tbuckley/cabot-search huggingface dataset:
Abstract 145: Isolation &amp; Characterization of Heart-field Specific Cardiomyocytes
Authors: Arash Pezhouman, James L Engel, Ngoc B Nguyen, Rhys J Skelton, Peng Zhao, Blake W Gilmore, Nicholas Hornstein, Reza Ardehali
Journal: Circulation Research (2019)

Cardiovascular disease (CVD) is the leading cause of death worldwide. Human embryonic stem cell (hESC)-derived cardiovascular progenitors (CVPs) or cardiomyocytes (CMs) represent a promising candidate for cell-based therapies to treat CVD. Myocardial infarction leads to extensive CM death mainly within the left ventricle, which is predominantly derived from the first heart field (FHF) during embryonic development. We postulate that the generation of chamber-specific CMs may play a key role in the development of safe and efficacious regenerative therapy. As a first step, we generated and characterized a FHF-specific TBX5-TdTomato +/W hESC reporter line. We show that TBX5 + cells represent an enriched population of FHF CVPs that can give rise to CMs, endothelial, and smooth muscle cells in vitro . Interestingly, we observed that TBX5 - cells can also generate contractile CMs. Bulk RNA-sequencing analysis at different stages of development suggested that TBX5 - cells are enriched for second heart field (SHF) CMs. To enable prospective isolation of FHF and SHF CMs, we generated a double transgenic TBX5-TdTomato +/W /NKX2-5 eGFP/W hESC reporter line. We performed detailed electrophysiological, functional, and transcriptional studies to characterize the heart-field specificity of these hESC-derived CMs. Electrophysiological studies revealed that, despite the presence of atrial and ventricular action potentials (APs) in both FHF and SHF, there are significant differences in their AP duration and cycle length. In addition, both FHF and SHF CMs responded appropriately to adrenergic stimuli. Single-cell RNA sequencing analysis confirmed the absence of nodal genes within these populations and provided evidence of unique molecular signatures for isolating FHF- and SHF-like CMs. Finally, we identified CORIN as a novel cell surface marker for FHF CMs. Our studies provide a platform for investigating in vitro cardiovascular development, drug screening, and may facilitate a safe approach for cell therapy in heart disease.
Comparative study of mucoadhesive and mucus-penetrative nanoparticles based on phospholipid complex to overcome the mucus barrier for inhaled delivery of baicalein
Authors: Wujun Dong, Jun Ye, Junzhuo Zhou, Weijue Wang, Hongliang Wang, Xu Zheng, Yanfang Yang, Xuejun Xia, Yuling Liu
Journal: Acta Pharmaceutica Sinica B (2019)

Efficient mucosal delivery remains a major challenge for the reason of the respiratory tract mucus act as a formidable barrier to nanocarriers by trapping and clearing foreign particulates. The surface property of nanoparticles determines their retention and penetration ability within the respiratory tract mucus. However, the interaction between nanoparticles and mucus, and how these interactions impact distribution has not been extensively investigated. In this study, polymeric nanoparticles loaded with a baicalein-phospholipid complex were modified with two kinds of polymers, mucoadhesive and mucus-penetrative polymer. Systematic investigations on the physicochemical property, mucus penetration, transepithelial transport, and tissue distribution were performed to evaluate the interaction of nanoparticles with the respiratory tract. Both nanoparticles had a similar particle size and good biocompatibility, exhibited a sustained-release profile, but showed a considerable difference in zeta potential. Interestingly, mucus-penetrative nanoparticles exhibited a higher diffusion rate in mucus, deeper penetration across the mucus layer, enhanced in vitro cellular uptake, increased drug distribution in airways, and superior local distribution and bioavailability as compared to mucoadhesive nanoparticles. These results indicate the potential of mucus-penetrative nanoparticles in design of a rational delivery system to improve the efficiency of inhaled therapy by promoting mucus penetration and increasing local distribution and bioavailability.
Safety and Efficacy of Haploidentical Peripheral Blood Stem Cell Transplantation for Myeloid Malignancies Using Post-Transplantation Cyclophosphamide and Anti-Thymocyte Globulin As Graft Versus Host Disease Prophylaxis
Authors: Queralt Salas Gay, Arjun Law, Wilson Lam, Zeyad Al-Shaibani, Fotios V. Michelis, Santhosh Thyagu, Dennis Dong Hwan Kim, Jeff H. Lipton, Rajat Kumar, Auro Viswabandya
Journal: Blood (2018)
Abstract 770: Potential Explanation of the Mechanism for Loss of Function with G233D Mutation in Platelet Glycoprotein Ibα: Results fromMolecular Dynamics Simulation
Authors: Shinichi Goto, Hideki Oka, Kengo Ayabe, Hiroto Ybushita, Terumitsu Hasebe, Hideo Yokota, Shu Takagi, Motoaki Sano, Shinya Goto
Journal: Circulation Research (2019)

