tbuckley/cabot-search huggingface dataset:
Abstract 1078: Identification of peptides binding to mesenchymal subtype breast cancer from phage display peptide library
Authors: Kelvin M. Jones, Rajeev Samant, Shree Singh, Deepa Bedi
Journal: Cancer Research (2018)

Abstract Most available therapeutic drugs efficiently treat tumors; however, absence of specificity has deleterious effects on patients. Identifying a tumor ablation method that has specificity with minimal to no side effects is needed. Phage display allows for expression of peptide and protein libraries on the surface of phage with a diversity of 109 peptides of different permutations, which leads to the selection of peptides and proteins, with high affinity and specificity. Phage display can be used as a tool to identify specific targets using a pIII phage library for identification of cell surface markers. To do so, we performed an initial depletion assay to isolate specific phages that express an affinity to human cells. We isolated a phage diversity of 10-2 from 109. Subsets of this population were used to identify phage and breast cancer cell interaction in vitro using an ELISA assay. Briefly, phages were exposed to epithelial and mesenchymal breast cancer cells and fibroblast cells. We have identified a phage profile that selectively targets tumor cells based on their transition from epithelial to mesenchymal. Interestingly, PE-26, a phage subset, indicated a greater affinity for more mesenchymal-like tumor cells. Moreover, we identified a 5-fold increase in the binding affinity for MDA-MB-231 and MCF-7 (overexpressed with TGF-β) in comparison to the control fibroblast cells. Additionally, PE-21 demonstrates a 6-fold increased affinity for breast cancer cells when contrasted with our control fibroblast cells. Our data provide further support that the identified phage profiles exhibit a preferential affinity for more mesenchymal-like tumor cells, which are known to be aggressive. This suggests their potential chemotherapeutic capability. Our future endeavors include further validation of selected phages and development of peptides to be employed as imaging agents to study EMT in vivo and as diagnostics to detect circulating tumor cells. Citation Format: Kelvin M. Jones, Rajeev Samant, Shree Singh, Deepa Bedi. Identification of peptides binding to mesenchymal subtype breast cancer from phage display peptide library [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1078.
Abstract 3771: Mechanistic and pharmacodynamic characterization of the immuno-oncological activity of RXDX-106, a novel TYRO3, AXL, and MER (TAM) inhibitor in clinical development
Authors: Amanda Albert, Erin D. Lew, Kristen Smith, Elizabeth A. Tindall, Yumi Yokoyama, Amy Diliberto, Heather Ely, Jack Lee, Robin Nevarez, Joanne Oh, Colin Walsh, Jason Christiansen, Gary Li, Robert Shoemaker
Journal: Cancer Research (2018)

