MEDICA@MUSC (Medical University of South Carolina)
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Discovery and Evaluation of a Small Molecule CD38 Inhibitor: Immunostimulation of Natural Killer Cells for the Treatment of Neuroblastoma
Get PDFHigh-risk neuroblastoma (NB) accounts for 15% of all pediatric cancer deaths. Refractory disease for high-risk NB patients is attributed to chemotherapy resistance and immunotherapy failure. The poor prognosis for high-risk NB patients demonstrates an unmet medical need for the development of new, more efficacious and accessible therapeutics. CD38 is an immunomodulating protein that is expressed constitutively on natural killer (NK) cells and other immune cells in the tumor microenvironment (TME). Furthermore, CD38 over expression is implicated in propagating an immunosuppressive milieu within the TME. Through virtual and biological screening, we have identified drug-like small molecule inhibitors of CD38 with low micromolar IC50 values. We have explored structure activity relationships for CD38 inhibition through derivatization of our most effective hit molecule to develop a new improved compound with lead-like physicochemical properties and improved potency. We have demonstrated that our derivatized inhibitor, compound 21, elicits immunomodulatory effects in NK cells by increasing cell viability by 190 ± 36% in multiple donors and by increasing interferon gamma by 759 ± 45%. Additionally, we have shown that NK cells exhibited enhanced cytotoxicity toward NB cells (14% reduction of NB cells over 90 minutes) when given a combination treatment of our inhibitor and the immunocytokine ch14.18-IL2. In this work, the synthesis and biological evaluation of small molecule CD38 inhibitors specifically for use in NB immunotherapy will be described
Telesimulation to Improve Critical Decision-Making in Prehospital Airway Management: A Feasibility Study
No full textObjectives: Telesimulation, in which learners and evaluators use technology to connect remotely to simulation-based learning activities, is effective for skills and decision-making review. Historical models in which learners are colocated with the simulation equipment have inherent issues, especially for emergency medical services (EMS) providers. This feasibility study placed the evaluators in the simulation center, whereas the learners were at a distance steering the scenario evolution through telehealth technologies. Methods: Volunteer EMS providers across South Carolina with varying levels of training and experience completed difficult airway management scenarios focused on clinical decision making. The program consisted of pre- and postexperience examinations, a lecture, and increasingly complicated simulations using high-fidelity mannequins that were facilitated by local trainers under the direction of remote trainees. Audio and video content, including vital signs and cardiac monitoring, were live streamed. Participants worked in two-person teams with lead providers on each scenario clinically assessing and managing cases of anaphylaxis. Data were collected from the simulations using Laerdal software, as well as examination and survey results. Results: A total of 24 participants completed all of the elements of the training. Trends toward improvement in times to bag-mask ventilation and initial epinephrine administration were noted. Average cognitive test scores increased by 9.6%, and learners reported improved comfort with simulation (75%, P ≥ 0.0001) and videoconferencing (83%, P ≥ 0.0001). They also reported high degrees of comfort with intubation (73.3%) following the training. Conclusions: This method of telesimulation appears to be a viable addition to continuing EMS education and may address access issues for some providers
Regulation of RNAi Recruitment and lncRNAs by Epithelial Adherens Junctions