Background: Platelet play crucial role for the onset of acute coronary syndrome. The initial binding following vessel injury is exclusively mediated by the binding of von Willebrand factor (VWF) and platelet glycoprotein (GP) Ib α . Previous biological experiments revealed loss of function of platelet expressing GPIb α with G233D mutation. Objective: To elucidate the mechanism underlining the loss of function in G233D mutant. Methods: Dynamic fluctuating three-dimensional structures and the Potential of Mean Force (PMF) were calculated for the binding of VWF and platelet GPIb α in wild-type or G233D mutant. PMF were calculated at each 0.5Å for 25 Å to 65 Å of mass center distance between GPIb α and VWF. The energy required to dissociate the bond between GPIb α and VWF was calculated by subtracting the lowest PMF from the PMF at 65 Å mass center distance. Chemistry at HARvard Molecular Mechanics (CHARMM) force field with NAnoscale Molecular Dynamics (NAMD) was used for calculation. The initial structure of each mutant was obtained by inducing single amino-acid substitution with Visual Molecular Dynamics (VMD) to the stable water-soluble binding structure of wild-type VWF and GPIb α . Results: The energetically most stable binding structure of VWF and GPIb α in wild-type and G233D did not differ substantially (Figure panel A). However, The energy required to dissociate the bond between GPIb α and VWF was 4.32 kcal/mol (19.5 %) lower for G233D mutant compared to wild-type (Figure panel B). Conclusions: Our results suggest that the reduction of dissociation energy of single molecule of G233D GPIb α mutant as a possible explanation for the reduced platelet adhesion under blood flow condition.
Guideline adherence and the strategy of chemotherapy dose reduction in metastatic colorectal cancer: A multicenter oncology practice experience.
Authors: Chinelo C. Orji, Carolyn M. Brown, J. Russell Hoverman, Kristin M. Richards
Journal: Journal of Clinical Oncology (2019)

24 Background: Current American Society of Clinical Oncology (ASCO) guidelines recommend prophylactic use of colony stimulating factors (CSF) for prevention of febrile neutropenia among cancer patients. ASCO also recommends chemotherapy dose reduction as a viable alternative to CSF administration, which may result in cost savings to patients and payers, but adherence to these guidelines has been less than ideal. The objectives of this study were i.) to determine the prevalence and prescribing patterns of CSF and dose reduction in metastatic colorectal cancer patients and ii.) to evaluate the impact of a program initiative on CSF prescribing patterns and on compliance to ASCO guidelines. Methods: In this retrospective study, we utilized data from the electronic health records of metastatic colorectal cancer patients who received care at a multi-center oncology practice network during two time periods: July 2013 to December 2014 and July to December 2017. In 2016, a site-wide program initiative that involved educational materials, appropriate non-use recommendations and prior authorization was introduced in the oncology practice network with an aim of reducing CSF overutilization. Descriptive statistics and chi squared tests were employed to explore CSF utilization across patient age, gender, disease, year of diagnosis, febrile neutropenia risk, line of therapy and duration of treatment. Results: There were 3426 chemotherapy regimens corresponding to 2968 patients. There was a total of 3095 CSF administrations and the CSF administered was pegfilgrastim. There were 343 (10%) CSF users. Among subjects who had data on dose reduction (N = 508), 58.7% received dose reduction. CSF use was significantly lower in the post-period, compared to the pre-period (p &lt; 0.0001). Compliance to guidelines was significantly higher in the post-period, compared to the pre-period (p &lt; 0.0001). Conclusions: Our results demonstrate that program initiatives have the potential to positively impact CSF prescription patterns. These findings could help prescribers adopt a cost-effective approach for this population, leading to enhanced clinical practice and value-based care.
Performance of the patient reported CAPLET2.0 physical functioning assessment tool.
Authors: Alexandra McCartney, Julia Singer, Reenika Aggarwal, Katrina Hueniken, Raiza Commiting, Shubhangi Shah, Susan Tang, Priya Bapat, Pansy Chow, Kristen Dietrich, Elizabeth Hall, M. Catherine Brown, Wei Xu, Geoffrey Liu
Journal: Journal of Clinical Oncology (2019)

