Browsing by Author "Martin, Holly"

Now showing 1 - 9 of 9
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    COOPERATION OF AML1-ETO AND ONCOGENIC KIT IN ACUTE MYELOGENOUS LEUKEMIA
    (Office of the Vice Chancellor for Research, 2010-04-09) Martin, Holly; Ma, Peilin; Ramdas, Baskar; Kapur, Reuben
    A significant portion of AML patients have the cytogenetic abnormality t(8;21) which generates the fusion protein AML1-ETO, leading to a disruption of the core binding factor complex that regulates transcription of hematological genes. Patients harboring the translocation alone usually have a good prognosis; however, a substantial portion of patients bearing an additional oncogenic receptor tyrosine kinase, KIT, mutation have significantly worse prognosis. A mutation of aspartic acid to valine (KITD814V) in the activation loop results in altered substrate recognition and utilization, constitutive tyrosine autophosphorylation, and promiscuous signaling. Little is known concerning possible mechanisms of cooperation between AML1-ETO and KITD814V. Using an IL3 dependent murine myeloid cell line, we show that growth of AML1-ETO bearing cells remain ligand dependent, while cells that express both AML1-ETO and KITD814V demonstrate ligand independent proliferation. Furthermore, functional assays show that expression of AML1-ETO and KITD814V leads to an increase in cell cycling and decrease in apoptosis that may contribute to the observed ligand independent proliferation. Using a syngenic murine transplantation model we demonstrate that mice transplanted with AML1-ETO and KITD814V bearing cells succumb to a fatal myeloproliferative disease (MPD)-like phenotype, while AML1-ETO expressing mice remain disease free. This suggests that AML1-ETO alone is not sufficient to induce ligand independent growth, nor MPD, but may cooperate with KITD814V to enhance proliferation. Continuing research aims to investigate mechanisms of cooperation between KITD814V and AML1-ETO that contribute to ligand independent growth in vitro, transformation in vivo, and poor overall prognosis in AML patients bearing the two mutations.
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    Impact of Telestroke Implementation on Emergency Department Transfer Rate
    (AAN, 2022-04) Lyerly, Michael; Daggy, Joanne; LaPradd, Michelle; Martin, Holly; Edwards, Brandon; Graham, Glenn D.; Martini, Sharyl; Anderson, Jane; Williams, Linda; Biostatistics, School of Public Health
    Background and Objectives Telestroke networks are associated with improved outcomes from acute ischemic stroke (AIS) and facilitate greater access to care, particularly in underserved regions. These networks also have the potential to influence patient disposition through avoiding unnecessary interhospital transfers. This study examines the effect of implementation of the VA National Telestroke Program (NTSP) on interhospital transfer among Veterans. Methods We analyzed patients with AIS presenting to the emergency departments of 21 VA hospitals before and after telestroke implementation. Transfer rates were determined through review of administrative data and chart review and patient and facility-level characteristics were collected to identify predictors of transfer. Comparisons were made using t test, Wilcoxon rank sum, and χ2 analysis. Multivariable logistic regression with sensitivity analysis was conducted to assess the influence of telestroke implementation on transfer rates. Results We analyzed 3,488 stroke encounters (1,056 pre-NTSP and 2,432 post-NTSP). Following implementation, we observed an absolute 14.4% decrease in transfers across all levels of stroke center designation. Younger age, higher stroke severity, and shorter duration from symptom onset were associated with transfer. At the facility level, hospitals with lower annual stroke volume were more likely to transfer; 1 hospital saw an increase in transfer rates following implementation. After adjusting for patient and facility characteristics, the implementation of VA NTSP resulted in a nearly 60% reduction in odds of transfer (odds ratio 0.39 [0.19, 0.77]). Discussion In addition to improving treatment in acute stroke, telestroke networks have the potential to positively affect the efficiency of interhospital networks through disposition optimization and the avoidance of unnecessary transfers.
