tbuckley/cabot-search huggingface dataset:
Microstructured thin-film electrode technology enables proof of concept of scalable, soft auditory brainstem implants
Authors: Nicolas Vachicouras, Osama Tarabichi, Vivek V. Kanumuri, Christina M. Tringides, Jennifer Macron, Florian Fallegger, Yohann Thenaisie, Lorenz Epprecht, Stephen McInturff, Ahad A. Qureshi, Valentina Paggi, Martin W. Kuklinski, M. Christian Brown, Daniel J. Lee, Stéphanie P. Lacour
Journal: Science Translational Medicine (2019)

Auditory brainstem implants (ABIs) provide sound awareness to deaf individuals who are not candidates for the cochlear implant. The ABI electrode array rests on the surface of the cochlear nucleus (CN) in the brainstem and delivers multichannel electrical stimulation. The complex anatomy and physiology of the CN, together with poor spatial selectivity of electrical stimulation and inherent stiffness of contemporary multichannel arrays, leads to only modest auditory outcomes among ABI users. Here, we hypothesized that a soft ABI could enhance biomechanical compatibility with the curved CN surface. We developed implantable ABIs that are compatible with surgical handling, conform to the curvature of the CN after placement, and deliver efficient electrical stimulation. The soft ABI array design relies on precise microstructuring of plastic-metal-plastic multilayers to enable mechanical compliance, patterning, and electrical function. We fabricated soft ABIs to the scale of mouse and human CN and validated them in vitro. Experiments in mice demonstrated that these implants reliably evoked auditory neural activity over 1 month in vivo. Evaluation in human cadaveric models confirmed compatibility after insertion using an endoscopic-assisted craniotomy surgery, ease of array positioning, and robustness and reliability of the soft electrodes. This neurotechnology offers an opportunity to treat deafness in patients who are not candidates for the cochlear implant, and the design and manufacturing principles are broadly applicable to implantable soft bioelectronics throughout the central and peripheral nervous system.
Root cause analysis: A framework using principles of high reliability.
Authors: Diane Denny, DBA, Caitlyn Shinners, Marjorie Hepler
Journal: Journal of Clinical Oncology (2019)

233 Background: Medical errors are the 4th leading cause of death in the US. Oncology providers are not immune to errors. A network of hospitals and outpatient centers recognized an opportunity to enhance and standardize our approach to root cause analyses (RCAs). As leaders, we have an imperative to prevent issues that can result in a safety event; yet we have an even greater moral obligation to correct causes once an event occurs to prevent it from happening again. Methods: A framework was established to prevent recurrence through a focus upon root solutions. Recognizing that human error is not the cause of the failure but a symptom, the goal is to understand why it made sense for individuals to do what they did by reconstructing the world in which they found themselves at the time of the event. The includes: 1) training staff on high reliability; 2) assigning an executive to remove barriers; 3) creating a charter; 4) conducting 1:1 interviews; 5) deploying tools (such as sequence of event diagramming, validation and verification of raw data, human error type classification; individual/system failure and event/causal factor charting); 6) transporting findings; and 7) action planning with controls. A 3-meeting model was embraced. Results: As of April 2019, 9 events have been investigated. Event types include: infusion hours/splitting orders, incorrect lab order, retained object, wrong patient medication administration, patient brachytherapy underdosing, wrong site delayed treatment, rapid response call delay, and delay in care for extravasation. The 12-month rolling average serious safety event rate per 10,000 patient days decreased from 1.93 to 1.33 since implementation. With 6 months experience under the enhanced framework, plans also exist to monitor events from similar root causes as a success measure. Summaries allowing this level of analyses include event description, immediate actions, proximate versus root causes, and corrective actions. Conclusions: The capacity to learn from experience is essential to patient safety. Adherence to the framework ensures movement beyond proximate to root causes. It is a means to spread knowledge using proven tools based upon principles of high reliability.
Impact Of Pre-Transplant Rituximab Sensitivity In Relapsed Follicular Lymphoma On Outcome After Autologous Transplant
Authors: Colin Phipps, Ajay K. Gopal, Barry E. Storer, Ryan D. Cassaday, Oliver W. Press, Brian G. Till, John M. Pagel, Mary Phillip, Maria Corinna Palanca-Wessels, William I. Bensinger, Leona Holmberg, Andrei R. Shustov, Damian J. Green, Thomas Chauncey, David G. Maloney, Edward N. Libby
Journal: Blood (2013)
Influence of Cytogenetic, Molecular Abnormalities and Other Risk Factors on the Outcomes of Children with Acute Myelogenous Leukemia Given An Unrelated Cord Blood Transplantation. A Survey on Behalf of Eurocord, ALWP and PDWP of EBMT
Authors: Renato Cunha, Gerard Michel, Tracey O'Brien, Mair Pedro de Souza, Henrique Bittencourt, Gérard Socié, Pierre Bordigoni, Franco Locatelli, Mouhab Ayas, Anna Paola Iori, Ajay J Vora, Jean-Hugues Dalle, José Sanches Toledo, Annalisa Ruggeri, Mohamad Mohty, Christina Peters, Eliane Gluckman, Vanderson Rocha
Journal: Blood (2011)
Abstract 836: Regulation of <i>Bmp7</i> and <i>Ctgf</i> Suppresses Dilated Cardiomyopathy and Cardiac Fibrosis
Authors: Jianming Jiang, Chia Yee Tan
Journal: Circulation Research (2019)