194 Background: CAPLET is a published patient reported outcome measure which assesses domains of physical function efficiently in cancer patients through a branching logic algorithm using a patient-reported outcome version of ECOG performance status and EQ5D-3L health utility score (PMID: 29982902; a total of 6 screening questions). We assessed the sensitivity and specificity of this tool after updating it with screening questions from the EQ5D-5L (CAPLET2.0) as opposed to the previously published EQ5D-3L screener (CAPLET). Methods: Eligible cancer patients across all outpatient clinics and disease sites (solid and liquid cancers) at the Princess Margaret Cancer Center completed a questionnaire on touch-screen technology containing the EQ5D-5L, patient-reported outcome (PRO)-ECOG performance scale, the gold standard WHODAS 2.0 (12 items) and HAQ-DI (20 items) physical functioning questionnaires, and a clinico-demographic survey. Results: Of 261 patients, 53% were female, 61% were Caucasian, and 71% had English as a first language. Disease sites included: 12% breast, 10% gastrointestinal, 12% genitourinary, 19% gynecological, 13% head and neck, 13% lung and 13% hematological cancers. The optimal branching logic cut-points were identified when PRO-ECOG, scored as 0-1 and individual EQ5D items scored with the best functioning category allowed specific WHODAS/HAQ-DI questions to be skipped. Against individual WHODAS-HAQ-DI items, CAPLET2.0 had sensitivities ranging from 83-100% (median 93%), and specificities of 50-82% (median 58%). Using CAPLET 2.0, 45% of patients could have skipped all but five questions measuring mental health and cognition which are always asked. Sensitivities, specificities and the proportion of questions that could have been skipped were all similar to the original CAPLET tool. Conclusions: CAPLET2.0, which uses the updated EQ5D-5L and PRO-ECOG as screening questions to assess physical function in cancer patients has comparable performance to the original CAPLET tool. CAPLET2.0 is therefore a viable alternative physical functioning screening tool for both routine and research use.
Prognostic impact of RAS-pathway mutations in patients with myelofibrosis
Authors: Fabio P. S. Santos, Bartlomiej Getta, Lucia Masarova, Christopher Famulare, Jessica Schulman, Tarcila S. Datoguia, Renato D. Puga, Raquel de Melo Alves Paiva, Maria E. Arcila, Nelson Hamerschlak, Hagop M. Kantarjian, Ross L. Levine, Paulo Vidal Campregher, Raajit K. Rampal, Srdan Verstovsek
Journal: Leukemia (2019)
Matt Morgan: Those three little words
Authors: Matt Morgan
Journal: BMJ (2019)

I still remember the first time I said those three little words. Growing up in a loving Welsh family, I’d heard them said many times. But the first time they roll off your tongue will always be different. You try to choose your moment, but sometimes the words take you, and the listener, by surprise.

If “I love you” are the three most important words in life, then “I don’t know” are the three most important in medicine. They’re also the most underused. Their power comes from admitting that doctors don’t, and can’t, know everything.

For me, the first time I admitted to a patient’s family that I didn’t know the answer was …
Randomized Multicenter Trial of Cladribine Alone (C) or in Combination with Cyclophosphamide (CC), and COP in Previously Untreated Low Grade B-Cell Non-Hodgkin Lymphoma Patients: The First Interim Analysis.
Authors: Ewa E. Kalinka, Jaroslaw J. Wajs, Kazimierz Sulek, Tadeusz Robak, Maria Blasinska-Morawiec, Jerzy Holowiecki, Joanna Sawczuk-Chabin, Bernadeta Ceglarek, Lech Konopka, Grzegorz Mazur, Irena Federowicz, Wieslaw Jerdrzejczak, Marzena Watek, Elzbieta Kisiel, Janusz Meder, Piotr Centkowski, Ilona Seferynska, Jaroslaw Czyz, Krzysztof Warzocha
Journal: Blood (2004)
Abstract 161: Il4 Increases Phagocytosis of Necrotic Cells in a Cd36-dependent Manner
Authors: Mingzhuang Chen
Journal: Circulation Research (2019)

