tbuckley/cabot-search huggingface dataset:
SYNERGY-AI: Artificial intelligence based precision oncology clinical trial matching and registry.
Authors: Selin Kurnaz, Arturo Loaiza-Bonilla, Jason Lawrence Freedman, Belisario Augusto Arango, Kristin Johnston, Paula Andrea Bonilla-Reyes, Cagatay M Culcuoglu
Journal: Journal of Clinical Oncology (2019)

TPS717 Background: Precision oncology encompasses the implementation of high level of evidence disease-specific and biomarker-driven diagnostic and treatment recommendations for optimized cancer care. Artificial Intelligence (AI), telemedicine and value-based care may optimize clinical trial enrollment (CTE) and overall cost-benefit. This ongoing, international registry for cancer pts evaluates the feasibility and clinical utility of an AI-based precision oncology clinical trial matching tool, powered by a virtual tumor boards (VTB) program, and its clinical impact on pts with advanced cancer to facilitate CTE, as well as the financial impact, and potential outcomes of the intervention. Methods: The SYNERGY-AI Registry is an international prospective, observational cohort study of eligible adult and pediatric pts with advanced solid and hematological malignancies, for whom the decision to consider CTE has already been made by their primary providers (PP). Using a proprietary application programming interface (API) linked to existing electronic health records (EHR) platforms, individual clinical data is extracted, analyzed and matched to a parametric database of existing institutional and non-institutional CTs. Machine learning algorithms allow for dynamic matching based on CT allocation and availability for optimized matching. Patients voluntarily enroll into registry, which is non-interventional with no protocol-mandated tests/procedures—all treatment decisions are made at the discretion of PP in consultation with their pts, based on the AI CT matching report, and VTB support. CTE will be assessed on variables including biomarkers, barriers to enrollment. Study duration anticipated as ~36 mo (~24-mo enrollment followed by 12 mo of data collection, to occur every 3 mo). The primary analysis will be performed 12 mo after last pt enrolled. The impact time to initiation of CTE on PFS and OS will be estimated by Kaplan-Meier and Cox multivariable survival analysis. Enrollment is ongoing, with a target of ≥ 1500 patients. Key inclusion criteria: Pts with solid and hematological malignancies; cancer-related biomarkers. Key exclusion criteria: ECOG PS &gt; 2; abnormal organ function; hospice enrollment Clinical trial information: NCT03452774.
Long-Term Efficacy and Safety of RPC4046, an Anti-Interleukin-13 Monoclonal Antibody, in Patients With Eosinophilic Esophagitis: Results From the Open-Label Extension of the HEROES Study
Authors: Evan S. Dellon, Margaret H. Collins, Yehudith Assouline-Dayan, Larry Evans, Sandeep Gupta, Alain Schoepfer, Alex Straumann, Ekaterina Safroneeva, Amy Woo, Allan Olson, Gregory J. Opiteck, Richard Aranda, Ikuo Hirano
Journal: Journal of Allergy and Clinical Immunology (2019)
Loss of ZBTB7A Facilitates RUNX1/RUNX1T1-Dependent Clonal Expansion and Sensitizes for Metabolic Inhibition
Authors: Enric Redondo Monte, Anja Wilding, Georg Leubolt, Luise Hartmann, Sayantanee Dutta, Wolfgang Hiddemann, Lingping Chen-Wichmann, Christian Wichmann, Philipp A. Greif
Journal: Blood (2018)
Stochastic Variational Inference for Bayesian Phylogenetics: A Case of CAT Model
Authors: Tung Dang, Hirohisa Kishino
Journal: Molecular Biology and Evolution (2019)

Abstract The pattern of molecular evolution varies among gene sites and genes in a genome. By taking into account the complex heterogeneity of evolutionary processes among sites in a genome, Bayesian infinite mixture models of genomic evolution enable robust phylogenetic inference. With large modern data sets, however, the computational burden of Markov chain Monte Carlo sampling techniques becomes prohibitive. Here, we have developed a variational Bayesian procedure to speed up the widely used PhyloBayes MPI program, which deals with the heterogeneity of amino acid profiles. Rather than sampling from the posterior distribution, the procedure approximates the (unknown) posterior distribution using a manageable distribution called the variational distribution. The parameters in the variational distribution are estimated by minimizing Kullback–Leibler divergence. To examine performance, we analyzed three empirical data sets consisting of mitochondrial, plastid-encoded, and nuclear proteins. Our variational method accurately approximated the Bayesian inference of phylogenetic tree, mixture proportions, and the amino acid propensity of each component of the mixture while using orders of magnitude less computational time.
Abstract A043: Bypass kinase pathways lead to acquired CDK4/6 inhibitor resistance in prostate cancer
Authors: Renee de Leeuw, Christopher M. McNair, Matthew J. Schiewer, Neermala P. Neupane, Michael A. Augello, Zhen Li, Larry Cheng, Akihiro Yoshida, J. Alan Diehl, E Starr Hazard, Sean M. McCourtney, Gary Hardiman, Maha H. Hussain, Justin M. Drake, Wm. Kevin Kelly, Karen E. Knudsen
Journal: Cancer Research (2018)

