tbuckley/cabot-search huggingface dataset:
TMOD-08. DEVELOPING DERIVATIVE GBM PDX, IN VIVO, FROM TREATMENT NAÏVE SOURCES
Authors: David James, Craig Horbinski, Roger Stupp, Atique Ahmed
Journal: Neuro-Oncology (2021)

Abstract PURPOSE Post-therapy recurrent glioblastoma (GBM) patient-derived xenografts (PDX), developed from corresponding treatment-naïve PDX, could serve as useful resources for identifying therapeutics with activity against recurrent GBM. The goal of this study was to determine whether treatment-naïve intracranial GBM PDX, in mice receiving radiotherapy (RT) and/or temozolomide (TMZ), acquire the same mutations that occur in post-RT+TMZ GBMs from patients. METHODS Luciferase-modified, treatment-naïve GBM PDX were engrafted in the brains of athymic nude mice, followed by treatment with RT only (2 Gy/day x 5), TMZ only (10 mg/kg/day x 5), or RT+TMZ. Bioluminescence imaging was used to monitor intracranial tumor growth, response to treatment, and recurrence from treatment. Some mice with recurrent tumors received additional TMZ treatment. When mice became symptomatic, intracranial tumors were resected and engrafted subcutaneously in a new mouse host, then sequentially propagated subcutaneously into additional host mice. After the third passage, whole-exome sequencing (WES) was done, comparing post-therapy with treatment-naïve PDX sequence variants. RESULTS Analysis of PDX WES showed the following: 1) TMZ consistently caused more genes to incur coding sequence mutations than RT, as much as 13x more; 2) TMZ-treated tumor mutations were mostly G-C to A-T transitions (71-92%), consistent with the known mutagenic effect of TMZ; and 3) post-therapy PDX acquire similar mutations as do recurrent GBMs in patients, for example involving DNA mismatch repair gene MSH6. One of the derivative PDX with MSH6 mutation has been retested for response to RT and TMZ, with results showing its having become TMZ, but not RT resistant. CONCLUSIONS The mutation profiles of RT+TMZ-treated PDX are similar to those reported for GBMs that recur after RT+TMZ in patients. The new PDX resources described here may prove useful for identifying effective treatments against recurrent GBM.
Prescriptions for Codeine or Hydrocodone Cough and Cold Medications to US Children and Adolescents Following US Food and Drug Administration Safety Communications
Authors: Kao-Ping Chua, Rena M. Conti
Journal: JAMA Network Open (2021)

This cross-sectional study uses national prescription data to assess whether safety communications from the US Food and Drug Administration (FDA) issued in 2017 and 2018 were associated with changes in prescriptions for codeine and hydrocodone cough and cold medications to children and adolescents.
Abstract 12673: An Unsupervised Machine-Learning-Based Approach Elucidates the Prognostic Value of Symptom Clusters in Heart Failure Patients Evaluated in the Emergency Department
Authors: Karina Kraevsky-phillips, Zeineb Bouzid, Abdullah Ahmad, Ziad Faramand, Salah S Al-Zaiti
Journal: Circulation (2021)

Introduction: Heart failure (HF) patients experience symptoms in clusters and growing evidence suggests that these clusters are predictive of future events. We sought to study the prognostic value of symptom clusters in HF patients seeking emergency care. Methods: This was a secondary analysis of a prospective observational cohort study of consecutive patients seen for chest pain (CP) or equivalent symptoms in the emergency department (ED) of three UPMC-affiliated tertiary care hospitals. Analysis included only patients with known HF. An independent reviewer extracted key data elements from electronic health records, including 12 subjective symptoms reported by patients at time of initial evaluation. Primary outcome was 30-day major adverse cardiac events (MACE) adjudicated by two independent reviewers (NCT04237688, clinicaltrials.gov). Secondary outcome was HF exacerbation. L2 norm and sign function were applied to the data matrix to standardize and normalize data. Principal