tbuckley/cabot-search huggingface dataset:
Abstract 353: Distinct cGMP Compartmentalization by Membrane Guanylate Cyclases
Authors: Hariharan Subramanian, Alexander Froese, Viacheslav Nikolaev
Journal: Circulation Research (2019)

Introduction: In adult cardiomyocytes (CM), cGMP produced by two membrane guanylate cyclases (GC-A and GC-B) play distinct roles. Using Förster Resonance Energy Transfer (FRET) and Scanning Ion Conductance Microscopy (SICM)-based approaches, cGMP compartmentation by GCs and phosphodiesterases (PDEs) were assessed. Methods: cGMP was measured in CM isolated from transgenic mice expressing membrane targeted cGMP sensor (red cGES-DE5). SICM was used to define the t-tubules across sarcolemma and its nano-pipette filled with natriuretic peptides (CNP and ANP) was used to locally stimulate GC in t-tubules and crest. Results: CNP activating GC-B induced maximum cGMP increase, while ANP activating GC-A did not increase cGMP. Pre-inhibiting PDE2 before ANP stimulation massively increased cGMP production to functionally significant levels as measured by PLN phosphorylation in western blot. cGMP in unstimulated cells was regulated mostly by PDE3. Local ANP stimulation in t-tubules, but not in crest, induced cGMP increase and CNP induced cGMP increase in both t-tubule and crest. After methyl-β-cyclodextrin treatment, ANP induced cGMP in both t-tubules and crest suggesting a role for lipid rafts in trapping GC-A in t-tubules. In transfected HEK293 cells, Fluorescence Recovery After Photobleeching (FRAP) showed that membrane diffusion of YFP-tagged GC-A was decreased after methyl-β-cyclodextrin treatment. Conclusions: GC-A exclusively located in T-tubules produce cGMP locally, which is tightly regulated by PDE2, while GC-B is expressed across the sarcolemma and produces global cGMP.
Abstract 237: Identifying the Transcriptome Signature of Calcium Channel Blocker in Human iPSC-Derived Cardiomyocytes
Authors: Chi Keung Lam, Lei Tian, Nadjet Belbachir, Alexa Wnorowski, Rajani Shrestha, Ning Ma, Tomoya Kitani, June W Rhee, Joseph C Wu
Journal: Circulation Research (2019)

Calcium channel blockers (CCBs) are important in treating cardiovascular diseases and the acute pharmacological actions of CCBs in the hearts have been extensively studied. However, we lack the knowledge of the drug-specific effect on human cardiomyocyte transcriptome and potential physiological change after long-term exposure as patients are usually prescribed with these medications for their lifetime after diagnosis. Thus, we aimed to simulate chronic CCB treatment in human cardiomyocytes and subsequently examine both the functional and transcriptomic alterations. We differentiated cardiomyocytes from three human induced pluripotent stem cell (iPSC) lines and exposed them to four different CCBs—nifedipine, amlodipine, diltiazem, and verapamil—at their physiological serum concentrations for two weeks. Without inducing cell death and damage to myofilament structure, CCBs elicited line specific inhibition on calcium kinetics and contractility. While all four CCBs exerted comparable inhibition on calcium kinetics, verapamil applied the strongest inhibition on cardiomyocyte contractile function. By examining cardiomyocyte transcriptome after treatment, we identified little overlap in their transcriptome signatures. Verapamil is the only inhibitor that reduced the expression of contraction related genes, such as myosin heavy chain and troponin I, consistent with its depressive effects on contractile function. Moreover, the alterations in these gene may help explain how HCM patients respond to verapamil in relieving outflow tract obstruction. In conclusion, we identified the distinct transcriptome signatures of different CCBs in human cardiomyocytes, suggesting that although the four inhibitors act on the same target, they may have distinct effects on normal cardiac cell physiology. The application of iPSC platform and transcriptomic findings may allow us to identify responders to verapamil treatment.
Monitoring Minimal Residual Disease in Acute Myeloid Leukemia Using Genomic or cfDNA with MyMRD®, a Targeted NGS Panel
Authors: Zhiyi Xie, Lisa Chamberlain, Andrew Carson, Veronika Atkinson, Valerie McClain, James Sprague, Ogeen Kiya, Peng Xia, Wenli Huang, Bradley Patay, Martin Blankfard, Jeffrey E Miller
Journal: Blood (2018)
Abstract 322: Identification of Novel Long Non Coding RNAs Involved in Pitx2&gt;Wnt&gt;microRNA Signaling Pathways Leading to Atrial Fibrillation
Authors: Diego Franco, Carlos Garcia-Padilla, Amelia E Aranega
Journal: Circulation Research (2019)

