning Process for the CTSA at KUMC and the Kansas City
RegionShortly after the RFA for the new CTSA awards, a planning
process was initiated at KU Medical Center to develop our university’s response to this new program.3 The various planning committees
and subcommittees were established in October 2005 (Figure 5) andbegan meeting regularly.

Figure 5. CTSA planning committees and sub-committees.

The timeline was that applications had to be submitted to the
NIH by March 27, 2006. At that time, the NIH was accepting two
types of applications. The first was a planning grant for $150,000
that would allow academic health centers time and some resources
to further develop a global CTSA application. The second type of
grant was a full CTSA application that could be as large as $6 million
dollars per year if pediatric clinical research was involved; up to $4
million dollars without clinical pediatric research. In addition to the$6 million dollar per year CTSA award, all existing K30, T32, andGCRC grants were to be rolled in the CTSA application. By doing so,a full CTSA application would become one of the largest institutional
research grants that an academic health center could receive. The
stated goal of the NIH was to fund 60 small CTSA planning grants
and five to seven full CTSA grants in the first round of applications.
Their ultimate goal was to fund 60 full CTSA awards throughout theUnited States by 2012.
As our planning committees met, we recognized there would be anumber of weaknesses and strengths for KU Medical Center CTSA
application. The weaknesses included:• No current GCRC NIH funding• No clinical T32 training grants• Relatively small number of clinical mentors and mentors withcurrent clinical R1 grants

16

KANSAS JOURNAL of M E D I C I N EGCRC AND CTSA PROGRAMS AT KUMC
continued.

The strength of KU Medical Center CTSA application included:• The existing NIH funded K30 program and the Masters of
Science and Clinical Research Program• The current existing GCRC infrastructure (before it was funded)• The Research Institute at KU Medical Center• The multidisciplinary and collaborative research efforts between
the School of Medicine, School of Nursing and School of Allied
Health (which became the School of Health Professions)• A strong bioinformatics center• Strong ties with programs at the University of Kansas-Lawrence
Campus, particularly drug development and the LifespanInstitute• Potential strong ties with partners in the community, otherregional academic centers and in private industry
As a result of the CTSA planning process, it was decided to submit
a CTSA planning grant before the March 2006 deadline.
Lauren Aaronson, Ph.D., RN, came to KUMC School of Nursing
in 1989 as the Associate Dean for Research. In 2004 she went to the
NIH in Bethesda as a senior advisor to the director of the National
Institute of Nursing Research (NINR) as part of an interagency personal agreement between NIH and KUMC to join the new Roadmap
for Research Initiative. One of her duties was to help craft components of the emerging CTSA plan and research announcement. Drs.
Barohn and Burns attended the NIH event to announce the CTSA
program in the Fall of 2005 and they met Dr. Aaronson. Dr. Aaronson’s time at the NIH ended in December 2005 and she returned
to KUMC. She immediately joined Dr. Barohn to begin the CTSA
Planning Grant application. Dr. Barohn took the lead in preparing the
GCRC grant and Dr. Aaronson took the lead in preparing the CTSA
Planning Grant, but they worked on each application intensely. Bothwere submitted within four months of each other. They remained
research grant ‘partners’ for the next 10 years, when Dr. Aaronson
retired.
Concept of a Heartland Institute for Clinical Research
Our CTSA planning grant application outlined the concept of a new
Heartland Institute for Clinical Research (HICR) as a new integrated home for clinical and translational research, both at KU Medical
Center and in the region. We anticipated that the HICR would consistof many centers, and each center would have a number of cores orprograms (Figures 6 and 7).3
The education center would house the existing Masters of Clinical Research and K30 programs and new additional K12 and T32
career development awards that can provide significant salary support
and thus release time so that young investigators can pursue training
in clinical research. The education center also encompassed developmental programs, including a recently initiated Introduction to
Clinical Research course that was launched in the fall of 2006 semester, as well as a proposed Research Coordinator Training Programthat was under development.

17

Figure 6. Early conception of HICR, 2006.

Figure 7. Early structure of HICR, 2006.

The current GCRC would be incorporated into a new ClinicalResearch Resource Center (CRRC). The CRRC would also include
a Clinical Research Pilot Grant Program where a junior investigatorcan apply for up to $25,000 seed funds for a new clinical research
project. The CRRC would also contain a new protocol development/
assistance core to aid a new investigator in preparing a grant submission. Within the Novel Methodology and Translational Technologies
Center, core technologies to facilitate translational research would
be housed. An investigator would be able to apply to the Novel Methodology and Translational Technologies Center for access to these
individual cores for their research protocols. For example, if a pilot
project required brain imaging at the Hoglund Brain Imaging Center,
the investigator would apply to the Novel Methodology and Translational Technologies Center for funding and intellectual support.
In addition, we planned to establish four important committees thatwould bring in partners from the external scientific community, theregional academic centers, the private sector, and lay community
organizations and institutions.
Plans to Create a Regional Translational Clinical Research CenterIn the early CTSA planning stages in 2006, Dr. Barohn and
KUMC leadership believed that including other partners in the
program would raise the level of research in the Kansas City region.
As Dr. Barohn was a graduate of the UMKC School of Medicine, this seemed natural and he still had ties to UMKC, Truman
Medical Center, Children’s Mercy Hospital and St. Luke’s Medical
Center. He asked for meetings with various leaders of these institutions to explain the new CTSA program and how obtaining a
CTSA award could benefit researchers at all of these institutions.

Initially in these meetings, there was no immediate buy-in to theplan. Over a series of meetings, the cross-town hesitancy to collaboratesoftened and by the time the CTSA planning grant was submitted theconcept of a regional enterprise was a component of the future HICR
(Figure 8).

Figure 8. Regional partnership plan for HICR, 2006.

After the planning grant was submitted in March 2006, Dr. Barohncontinued to have meetings with leaders in Missouri, to determine
who could be included from these institutions in the Fall CTSA
submission. Dr. Barohn found welcome partners in the School of
Medicine, including Dr. Gary Salzman who was a classmate of Dr.
Barohn’s. He also met frequently with leaders of Children’s Mercy
Hospital research unit, one of which was Dr. Ralph Kauffman. Steve
Leeder, Pharm.D., Ph.D., at CMH also became involved. Dr. Barohn
was introduced to Dr. John Spertus at St. Luke’s who ultimately would
become a leader in the CTSA program.
The Kansas City VA Medical Center was initially included asa partner as well. And of course, all KU Faculty on the Lawrence
campus and in the Wichita School of Medicine were all partners. The
concept was that if an institution was a partner in the HICR, then all
the faculty of that institution would have access to the components of
the institute.
The name of the institute was ultimately changed to the HICTRHeartland Institute for Clinical Translational Research. Views weresplit on how favorable or unfavorable the acronym HICTR was perceived. Dr. Atkinson often expressed her unfavorable view. But theacronym HICR was used for the CTSA planning grant submission in
2006, and HICTR for the full grant submission.
Both the GCRC and CTSA planning grants were funded in 2007.
The planning grant was small, providing $150,000 direct funds for one
year compared to GCRC grant ($3 million dollars/year for 3 years.)
For 12 months the HICTR grant writing team prepared the large
paper application that was submitted in 2008. The Office of Grants
and Research in the SON and Dr. Marge Bott (Associate Dean for

KANSAS JOURNAL

							of M E D I C I N EGCRC AND CTSA PROGRAMS AT KUMC
continued.
Research, SON) and her staff played a critical role in the grant preparation and assembly, along with the GCRC staff. Dr. Atkinson had
announced the official launch of the HICTR several months before
the grant submission, with Drs. Barohn and Atkinson as director andco-director, respectively. An event was held at Union Station to celebrate the launch of the HICTR and was well attended by leadersfrom all partner institutions.
We received our score in February 2009. It was not good - 311. In
fact, it was a terrible score. I recall Dr. Aaronson calling me with thescore when I was away in Dallas and she said “Rick, are you sitting
down? If not, you need to.” But we believed we could fix the critiques.
In the Fall of 2009, we resubmitted. In February 2010, we got ourscore, which was much better, but still not fundable – 31. The NIH had
moved to a two-digit grading system and a perfect score was 10. In thecritiques it was clear a major problem was our informatics program.
We assembled an External Advisory Board led by Dr. Claire Pomeroy(Dean of the School of Medicine, University of California, Davis) andother leaders from institutions with CTSA grants. They gave us a clear
idea of how we could improve the application. We began a search for
an informatics leader. We recruited Dr. Russ Waitman to fill this role.
Dr. Waitman arrived in 2010 and rewrote the informatics section as
he simultaneously set up a system to extract medical data from the
Epic electronic medical record for research using the I2b2 softwareand a new program code he and his team wrote. He called the program
HERON. HERON quickly became a highly useful research tool forfaculty.
The CTSA application was submitted for a third time by Drs.
Barohn and Aaronson and their team in the fall of 2010. In February
2011, we received our score while Drs. Barohn and Aaronson were in
Dr. Atkinson’s EVC office. At the beginning of their meeting, no score
had been posted. Forty-five minutes later Dr. Atkinson checked again.
The score was 14. The three professors yelled “Fourteen!” and as I
recall there was a three-person hug and some jumping up and down.
Two other major changes occurred in our CTSA program. In
addition to hiring external consultants, we had internal brainstorming sessions to see if there was a better name than HICTR for our
program. C.J. Janovy, our director of communications at the time,came up with the name Frontiers. It seemed perfect and although I
hated to give up HICTR, I was clearly in the minority and since thenwe are Frontiers. Both regional and nationally, we are Frontiers. We
made this name change after we were funded in 2011.
The other major change was the Johnson County Education
Research Triangle (JCERT) initiative and the move to Fairway. Dr.
Atkinson and her leadership team, with the help of local community leaders, accomplished the amazing fete of getting a sales tax forresearch passed by the voters of Johnson County in November 2008,
in the middle of a severe recession. This sales tax provided funds inperpetuity for KUMC research at two office buildings (purchasedby the Hall Foundation and donated to KUMC) in what is now our18KANSAS JOURNAL of M E D I C I N EGCRC AND CTSA PROGRAMS AT KUMC
continued.

Fairway campus. The tax also provides funds for the KU Edwards
Campus and to the K-State Olathe campus. The KUMC Fairway
funds paid for renovations of the buildings and on-going maintenanceand operations. A major focus of the Fairway campus was to createa phase 1 trial unit for the cancer institute on the second floor. We
moved the GCRC to the third floor and called it the Clinical Translational Science Unit (CTSU). This is what we called the unit when
we submitted the CTSA grant in 2010 and we moved into the newunit just before the grant submission. The new CTSU was a major
expansion. We now had 23 research rooms to see research participants, and a large infusion suite with eight bays, a large exercise lab,a large metabolic kitchen, and three extended stay rooms with beds
for patients who needed extended stays for PK/PD studies. In thisnew expanded CTSU, Dr. Jeffrey Burns became the director in 2011.
Dr. Burns was recruited to KUMC because we were opening a GCRC
in 2006 and we built an exercise unit in large part for his researchneeds as noted above. Therefore, this was another example of a juniorfaculty member using the GCRC who eventually moved into a leadership role in Frontiers.
In July 2011, Frontiers was funded at $4 million dollars a year for
five years. In the fall of 2010 Drs. Russ Swerdlow and Jeffrey Burns
were funded for an NIH Alzheimer’s Disease Center. Also, in 2011
Dr. Roy Jenson and his team were funded for a NIH Cancer Center.
All three centers were funded within 12 months. The year 1905 has
been referred to as Einstein’s “Annus mirabilis” because he had four
groundbreaking papers published that year and he went from obscurity to worldwide recognition.4 While probably not as scientificallyand culturally significant as Einstein’s 1905 breakthroughs, the 12months in 2010 and 2011 was KUMCs “annus mirabilis” and pulled
KUMC research from obscurity to national relevance.

19

FUNDING SUPPORTThis work was supported by a CTSA grant from NCATS awarded
to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (#UL1TR002366). The
contents are solely the responsibility of the author and do not necessarily represent the official views of the NIH or NCATS.
REFERENCES

Barohn RJ. Clinical research resources at the University of Kansas
Medical Center: General Clinical Research Centers (GCRC) and ClinicalTranslation Science Awards (CTSA). Merrill Advanced Studies Center,
Report 2006; 110:51-60.
2.
Zerhouni EA. Translational and clinical science - time for a new vision. N
EnglJ Med 2005; 353(15):1621-1623. PMID: 16221788.
3.
Barohn RJ, Aaronson LS. The General Clinical Research Center (GCRC)
and The Heartland Institute for Clinical and Translational Research(HICTR) at the University of Kansas Medical Center (KUMC). Merrill
Series on The Research Mission of Public Universities 2007; 111:32-43.
4.
Gribbin M, Gribbin J. Annus Mirabilis: 1905, Albert Einstein, and theTheory of Relativity. New York, NY: The Penguin Group, 2005.
1.

Keywords: GCRC, CTSA, Frontiers

Navigating the NIH Public Access Policy
for Peer-Reviewed Manuscripts - Why andHow to get a PMCID Number
Robin Liston, MPH, Richard J. Barohn, M.D.
University of Kansas Medical Center, Frontiers: University of
Kansas Clinical and Translational Science InstituteReceived Feb. 7, 2020; Accepted for publication Feb. 7, 2020; Published online Feb. 26, 2020

BACKGROUND
In 2008, the National Institutes of Health (NIH) enacted the Public
Access Policy requiring all NIH-funded investigators to submit accepted,
peer-reviewed manuscripts to the National Library of Medicine’s digital
repository PubMed Central. The purpose of the policy is to “ensure
the public has access to the published results of NIH-funded research.”(Accessed Jan. 14, 2020 at https://www.nih.gov/health-information/
nih-clinical-research-trials-you/what-is-nih-public-access-policy).
Historically, the burden of cost to access manuscripts was on readers;
however, the policy shifted the responsibility to researchers. Publishinga manuscript costs on average between $1,500 - $3,000, but these costs
can be included in grant proposal budgets.
The NIH’s National Library of Medicine (NLM), established in
1836, originated with a few books in the office of the Surgeon Generalof the Army. Over the next century the NLM amassed millions of publications related to medicine, public health and the allied sciences for use
by physicians and health professionals throughout the United States.
The computer and technology era enhanced the reach of literatureand produced numerous NIH online resources including the National
Center for Biotechnology Information, MEDLINE, ClinicalTrials.
gov, PubMed and PubMed Central (PMC). The NLM continues tomaintain an immense amount of medical publications and biomedical
clinical research manuscripts, primarily in online databases.
Why it is Important to Comply with the NIH Public Access Policy
Medical and public health researchers have a shared goal of developing innovative strategies to improve population health and of utmost
importance is translating the effective discoveries to individuals. One
approach to accelerate research findings to improve population healthis to ensure the scientific and lay community has access to publishedresearch outcomes in a timely manner.
While translating effective strategies to improve population healthis important to investigators, it is also imperative researchers comply
with the NIH Public Access Policy to avoid interruption to scientificdiscovery. Any NIH Institute or Center can withhold future funding
from the primary author of a manuscript and the principal investigatorof acknowledged funding support, including non-competitive renewals
and new grant proposals in non-compliance with the policy.
What Non-Compliance to the NIH Public Access Policy Means
Manuscripts are required to be publicly available no later than 12
months following original publication date depending on the embargo
period of the publisher; however, manuscripts are non-compliant if
the PubMed Central Identification (PMCID) number has not beenacquired 90 days after the original publication date. Steps to acquirea PMCID are provided below. Embargo periods for each journal in
PMC can be found in the “Free Access” column on the PMC Journal
List. The exact release date for each article under embargo is displayed

KANSAS JOURNAL of M E D I C I N E
in PMC search results, on the table of contents for the issue, or in thecorresponding PubMed record. To obtain access to an article prior to
its availability in PMC, individuals must contact the respective journal
publisher directly.
NATIONAL INSTITUTE OF HEALTH MANUSCRIPTSUBMISSION (NIHMS) PROCESS OVERVIEW
Step-by-Step Guide to Move Manuscripts through the NIH’s
Databases to Acquire a PubMed Central Identification (PMCID)
Number

Step 1: Deposit Files into the NIHMS
1. Select Submit New Manuscript - Primary Author or Principal Investigator (PI; or a delegate assigned in eRA Commons) of funding
mechanism that supported the research can process manuscripts
through the NIHMS database. The individual that initiates theprocess will need to complete all remaining steps. Delegates cannot
serve as a Reviewer for the Initial or Final Approvals.
a. This process should be initiated immediately following official publication. Some journals may deposit the paper into the
NIHMS for authors, but have a 12-month timeframe for submission, which is not within the 90 day compliance window.