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    Patient acceptance of teleneurology across neurologic conditions
    (Springer, 2024) Seigel, Courtney R.; Martin, Holly; Bastin, Grace; Myers, Laura J.; Taylor, Stan; Pike, Francis; Wilkinson, Jayne; Williams, Linda S.; Epidemiology, Richard M. Fairbanks School of Public Health
    Introduction: Patient acceptability with outpatient teleneurology has been reported within specific conditions, but less is known about acceptability across neurologic conditions. The study objective was to compare the acceptability of teleneurology between patients with various neurological conditions and determine what other factors influence acceptability. Methods: This was a prospective study of Veterans who completed new outpatient teleneurology visits with the Department of Veterans Affairs National Teleneurology Program. Visits were conducted via video to home or video to the outpatient clinic. Patient acceptability was assessed via telephone interview two weeks post-visit. Acceptability was a summed score (3-21) of three 7-point Likert questions (higher = more acceptable). Clinical diagnosis categories were based on the neurologists' ICD10 diagnosis code. Acceptability score was modeled using a censored Tobit model controlling for demographics, type of tele-visit, medical comorbidity, and ICD10 category. Results: In FY 2021, 277 of 637 (43.5%) patients completed an interview with analyzable acceptability data. Of these 277, 70 (25.3%) had codes indicating headache, 46 (16.6%) movement disorder, 45 (16.2%) general symptoms, and 116 (41.9%) for all other categories. Mean patient acceptability was 18.3 (SD 3.2). There was no significant difference in scores between these groups. The only factor independently related to acceptability was medical comorbidity, with higher comorbidity associated with higher acceptability scores. Discussion: Patients find their outpatient teleneurology experience highly acceptable independent of neurologic condition. Those with more comorbidity report higher acceptability. Use of teleneurology may be useful and acceptable across many outpatient neurologic conditions including for more medically complex patients.
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    Provider Communication and Telepresence Enhance Veteran Satisfaction With Telestroke Consultations
    (American Heart Association, 2021) Lyerly, Michael; Selch, Griffin; Martin, Holly; LaPradd, Michelle; Ofner, Susan; Graham, Glenn; Anderson, Jane; Martini, Sharyl; Williams, Linda S.; Biostatistics and Health Data Science, School of Medicine
    Background and purpose: Telestroke has been demonstrated to be a cost-effective means to expand access to care and improve outcomes in stroke; however, information on patient perceptions of this system of care delivery are limited. This study seeks to examine patient feedback of a national telestroke system within the Veterans Health Administration. Methods: Patients who received a telestroke consultation were eligible for a phone interview 2 weeks later, including questions about technology quality, telepresence, and telestroke provider communication. Satisfaction scores ranged from 1 to 7 (higher=more satisfied) and for analyses were dichotomized as 6 to 7 indicating high satisfaction versus <6. Patient variables including stroke severity (measured by the National Institutes of Health Stroke Scale) were obtained from study records. Generalized estimating equation models were used to determine what factors were associated with patient satisfaction. Results: Over 18 months, 186 interviews were completed, and 142 (76%) reported high satisfaction with telestroke. Patients with more severe stroke were less likely to recall the consultation. Factors significantly associated with patient satisfaction were higher ratings of the technology (P<0.0001), telepresence (P<0.0001), provider communication ratings (P<0.0001), and overall Veterans Affairs satisfaction (P=0.02). In the multivariate model, telepresence (odds ratio, 3.10 [95% CI, 1.81-5.31]) and provider ratings (odds ratio, 2.37 [95% CI, 1.20-4.68]) were independently associated with satisfaction. Veterans who were satisfied were more likely to recommend the technology (P<0.0001). Conclusions: Provider qualities, including telepresence and provider ratings, were associated with overall Veteran satisfaction with the telestroke consultation. Technology quality may be necessary but not sufficient to impact patient experience. Training providers to improve telepresence could improve patient experience with telestroke consultation.
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    Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3 and KIT driven Leukemogenesis
    (Elsevier B.V., 2014-11-20) Chatterjee, Anindya; Ghosh, Joydeep; Ramdas, Baskar; Mali, Raghuveer Singh; Martin, Holly; Kobayashi, Michihiro; Vemula, Sasidhar; Canela, Victor H.; Waskow, Emily R.; Visconte, Valeria; Tiu, Ramon V.; Smith, Catherine C.; Shah, Neil; Bunting, Kevin D.; Boswell, H. Scott; Liu, Yan; Chan, Rebecca J.; Kapur, Reuben; Department of Pediatrics, IU School of Medicine
    Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN) and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK), whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.