Atrial fibrillation is the most prevalent cardiac arrhythmia in humans. Genetic and genomic analyses have recently demonstrated that the homeobox transcription factor Pitx2 plays a fundamental role regulating expression of distinct growth factors, microRNAs and ion channels leading to morphological and molecular alterations that promote the onset of atrial fibrillation. We now address the plausible contribution of a novel class of non-coding RNA in this Pitx2&gt;Wnt&gt;miRNA signaling pathway, i.e. long non coding RNAs (lncRNAs). In silico analyses of annotated lncRNAs in the vicinity of Pitx2, Wnt8 and Wnt11 chromosomal loci identified five novel lncRNAs with differential expression during cardiac development. Among them, Wnt11_45188, Wnt11_44934 and Wnt8_2010Rik displayed preferential atrial-specific expression during embryogenesis. In addition, Wnt11_44653 displayed moderate expression during embryogenesis but peaked preferentially in the right atrium vs left atrium and ventricle in adulthood. Wnt11_45188, Wnt11_44934 and Wnt8_2010Rik were distinctly regulated by Pitx2, Wnt8 and Wnt11 and Wnt8_2010Rik is severely up-regulated in conditional atrial-specific Pitx2 deficient mice. We also demonstrate that arrhythmogenic microRNAs such as miR-1, miR-133 and miR-29 distinctly regulate these lncRNAs. Furthermore, angiotensin II administration to atrial cardiomyocyte cell cultures leads to significant up-regulation of these three newly identified lncRNAs, supporting a link to AF cardiovascular risk factor, i.e. hypertension. Overall, we have identified three novel lncRNAs that are distinctly regulated in the Pitx2&gt;Wnt&gt;miRNA signaling pathways which might be therefore implicated in the gene regulatory network leading to atrial arrhythmogenesis.
Reply to Xiaoling Lin, Brian T. Helfand, and Jianfeng Xu's Letter to the Editor re: Daniel A. Leongamornlert, Edward J. Saunders, Sarah Wakerell, et al. Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel. Eur Urol 2019;76:329–37
Authors: Zsofia Kote-Jarai, Daniel A. Leongamornlert, Edward J. Saunders, David V. Conti, Rosalind A. Eeles
Journal: European Urology (2019)
Impact of Creatinine Clearance in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP : A Real-World Long-Term Observation Analysis at a Single Institute
Authors: Noriko Nishimura, Takanori Fukuta, Anna Nishihara, Yuko Shirouchi, Hideki Uryu, Norihito Inoue, Yoshiharu Kusano, Naoko Tsuyama, Kengo Takeuchi, Yuko Mishima, Masahiro Yokoyama, Yasuhito Terui
Journal: Blood (2018)
Adult Patients with Hemophagocytic Lymphohistiocytosis (HLH) in Germany: A Retrospective Multicenter Case Study of 29 Patients
Authors: Thomas Schenk, Georg Maschmeyer, Frank Rothmann, Thomas Weber, Maximilian Christopeit, Olaf Penack, Daniela Goy, Jens Panse, Gritta Janka, Andreas Hochhaus, Paul La Rosee
Journal: Blood (2012)
Partnering with patients and caregivers to improve systemic treatment regimen information.
Authors: Andrea Crespo, Heidi Amernic, Sarah McBain, Nita Lakhani, Daniela Gallo-Hershberg, Annie Cheung, Jessica Ng, Sarah Salama, Kathy Vu, Leta Marie Forbes
Journal: Journal of Clinical Oncology (2019)