component analysis (PCA) was used to reduce symptom dimensionality and resulting eigenvalues were fed into a k-means clustering algorithm to derive group centers. Association between cluster membership and outcome data was assessed using logistic regression. Analyses were completed using Python 3.8. Results: The sample included 438 patients (age 66 ± 14; 45% females, 49% Black, 18% HF exacerbation, 32% MACE). PCA identified seven main components that were mapped by k-means to two patient clusters: cluster A (n=204, 47%) and cluster B (n=234, 53%). Compared to cluster A, cluster B exclusively included patients with dyspnea (100% vs 0%), more patients with cough/flu-like symptoms (15% vs 4%), and diaphoresis (14% vs 9%). Those patients were significantly more likely to be Black (53% vs 43%), diabetic (53% vs 42%), and have COPD (44% vs 30%). They were also triaged at higher risk with HEART score &gt;4 (64% vs 56%), translating into longer median length of stay (2.3 vs. 1.6 days). Patients in cluster B were more likely to have HF exacerbation (OR = 1.8, 95% CI 1.1-3.0) and to experience 30-day MACE (OR = 1.8, 95% CI 1.2-2.7). Conclusion: Clusters indicate HF patients seen in the ED for CP who report dyspnea should be triaged as high risk and evaluated for more aggressive care and closer follow up.
Covid-19: Release of JCVI minutes prompts more questions over committee’s decisions
Authors: Elisabeth Mahase
Journal: BMJ (2021)

The release of long delayed minutes from meetings of the UK government’s vaccine advisory committee has raised more questions about its decision not to vaccinate all children aged 12 to 17 against SARS-CoV-2.

A raft of documents covering meetings in May, June, and July this year outline the Joint Committee on Vaccination and Immunisation’s discussions of childhood vaccination and long covid in children. They show that in June the JCVI looked at modelling by the University of Warwick showing that if there were 80% covid vaccination coverage of 12-17 year olds there would be a “reduction in hospitalisations in all ages, with a substantial reduction in hospitalisations” and infections among 12 to 17 year olds after vaccination. The number of hospital admissions that could be avoided could reach 20 000, depending on public behaviour, the modelling showed.

Vaccinating children could also have benefits on children’s mental health, it showed, especially in terms of “anxiety of getting covid-19 or …
Relapsed/Refractory Multiple Myeloma Patients. a Multicenter Retrospective Analysis of Eligibility Criteria for CAR-T Cell Therapy
Authors: Francesca Fazio, Alice Di Rocco, Tommaso Za, Valeria Tomarchio, Angela Rago, Alfonso Piciocchi, Tommaso Caravita di Toritto, Ombretta Annibali, Valerio De Stefano, Robin Foa, Maurizio Martelli, Maria Teresa Petrucci
Journal: Blood (2021)
Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic
Authors: Meral Beksac, Tulin Tuglular, Ali Unal, Michele Cavo, Francesca Gay, Eirini Katodritou, Guner Hayri Ozsan, Guldane Cengiz, Omur Gokmen Sevindik, Serena Merante, Kyriaki Manousou, Pieter Sonneveld, Evangelos Terpos
Journal: Blood (2021)
The Prognostic Value of Early Measurable Residual Disease Assessment in Patients with Acute Myeloid Leukemia Treated with Intensive Chemotherapy - Preliminary Results of Polish Adult Leukemia Group PALG-AML1/2016 Study
Authors: Agnieszka Wierzbowska, Agnieszka Pluta, Anna Czyz, Marta Antonina Libura, Sebastian Giebel, Magdalena Czemerska, Piotr Stelmach, Michal Soin, Anna Kopinska, Krzysztof Wozniczka, Grzegorz Helbig, Marta Sobas, Tomasz Wróbel, Andrzej Szczepaniak, Lidia Gil, Karol Wojcik, Malgorzata Razny, Magdalena Dutka, Maria Bieniaszewska, Janusz Halka, Tomasz Gromek, Marek Hus, Elzbieta Patkowska, Jolanta Wozniak, Edyta Cichocka, Agata Obara, Agnieszka Kopacz, Katarzyna Dulik, Jerzy Holowiecki, Damian Mikulski, Ewelina Perdas, Wojciech Fendler, Nicole M. Cruz, Nuria Mencia-Trinchant, Pinkal Desai, Sangmin Lee, Michael B. Samuel, Justin D. Kaner, Ellen Ritchie, Monica L. Guzman, Gail J. Roboz