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    ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells
    (Impact Journals, LLC, 2016-03-29) Kapur, Reuben; Shi, Jianjian; Ghosh, Joydeep; Munugalavadla, Veerendra; Sims, Emily; Martin, Holly; Wei, Lei; Mali, Raghuveer Singh; Department of Pediatrics, IU School of Medicine
    Understanding mast cell development is essential due to their critical role in regulating immunity and autoimmune diseases. Here, we show how Rho kinases (ROCK) regulate mast cell development and can function as therapeutic targets for treating allergic diseases. Rock1 deficiency results in delayed maturation of bone marrow derived mast cells (BMMCs) in response to IL-3 stimulation and reduced growth in response to stem cell factor (SCF) stimulation. Further, integrin-mediated adhesion and migration, and IgE-mediated degranulation are all impaired in Rock1-deficient BMMCs. To understand the mechanism behind altered mast cell development in Rock1-/- BMMCs, we analyzed the activation of ROCK and its downstream targets including LIM kinase (LIMK). We observed reduced activation of ROCK, LIMK, AKT and ERK1/2 in Rock1-deficient BMMCs in response to SCF stimulation. Further, loss of either Limk1 or Limk2 also demonstrated altered BMMC maturation and growth; combined deletion of both Limk1 and Limk2 resulted in further reduction in BMMC maturation and growth. In passive cutaneous anaphylaxis model, deficiency of Rock1 or treatment with ROCK inhibitor Fasudil protected mice against IgE-mediated challenge. Our results identify ROCK/LIMK pathway as a novel therapeutic target for treating allergic diseases involving mast cells.
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    Role of intracellular tyrosines in activating KIT induced myeloproliferative disease
    (Nature Publishing Group, 2012-07) Ma, Peilin; Mali, Raghuveer Singh; Martin, Holly; Ramdas, Baskar; Sims, Emily; Kapur, Reuben; Department of Pediatrics, IU School of Medicine
    Gain-of-function mutations in KIT receptor in humans are associated with gastrointestinal stromal tumors (GIST), systemic mastocytosis (SM), and acute myelogenous leukemia (AML). The intracellular signals that contribute to oncogenic KIT induced myeloproliferative disease (MPD) are poorly understood. Here, we show that oncogenic KITD814V induced MPD occurs in the absence of ligand stimulation. The intracellular tyrosine residues are important for KITD814V induced MPD, albeit to varying degrees. Among the seven intracellular tyrosines examined, tyrosine 719 alone plays a unique role in regulating KITD814V induced proliferation and survival in vitro, and MPD in vivo. Importantly, the extent to which AKT, ERK and Stat5 signaling pathways are activated via the seven intracellular tyrosines in KITD814V impacts the latency of MPD and severity of the disease. Our results identify critical signaling molecules involved in regulating KITD814V induced MPD, which might be useful for developing novel therapeutic targets for hematologic malignancies involving this mutation.
