tbuckley/cabot-search huggingface dataset:
Pathophysiology and diagnosis of coronary microvascular dysfunction in ST-elevation myocardial infarction
Authors: Lara S F Konijnenberg, Peter Damman, Dirk J Duncker, Robert A Kloner, Robin Nijveldt, Robert-Jan M van Geuns, Colin Berry, Niels P Riksen, Javier Escaned, Niels van Royen
Journal: Cardiovascular Research (2019)

Early mechanical reperfusion of the epicardial coronary artery by primary percutaneous coronary intervention (PCI) is the guideline-recommended treatment for ST-elevation myocardial infarction (STEMI). Successful restoration of epicardial coronary blood flow can be achieved in over 95% of PCI procedures. However, despite angiographically complete epicardial coronary artery patency, in about half of the patients perfusion to the distal coronary microvasculature is not fully restored, which is associated with increased morbidity and mortality. The exact pathophysiological mechanism of post-ischaemic coronary microvascular dysfunction (CMD) is still debated. Therefore, the current review discusses invasive and non-invasive techniques for the diagnosis and quantification of CMD in STEMI in the clinical setting as well as results from experimental in vitro and in vivo models focusing on ischaemic-, reperfusion-, and inflammatory damage to the coronary microvascular endothelial cells. Finally, we discuss future opportunities to prevent or treat CMD in STEMI patients.
Performance of surveillance case definitions for respiratory syncytial virus infections through the sentinel influenza surveillance system, Portugal, 2010 to 2018
Authors: Emma Sáez-López, Pedro Pechirra, Inês Costa, Paula Cristóvão, Patrícia Conde, Ausenda Machado, Ana Paula Rodrigues, Raquel Guiomar
Journal: Eurosurveillance (2019)

BackgroundWell-established influenza surveillance systems (ISS) can be used for respiratory syncytial virus (RSV) surveillance. In Portugal, RSV cases are detected through the ISS using the European Union (EU) influenza-like illness (ILI) case definition.AimTo investigate clinical predictors for RSV infection and how three case definitions (EU ILI, a modified EU acute respiratory infection, and one respiratory symptom) performed in detecting RSV infections in Portugal.MethodsThis observational retrospective study used epidemiological and laboratory surveillance data (October 2010-May 2018). Associations between clinical characteristics and RSV detection were analysed using logistic regression. Accuracy of case definitions was assessed through sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). A 0.05 significance level was accepted.ResultsThe study involved 6,523 persons, including 190 (2.9%) RSV cases. Among 183 cases with age information, RSV infection was significantly more frequent among individuals < 5 years (n = 23; 12.6%) and ≥ 65 years (n = 45; 24.6%) compared with other age groups (p < 0.0001). Cough (odds ratio (OR): 2.4; 95% confidence interval (CI): 1.2-6.5) was the best RSV-infection predictor considering all age groups, while shortness of breath was particularly associated with RSV-positivity among ≤ 14 year olds (OR: 6.7; 95% CI: 2.6-17.4 for 0-4 year olds and OR: 6.7; 95% CI: 1.5-28.8 for 5-14 year olds). Systemic symptoms were significantly associated with RSV-negative and influenza-positive cases. None of the case definitions were suitable to detect RSV infections (AUC = 0.51).ConclusionTo avoid underestimating the RSV disease burden, RSV surveillance within the Portuguese sentinel ISS would require a more sensitive case definition than ILI and, even a different case definition according to age.
Enhanced Functional Response to CXCL12/SDF-1 through Retroviral Overexpression of CXCR4: Implications for Hematopoietic Stem &amp; Progenitor Cell Homing and Engraftment.