2. Select submission method. Recommend using PubMed, as mostjournals submit abstracts to PubMed upon publication. Enter in the
PubMed Identification (PMID) number or manuscript title in the
PubMed search field.
a. PubMed is an online, free database comprised of over 30 million
published biomedical abstracts and citations. PubMed’s aim isto support retrieval of abstracts and citations to improve population health. PubMed was created by and is sustained by the
National Center for Biotechnology Information (NCBI) of the
NLM.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

20

KANSAS JOURNAL of M E D I C I N E
NIH PUBLIC ACCESS
continued.
b. Many journals provide abstracts and citations to NCBI, whichthen populates PubMed. While some links to full text articles
are provided, PubMed is not a full-text repository. PMC wasdeveloped to be a full-text repository for biomedical andlife science literature to ensure the public has free access toresearch outcomes. The NIH Manuscript Submission System(NIHMS) was developed to “facilitate the submission of peerreviewed manuscripts for inclusion in PMC in support of the
NIH Public Access Policy” (Accessed Jan. 6, 2020 at https://www.nihms.nih.gov/db/sub.cgi?page=overview).

••

Manuscript data will populate into the NIHMS. Select Next.

3. Select “My Funding” to open a list of grant awards. Choose the“Award ID(s)” associated with the manuscript. Select Next.

21

a. Selecting funding links this manuscript to the PI(s) of thefunding mechanism. The citation will be added to the PIs“MyNCBI”, the NCBI investigator-specific dashboard forresearchers to manage and track their publications. NCBI
maintains a series of databases containing biomedical andgenomic data for use by scientists, contributing to the missionof the NIH to “uncover new knowledge”.

4. Upload all files associated with the manuscript. The manuscript
must be the final, published PDF. Naming convention: PILastName_et_al_year published_Journal name. Confirm that all
figures, tables, videos and/or supplemental materials are includedin the PDF. Some online publishers link to these items instead ofincluding them with the manuscript. If not included, upload materials. Select Next.

5. Assign Reviewer and Release Delay (Embargo)
a. When an article is under an embargo it means that there is adelay, as specified by the publisher, between when the article ispublished and when its full version can be made freely available
in PMC. The default embargo for each journal in PMC can befound under the “Free Access” column on the PMC Journal
List. The exact release date for each article under embargo isdisplayed in PMC search results, on the table of contents forthe issue, or in the corresponding PubMed record.
Step 2: Initial Approval
1. Review Submission Statement. Select Agree.

KANSAS JOURNAL of M E D I C I N E
NIH PUBLIC ACCESS
continued.
Note: PMCID is assigned when the following two criteria are met:
1. Converted materials (i.e., the PMC-ready documents) have been
approved by the Reviewer.
2. The manuscript has been matched to a PubMed record for one of
the following: a final print publication date or an electronic publication date for a journal that is an electronic publication onlyor an electronic publication date for a journal where PubMed has
not received the final print publication date within six months ofthe electronic publication date
Steps for Processing Non-compliant Manuscripts Associatedwith Funding
The following three steps are provided to assist investigators withprocessing a non-compliant publication linked to their funding. Following completion of the three steps below, proceed to Step 1 above.
Step 1.i: Select Manage my Bibliography

Step 3: NIHMS Conversion
The NIHMS conversion typically takes two-three weeks. NIHMS
converts the deposited manuscript files into archival XML format.
In this way, NIHMS makes papers publicly available in a format
that ensures the permanent preservation of these research findings
and makes the results of this research more readily accessible to the
public, healthcare providers, educators, and the scientific community (Accessed Jan. 31, 2020 at https://www.nihms.nih.gov/about/publicaccess/).

Step 2.i: Select Edit Status

Step 4: Final Approval
The individual that initiated the process in Step 1 will receive
an email from nihms-help@ncbi.nlm.nih.gov with the subject line
reading [nihms] Manuscript #1031896: Please review the PMCready Documents. *See Appendix A. Log into NIHMS to Review andApprove the submission for it to be rerouted to undergo conversion
to PMC documents.
Step 5: PMCID Assigned
Once approved by the NIHMS the manuscript undergoes conversion to PMC documents. After file conversion the individual that
initiated the process will receive an email from nihms-help@ncbi.
nlm.nih.gov with the subject line: [nihms] Manuscript #1503085:
Your manuscript is available in PMC. *See Appendix B. PI or primaryauthor must again APPROVE the PMC-ready or final manuscript.

22

KANSAS JOURNAL of M E D I C I N E

APPENDIX A

NIH PUBLIC ACCESS
continued.
Step 3.i: Select Begin submission in the NIHMS. Save.

Step 4.i: Follow Steps 1-5
Step 1: Deposit Files into the NIHMS
Step 2: Initial Approval
Step 3: NIHMS Conversion
Step 4: Final Approval
Step 5: PMCID Assigned
FUNDING SUPPORTThis work was supported by a CTSA grant from NCATS awarded to the
University of Kansas for Frontiers: University of Kansas Clinical andTranslational Science Institute (# UL1TR002366). The contents aresolely the responsibility of the authors and do not necessarily represent
the official views of the NIH or NCATS.
Keywords: Public Access Policy, non-compliance, PMCID, NIHMS

APPENDIX B

23

Step-by-Step Guide for Setting up a
Company in Kansas and Missouri

James W. Mitchell, Ph.D.1, Steve O’Connor, Ph.D.2,
Maria Meyers3, Rajiv Kulkarni4, Richard J. Barohn, M.D.5
1Midwest Stem Cell Therapy Center, University of Kansas
Medical Center2
Flux Tensor Corporation, Shift Pharmaceuticals,
Entrepreneur in Residence, University of Kansas Medical
Center3
University of Missouri-Kansas City Innovation Center
4
University of Kansas Center for Technology
Commercialization
5
Frontiers: University of Kansas Clinical and Translational
Science Institute, University of Kansas Medical Center
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

Company Formation
The process of forming a company (startup) can be done online
by individuals or with the assistance of an attorney. The first step tomake your business legal is to decide what kind of business entity(legal structure) is best for you. This is an important step in entrepreneurship.
• The Kansas Business One Stop is the one-stop shop for planning, starting, operating and growing a business in Kansas.
• Search for company name availability on the Kansas
Business Center website• Create a KanAccess account to begin process of businessregistration online with the Kansas Secretary of State forcorporations, LLCs and LPs• Follow links appropriate for type of business• The Missouri Corporations Unit of the Secretary of State is
responsible for the creation and maintenance filings for all
domestic and out-of-state business entities doing business in
Missouri.
• Search for company name availability.
• Follow links appropriate to type of business. For articles
of incorporation, you can use a standard set of articles
that outline the owners. File the articles and pay fees via
credit card. If you want to pay through a company bankaccount, you must establish the bank account first with
sufficient funds to support the registration process.
• Obtain a Federal Tax Identification Number• Obtain a Certificate in Good Standing from Kansas or Missouri• Establish a bank account• Register for state taxes through the Department of Revenue
and Department of Labor• Obtain appropriate industry and professional licenses and registrations• Check with the local city and county for local permits and registrations• Acquire a Dun & Bradstreet D-U-N-S Number. A DUNS
number is a unique identifier assigned to businesses, following a patented identity process identifies the company as being

KANSAS JOURNAL of M E D I C I N E
unique from any others. To expedite the process if applying forfederal grants, calling is suggested.
Applying for Federal Grants
To apply for a Small Business Innovation Research (SBIR) or Small
Business Technology Transfer (STTR) grant numerous accounts
need to be established prior to submission.
What is the SBIR program? A highly competitive program thatencourages domestic small businesses to engage in Federal Research/
Research and Development (R/R&D) that has the potential for commercialization. Through a competitive awards-based program, SBIR
enables small businesses to explore their technological potential andprovides the incentive to profit from its commercialization (Accessed
Jan. 30, 2020 at https://www.sbir.gov/about).
What is the STTR program? It expands funding opportunities in
the federal innovation research and development arena. Central tothe program is expansion of the public/private sector partnership toinclude the joint venture opportunities for small businesses and nonprofit research institutions (Accessed Jan. 30, 2020 at https://www.
sbir.gov/about). The DUNS number is needed for all registrations so
do it first. Also, all registrations must be completed prior to the application being submitted. Registration can take six weeks or more, so
applicants should begin the registration process as soon as possible.
The NIH Policy on Late Submission of Grant Applications states that
failure to complete registrations in advance of a due date is not a valid
reason for a late submission. The accounts are:• System for Award Management (SAM) – Applicants mustcomplete and maintain an active registration, which requires
renewal at least annually. The renewal process may requireas much time as the initial registration. SAM registration
includes the assignment of a Commercial and Government
Entity (CAGE) Code for domestic organizations which havenot already been assigned a CAGE Code.
• SBA Company Registry –See “SF424(R&R) Other Project
Information Component” for instructions on how to registerand how to attach proof of registration to your grant application package. SBA Company registration is NOT required
before SAM, Grants.gov or eRA Commons registration.
• eRA Commons - Organizations can register with the eRA
Commons as they are working through their SAM or Grants.
gov registration, but all registrations must be in place by time ofsubmission. eRA Commons requires organizations to identify
at least one Signing Official (SO) and at least one Program
Director/Principal Investigator (PD/PI) account in order tosubmit an application.
• Grants.gov – Both a DUNS number and SAM registration areneeded in order to complete the Grants.gov registration.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

24

KANSAS JOURNAL of M E D I C I N E
SETTING UP A COMPANY
continued.
Notes: 1) Login to these websites periodically, as some will automatically expire passwords if the account is not accessed. 2) Thesewebsites may have incorrect or outdated instructions. If problems areencountered while following guidance, call the appropriate help desk.
Other Considerations• Federal Contacting Assistance Programs are designed to help
small businesses secure at least 23% of all federal contracting
dollars annually.
• Explore the advantages of small, women, minority and veteran-owned businesses through the Associate of Procurement
Technical Assistance Centers in Kansas and Missouri.
University of Kansas faculty and staff: If the company is going touse intellectual property owned by the University of Kansas, contact
University of Kansas Center for Technology Commercialization(KUCTC) at kuctc@ku.edu. It is recommended that the company
execute an Option or a License Agreement with KUCTC when an
SBIR/STTR is funded. KUCTC staff will guide the company throughthe licensing process.
Resources
1. KCSourceLink provides an online startup guide that helps people
start a business with information for Kansas and Missouri
2. Early-stage business set up checklist
3. Startup e-book
4. Start, Register and License a Business in Kansas
FUNDING SUPPORTThis work was supported by a CTSA grant from NCATS awarded
to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The
contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS.
Keywords: entrepreneurship, company, startup, SBIR/STTR, DUNS

25

Dedicated to the Pipeline: KU Frontiers’
Pursuit of Maintaining and Cultivating theCareers of Current and Future PhysicianScientists
Amy M. Smith, M.S. , MBA1, Won S. Choi, Ph.D.2
1
Frontiers: University of Kansas Clinical and Translational
Science Institute, Kansas City, KS
2
University of Kansas Medical Center, Department ofPopulation Health, Kansas City, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

INTRODUCTION
The decline in the number of physician-scientists regionally andnationally represents a real and existential threat to the biomedical
research community. The meager number of physicians substantially engaged in investigation is cause for concern, as the speed atwhich medical discovery translates to patient care depends on theircommitment to conducting research. As a Clinical and Translation Science Association (CTSA)-funded institution, KU Frontiers
is on the front lines of enriching the clinician-scientist and physician-scientist pipelines, by providing resources and robust training
opportunities to junior, developing researchers. Through the KL2Career Development Award and the TL1 Pre- and Postdoctoral
Clinical and Translational Research Training Awards, KU Frontiers
actively trains, educates and motivates the future leaders of medical
advancement. The Frontiers training programs, along with the services and resources extended to trainees and scholars provides the
structure and support needed to develop and foster physician-scientists, without whom medical innovation and discovery could bestunted and jeopardized.
Section 1: A Dwindling Physician-Scientist Population: Whatis the Problem?
Age is More Than a Number
The decline in the number of practicing physician-scientists has
been well documented over the past 40 years. Data from the 1980s
compared to that of 2014 indicates that the number of physicians
dedicating substantial aspects of their professional time to researchhas declined from around 5% to 1.5%.1 Further, the physician-scientist population is aging quickly, with 1.6 times more investigators over
the age of 61 than under the age of 50 as of 2012.2 The pipeline is aging
and the number of physician-scientists between the ages of 31 and50 has been declining.2 This particular trend is alarming because of
the unique and vital skillset physician-scientists bring to the realm of
biomedical research. The ever-widening gap from bench to bedsidedictates the need for physicians from a variety of disciplines who canuse their expertise to navigate the world of discovery and clinicalcare. Historically, physician-scientists have been and need to be vital
players in bridging the gap because of their ability to bring scientificinnovation to the bedside of their patients quickly and efficiently toaffect outcomes.

