tbuckley/cabot-search huggingface dataset:
Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens
Authors: Pargol Hashemi, Ivan Sadowski
Journal: Medicinal Research Reviews (2019)

Abstract The latency phenomenon produced by human immunodeficiency virus (HIV‐1) prevents viral clearance by current therapies, and consequently development of a cure for HIV‐1 disease represents a formidable challenge. Research over the past decade has resulted in identification of small molecules that are capable of exposing HIV‐1 latent reservoirs, by reactivation of viral transcription, which is intended to render these infected cells sensitive to elimination by immune defense recognition or apoptosis. Molecules with this capability, known as latency‐reversing agents (LRAs) could lead to realization of proposed HIV‐1 cure strategies collectively termed “shock and kill,” which are intended to eliminate the latently infected population by forced reactivation of virus replication in combination with additional interventions that enhance killing by the immune system or virus‐mediated apoptosis. Here, we review efforts to discover novel LRAs via low‐ and high‐throughput small molecule screens, and summarize characteristics and biochemical properties of chemical structures with this activity. We expect this analysis will provide insight toward further research into optimized designs for new classes of more potent LRAs.
Inhibition of uptake of transferrin-bound iron by human hepatoma cells by nontransferrin-bound iron
Authors: D Trinder, E Morgan
Journal: Hepatology (1997)

The liver acquires iron from transferrin by transferrin receptor-mediated (TR) and transferrin receptor-independent pathways (NTR) and from nontransferrin-bound iron (NTB-Fe). Iron uptake by the NTR processes involves an iron-carrier mediated step. Experiments, using human hepatoma cells (HuH7) transfected with TR antisense (sense for control) RNA expression vectors to suppress TR expression, were performed to examine the effect of unlabeled NTB-Fe as iron citrate on the uptake of 59 Fe- 125 I-transferrin. This was to determine if the uptake of transferrin-bound iron (Tf-Fe) and NTB-Fe uptake is mediated by a common iron-carrier. Iron citrate inhibited the uptake of 59 Fe-transferrin (2.5 micromol/L Fe) in a concentration-dependent manner with a maximum effect when the citrate-iron:Tf-Fe molar ratio was 10:1. Transferrin uptake was not affected. At a lower Tf-Fe concentration of (0.125 micromol/L) when uptake of iron is TR-mediated, a 10-fold molar excess of iron citrate had no effect on Tf-Fe uptake by HuH7 TR antisense and sense cells. However, at a higher Tf-Fe concentration (2.5 micromol/L), when uptake occurs mainly by the NTR-mediated process, there was a 40% reduction in the membrane-bound and intracellular uptake of iron. Iron citrate did not affect the maximum rate (V max ) of Tf-Fe uptake but the Michaelis-Menten constant (K m ) for Tf-Fe uptake by the NTR-mediated process was increased, indicating there was competitive inhibition of Tf-Fe uptake by iron citrate. These results suggest that the uptake of NTB-Fe and Tf-Fe by the NTR-mediated process occurs by the same cellular pathway, using a common iron-carrier.
BCL6-Mediated Repression of p53 Is Critical for Leukemia Stem Cell Survival in Chronic Myeloid Leukemia
Authors: Christian Hurtz, Katerina Hatzi, Leandro Cerchietti, Eugene Park, Yong-Mi Kim, Parham Ramezani-Rad, Hassan Jumaa, Martin C Muller, Wolf-Karsten Hofmann, Andreas Hochhaus, Anupriya Agarwal, Neil Shah, Ari Melnick, Brian J. Druker, Markus Muschen
Journal: Blood (2011)
SEPATH: benchmarking the search for pathogens in human tissue whole genome sequence data leads to template pipelines
Authors: Abraham Gihawi, Ghanasyam Rallapalli, Rachel Hurst, Colin S. Cooper, Richard M. Leggett, Daniel S. Brewer
Journal: Genome biology (2019)