Authors: Kent W. Christopherson, Nehal K. Porecha, Giao Hangoc, Hal E. Broxmeyer
Journal: Blood (2004)
Recreation of t(7;12)(q36;p13) in Human Induced Pluripotent Stem Cells Using CRISPR/Cas9 Generates a Useful Model for Studying Acute Myeloid Leukemia
Authors: Tina Nilsson, Ahmed Waraky, Anders Östlund, Laleh Arabanian, Julia Asp, Linda Fogelstrand, Lars Palmqvist
Journal: Blood (2019)
NIMG-23. BRAIN TUMOR REPORTING AND DATA SYSTEM (BT-RADS) AND QUANTITATIVE TOOLS TO GUIDE ITS IMPLEMENTATION
Authors: Brent Weinberg, Karthik Ramesh, Saumya Gurbani, Eduard Schreibmann, Lawrence Kleinberg, Hui-Kuo Shu, Hyunsuk Shim
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma is the most aggressive primary adult brain tumor, with median survival of 15 months despite surgery and chemoradiation. MRI is used to guide treatment decisions, but imaging interpretation is challenging because of subtle findings with overlap between treatment effect and disease progression. The most frequently used quantitative brain tumor assessment metric is the Response Assessment in Neuro-Oncology (RANO), but this scoring system requires manual delineation 2-D metrics which can be subjective and is not directly tied to patient management decisions. The Brain Tumor Reporting and Data System (BT-RADS) is a novel, management-based reporting system developed by the Emory brain tumor team to improve quantitation and reduce bias in imaging assessment. BT-RADS scoring incorporates quantitative volumetric changes in contrast-enhanced T1-weighted (CE-T1w) and fluid attenuation inversion recovery (FLAIR) MRI, patient medications, clinical outcome, and treatment dates, and has been aligned closely with management decisions. To improve repeatability and reliability of scoring, we have begun to develop a cloud platform to help physicians utilizing BT-RADS. Longitudinal MRI data from each patient are automatically co-registered using rigid registration and aligned using trilinear interpolation, enabling voxel-to-voxel comparisons across multiple scans. The platform implements a semi-automated algorithm to segment tumor volumes using curvature flow, thresholding, and morphological filtering which expedites clinical review, as physicians simply edit and confirm segmentation accuracy rather than manual segmenting and measuring 2D images. Additionally, radiation dose maps can be overlaid on clinical images to determine what may be treatment effect and in-field vs. out-of-field recurrence. A secure web interface allows easy use by the entire treatment team, e.g. in a “tumor board” setting. Future plans include incorporating clinical and genomic data and fully automating tumor segmentation. The goal of this work is to provide more quantitative and objective follow-up metrics that can guide clinical decision making in glioblastoma patients.
Efficient Elimination of Acute Myeloid Leukemia Cells through Inhibition of KDM4A in Combination with PARP Inhibition
Authors: Laura Monaghan, Matthew Edward Massett, Roderick P Bunschoten, Petrisor Alin Pirvan, Alex Hoose, Taeju Park, Joana Bittencourt-Silvestre, Robert M J Liskamp, Heather G Jørgensen, Xu Huang
Journal: Blood (2019)
Estimating malaria burden among pregnant women using data from antenatal care centres in Tanzania: a population-based study
Authors: Chonge Kitojo, Julie R Gutman, Frank Chacky, Emmanuel Kigadye, Sigsbert Mkude, Renata Mandike, Ally Mohamed, Erik J Reaves, Patrick Walker, Deus S Ishengoma
Journal: The Lancet Global Health (2019)

More timely estimates of malaria prevalence are needed to inform optimal control strategies and measure progress. Since 2014, Tanzania has implemented nationwide malaria screening for all pregnant women within the antenatal care system. We aimed to compare malaria test results during antenatal care to two population-based prevalence surveys in Tanzanian children aged 6-59 months to examine their potential in measuring malaria trends and progress towards elimination.Malaria test results from pregnant women screened at their first antenatal care visits at health-care facilities (private and public) in all 184 districts of Tanzania between Jan 1, 2014, and Dec 31, 2017, were collected from the Health Management Information Systems and District Health Information System 2. We excluded facilities with no recorded antenatal care attendees during the time period. We standardised results to account for testing uptake and weighted them by the timing of two population-based surveys of childhood malaria prevalence done in 2015-16 (Demographic and Health Survey) and 2017 (Malaria Indicator Survey). We assessed regional-level correlation using Spearman's coefficient and assessed the consistency of monthly district-level prevalence ranking using Kendall's correlation coefficient.Correlation between malaria prevalence at antenatal care and among children younger than 5 years was high (r≥0·83 for both surveys), although declines in prevalence at antenatal care were generally smaller than among children. Consistent heterogeneity (p<0·05) in antenatal care prevalence at the district level was evident in all but one region (Kilimanjaro). Data from antenatal care showed declining prevalence in three regions (Arusha, Kilimanjaro, and Manyara) where surveys estimated zero prevalence.Routine antenatal care-based screening can be used to assess heterogeneity in transmission at finer resolution than population-based surveys, and provides sample sizes powered to detect changes, notably in areas of low transmission where surveys lack power. Declines in prevalence at antenatal care might lag behind those among children, highlighting the value of monitoring burden and continuing prevention efforts among pregnant women as transmission declines. The pregnancy-specific benefits and cost-effectiveness of antenatal care-based screening remain to be assessed.None.