Get PDFAdherens junctions (AJs) are architectural components of the cell that are essential for epithelial tissue integrity. These adhesive structures tether intracellularly to an apical actin ring to form the zonula adherens (ZA). Our previous work revealed that PLEKHA7, a E-cadherin-p120 catenin partner at the ZA, recruits the microprocessor, the RNA-induced silencing complex (RISC), and distinct sets of miRNAs and mRNAs specifically to the ZA. There, the processing of and silencing by a set of miRNAs suppresses oncogenic mRNA expression. PLEKHA7 depletion results in compromised epithelial integrity, altered miRNA function, and pro-tumorigenic cell transformation; we have found extensive dysregulation of this mechanism in colon cancer. Notably, we have also identified lncRNAs associated with PLEKHA7, though the functional significance of junctional lncRNA localization has not been explored. Here, we examined the regulation of lncRNAs by this PLEKHA7-associated RNAi complex and its implications for cellular homeostasis. We also addressed a critical remaining question: why are these RNAi complexes specifically recruited to the ZA? RNA-sequencing revealed that PLEKHA7 regulates the levels of a set of lncRNAs. The most significantly upregulated junction-associated lncRNA following PLEKHA7 depletion was a previously unrecognized short isoform of the MIR17HG lncRNA, which we named MIR17HG_S. Through mechanistic interrogation, we demonstrate that PLEKHA7 suppresses MIR17HG_S levels via the junctional RISC, specifically AGO2 and miR-203a. MIR17HG_S overexpression promoted cellular transformation, whereas expression analysis revealed that MIR17HG_S is significantly upregulated in patient colon tumor tissues. These findings identify a novel localized mechanism of lncRNA regulation at the ZA and identify MIR17HG_S as a pro-tumorigenic lncRNA, downstream of disrupted junctional RNAi. Further, we demonstrate ZA-specific recruitment of AGO2 depends on both the structural and tensile integrity of the actomyosin cytoskeleton. We show that PLEKHA7 and AGO2 interact with three LIM domain-containing proteins, namely LMO7, LIMCH1, and PDLIM1, all of which regulate actomyosin organization and consequently mediate AGO2 ZA recruitment. Together, this work identifies a mechanosensitive RNAi complex at the ZA that regulates lncRNAs with critical roles in cell behavior, such as MIR17HG_S. Future work will address how distinct mechanosensitive cues may be regulating non-coding RNA function and influencing cell behavior, not only in diseases, like cancer, but also in physiological processes that require actin remodeling, such as tissue morphogenesis
Top-Down Negative Emotion Regulation in Tobacco-Use Disorder:Corticolimbic Circuitry of Reappraisal During Satiety and Abstinence
No full textBackground. Smoking maintenance is chiefly driven by negative affects, such as craving and aversion—and disrupted attentional control—mediated by the amygdala and insula in concert with the prefrontal cortex. Cognitive emotion regulation [CER] can modulate amygdala function and improve mood but may be compromised among individuals with TUD. This project aimed to identify corticolimbic negative CER task-state functional connectivity [tsFC] neurocircuits in TUD and abstinence, assess experiential CER effectiveness, and explore brain-behavior correlates of relapse vulnerability. Methods. On two fMRI visits, nonsmokers (n=23) and smokers (n=18) underwent fMRI during a negative CER task followed by an out-of-scanner Smoking-Relapse Task [SRT]. BOLD fMRI task data were preprocessed and denoised in CONN21.a, explicitly masked to isolate negative emotional information processing regions, and thresholded (negative \u3e neutral) via t-contrast (p \u3c 0.05 cluster-level FWE). Surviving regions’ data were then denoised for explicitly-masked tsFC analyses. Seed-to-voxel correlation maps were estimated using functionally-defined amygdala seeds, and tsFC neurocircuits were identified for each aim using F-contrast (p \u3c 0.05 cluster-level FWE). Neurocircuits identified showing significant non-zero tsFC with an amygdala seed were characterized by extracting rZ values into SPSS. Results. In Aim 1, (nonsmokers vs. sated smokers), bilateral amygdala seeds showed positive tsFC with bilateral OFC/insula, vlPFC, and vmPFC. L.Amygdala—L.vlPFC evidenced an effect of negative reappraisal increasing tsFC. Smokers evidenced stronger tsFC between L.Amygdala—R.vlPFC across strategies, and between the R.Amygdala-vmPFC during negative view. Both groups significantly improved their self-reported mood by CER. No brain-behavioral associations were identified. In Aim 2, (abstinence vs. sated), positive tsFC was identified between bilateral amygdala seeds and bilateral OFC/insula, right vlPFC, and between right and left amygdala. Abstinence increased negative view tsFC between L.Amygdala—bilateral OFC/insula, and between L.Amygdala-R.vlPFC, where an interaction was additionally identified; abstinence also decreased L.Amygdala-R.vlPFC tsFC during negative reappraise. In R.Amygdala—L.Amygdala, negative reappraise decreased tsFC from negative view during satiety but not abstinence. Smokers improved mood