Abstract Cyclin dependent kinase-4/6 (CDK4/6) kinase inhibitors have shown clinical benefit in treatment of solid tumor types, including breast cancer. However, resistance is common, and the underpinning mechanisms of action are not well understood. Given the dependence of CDK4/6 inhibitors on retinoblastoma tumor suppressor (RB) function for activity, this class of agents may be particularly effective in tumor types for which RB loss is infrequent or occurs late in tumor progression. Here, models of acquired palbociclib resistance were generated in early-stage, RB-positive cancers, wherein it was shown that acquired palbociclib resistance resulted in cross-resistance to other CDK4/6 inhibitors under clinical testing. Furthermore, cells showing acquired resistance exhibited aggressive in vitro and in vivo phenotypes without genetic loss of RB or RB pathway members, including enhanced proliferative capacity, migratory potential, and characteristics of epithelial-to-mesenchymal transition. Further analyses through integration of RNA sequencing and phospho-proteomics identified activation of the MAPK signaling pathway as a mediator of CDK4/6 inhibitor resistance, capable of bypassing CDK4/6 activity. However, this altered kinase dependence resulted in sensitization to MEK inhibitors, suggestive of new clinical opportunities in CDK4/6-resistant tumors. In sum, the studies herein not only identify activation of the MAPK pathway as capable of bypassing the CDK4/6 requirement and promoting aggressive tumor characteristics, but also nominate MEK inhibitors as potential mechanisms to treat or prevent CDK4/6 inhibitor resistance. Citation Format: Renee de Leeuw, Christopher M. McNair, Matthew J. Schiewer, Neermala P. Neupane, Michael A. Augello, Zhen Li, Larry Cheng, Akihiro Yoshida, J. Alan Diehl, E Starr Hazard, Sean M. McCourtney, Gary Hardiman, Maha H. Hussain, Justin M. Drake, Wm. Kevin Kelly, Karen E. Knudsen. Bypass kinase pathways lead to acquired CDK4/6 inhibitor resistance in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A043.
Expanded RAS and BRAF V600 testing as predictive biomarkers for single agent cetuximab in the randomized phase III CO.17 trial.
Authors: Jonathan M. Loree, Anthony Dowers, Dongsheng Tu, Christopher J. O'Callaghan, Dan Edelstein, Hannah Quinn, Derek J. Jonker, Chris Karapetis, Timothy Jay Price, John Raymond Zalcberg, Malcolm J. Moore, Paul Michael Waring, Hagen F. Kennecke, Stanley R. Hamilton, Scott Kopetz
Journal: Journal of Clinical Oncology (2019)

537 Background: KRAS/NRAS ( RAS) testing of exons 2, 3 and 4 is standard prior to anti-EGFR treatment in metastatic colorectal cancer and many consider BRAFV600 ( BRAF) mutations predictive. CO.17 was a randomized phase III trial comparing cetuximab vs best supportive care (BSC) in unselected patients (pts). Re-analysis tested only KRAS exon 2, thus the benefit of cetuximab in RAS/BRAF wild type (WT) pts is unclear. Methods: We retrospectively performed expanded RAS/BRAF testing using a highly sensitive digital PCR method (BEAMing; 1% allele frequency detection limit) on micro-dissected archival tissue from 248 CO.17 pts. Additional pts without available archival tissue, with prior Sanger sequencing or therascreen results were included in analyses if mutations were previously detected (n = 77). Overall survival (OS), progression free survival (PFS), and response rates (RR) were compared by molecular profile. Results: Of 248 sequenced pts, 139 (56%) were RAS mutant, with 112 (45%) exon 2, 11 (4%) exon 3 and 6 (2%) exon 4 KRAS mutant, and 10 (4%) NRAS mutant pts. Seven (3%) BRAF mutant, and 97 (30%) confirmed RAS/BRAF WT pts were identified. Results are summarized below. A test of interaction indicated RAS status was predictive for PFS (p = 0.0001) and OS (p = 0.037) and BRAF status neared significance as a predictive marker for PFS (p = 0.089) but not OS (p = 0.24). Conclusions: These updated results demonstrate an improved PFS (HR 0.25 vs 0.40 previously) and OS (HR 0.51 vs 0.55 previously) for cetuximab in RAS/BRAF WT pts compared to prior analyses that included only KRAS exon 2 mutation status. We provide an estimate of single agent cetuximab efficacy for future anti-EGFR re-challenge studies and demonstrate further support that BRAF mutations may predict lack of benefit from anti-EGFR therapy. Clinical trial information: NCT00079066. [Table: see text]
A First-in-Class Inhibitor of ISWI-Mediated (ATP-Dependent) Transcription Repression Releases Terminal-Differentiation in AML Cells While Sparing Normal Hematopoiesis
Authors: Ashwin Kishtagari, Kwok Peng Ng, Charlotte Jarman, Anand D. Tiwari, James G Phillips, Caroline Schuerger, Babal K. Jha, Yogenthiran Saunthararajah
Journal: Blood (2018)
David Oliver: Is hospital avoidance an elusive holy grail?
Authors: David Oliver
Journal: BMJ (2019)