Giant Vesical Calculus
Authors: Harry M. Burros, William H. Cooner, Carlos Pena
Journal: JAMA (1964)

A RECENTLY ENCOUNTERED case of giant vesical calculus is thought to be of sufficient interest and rarity to warrant its being reported. <h3>Report of a Case</h3> A 71-year-old white male was admitted to the hospital with a complaint of inability to urinate for the preceding six hours. Prior to onset of this episode of retention, there had been a gradual increase in diurnal frequency to about eight, with nocturia twice each night. One year before admission there had been a brief period of about four days during which time he had experienced urgency and marked increase in urinary frequency. This subsided spontaneously. He reported no subsequent urgency, diminution in stream caliber or force, hesitancy, hematuria, passage of urinary calculi, or recent febrile episodes. Review of the patient's history revealed no evidence of previous surgery or injuries. There had been no known parathyroid disease, arthritis, tuberculosis, diabetes, venereal disease, or urethral
Liver-Directed AAV Gene Therapy for Gaucher Disease
Authors: Carlos J Miranda, Miriam Canavese, Elisa Chisari, Jalpa Pandya, Clement Cocita, Maria Portillo, Jenny McIntosh, Azadeh Kia, Jonathan H. Foley, Allison Dane, Jey M Jeyakumar, Rose Sheridan, Romuald Corbau, Amit C. Nathwani
Journal: Blood (2019)
P1.11 Multicenter Study of Histological Types Incidence and Pathological Features of Malignant Pleural Mesothelioma (MPM) in AR
Authors: C. Poleri, G. Acosta Haab, N. Falcoff, G. Guman, L. Dalurzo, A. Iotti, M.E. Martín, G. Olmedo, M. Rayá, A. Reginatto, A. Werbach, G. Demellis, M.J. Labanca, L. Leguina, M.F. Mora
Journal: Journal of Thoracic Oncology (2019)
DDIS-20. IMIPRIDONE STRUCTURE ACTIVITY RELATIONSHIP UNCOVERS ONC206 AS THE NEXT BITOPIC DRD2 ANTAGONIST FOR ONCOLOGY WITH DIFFERENTIATED RECEPTOR PHARMACOLOGY
Authors: Varun Prabhu, Caroline Cuoco, Jinkyu Jung, Abed Rahman Kawakibi, Blair Willette, Marilyn Day, Lakshmi Anantharaman, Neil Charter, Joseph Rucker, Benjamin Doranz, Wolfgang Oster, Martin Stogniew, Mark Gilbert, R Benjamin Free, David Sibley, Joshua Allen
Journal: Neuro-Oncology (2019)

Abstract ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) in oncology clinical trials, which have shown that the small molecule is well tolerated and induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC201 possesses a unique tri-heterocyclic core structure that prompted a medicinal chemistry exploration following its successful clinical translation. Chemical derivatization of the ONC201 pharmacophore from an angular to a linear isomer ablated DRD2 antagonist activity and anti-cancer activity, indicating the core structure integrity is critical. A series of analogs that share the same core structure, called imipridones, were profiled for modulation of β-arrestin recruitment to GPCRs and anti-cancer efficacy. The profiled imipridones exhibited a heterogeneous spectrum of GPCR agonist/antagonist activity that was exclusive to Class A GPCRs. The addition of electron withdrawing groups to one of two peripheral benzyl rings enhanced the potency of GPCR engagement and anti-cancer effects, while derivatization of the other benzyl ring was inactivating. Among the GPCR hits identified, maximal variance in imipridone GPCR antagonism was identified for DRD2/DRD3. ONC206 emerged as the most selective and potent antagonist for DRD2/DRD3 with a Ki of ~320nM for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics but similar to ONC201. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites. Six residues were critical for ONC201 and ONC206, however the impact varied between the two compounds and one allosteric residue was exclusive to ONC206. Structural mapping revealed that some ONC206-critical allosteric residue interactions are located at the interface of TM-IV and –V that mediates the DRD2 homodimer interface. Thus, ONC206 is a bitopic DRD2 antagonist that may be poised to address oncogenic DRD2 monomers or dimers.