Macrophages are a population of immune cells with high heterogeneity, which can acquire distinctive phenotypes under different stimuli, and each subtype has specific function in immune surveillance and tissue homeostasis. Different with traditional activated macrophages, which are mainly primed by pathogen motifs or inflammatory stimuli and are involved in pathogen clearance and immune defence, alternatively activated macrophages by Th2 cytokine IL4 have been shown to be functioning in cell debridement, promising a crucial role in tissue repair and tissue homeostasis. However, the mechanisms underlying how IL4 signaling promotes cell debridement have not been fully understood. To address this question, we aim to investigate whether and how IL4 signaling promotes necrotic cell clearance, which is the primary source of cell debris and share similar biological properties. In our study, we demonstrated that IL4 enhances phagocytosis of necrotic cells, and the downstream IL4Rα-STAT6 axis signaling pathway is involved. We also found that CD36, a class B scavenger receptor, may be, at least to some extent, responsible for IL4-accelerated phagocytosis. Beside increasing engulfment of necrotic cells, IL4 treatment also enhances the processing of engulfed material, indicating multi-dimensional effects of IL4 on phagocytosis activity of macrophages. By uncovering the molecular mechanisms of IL4 promoting phagocytosis activity of macrophages, we are able to better understand the role of IL4 signaling in cell debridement, and this may help to develop new strategies in promoting tissue repair and regeneration in chronic diseases.
Centralizing mixing of infusion drugs: A process to comply with USP 797/800, improve efficiency, and reduce costs in a multisite oncology infusion practice.
Authors: Manuel Perry, Theresa Dolson, Gianna Lindros, Courtney Welyczko, Scott Hines
Journal: Journal of Clinical Oncology (2019)

295 Background: In oncology practices with multiple infusion sites, compliance with USP 797/800 will be difficult to achieve due to increased building costs. Mixing oncology medications in a single-site referred to as “centralized mixing” is an attempt to comply with USP regulations as well to improve safety, quality and decrease costs. Methods: The centralized mixing process was initiated in June 2017 and required patients to have labs drawn 24-48 hours prior to infusion. If results were adequate, infusion nurses contacted the patient to review a symptom checklist to report findings which would preclude treatment. The next day, pharmacists began drug mixing at 6 am and distributed them by courier to five other practice sites by 10am. When patients arrived for treatment, they went directly to the infusion suite. A follow up visit was arranged mid-cycle to see their oncologist prior to the next scheduled infusion. If weekly infusions were required, then follow up visits were scheduled at the discretion of the oncologist. Results: Data from the fourth quarter of 2016 (prior to centralized mixing) was compared to the fourth quarter of 2018. Although physician total work RVUs increased from 12,198 to 16,254, labor costs decreased by $15,194. After implementation of centralized mixing, there were four fewer infusion nurse FTE’s while two registered pharmacists were hired. Labor costs per total work RVU decreased from $38.51 to $27.97 resulting in a quarterly savings of $42,790. Conclusions: Centralized mixing of oncology medication has reduced the cost per physician work RVU of administering chemotherapy by 27.3% and has lead to an annualized savings of $171,160. Increased infusion capacity and improved efficiency were due to streamlining the patient experience: there is no need to wait for drugs to be mixed, for lab results to return or to see their oncologist prior to treatment. The practice is now able to improve environmental safety with USP 797/800 at a single site, improve quality by limiting staff who mix chemotherapy to only two pharmacists, reduce training time for our infusion nurses by six weeks and to delay the need to build additional infusion suites.
Redesigning care for older people to preserve physical and mental capacity: WHO guidelines on community-level interventions in integrated care
Authors: Jotheeswaran Amuthavalli Thiyagarajan, Islene Araujo de Carvalho, Juan Pablo Peña-Rosas, Shelly Chadha, Silvio Paolo Mariotti, Tarun Dua, Emiliano Albanese, Olivier Bruyère, Matteo Cesari, Alan Dangour, Amit Dias, Mariella Guerra, Jill Keeffe, Ngaire Kerse, Qurat ul Ain Khan, Chiung-ju Liu, Gudlavalleti V. S. Murthy, Serah Nyambura Ndegwa, Jean-Yves Reginster, Luis Miguel F. Gutiérrez Robledo, Kelly Tremblay, Jean Woo, Martin Prince, John R. Beard
Journal: PLoS Medicine (2019)

Numerous underlying physiological changes occur with increasing age, and for older people, the risks of developing chronic diseases and care dependency increase.• Health systems are often better designed to respond to episodic health needs than to the more complex and chronic health needs that tend to arise with increasing age, and reprioritization is required to meet the needs of ageing populations.• Significant losses in capacity and care dependency in later life can be delayed or avoided if health interventions are introduced earlier in the process of functional decline.• We discuss the recommendations of the WHO Integrated Care for Older People (ICOPE) Guidelines, which provide evidence-based recommendations for managing
Cross training of APPs on inpatient oncology units as a safe and cost-effective model.
Authors: Heather Koniarczyk, Helen Tackitt
Journal: Journal of Clinical Oncology (2019)