185 Background: Cancer Care Ontario’s Drug Formulary is a web-based drug information resource. Patient information is currently provided as single-drug information sheets, with a limited number of multi-drug regimen information sheets (RIS) for breast and lung cancer treatments. Patients identified a need to create additional, high-quality, “user-friendly” RIS. Objectives of this project were to 1) engage patients and caregivers in RIS redesign; 2) evaluate the original vs a redesigned model RIS; and 3) use the model RIS template to create additional RIS across disease sites. Methods: The project team included a patient and family advisor (PFA) and clinical and research experts. This was a qualitative study between August 2017 to May 2019. A focus group (FG) was conducted with 5 PFAs to identify and prioritize drug information needs. A model RIS was designed, incorporating FG input and health literacy best practices. RIS were evaluated through blinded comparative cognitive interviews with 13 PFAs, to assess RIS for usability, understandability and content relevance. Evaluation informed iterative revisions. RIS were also evaluated by clinical and education experts using the Patient Education Materials Assessment Tool (PEMAT). An RIS style guide was developed to inform the creation of future RIS. Ethics approval was obtained from the University of Toronto. Results: The FG prioritized information on regimen details, Dos and Don’ts while on treatment, drug interactions, side effects and contact information. Guidance was provided on simplifying language, highlighting important information and aesthetics. Cognitive interviews consistently reported preference for model RIS over original RIS in most domains. PEMAT scores for original versus model RIS were 64% and 94% respectively (for understandability) and 60% and 82% respectively (for actionability). To date, the style guide has informed the creation of RIS for 10 high-use regimens. Conclusions: PFA and clinician co-design along with health literacy best practices informed measurable improvements in RIS. The style guide will enable the future creation and ongoing evaluation of high-quality RIS to enhance the cancer treatment experience for patients and caregivers.
Abstract 570: Mechanism Of Mitochondrial Calcium Uniporter Regulation
Authors: Vivek Garg, Ishan Paranjpe, Tiffany Unsulangi, Junji Suzuki, Lorin S Milescu, Yuriy Kirichok
Journal: Circulation Research (2019)

Calcium uptake by mitochondria plays an important role in sequestering cytosolic calcium, regulating ATP production and maintaining the redox homeostasis. Mitochondrial calcium uniporter (MCU), a macromolecular channel complex that resides in the inner mitochondrial membrane, is the primary electrogenic pathway for calcium influx into the matrix. Because calcium uptake by mitochondria is dictated by the kinetic equilibrium between the influx and efflux machinery, the patch clamp is the best method to measure electrogenic MCU activity in isolation from the efflux mechanisms. Here we report the development of a system for heterologous expression of MCU and its associated subunits, essential MCU regulator (EMRE), MCUb and MICU1–3. Using this system, we investigated the biophysical properties of the MCU pore and its regulation. The system is based on a recombinant cell line (Drp1 -/- mouse embryonic fibroblasts) in which knockouts for all subunits of the MCU complex have been generated. This system allowed both optical and direct electrophysiological studies of the structure-function relationships in the MCU complex with a relative ease in comparison to other cell lines. We confirmed the essential role of pore-forming MCU and EMRE subunits in mediating the MCU current. Importantly, fast-step solution exchange and single-channel recordings allowed us to gain novel insights into the biophysical properties of MCU e.g. inward rectification, kinetics of activation and selectivity to monovalent vs divalent ions.
Challenges in implementing a mobile-based patient-reported outcome (PRO) tool for cancer patients.
Authors: Liana Yocavitch, Adam Binder, Amy Leader, Gregory D. Garber, Andrew E. Chapman, Nathan Handley
Journal: Journal of Clinical Oncology (2019)