by CER across states, with less aversive perturbation of mood from negative view while abstinent. No brain-behavior relations were identified between tsFC and relapse-factors, although abstinence increased withdrawal-indices of craving and negative affect. Discussion. Smokers did not evidence any specific CER deficits relative to nonsmokers, or during abstinence, although several patterns of hyperconnectivity related to negative view were identified. Future Directions. Relations between tsFC, BOLD, and dispositional ER, along with a priori investigation of these neurocircuits to predict relapse outcomes and relating neurocircuit dynamics to more nuanced probes of mood state (e.g., heart-rate variability) may be warranted
Bayesian Space-Time Surveillance for Infectious Disease Outbreaks
No full textThe COVID-19 Pandemic for the last three years brought enormous challenges to public health surveillance and underscored the importance of developing and maintaining robust systems for accurate surveillance. Keeping pace with public health data collection efforts, there is a critical need for infectious disease modeling researchers to continue to develop surveillance metrics and statistical models to accurately predict future disease trends and high-risk regions. In the first aim, we evaluated the performance of Bayesian spatio-temporal models for the infectious disease outbreak whether these models accommodate large variability of the data and different historic data usage for timely prediction. Our choice of the likelihood and spatio-temporal mean models was influenced by the length of the past data and the variability of the data. Through the evaluation of these models, we provided future infectious disease outbreak modeling guidelines for Bayesian spatio-temporal analysis. In the second aim, the novel cluster prediction surveillance metric based on a Bayesian spatio-temporal model was proposed. Exceedance probability, which has been commonly used for hotspot detection in statistical epidemiology, was extended to predict high-risk clusters. The proposed metric consists of three components: the area\u27s own risk profile, temporal risk trend, and spatial neighborhood influence. We also introduced a weighting scheme to balance these three components, which accommodates the characteristics of the infectious disease outbreak, spatial properties, and disease trends. Through simulation study and real data analysis, the optimal weighting schemes were studied, and the performance of the proposed cluster prediction surveillance metric was evaluated. Even though the COVID-19 pandemic drove the rapid growth of public health informatics area, the visualization tools specialized in neighborhood investigation and disease hotspots/clusters of spatio-temporal domains are limited. In the third aim, the software of the neighborhood clustering surveillance system is introduced. It was developed with R Shiny technology and provides an interactive map and time-series plotting tool. The county-level United States map on both entire state-level disease mapping and subsequent in-depth neighborhood analyses was provided. This visualization software will contribute to spatial epidemiology research and public health surveillance to provide an easy-to-use and effective graphics tool and facilitate the understanding of public health practitioners and public audiences
Discussing Systemic Racism and Racial Privilege at a Large, Academic Health Center
No full textCOVID-19 and its effects overwhelmed conversations; however, we realized we were missing critical discussions about systematic racism, especially after the unjust murders of Mr. Ahmaud Arbery, Ms. Breonna Taylor, and Mr. George Floyd. Many colleagues did not know how to reach out to their minoritized colleagues, particularly Black Americans, who may have been struggling with the continued senseless killings of Blacks in America in addition to the harmful effects of COVID-19 (Brown & White, 2020). Academic Health Centers (AHC) cannot afford to ignore privilege, specifically as it relates to race and racism and its impact on workers and patients (Romano, 2018). Privilege may come in the form of being White (vs. a minoritized individual), heterosexual (vs. lesbian, gay, bisexual, or transgender), wealthy (vs. low income), insured (vs. uninsured), and so forth. Privilege may even be generational where family members pass down opportunities to younger generations (knowledge, resources, education, income, etc.). There is a motivation for organizations and society to better understand race and racism from the perspective of minoritized individuals. The first step is being aware of privileges and then taking action to correct thinking, decisions, and policies that do not support minoritized individuals and communities. Our college held several virtual Modified Privilege Walks (MPW) to promote privilege awareness and begin those difficult conversations.https://medica-musc.researchcommons.org/posters/1019/thumbnail.jp