Abstract The TAM family of receptor tyrosine kinases (RTKs) includes TYRO3, AXL, and MER, and is a unique set of molecular targets for cancer immunotherapy. TAM RTKs play a key role in the tumor microenvironment (TME) as negative regulators of innate immune responses and contribute to the evasion of cancer cells from immunosurveillance. RXDX-106 is a novel small molecule TAM inhibitor with single-digit nanomolar kinase inhibition and slow dissociation binding kinetics resulting in potent and durable target inhibition. In preclinical studies, RXDX-106 has demonstrated immune-mediated single agent in vivo activity in multiple syngeneic tumor models and potentiated anti-tumor activity in combination with immune checkpoint inhibitors. To characterize the mechanism of action of and pharmacodynamic responses to RXDX-106 treatment, an integrated approach was employed to explore RXDX-106-mediated immune modulatory effects at the cellular, protein, and transcriptional levels. In syngeneic tumor models, RXDX-106 treatment resulted in the recruitment of both innate and adaptive immune cell subtypes to the TME. Specifically, RXDX-106 treatment resulted in increased immune cell infiltration, macrophage polarization towards an antitumor M1 phenotype, activation of T cell and NK cell function, and modulation of immune markers at both the protein and RNA level, indicative of a pro-inflammatory and anti-tumorigenic effect. Importantly, the immune modulatory effects of RXDX-106 were concordant across platforms. Immune modulation was further characterized in a dose-dependent manner, with increasing immune cell infiltration observed with escalating doses of RXDX-106. In summary, RXDX-106 has the potential to restore and enhance immune function by modulating the local immunosuppressive TME. The unique mechanism of activating both innate and adaptive immunity, and regulating cross-talk between immune cells and tumor cells, supports clinical evaluation of RXDX-106 as an immunomodulatory agent for the treatment of a variety of cancers. Citation Format: Amanda Albert, Erin D. Lew, Kristen Smith, Elizabeth A. Tindall, Yumi Yokoyama, Amy Diliberto, Heather Ely, Jack Lee, Robin Nevarez, Joanne Oh, Colin Walsh, Jason Christiansen, Gary Li, Robert Shoemaker. Mechanistic and pharmacodynamic characterization of the immuno-oncological activity of RXDX-106, a novel TYRO3, AXL, and MER (TAM) inhibitor in clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3771.
Abstract 20617: Temporal Trends in Drug Abuse in Adults With Atrial Fibrillation show Worse Outcomes
Authors: Zeeshan Mansuri, Muhammad H Gul, Aditya Ganti, Divyank Patel, Kinsuk Chauhan, Achint Patel
Journal: Circulation (2016)

Objective: We sought to determine temporal trends, invasive treatment utilization and impact on outcomes of pre- stroke drug abuse on Atrial Fibrillation (AF) in adults. Background: Drug abuse is a...
Abstract 16636: Superior Vena Caval Occlusion: A Novel Approach to Improve Cardiac Function in Heart Failure
Authors: Navin K Kapur, Vikram Paruchuri, Shiva Annamalai, Lyanne Buiten, Marvin A Konstam, Richard H Karas
Journal: Circulation (2015)

Cardiac preload is a primary target of drug therapy for heart failure. No device based approaches to limit preload in heart failure exist. The inferior (IVC) and superior vena cava (SVC) provide two-thirds and one-third of venous return, respectively. We hypothesized that mechanical occlusion of the SVC improves biventricular function in heart failure by reducing ventricular preload. Methods and Results: To test this hypothesis, 4 adult swine underwent 60 minutes of left anterior descending artery occlusion followed by 60 minutes of reperfusion. 1 animal expired due to ventricular fibrillation after reperfusion. The acute hemodynamic effects of transient sequential percutaneous balloon occlusion of the SVC or IVC (n=4) were studied using conductance catheters before the onset of left ventricular (LV) injury. Transient IVC occlusion significantly reduced biventricular volumes, reduced LV stroke volume, and reduced LV peak-systolic pressure (Figure). In contrast, transient SVC occlusion reduced biventricular volumes but increased LV stroke volume, without decreasing LV peak-systolic pressure (Figure). IVC occlusion increased renal vein pressure from 10 to 24 mmHg, whereas SVC occlusion did not alter renal vein pressure. One week after LV injury, the hemodynamics of prolonged SVC occlusion were studied (n=3). Full SVC occlusion for 2 hours reduced biventricular volumes, and increased LV stroke volume, without decreasing LV peak-systolic or systemic blood pressure. Conclusions: SVC occlusion represents a novel device based approach that targets cardiac preload. In contrast to IVC occlusion, transient and prolonged full SVC occlusion was well tolerated. SVC occlusion reduces biventricular volume, while increasing cardiac output and sustaining systemic blood pressure, without adversely affecting renal hemodynamics. Future studies will test the clinical utility of continuous and intermittent SVC occlusion in acute and chronic heart failure.
Abstract 5799: Characterization and profiling of CB-103, a novel small-molecule protein-protein interaction inhibitor targeting the NOTCH transcription complex
Authors: Rajwinder Lehal, Charlotte Urech, Michele Vigolo, Maximilien Murone, Freddy Radtke
Journal: Cancer Research (2018)