206 Background: Electronic patient reported outcomes (ePROs) can bridge the communication gap with a patient’s care, providing insight into patients’ symptoms between clinical visits and improving both symptom management and overall survival. PROs are typically monitored through standardized questionnaires given to patients at specific times during their treatment. We endeavored to implement a mobile application-based ePRO tool at an urban academic cancer center. Methods: During an 8-week period, cancer patients on active intravenous chemotherapy were approached for enrollment during their infusion appointment. English-speaking patients with a smartphone and an active email address were eligible to download the app and enroll in the program. Two patient coordinators enrolled patients and demonstrated the use of the ePRO tool. Barriers to enrollment were tracked; subsequent utilization by enrolled patients was assessed. Results: 108 patients (63% White, 22% African American, 7% Asian, 2% Hispanic, 6% unknown; mean age 65 years) were approached for enrollment. Among those, 32 (30%) were ineligible. The most common reasons for ineligibility were the lack of a smart phone or active email address. 76 patients (70%) were eligible for enrollment. Of the 76 patients, 19 (25%) declined, 20 (26 %) were unable to complete registration due to technical barriers, and 37 patients (49 %) successfully registered. Of registered patients, 19 (25%) utilized the ePRO tool on at least one occasion. Patients who utilized the ePRO tool tended to be younger, female, and white. Conclusions: A mobile application-based ePRO presented several challenges to implementation in our patient population. Nearly 50% of patients were either ineligible or experienced technical issues that precluded enrollment. Successful ePRO implementation may benefit from a variety of mechanisms by which to collect data, such desktop-based, text-based, and or telephonic-based approaches. Ongoing iterations are in process at our institution.
Molecular Genetic Analysis of Myelodysplastic Syndromes (MDS) Patients with Ring Sideroblasts (RS); Independent Confirmation of Association of SF3B1 Mutations with Better Prognosis
Authors: Abdullah Mahmood Ali, Nicholas Iverson, Alexander Penson, Allison Scott, Tabish Riaz, Raul Rabadan, Siddhartha Mukherjee, Azra Raza
Journal: Blood (2014)
Targeted PEG-poly(glutamic acid) complexes for inhalation protein delivery to the lung
Authors: A. Nieto-Orellana, H. Li, R. Rosiere, N. Wauthoz, H. Williams, C.J. Monteiro, C. Bosquillon, N. Childerhouse, G. Keegan, D. Coghlan, G. Mantovani, S. Stolnik
Journal: Journal of Controlled Release (2019)
Using an ePRO tool to help meet quality metrics in a clinical oncology practice.
Authors: Joanne S. Buzaglo, Edward Stepanski, Mary Joiner, Deb Taylor, Cynthia Tankersley, Ari M. Vanderwalde, Lee S. Schwartzberg
Journal: Journal of Clinical Oncology (2019)