KANSAS JOURNAL of M E D I C I N E
The Long Road Ahead
One of the most frequently noted barriers to becoming a physician-scientist is the training timeline. For those who desire to becomea physician-scientist, the MD-PhD career path is a consideration.
However, those interested in the MD-PhD report dissatisfaction withthe length of the program, which can take an average of eight years tocomplete.3 With the realities of a hefty time commitment and mounting student debt, the MD-PhD route has become unappealing with
only 609 students entering an MD-PhD program in the U.S. in 2013.4
The combination of mounting debt and a daunting timeline leads
those with an interest in research with few other choices for investigative exposure. Medical students experience very limited (if any)
time or training opportunities to perform research, with the same
limitations plaguing the physician-scientist pipeline throughout mostresidency programs. Hopeful physician-scientists may not have a true
opportunity to perform research until fellowship, which only underscores the missed opportunities to engage physicians early in theirtraining.
Mentorship and Role Models
There are nuances to mentorship that make significant differencesin the experience and outcomes of the mentoring relationship. The
needs of a physician-scientist are unique to that particular career path.
To optimize the growth of a junior physician-scientist, it is helpful
to have a physician-scientist mentor. However, those opportunities
are limited not only by the small number of physician-scientists, but
the aging physician-scientist population who will be or currently arelooking toward retirement.
In addition to the small number of mentors available, there is aneed for increased diversity in terms of fields of study and ethnic andracial backgrounds in the physician-scientist pipeline. Both womenand minority groups such as African Americans and Hispanics areunderrepresented in the physician-scientist pipeline. Women makeup 42% of MD-PhD graduates, yet recent data indicates that womenmake up only 22% of NIH grant recipients with the dual degrees.5
The disparity between white and non-whites (African American,
Hispanic or Native American) is even more striking than that of men
compared to women with only 5% of those combined minority groups
receiving NIH funding as physician-scientists.5
Section 2: Combatting the Problem
Stage-Specific Exposure and Training
With the rising age of the physician-scientist population, it isimportant to expose those young in their medical training to research.
KU Frontiers is committed to fostering trainees and scholars at the
predoctoral, postdoctoral and junior faculty stages in their careers
via the TL1 Research Training Program (pre- and postdoctoral
tracks) and the KL2 Mentored Career Development Program ( juniorfaculty). Each specific track offers a condensed (1 to 2-year), immersive research experience, with clearly delineated milestones for theThis is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

26

KANSAS JOURNAL of M E D I C I N E

DEDICATED TO THE PHYSICIAN-SCIENTIST PIPELINE
continued.
trainees and scholars to meet on their way to carving out a career asboth a clinician and a scientist. With a primary concern of those interested in a career as a physician-scientist being the lengthy training
time2 the TL1 and KL2 programs address that concern by protecting
trainee’s time from clinical duties and allowing them to focus on an
intensive research experience to acquire the skills that their clinicalprograms didn’t offer enough of or at all. At the conclusion of both the
postdoctoral TL1 program and the KL2 program, the expectation isfor participants to have used their research projects and experience
to apply for extramural funding to demarcate the beginning of their
independent research careers.
Both the KL2 and TL1 programs take an integrative approach totraining, by bringing members of each program together to study
and address the most critical components of becoming a successful
researcher. As displayed in Table 1, Frontiers Scholar’s Club addresses
relevant and timely topics such as grant writing, career development
and study design. The members of the TL1 and KL2 programs work
together in these sessions to better understand each area and how
they will utilize it to prepare themselves to become independent
researchers. The integration of the groups allows the junior researchers to not only learn from mentors and senior scientists, but to learn
from each other and accelerate their progress on their way to becoming independent investigators.
Table 1. 2019-2020 sampling of Frontiers Scholar’s Club sessions.
Scholar’s
Clubsessions

TopicsSpeakers

R01 Mock Grant Review

Ed Ellerbeck, M.D., MPH, KL2
PI, Chair of Population Health;
John Spertus, M.D., MPH, KL2
PI, Endowed Chair in Metabolic and
Vascular Disease Research; Won
Choi, Ph.D., MPH, TL1 PI, Vice
Chair of Education

Session 2

Tenure and Promotion

Kim Richter, Ph.D., MPH, Joy
McCann Professor of Women I.
Medicine and Science; Laura
Martin, Ph.D., Associate Professorand Associate Director of fMRI

Session 3

The Overlap of Between
Research and Clinical Care:
Addressing IRB and HIPPA
Issues in Records-Based
Research

Karen Blackwell, Director of
Human Research Protections
Program

Session 4

The Learning Health
Systems Framework and the
Implications for Research

Tamara Winden, Ph.D., Chief
Research Informatics Officer

Session 5

Manuscript Writing andData Visualization

John Spertus, M.D., MPH,
Endowed Chair in Metabolic and
Vascular Disease Research

Session 6

Biostatistics, Epidemiology,
Research Design (BERD):
Understanding and Utilizing
BERD Resources andAlternative Study Design

Matt Mayo, Ph.D., MBA, Founding
Chair and Professor, Department of
Biostatistics & Data Science

Session 1

As an added benefit, the integration of the program also facilitatescollaborative partnerships. In 2019, a member of the KL2 programand a postdoctoral TL1 trainee were able to leverage their expertise27

as a team and procure pilot funding on their first submission. The
combination of stage-specific training and the integration of the KL2
scholars and TL1 trainees continues to provide great value in a considerably brief amount of time.
Over the lifetime of the training programs, the efforts appear to be
paying off as 58% of KL2 graduates currently have NIH funding, withthree leading multi-site NIH projects. With only one graduated cohortof postdoctoral graduates, results are still up for debate. However, twoof the most recent TL1 graduates were awarded internal funding, withthe other two graduates recently submitting for individual K awards.
The trajectory of the programs is quite promising, as KU Frontiersremains steadfastly committed to providing immersive training experiences in a brief, manageable timeframe.
Adapt and Evolve
With the noted cost burden and time commitment associated withtraining as a physician-scientist, it is critical to think about innovative ways to cut down on both, while offering ample opportunities forphysicians to get involved in research. For those who are not in a TL1or KL2 program, there needs to be accessible options to pique theirinterest and encourage their ambition and curiosity. The Departmentof Population Health at Kansas University Medical Center (KUMC)
recently created a four-week didactic training course for residents
and fellows interested in obtaining the foundational knowledge ofthe clinical research process. Admittedly, the knowledge and experience obtained from the class alone is not enough to solidify a career
as a physician-scientist. However, the course will set the foundation
for a resident or fellow to begin to conduct their own research, whileworking with a faculty mentor to produce an abstract and submit apublication within a six-month period.
Those enrolled in the first iteration of the course (residents andfellows) were young in their careers and eager to learn and do more.
By fostering that drive and innate curiosity with a brief, intensive,
crash course in research methods (e.g., protocol design, basic biostatistics, regulatory issues, etc.), KUMC and Frontiers are doing theirdue diligence by training physicians and arming them with the basic
skillsets to do their own research and carve out a career with investigation as an important element.
Recruitment to Enrich the Pipeline
The TL1 and KL2 programs spend several months each year
recruiting the best and brightest from each of the Kansas and Missouri-based Frontiers affiliates, as well as nationally. The recruitment
process is carefully and intentionally focused on enriching the pipelineof junior investigators, with an eye on both growth and diversification.
Both programs have managed to attract female investigators at especially high rates, with 63% of women making up the KL2 program
participants over its lifetime and 56% for pre- and postdoctoral
TL1 programs, respectively. Admittedly, both the KL2 and TL1 programs have struggled with attracting underrepresented minorities
to its programs. Tables 2 and 3 indicate the demographic makeup ofeach KL2 and TL1 graduating cohort. While women are well represented, African Americans and Latinos are not, making up only 7.5%of our awardees in the combined KL2 and TL1 graduated cohorts.

KANSAS JOURNAL of M E D I C I N E

Table 2. TL1 graduate demographics.
Graduates by year

Male

FemaleNon-URM

URM

2012

2

2

4

0

2013

3

1

4

0

2014

3

1

4

0

2015

1

3

2

2

2016

2

2

4

0

2017

0

0

0

0

2018

0

2

2

0

2019

3

3

5

1

50% female; 10.7% URM

Table 3. KL2 graduate demographics.
Graduates by year

Male

FemaleNon-URM

URM

2014

1

5

6

0

2017

2

4

6

0

75% female; 0% URM

Both the TL1 and KL2 programs recognize the unique challengesof recruiting a diverse group of trainees into each program, particularly in Kansas and Missouri. Therefore, we refocused our approachto attracting diverse candidates in 2019 and re-engaged the Directorof Diversity and Multicultural Affairs and the Office of Diversity andInclusion to ensure the programs are reaching groups of students that
historically have had limited opportunities in biomedical research. As
a result, the 2019 award recipients for the pre- and postdoctoral TL1
programs represent the most diverse cohort that we have ever worked
with, with 50% of those onboarded in July of 2019 being from anunderrepresented minority group (Table 4).
Table 4. Current TL1 trainee demographics.
Current TL1 trainees

Male

FemaleNon-URM

URM

2019

1

5

3

3

83.3% female; 50% URM

Two of our current predoctoral awardees were both members of
the KUMC Pre-Admissions Program and the Pre-Matriculation
Program, which are run out of the Office of Diversity and Inclusion.
The goal of both programs is to recruit and prepare underrepresented
minorities to succeed as medical students, and prepare them for a
career as physicians and physician-scientists. Having programs inplace to assist students in overcoming barriers and addressing any
concerns from minority groups in particular, has proven successful inengaging women and others from underrepresented minority groups.
Physician-Scientist Advisors
Engaging the right advisor can make a significant difference in ajunior investigator’s career, especially when pursuing a career as aphysician-scientist.2 With full appreciation for such a challenge, KU
Frontiers selected two accomplished, active, physician-scientists
to lead the KL2 program and to act as advisors for the participants.
Although the KL2 and TL1 awards are not limited to only physician-scientists, 50% of the training program participants are either studying tobe physicians, while engaging in their research projects or are alreadyphysicians carving out careers as physician-scientists. With intentionality and care, the training programs have made a concerted effort

DEDICATED TO THE PHYSICIAN-SCIENTISTPIPELINE
continued.

to have a support structure in place for those pursuing the physicianscientist career path.
The experience of becoming a physician-scientist is a unique andarduous career choice, and, reportedly, can feel a little uncomfortable,
based on individuals not fitting in with medical or research colleagues,
wholly.2 To temper the risk of experiencing those feelings, the training programs are structured as the ideal environment for those whoare interested in the physician-scientist career path. KU Frontiersand its programs continue to be well-positioned to cultivate and train
the next generation of physician-scientists and enrich the pipeline ata most critical time.
CONCLUSIONKU Frontiers and its training programs are fully dedicated toaccelerating research to better reach patients in an innovative andefficient fashion. With an eye on medical advancement, KU Frontiers
is well-positioned to assist in adding to the dwindling physician-scientist pipeline. Its investment in stage-specific training opportunities,
recruitment, diversity, expediency, mentorship and advising sets thefoundation for investigators locally and nationally to springboard
their careers and enhance the likelihood of impactful medical discovery.
In particular, KU Frontiers and its TL1 and KL2 training programs
continue to create an environment in which physician-scientists canflourish. It is the physician-scientist who is uniquely qualified to close
the gap between making medical discoveries and providing innovative care to the patient’s bedside based on those discoveries. With
the declining number of physician-scientists posing a threat to the
future of biomedical research, it is more important than ever to meettheir needs and provide the right environment for them to grow into
their research careers, and hopefully, grow in number. With a focus on
innovation and steady growth, KU Frontiers and its training programs
will continue providing intensive and expedited training experiences
for those eager to carve out a path as clinicians and investigators.
FUNDING SUPPORTThis work was supported by a CTSA grant from NCATS awarded
to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (#UL1TR002366). The
contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS.
REFERENCES

Cornfield DN, Lane R, Rosenblum ND, et al. Patching the pipeline: Creation and retention of the next generation of physician–scientists for childhealth research. J Pediatr 2014; 165(5):882-884.e1. PMID: 24551382.
2.
Blish CA. Maintaining a robust pipeline of future physician-scientists. J
Infect Dis 2018; 218(suppl_1):S40-S43. PMID: 30124975.
3.
Akabas MH, Tartakovsky I, Brass LF. The National MD-PhD Program
Outcomes Study. American Association of Medical College Reports 2018.
4.
Feldman AM. The National Institutes of Health Physician-Scientist
Workforce Working Group report: A roadmap for preserving the physicianscientist. Clin Transl Sci 2014; 7(4):289-290. PMID: 25123835.
5.
Behera A, Tan J, Erickson H. Diversity and the next-generation physicianscientist. J Clin Transl Sci 2019; 3(2-3):47-49. PMID: 31660227.
1.

Keywords: physician-scientist, pipeline, training programs, mentorship28

KANSAS JOURNAL of M E D I C I N E
Letter to the Editor: A Randomized,
Double-Blinded, Placebo-Controlled, Cross
Over Study Evaluating the Efficacy and
Safety of Timolol Ophthalmic Solution as
an Acute Treatment of Migraine
John C. Hagan III, M.D., FACS, FAAO
Discover Vision Center, Kansas City, MO

Received Feb. 28, 2020; Accepted for publication March 2, 2020; Published online March 2, 2020

I am an experienced and published researcher using timolol betablocker ophthalmic eyedrops for the successful treatment of acutemigraines.1-5 The above referenced paper contains many errors in study
design and conduct.6 The statistics, discussion, and conclusion are misleading.
Beta blockers are FDA approved and often effective for chronic
migraine prevention by taking daily oral doses that maintain therapeutic blood levels. For acute migraine, oral beta blockers have not worked
well because they take too long to achieve therapeutic blood levels.1,2
There are three other ways beta blocker solutions can be used to quickly
achieve therapeutic blood levels. The first is promptly and properly
applied topical beta blocker eyedrops to normal eyes/eyelids/nasolacrimal ducts/nasal mucosa. Faster is sublingual beta blocker drops and thefastest is beta blocker nasal spray.1,2 These last two preferred methods
were not discussed in Aggarwal’s paper.6
Ophthalmologists spend their careers listening to patients complain
about the difficulties of using eye drops. Sublingual application has beenstudied and found effective for glaucoma control in a subgroup of dropchallenged patients.7 Most acute migraine patients I have treated withtimolol 0.5% eye drops prefer to take them sublingual for ease of application and efficacy rather than topical to the eyes.
Absorption of beta blockers and subsequent beta receptor blockade has been studied.1,8 Of these three methods, nasal application has
been shown to the be fastest and equivalent to intravenous beta blocker
administration in a study of 80 human volunteers.8 Until recently, nobeta blocker nasal spray was commercially available. O’Brien Pharmacy(https://obrienrx.com/) now prepares a compounded nasal spray oftimolol with MucoluxTM delivering 0.125 mg/0.1 ml spray. The nasal
spray is shaken and one spray delivered into each nostril at first onset of
migraine symptoms. Patients may also take their other acute migraine
medications with the beta blocker nasal spray. If migraine headache persists a second set of one spray per nostril is repeated in 10-15 minutes. A
maximum of 4 sprays per 24 hours is specified. An O’Brien pharmacist
contacts the patient on receiving a prescription from a licensed physician and inquires about beta blocker contra-indication and instructs
on use. The cost of the medication at this writing is $30 for a 10 ml
bottle plus postage. All future research on using beta blockers for acutemigraine should be done using nasal delivery. I have no financial interestin this product.