Introduction: Cardiac Lmna insufficiency causes dilated cardiomyopathy (DCM) coupled with cardiac fibrosis and inflammation. TGFβ family members are key mediators for cardiac performance, cardiac fibrosis and inflammation. However, how TGFβ family members are regulated in heart is unknown. Hypothesis: Modulation of downstream pathways could be served as a therapeutic strategy. Methods and Results: We demonstrate that regulation of Bmp7 and Ctgf suppresses Lmna DCM and cardiac fibrosis. Upregulation of Bmp7 alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of Bmp7 together with Ctgf silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, downregulation of Ctgf inhibited TGFβ/Smad signaling pathway in DCM hearts. Co-modulation of Bmp7 and Ctgf reduced infiltration of T cells in hearts. A screen of cardiac related factors identified Yy1 enhanced Bmp7 promoter activity and prevent the upregulation of Ctgf promoter activity. Yy1 suppressed Lmna DCM by inducing Bmp7 expression and reduced Ctgf upregulation in cardiomyocytes. Importantly, knockdown of upregulated Bmp7 attenuated the suppressive effect of Yy1 on DCM and cardiac fibrosis. Conclusions: Our findings demonstrate that DCM caused by LMNA insufficiency can be treated with co-modulation of Bmp7 and Ctgf .
Abstract 415: Electrical Stimulation of Pediatric Cardiac-derived c-kit <sup>+</sup> Progenitor Cells Improves Retention and Cardiac Function in Right Ventricular Heart Failure
Authors: Joshua T Maxwell, David Trac, Ming Shen, Milton Brown, Michael E Davis, Carly Zaladonis, Emily Baker, Martin L Li, Daniel I Jacobs
Journal: Circulation Research (2019)