The first weeks of 2019 saw NHS England publish the long term plan for the NHS,1 the new five year GP contract framework,2 and the plan for universal personalised care.3 They all include an overarching idea that we should be trying to prevent people attending or being admitted to hospital.

The GP contract and the promised additional £4.5bn for primary and community services are linked to a requirement that the new GP networks will be financially incentivised to cut emergency department attendances and hospital admissions. The NHS plan aims to reduce acute hospital bed use …
irRECIST for the Evaluation of Candidate Biomarkers of Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: Analysis of a Phase II Prospective Clinical Trial
Authors: Jean-Christophe Pignon, Opeyemi Jegede, Sachet A. Shukla, David A. Braun, Christine E. Horak, Megan Wind-Rotolo, Yuko Ishii, Paul J. Catalano, Jonian Grosha, Abdallah Flaifel, Jesse S. Novak, Kathleen M. Mahoney, Gordon J. Freeman, Arlene H. Sharpe, F. Stephen Hodi, Robert J. Motzer, Toni K. Choueiri, Catherine J. Wu, Michael B. Atkins, David F. McDermott, Sabina Signoretti
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared with standard clinical endpoints (RECISTv1.1). Experimental Design: Endpoints based on RECISTv1.1 [objective response rate (ORR)/progression-free survival (PFS)] or irRECIST [immune-related ORR (irORR)/immune-related PFS (irPFS)] were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 IHC, and by multiplex immunofluorescence for CD8, PD-1, TIM-3, and LAG-3. T-cell activation signatures were assessed by RNA sequencing. Results: Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR, but immune-related progressive disease (irPD) rate was significantly lower than progressive disease (PD) rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR, but patients with TC PD-L1 ≥1% had longer median irPFS and higher irORR. High percentage of CD8+ tumor-infiltrating cells (TIC) that are PD-1+TIM-3−LAG-3− (% CD8+PD-1+TIM-3−LAG-3− TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8+PD-1+TIM-3−LAG-3− TIC identified three groups of patients for which irPFS and irORR were significantly different. Conclusions: Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared with RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8+ TIC may predict outcome on nivolumab in mccRCC.
Activated Ral and Mutated RAS Are Independent Drivers of Multiple Myeloma Cell Survival.
Authors: Marcel Seibold, Thorsten Stuehmer, Anja Mottok, Claus J Scholz, Manik Chatterjee, Ellen Leich, Martin Kortüm, Andreas Schlosser, Hermann Einsele, Andreas Rosenwald, Ralf C Bargou, Torsten Steinbrunn
Journal: Blood (2018)
Progress in Understanding and Treating Idiopathic Pulmonary Fibrosis
Authors: Jonathan A. Kropski, Timothy S. Blackwell
Journal: Annual Review of Medicine (2019)