Journal: Blood (2021)
Pooled Analysis of First-Line Treatment with Targeted Agents in Patients with Chronic Lymphocytic Leukemia (CLL) Aged 80 Years and Older
Authors: Florian Simon, Adam Giza, Sandra Robrecht, Anna-Maria Fink, Paula Cramer, Julia Von Tresckow, Moritz Fürstenau, Valentin Goede, Eugen Tausch, Christof Schneider, Stephan Stilgenbauer, Clemens-Martin Wendtner, Barbara Eichhorst, Kirsten Fischer, Michael Hallek, Othman Al-Sawaf
Journal: Blood (2021)
Assessing therapy response in patient-derived xenografts
Authors: Janosch Ortmann, Ladislav Rampášek, Elijah Tai, Arvind Singh Mer, Ruoshi Shi, Erin L. Stewart, Celine Mascaux, Aline Fares, Nhu-An Pham, Gangesh Beri, Christopher Eeles, Denis Tkachuk, Chantal Ho, Shingo Sakashita, Jessica Weiss, Xiaoqian Jiang, Geoffrey Liu, David W. Cescon, Catherine A. O’Brien, Sheng Guo, Ming-Sound Tsao, Benjamin Haibe-Kains, Anna Goldenberg
Journal: Science Translational Medicine (2021)

We propose a measure for robust quantification of in vivo drug response that accounts for variation across both treatment and control replicates.
80 Cancer testis antigen burden: A novel predictive biomarker for immunotherapy in solid tumors
Authors: Sarabjot Pabla, RJ Seager, Yong Hee Lee, Erik Van Roey, Shuang Gao, Vincent Giamo, Blake Burgher, Paul DePietro, Mary Nesline, Sean Glenn, Shengle Zhang, Jeffrey Conroy
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background When expressed in cancer cells, cancer testis antigens (CTAs) are highly immunogenic and have the capacity to elicit cancer-specific immune responses in diverse malignancies. With their expression limited to tumor cells, CTAs have become a prime target of natural T cell response, immune cell-based therapy, and cancer vaccines. In this study, we investigated CTA burden in real-world clinical tumors spanning multiple histologies, revealing a novel prognostic gene expression-based biomarker. Methods Targeted RNA-seq was performed on 5450 FFPE tumors representing 39 histologic types, predominantly composed of lung cancer (40.4%) followed by colorectal cancer (10.6%) and breast cancer (8.6%). Using an amplicon-based NGS approach, expression levels of 17 CTA genes were ranked against a reference population. Cancer Testis Antigen Burden (CTAB) was calculated as the sum of the gene expression rank for each CTA gene. The median CTAB of ≥171 was used as cutoff for CTAB High versus Low classification. We estimated Pearson’s correlation for all CTA genes to discover co-expression patterns between CTAs and histologies. Overall survival (OS) analysis was performed using CoxPh regression model whereas response analysis was performed using logistic regression model with p-values reported. Results Within the tumor samples, CTAB values ranged from 0–1700, with kidney cancer demonstrating overall lowest mean CTAB (110) and melanoma the highest (550). NSCLC had an average CTAB of 283. In an immune checkpoint blockade treated retrospective cohort of 110 NSCLC patients, High CTAB showed better OS compared to Low CTA (HR: 0.55, p=0.07). Additionally, when combined with tumor inflammation and cell proliferation biomarkers, highly inflamed but poorly proliferative tumors with High CTAB had improved OS (HR: 0.27, p=0.05). No significant association with response was detected Conclusions Our studies show that co-expression of multiple CTA genes occurs in many tumor types and can be reliably detected using a targeted RNA-seq approach. Utilization of this co-expression pattern to calculate CTAB reveals tumor-type associated signatures, which in a small NSCLC cohort is associated with the overall survival. The findings suggest that these immunogenic antigens expose the tumor cells to natural or immunotherapy augmented cell-based immune response, and that CTAB is a potential predictive marker for therapeutic response to checkpoint inhibitors. Further studies are needed to establish the predictive value in other tumor types, as well as the role of CTAB in immune cell therapies and vaccinations.