171 Background: ASCO has implemented the Quality Oncology Practice Initiative (QOPI), a certification program established to evaluate oncology practice performance. However, practices often lack the necessary resources to meet the required standards and fulfill required metric reporting. The study purpose was to document the effectiveness of using an electronic Patient Reported Outcome (ePRO) system to facilitate compliance with two QOPI standards: pain assessment and depression screening. Methods: This study used a retrospective, observational design with ePRO and clinical data collected via the Patient Care Monitor (PCM), a web-based ePRO system linked to electronic medical record data. All study data were collected as part of routine clinical care at a community oncology practice during a 4-month interval (1/1–4/26/19). Patients at an initial oncology clinic visit completed the PCM Core Symptom survey and the PHQ2/PHQ9 to screen for pain and depression respectively via a handheld e-tablet. Results: Overall, 10,449 patients completed the PCM survey (mean age 63; 30% male/70% female; 62% White, 34% Black). Cancer type was known for 53% of all patients (22% breast, 9% hematologic, 4% lung, 5% colorectal, 3% prostate, 11% other types). Fifteen percent of patients (n = 1584) met the pain threshold (scored 7 or above on a 0-10 scale) that signaled an alert to the physician for further evaluation. About 3% of patients (n = 413) skipped the pain question on the PCM Core Symptom survey. With respect to depression, 5% (n = 559) reported a PHQ2 threshold level that triggered the remaining PHQ9 items. Among those at higher risk for depression, 16% (n = 92) met criteria for moderate to severe depression warranting further clinical evaluation and the PCM signaled a real-time alert to the physician in advance of the patient consultation. Approximately 4% (n = 413) skipped the PHQ2. Conclusions: This study demonstrates that using an ePRO system is an effective way to screen for pain and depression and can be used to: 1) monitor symptoms to enhance physician-patient communication during the consultation; 2) provide an audit trail for QOPI metric reporting. Overall, an ePRO system contributes to creating a culture of excellence at community oncology practices.
Assessing Potential Genotoxicity of Sleeping Beauty Transposition Events in T-Cell Immunotherapy by Supercomputer-Based High Throughput Profiling,
Authors: Sonny O. Ang, Sourindra Maiti, Branden Moriarity, Martin Ossowski, Kim Andrews, Kathy Tzeng, Richard Talbot, Denise Kellar, Helen Huls, Partow Kebriaei, David A. Largaespada, Richard Champlin, Perry Hackett, Laurence J N Cooper
Journal: Blood (2011)
On-chip drug testing of an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor by kinase activity profiling.
Authors: Rob Ruijtenbeek, Adrienne van den Berg, Riet Hilhorst, Stefan Kueffer, Timo Gaiter, Tim Kievits, Matthias Ebert
Journal: Journal of Clinical Oncology (2013)

e14702 Background: A patient presented with an expansivetumor of the liver, which infiltrated diaphragm, duodenum, gastric wall, pancreas and gall bladder. Pathological examination revealed a tumor dominated by infiltrating sheets of epithelioid-to-round cells with a prominent inflammatory infiltrate. Immunohistochemistry showed a positive reaction for vimentin but stained negative for S100, HMB45, Aktin, Desmin, CD117, DOG1, WT1, CDK4, mdm2 and ALK. Diagnosis of an ALK negative aggressive intra-abdominal variant of Inflammatory Myofibroblastic Tumor (IMT) was established. While it is know that approximately 50% of IMTs contain clonal rearrangements involving the ALK gene (Am. J. Surg. Pathol. 2011 135-144), little is known about the ALK-negative variant. The aim of the current study was to gain insights in potential aberrant signaling pathways in this rare tumor and potentially identify alternative druggable pathways. Methods: Kinase activity profiles of the tumor lysate were generated on PamChip peptide microarrays in the presence and absence of a concentration series of the protein kinase inhibitors (PKIs) erlotinib, imatinib, sorafenib, masitinib, crenolanib and tivozanib. Inhibitor effects on this IMT tumor lysate were compared to those on lysates from other tumor types, followed by bioinformatic analysis. Results: Comparing the different kinase inhibition profiles, erlotinib was the least effective inhibitor, while sorafenib and imatinib inhibited phosphorylation of a set of peptides that are known to be substrates for their kinase targets c-KIT, PDGFRα and PDGFRβ. The degree of inhibition in the IMT sample was higher than in tumor samples where these drugs are approved like CML and RCC (as well as in non-approved indications like CRC and AML). In the closely related sarcoma GIST, these kinases are successful targets. Additional prove of their involvement in this IMT variant was found in the positive inhibition profiles using crenolanib and masitinib. Conclusions: c-Kit and PDGFR and corresponding kinase inhibitors would be a pathway/drug combination of choice for drug development in this variant of IMT.
Asymptomatic Cardiac Ischemia Pilot (ACIP) Study
Authors: Peter H. Stone, Bernard R. Chaitman, Robert P. McMahon, Thomas C. Andrews, Gail MacCallum, Barry Sharaf, William Frishman, John E. Deanfield, George Sopko, Craig Pratt, A. David Goldberg, William J. Rogers, James Hill, Michael Proschan, Carl J. Pepine, Martial G. Bourassa, C. Richard Conti
Journal: Circulation (1996)