Abstract Background Human tissue is increasingly being whole genome sequenced as we transition into an era of genomic medicine. With this arises the potential to detect sequences originating from microorganisms, including pathogens amid the plethora of human sequencing reads. In cancer research, the tumorigenic ability of pathogens is being recognized, for example, Helicobacter pylori and human papillomavirus in the cases of gastric non-cardia and cervical carcinomas, respectively. As of yet, no benchmark has been carried out on the performance of computational approaches for bacterial and viral detection within host-dominated sequence data. Results We present the results of benchmarking over 70 distinct combinations of tools and parameters on 100 simulated cancer datasets spiked with realistic proportions of bacteria. mOTUs2 and Kraken are the highest performing individual tools achieving median genus-level F1 scores of 0.90 and 0.91, respectively. mOTUs2 demonstrates a high performance in estimating bacterial proportions. Employing Kraken on unassembled sequencing reads produces a good but variable performance depending on post-classification filtering parameters. These approaches are investigated on a selection of cervical and gastric cancer whole genome sequences where Alphapapillomavirus and Helicobacter are detected in addition to a variety of other interesting genera. Conclusions We provide the top-performing pipelines from this benchmark in a unifying tool called SEPATH, which is amenable to high throughput sequencing studies across a range of high-performance computing clusters. SEPATH provides a benchmarked and convenient approach to detect pathogens in tissue sequence data helping to determine the relationship between metagenomics and disease.
Identification of Recurrent Submicroscopic Deletions of chromosome1q31.3 As Possible Molecular Prognostic Markers in Acute Promyelocytic Leukemia (APL)
Authors: Daniel Nowak, Marion Klaumuenzer, Benjamin Hanfstein, Maximilian Mossner, Florian Nolte, Verena Nowak, Julia Oblaender, Anna Hecht, Gero Hütter, Seishi Ogawa, Alexander Kohlmann, Claudia Haferlach, Brigitte Schlegelberger, Jan Braess, Wolfgang Seifarth, Alice Fabarius, Philipp Erben, Susanne Saussele, Martin C. Müller, Thomas Buechner, Christel Weiss, Wolf-Karsten Hofmann, Eva Lengfelder
Journal: Blood (2011)
Using deep learning with registry linked claims data to predict hospitalization during chemotherapy: Feasibility study.
Authors: Laura Elizabeth Panattoni, Li Li, Catherine R. Fedorenko, Emily Silgard, Scott White, Adam Rhine, Karma L. Kreizenbeck, Kathryn Egan, Annika Ittes, Scott David Ramsey
Journal: Journal of Clinical Oncology (2019)

270 Background: Approximately half of cancer patients undergoing outpatient chemotherapy experience unplanned Emergency Department (ED) visits and Inpatient (IP) stays. Current machine learning algorithms that identify high-risk patients are based on pre-treatment variables which can not detect changes in risk over time. Deep learning recurrent neural networks can model complex longitudinal patient histories. This study tests the feasibility of using an interpretable recurrent neural network to predict a patient’s daily likelihood of ED and unplanned IP stays in the six months following chemotherapy initiation. Methods: Medicare and commercial claims data were linked with cancer registry records for patients in Washington State from 2011 to 2017. The study included patients diagnosed with any primary tumor site, excluding leukemia, and treated with chemotherapy. We used the Reverse Time Attention model (RETAIN) with a 1:10 case-control match and included registry elements; diagnoses, procedures, medication, and utilization pre-and post-chemotherapy initiation. Patients were randomly divided into internal training, validation, and test sets (75%, 10%, 15%). Model accuracy was measured by the areas under the receiver operating curve (ROC) and precision-recall curve (PRC), and the Youden sensitivity and specificity. Results: Of the 15,400 eligible patients; 4,037 (26.2%) visited the ED a median of 1 time (6,080 total visits); 5,116 (33.2%) had a median of 1 IP stay (7,839 total stays). Both models had good predictive accuracy: The top 20 predictors for ED visits included 5 chemotherapy regimes, 12 procedures, and 2 tumor characteristics; IP stays included all chemotherapy regimes. Conclusions: The promising performance of RETAIN supports the possibility of building a tool capable of estimating daily hospitalization risk. However, future research, particularly with alternative data sources, may be required to predict hospitalization in a real time clinical setting. [Table: see text]
Abstract 902: Leveraging Natural Cardiomyocyte Variability to Investigate Downregulation of β-1 Adrenoceptors Following Dobutamine Treatment
Authors: J. Alexander Clark, Jonathan Weiss, Stuart Campbell
Journal: Circulation Research (2019)