29

The Aggarwal study6 has so many other deficiencies that for reasonsof space I can only list them without much discussion: patients not beta
blocker naïve were included; retrospective exclusion of them taints thealready scant data; the patients were not instructed to take the eye drops
as quickly as possible with migraine onset; instead they had to fill out aquestionnaire about the migraine; the study does not state if or when asecond set of eye drops were to be instilled (ideally 10 minutes after the
first if migraine persists); it is not stated whether patients were allowed
to take their usual acute migraine medications which they should havebeen; the migraine patients were recruited from a tertiary neurological referral center with a high number of refractory migraineurs. Most
important, per their own analysis, the number of patients studied does
not allow any reliable statistical validity which Aggarwal neverthelesserroneously claimed. Their discussion does not include considerationof the more effective and easier to use sublingual or nasal beta blocker
administration; the discussion attributes findings and conclusions toanother study9 that are inaccurate and ignores optimistic statements of
those authors about further study of beta blockers for acute migraine.10
Cossack et al.9 reported that 4 of their 10 studied patients found themasked beta blocker eye drop a useful addition to their acute migraine
therapy versus only 1 in favor of masked placebo. They did allow a second
set of eye drops but no sooner than 30 minutes because of Institutional
Review Board concerns. They did discuss that if used 10-15 minutes
post first insertion it might have improved their results. They did not
claim statistical significance of their study but determined that “A future
crossover study will require 86 patients to power a study with α≤0.05
and β≤0.2.”9,10 Cossack and Gratton conclude their discussion, “We
believe that, together, our work advances the notion that timolol drops
are a safe effective, and already widely available abortive treatment inselect migraineurs.”10 Neither the Cossack et al.9 or the Aggarwal studies
were large enough for statistical significance so it is a misrepresentation
for Aggarwal et al.6 to state “we now have two randomized-controlled
trials that would not demonstrate a marked effect of the drug comparedto placebo.”
I hope that either the pharmaceutical industry or grant funding willsoon conduct a large, adequately-powered (N ≥ 86), placebo-controlled,
cross-over study using the newly available nasal spray delivery as a novel,safe, relatively inexpensive treatment for acute migraines.
REFERENCES

Migliazzo CV, Hagan JC III. Beta blocker eye drops for treatment of acutemigraine. Mo Med 2014; 111(4):283-288. PMID: 25211851.
2
Hagan JC III. Are drops the solution? A Eureka moment? Beta blocker eye
drops for acute migraines. Mo Med 2014; 111(4):280-281. PMID: 25211850.
3
Migliazzo CV, Hagan JC III. Topical beta blockers for the treatment of
acute migraines in 2019. Mo Med 2018; 115(6):522-524. PMID: 30643344.
4
Lipner M. Beta blocker eye drops soothe acute migraines. February
2015. https://www.eyeworld.org/article-beta-blocker-drops-soothe-acutemigraines. Accessed March 3, 2020.
5
Ophthalmology Times. Acute migraine sufferers may find relief with betablocker eye drops. October 15, 2015. https://www.ophthalmologytimes.com/
modern-medicine-feature-articles/acute-migraine-sufferers-may-findrelief-beta-blocker-eye-drops. Access March 3, 2020.
6
Aggarwal D, Heim AJ, Bittel B, et al. A randomized, double-blinded, placebo-controlled, cross over study evaluating the efficacy and safety of timolol
ophthalmic solution as an acute treatment of migraine. Kans J Med 2020;
13(suppl 2):2-5.
7
Sadiq SA, Vernon SA. Sublingual timolol--an alternative to topical medication in glaucoma? Br J Ophthalmol 1996; 80(6):532-535. PMID: 8759264.
1This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Duchateau GS, Zuidema J, Merkus FW. Bioavailability of propranolol after
oral, sublingual, and intranasal administration. Pharm Res 1986: 3(2):108111. PMID: 24271469.
9
Cossack M, Nabrinsky E, Turner H, Abraham A, Gratton S. Timolol eyedrops in the treatment of acute migraine attacks: A randomized crossoverstudy. JAMA Neurol 2018; 75(8):1024-1025. PMID: 29799915.
10
Gratton S, Cossack M. Answering the call: A prospective look at the role oftimolol eye drops in the treatment of acute migraine attacks. Mo Med 2018;
115(6):520-521. PMID: 30643343.
8

KANSAS JOURNAL of M E D I C I N E
LETTER TO THE EDITOR
continued.

Keywords: timolol, ophthalmic solution, migraines, letter

30

Abstracts from Frontiers Research Day
University of Kansas Medical Center, Kansas City, KS
March 4, 2020
31

Racial Disparities in Cesarean Delivery in Singleton Pregnancies
Jenifer Allsworth, Ph.D.

32

The Chaning Health and Social Circumstances of Women Leaving Jails: A Three-Year Longitudinal Study
Stephanie Assimonye, B.S., Jaehoon Lee, Ph.D., Sharla Smith, Ph.D., MPH, Jason Glenn, Ph.D.,
Megha Ramaswarmy, Ph.D., MPH

33

Estimation and Construction of Confidence Intervals for the Cutoff-Points of Continuous Biomarkers Under
the Euclidean Distance in 3D Settings
Brian Mosier, B.S., Leonidas Bantis, Ph.D.

34 Humanized Mouse Models for Studying the Role of Immune Cells in Breast Cancer Progression
Hanan Elsarraj, Carolyn Kafuman, Darlene Limback, Yan Hong, Haleigh Harper, Lawrence R. Ricci, Fang Fan,
Ossama Tawfik, Lisa May, Therese Cusick, Marc Inciardi, Mark Redick, Jason Gatewood, Onalisa Winblad,
Tim Fields, Carol Fabian, Andrew K. Godwin, Patrick E. Fields, Ruby Meierotto, Linheng Li, John Perry,
Fariba Behbod
35

Evaluating the Adverse Effects of Hyperglycemia on the Airway Epithelium in Cystic Fibrosis and CF-related
DiabetesCharles Bengston, M.D.

36

University of Kansas Medical Center Genomics Core
Clark Bloomer, B.S.

37

Analysis of Mitochondrial Haplogroups with Alzheimer Disease Risk
Palash Sharma, M.S., Jonathan Mahnken, Ph.D., Dongwei Hui, Ph.D., Mary Michaelis, Ph.D.,
Elias Michaelis, M.D., Ph.D., Russell Swerdlow, M.D., Prabhakar Chalise, Ph.D.

38

Live Cell and Intravital Imaging Reveals Differences in Mitochondrial Redox State, Morphology and Number
between Osteoblasts and Osteocytes
Sarah Dallas, Ph.D.

39

Targeting Prolactin Receptor Using FDA-Approved Drugs: A Molecular Docking Approach and Drug Binding
Studies
Prasad Dandawate, Ph.D.

40 Neural Predictors of “Rapid Response” in Anorexia Nervosa
Victoria Perko, Kelsi Forbush, Ph.D., Sara Gould, Brianne Richson, Kylie Christian, Danielle Chapa,
Laura Martin
41

A High Throughput Assay for Quantitating β-catenin Signaling in the MLO-Y4 Osteocyte-like Cell LineMark Johnson, Ph.D.

42 Exploratory Evaluation of an Online Educational Intervention for JUUL Use
Matthew J. Carpenter, Ph.D., Tracy T. Smith, Ph.D., Nikki Nollen, Ph.D., Eleanor Leavens, Ph.D.
43 American Indian College Students’ Knowledge, Attitudes, Beliefs, and Behaviors Surrounding Alternative
Tobacco ProductsCharley Lewis, MPH
44 Low Dose Daunorubicin Targets the Leukemia Stem Cell in AML
Tara L. Lin, M.D., John M. Perry, Ph.D., Xi He, Ph.D., Gregory Reed, Ph.D., Na Zhang, Ph.D.,
Scott Weir, Pharm.D., Joseph P. McGuirk, D.O., Linheng Li, Ph.D.

Abstracts from Frontiers Research Day
University of Kansas Medical Center, Kansas City, KS
March 4, 2020
45 In Our Sacred Voice: An Exploration of Tribal and Community Leader Perceptions as Health Communicatorsof Disease Prevention among American Indians in the Plains
Crystal Y. Lumpkins, Ph.D., M.A., Ryan Goeckner, M.A., Jason Hale, M.A., Charley Lewis, MPH,
Jordyn Gunville, MPH, River Gunville, B.A., Chris M. Daley, Ph.D., M.A.
46 Not About Us, Without Us: An Exploratory Study of Underserved and Minority Patients’ Views of CancerRelated Genetic Counseling and Testing Communication
Crystal Y. Lumpkins, Ph.D., M.A., Alisdair Philp, Ph.D., M.S., CGC, Kim Kimminau, Ph.D.,
Mariana Ramirez-Mantilla, LMSW, Reem Mustafa, MBBS, Ph.D., MPH, Andrew Godwin, Ph.D.,
Yani Vazquez, MBA, Nancy Washington, Kim Jones, Shaton Freeman
47

Changing how the Brain Responds when Making Decisions: Translating Neuroscience to Population Health
Laura E. Martin, Ph.D., Morgan G. Brucks, B.A., Andrew Fox, Ph.D., Vlad B. Papa, B.A.,
Noreen D. Mdege, Ph.D., MPH, Austin S. Baldwin, Ph.D., Elisa M. Trucco, Ph.D., Nina A. Cooperman, Psy.D.,
Angelos P. Kassianos, Ph.D., Sara M. Levens, Ph.D.

48 Engaging Patients and Defining Outcomes: A Minority Engagement Effort
Reem Mustafa, M.D., MPH, Ph.D.
49 Race-Related Stress and Food Decision Making in African American Women
Ebony Onianwa, B.S.
50 Low Socioeconomic Status and Residential Distance of Less than 10 Miles from a Frontier-State
NCI-Designated Cancer Center is Associated with Worse Ovarian Cancer Survival
Shariska Petersen, M.D.
51

Understanding Race Bias in the Decision to Shoot with an Integrated Model of Decision Making
Timothy J. Pleskac, Ph.D., Sergej Grunevski, B.S., Taosheng Liu, Ph.D., Joseph Cesario, Ph.D.

52

A Developing Shared Resource: Emerging Imaging Technologies and Applications Laboratory
Eduardo Rosa-Molinar, Ph.D.

53

Influence of Vision and Proprioception on Motor Control in ASD
Robin L. Shafer, Ph.D., Zheng Wang, Ph.D., Matthew W. Mosconi, Ph.D.

54 Health through Enhancing Awareness and Learning about Breast and Cervical Cancer Screening among
African American Women (HEAL)
Sharla Smith, MPH, Ph.D., Jannette Berkley-Patton, Ph.D., Megha Ramaswamy, MPH, Ph.D., Joi Wickliffe, MPH
55

RITUXimab IMmunogenicity in ANCA-associated Vasculitis (RITUXIMAV)Jason Springer, M.D., M.S., Ryan Funk, Pharm.D., Ph.D.

56

Open-Label Pilot Study of Ranolazine for Cramps in Amyotrophic Lateral Sclerosis
Jeffrey Statland, M.D.

57

Skin Carotenoid Measurement: A Biomarker for Dietary Fruit and Vegetable Intake
Debra Sullivan, Ph.D., RD

58

Cognitive Function and Relationships with Intervention Dropout, Adherence and Weight Loss
Amanda Szabo-Reed, Ph.D.

59

Adolescent Mothers’ Early Breastfeeding Experiences
Karen Wambach, Ph.D., RN, IBCLC, FILCA, FAAN

60 A Therapeutic Trial Validating the Physiologically Based Pharmacokinetic Simulation of the Dose-Exposure
Relationship of Metformin in Young Children
Karen Wambach, Ph.D., RN, IBCLC, FILCA, FAAN

Abstracts from Frontiers Research Day
University of Kansas Medical Center, Kansas City, KS
March 4, 2020
61

A Therapeutic Trial Validating the Physiologically Based Pharmacokinetic Simulation of the Dose-Exposure
Relationship of Metformin in Young Children with Insulin Resistance or Type 2 Diabetes Mellitus
Chelsea Cojocari, Ph.D., Rachel Frazier, RN, BSN, CCRC, Kelsee Halpin, M.D., Paul Toren, Ph.D.,
J. Steven Leeder, Pharm.D., Ph.D., Yun Yan, M.D.

62

Targeting RNA-Binding Protein HuR in Human Liver Cancer
Priyanka Ghosh, Lin He, Nancy Magee, Forkan Ahamed, Xiaoqing Wu, Liang Xu, Yuxia Zhang

KANSAS JOURNAL of M E D I C I N E

Jenifer Allsworth, Ph.D.
Associate Professor
Department(s) of Biomedical and Health Informatics
University of Missouri-Kansas City
Frontiers Clinical and Translational Pilot Research Grant Recipient
Racial Disparities in Cesarean Delivery in Singleton Pregnancies
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: The past two decades have seen a revolution in the management of labor and delivery; rates of cesarean delivery (CD), medical
induction, and electronic fetal monitoring have increased dramatically. CD occurs in one third of deliveries and is the most common inpatient surgery. The increase in CD has occurred despite concerns about maternal complications (infection, blood loss, hysterectomy, uterine
rupture) and racial disparities. Since 1993, black and white women have gone from comparable CD rates to rates 40% higher among black
women compared to white women.
Methods: This project has assembled a cohort of over 800,000 deliveries from the Cerner Corporation’s Health Facts® database. HealthFacts contains 63 million unique patients from over 600 U.S. healthcare facilities. Data include comprehensive clinical records from inpatientand outpatient encounters and includes data from pharmacy, laboratory, registration and billing data.
Results: CD was identified using a validated definition that incorporates International Classification of Disease (Version 9, Clinical Modification) codes for delivery outcome and relevant diagnosis-related groups and procedures. We examined 618,582 singleton deliveries to black
and white women and identified 177,564 cesarean deliveries (28.7%).
Conclusions: The rate of cesarean was higher for black women overall and during the years 2000 - 2006 and 2011 - 2015 the CD rate forblack women was significantly higher than for white women. Of note, during the period from 2007 - 2010 rates of cesarean were similar
among black and white women. The rate of repeat cesarean was lower among black women, while the rate of induction of labor was higher.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

31

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

KANSAS JOURNAL of M E D I C I N EStephanie Assimonye, B.S.
Department of Population Health
University of Kansas Medical Center
Frontiers Predoctoral Trainee Scholar (TL1)

