tbuckley/cabot-search huggingface dataset:
Discovery of extracellular vesicles derived miR-181a-5p in patient's serum as an indicator for bone-metastatic prostate cancer
Authors: Yanqing Wang, Yu-Xiang Fang, Baijun Dong, Xinxing Du, Jialin Wang, Xiao Wang, Wei-Qiang Gao, Wei Xue
Journal: Theranostics (2020)

Purpose: To identify extracellular vesicle (EV)-delivered microRNAs in the patient's serum as indicators for bone-metastatic prostate cancer. Methods: First, the profiling change of serum EV-delivered miRNAs in patients with either benign prostatic hyperplasia (BPH), non-bone metastatic prostate cancer or bone-metastatic prostate cancer was detected by microRNA deep sequencing assay and microRNA-chip array assay, respectively. Second, the candidates were further confirmed using TaqMan microRNA assay in two independent validation cohorts of total 176 patients with either BPH, non-bone metastatic prostate cancer or bone metastatic prostate cancer to seek the most valuable microRNA(s). Results: Through microRNA deep sequencing and microRNA-chip array, we found 4 prospective EV-delivered miRNAs including miR-181a-5p with significantly upregulated expression in bone metastatic groups than in non-bone metastatic prostate cancer groups (p < 0.05). In the validation cohorts, logistic regression analysis was performed to evaluate the diagnostic association of candidates with bone metastasis, which indicated that miR-181a-5p was significantly associated with bone metastatic prostate cancer. Furthermore, accuracy estimate of each candidate for the diagnosis of bone metastatic prostate cancer was quantified using the area under the receiver-operating characteristic curve (AUC), which identified miR-181a-5p as the best biomarker with the AUCs of 85.6% for diagnosis of prostate cancer and 73.8% for diagnosis of bone metastatic prostate cancer. Conclusion: EV-delivered miR-181a-5p from patient's serum is a promising diagnostic biomarker for bone metastatic prostate cancer.
Extensive Changes of the Immune Microenvironment Are Associated with Progression from Precursor Stages to Multiple Myeloma
Authors: Elisabet E. Manasanch, Guangchun Han, Zheng Zhang, Minghao Dang, Manisha Singh, Maliha Khan, Shubhra Singh, Hans C. Lee, Krina K. Patel, Gregory P. Kaufman, Behrang Amini, Qaiser Bashir, Samer A. Srour, Yago Nieto, Muzaffar H. Qazilbash, Zuzana Berkova, Pei Lin, Donald Berry, Sheeba K. Thomas, Donna M. Weber, P. Andrew Futreal, Linghua Wang, Robert Z. Orlowski, Sattva S. Neelapu
Journal: Blood (2020)
Abstract 276: NOTCH1 is Essential for Ventricular Cardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells
Authors: Mingtao Zhao, Shiqiao Ye, Joe Zhang, Ningyi Shao, Chun Liu, Yang Zhou, Masataka Nishiga, Yang Yang, Bianxiao Cui, Vidu Garg, Joseph C Wu
Journal: Circulation Research (2020)

Pathogenic variants in NOTCH1 have been implicated in multiple types of congenital heart defects, such as bicuspid aortic valve, Tetralogy of Fallot, and hypoplastic left heart syndrome (HLHS). However, the mechanisms by which NOTCH1 pathogenic variants cause abnormalities in human embryonic heart development are largely unknown. Here, we used CRISPR/Cas9-mediated genome editing to genetically delete NOTCH1 in human induced pluripotent stem cells (iPSCs). We found that NOTCH1 was dispensable for mesodermal and vascular endothelial differentiation of human iPSCs. Disruption of NOTCH activity promoted venous-specific gene expression but suppressed arterial-specific gene expression in iPSC-derived endothelial cells (iPSC-ECs). Intriguingly, NOTCH1 deletion significantly impaired the cardiac differentiation efficiency. In NOTCH1 homozygous knockout ( NOTCH1 -/- ) iPSC-derived cardiomyocytes (iPSC-CMs), atrial-specific genes ( NR2F2, KCNJ3 , and MYL7 ) were upregulated whereas ventricular-specific genes ( MYL2, IRX4 , and MYH7 ) were downregulated. Electrophysiological analysis by patch clamp and optical mapping indicated that atrial-like cardiomyocytes were dominant whereas the percentage of ventricular-like iPSC-CMs was dramatically reduced (&lt;1%) in NOTCH1 -/- iPSC-CMs. In addition, mitochondrial respiration was reduced in NOTCH1 deficient iPSC-CMs compared to wild-type controls, which was likely attributed to the reduction of ventricular cardiomyocytes in NOTCH1 -/- iPSC-CMs. As NOTCH1 is primarily expressed in endothelial cells rather than cardiomyocytes, we conclude that NOTCH1 affects ventricular cardiomyocyte lineage commitment possibly through controlling cell fate determination of cardiac progenitors during human iPSC differentiation. Our study may provide novel insights into the mechanisms by which NOTCH1 mutations lead to left ventricular hypoplasia in HLHS patients.