RTHP-26. DOSIMETRIC FEASIBILITY STUDY USING HIPPOCAMPAL AVOIDANCE WITH SIMULTANEOUS INTEGRATED BOOST WHOLE BRAIN RADIOTHERAPY (HA-SIB-WBRT)
Authors: Brendan Seng Hup Chia, Ashley Li Kuan Ong, Zubin Master
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Recently Hippocampal Avoidance (HA-) WBRT has become a recommended treatment option in patients with multiple (≥ 5) brain metastases and good prognosis. We wanted to investigate the dosimetric feasibility of dose painting technique combining HA-WBRT with a simultaneous integrated boost (SIB) to tumours. METHOD 5 patients who had a CT simulation fused with brain MRI with fine cuts, were selected for this study. Volumes were contoured on T1w contrast images. Whole brain prescription dose was 30Gy in 12 fractions. A PTV margin of 2mm was applied to lesions, except when these were ≤5mm from organs at risks (OARs). A simultaneous integrated boost (SIB) of 48Gy and 40.2Gy was prescribed to these volumes respectively. Hippocampal constraints followed RTOG 0933 protocol. For lesions ≤5mm from OARs, the acceptable D0.03cc≤42Gy was allowed. All plans were planned on EclipseTM v.13.6 TPS using 6MV photons, VMAT technique with 3 coplanar and 1 non-coplanar arcs for Varian TrueBeam machine. RESULTS Plans had between 6–24 lesions with GTV and PTV of 3.02–11.32cc and 7.05–31.74cc respectively. 3 of the plans had lesions within/adjacent to brainstem or hippocampus. The achieved PTV_40.2Gy D95% 37.42–39.05Gy with Conformity Index (CI)(95%) 0.63–1.06, PTV_48Gy D95% 44.64–47.04Gy with CI(95%) 0.75–0.97 and GTV_48Gy D95% 47.44–50.16Gy. Whole brain Dmean 31.87–33.15Gy with a Homogeneity Index (D2%-D98%/Dmean) 0.18–0.58. Hippocampal D100% 8.69–10.1Gy, D0.03cc 16.5–40.43Gy and Dmean 12.66–24.68Gy. SUMMARY: There was a steep learning curve when adopting this technique and multiple plan iterations were made to achieve target constraints. To meet acceptable OAR constraints, SIB coverage was compromised. Lesions ≤5mm from hippocampus resulted in higher Hippocampal average Dmean 22.8Gy vs. 12.8Gy. The significance of this value should be tested in clinical trials. Overall, HA-SIB-WBRT seems feasible even with ≥ 5 brain metastases and could result in better brain metastases control then HA-WBRT alone.