In heart failure, the most consistent effect on the myocardial beta-adrenergic pathway is a downregulation of β-1 adrenoceptors (β1AR). This loss of receptors impairs the ability of the heart to respond to increases in cardiac demand, and can lead to decreased myocyte function even at rest. As a model of the process that leads to downregulation of β1AR, we measured intracellular Ca 2+ transients and unloaded sarcomere shortening in electrically stimulated isolated adult rat cardiomyocytes undergoing 30 minutes of exposure to 40 nM dobutamine. These experiments were facilitated by a custom device containing micro-patterned wells that orient and immobilize the cardiomyocytes, allowing for rapid and consistent measurements over an extended time period. After functional measurements, cells are picked up individually with a computerized micro-aspirator and subjected to single-cell RT-qPCR to quantify abundance of transcripts of interest. In this way, the physiological responses of individual cells to β1AR stimulus can be correlated to gene expression levels. We found a surprising diversity in the single-cell responses to dobutamine exposure. Although average cardiomyocyte contractility increased significantly, several apparently healthy cells registered no change or even a decrease in sarcomere shortening in the presence of dobutamine. Gene expression was quantified in cardiomyocytes representing a spectrum of sensitivities to dobutamine (n = 7). The transcript for β1AR was significantly downregulated in all cells after 30 minutes, indicating consistent adaptation to chronic stimulus. However, abundance of the gene encoding PKA was negatively correlated with dobutamine-triggered augmentation of Ca 2+ release (p-value: 0.0201). In other words, PKA expression was reduced in cells that experienced potent increases in Ca 2+ release after dobutamine treatment. These data suggest the presence of gene regulatory circuits that modulate individual components of the β1AR pathway independent of overall β1AR abundance. These circuits may be critical to restoring β1AR sensitivity in the failing heart.
PDZ Binding Kinase (PBK) - a Novel Gene Driving Genomic Evolution in Multiple Myeloma
Authors: Subodh Kumar, Leutz Buon, Srikanth Talluri, Jialan Shi, Hervé Avet-Loiseau, Mehmet Kemal Samur, Masood A. Shammas, Nikhil Munshi
Journal: Blood (2018)
miR106a-363 Cluster Has Oncogenic Potential in Childhood T-Cell Acute Lymphoblastic Leukemia
Authors: Monika Drobna, Bronislawa Szarzynska-Zawadzka, Maria Kosmalska, Roman Jaksik, Tomasz Szczepanski, Michał Witt, Małgorzata Dawidowska
Journal: Blood (2018)
Call center performance to drive patient access.
Authors: Chad W. Cummings, George Comer, Nicole Bealer, Patricia Costantino, Jonathan Davis, Laphia Heard, Markita Johnson, Deborah Kantzes, Josette M. Snyder, Kimberly Oh
Journal: Journal of Clinical Oncology (2019)

135 Background: Access to oncology care through a specialty call center within a large academic institution was analyzed to determine service levels necessary to schedule patient consults within 7 days of contact. The specialty call center is the primary resource for ambulatory appointment scheduling, and staffed by 1 licensed provider and 6 agents who administratively coordinate patient care. Hours of operation are 8AM-5PM. Methods: Data was analyzed between a period of 1/1/2018 and 9/30/2018 (P1), providing call statistics (S1): inbound &amp; outbound calls, calls not answered, average speed of answer, agent availability. Observations of agents identified key processes, staffing analysis, and productivity levels. A dependency map was developed to identify key inputs and outputs for all call center activities. The number of dependencies were identified for each activity. Results: A dependency map identified 22 unique agent activities, categorized by administrative tasks (n = 9), multi-disciplinary team coordination (n = 7), direct patient interaction (n = 5), and patient benefit processing (n = 3). Average number of inputs per activity yielded 2.4 (Range = 0 to 8), while outputs were 2.0 (Range = 0 to 6). Inbound and outbound calls spanned multiple categories, with 28,730 calls received or placed during P1. 77% of inbound calls were answered, and remaining calls were directed to voicemail. 89% of all calls occurred between 9AM and 4PM, with slight variation each hour. Staffing Analysis revealed 91.3% availability rate equivalent to 5.48 agents available per day. Average call hours (inbound and outbound) per agent ranged from 2.45hrs/day to 5.18 hours/day, with variation attributed to the unique activities. An algorithm was created to determine appropriate staffing levels to ensure S1 requirements and timely coordination of care. Conclusions: A specialty call center requires a detailed understanding of dependencies that contribute to timely scheduling, while maximizing customer service. Dependency mapping provides visibility to clinical and non-clinical teams of necessary activities to coordinate appointments. Staffing models can assist in understanding the variables that influence S1, and provide support for staffing decisions in periods of high/low demand.
Abstract 926: Regulation of Fibrosis by Phospholipase C&amp;#949;in Cardiac Fibroblasts
Authors: Loren M Brown, Alan V Smrcka
Journal: Circulation Research (2019)