Immune and Epigenetic Landscape of <i>TP53-</i>mutated Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes (HR-MDS)
Authors: Amer M. Zeidan, Jan Philipp Philipp Bewersdorf, Vanessa Hasle, Ethan G. Thompson, Daniel Lopes de Menezes, Shelonitda Rose, Isaac Boss, Brian Fox
Journal: Blood (2021)
Circadian Blood Pressure Variability in Hypertensive Patients with Coronary Heart Disease.
Authors: Jorge Luis León Alvarez, Michel Curbelo López, Tania Hidalgo Costa, Miguel Ángel Yanes Quesada, Raúl Orlando Calderín Bouza, Andrew Sefenu Yao Dzebu
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Introduction and objectives: Coronary heart disease is one of the complications of hypertension. Ambulatory blood pressure monitoring allows studying the different circadian patterns of blood pressure, but there is not enough evidence linking coronary heart disease with different circadian patterns. This research was carried out with the purpose of characterizing the circadian patterns of blood pressure in patients with essential hypertension and coronary heart disease. Methods: Descriptive and transversal research in 68 hypertensive patients with coronary heart disease who underwent ambulatory blood pressure monitoring. The different circadian patterns of blood pressure were related to the different forms of coronary heart disease and to the control of blood pressure. Results: In the sample, women (60.3%) predominated over men (39.7%). The ages were between 45 to 59 (63.3%) and those 60 and over (36.7%). 44.1% did not have their blood pressure under control, 45.6% were overweight and 38.2% were obese. The abnormal patterns were dipper 42.6%, non-dipper 41.2%, extreme dipper 7.4% and riser 8.8%. Morning surge was observed in 29 patients (42.6%), statistically significant in relation to the control of blood pressure (p = 0.033), but not with the different types of coronary heart disease studied. Conclusions: A statistically significant relationship was found between morning surge and control of blood pressure.
Mutational Landscape of MDS Patients with HMA Failure Revealed By the Correlative Analysis from Inspire Trial
Authors: Koichi Takahashi, Anna Jonasova, Selina M. Luger, Aref Al-Kali, David Valcarcel, Erica D. Warlick, Maria Diez-Campelo, Michael K Keng, Feng Wang, Ken Furudate, Patrick S. Zbyszewski, Matthew Parris, Steven M. Fruchtman, Guillermo Garcia-Manero
Journal: Blood (2021)
Targeting Polo-like Kinase 4 Triggers Polyploidy and Apoptotic Cell Death in TP53-Mutant Acute Myeloid Leukemia
Authors: Edward Ayoub, Rafael Heinz Montoya, Vakul Mohanty, Wencke Walter, Tallie Patsilevas, Ghayas C. Issa, Gautam Borthakur, Ken Chen, Marina Konopleva, Nicholas Navin, Torsten Haferlach, Michael Andreeff
Journal: Blood (2021)
Phosphoproteomic Analysis of Primary Myeloma Patient Samples Identifies Distinct Phosphorylation Signatures Correlating with Chemo-Sensitivity Profiles in an Ex Vivo Drug Sensitivity Testing Platform