Differential Contributions of Pre- and Post-EMT Tumor Cells in Breast Cancer Metastasis
Authors: Ana Rita Lourenco, Yi Ban, Michael J. Crowley, Sharrell B. Lee, Divya Ramchandani, Wei Du, Olivier Elemento, Jason T. George, Mohit Kumar Jolly, Herbert Levine, Jianting Sheng, Stephen T. Wong, Nasser K. Altorki, Dingcheng Gao
Journal: Cancer Research (2019)

Metastases are responsible for the majority of breast cancer-associated deaths. The contribution of epithelial-to-mesenchymal transition (EMT) in the establishment of metastases is still controversial. To obtain in vivo evidence of EMT in metastasis, we established an EMT lineage tracing (Tri-PyMT) model, in which tumor cells undergoing EMT would irreversibly switch their fluorescent marker from RFP+ to GFP+ due to mesenchymal-specific Cre expression. Surprisingly, we found that lung metastases were predominantly derived from the epithelial compartment of breast tumors. However, concerns were raised on the fidelity and sensitivity of RFP-to-GFP switch of this model in reporting EMT of metastatic tumor cells. Here, we evaluated Tri-PyMT cells at the single-cell level using single-cell RNA-sequencing and found that the Tri-PyMT cells exhibited a spectrum of EMT phenotypes, with EMT-related genes concomitantly expressed with the activation of GFP. The fluorescent color switch in these cells precisely marked an unequivocal change in EMT status, defining the pre-EMT and post-EMT compartments within the tumor. Consistently, the pre-EMT cells played dominant roles in metastasis, while the post-EMT cells were supportive in promoting tumor invasion and angiogenesis. Importantly, the post-EMT (GFP+) cells in the Tri-PyMT model were not permanently committed to the mesenchymal phenotype; they were still capable of reverting to the epithelial phenotype and giving rise to secondary tumors, suggesting their persistent EMT plasticity. Our study addressed major concerns with the Tri-PyMT EMT lineage tracing model, which provides us with a powerful tool to investigate the dynamic EMT process in tumor biology. SIGNIFICANCE: These findings confirm the fidelity and sensitivity of the EMT lineage tracing (Tri-PyMT) model and highlight the differential contributions of pre- and post-EMT tumor cells in breast cancer metastasis.See related commentary by Bunz, p. 153.
The Location of CD4+FoxP3+ Cells with Regard to CD25 and TNFRSF25 Receptor Signals Matters: Different Requirements for GI and Peripheral Tregs
Authors: Casey O. Lightbourn, Clarisel Lozano, Cameron S. Bader, Sabrina N. Copsel, Dietlinde Wolf, Henry Barreras, Robert B. Levy
Journal: Blood (2019)
Optimization of Tacrolimus Serum Levels When Combined with Post-Transplant Cyclophosphamide As Graft-Versus-Host Disease Prophylaxis after Hematopoietic Cell Transplantation: Outcome Data Analysis
Authors: Janny M. Yao, Dongyun Yang, Saloomeh Mokhtari, Amandeep Salhotra, Haris Ali, Shukaib Arslan, Salman Otoukesh, Ibrahim Aldoss, Karamjeet S. Sandhu, Anthony Stein, David Snyder, Vinod A. Pullarkat, Guido Marcucci, Stephen J Forman, Ryotaro Nakamura, Monzr M. Al Malki
Journal: Blood (2019)
PDTM-14. INTERACTIONS BETWEEN IMMUNE MICROENVIRONMENT, STEM CELLS, AND CELL PROLIFERATION IN PEDIATRIC EMBRYONAL CENTRAL NERVOUS SYSTEM [CNS] TUMORS
Authors: Kristian Schafernak, Emma Utagawa, Shwetal Mehta, Tiffany Di Modica, Elliott Mufson, Sylvia Perez
Journal: Neuro-Oncology (2019)