Abstract NOTCH signalling is a key development pathway whose aberrant activation is known to play a role in multiple human cancers. In human tumors the NOTCH pathway can be activated by various genetic lesions such over expression of ligands/receptors, GOF mutations in NOTCH receptors, including protein stabilizing mutations in the PEST domain of NOTCH, chromosomal translocations, or loss-of-function mutations in the E3 ubiquitin ligase FBXW7 and other negative regulators of the pathway (SPEN, NUMB). Activation of signalling due to above mentioned mechanisms can be addressed in part using blocking antibodies against NOTCH ligands/receptors or small molecule inhibitors of the gamma secretase enzyme (GSIs). However, in human tumors where NOTCH signalling is constitutively activated due to chromosomal translocations in the NOTCH receptors (NOTCH1 and 2), none of the above-mentioned strategies will be effective. Moreover, due to on-target and off-target toxicities associated with blocking antibodies and GSIs, these anti-NOTCH agents failed to advance in clinical trials, although some of them showed signs of clinical efficacy. Given the role of NOTCH signalling in human tumors, there is a need to identify novel targets in the NOTCH pathway and develop new and more selective anti-NOTCH agents. To inhibit pan-NOTCH signalling in human tumors independently of the mechanisms of NOTCH activation, and in the most downstream part of the pathway, we have previously reported the discovery of a new class of small molecules able to target the NOTCH transcription complex enabling the specific inhibition of NOTCH target gene expression (e.g. cMYC, HES1, DTX1, CCND1). These small molecules act as protein-protein interaction inhibitors, and thereby compromise the assembly of functional NOTCH transcription complex. Here we present further in vitro and in vivo characterization of the lead molecule CB-103. The anti-cancer activity of CB-103 was extensively profiled in several human cancer cell lines representing NOTCH positive solid tumors, leukemias and lymphomas. Moreover, CB-103 responsiveness of these cell lines correlates with a downregulation of the NOTCH signature following treatment with CB-103. Specifically, we will present data outlining the in vivo pharmacokinetic and pharmacodynamic properties of CB-103. Citation Format: Rajwinder Lehal, Charlotte Urech, Michele Vigolo, Maximilien Murone, Freddy Radtke. Characterization and profiling of CB-103, a novel small-molecule protein-protein interaction inhibitor targeting the NOTCH transcription complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5799.
Negative Regulation of Mitochondrial Antiviral Signaling Protein–Mediated Antiviral Signaling by the Mitochondrial Protein LRPPRC During Hepatitis C Virus Infection
Authors: Giulia Refolo, Fabiola Ciccosanti, Martina Di Rienzo, Ariel Basulto Perdomo, Marta Romani, Tonino Alonzi, Marco Tripodi, Giuseppe Ippolito, Mauro Piacentini, Gian Maria Fimia
Journal: Hepatology (2018)

Hepatitis C virus (HCV) is highly efficient in establishing a chronic infection, having evolved multiple strategies to suppress the host antiviral responses. The HCV nonstructural 5A (NS5A) protein, in addition to its role in viral replication and assembly, has long been known to hamper the interferon (IFN) response. However, the mechanism of this inhibitory activity of NS5A remains partly characterized. In a functional proteomic screening carried out in HCV replicon cells, we identified the mitochondrial protein LRPPRC as an NS5A binding factor. Notably, we found that downregulation of LRPPRC expression results in a significant inhibition of HCV infection, which is associated with an increased activation of the IFN response. Moreover, we showed that LRPPRC acts as a negative regulator of the mitochondrial-mediated antiviral immunity, by interacting with mitochondrial antiviral signaling protein (MAVS) and inhibiting its association with TRAF3 and TRAF6. Finally, we demonstrated that NS5A is able to interfere with MAVS activity in a LRPPRC-dependent manner. Conclusion: Overall, our results indicate that NS5A contributes to the inhibition of innate immune pathways during HCV infection by exploiting the ability of LRPPRC to inhibit MAVS-regulated antiviral signaling.
Effect of Peer Comparison Letters for High-Volume Primary Care Prescribers of Quetiapine in Older and Disabled Adults
Authors: Adam Sacarny, Michael L. Barnett, Jackson Le, Frank Tetkoski, David Yokum, Shantanu Agrawal
Journal: JAMA Psychiatry (2018)