Abnormal FDG Uptake on PET/CT Due to Periosteal Reaction Caused by Hypervitaminosis D in a Pediatric Patient
Authors: Jun Liu, Wei Wang, Jigang Yang
Journal: Clinical Nuclear Medicine (2020)

Abstract A 7-year-old boy presented with diffuse bone pain. FDG PET/CT was performed to find the possible underlying malignant cause of hypercalcemia. The images demonstrated multiple foci of abnormal FDG activity at the sites of periosteal reaction. In addition, calcium deposit was noted in the basal ganglia, stomach, and the colon. History taking revealed that the patient had routinely taken an over-the-counter “supplement” that contains a high dose of vitamin D. One week after calcitonin therapy and stopping the supplement, the patient became symptom free. This case suggests that hypervitaminosis D might cause hypermetabolic periosteal reaction on FDG PET/CT imaging.
A Phase 1 Multicenter Open-Label Study of Escalating Doses of the Novel Anti-CD20-Targeting Engineered Toxin Body MT-3724 in Subjects with Relapsed or Refractory Mantle Cell Lymphoma
Authors: Michael Wang, Preetesh Jain, Lei Feng, Maria Badillo, Vivian Graham, Christine Burnett, Thomas Strack
Journal: Blood (2020)
A First in Human Study Planned to Evaluate Hdp-101, an Anti-BCMA Amanitin Antibody-Drug Conjugate with a New Payload and a New Mode of Action, in Multiple Myeloma
Authors: Andras Strassz, Marc S. Raab, Robert Z. Orlowski, Michael Kulke, Gudrun Schiedner, Andreas Pahl
Journal: Blood (2020)
Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort
Authors: Ewan C. Goligher, Annemijn H. Jonkman, Jose Dianti, Katerina Vaporidi, Jeremy R. Beitler, Bhakti K. Patel, Takeshi Yoshida, Samir Jaber, Martin Dres, Tommaso Mauri, Giacomo Bellani, Alexandre Demoule, Laurent Brochard, Leo Heunks
Journal: Intensive Care Medicine (2020)

Mechanical ventilation may have adverse effects on both the lung and the diaphragm. Injury to the lung is mediated by excessive mechanical stress and strain, whereas the diaphragm develops atrophy as a consequence of low respiratory effort and injury in case of excessive effort. The lung and diaphragm-protective mechanical ventilation approach aims to protect both organs simultaneously whenever possible. This review summarizes practical strategies for achieving lung and diaphragm-protective targets at the bedside, focusing on inspiratory and expiratory ventilator settings, monitoring of inspiratory effort or respiratory drive, management of dyssynchrony, and sedation considerations. A number of potential future adjunctive strategies including extracorporeal CO2 removal, partial neuromuscular blockade, and neuromuscular stimulation are also discussed. While clinical trials to confirm the benefit of these approaches are awaited, clinicians should become familiar with assessing and managing patients' respiratory effort, based on existing physiological principles. To protect the lung and the diaphragm, ventilation and sedation might be applied to avoid excessively weak or very strong respiratory efforts and patient-ventilator dysynchrony.
Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy
Authors: Sarah-Maria Fendt, Christian Frezza, Ayelet Erez
Journal: Cancer Discovery (2020)

Cancer cells continuously rewire their metabolism to fulfill their need for rapid growth and survival while subject to changes in environmental cues. Thus, a vital component of a cancer cell lies in its metabolic adaptability. The constant demand for metabolic alterations requires flexibility, that is, the ability to utilize different metabolic substrates; as well as plasticity, that is, the ability to process metabolic substrates in different ways. In this review, we discuss how dynamic changes in cancer metabolism affect tumor progression and the consequential implications for cancer therapy. SIGNIFICANCE: Recognizing cancer dynamic metabolic adaptability as an entity can lead to targeted therapy that is expected to decrease drug resistance.
Risk-Adapted Intensive Chemotherapy for Primary ACUTE Myeloid Leukemia during the Last 25 YEARS: Increase in Complete Remission RATE, Hematopoietic Cell Transplantation Access and Decrease in Relapse Incidence Have LED to Improved Survival
Authors: Ana Garrido, Montserrat Hoyos, Marina Diaz-Beyá, Montserrat Arnan, Susana Vives, Marisa Calabuig, Olga Salamero, David Gallardo, Maria Paz Queipo De Llano, Lourdes Escoda, Antonia Sampol, Ferran Vall-Llovera, Antonio Garcia-Guiñon, Merchan Brayan, Joan Bargay, J Pio Torres, Xavier Ortin, M Luz Amigo, Jose Maria Moraleda, José F. Falantes, David Valcarcel, Mar Tormo, Josep-Maria Ribera, Salut Brunet, Anna Sureda Balari, Jordi Esteve, Jorge Sierra
Journal: Blood (2020)
Evaluation of Eligibility for CAR-T Cell Therapy in a Population-Based Cohort of 3550 Patients with Incident Diffuse Large B-Cell Lymphoma (DLBCL) in Sweden
Authors: Karin Ekstroem Smedby, Sara Harrysson, Sara Ekberg, Mats Jerkeman, Per-Ola Andersson, Gunilla Enblad, Sandra Eloranta
Journal: Blood (2020)
Pharmacogenomics Drives Lenalidomide Efficacy and MRD Kinetics in Mantle Cell Lymphoma after Autologous Transplantation: Results from the MCL0208 Multicenter, Phase III, Randomized Clinical Trial from the Fondazione Italiana Linfomi (FIL)
Authors: Simone Ferrero, Daniele Grimaldi, Elena Arrigoni, Gian Maria Zaccaria, Beatrice Alessandria, Elisa Genuardi, Gabriele De Luca, Marco Ghislieri, Alice Di Rocco, Alessandro Re, Vittorio Stefoni, Federica Cavallo, Carola Boccomini, Monica Balzarotti, Vittorio Ruggero Zilioli, Gomes da Silva Maria, Luca Arcaini, Anna Lia Molinari, Filippo Ballerini, Andres JM Ferreri, Benedetta Puccini, Giuseppe A. Palumbo, Sara Galimberti, Sergio Cortelazzo, Antonello Di Paolo, Marco Ladetto
Journal: Blood (2020)
Impact of <i>DNMT3a</i> Status on Post Induction <i>NPM1</i> MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively
Authors: Maël Heiblig, Hélène Labussière, Marie Virginie Larcher, Gaelle Fossard, Marie Balsat, Sophie Ducastelle, Sandrine Loron, Sandrine Hayette, Sarah Huet, Pierre Sujobert, Fiorenza Barraco, Xavier Thomas, Alice Marceau, Delphine Lebon, Laure Goursaud, Isabelle Plantier, Laure Stalnikiewich, Cecile Frimat, Nathalie Cambier, Nicolas Duployez, Herve Ghesquieres, Claude Preudhomme
Journal: Blood (2020)
Abstract 323: Gamma-Enolase in Adult Cardiac Myocytes: A Study of Subcellular Localization and Post-Myocardial Infarction Modulation
Authors: Andrew T Milcarek, Eduard I Dedkov
Journal: Circulation Research (2020)

Background: Gamma-enolase, or neuron-specific enolase, is a multifunctional protein which is primarily found in neurons and neuroendocrine cells. Although the main role of gamma-enolase is associated with enzymatic activity during aerobic glycolysis, recently, it has been implicated in a variety of pathophysiological processes including inflammation, extracellular matrix degradation and cell survival after ischemic insult. Over the last decades, there have been a number of reports demonstrating the expression of gamma-enolase in the heart. Surprisingly, the latter finding has not received much attention in the past. Considering that this protein can play an important role in cellular adaptation to the ischemic environment we decided to examine the expression of gamma-enolase in the heart at different time points following a myocardial infarction (MI). Methods: A transmural MI was induced in male, middle-aged Sprague-Dawley rats by