The Changing Health and Social Circumstances of Women Leaving Jails: A Three-Year Longitudinal Study
Stephanie Assimonye1, Jaehoon Lee2, Ph.D., Sharla Smith3, Ph.D., MPH, Jason Glenn4, Ph.D., Megha Ramaswamy1, Ph.D., MPH
1
University of Kansas School of Medicine, Department of Preventative Medicine and Public Health, Kansas City, KS
2Texas Tech University, College of Education, Institute for Measurement, Methodology, Analysis, and Policy (IMMAP), Lubbock, TX
3
University of Kansas School of Medicine-Wichita, Preventive Medicine and Public Health, Wichita, KS
4
University of Kansas School of Medicine, Department of History and Philosophy of Medicine, Kansas City, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Ninety-five percent of all inmates are eventually released back into communities, with many being released without accessto the most basic of necessities. Women in particular face complex health and social challenges – children, partners, strained employment
opportunities, health problems – before incarceration that they must also face upon reentry. This poses a barrier to their successful reintegration back into society.
Methods: The present study analyzes data collected as part of the sexual health empowerment (SHE Project) health literacy intervention.
Participants were recruited from three county jails in the greater Kansas City area. At baseline, participants completed a survey that assessedsociodemographic characteristics and social histories prior to incarceration. Women were followed annually after program completion tocomplete surveys to assess their long-term health and social circumstances. The present study is a secondary analysis of baseline and followup data.
Anticipated Results: We use Hobfoll’s Conservation of Resources (COR) Theory to conceptualize the stress that justice-involved women
may experience as a result of perceived or actual loss of resources. We hypothesize that “loss spirals”, a term coined by Stevan Hobfoll, creates
psychological stress that drives justice-involved women to assume risky sex and drug behaviors that will generate more resources and help
to cope with the stress.
Significance of Impact: This study aims to define a succinct longitudinal timeline assessing biopsychosocial outcomes of women released
from jail in order to improve prevention and intervention techniques for improvement in social and health circumstances of women leaving
jail and their reduction in recidivism.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

32

KANSAS JOURNAL of M E D I C I N E

Leonidas Bantis, Ph.D.
Assistant Professor
Department of Biostatistics & Data Science
Biostatistics, Epidemiology and Research Design (BERD) Trailblazer Award Recipient
Estimation and Construction of Confidence Intervals for the Cutoff-Points of Continuous Biomarkers Under the Euclidean
Distance in 3D Settings
Brian Mosier, B.S., Leonidas Bantis, Ph.D.
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with a five-year survival rate ~7%. Thus, early detection
could be key to reducing its mortality. Finding effective biomarkers is crucial to early detection. Pancreatic cancer biomarker studies typically consider more than two classes (i.e., recruited individuals that are either healthy, suffering from pancreatitis/cysts, or from aggressivePDAC). Conventional ROC curve analysis is the most popular tool to assess the discriminatory ability of biomarkers in distinguishing between
two groups. For more than two groups, this approach is inadequate to determine decision cutoffs for decision-making purposes. Currently
there is no accuracy-based statistical approach that is immune to the prevalence of the disease and is able to accommodate information fromall three groups to optimally determine a decision rule for classification of patients. We propose a Euclidian distance-based approach as amethod of estimating optimal cutoff values. We provide a full analysis framework when interest lies in decision-making and provide parametric and nonparametric approaches. Our approaches can easily be generalized into k-class problems when we are interested in distinguishing
between four or more classes. We can extend our methods to consider the costs of incorrect decision making for each of the groups and weighthem accordingly. Additionally, combinations of biomarkers or relevant clinical information can also be accommodated straightforwardly to
improve decision rules. We illustrate the usefulness of our approaches by analyzing a pancreatic cancer biomarker study conducted at the
University of Texas MD Anderson Cancer Center.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
33 Thisorg/licenses/by-nc-nd/4.0/)

Fariba Behbod, Pharm.D., Ph.D.
Professor
Department of Pathology & Laboratory Medicine
University of Kansas Medical Center
Pathology

KANSAS JOURNAL of M E D I C I N ECTSA Inter-Institutional Pilot Project Award Recipient
Humanized Mouse Models for Studying the Role of Immune Cells in Breast Cancer Progression
Hanan Elsarraj , Carolyn Kafuman1, Darlene Limback1, Yan Hong1, Haleigh Harper1, Lawrence R. Ricci3, Fang Fan1, Ossama Tawfik4, Lisa
May2, Therese Cusick2, Marc Inciardi1, Mark Redick1, Jason Gatewood1, Onalisa Winblad1, Tim Fields1, Carol Fabian1, Andrew K. Godwin1,
Patrick E. Fields1, Ruby Meierotto4, Linheng Li5, John Perry6, Fariba Behbod1
1
University of Kansas Medical Center, Kansas City, KS
2
University of Kansas School of Medicine-Wichita, Wichita, KS
3
Truman Medical Center, Kansas City, MO
4
St. Luke’s Hospital, Kansas City, MO
5Stowers Institute for Medical Research, Kansas City, MO
6Children’s Mercy Hospital, Kansas City, MO
1Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: To study breast cancer progression, we developed the Mouse-Intraductal (MIND) model which involves intraductal injectionof breast cancer cells into the mammary ducts of immunocompromised mice, where they display a course remarkably similar to the evolutionof human breast cancer, with the formation of lesions in situ followed by invasion into the surrounding stroma. More recently, we are collecting peripheral blood from these same women and have been successful in humanizing mice with the patient’s own hematopoietic stem cells(HSC).
Preliminary Data: We have achieved successful engraftment of peripheral blood-derived and bone marrow-derived human CD34+ cells
into NSG (immunodeficient NOD-SCID Il2rg-/-), MISTRG (immunodeficient Rag2-/-Il2rg-/- transgene SIRPa expressing GM-CSF,
IL-3, M-CSF, TPO) and MISTRG6 mice (plus IL-6) and observed recruitment of their progenitors to breast cancer lesions. Our preliminary
studies demonstrate preferential myeloid development when using peripheral blood derived CD34+ cells, while both myeloid and lymphoiddevelopment are achieved when using bone marrow derived CD34+ cells. Furthermore, MISTRG6 mice show improved development of bothhuman myeloid and lymphoid hematopoietic cells compared to MISTRG and NSG mice.
Impact and Future Aims: The major advantage of our model is the ability to observe progression of patient breast cancer and their associated immune cells in vivo. Analyzing patient samples eliminates the ability to track the progression of lesions and their associated immune
cells in vivo. By maximizing these unique advantages, we hope our results will help guide individualized immunotherapy in future patient care.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.
								This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

34

KANSAS JOURNAL of M E D I C I N ECharles Bengston, M.D.
Assistant Professor
Department of Internal Medicine
University of Kansas Medical Center
Frontiers Postdoctoral Trainee Scholar (TL1)
Evaluating the Adverse Effects of Hyperglycemia on the Airway Epithelium in Cystic Fibrosis and CF-Related DiabetesReceived Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Although causal linkage between hyperglycemia and decreased lung function in cystic fibrosis (CF) is unknown, it is thought
to be related to excess inflammation and ion channel dysfunction.
Methods: We utilized complementary in vitro and in vivo approaches to assess the effects of hyperglycemia on the CF airway epithelium.
In vitro: Primary CF bronchial epithelial (CFBE) cells at the air-liquid interface under hyperglycemic (HG; 255 mg/dL) or normoglycemic(NG; 100 mg/dL) conditions. Airway surface liquid (ASL) was measured by meniscus scanning and apical K+ (BK) ion channel current wasmeasured in Ussing chambers. In vivo: In CF subjects with or without CF related diabetes (CFRD), glycemic control was measured using
continuous glucose monitoring.
Results: Nasal epithelial cells were collected and analyzed by qPCR for the expression of RAGE, TGF-1, and LRRC26, the regulatory subunitof BK. Compared to normoglycemia, CFBE cells under hyperglycemia show significantly reduced ASL (68.4 ± 17.4 μL, NG vs. 51.5 ± 18.1 μL,
HG; p<0.05), a significant decrease in BK activity (-10.6 ± 0.8 μA/cm2, NG vs. -1.6 ± 0.5 μA/cm2, HG), and a 69% increase in mRNA expression of RAGE (p<0.05). From our in vivo studies, CF patients with and without CFRD showed significant negative correlation between themRNA expressions of TGF-1 and LRRC26 (R2=0.73, p<0.05).
Conclusions: In vitro data suggests hyperglycemia adversely affects airway hydration, in part, by impairing BK channel function. Reduction of LRRC26 expression in subjects with elevated TGF-1 and those with glycemic abnormalities point to BK as a target for therapeuticintervention in CFRD.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

35

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Clark Bloomer, B.S.
Project Manager - Genomics Core
Kansas Intellectual Developmental Disability Research Center
University of Kansas Medical Center

KANSAS JOURNAL of M E D I C I N E

Frontiers Infrastructure Award Recipient
University of Kansas Medical Center Genomics Core
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTThe University of Kansas Medical Center – Genomics Core leveraged the Frontiers: KU Clinical and Translational Science Institute infrastructure award to purchase an Eppendorf MasterCycler Pro thermal cycler and Countess II Automated Cell Counter to support the single
cell initiative of the Genomics Core at KUMC. The MasterCycler Pro and Countess II are used to support the 10X Genomics Chromium
Controller for performing the full suite of 10X Genomics single cell applications which include Single Cell 3’ Gene Expression, Single Cell 5’
Expression and V(D)J Enrichment and Single Cell ATAC – Chromatin Profiling.
The Countess II Automated Cell Counter is used to ensure that adequate cell counts and high viability of submitted samples are present. The
Countess also allows visualization of any cellular debris or cell clumping which will interfere with a successful 10X emulsification procedurerequired for a successful single cell library preparation. The MasterCycler Pro has been sequestered to exclusively support single cell library
preparations. The MasterCycler performs the initial single strand synthesis which incorporates the 10X GEM barcode and Unique Molecular
Identifier (UMI), second strand synthesis and Illumina adapter ligation to complete the 10X library preparation.
These instruments have proven critical to the successful execution of 16 single cell projects in support of seven different investigators. Frontiers’ investment in the single cell initiative has had a positive impact on cutting edge single cell expression and epigenetic research performedat the University of Kansas Medical Center.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

36

KANSAS JOURNAL of M E D I C I N E
Prabhakar Chalise, Ph.D.
Assistant Professor
University of Kansas Medical Center
Department of Biostatistics and Data Science
Biostatistics, Epidemiology and Research Design (BERD) Trailblazer Award Recipient
Analysis of Mitochondrial Haplogroups with Alzheimer Disease Risk
Palash Sharma, M.S. , Jonathan Mahnken, Ph.D.1, Dongwei Hui, Ph.D.2, Mary Michaelis, Ph.D.2, Elias Michaelis, M.D., Ph.D.2, Russell
Swerdlow, M.D.3, Prabhakar Chalise, Ph.D.1
1
University of Kansas Medical Center, Department of Biostatistics and Data Science, Kansas City, KS
2
University of Kansas, Higuchi Biosciences Center, Lawrence, KS
3
University of Kansas Medical Center, Department of Neurology, Kansas City, KS
1

Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Alzheimer’s disease (AD) is the most common form of irreversible, progressive dementia that affects memory loss, cognitive
capabilities, and behavior. Although, significant progress has been made to understand genetic and clinical risk factors associated with AD,
our understanding of AD remains incomplete resulting in ineffective prevention or cure.
Methods: Several studies have indicated that the polymorphisms in the mitochondrial DNA (mtDNA) play an important role in the mechanism of AD. Therefore, in order to understand the association of the mitochondrial genetic alteration with AD, we carried out cross-sectional
association analysis using the clinical and mitochondrial single nucleotide polymorphism (SNP) data. We used the data collected at University of Kansas Alzheimer’s Disease Center (KU ADC) to carry out the analyses. We also used the data from Alzheimer’s Disease Neuroimaging
Initiative (ADNI) for the replication and validation analyses.
Results: The KU ADC data consists of 146 AD and 265 cognitively normal subjects, and ADNI data has 244 AD and 242 controls. For bothdatasets, the haplogroups information for each subject and APOE ε4 carrier status were also available.
Conclusions: We found that the rates of incidence of AD were statistically significantly different among the haplogroups, with differingstrengths of association for different haplogroups. APOE ε4 was significantly associated with AD overall (p-value = 1.9×10-11) and the association varied by haplogroups (i.e., interaction). The results were consistent with the ADNI data. Our study has generated hypothesis andthe data for further studies ahead to understand the etiology of AD.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

37

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Sarah Dallas, Ph.D.
Lee M. and William Lefkowitz Endowed Professor
Department of Oral and Craniofacial Sciences,
University of Missouri-Kansas City School of Dentistry

KANSAS JOURNAL of M E D I C I N E

Frontiers Infrastructure Award RecipientLive Cell and Intravital Imaging Reveals Differences in Mitochondrial Redox State, Morphology and Number between Osteoblasts and Osteocytes
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Age-related bone loss and associated fracture risk is an increasing concern worldwide. Oxidative stress causes mitochondrial
damage and is associated with age-related degeneration in many cell systems, including bone cells.
Methods: To understand mitochondrial function in bone cells in situ, live-cell and intravital imaging of mitochondrial NADH and mitochondrial morphology was performed using transgenic mice expressing GFP in osteocytes as well as in MLO-Y4 osteocyte-like cells and
OmGFP66 cells, which model osteoblast-to-osteocyte transition. NADH excitation and emission spectra in live osteocytes and osteoblasts
matched well with pure NADH, with maximal multiphoton excitation at 740 - 760nm, resulting in blue NADH autofluorescence. With 760nm
excitation, maximal NADH emission occurred at 460nm. Metabolic challenge was performed with carbonylcyanide-3-chlorophenylhydrazone and sodium cyanide, which convert NADH to its maximally oxidized or reduced states.
Results: This showed that osteoblasts had a lower resting redox state, with 40% of their NADH in a reduced state, compared to osteocyteswith 75 - 80%. Live imaging using mitotracker Red-CMXRos showed that osteocytes have fewer mitochondria, lower mitochondrial area
and % area, and increased solidity.
Conclusions: These data show that osteocytes in vivo under normoxic conditions have significant levels of mitochondrial NADH and show
differences in mitochondrial number, morphology and function compared to osteoblasts. These live-cell imaging techniques can be used
to determine changes in mitochondrial function during aging/cellular senescence and disease. These studies were supported by Frontiers
equipment funding, including a Tokai-Hit CO2 incubation system, Leica 16x and 20x objectives and Imaris9.2 software which are available
to other investigators through the UMKC Confocal Imaging Core.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

38

KANSAS JOURNAL of M E D I C I N E

Prasad Dandawate, Ph.D.
Research Assistant Professor
Department of Cancer Biology
University of Kansas Medical Center
Frontiers Infrastructure Award Recipient
Targeting Prolactin Receptor Using FDA-Approved Drugs: A Molecular Docking Approach and Drug Binding Studies
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Pancreatic cancer (PDAC) is the fourth leading cause of cancer-related deaths in the U.S. Gemcitabine remains the drugof choice for metastatic disease, but only little improvement is seen in survival rates. Hence, there is a dire need for novel therapeutics for
PDAC. We found that PRLR is overexpressed in PDAC tissues and cell lines and knockdown of the receptor resulted in reduced tumor
formation in mice. Hence, PRLR is a novel target for therapeutic interventions in PDAC.
Methods: As there is no small molecular inhibitor available for targeting the receptor, we developed a homology model of the intracellulardomain of PRLR that encodes the JAK2 binding site, and then performed a virtual screening of small molecules using IDOCK and I-TASSER servers. Using Fragment-based drug design, we derived commercially available compounds for virtual screening. We selected several
compounds that came out of the virtual screening and performed in vitro proliferation assays in the PDAC cells. We identified antipsychotic drugs including penfluridol that can inhibit the proliferation of PDAC cell lines. Moreover, pretreatment of these antipsychotic drugs
inhibited PRL-induced STAT3 and ERK phosphorylation in PDAC cell lines. Further, we used cellular thermal shift assay and drug affinity
binding assay to confirm the binding of Penfluridol and PRLR. We also used cell-free systems such as surface plasmon resonance (SPR)
and magnetic relaxometry to confirm the drug binding. Moreover, Penfluridol treatment significantly decreased pancreatic tumor burden inanimal models. In conclusion, we identified penfluridol is a potential drug candidate for targeting PRLR in PDAC.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