Background We investigated whether the presence and frequency of asymptomatic ischemic episodes recorded during ambulatory ECG (AECG) monitoring could be predicted on the basis of clinical characteristics or exercise treadmill test (ETT) performance in patients with stable coronary disease and whether the estimate of ischemia severity was similar between the AECG and ETT. Methods and Results Patients screened for the Asymptomatic Cardiac Ischemia Pilot (ACIP) study were selected for the current analysis if data were available from 48-hour AECG monitoring as well as from an ETT during which the patient developed ≥1-mm ST-segment depression. Exercise ECG data were available for 143 of the 910 patients without ischemic episodes and for 659 of the 910 patients with ischemic episodes during AECG monitoring. Angina was more frequent among patients with ambulatory ischemic episodes than among patients without such ischemia ( P &lt;.001). Patients with AECG ischemia had a consistently more marked ischemic response on the ETT than patients without AECG ischemia; patients likely to have AECG ischemia could be predicted on the basis of ETT performance characteristics. However, the correlation coefficients between the severity of ischemia estimated by ETT and by AECG were small. Conclusions There are significant relations between ischemia detected by AECG monitoring and by ETT, but the relations are limited, indicating that the two tests are not redundant to characterize coronary patients. A larger study investigating the prognostic significance of the ischemia identified by each modality, with follow-up for clinical events, will be necessary to determine the most appropriate methods to evaluate patients with stable coronary disease.
No Benefit from Rituximab Containing Regimens in Patients with Primary Extranodal Diffuse Large B-Cell Lymphoma
Authors: Gonzalo Gutiérrez-García, Luis Colomo, Neus Villamor, Leonor Arenillas, Antonio Martínez, Mireia Camós, Marina Diaz-Beyá, Carlos Fernández de Larrea, Xavier Calvo, Eva Giné, Francesc Bosch, Elias Campo, Emili Montserrat, Armando López-Guillermo
Journal: Blood (2008)
Personalised screening for colorectal cancer, ready for take-off
Authors: Ernst J Kuipers, Esmée J Grobbee
Journal: Gut (2019)

Colorectal cancer (CRC) is among the most common causes of cancer-related mortality.1 For the purpose of population-based CRC screening, faecal immunochemical tests (FIT) have been widely accepted.2 FIT can both be used in a qualitative manner, leading to either a positive or negative result, or a quantitative manner resulting in the reporting of microgram faecal haemoglobin (Hb) per gram faeces. Screenees with a FIT result above a prespecified threshold are referred for colonoscopy. A higher faecal Hb concentration is associated with a higher risk of advanced neoplasia.3 4 Most screening programmes use quantitative FIT. The results are however habitually reported in a dichotomised manner (ie, below or above a prespecified threshold). Such a dichotomised strategy subsequently misses out on countless possibilities in which the exact faecal Hb concentration could guide clinical decision-making. One of these possibilities is the use of negative FIT results, in other words faecal Hb concentrations below the accepted cut-off, as a predictor for the risk of advanced neoplasia in following screening rounds.

The beautiful paper by Senore and colleagues in Gut provides additional support for this concept in exploring the predictive value of faecal Hb …
Next Generation Flow for Multiple Myeloma Minimal Residual Disease: Igh Rearrangement NGS Is Complement to the NGF
Authors: Sung-Min Kim, Jung-Ah Kim, Dajeong Jeong, Jiwon Yun, Kyu Min Lim, Sang Mee Hwang, Sung-Soo Yoon, Dong Soon Lee
Journal: Blood (2018)