Authors: Katie Dunphy, Paul Dowling, Juho J. Miettinen, Caroline A. Heckman, Paula Meleady, Michael Henry, Despina Bazou, Peter O'Gorman
Journal: Blood (2021)
A Molecular Classifier Increased the Accuracy of Lymphoma Diagnosis By Expert Pathologists in the Diffuse Large B-Cell Lymphoma Gained Trial from the Lysa
Authors: Amine Moslemi, Victor Bobée, Paul Blanc-Durand, Fanny Drieux, Fabienne Desmots-Loyer, Josette Briere, Olivier Casasnovas, Danielle Canioni, Herve Ghesquieres, Philippe Gaulard, Lucie Oberic, Diane Damotte, Franck Morschhauser, Antoine Martin, Hervé Tilly, Catherine Thieblemont, Vincent Ribrag, Olivier Hermine, Corinne Haioun, Thierry Lamy, Thierry Fest, Fabrice Jardin, Steven Le Gouill, Emmanuel Itti, Philippe Ruminy, Thierry Jo Molina
Journal: Blood (2021)
Post-Transplant Inotuzumab Ozogamicin for Acute Lymphoblastic Leukemia
Authors: Leland Metheny, Ronald M. Sobecks, Christina Cho, Paolo F. Caimi, Navneet S. Majhail, Folashade Otegbeye, Kirsten M Boughan, Brenda W. Cooper, Erin Galloway, Molly Gallogly, Ehsan Malek, Benjamin Tomlinson, Aaron T. Gerds, Betty K. Hamilton, Matt Kalaycio, Sergio A Giralt, Marcos J.G. de Lima
Journal: Blood (2021)
Management of Steroid-Refractory Graft-Versus-Host Disease - a Survey By the Transplant Complications Working Party of the EBMT
Authors: Zinaida Peric, Helene Schoemans, Christophe Peczynski, Christian Koenecke, Ivan S. Moiseev, Grzegorz W Basak, William Boreland, Hildegard T. Greinix, Daniel Wolff, Olaf Penack
Journal: Blood (2021)
Emicizumab Prophylaxis in Persons with Hemophilia A, Aged ≥50 Years, with Comorbidities - Pooled Data from Four Phase III Studies (HAVEN 1, 3, and 4, and STASEY)
Authors: Víctor Jiménez-Yuste, Johannes Oldenburg, Eunice Tzeng, Ben Trzaskoma, Fabian Sanabria, Johnny Mahlangu
Journal: Blood (2021)
CanDIG: Federated network across Canada for multi-omic and health data discovery and analysis
Authors: L. Jonathan Dursi, Zoltan Bozoky, Richard de Borja, Haoyuan Li, David Bujold, Adam Lipski, Shaikh Farhan Rashid, Amanjeev Sethi, Neelam Memon, Dashaylan Naidoo, Felipe Coral-Sasso, Matthew Wong, P-O Quirion, Zhibin Lu, Samarth Agarwal, Yuriy Pavlov, Andrew Ponomarev, Mia Husic, Krista Pace, Samantha Palmer, Stephanie A. Grover, Sevan Hakgor, Lillian L. Siu, David Malkin, Carl Virtanen, Trevor J. Pugh, Pierre-Étienne Jacques, Yann Joly, Steven J.M. Jones, Guillaume Bourque, Michael Brudno
Journal: Cell Genomics (2021)

We present the Canadian Distributed Infrastructure for Genomics (CanDIG) platform, which enables federated querying and analysis of human genomics and linked biomedical data. CanDIG leverages the standards and frameworks of the Global Alliance for Genomics and Health (GA4GH) and currently hosts data for five pan-Canadian projects. We describe CanDIG's key design decisions and features as a guide for other federated data systems.