permanent left coronary artery ligation. The rats were euthanized 3 days, 1, 2, 4 and 8 weeks after MI and their hearts were processed into paraffin for immunostaining and quantitative morphometry. Results: We found that in post-MI heart gamma-enolase protein was expressed in cardiac myocytes of the remote myocardium as well as in the muscle cells surviving inside the transmural scar. On a subcellular level, the gamma-enolase expression overlapped with the I-bands of the sarcomeres. Despite the heterogeneity of the gamma-enolase fluorescence intensity among individual cardiac myocytes, there was no evident correlation between the size of the cells and the intensity of the gamma-enolase immunofluorescence in any region of the post-MI heart, although the immunofluorescence intensity of gamma-enolase in myocytes of the remote myocardium was always greater than that in myocytes surviving within the transmural scar. Most importantly, we determined that the intensity of gamma-enolase immunofluorescence recorded in cardiac myocytes has experienced an evident stepwise reduction at 1 and 8 weeks following MI. Conclusions: Taken together, our findings reveal that the cardiac myocytes of the adult rat heart express gamma-enolase and that the expression of this protein has been altered during post-MI cardiac remodeling.
FRI0007 Preferences of rheumatologists for the treatment of rheumatoid arthritis flare: is there a standard of care?
Authors: Y Yazici, D Erkan, MJ Harrison, SA Paget
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Differences in physician evaluations, heterogeneity of disease and within patient variability contribute to the lack of a uniform definition of RA flare. As a result, a standardised approach to treatment of RA flare is not likely to exist. However, when presented with the same case scenario, rheumatologists' choice of treatment should establish a standard of care. <h3>Objectives</h3> To identify physician medication preferences and the role of steroids in the treatment of rheumatoid arthritis (RA) flare. <h3>Methods</h3> A questionnaire describing two versions of the same case of a previously stable RA patient maintained on 17.5 mg/week of methotrexate (MTX), hydroxycholoroquine and NSAIDs, and presenting with signs and symptoms suggesting an increase in disease activity was developed; the second version included the addition of a standing dose of 5 mg of prednisone. Rheumatologists were asked to identify their choice (s) of first-line therapy for each version of the case. The questionnaire was mailed to rheumatologists (adult practice) (n = 995) who were identified through the ACR membership directory. Only physicians currently in practice were included. <h3>Results</h3> 375 (37.7%) questionnaires were returned between March 12, 2000 and April 25, 2000. 280 qualified for analysis. The results (A: No baseline steroid use, B: 5 mg/d prednisone) below illustrates the frequency with which rheumatologists cited each drug or drug combination as their first choice of treatment for each scenario. The most common change in medication for both cases was addition/adjustment of prednisone (A: n = 248; B: n = 229, C2 = 4.58, p = 0.03). Of those given oral steroids for a limited amount of time, mean increase in daily dose of prednisone was A: 16.4 ± 12.5 mg, B: 18.3 ± 12.5 mg. Duration of increased dose was highly variable ranging from 1 day (bolus) to 3 months. Some rheumatologists chose to continue increased prednisone indefinitely, (A: n = 19; B: n = 14). There appeared to be no consistent relationship between steroid dose and duration. For both cases there was no difference in the number of rheumatologists who increased MTX dose (A: n = 84; B: n = 85). The number of rheumatologists who added another DMARD to the patient's regimen were more in group A and differed significantly (x2 = 3.97, p = 0.046) from group B. Similarly, rates of initiation of anti-TNF therapy was higher in group A (x2 = 4.68, p = 0.03). However, rates of addition of leflunomide showed no statistically significant difference. <h3>Conclusion</h3> Though the cases presented were accepted by rheumatologists as RA flare requiring intervention; no consistency of practice other than an increase in steroids could be identified. Further studies determining optimal therapy for increases in RA activity are necessary.