Nearly 1% of babies born in the US will be diagnosed with a congenital heart defect (CHD). While surgical therapy has improved survival, many of these children go on to develop right ventricular heart failure (RVHF). The emergence of cardiovascular regenerative medicine as a potential therapeutic strategy for pediatric HF has provided new avenues for treatment with a focus on repairing or regenerating the diseased myocardium to restore cardiac function. While primarily tried using adult cells and adult disease models, stem cell therapy is relatively untested in the pediatric population. Cardiac-derived c-kit + progenitor cells (CPCs) have been widely studied as a cell-based therapy for cardiac pathologies; however, unless these cells are extracted at a very young age their therapeutic efficacy has been shown to be diminished. Finding novel ways to enhance the reparative potential of these cells is thus of critical significance. We previously reported pediatric CPCs (isolated from patients between 1-5 years of age) respond to electrical stimulation (ES) by initiating intracellular calcium oscillations. Here, we investigate the ability of ES to enhance the retention and therapeutic function of pediatric CPCs in an animal model of RVHF. Human CPCs isolated from pediatric patients were exposed to chronic ES and implanted into the RV myocardium of rats. Cardiac function and cellular retention analysis showed electrically stimulated CPCs (ES-CPCs) were retained in the heart at a significantly higher level and longer time than control CPCs and also significantly improved right ventricular functional parameters. ES also induced upregulation of extracellular matrix and adhesion genes, such as integrins β1 and β5, and significantly increased in vitro survival and adhesion of cells. Lastly, we show that ES induces CPCs to release higher levels of reported pro-reparative factors in vitro, including angiogenin, FGF, HGF, and VEGF. These findings suggest electrical stimulation can be utilized to increase the retention, survival, and therapeutic effect of human c- kit + progenitor cells. Furthermore, our insights into the mechanisms of increased retention and paracrine function of ES-CPCs can have implications on a variety of cell-based therapies.
TIGIT Expression Positively Associates with NK Cell Function in AML Patients
Authors: Bei Jia, Chenchen Zhao, David F. Claxton, W. Christopher Ehmann, Witold B. Rybka, Shin Mineishi, Seema Naik, Natthapol Songdej, Muhammad Khawaja, Raymond J. Hohl, Hong Zheng
Journal: Blood (2018)
Clinical and Genetic Variability of Red Blood Cell Hemolysis in Sickle Cell Anemia
Authors: Jacqueline N Milton, Paola Sebastiani, Yingze Zhang, Mehdi Nouraie, Janet Lee, Clinton T. Baldwin, Xuejun Zhao, Zeyu Xiong, Qilu Zeng, Gregory J. Kato, Jonathan C. Goldsmith, James G. Taylor, Onyinye Onyekwere, Victor R. Gordeuk, Roberto F Machado, Martin H Steinberg, Mark T Gladwin
Journal: Blood (2011)
Getting to the heart of the matter: detecting and managing cardiac complications in systemic sclerosis
Authors: John Varga, Daniel C Lee
Journal: Annals of the Rheumatic Diseases (2019)

Cardiac complications of systemic sclerosis (SSc) are well-deservedly gaining the attention of the medical community. This increased interest is driven by technological advances in non-invasive imaging technologies such as tissue Doppler echocardiography and cardiac MR (CMR) that reveal frequent involvement of the heart and its clinical importance in SSc. Historically, autopsy studies in SSc indicate a high prevalence (>50%) of cardiac fibrosis,1 and clinically evident cardiac involvement has long been considered a poor prognostic marker in SSc.2 3 Indeed, the European Clinical Trials and Research Group reported that 26% of SSc disease-related mortality could be attributed to cardiac causes.4 However, the overall prevalence of cardiac disease in SSc is unknown, in part due to the lack of a consensus definition, classification of ‘subclinical’ cardiac involvement, and the plethora of diverse approaches employed for its detection.5 

The cardiac complications of SSc encompass multiple distinct entities including primary cardiac involvement manifested by diastolic dysfunction (an early manifestation of cardiac fibrosis), heart failure with preserved ejection faction, conduction blocks and arrhythmias, myocarditis, as well as pericardial disease; and cardiac involvement secondary to systemic or pulmonary arterial hypertension, renal failure, amyloidosis and other SSc complications. The pathogenesis of SSc-associated primary cardiac involvement is not well understood, and likely encompasses small vessel damage, vasoconstriction and chronic ischaemia-reperfusion injury, cardiac inflammation and fibrosis.

Although systolic dysfunction in SSc is uncommon, diastolic dysfunction is common and predicts poor outcomes. In an observational study of 153 consecutive SSc patients, we showed that 23% had echocardiographically defined left ventricular diastolic dysfunction (often asymptomatic), and its presence was predictive of mortality.6 A recent study in a large and unselected cohort of SSc patients similarly found that the incidence of diastolic dysfunction was 17% at baseline, and increased to 29% during follow-up of 3.4 years.7 …
Differential DNA Methylation Predicts Response To Combined Treatment Regimens With a DNA Methyltransferase Inhibitor In Acute Myeloid Leukemia (AML)
Authors: Maximilian Schmutz, Manuela Zucknick, Richard F. Schlenk, Konstanze Döhner, Hartmut Döhner, Christoph Plass, Lars Bullinger, Rainer Claus
Journal: Blood (2013)
Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors
Authors: Li Zhu, Jessica L. Narloch, Sayali Onkar, Marion Joy, Gloria Broadwater, Catherine Luedke, Allison Hall, Rim Kim, Katherine Pogue-Geile, Sarah Sammons, Naema Nayyar, Ugonma Chukwueke, Priscilla K. Brastianos, Carey K. Anders, Adam C. Soloff, Dario A. A. Vignali, George C. Tseng, Leisha A. Emens, Peter C. Lucas, Kimberly L. Blackwell, Steffi Oesterreich, Adrian V. Lee
Journal: Journal for ImmunoTherapy of Cancer (2019)