This is a time of substantial progress in the evaluation and care of patients with idiopathic pulmonary fibrosis (IPF). In addition to the approval and widespread availability of the first IPF-specific therapies, there have been improvements in imaging interpretation and lung biopsy methods to enable more expeditious and more accurate diagnosis. Recent advances in identifying genetic factors that underlie susceptibility to IPF and affect prognosis have raised the possibility of personalized therapeutic approaches in the future. Further, evolving work is elucidating novel mechanisms influencing epithelial, mesenchymal, and inflammatory cell responses during the injury-repair process, thus advancing understanding of disease pathogenesis. As analytic approaches mature, the field is now poised to harness the power of rapidly advancing “omics” technologies to further accelerate progress.
Natural course and factors associated with allergic diseases in the first 2 years: Data from a Developing Asian Countries
Authors: Thansinee Saetae, Pantipa Chatchatee, Kanlada Wongworapat, Athipat Athipongarporn, Yong Poovorawan, Nasamon Wanlapakorn, Wallapa Weerapakorn, Elke Leuridan, Surasith Chaithongwongwatthana, Jarungchit Ngamphaiboon, Narissara Suratannon
Journal: Journal of Allergy and Clinical Immunology (2019)
Peri-Coronary Adipose Tissue Density Is Associated With 18F-Sodium Fluoride Coronary Uptake in Stable Patients With High-Risk Plaques
Authors: Jacek Kwiecinski, Damini Dey, Sebastien Cadet, Sang-Eun Lee, Yuka Otaki, Phi T. Huynh, Mhairi K. Doris, Evann Eisenberg, Mijin Yun, Maurits A. Jansen, Michelle C. Williams, Balaji K. Tamarappoo, John D. Friedman, Marc R. Dweck, David E. Newby, Hyuk-Jae Chang, Piotr J. Slomka, Daniel S. Berman
Journal: JACC. Cardiovascular imaging (2019)
T-Cell Suppression By Src/ABL Kinase Inhibitors When Combined with Blinatumomab in Ph+ Acute Lymphoblastic Leukemia
Authors: Jessica Leonard, Yoko Kosaka, Pavani Malla, Brandon Hayes-Lattin, Adam J. Lamble, Brian J. Druker, Jeffrey W. Tyner, Bill H. Chang, Evan F. Lind
Journal: Blood (2018)
Abstract 16946: Presence of Obstructive Sleep Apnea, a Clinical Correlate of Cardiac Preconditioning, is Associated With Improved Survival in Patients With Acute Myocardial Infarction
Authors: Vaibhav Gupta, Rafath Ullah, Tadele W Mengesha, Beneet Pandey, Amina Adil, M. Fuad Jan, Sulaiman Sultan, Khawaja Afzal Ammar, Suhail Q. Allaqaband, Frank X Downey, Tanvir Bajwa, Arshad Jahangir
Journal: Circulation (2017)

Background: Ischemic preconditioning, whereby transient ischemic episodes induce endogenous cardioprotective responses to enhance tolerance of the heart to sustained ischemia/reperfusion injury, is reproducibly demonstrated in animal models, but clinical correlation in humans is not well established. Hypothesis: Episodic hypoxemia in obstructive sleep apnea (OSA) may precondition the heart to injury increasing tolerance to acute myocardial infarction (AMI) compared to non-OSA patients, resulting in improved in-hospital survival. Methods: Using the Nationwide Inpatient Sample database, all patients hospitalized with AMI in 2012 were identified. OSA (ICD-9 code 327.23) was 1:1 propensity score matched (age, sex, BMI and major comorbidities) with no OSA group. Baseline characteristics and clinical outcomes between the two groups were compared using Wilcoxon, T-test and Chi square test. Logistic regression model was used to identify independent predictors of mortality. Results: Out of 188,950 patients (mean a...
Association Between Financial Incentives and Participant Deception About Study Eligibility
Authors: Holly Fernandez Lynch, Steven Joffe, Harsha Thirumurthy, Dawei Xie, Emily A. Largent
Journal: JAMA Network Open (2019)

Offers of payment for research participation are ubiquitous but may lead prospective participants to deceive about eligibility, jeopardizing study integrity and participant protection. To date, neither the rate of payment-induced deception nor the influence of payment amount has been systematically studied in a nationally representative randomized survey experiment.To estimate payment-associated deception about eligibility for an online survey and to assess whether there is an association between payment amount and deception frequency.Randomized, 7-group survey experiment. Data were collected in March 2018 and analyzed from March to August 2018. The setting was a nationally representative online survey among US adults drawn from the GfK KnowledgePanel.Varying payment amounts for participation ($5, $10, or $20 cash equivalent) and direction of eligibility criterion (having received or not having received an influenza vaccination in the past 6 months).Proportion of respondents reporting recent influenza vaccination.In total, 2275 individuals participated in the survey, a 59.4% (2275 of 3829) response rate; 51.8% (1108) were female, and 21.1% of respondents (399) were aged 18 to 29 years, 24.9% (532) were aged 30 to 44 years, 26.0% (601) were aged 45 to 59 years, and 28.0% (738) were 60 years or older. For participants offered a $5 incentive, the reported frequency of recent influenza vaccination was 16.6% higher (95% CI, 9.1%-24.1%) among those told that eligibility (and thus payment) required recent vaccination than among those told that eligibility required no recent vaccination. The corresponding differences were 21.0% (95% CI, 13.5%-28.5%) among those offered $10 and 15.4% (95% CI, 7.8%-23.0%) among those offered $20. Estimated proportions of ineligible individuals who responded deceptively regarding eligibility ranged from 10.5% to 22.8% across study groups. There was no evidence that higher payment was associated with higher frequency of deception.In a nationally representative randomized survey experiment to evaluate whether and to what extent payment is associated with participants misleading investigators about their research eligibility, this study found evidence of significant deception. However, no association was observed between payment amount and frequency of deception. Further research is needed to extend these findings to clinical research. These data suggest that, when possible, investigators should rely on objective tests of eligibility rather than self-report.
Abstract 13758: Intrapulmonary Shunt and Cryptogenic Stroke in Older Patients: True Cause of Paradoxical Embolism?
Authors: Dae-gyun Park, Ji-Yeon Hong, Sung-Eun Kim, Jun-Hee Lee, Kyoo-Rok Han, Dong-Jin Oh
Journal: Circulation (2011)