<h3>Importance</h3> Antipsychotic agents, such as quetiapine fumarate, are frequently overprescribed for indications not supported by clinical evidence, potentially causing harm. <h3>Objective</h3> To investigate if peer comparison letters targeting high-volume primary care prescribers of quetiapine meaningfully reduce their prescribing. <h3>Design, Setting, and Participants</h3> Randomized clinical trial (intent to treat) conducted from 2015 to 2017 of prescribers and their patients nationwide in the Medicare program. The trial targeted the 5055 highest-volume primary care prescribers of quetiapine in 2013 and 2014 (approximately 5% of all primary care prescribers of quetiapine). <h3>Interventions</h3> Prescribers were randomized (1:1 ratio) to receive a placebo letter or 3 peer comparison letters stating that their quetiapine prescribing was high relative to their peers and was under review by Medicare. <h3>Main Outcomes and Measures</h3> The primary outcome was the total quetiapine days supplied by prescribers from the intervention start to 9 months. Secondary outcomes included quetiapine receipt from all prescribers by baseline patients, quetiapine receipt by patients with low-value or guideline-concordant indications for therapy, mortality, and hospital use. In exploratory analyses, the study followed outcomes to 2 years. <h3>Results</h3> Of the 5055 prescribers, 231 (4.6%) were general practitioners, 2428 (48.0%) were in family medicine, and 2396 (47.4%) were in internal medicine; 4155 (82.2%) were male. All were included in the analyses. Over 9 months, the treatment arm supplied 11.1% fewer quetiapine days per prescriber vs the control arm (2456 vs 2864 days; percentage difference, 11.1% fewer days; 95% CI, −13.1% to −9.2% days;<i>P</i> &lt; .001; adjusted difference, −319 days; 95% CI, −374 to −263 days;<i>P</i> &lt; .001), which persisted through 2 years (15.6% fewer days; 95% CI, −18.1% to −13.0%;<i>P</i> &lt; .001). At the patient level, individuals in the treatment arm received 3.9% (95% CI, −5.0% to −2.9%;<i>P</i> &lt; .001) fewer days of quetiapine from all prescribers over 9 months, with a larger decrease among patients with low-value vs guideline-concordant indications (−5.9% [95% CI, −8.0% to −3.9%] vs −2.4% [95% CI, −4.0% to −0.9%],<i>P</i> = .01 for test that effects were equal for both patient groups). There was no evidence of substitution to other antipsychotics, and 9-month mortality and hospital use were similar between the treatment vs control arms. <h3>Conclusions and Relevance</h3> Peer comparison letters caused substantial and durable reductions in quetiapine prescribing, with no evidence of negative effects on patients. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT02467933
Abstract P098: Is There a Mismatch Between Length of Hospital Stay and Prognosis in Medicare Beneficiaries Hospitalized for Heart Failure?
Authors: Matthew S Loop, Melissa K Van Dyke, Ligong Chen, Todd M Brown, Raegan W Durant, Monika M Safford, Emily B Levitan
Journal: Circulation (2016)