Abstract Mounting evidence suggests the brain’s own immune cells, microglia, and perivascular macrophages play important roles in immune surveillance/inflammation, but also support proliferation/growth of gliomas, possibly through interactions with tumor stem cells. Immune cells are increasingly regarded as potential targets for cancer therapy, however, the immune microenvironment has not been well-studied in pediatric embryonal CNS tumors. In a series of 13 medulloblastomas, 7 PNETs and 6 ATRTs, we quantified the number of cells immunopositive for macrophage/microglia Ionizing calcium binding adaptor molecule 1 [Iba1], CD68 (expressed on both “M1” antitumor/proinflammatory macrophages and “M2” protumor/anti-inflammatory macrophages), CD163 (“M2” macrophages), CD3 (T-cell marker), CD4 (helper T cell), CD8 (cytotoxic T cell) and CD20 (B-cell marker) and correlated these findings with the stem-cell marker nestin and the Ki67/MIB1 proliferation index. Significant results were as follows: Across groups, CD68 showed a strong Spearman rank-order correlation with both CD163 (r=0.610, p=0.0007) and nestin (r=0.577, p=0.0017), while CD3 correlated strongly with CD8 (r=0.601, p=0.004), CD4 (r=0.526, p=0.005) and CD20 (r=0.499, p=0.008). Between groups, the number of CD163-positive cells was significantly higher in PNETs compared to medulloblastomas (p=0.035). Within the medulloblastoma group, CD68 showed a significant relationship with nestin (r=0.595, p=0.0387) and Ki67 (r=0.606, p=0.0333), and there was a robust correlation between CD4 and CD8 values (r=0.846, p=0.0000002). Within PNETs, there was a strong negative correlation between CD163 and nestin (r=-0.883, p=0.0000002), while CD68 correlated with CD4 (r=0.803, p=0.006). Within ATRTs, nestin and Ki67 were strongly correlated (r=1.000, p=0.0028) as were CD68 and CD163 (r=0.943, p=0.017). These data suggest a role for blocking embryonal CNS tumor-associated macrophages by inhibiting the CSF1R pathway (perhaps in conjunction with CD8-positive T cells which could antagonize the immunosuppressive function of tumor-associated macrophages) or reprogramming them from an M2 to an M1 phenotype (particularly in PNETs, which had the highest number of CD163-positive cells).
Optimizing the Design of Latent Tuberculosis Treatment Trials: Insights from Mathematical Modeling
Authors: Jason E. Stout, Nicholas A. Turner, Robert W. Belknap, C. Robert Horsburgh, Timothy R. Sterling, Patrick P. J. Phillips
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Noninferiority trials of treatment for latent tuberculosis infection (LTBI) are challenging because of imperfect LTBI diagnostic tests.
Clinical Activity of CC-90009, a Cereblon E3 Ligase Modulator and First-in-Class GSPT1 Degrader, As a Single Agent in Patients with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML): First Results from a Phase I Dose-Finding Study
Authors: Geoffrey L. Uy, Mark D. Minden, Pau Montesinos, Daniel J. DeAngelo, Jessica K. Altman, Jamie Koprivnikar, Paresh Vyas, Yngvar Fløisand, María Belén Vidriales, Bjørn Tore Gjertsen, Jordi Esteve, Tonia J. Buchholz, Suzana Couto, Jinhong Fan, Bishoy Hanna, Li Li, Daniel W. Pierce, Kristen Hege, Michael Pourdehnad, Amer M. Zeidan
Journal: Blood (2019)
Carfilzomib-Revlimid-Dexamethasone Vs. Carfilzomib-Thalidomide-Dexamethasone Weekly (After 2 Twice Weekly Cycles) Followed By Carfilzomib Maintenance Vs. Control in Transplant Non-Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) - Interim Efficacy Analysis of Combined Data (AGMT MM-02)
Authors: Heinz Ludwig, Siegfried Sormann, Niklas Zojer, Johannes Andel, Bernd L. Hartmann, Christoph Tinchon, Eberhard Gunsilius, Klaus Podar, Alexander Egle, Wolfgang Willenbacher, Ewald Wöll, Reinhard Ruckser, Boris Bozic, Maria-Theresa Krauth, Andreas Petzer, Clemens A. Schmitt, Sigrid Machherndl-Spandl, Hermine Agis, Bruno Paiva, Richard Greil
Journal: Blood (2019)