39

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Kelsie Forbush, Ph.D.
Associate Professor
Department of Psychology
University of Kansas

KANSAS JOURNAL of M E D I C I N E

Frontiers Dr. Lauren S. Aaronson Trailblazer Recipient
Neural Predictors of “Rapid Response” in Anorexia Nervosa
Victoria Perko , Kelsie Forbush1, Sara Gould1,2, Brianne Richson1, Kylie Christian1, Danielle Chapa1, Laura Martin3
1
University of Kansas, Lawrence, KS
2Children’s Mercy Hospital, Kansas City, MO
3
University of Kansas Medical Center, Kansas City, KS
1

Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Anorexia nervosa (AN) is a serious condition associated with numerous medical complications, psychiatric comorbidity, andthe highest mortality rate of any psychiatric disorder. Relapse rates remain high and for many, AN becomes an enduring condition. The only
reliable prognostic indicator for AN is “rapid response” (i.e., weight gain over the first four weeks of treatment). Yet, there are no reliablepredictors of rapid response at baseline. There is a pressing need to identify novel neuro-markers that confer early risk for poor treatment
outcome.
Methods: Study goals were to systematically identify potential neuro-markers related to short-term AN outcomes by assessing brain activation associated with delayed discounting (capacity to delay immediate gratification), sensitivity to food reward (responses to rewarding foods
and decisions to choose palatable foods), and threat sensitivity (heightened reactivity to potential danger or harm). The purpose of this study
was to identify neural predictors of short-term treatment response in adolescents with AN. Participants were adolescent females with AN
who entered their first course of eating-disorder treatment within the past six months.
Specific aims: 1) Test neural activation during tasks measuring delayed discounting, food reinforcement, and threat and 2) Identify prospective associations of task-performance and task-based neural activation with eating-disorder symptoms at one-month follow-up.
Conclusions: Differentiating neurobiological processes that contribute to AN chronicity may lead to the development of prognostic indicators at initial treatment presentation. These neuromarkers may improve clinical decision-making and allow providers to identify patientsrequiring more intensive treatment interventions to prevent chronicity and mortality.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

40

KANSAS JOURNAL of M E D I C I N EMark Johnson, Ph.D.
Professor and Chair
Department of Oral and Craniofacial Sciences,
University of Missouri-Kansas City School of Dentistry
Frontiers Infrastructure Award Recipient
A High Throughput Assay for Quantitating β-catenin Signaling in the MLO-Y4 Osteocyte-like Cell Line
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Osteocytes are the primary mechanosensory cell in bone and activate β-catenin signaling in response to mechanical loadingof bone.
Methods: In order to understand the mechanism by which osteocytes activate β-catenin signaling, we have developed a stably transfected
osteocyte cell line that expresses luciferase when β-catenin signaling occurs in the nucleus. To quantitate luciferase activity, we purchased a
VICTOR Nivo Multimode Plate Reader (Perkin-Elmer) with the support of Frontiers funding. This instrument quantitatively measures luciferase activity (fluorescence and absorbance) in several plate formats, thus permitting high throughput screening of compounds that activate
β-catenin signaling. We stably transfected the MLO-Y4 osteocyte-like cell line with the TOPflash vector pGL4.9[luc2P/TCF_LEFRE/Hygro](Promega). Clone A3-F9 gave a dose response to increasing concentrations of Wnt3a (1-100ng/ml) and activation with 10mM LiCl gave theequivalent of a submaximal dose of Wnt3a (10ng/ml).
Results: We demonstrated that C2C12 myotubes, but not myoblasts, produce a factor that activates β-catenin signaling two-fold using these
TOPflash-MLO-Y4 cells, but in combination with Wnt3a (10 ng/ml; 10-fold activation) produces a 20-30-fold increase in activity measured
in our luciferase assay. We demonstrated that production of this factor by C2C12 myotubes is partially regulated by mTOR signaling. We are
currently seeking to identify this factor using our TOPflash-MLO-Y4 cells.
Conclusions: The acquisition of the VICTOR Nivo Multiplate reader provides us the means to conduct a high throughput screening approach
to identify this factor(s). This instrument is part of a Core in the UMKC School of Dentistry Department of Oral and Craniofacial Sciences
and available to other investigators for their studies.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

41

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Eleanor Leavens, Ph.D.
Department of Population Health
University of Kansas Medical Center

KANSAS JOURNAL of M E D I C I N E

Frontiers Postdoctoral Fellow (TL1)
Exploratory Evaluation of an Online Educational Intervention for JUUL Use
Matthew J. Carpenter, Ph.D.1, Tracy T. Smith, Ph.D.1, Nikki Nollen, Ph.D.2, Eleanor Leavens, Ph.D.2
1
Medical University of South Carolina, Charleston, SC
2
University of Kansas Medical Center, Kansas City, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Initiation of JUUL use by young adults is one of the most significant issues of concern within the debate on vaping. Despite
the proliferation of products and the surge in prevalence, no studies have investigated individual-level interventions or prevention strategies
for pod-mod use.
Methods: Participants (N = 947) were young adults (< 30 years old) recruited from Amazon’s Mechanical Turk based on smoking (never,former, and current smokers) and JUUL use status (never and current users). In a pre-post design, participants completed baseline assessments, were presented with a brief JUUL-specific educational intervention and completed post-assessment measures. Primary outcomes
were changes in JUUL knowledge, perceived harmfulness, intentions for future use, and motivation to change.
Results: Participants (Mean age = 26.1) were male (57%) and White (75%). Overall, the intervention increased JUUL-related knowledge,
risk perceptions, commitment to quitting, and readiness to quit JUUL (all p ≤ 0.001). Similarly, participants showed decreased interest in
future JUUL use, interest in purchasing JUUL, and interest in future regular JUUL use (all p ≤ 0.001). There were significant Time X Group
interactions for JUUL-related knowledge (p < 0.001), with never JUUL/never smokers showing the greatest increase in product knowledge
following the intervention. However, no other interaction effects were significant.
Discussion: The intervention was effective in increasing knowledge and risk perceptions while reducing intentions for future use. The intervention was most effective in increasing knowledge among non-users, suggesting that brief educational interventions may be useful tools forpreventing pod-mod initiation while more intensive interventions may be necessary to alter attitudes and use behaviors among current users.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

42

KANSAS JOURNAL of M E D I C I N ECharley Lewis, MPH
Research Instructor
Center for American Indian Community Health
University of Kansas Medical Center
Frontiers Clinical and Translational Pilot Research Grant Recipient
American Indian College Students’ Knowledge, Attitudes, Beliefs, and Behaviors Surrounding Alternative Tobacco ProductsReceived Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: American Indians (AI) have the highest rates of smoking and smokeless tobacco (SLT) use among all major racial/ethnic
groups. There is limited information about the use of alternative tobacco (AT) products such as electronic cigarettes. The objective of thispilot study is to understand the knowledge, attitudes, beliefs, and behaviors (KABB) surrounding AT product use among AI college students.
Methods: We conducted 19 focus groups with AI college students age 18 and older. Participants were stratified by AT use, cigarette use, andnever users of tobacco products. Focus groups were audio-recorded and transcribed verbatim in preparation for coding and standard text
analysis. Participants completed a short survey that collected information on demographics and KABB about tobacco products. Surveys wereanalyzed with frequencies and measures of central tendencies.
Results: Participants included 105 AI college students. Participant’s mean age was 21 years and 50% were female. Focus groups ranged in size
from two to nine. Related to e-cigarette use, participants cited flavors, discreteness, stress, and social aspects as factors for use. Survey results
indicate that 35% of participants were current e-cigarette users, 30% were current smokers, and 9% were current SLT users.
Conclusion: This pilot study confirms that AI college students are following a similar trend to other racial/ethnic groups in terms of AT use.
It is important that we obtain estimates of AT use and include AI in prevention and cessation efforts. This study will help develop appropriate
prevention and cessation messaging for this population.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
43 Thisorg/licenses/by-nc-nd/4.0/)

KANSAS JOURNAL of M E D I C I N ETara Lin, M.D., M.S.
Associate Professor
University of Kansas Medical Center
University of Kansas Cancer Center
Frontiers Clinical and Translational Pilot Research Grant Recipient

Low Dose Daunorubicin Targets the Leukemia Stem Cell in AML
Tara L. Lin, M.D.1,2, John M. Perry, Ph.D.4, Xi He, Ph.D.3, Gregory Reed, Ph.D.1, Na Zhang, Ph.D.1, Scott Weir, Pharm.D.1,5,
Joseph P. McGuirk, D.O.1,2, Linheng Li, Ph.D.1,3
1
University of Kansas Cancer Center, Kansas City, KS
2
University of Kansas, Division of Hematologic Malignancies & Cellular Therapeutics, Kansas City, KS
3
Stowers Institute for Medical Research, Kansas City, MO
4Children’s Mercy Hospital and Clinics, Kansas City, MO
5
University of Kansas, Division of Medical Oncology, Kansas City, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: A proof of concept trial (NCT02914977) was designed to measure the ability of low dose DNR to inhibit pS552-β-cateninin LSCs of adult relapsed/refractory AML patients. A protocol amendment added a second cohort of patients with newly diagnosed AML
undergoing standard chemotherapy with DNR and cytarabine (7+3 induction).
Methods: Treatment in each cohort consisted of DNR given at a dose of 6.75mg/m2/day x five days. Patients with relapsed/refractory AML
had bone marrow aspiration pre-treatment prior to day 1, followed by DNR on days 1-5, and a post-treatment bone marrow aspiration on day
8. Patients with newly diagnosed AML were treated with conventional 7+3 chemotherapy.
Results: A sample from the day 14 bone marrow was collected. DNR was given on days 15 - 19. Bone marrow aspiration was performed withblood count recovery and samples sent for LSC marker assessment.
Discussion: In this study, we will determine the safety, pharmacokinetics, and pharmacodynamic effects of low dose DNR. The LSC population and phosphorylation status of β-catenin will be measured pre-and post-treatment. Two or more prior induction attempts are required
for study entry for refractory patients; relapsed patients require only one prior induction. The trial completed its accrual goal of 18 patients.
Low-dose DNR treatment was well-tolerated with no unexpected adverse events. In this pilot proof of concept trial, we will demonstrate thefeasibility of serial bone marrow aspiration to measure biomarkers of LSC response.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

44

KANSAS JOURNAL of M E D I C I N E

Crystal Lumpkins, Ph.D., M.A.
Associate Professor
Center for American Indian Community Health
Department of Family Medicine & Community Health
University of Kansas Medical Center
Frontiers Pilot and Collaborative Studies Funding Program Award Recipient
In Our Sacred Voice: An Exploration of Tribal and Community Leader Perceptions as Health Communicators of Disease
Prevention among American Indians in the Plains
1,3
Crystal Y. Lumpkins, Ph.D., M.A. , Ryan Goeckner, M.A.2, Jason Hale, M.A.1, Charley Lewis, MPH1, Jordyn Gunville, MPH1,
River Gunville, B.A.1, Chris M. Daley, Ph.D., M.A.1
1
University of Kansas Medical Center, Center for American Indian Community Health,
Department of Family Medicine & Community Health, Kansas City, KS
2Ohio State University, Columbus, OH
3
University of Kansas, William Allen White School of Journalism and Mass Communication, Lawrence, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: American Indians (AI) are disproportionately and significantly impacted by disease morbidity, mortality and poor behavioral
health outcomes. Based on data from the National Vital Statistics Reports, the leading cause of death among AI is cancer (19%), followed
by heart disease (18%). Regionally, health disparities among AIs reflect national statistics. Health communication targeted to address these
health disparities exist; however, few evidence-based strategies integrate holistic approaches. The impact of health communication researchand practice is evolving and continues to emerge as a core part of health promotion. Strategies that appeal and increase persuasiveness ofhealth messages are more likely to penetrate existing cultural beliefs and positively influence health behavior outcomes. The objective of thisstudy was to explore how tribal and elder leaders throughout the Plains viewed themselves as health communicators within their communities.
Methods: Members of the Center for American Indian Community Health conducted 39 in-depth interviews from December 2017 to
December 2018 with members of federally recognized tribes living in reservation communities, as well as urban tribal communities acrossthe region.
Results: Results from this sample show that these individuals do not see themselves as the “authority” health communicator within theirtribe and community. The term health promoter was viewed as problematic in Native communities for cultural reasons.
Conclusion: Overarching themes included seeing themselves as communicators of holistic health, specific health prevention programs,
access, targeted communication and health promoters as a collective unit. Collective social and cultural authority in tailored messages isperceived to bolster health communication and positively impact health outcome.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

45

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Crystal Lumpkins, Ph.D., M.A.
Associate Professor
Center for American Indian Community Health
Department of Family Medicine & Community Health
University of Kansas Medical Center

KANSAS JOURNAL of M E D I C I N E

Frontiers Pilot and Collaborative Studies Funding Program Award Recipient
Not About Us, Without Us - An Exploratory Study of Underserved and Minority Patients’ Views of Cancer-Related Genetic
Counseling and Testing Communication
Crystal Y. Lumpkins, Ph.D., M.A.1, Alisdair Philp, Ph.D., M.S., CGC2, Kim Kimminau, Ph.D.1, Mariana Ramirez–Mantilla, LMSW3,5,
Reem Mustafa, M.B.B.S., Ph.D., MPH2, Andrew Godwin, Ph.D.4, Yani Vazquez, MBA7, Nancy Washington8, Kim Jones6,8, Shaton Freeman6,8
University of Kansas Medical Center, Kansas City, KS
1
Department of Family Medicine and Community Health2
Department of Internal Medicine
3
Department of Population Health4
Department of Pathology and Laboratory Medicine
5
Juntos Center for Advancing Latino Health, Kansas City, KS
6Sisters Living Beyond the Ribbon, Kansas City, MO
7
Hispanic Chamber of Commerce of Greater Kansas City, Kansas City, MO
8
University of Kansas Cancer Center, Patient and Investigator Voices Organizing Together (PIVOT) Team, Kansas City, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Minority and underserved populations carry the largest cancer burden for the United States (ACS, 2016). Genetic counseling, testing and technologies show promise to help reduce cancer through personalized medicine opportunities however disproportions ofgenetic services, uptake and research about genetic testing among these populations exist (Ricker, et al., 2018). Inequitable cancer-related
genetic and genomic testing (CGT) communication among minority and underserved populations and other barriers (e.g., genetic counselorbias) may contribute to CGT disparities. Exploring existing attitudes, perceptions and beliefs toward CGT among minority and underserved
patient populations may bolster strategies to address communication inequities. The study aims were to explore an under-researched area ofprecision medicine, i.e., the communication of genetic risk factors among minority and underserved patient populations with high to moderaterisk and disseminate and share findings with the community.
Methods: A Community Advisory Board comprised of researchers, cancer survivors and family members of cancer patients met from December 2018 - March 2019 to discuss research design and data collection. Six stratified focus group discussions (N = 53) were held March - May2019 where a pre-focus group survey was administered.
Results: Survey results show most had not talked to their doctor/health care provider about genetic testing (87%). African Americans (AA)and Latinos expressed a lack of awareness and knowledge about CGT and the importance of cultural tailoring.
Conclusion: Separate themes that emerged among Latinos included immigration status and language as barriers to CGT. Among AA, participants were highly distrustful of medical personnel and expressed outrage about the lack of recommendation for CGT.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