Cardiac fibrosis is commonly associated with heart diseases, such as cardiac hypertrophy and myocardial infarction. Upon injury to the heart, cardiac fibroblasts transition to an activated myofibroblast state, driven by TGFβ or angiotensin II (AngII) signaling, characterized by expression of α-smooth muscle actin (αSMA). Fibrosis is driven by the activity of both cardiac myofibroblasts and inflammatory cells. Activation of cardiac fibroblasts leads to the induction of pro-inflammatory cytokines that are important for recruitment of immune cells and regulation of cardiac remodeling. Monocyte Chemoattractant Protein (MCP)-1/CCL2 is a chemokine expressed by cardiac myofibroblasts through activation of Nuclear Factor-kB (NF-kB) that leads to recruitment of mononuclear cells. Phospholipase Cε (PLCε) is highly expressed in cardiac fibroblasts and is activated by multiple upstream stimuli including GPCRs and RTKs, leading to protein kinase C (PKC) and D (PKD) activation and Calcium release. In this study to elucidate the role of PLCε in neonatal rat cardiac fibroblasts adenovirus encoding for a PLCε-shRNA was used to knockdown PLCε in fibroblasts. Treatment with PLCε-shRNA strongly inhibited the transition to myofibroblasts induced by TGFβ as assessed by staining of αSMA. PLCε knockdown did not inhibit the ability of TGFβ to induce SMAD nuclear translocation. PLCε depletion also strongly inhibited, basal, Thrombin, and AngII mediated PLC activity in cardiac fibroblasts, indicating PLCε is a dominant regulator of phosphoinositide hydrolysis in these cells. PLCε shRNA also decreased expression of MCP-1 mRNA and reduced the ability of pro-fibrotic stimuli to induce MCP-1 mRNA expression. Knockdown of PLCε or inhibition of PKD with the small molecule inhibitor NB 142-70 reduced the ability of thrombin to activate NF-kB. These data indicate that PLC signaling, and PLCε in particular, plays an important role in pro-fibrotic processes in cardiac fibroblasts, through both cell autonomous and paracrine mechanisms. Future studies will focus on further elucidating the mechanistic role of PLCε in the transition to myofibroblasts, and will study in in vivo models of cardiac fibrosis.
"Cancer Life ReiMagined:" The CaLM model of whole-person cancer care.
Authors: Rebekkah Schear, S. Gail Eckhardt, Elizabeth Ann Kvale, Robin Richardson, Barbara L. Jones
Journal: Journal of Clinical Oncology (2019)