Functional Effects of R-Ras Subfamily Proteins on Malignant Peripheral Nerve Sheath Tumor Progression
No full textIn patients with the genetic disorder Neurofibromatosis type 1 (NF1), the loss of the Ras GTPase-activating tumor suppressor protein neurofibromin (also NF1) promotes the development of multiple nervous system tumors and other clinical manifestations. Neurofibromin loss potentially results in hyperactivation of both classic Ras (H-Ras, N-Ras, K-Ras) and non-classical Ras (R-Ras, R- Ras2/TC21, R-Ras3/M-Ras) subfamilies of proteins, thus promoting transformation and malignancy. Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are often associated with NF1 loss and we have previously shown that the resulting hyperactivation of classic Ras proteins contribute to MPNST proliferation and survival. However, the roles of R-Ras subfamily proteins in MPNSTs have not previously been elucidated. We found that R-Ras and R-Ras2 are expressed and functional in neurofibromin-null MPNST cells. We discovered that R-Ras mediated signaling promotes MPNST mitogenesis, migration, and an invasive growth phenotype. Using a dominant negative (DN) R-Ras expression vector and mass spectrometry-based phosphoproteomics, we identified thirteen R-Ras specific regulatory networks. The most prominently affected networks involved cellular movement. We validated a key migration and cytoskeletal organization regulator, ROCK1, as an essential effector molecule downstream of activated R-Ras in MPNSTs that could be therapeutically targeted. Due to the drug resistant nature of MPNSTs, we sought to identify a combinatorial regimen by identifying a novel target upstream of R-Ras. Using a global approach, we identified the LPA receptors as upstream mediators of R- Ras signaling. We discovered that LPA functions in a receptor dependent manner, with LPAR1 working through R-Ras and ROCK1 to specifically promote migration while LPAR3 specifically promotes proliferation of MPNST cells. We conclude that R-Ras activated proteins promote tumorigenesis via signaling pathways distinct from the more-studied classic Ras proteins in MPNSTs. In this dissertation, we show that LPA and R-Ras orchestrate mechanisms regulating proliferation, invasion, and migration in MPNSTs thus providing potential novel therapeutic targets for patients with MPNSTs
Automating the Identification of Patients at Risk for Hereditary Cancer with Chatbots, Clinical Practice Guidelines, Ontologies, and Web Services
No full textProblem: Identifying patients at risk of hereditary cancer based on their family health history (FHx) is a highly nuanced task. Frequently, patients at risk are not referred for genetic counseling because providers lack time and training to collect and assess FHx. Consequently, patients at risk are not receiving the genetic counseling and testing they need to determine the preventive steps they should take to mitigate their hereditary cancer risk. Methods: We combined chatbots, web application programming interfaces (APIs), clinical practice guidelines (CPGs), and ontologies into a web-service-oriented system that can automate FHx collection and assessment. We developed a lightweight, patient-centric, domain ontology using clinical practice guidelines; recruited users with ad campaigns; coded and compared user’s results for complementary guidelines; and regressed concordance with CPGs implemented by the system on type of healthcare professional using surveys and logistic regression. Results: The domain ontology has 758 concepts and encompasses 44 cancers, 144 genes, and 113 clinical practice guideline criteria. We reached 14,140 users in November 2019 through online marketing campaigns (Facebook, Google, and previous ItRunsInMyFamily (ItRuns) users). The final dataset contains 4,915 completed family histories, of which 2,221 met criteria and 2,694 did not. Of the 2,694 probands who did not meet criteria, 90.6% of them reported at least one cancer in their personal or family cancer history. Genetic counselors (GCs) had the best overall concordance