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KANSAS JOURNAL of M E D I C I N E

Laura Martin, Ph.D.
Associate Professor
Department of Population Health
University of Kansas Medical Center
Frontiers Clinical and Translational Pilot Research Grant Recipient
Changing how the Brain Responds When Making Decisions: Translating Neuroscience to Population Health
Laura E. Martin, Ph.D.1, Morgan G. Brucks, B.A.1, Andrew Fox, Ph.D.1, Vlad B. Papa, B.A.1, Noreen D. Mdege, Ph.D., MPH2,
Austin S. Baldwin, Ph.D.3, Elisa M. Trucco, Ph.D.4, Nina A. Cooperman, Psy.D.5, Angelos P. Kassianos, Ph.D.6, Sara M. Levens, Ph.D.7
1
University of Kansas Medical Center, Kansas City, KS
2
University of York, United Kingdom
3Southern Methodist University, Dallas, TX
4Florida International University, Miami, FL
5Rutgers University, New Brunswick, NJ
6
University College London, United Kingdom
7
University of North Carolina-Charlotte, Charlotte, NC
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Engaging in healthy behaviors is not always rewarding (e.g., carrot vs. cake). Neural models of healthy behaviors focus on thebalance between reward and regulation brain regions. This pilot study examines the engagement of reward and regulation regions during
the evaluation of food and nonfood cues before and after a guided imagery exercise targeting positive associations with food and regulation.
Our long-term goal is to understand the interaction between positive associations with healthy foods and thinking about future rewards may
influence healthy decision-making. The objective of the current study is to empirically test the combined effects of positive affect and positive
episodic future thinking on brain activation.
Methods: The project examined the effect of positive affect and episodic future thinking guided imagery on brain activation in regulation andreward regions. Participants included individuals with a body mass index greater than 25 (n = 20).
Results: Functional neuroimaging showed reduced activation in regulation-related brain regions (i.e., dorsomedial prefrontal cortex) tohealthy and unhealthy food following guided imagery.
Conclusions: These results suggest more efficient regulation-related brain activation after positive episodic future thinking guided imagery.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
47 Thisorg/licenses/by-nc-nd/4.0/)

KANSAS JOURNAL of M E D I C I N E

Reem Mustafa, M.D., MPH, Ph.D.
Associate Professor
Department of Internal Medicine
Kidney Institute
University of Kansas Medical Center
Frontiers Dr. Lauren S. Aaronson Trailblazer Recipient

Engaging Patients and Defining Outcomes: A Minority Engagement Effort
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: The Establishing Meaningful Patient-centered Outcomes With Relevance for patients with Polycystic Kidney Disease(EMPOWER PKD) initiative aims to engage PKD stakeholders and patients to learn about health priorities, insurance issues, and patientengagement.
Methods: We utilized semi-structured focus groups. We developed and pre-piloted a guide that allowed for both conversational flow andconsistency in questions among groups. We audio-recorded each group and transcribed the conversations verbatim. We performed an inductive thematic analysis. Two investigators completed all data coding independently and in duplicate. We compare the results of an ethnicallydiverse focus group to the other seven that mainly included Caucasian participants.
Results: 14 individuals participated in this part of the study. Of these, (64.2%) reported having PKD, and (14.2%) being caregivers. The mean
age of participants was 48.8 (range 29 - 75) years. The group included 85.75% African American and 7.1% reported more than one race.
Conclusions: It was challenging to recruit this group and it required establishing a relation with community nephrologists and faith-basedorganizations leads. Multiple participants stated that they would not have participated if the group was not exclusively ethnically diverse as
they fear that their opinion may be outnumbered by a Caucasian majority. Some discussed believing that PKD was a “white” disease. Many
discussed hiding their diagnosis which affected their activation and engagement and came with unanticipated psychological impacts. Participants unanimously described lack of trust-worthy, easy to understand educational resources for minorities as a main barrier to engagement.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

48

KANSAS JOURNAL of M E D I C I N E

Ebony Onianwa, B.S.
Department of Population Health
University of Kansas Medical Center
Frontiers Predoctoral Trainee Scholar (TL1)
Race-Related Stress and Food Decision Making in African American Women
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: The highest rates of obesity in the U.S. are among black women with a prevalence of 54.8%. Psychosocial factors, such as
stress from racism, have been proposed as contributors to this disparity, but the mechanisms are unclear. The objective of this study is tounderstand the relationship between race-related stress and food choice among black women.
Methods: Forty-five participants were asked to come in fasted for two appointments, randomized to the order of stress exposure in a within
subject design. Forty images for each condition were collected from two validated picture sets (International Affective Picture set and Socio
Moral Image Database). The images were shown in random order and contained either racially charged scenes (e.g., Ku Klux Klan) or nonracially charged scenes (e.g., aggressive dog) matched on valence (pleasant vs. unpleasant) and arousal (physiologically stimulating). Foodchoice and food demand tasks were completed pre and post stress exposure. Participants were surveyed on their stress levels, past experiences of racism, and trauma.
Anticipated Results: It is expected that preferences for unhealthy foods will be greater after race related stress exposure compared to theother stress condition. We anticipate that those who have higher BMI’s are more likely to be affected in their changes in eating behaviors inboth stress exposure states, with a larger impact from the race related stress induction. Data collection is ongoing.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

49

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Shariska Petersen, M.D.
Department of Obstetrics and Gynecology
University of Kansas Medical Center

KANSAS JOURNAL of M E D I C I N E

Frontiers Postdoctoral Fellow (TL1)
Low Socioeconomic Status and Residential Distance of Less Than 10 Miles From a Frontier-State NCI-Designated Cancer
Center is Associated with Worse Ovarian Cancer Survival
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntrodution: To examine the impact of residential distance and socioeconomic status on survival outcomes for patients receiving treatment
for ovarian cancer at an NCI-CC.
Methods: Patients who were treated for ovarian cancer at a single institution from 2010 - 2015 were identified. Age at diagnosis, insurance
status, and distance from the patient’s home to the institution were abstracted. Clinical data including stage at diagnosis, surgical status,
chemotherapy cycles, dates of diagnosis, recurrence, and death were obtained. Patients treated at other institutions and those with nonepithelial pathology were excluded. Patients were stratified into three groups based on distance from the institution. Overall survival (OS)and progression free survival (PFS) were generated by Kaplan Meier survival curves and Cox proportional hazard models using SAS v9.4.
Results: Two hundred and three patients were identified. Survival analysis based on distance demonstrated that patients who lived less than
10 miles from the institution have worse survival (p = 0.0412). Lower median income (< 56,179) regardless of distance to institution was also
associated with worse survival, p = 0.0283. After adjusting for stage of disease, age at diagnosis, surgery status, chemotherapy resistance,
income quartile and presence of comorbid conditions, distance < 10 miles from the institution was still a significant predictor of worse overall
survival, HR 2.62 95% CI (1.333 - 5.142), p = 0.0052.
Conclusion: Among patients who received guideline-adherent care for ovarian cancer, lower median income and residential distance lessthan 10 miles to an NCI-CC was associated with worse overall survival.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

50

KANSAS JOURNAL of M E D I C I N E

Timothy Pleskac, Ph.D.
Professor
Department of Psychology
University of Kansas
Frontiers Infrastructure Award Recipient
Understanding Race Bias in the Decision to Shoot with an Integrated Model of Decision Making
Timothy J. Pleskac, Ph.D.1, Sergej Grunevski, B.S.1, Taosheng Liu, Ph.D.2, Joseph Cesario, Ph.D.2
1
University of Kansas, Lawrence, KS
2Michigan State University, East Lansing, MI
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: The shooting of unarmed citizens by police officers is a topic at the forefront of public awareness. The disproportionate rate at
which unarmed Black citizens are shot is believed to reflect widespread racial bias on behalf of officers, which erodes public trust and reduces
policing effectiveness.
Methods: We have developed an Attention-integrated Model-based Shooting Simulator (AiMSS) to gain a deeper understanding of themechanisms underlying the decision to shoot. The AiMSS combines computational models of decision making, visual psychophysics andeye-tracking methods, and an immersive decision simulator to map the processes police officers use to decide to shoot.
Results: Results with the AiMSS reveal that policing scenario and suspect behavior accounted for the most variation in decisions. Processlevel measures show little evidence of an initial bias to shoot Black suspects. Instead, results reveal a diminished ability to distinguish objects
held by Black suspects.
Conclusions: This work emphasizes the importance of contextual factors in the decision to shoot and highlights how past experimental
studies on racial bias have neglected critical inputs into officer deadly force decisions.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

51

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Eduardo Rosa-Molinar, Ph.D.
Professor and Director
Emerging Imaging Technologies and Applications Laboratory andMicroscopy and Analytical Imaging Research Resource Core
Laboratory
University of Kansas

KANSAS JOURNAL of M E D I C I N E

Frontiers Infrastructure Award Recipient
A Developing Shared Resource: Emerging Imaging Technologies and Applications Laboratory
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTThe Emerging Imaging Technologies and Applications Laboratory (EITAL) is a shared resource serving as a proof-of-concept hub for
performing innovative and rigorous fundamental cancer biology research at subcellular to cellular length-scales in conjunction with thedevelopment and translation of advanced imaging technologies and applications. The scientific staff of EITAL are experts in developing andimproving reagents, methods, and optical and electron microscopic imaging technologies, antibody development, screening, and characterization, immunohistochemistry, immunocytochemistry, correlative optical and electron microscopy, immunoelectron microscopy, workflow
development, and experimental design and data analysis of imaging studies. EITAL promotes synergies between its imaging technology
developers and University of Kansas Cancer Center (KUCC) cancer biology researchers. EITAL also provides research training and careerdevelopment programs to ensure a talented and diverse workforce engaged in cellular tumor cancer biology imaging research. The collaboration between EITAL and the University of Kansas (KU) Microscopy and Analytical Imaging Research Resource Core Laboratory (MAI)
imaging scientists, enables imaging research at the level of the whole animal, individual cells, as well as molecules inside the cells, and provides
instrumentation and expertise for optical and electron microscopies, resulting in multi-scale/multi-dimensional correlative imaging researchof living and fixed cells and tissues. The KUCC Support Grant (P30 CA168524) supports EITAL.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

52

KANSAS JOURNAL of M E D I C I N ERobin Shafer, Ph.D.
Schiefelbusch Institute for Life Span Studies
University of Kansas
Frontiers Postdoctoral Fellow (TL1)
Influence of Vision and Proprioception on Motor Control in ASD
Robin L. Shafer, Ph.D.1,2, Zheng Wang, Ph.D.3, Matthew W. Mosconi, Ph.D.1,2,4
1
Schiefelbusch Institute for Life Span Studies, University of Kansas, Lawrence, KS
2Kansas Center for Autism Research and Training, University of Kansas, Lawrence, KS
3
Department of Occupational Therapy, University of Florida, Gainesville, FL
4Clinical Child Psychology Program, University of Kansas, Lawrence, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Sensorimotor integration deficits are common in Autism Spectrum Disorders (ASD). Evidence exists for an over-reliance on
both visual and proprioceptive feedback during motor control in ASD, suggesting deficits in the modulation of sensory feedback processing
and inability to use the most reliable input. This study aims to test this hypothesis.
Methods: Forty persons with ASD (10 - 33 yrs) and 25 age-, sex- and nonverbal IQ-matched controls completed precision gripping tasks.
They squeezed a force sensor with their index finger and thumb and tried to match their force output to a target force. Visual feedback waspresented on a computer screen across low, medium, and high gain levels; the force output bar moved a greater distance per change in force at
higher gains. A stationary bar represented the target force. 80Hz tendon vibration was applied at the wrist to create a proprioceptive illusionof muscle contraction. Force regularity (approximate entropy; ApEn) was examined.
Results: Preliminary results from 18 participants with ASD and 13 controls indicate a Group x Tendon Vibration x Visual Gain interaction
for ApEn (F = 1.559, p = 0.023). Controls showed increased ApEn during 80Hz tendon vibration at low visual gain but decreased ApEn withvibration at high visual gain. Individuals with ASD show slight increases in ApEn with 80Hz vibration across visual conditions.
Conclusions: Early findings indicate that controls shift to a secondary source of sensory feedback (e.g., proprioception) when the primarysource (e.g., vision) is degraded. Persons with ASD fail to dynamically recalibrate feedback processes across sensory systems when feedback
conditions change.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
53 Thisorg/licenses/by-nc-nd/4.0/)

Sharla Smith, Ph.D., MPH
Assistant Professor
Department of Population Health
University of Kansas School of Medicine-Wichita

KANSAS JOURNAL of M E D I C I N E

Diversity Trailblazer Award Recipient
Health through Enhancing Awareness and Learning about Breast and Cervical Cancer Screening among
African American Women (HEAL)
Sharla Smith, MPH, Ph.D.1, Jannette Berkley-Patton, Ph.D.2, Megha Ramaswamy, MPH, Ph.D.3, Joi Wickliffe, MPH3
1
University of Kansas School of Medicine-Wichita, Wichita, KS
2
University of Missouri-Kansas City, Kansas City, MO
3
University of Kansas School of Medicine, Kansas City, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: African American women experience higher incidence and mortality rates of cervical and breast cancer. The purpose of thisstudy is to develop and implement a breast and cervical cancer screening intervention to increase awareness, uptake of screening, and followup among an African American female church-population in Sedgwick County, Kansas.
Methods: Academic researchers recruited local pastors (N = 11) to develop a faith taskforce. Using intervention mapping, we conducted threefocus groups with the taskforce to assess barriers and facilitators to seeking breast and cervical screenings and multi-component strategies toimprove education and awareness of breast and cervical cancer screening recommendations, screening rates, and follow-up among African
American women.
Preliminary Results: Of the 11 faith taskforce pastors, three were females. The key identified themes focused on barriers and facilitators to
implementation of church-based cervical/breast cancer interventions, such as time constraints, limited expertise in conducting faith-based
interventions, and lack of awareness on burden of cancer in the community, awareness of screening recommendations, and support/accountability in cancer screening and follow-up. Participants also indicated that a mobile phone app to track screenings, follow-up appointments,
and promote education about risk factors and a church health navigator to assist with app utilization and track screenings and follow-up
appointments would need to be primary intervention components.
Conclusions: Findings from the taskforce focus groups highlight the need for multi-component church-based interventions that include amHealth app and church health navigators to improve awareness and adherence to breast/cervical cancer screening recommendations andfollow-up among African American female church populations.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