74 Background: Despite advances in cancer treatment, the orientation of our health system does not address the whole cancer patient or support the wellbeing of the heart, soul, and mind. We launched the CaLM Model of Whole Person Cancer Care, an oncology medical home approach that integrates high acuity, sub-specialty clinical cancer care with comprehensive, ongoing supportive care. The CaLM Model operationalizes the six components in the conceptual framework set forth in the NASEM’s 2013 report. Delivering High-Quality Cancer Care. Methods: Beginning December 2018, we piloted a “flipped” ambulatory care model in GYN and GI oncology delivering daily care through a subset of providers, the SWAT Team: a palliative NP, med onc NP, clinical social worker, and navigator. The SWAT Team triages all physical and social needs. As opposed to anchoring care with the oncologist and referring the patient out to social services, the SWAT team anchors care and the oncologist plugs in for treatment planning. The CaLM Model also utilizes coordinated, interdisciplinary care including financial and fertility navigation, nutrition, genetic counseling, pharmacy, and psychiatry, to manage the patient’s needs via a team-based approach by assessing and addressing the patient’s needs according to their values and preferences. We designed a new clinical and psychosocial assessment tool and patient-facing care plan; launched a Multi-Disciplinary “whole-person” case review process with all interdisciplinary providers and measured patient reported outcomes using the FACT-G, PHQ, GAD, and MD Anderson Symptom Inventory at baseline (initial visit) and every clinical visit. Measured at initial visit and every 6 months. Results: Early data show that the CaLM Model reduces patient symptom burden while improving quality of life. Conclusions: The CaLM Model is an efficient use of resources, compared to a traditional oncologist-focused model of cancer care. Further research is underway to assess cost benefit to the system, the patient and the payers. Ultimately, the CaLM Model may shift the paradigm of cancer care by demonstrating the feasibility and effectiveness of a patient-centered model of care delivery that builds a foundation for a value-based payment model.
Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning
Authors: Jessica L. Bridgford, Su Min Lee, Christine M. M. Lee, Paola Guglielmelli, Elisa Rumi, Daniela Pietra, Stephen Wilcox, Yash Chhabra, Alan F. Rubin, Mario Cazzola, Alessandro M. Vannucchi, Andrew J. Brooks, Matthew E. Call, Melissa J. Call
Journal: Blood (2019)
Multi-Year Study of Unfractionated Heparin Serotonin Release Testing at a Large U.S. Reference Laboratory
Authors: Edward C.C. Wong, Mervyn A. Sahud, Lina J. Noh, Amal M. Aboueyada, Ruth A. Frock, Christine L. Haley, William W. Wu, Jeffrey S. Dlott
Journal: Blood (2018)
Phosphatidylserine-Mediated Procoagulant Activity of Microparticles and Their Originating Cells Contributes to Hypercoagulability in Lupus Nephritis
Authors: Li Hou, Tao Li, Yan Zhang, Baorong LI, Yingmiao LIU, Cong Zhang, Yan Kou, Lili Zou, Hui Liang, Yuqing Guan, Xiaojing Chen, Jialan Shi, Rujuan Xie
Journal: Blood (2018)
Adult B-Cell Precursor Acute Lymphoblastic Leukemia (BC-ALL) Negative For Recurrent Fusion Genes Are Characterized By a High Complex Genetic Heterogeneity Influencing Prognosis
Authors: Ilaria Iacobucci, Anna Ferrari, Margherita Perricone, Valentina Robustelli, Cristina Papayannidis, Roberta Zuntini, Maria Chiara Abbenante, Claudia Venturi, Carmen Baldazzi, Emanuela Ottaviani, Barbara Giannini, Andrea Ghelli Luserna Di Rorà, Annalisa Lonetti, Antonella Vitale, Loredana Elia, Viviana Guadagnuolo, Nicoletta Testoni, Simona Soverini, Stefania Paolini, Sarah Parisi, Chiara Sartor, Federica Cattina, Domenico Russo, Robin Foà, Sabina Chiaretti, Alexander Kohlmann, Giovanni Martinelli
Journal: Blood (2013)
DA-EPOCH Was Not Better Than CHOP for Acquired Immunodeficiency Syndrome-Related Diffuse Large B Cell Lymphoma Patients Treated in a South Brazilian University Hospital
Authors: Carolina F Gomes, Tito Vanelli, Gueverson Rocha, Jeziel Basso, Juliana Collman Silva, Nicole Teixeira Carvalho, Tatiana de Campos, Harold Fabian Ibanez Torres, Lucia Silla, Paz Aparecida Alessandra, Laura Maria Fogliatto
Journal: Blood (2018)
Capnography: Clinical Aspects
Authors: C Mark Harper
Journal: Journal of the Royal Society of Medicine (2005)

Despite having enjoyed several of his other works, I opened Ian McEwan's latest novel expecting disappointment.As I read it in the surgeons' coffee room, a consultant grabbed it from me.'A novel about a neurosurgeon?I bet it's just one big cliche ´,' he said, expressing concern that I wasn't reading Bailey and Love or some other such character-building surgical text.His assumption about the book was not unfounded.Neurosurgery enjoys a certain mystique in public perception.Many outside medicine consider it on a par with rocket science in its technical difficulties and intellectual challenges.And the media has played upon this image.One example is in the American television sitcom Friends in which the witless actor Joey lands his most famous role playing suave Portuguese neurosurgeon Drake Ramore in a TV soap.A leading article in The New Yorker even elevates the discipline to a high-performance art form, comparing the 'physical genius' of Californian neurosurgeon Charlie Wilson to that of Wayne Gretzky at ice-hockey or Yo-Yo Ma in a cello concerto. 1Even the British Medical Association's recommended careers guide for medical students and junior doctors, entitled So You Want to be a Brain Surgeon?, panders to the popular image of neurosurgery 2 -though many outside the specialty find truth in its tongue-in-cheek description of neurosurgeons as 'clever egotists, some of whose patients end up as cabbages'.Few could deny that neurosurgery is a specialty with little margin for error and a need for both pragmatism and optimism.Any specialty that invents a disability rating scale where a corpse scores a fifth of the available points, as they would in the Glasgow Coma Score, deserves such a
Markers for Minimal Residual Disease (MRD) in B-Lineage Acute Lymphoblastic Leukemia (B-ALL): Analysis of IgH Gene Rearrangement Repertoire (AIRR) vs Conventional Strategy.
Authors: Alexander Morley, Michael Brisco, Sue Latham, Vicki Wilczek, Elisabeth Hughes, Brad Budgen, Rosemary Sutton, Anita Bahar, Maria Malek, Glenn Marshall
Journal: Blood (2007)