with clinical practice guidelines (CPGs) at 82.2%, followed by oncologists with 66.0%, and primary care providers (PCP) with 60.6%. GCs had statistically better concordance with CPGs (p\u3c.001) than non-GCs. All providers had higher concordance with CPGs for family health history (FHx) cases that met criteria than for cases that did not. Conclusions: Our results demonstrate that it is possible to gather FHx information at the population level, with high levels of engagement and interest, and more efficiently identify patients at risk of hereditary cancer using evidence-based guidelines. Earlier and consistent identification of patients at risk of hereditary cancer will lead to more effective screening and preventive actions leading to better long term health outcomes
A Management Checklist for Primary Care Practice Mergers, Expansions, or Acquisitions – Critical Components for Financial Planning, Space and Staffing Management, Training and Start-up
Get PDFPeak Trailing Limb Angle and Propulsion Symmetry in Individuals with Below Knee Amputation
Get PDFBackground: Individuals with lower extremity amputation often present with kinematic and kinetic gait asymmetries and often have difficulty achieving symmetrical walking using their prescribed prosthesis. To understand the impact of limb loss on gait measures, studies often compare individuals with lower limb amputation to healthy control participants or compare the amputated limb to the uninvolved limb while completing a specified task like steady state walking. Commonly implemented treatments for individuals with lower limb amputation are based upon the assumption that equal use of both legs (symmetry) while completing bipedal tasks (e.g., walking) would be beneficial, matching the behavior seen in healthy control individuals. Underlying kinematic or kinetic symmetry, as well as a potential relationship of the two biomechanical gait variables in individuals with below knee amputation have not been thoroughly evaluated during steady state treadmill walking. Methods: We explored potential underlying (a)symmetries in peak trailing limb angle (kinematic) and peak anterior ground reaction force (kinetic) in individuals with below knee amputation walking at self-selected walking speed on a treadmill without upper extremity support. We then implemented real-time visual feedback to alter symmetry and examine the potential relationship between peak trailing limb angle and peak anterior ground reaction force. Later, we recruited and tested healthy control individuals with and without a solid ankle foot orthosis (SAFO) walking at their self-selected walking speed on a treadmill and exposed them to a similar visual feedback program to alter their baseline (a)symmetry. Population: We enrolled eleven of the planned twenty-four individuals with unilateral below knee amputation and fourteen healthy control participants without any lower extremity pathology or gait abnormality. Results: We found that individuals with below knee amputation do have peak trailing limb and anterior ground reaction force asymmetries and unencumbered healthy control individuals demonstrate symmetry of the same outcome measures while walking on a treadmill at self-selected walking speed. The use of real time visual feedback yielded statistically significant differences in peak trailing limb angle in healthy control participants without a solid ankle foot orthosis (p=0.04), peak and impulse anterior ground reaction forces when wearing a solid ankle foot orthosis (p=0.04). Statistically significant correlation between peak trailing limb angle and peak anterior ground reaction force were found in individuals with below knee amputation at baseline (p=0.0004), with real time visual feedback for peak trailing limb angle (p\u3c0.0001), and peak anterior ground reaction force (p=0.0002). Conclusions: Real time visual feedback is one intervention used to alter walking symmetry. Our results do not demonstrate an overwhelming response to real time visual feedback by individuals with below knee amputation or their healthy control counterparts and should be interpreted with caution. This work does provide meaningful information for further studies and interventions to alter symmetry during steady state walking and begins to explore the potential relationship between peak trailing limb angel and peak anterior ground reaction force production during self-selected treadmill walking in individuals with below knee amputation as well as otherwise healthy control individuals