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TILs) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs had a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain METs (BRMs) by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.
Abstract 227: Intravital Multiphoton Microscopy Reveals Increased Capillary Patrolling by Leukocytes and Cardiomyocyte Dysfunction in High Fat Diet Induced Hypertrophy
Authors: David M Small, Nathaniel H Allan-Rahill, Michael R Lamont, Salomon Djakpa, Marvarakumari G Jhala, Yvette Zhu, Nozomi Nishimura
Journal: Circulation Research (2019)

Background: The study of functional cardiomyocyte adaptation and inflammatory cell behavior at the micro-scale in vivo has been challenging due to limited imaging tools. We recently developed intravital multiphoton microscopy (MPM) methods that enable visualization and quantification of cardiac dynamics at a cell-scale throughout the cardiac cycle. We aimed to determine the dynamic cellular changes that occur due to high fat diet (HFD) induced hypertrophy using intravital cardiac MPM. Methods: ApoE -/- C57Bl6 mice started a HFD at 6 weeks of age (ApoE -/- -HFD, n=11), while age-matched wild-type mice (WT-ND, n=10) were fed a normal chow diet. At 26-weeks, mice were assessed by cardiac echocardiography and intravital MPM in the intact beating heart. Intravenous injections of rhodamine-6G (R6g) labeled cardiomyocytes and leukocytes, and Texas-Red dextran labeled vasculature. 3D volumes were reconstructed throughout the cardiac cycle to quantify cell motion using automated algorithms. Results: ApoE -/- -HFD hearts underwent hypertrophy compared to WT-ND with increased heart weight-to-tibial length ratio (10±0.8 vs 13±1.1) and left ventricle wall thickness (1.07±0.03 mm vs 1.13±0.06 mm, respectively, p&lt;0.05 for both) while ejection fraction remained similar (66±3 % vs 59±3 %). In vivo MPM demonstrated that cells move a greater total distance in each cardiac cycle in ApoE -/- -HFD vs WT-ND. Maximum displacement in the apex-base and anterior-posterior directions increased by 46 % in ApoE -/- -HFD compared to WT-ND (30 μm vs 14 μm). R6g+ leukocytes were visible moving in capillaries. The incidence of patrolling behavior (defined as slowing moving cells, visible for longer than one heart beat) increased in capillaries of ApoE -/- -HFD compared to WT-ND (3.4±0.5/min vs 0.12±0.1/min, p&lt;0.01). Conclusion: These results suggest that hypertrophied cardiomyocytes increase myocardial displacement, and increased leukocyte patrolling behavior is associated with HFD induced cardiac hypertrophy. Intravital cardiac MPM provides a novel perspective to study HFD induced cardiac hypertrophy by capturing the simultaneous contributions of inflammatory cells and myocyte function in the beating heart.
The Novel KSP Inhibitor ARRY-520 Is Active Both with and without Low-Dose Dexamethasone in Patients with Multiple Myeloma Refractory to Bortezomib and Lenalidomide: Results From a Phase 2 Study
Authors: Jatin J. Shah, Jeffrey A. Zonder, Adam Cohen, William Bensinger, Jonathan L. Kaufman, Robert Z. Orlowski, R. Donald Harvey, Muneer H. Abidi, Sheeba K. Thomas, Duncan Walker, Brandi Hilder, Ann Marie Ptaszynski, Sagar Lonial
Journal: Blood (2012)
Improving advance directive documentation in the electronic medical records at a comprehensive community cancer center.
Authors: Kevin C. Wood, Sobeida Santana-Joseph, Ayelet Spitzer, Steve Power, Ephraim S. Casper
Journal: Journal of Clinical Oncology (2019)