56 Background: Oncology Advanced Practice Providers (APPs) have not been optimally trained to care for each other’s sub specialty of patients. In times of high census and/or short staffing, inpatient APPs are left to care for and manage high volumes of acutely ill patients. This is concerning for patient safety, burning out as well as dissatisfactions when vacation and meetings are denied because there is no backup coverage available. Methods: In order to minimize the use of overtime pay, physician moonlighting pay and additional positions in times of short staffing, we proposed to cross train experienced APPs to see if the staffing needs could be met. The disease groups consisted of transplant, leukemia and lymphoma. Each disease group has a lead APP involved in the strategic planning and implementation process. They were instrumental in working through and identifying risks and benefits of this training plan and were the first to be trained, as to lead by example. Buy in from APPs was achieved by promoting the flexibility of scheduling that would result from having more coverage. Some were also motivated to add to their skill set by learning how to care for a new disease group. Results: The APPs felt comfortable taking patients after around 2 training shifts. They felt the patients were more alike than different and the workflow for most job duties were identical, and enjoyed working with fellow oncology APPs they hadn’t interacted much with. Cross training was proposed to add a financial benefit to our institution. Key metrics we monitored were productivity and supplemental pay. The financial savings from avoiding supplemental overtime or fellow moonlighting wages for 2018 was $8,540, and $14,640 for quarter1 2019. The APPs had no decrease in productivity to date, and no decrease in quality metrics and no adverse events related. Conclusions: Cross training as a means to reduce short staffing financial burdens while advancing the scope of practice of APPs is a safe and possible alternative to adding positions, or paying overtime/moonlighting pay. Training of cross covering APPs was not overall a major constraint. Buy-in from leadership as well as APPs is instrumental in not only initiating a cross training program, but maintaining it as well.
Abstract 15485: Long-Term Regression of Left Ventricular Hypertrophy Through Inward Remodeling with Specific Treatment of Primary Aldosteronism
Authors: Gian Paolo Rossi, Maurizio Cesari, giuseppe maiolino, Maria Verena Cicala, Cesare Cuspidi, Franco Mantero, Giacomo Rossitto, Achille Cesare Pessina
Journal: Circulation (2012)

Context: Primary aldosteronism (PA), a highly prevalent curable form of high blood pressure, causes left ventricular (LV) hypertrophy and an excess rate of cardiovascular (CV) events, including atr...
Understanding the challenges for oncologists in predicting the end-of-life phase of care in cancer patients with advanced solid tumor diagnoses.
Authors: Aaron J. Lyss, Cheryl A. Crouse, Natalie R. Dickson, Jeffrey Patton, Christopher A. Waynick, Stephen Matthew Schleicher
Journal: Journal of Clinical Oncology (2019)

281 Background: Early advanced care planning and palliative care improves outcomes during the end-of-life phase of care (EOL) for metastatic cancer patients. Identifying patients who are likely to transition to EOL is a necessary step to prioritize limited palliative care resources and is integral to success in value-based payment models. We analyzed whether physician documentation of prognosis in a clinical pathways system (CPS) could reliably predict when patients are nearing EOL for a large community oncology practice of more than 70 medical oncologists. Methods: Tennessee Oncology (TO) requires physicians to use CPS for all Medicare patients. CPS prompts physicians to answer the “prognostic question” “would you be surprised if this patient died in the next year?” for all OCM patients with advanced solid tumors at the beginning of treatment or at the time of a change in treatment plan. Prognostic question responses were compared to actual dates of death documented in the practice management system. Results: A total of 5,266 distinct patients were expected to trigger an OCM episode during 2017. The CPS prompted a response to the prognostic question for 1,228 (23%) of these OCM patients. There were 665 (54%) positive prognoses (expect patient to live more than 1 year) and 563 (46%) negative prognoses (expect patient to die within 1 year). Physicians documented accurate prognoses in 712 (58%) of cases. For patients with positive prognosis 557 (84%) were accurate. For patients with negative prognosis 155 (21.8%) were accurate. Conclusions: We found that for patients with terminal cancer, it is difficult for physicians to accurately predict prognosis. These findings support the importance of ASCO guidelines pertaining to patient access to palliative care during the entirety of cancer treatment for all patients with metastatic cancer. [Table: see text]