Abstract MP100: Scalable Functional Classification of Heart Failure-associated Genetic Variants in Cardiac Troponin T
Authors: Anthony M PETTINATO, Feria A Ladha, David Mellert, Nicholas Legere, Rachel Cohn, Robert Romano, Ketan Thakar, Yu-Sheng Chen, John T Hinson
Journal: Circulation Research (2020)

Sarcomere gene mutations are the most common inheritable risk factor for heart failure, a disease with high morbidity and mortality, yet the pathogenicity of a large proportion of sarcomere gene variants remains unknown. The knowledge of which and how sarcomere gene variants result in heart failure would provide valuable prognostic and diagnostic information for individuals harboring sarcomere gene variants. Here, we developed a transgenic human cardiomyocyte model that enables scalable delivery of genetic variants in cardiac troponin T (cTnT; encoded by TNNT2 ), empowering high-throughput analysis of variant-specific sarcomere function. Using this model, in conjunction with CRISPR-derived isogenic standards and biomimetic cardiac tissues, we demonstrate that hypertrophic cardiomyopathy (HCM) variants in TNNT2 evoke elevated cardiac tissue contractile function, while dilated cardiomyopathy (DCM) variants produce decreased contractile function. RNA-seq revealed a transcriptional network that correlates with contractile function and identified NPPB expression as a molecular signature of contraction. Through the development of a cellular NPPB reporter, we functionally screen a panel of 51 TNNT2 variants, and provide molecular and tissue-level evidence for the functional reclassification of TNNT2 “variants of unknown significance” to pathogenic, and “pathogenic” variants to benign. Finally, adaption of this cellular reporter to assess variant calcium sensitivity, together with analysis of myofilament-localized calcium transients, demonstrates a parallel between contractile function and calcium sensitivity in human cardiomyocytes. This study establishes a new tool to study sarcomere genetic variants at scale, reclassifies the pathogenicity of previously-identified TNNT2 variants, and provides new insights into the cellular pathogenesis of human heart failure.