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    The VA National Teleneurology Program (NTNP): Implementing Teleneurology to Improve Equitable Access to Outpatient Neurology Care
    (Springer, 2023) Wilkinson, Jayne; Myers, Laura; Daggy, Joanne; Martin, Holly; Bastin, Grace; Yang, Ziyi; Damush, Teresa; Narechania, Aditi; Schriber, Steve; Williams, Linda S.; Biostatistics and Health Data Science, School of Medicine
    Background: Telehealth is increasingly utilized in many healthcare systems to improve access to specialty care and better allocate limited resources, especially for rurally residing persons who face unique barriers to care. Objectives: The VHA sought to address critical gaps in access to neurology care by developing and implementing the first outpatient National Teleneurology Program (NTNP). Design: Pre-post evaluation of intervention and control sites. Participants: NTNP sites and VA control sites; Veterans completing an NTNP consult and their referring providers. Intervention: Implementation of the NTNP at participating sites. Main measures: NTNP and community care neurology (CCN) volume of consults before and after implementation; time to schedule and complete consults; Veteran satisfaction. Key results: In FY2021, the NTNP was implemented at 12 VA sites; 1521 consults were placed and 1084 (71.3%) were completed. NTNP consults were scheduled (10.1 vs 29.0 days, p < 0.001) and completed (44.0 vs 96.9 days, p < 0.001) significantly faster than CCN consults. Post-implementation, monthly CCN consult volume was unchanged at NTNP sites compared to pre-implementation (mean change of 4.6 consults per month, [95% CI - 4.3, 13.6]), but control sites had a significant increase (mean change of 24.4 [5.2, 43.7]). The estimated difference in mean change in CCN consults between NTNP and control sites persisted after adjusting for local neurology availability (p < 0.001). Veterans (N = 259) were highly satisfied with NTNP care (mean (SD) overall satisfaction score 6.3 (1.2) on a 7-point Likert scale). Conclusions: Implementation of NTNP resulted in more timely neurologic care than care in the community. The observed significant increase in monthly CCN consults at non-participating sites during the post-implementation period was not seen at NTNP sites. Veterans were highly satisfied with Teleneurology care.
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    The VA National TeleNeurology Program implementation: a mixed-methods evaluation guided by RE-AIM framework
    (Frontiers Media, 2023-08-24) Damush, Teresa M.; Wilkinson, Jayne R.; Martin, Holly; Miech, Edward J.; Tang, Qing; Taylor, Stanley; Daggy, Joanne K.; Bastin, Grace; Islam, Robin; Myers, Laura J.; Penney, Lauren S.; Narechania, Aditi; Schreiber, Steve S.; Williams, Linda S.; Medicine, School of Medicine
    Introduction: The Veteran Affairs (VA) Office of Rural Health (ORH) funded the Veterans Health Administration (VHA) National TeleNeurology Program (NTNP) as an Enterprise-Wide Initiative (EWI). NTNP is an innovative healthcare delivery model designed to fill the patient access gap for outpatient neurological care especially for Veterans residing in rural communities. The specific aim was to apply the RE-AIM framework in a pragmatic evaluation of NTNP services. Materials and methods: We conducted a prospective implementation evaluation. Guided by the pragmatic application of the RE-AIM framework, we conceptualized a mixed-methods evaluation for key metrics: (1) reach into the Veteran patient population assessed as total NTNP new patient consult volume and total NTNP clinical encounters (new and return); (2) effectiveness through configurational analysis of conditions leading to high Veteran satisfaction and referring providers perceived effectiveness; (3) adoption and implementation by VA sites through site staff and NTNP interviews; (4) implementation success through perceived management, implementation barriers, facilitators, and adaptations and through rapid qualitative analysis of multiple stakeholders' assessments; and (5) maintenance of NTNP through monitoring quarterly TeleNeurology consultation volume. Results: NTNP was successfully implemented in 13 VA Medical Centers over 2 years. The total NTNP new patient consult volume in fiscal year 2021 (FY21) was 836 (58% rurally residing); this increased to 1,706 in fiscal year 2022 (FY22) (55% rurally residing). Total (new and follow-up) NTNP clinical encounters were 1,306 in FY21 and 3,730 in FY22. Overall, the sites reported positive experiences with program implementation and perceived that the program was serving Veterans with little access to neurological care. Veterans also reported high satisfaction with the NTNP program. We identified the patient level of perceived excellent teleneurologist-patient communications, reduced need to drive to get care, and that NTNP provided care that the Veteran otherwise could not access as key factors related to high Veteran satisfaction. Conclusions: The VA NTNP demonstrated substantial reach, adoption, effectiveness, implementation success, and maintenance over the first 2 years of the program. The NTNP was highly acceptable to both the clinical providers making the referrals and the Veterans receiving the referred video care. The pragmatic application of the RE-AIM framework to guide implementation evaluations is appropriate, comprehensive, and recommended for future applications.