Crizanlizumab Therapy Is Associated with Lower Levels of Circulating Extracellular Vesicles in Sickle Cell Disease Patients
Authors: Cristiane Maria de Souza, Carolina Lanaro, Irene Pereira dos Santos, Oladele Olatunya, Sara T Olalla Saad, Bruno Deltreggia Benites, Paula De Melo Campos, Kleber Yotsumoto Fertrin, Fernando Ferreira Costa
Journal: Blood (2021)
Definition and Clinical Significance of the MGUS-like Phenotype: A Study in 5,114 Patients (Pts) with Monoclonal Gammopathies
Authors: Leire Burgos, Luis Esteban Tamariz-Amador, Noemí Puig, María Teresa Cedena, Tomas Jelinek, Sarah K Johnson, Paolo Milani, Lourdes Cordon, José J Pérez, Marta Lasa, Rosalinda Termini, Albert Oriol, Miguel-Teodoro Hernández, Luis Palomera, Rafael Martinez Martinez, Javier de la Rubia, Felipe De Arriba, Rafael Rios, Maria Esther González, Mercedes Gironella, Valentin Cabañas, Maria Casanova, Isabel Krsnik, Albert Pérez, Veronica Gonzalez De La Calle, Paula Rodríguez-Otero, Vladimir Maisnar, Roman Hajek, Frits van Rhee, Victor H Jimenez-Zepeda, Giovanni Palladini, Paolo Milani, Alberto Orfao, Laura Rosinol, Joan Bladé Creixenti, Joaquín Martínez-López, Juan-José Lahuerta, Maria-Victoria Mateos, Jesús F. San-Miguel, Bruno Paiva
Journal: Blood (2021)
Abstract 8872: Comparative Effectiveness of Dosing of Medical Therapy for Heart Failure: From the CHAMP-HF Registry
Authors: Stephen J Greene, Javed Butler, Anne Hellkamp, John Spertus, Muthiah Vaduganathan, Adam D Devore, Nancy M Albert, J Herbert Patterson, Laine E Thomas, Fredonia Williams, Adrian F Hernandez, Gregg C Fonarow
Journal: Circulation (2021)

Introduction: The comparative effectiveness of differing doses of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) on clinical and patient-reported outcomes in US clinical practice is unknown. Methods: This analysis included 4,832 US outpatients with chronic HFrEF in the CHAMP-HF registry with available medication data and no contraindications at baseline. Baseline dosing of ACE inhibitor (ACEI)/ angiotensin II receptor blocker (ARB)/ angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) therapies were examined. Multivariable models assessed associations between medication dosing and clinical outcomes over 24 months (all-cause mortality, HF hospitalization) and patient-reported outcomes at 12 months (change in Kansas City Cardiomyopathy Questionnaire Overall Summary Score [KCCQ-OS]). Results: After adjustment, compared with target dosing, lower dosing was independently associated with higher all-cause mortality for ACEI/ARB/ARNI (overall p&lt;0.001) and beta-blocker therapies (overall p=0.042) (Table) . Lower dosing of ACEI/ARB/ARNI was independently associated with higher risk of HF hospitalization (overall p=0.046), but beta-blocker dosing was not. Target dosing of MRA was not associated with risk of mortality or HF hospitalization. For each GDMT, compared with target dosing, lower dosing was not associated with change in KCCQ-OS at 12 months, with potential exception of worsening KCCQ-OS with lower dosing of ACEI/ARB/ARNI. Conclusions: In this contemporary US outpatient HFrEF registry, target dosing of ACEI/ARB/ARNI and beta-blocker was associated with reduced mortality, and variably associated with other outcomes. MRA dosing was not associated with outcomes. Unmeasured differences between patients receiving differing dosages may explain differences between results seen here compared with randomized trials.
Subcutaneous Epcoritamab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Preliminary Results from the Epcore CLL-1 Trial
Authors: Arnon P. Kater, Jacob Haaber Christensen, Hans Herluf Bentzen, Carsten Utoft Niemann, Martin Hutchings, Jenny Chen, Marcia Rios, Tammy Palenski, Tommy Li, Anthony R. Mato
Journal: Blood (2021)
Outcomes after Reinfusion of CD19-Specific Chimeric Antigen Receptor (CAR)-Modified T Cells in Children and Young Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia
Authors: Regina M. Myers, Kaitlin Devine, Yimei Li, Sophie Lawrence, Allison Barz Leahy, Hongyan Liu, Lauren Vernau, Colleen Callahan, Diane Baniewicz, Stephan Kadauke, Regina McGuire, Margaret A Cameron, Amanda M. DiNofia, Susan R. Rheingold, Richard Aplenc, Carl H June, Stephan A. Grupp, Lisa Wray, Shannon L. Maude
Journal: Blood (2021)