Background: Length of stay (LOS) during heart failure (HF) hospitalizations has decreased, accompanied by recent increases in post-discharge mortality and 30-day readmission rates among these patients. Methods: We conducted a retrospective cohort study of 19,477 Medicare beneficiaries in order to determine whether patients with the longest LOS also had the highest risk of death or readmission. We included patients hospitalized for HF and discharged alive between 2007 and 2011 with documented left ventricular (LV) systolic, diastolic, or combined dysfunction. We estimated the associations of LOS, risk for 30-day mortality, and risk for 30-day readmission with: type of LV dysfunction, HF severity, comorbidity burden, discharge disposition, demographics, nursing home residence, and calendar year. Gamma regression, Poisson regression, and Cox proportional hazards were used to model LOS, 30-day mortality, and 30-day readmission, respectively. Each model included all covariates. Results: The mean (IQR) LOS was 5 (4 - 8) days, 7% of the patients died within 30 days, and 23% of the patients were readmitted within 30 days. Patients with isolated diastolic dysfunction (DD) had 2% shorter LOS than patients with any systolic dysfunction (SD), but had 10% lower 30-day mortality. Comorbidities were associated with a 3% to 10% longer LOS, with the exception of chronic kidney disease (CKD) (16% longer) and malnutrition (30% longer). Only CKD, malnutrition, and chronic obstructive pulmonary disease (COPD) were associated with 30-day mortality (22%, 51%, and 14% higher risk, respectively). Most comorbidities were associated with 10% - 20% higher risk of 30-day readmission. Regarding discharge disposition, patients discharged home had 40% shorter LOS, 78% lower 30-day mortality, and 11% lower risk for 30-day readmission than patients discharged to a skilled nursing facility (SNF). Conclusions: We found no mismatch between LOS and prognosis among Medicare beneficiaries hospitalized for HF.
Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts.
Authors: Maeve Aine Lowery, Ghassan K. Abou-Alfa, Howard A. Burris, Filip Janku, Rachna T. Shroff, James M. Cleary, Nilofer Saba Azad, Lipika Goyal, Elizabeth A. Maher, Lia Gore, Antoine Hollebecque, Muralidhar Beeram, Jonathan C. Trent, Liewen Jiang, Yuko Ishii, Julia Auer, Camelia Gliser, Samuel V. Agresta, Shuchi Sumant Pandya, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2017)

4015 Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC. Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses. Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1–5), ECOG 0–1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year. Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy). Clinical trial information: NCT02073994.
Abstract 291: Platelet Function Monitoring After Percutaneous Coronary Intervention: Updated Meta-analysis of Randomized Trials.
Authors: Akintunde M Akinjero, Oluwole Adegbala, Esosa Edo-Osagie, Nike Akinjero, Tomi Akinyemiju
Journal: Circulation Research (2017)

Background: The need to balance bleeding and clotting risks after percutaneous coronary intervention (PCI) has led to interest in platelet function monitoring as a strategy to improve post-PCI outcomes. The prognostic value of platelet function testing in monitoring response to antiplatelet therapy after PCI remains unclear. Prior studies have been inconclusive. We sought to conduct an updated meta-analysis to address this gap in knowledge. Methods: We conducted a systematic search of EMBASE, PUBMED and the Cochrane libraries for studies since inception to December 2016 on platelet function monitoring. Our search yielded 203 studies, out of which 83 were extracted for full-text review. Only 3 studies met inclusion criteria. We pooled odds ratios using random-effects statistics, Mantel-Haenszel method. I2 and Chi- squared statistic was used to evaluate for heterogeneity. Publication bias was assessed using the funnel plot. Primary outcome was major adverse cardiovascular events (MACE). This was defined in the studies as a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and bleeding complications. Results: The 3 randomized controlled trials that were analyzed involved 3701 patients. There were 550 MACE (29.76%) in the platelet function monitored group compared with 514 (27.74%) in the control. MACE (Figure 1) was not significantly higher for the platelet function monitored group during follow-up compared with control (pooled Odds Ratio:1.11 [95% CI: 0.96-1.28], p = 0.15). Tests for heterogeneity were not significant, with I2 of 0%, Chi2 = 1.52 (p = 0.47); and small study bias was absent on visual inspection of the funnel plot. Conclusions: Platelet function monitoring continues to be used in practice. Results from this meta-analysis show no benefit of platelet function monitoring compared with conventional strategy with regards to MACE after PCI. Future research is needed to further evaluate this finding.