Pre- Transplant Ferritin Predicts Overall Survival and Non-Relapse Mortality in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis
Authors: Xavier A Andrade-Gonzalez, Ayalew Tefferi, Animesh Pardanani, Naseema Gangat, Mrinal M. Patnaik, Jeanne M. Palmer, Mohamed A. Kharfan-Dabaja, Mark Litzow, Mithun Vinod Shah, William J Hogan, Hassan B. Alkhateeb
Journal: Blood (2020)
Clinical Course, Outcomes and Genetic Characterization of Patients with Isolated Myeloid Sarcoma
Authors: Hussein A Abbas, Patrick K Reville, Alexis Geppner, Maro Ohanian, Koji Sasaki, Gautam Borthakur, Naval Daver, Courtney D. DiNardo, Carlos E. Bueso-Ramos, Michael Andreeff, Nicholas J. Short, Sherry A. Pierce, Elias Jabbour, Guillermo Garcia-Manero, Marina Konopleva, Farhad Ravandi, Hagop M. Kantarjian, Tapan M. Kadia
Journal: Blood (2020)
Differential Modulation of Plasminogen Activator Mediated Thrombolysis By Recombinant Thrombomodulin and Activated Protein C
Authors: Jawed Fareed, Zafar Siddiqui, Sanchayana Raghuvir, Sid Mehrota, Omer Iqbal, Walter Jeske, Debra Hoppensteadt, Kosuke Tanaka, Kazuhisa Tsuruta
Journal: Blood (2017)
Study of the Effect of Fibrinogen, Factor XIII and Recombinant Activated Factor VII in a Model of Trauma-Induced Coagulopathy
Authors: Manuel Quintana, Kapil Nanwani, Charbel Maroun, Elena Elena Muñoz, Ana María Martínez, Mar Gutierrez, Elena G Arias-Salgado, Dolores Hernández-Maraver, Ana Kerguelen Fuentes, Rosario Torres, Miguel A Canales, Aurora Viejo, Nora V. Butta, María Teresa Alvarez Román, Víctor Jiménez-Yuste
Journal: Blood (2020)
Medicaid Expansion and Mortality Among Patients With Breast, Lung, and Colorectal Cancer
Authors: Miranda B. Lam, Jessica Phelan, E. John Orav, Ashish K. Jha, Nancy L. Keating
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Medicaid expansion under the Patient Protection and Affordable Care Act may be associated with increased screening and may improve access to earlier treatment for cancer, but its association with mortality for patients with cancer is uncertain. <h3>Objective</h3> To determine whether Medicaid expansion is associated with improved mortality among patients with cancer. <h3>Design, Setting, and Participants</h3> This is a quasi-experimental, difference-in-difference (DID), cross-sectional, population-based study. Patients in the National Cancer Database with breast, lung, or colorectal cancer newly diagnosed from January 1, 2012, to December 31, 2015, were included. Data analysis was performed from January to May 2020. <h3>Exposure</h3> Living in a state where Medicaid was expanded vs a nonexpansion state. <h3>Main Outcomes and Measures</h3> The main outcome was mortality rate according to whether the patient lived in a state where Medicaid was expanded. <h3>Results</h3> A total of 523 802 patients (385 739 women [73.6%]; mean [SD] age, 54.8 [6.5] years) had a new diagnosis of invasive breast (273 272 patients [52.2%]), colorectal (111 720 patients [21.3%]), or lung (138 810 patients [26.5%]) cancer; 289 330 patients (55.2%) lived in Medicaid expansion states, and 234 472 patients (44.8%) lived in nonexpansion states. After Medicaid expansion, mortality significantly decreased in expansion states (hazard ratio [HR], 0.98; 95% CI, 0.97-0.99;<i>P</i> = .008) but not in nonexpansion states (HR, 1.01; 95% CI, 0.99-1.02;<i>P</i> = .43), resulting in a significant DID (HR, 1.03; 95% CI, 1.01-1.05;<i>P</i> = .01). This difference was seen primarily in patients with nonmetastatic cancer (stages I-III). After adjusting for cancer stage, the mortality improvement in expansion states from the periods before and after expansion was no longer evident (HR, 1.00; 95% CI, 0.98-1.02;<i>P</i> = .94), nor was the difference between expansion vs nonexpansion states (DID HR, 1.00; 95% CI, 0.98-1.02;<i>P</i> = .84). <h3>Conclusions and Relevance</h3> Among patients with newly diagnosed breast, colorectal, and lung cancer, Medicaid expansion was associated with a decreased hazard of mortality in the postexpansion period, which was mediated by earlier stage of diagnosis.
Ixazomib with or without Rituximab Following Immunochemotherapy and Autologous Stem Cell Transplant in Mantle Cell Lymphoma
Authors: Jason T. Romancik, Pamela B. Allen, Edmund K. Waller, Zhengjia Chen, Kelly Valla, Kaylan Dixon, David J. Reagan, Amanda B. Colbert, Cecilia Rosand, Alexandra Palmer, Christopher Flowers, Jonathon B. Cohen
Journal: Blood (2020)