191 Background: Advance directives (AD) are critical to understanding a patient’s wishes should they be unable to communicate. Lacking these documents may lead to decreased knowledge regarding end-of-life wishes, and hinder end-of-life care. Having an AD uploaded into the electronic medical record (EMR) ensures these documents are available to all providers. This project sought to improve, from a cohort of patients with documented discussions regarding ADs, the proportion with the document in the EMR. At Valley-Mount Sinai Comprehensive Cancer Care, baseline data analysis shows only 20% of clinic patients for whom an AD was documented had an AD uploaded to their EMR. Methods: This project was created through the ASCO Quality Training Program and sought to increase the proportion of AD’s in patient’s EMR's. The current workflow of obtaining AD's at Valley-Mount Sinai was first identified. In our setting, the medical assistant (MA) asks new patient if they have an AD and uploads the AD into the chart if available. Following a structured cause and effect exercise, two Plan-Do-Study-Act (PDSA) cycles were prioritized. The first, beginning 10/15/18, required that the new patient nurse navigator discuss the value of AD’s with the patient when scheduling initial visits. The second PDSA, completed 11/12/18 for the MA’s, was an educational session reviewing AD’s and how to discuss them. Results: Pre- and post-intervention data is depicted in the Table. At baseline, 20% of the 114 patients with existing AD discussions had these documents uploaded into their EMR. After PDSA-2, 37.1% of the 78 patient cohort had an AD uploaded. Conclusions: Through clinical education and revising the current process, this project increased uploading AD’s into EMR’s from 20% to 37.1%. This demonstrates that small but effective interventions can increase the proportion of patients with AD’s in their charts. Future PDSA’s will focus on patient and RN education to further improve these numbers. [Table: see text]
Abstract 362: Live Tracking Mouse Model for Endogenous Exosomes from Heart
Authors: Weijia Luo, Yuan Dai, Jiang Chang
Journal: Circulation Research (2019)

Exosomes are emerging new category of messengers communicating among cells, tissues and organs. Understanding the kinetics of exosome communication in vivo are a critical foundation for studying exosome functions and developing exosome based drug-delivery models. Current studies of exosome in vivo trafficking largely rely on the administration of labeled exogenous exosomes. These methods may not fully represent endogenous exosome kinetics due to ex vivo exosome manipulations. Here, we established the first inducible endogenous exosome tracking mouse model that tracks endogenous exosome released from cardiomyocytes in vivo . The ultrasensitive and stable Nano-luciferase (NanoLuc) was selected as a reporter due to its 150-fold stronger signal intensity compared to traditional Firefly and Renilla luciferases, and the longest luminescent half-life amongst all known luciferases. We fused NanoLuc reporter with exosome surface marker CD63 for specific labeling of exosomes. The cardiomyocyte-specific αMHC promoter followed by a loxP-STOP-loxP cassette was engineered for a temporal control of labeled exosomes originating from cardiomyocytes. We crossed this cardiomyocyte-specific transgenic mouse with a tamoxifen-inducible Cre mouse (R26CreERT2) to achieve an inducible expression of the reporter. The exosome labeling and distribution were assessed by a luciferase assay and non-invasive bioluminescent live imaging. As expected, CD63NanoLuc expression was tightly controlled and only detected in cardiomyocytes upon induction. The endogenous exosomes released from cardiomyocytes were labeled and detected in vitro in a cell culture supernatant, and in vivo in the animal plasma. A paracrine uptaken of the Nanoluc-labeled exosomes by cardiac fibroblasts in vivo was demonstrated and quantified. A signature distribution profile of the endogenous exosomes released from cardiomyocytes was exhibited. For the first time, this exosome tracking model enables elucidating the endogenous exosome trafficking pattern, and allows future studies of exosome behavior under different conditions. It provides a useful tool for the exploration of biological functions, mechanisms and clinical applications of exosomes in a broad spectrum of researches.