Background: The association between the presence of patent foramen ovale (PFO) and cryptogenic stroke in older patients is controversial. Intrapulmonary shunt is frequently detected in agitated sal...
A Novel Anti-Glycoprotein (GP) Iba-Targeting Chimeric Fibrinolytic Agent Demonstrates In Vivo Efficacy Against Human Platelet-Enriched Thrombi in Mice
Authors: Randolph Lyde, Hyunsook Ahn, Vincent Hayes, Sergei Zaistev, Shu-Wha Lin, Zaverio M. Ruggeri, Renhao Li, Vladimir Muzykantov, Douglas B. Cines, Mortimer Poncz
Journal: Blood (2018)
Sarcolemmal α2-adrenoceptors in feedback control of myocardial response to sympathetic challenge
Authors: Alexey E. Alekseev, Sungjo Park, Oleg Yu. Pimenov, Santiago Reyes, Andre Terzic
Journal: Pharmacology & Therapeutics (2019)

α2-adrenoceptor (α2-AR) isoforms, abundant in sympathetic synapses and noradrenergic neurons of the central nervous system, are integral in the presynaptic feed-back loop mechanism that moderates norepinephrine surges. We recently identified that postsynaptic α2-ARs, found in the myocellular sarcolemma, also contribute to a muscle-delimited feedback control capable of attenuating mobilization of intracellular Ca2+ and myocardial contractility. This previously unrecognized α2-AR-dependent rheostat is able to counteract competing adrenergic receptor actions in cardiac muscle. Specifically, in ventricular myocytes, nitric oxide (NO) and cGMP are the intracellular messengers of α2-AR signal transduction pathways that gauge the kinase-phosphatase balance and manage cellular Ca2+ handling preventing catecholamine-induced Ca2+ overload. Moreover, α2-AR signaling counterbalances phospholipase C – PKC-dependent mechanisms underscoring a broader cardioprotective potential under sympathoadrenergic and angiotensinergic challenge. Recruitment of such tissue-specific features of α2-AR under sustained sympathoadrenergic drive may, in principle, be harnessed to mitigate or prevent cardiac malfunction. However, cardiovascular disease may compromise peripheral α2-AR signaling limiting pharmacological targeting of these receptors. Prospective cardiac-specific gene or cell-based therapeutic approaches aimed at repairing or improving stress-protective α2-AR signaling may offer an alternative towards enhanced preservation of cardiac muscle structure and function.
TCT-36 Delayed coronary obstruction after transcatheter aortic valve replacement
Authors: Richard Jabbour, Akihito Tanaka, Ariel Finkelstein, Michael Mack, Corrado Tamburino, Nicolas Van Mieghem, Ole De Backer, Pamela Gatto, Zouhair Rahhab, Verena Veulemans, Anja Stundl, Marco Barbanti, Roberto Nerla, Jan-Malte Sinning, Danny Dvir, Giuseppe Tarantini, Molly Szerlip, Didier Tchetche, Fausto Castriota, Christian Butter, Mohamed Abdel-Wahab, Horst Sievert, Ottavio Alfieri, John Webb, Josep Rodés-Cabau, Antonio Colombo, Azeem Latib
Journal: Journal of the American College of Cardiology (2017)
Screening for asymptomatic β-cell autoimmunity in young children
Authors: Anette-G Ziegler, Georg F Hoffmann, Joerg Hasford, Helena Elding Larsson, Thomas Danne, Reinhard Berner, Megan Penno, Anne Koralova, Jessica Dunne, Ezio Bonifacio
Journal: The Lancet Child & Adolescent Health (2019)