54

KANSAS JOURNAL of M E D I C I N E
Jason Springer, M.D., M.S.
Assistant Professor
Division of Allergy, Clinical Immunology and Rheumatology
Department of Internal Medicine
University of Kansas Medical Center
Frontiers Clinical and Translational Pilot Research Grant Recipient
RITUXimab IMmunogenicity in ANCA-associated Vasculitis (RITUXIMAV)Jason Springer, M.D., M.S., Ryan Funk, Pharm.D., Ph.D.
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Rituximab (RTX) is an effective maintenance therapy in forms of ANCA-associated vasculitis (AAV), specifically granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) (MAINRITSAN trial). Sixteen percent of patients will relapse despite
RTX. Infliximab, an anti-chimeric antibody like RTX, is associated with a high rate of anti-drug antibody formation which effects its efficacy.
The aims of this study are to a) evaluate the incidence of immunogenicity toward rituximab in AVV; and b) evaluate the relationship between
anti-RTX antibodies and drug response. Herein we present the baseline data.
Methods: Inclusion criteria: a) meet either 1990 ACR and/or 2012 revised CHCC criteria for GPA or MPA; b) remission at entry; c) received
Rituximab in last 12 months; d) plan to continue Rituximab; and e) no contraindications for receiving further RTX infusions.
Results: 30 participants (25 GPA and 5 MPA) were enrolled. ANCA by EIA was MPO positive in 14 (47%), PR3 positive in 13 (43%) andnegative in 3 (10%). Mean age at enrollment was 62.5 years (IQR 46.5 - 67.5). 70% were female. The average immunoglobulin G (IgG) atbaseline was 663 mg/dl (95% CI 566 - 760). 67% of participants had undetectable B-cells at baseline. Average time between the last Rituximab infusion and the first study Rituximab infusion was 34 weeks (95% CI 28 - 40 weeks).
Conclusions: At study baseline most of the participants were found to be B-cell depleted and mildly hypogammaglobulinemic. The average
duration since the last Rituximab infusion at entry (8.5 months) was slightly longer than in the MAINRITSAN trial (six months).
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

55

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Jeffrey Statland, M.D.
Assistant Professor
Department of Neurology
University of Kansas Medical Center

KANSAS JOURNAL of M E D I C I N E

Institute for Advancing Medical Innovation (IAMI) Trailblazer Award Recipient
Open-Label Pilot Study of Ranolazine for Cramps in Amyotrophic Lateral Sclerosis
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACT
Objective: To determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence ofdrug-target engagement.
Background: Ranolazine, an FDA-approved drug for angina which inhibits the late Na+ current and intracellular Ca2+ accumulation, may
be neuroprotective in ALS and reduce cramp frequency by reducing neuronal hyperexcitability.
Design/Methods: Open-label dose-ascending study of ranolazine with 12 participants in two sequential cohorts: 500 mg and 1,000 mg
orally twice daily. Each has a two-week run-in period, four-week drug administration and six-week safety follow up. Primary outcome is thefrequency of dose limiting toxicities and adverse events. Exploratory measures include cramp frequency and severity, fasciculation frequency(on ultrasound), cramp potential duration, ALS Functional Rating Scale-revised (ALSFRS-r), and forced vital capacity (FVC) comparedfrom baseline to week six.
Results: The 10 currently enrolled patients (Cohort 1, n = 6; Cohort 2, n = 4) are mostly male (80%), and middle aged (median 53 years).
There were no serious adverse events. One subject in cohort 2 discontinued the drug due to constipation. The most frequent drug-related
adverse event was gastrointestinal (38%). Cramp frequency reduced by 44% (p = 0.01) and severity decreased by 36% (p = 0.002), withdecreased awakening due to cramps and cramps interfering with daily activities or causing activity avoidance. Fasciculations, cramp potential
duration, ALSFRS-r and FVC did not change.
Conclusion: Ranolazine was well tolerated in ALS up to 2,000 mg daily with gastrointestinal side effects being the most frequent. Ranolazine
reduced cramp frequency and severity without significant effect on fasciculations, ALSFRS-r or FVC.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

56

KANSAS JOURNAL of M E D I C I N E

Debra Sullivan, Ph.D., RD
Chair
Department of Dietetics and Nutrition
University of Kansas Medical Center
Frontiers Infrastructure Award Recipient
Skin Carotenoid Measurement: A Biomarker for Dietary Fruit and Vegetable Intake
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACT
Dietary intake of fruits and vegetables is consistently related to chronic disease risk. Unfortunately, measurement of fruit and vegetableintake is most often by self-report and thus, there are concerns about the validity of the data. The Veggie Meter (VM) uses ResonanceRaman light scattering spectroscopy (RRS) to non-invasively measure skin carotenoid content. Skin carotenoids have recently beenreported as a reproducible and valid biomarker for dietary intake of fruits and vegetables. In August of 2017, we purchased a VM and began
using it in several studies. Due to demand, we were unable to accommodate all studies. Thus, in July 2018 Frontiers provided funds to purchase another VM. To date, we have used VM in seven completed pilot studies (six interventions and one observational study) and are using
it in three ongoing studies. Specifically, the Frontiers-purchased machine is being used in two NIH-funded clinical trials. It is also used incommunity outreach events. The average age of individuals screened using this VM is 74.9 years and the VM score is 281.9 ± 70.1, indicating poor intake similar to the national average. Within 54 healthy older adults, VM scores correlated with intake of vegetables (r2 = 0.2, p= 0.001), fruits and vegetables (r2 = 0.15, p < 0.01), and four individual carotenoids (r2 > 0.18 & p < 0.01 for all) derived from self-reported
3-day food records. The VM is quick, non-invasive, and easy to use. It provides an objective measure of fruit and vegetable intake and willcontinue to be incorporated into our nutrition clinical trials and observational studies.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

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This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Amanda Szabo-Reed, Ph.D.
Assistant Research Professor
University of Kansas Medical Center
Internal Medicine

KANSAS JOURNAL of M E D I C I N E

Frontiers Mentored Career Development Scholar (KL2)
Cognitive Function and Relationships with Intervention Dropout, Adherence and Weight Loss
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACT
Objective: Greater cognitive function (CF) is associated with adherence to prescription medications, better program adherence and weightloss (WL) following bariatric surgery. The purpose of this study was to evaluate the association between baseline CF, intervention dropout,adherence and three-month WL.
Methods: One hundred and seven (Mean age = 40.9 yrs.), overweight/obese (BMI = 35.6 kg/m2) men (N = 17) and women (N = 90) completed a three-month WL intervention. Participants were asked to attend weekly behavioral sessions, comply with a reduced calorie dietand complete 100 min of moderate intensity physical activity (PA)/wk. CF tasks including Flanker (attention), Stroop (Executive control)
and working memory, body weight and cardiovascular fitness (covariate) were assessed at baseline and three-months. Session attendance,
adherence to PA and diet prescriptions and number of off-diet episodes were recorded weekly.
Results: Results indicated that attention was positively correlated with session attendance (p = 0.016), adherence to the diet (p < 0.01) and PA(p = 0.023). Executive control was positively correlated with WL (p = 0.042). Working memory (two tasks) was also positively correlated withWL (p = 0.017 and p = 0.025). Analysis of variance (ANOVA) indicated that baseline attention (p = 0.012) was positively related to WL andnegatively associated with drop out (p < 0.05). Hierarchical linear regression showed executive control (p = 0.036, R2 = 0.054) and working
memory (p = 0.013, R2 = 0.073 and p = 0.017, R2 = 0.068) were associated with WL when controlling for fitness.
Significance: These results suggest that stronger baseline attention is associated with completion of a three-month WL intervention. Executive control and working memory are associated with amount of WL achieved. Additional, larger and longer trials to assess the role of baseline
CF on WL and evaluating the impact of interventions designed to improve CF on WL are indicated.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

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KANSAS JOURNAL of M E D I C I N E
Karen Wambach Ph.D., RN, IBCLC, FILCA, FAAN
Professor
School of Nursing
University of Kansas Medical Center
Frontiers Dr. Lauren S. Aaronson Trailblazer Recipient
Adolescent Mothers’ Early Breastfeeding Experiences
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Adolescent mothers are less likely to initiate and sustain exclusive or partial breastfeeding. About 70% of mothers under age 20
initiate breastfeeding, compared to 80% of 20 - 29-year-old mothers. Duration of breastfeeding to six months and one year by young mothers
is 28% and 18%, compared to 48% and 28% in 20 - 29-year olds. Early breastfeeding experiences can adversely influence duration of breastfeeding. This study describes the early postpartum breastfeeding experiences among mothers 16 - 19 years of age.
Methods: This is a descriptive study within a larger pilot clinical trial. Four to eight weeks after giving birth, participants completed the Breastfeeding Experience Scale (BES), a 30-item measure which documents breastfeeding experiences, feeding patterns, and weaning. Severity of
18 early experiences are rated on a Likert type scale of 1 - 5 (1 = “not at all” to 5 = “unbearable”). Cronbach’s alpha for the 18-item summatedscale of the BES was 0.80. Descriptive statistics characterized experiences for this in-progress study.
Results: Thirty breastfeeding participants, ages 16 - 19 (X = 17.97, SD = 0.96) completed the BES. Twenty-one (70%) were breastfeeding attime of survey and 57% were doing so exclusively. The most frequently reported breastfeeding problems were engorgement and leaking whichwere rated mild to moderate in severity (X = 2.97, SD = 1.03). Nine mothers (30%) weaned between 14 and 30 days after birth; engorgement,
latching difficulty, and drop in milk supply were most common reasons.
Conclusions: Most teenage mothers in this sample maintained breastfeeding past one month after birth and reported few problems.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

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This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

Yun Yan, M.D.
Pediatric Endocrinologist
Children’s Mercy Kansas CityKANSAS JOURNAL of M E D I C I N E

Institute for Advancing Medical Innovation (IAMI) Trailblazer Award Recipient
A Therapeutic Trial Validating the Physiologically Based Pharmacokinetic Simulation of the Dose-Exposure Relationship ofMetformin in Young Children with Insulin Resistance or Type 2 Diabetes Mellitus
Chelsea Cojocari, Ph.D., Rachel Frazier, RN, BSN, CCRC, Kelsee Halpin, M.D., Paul Toren, Ph.D.,
J. Steven Leeder, Pharm.D., Ph.D., Yun Yan, M.D.
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Obesity affects ~14 million children/adolescents in the U.S. (8.9% of 2 - 5-year-olds; 17.5% of 6 - 11-year-olds) and increases therisk of developing type 2 diabetes (T2DM). Early metformin intervention may delay or halt progression to T2DM. However, clinical response
to metformin in children with insulin resistance or T2DM is unpredictable. Additionally, no dosing recommendations exist for children < 10years. Preliminary data show that clinical response to metformin may depend on the amount of metformin present in the body over time (systemic exposure), with maximum response observed at exposures = 30 mg/L*h. Modelling and simulations can help determine individualized
doses to achieve this exposure, ideally achieving favorable response for every patient. This study aims to prospectively validate simulations of
the metformin dose-exposure relationship in young children.
Methods: A 24-hour pharmacokinetic study (measuring systemic exposure) of 500 mg metformin in children (6 - 12 years) with IR.
Pharmacokinetic simulations including individual parameters (e.g., sex, age, weight) were conducted for each subject using Simcyp, a physiologically-based pharmacokinetic simulator.
Results: Two out of 12 subjects have completed the research study: Subject 1: Female, 12 years, 158.6 cm, 70.2 kg, BMI: 97.44 percentile,
HbA1C: 6.7%; simulation-recommended dose: 1750 mg. Subject 2: Male, 8 years, 134.9 cm, 36.5 kg. BMI 95.58 percentile, HbA1C: 6.5%;
simulation-recommended dose: 1100 mg. Clinical pharmacokinetic data is not yet available.
Conclusion: Individualized doses of metformin may benefit young children with IR. Smaller/younger patients may require smaller doses of
metformin than larger/older children; clinical pharmacokinetic data is needed to support simulation-guided individualized dosing.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

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KANSAS JOURNAL of M E D I C I N E
Yuxia (Lisa) Zhang, Ph.D.
Assistant Professor
Department of Pharmacology, Toxicology, and Therapeutics
University of Kansas Medical Center
Frontiers Clinical and Translational Pilot Research Grant Recipient
Targeting RNA-Binding Protein HuR in Human Liver Cancer
Priyanka Ghosh1, Lin He1, Nancy Magee1, Forkan Ahamed1, Xiaoqing Wu2, Liang Xu2, Yuxia Zhang1
1
University of Kansas Medical Center, Department of Pharmacology, Toxicology & Therapeutics, Kansas City, KS
2
University of Kansas, Department of Molecular Bioscience, Lawrence, KS
Received Feb. 7, 2020; Accepted for publication Feb. 10, 2020; Published online Feb. 26, 2020

ABSTRACTIntroduction: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has one of the worst one-year survival
rates of any cancers. Understanding molecular mechanisms leading to HCC and developing novel strategies for effective prevention andtreatment are urgent medical needs. HCC arises exclusively on the background of chronic liver injury and inflammation. Thus, an attractive
therapeutic approach is to target key genes that regulate both inflammation and oncogenic pathways in HCC. RNA-binding protein Hu Antigen
R (HuR) is one such candidate that controls the translation of multiple genes involved in inflammation and oncogenic process. The objectiveof this study is to characterize HuR targets in human HCC and test HuR-targeted intervention for HCC treatment.
Methods: HuR knockout (HuR-KO) in HCC cell line MHCC97H cells was accomplished by CRISPR/Cas9 gene editing system. The transcriptome comparison identified 1,516 differentially-expressed genes between HuR-KO cells and wild type controls. The top pathways alteredby HuR knockout were cell proliferation, hippo signaling, beta integrin, pluripotent stem cells, EGFR, WNT, and FAK-PI3K-Akt-mTOR. To
test HuR-targeted intervention for HCC treatment in vivo, MHCC97H cells were subcutaneously injected into athymic nude mice to establish
HCC xenografts. Mice were then treated with a novel synthetic HuR inhibitor KH-3 for four weeks.
Results and Conclusions: Strikingly, KH-3 treatment significantly inhibited the growth of HCC xenografts. Taken together, our study
provides a foundation for understanding the role of HuR in HCC. The mechanistic insights elucidated from our study may pave the way fordeveloping therapeutic strategies to specifically target HuR for HCC treatment.
Funding Support: This work was supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of
Kansas Clinical and Translational Science Institute (#UL1TR002366). The contents are solely the responsibility of the authors and do notnecessarily represent the official views of the NIH or NCATS.

61

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0: https://creativecommons.
org/licenses/by-nc-nd/4.0/)

KANSAS JOURNAL of M E D I C I N E

K ANSAS JOURNAL OF MEDICINEVOLUME 13 • 2020 • SUPPLEMENT 2

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