tbuckley/cabot-search huggingface dataset:
Cariprazine Benefits Patients With Bipolar Depression
Authors: Anita Slomski
Journal: JAMA (2019)

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Prospective target assessment and multimodal prediction of survival for personalized and risk-adapted treatment strategies in multiple myeloma in the GMMG-MM5 multicenter trial
Authors: Dirk Hose, Susanne Beck, Hans Salwender, Martina Emde, Uta Bertsch, Christina Kunz, Christoph Scheid, Mathias Hänel, Katja Weisel, Thomas Hielscher, Marc S. Raab, Hartmut Goldschmidt, Anna Jauch, Jérôme Moreaux, Anja Seckinger
Journal: Journal of Hematology & Oncology (2019)

Personalized and risk-adapted treatment strategies in multiple myeloma prerequisite feasibility of prospective assessment, reporting of targets, and prediction of survival probability in clinical routine. Our aim was first to set up and prospectively test our experimental and analysis strategy to perform advanced molecular diagnostics, i.e., interphase fluorescence in-situ hybridization (iFISH) in ≥ 90% and gene expression profiling (GEP) in ≥ 80% of patients within the first cycle of induction chemotherapy in a phase III trial, seen as prerequisite for target expression-based personalized treatment strategies. Secondly, whether the assessment of risk based on the integration of clinical, cytogenetic, and expression-based parameters ("metascoring") is possible in this setting and superior to the use of single prognostic factors.We prospectively performed plasma cell purification, GEP using DNA-microarrays, and iFISH within our randomized multicenter GMMG-MM5-trial recruiting 604 patients between July 2010 and November 2013. Patient data were analyzed using our published gene expression report (GEP-R): after quality and identity control, integrated risk assessment (HM metascore) and targets were reported in clinical routine as pdf-document.Bone marrow aspirates were obtained from 573/604 patients (95%) and could be CD138-purified in 559/573 (97.6%). Of these, iFISH-analysis was possible in 556 (99.5%), GEP in 458 (82%). Identity control using predictors for sex, light and heavy chain type allowed the exclusion of potential sample interchanges (none occurred). All samples passed quality control. As exemplary targets, IGF1R-expression was reported expressed in 33.1%, AURKA in 43.2% of patients. Risk stratification using an integrated approach, i.e., HM metascore, delineated 10/77/13% of patients as high/medium/low risk, transmitting into significantly different median progression-free survival (PFS) of 15 vs. 39 months vs. not reached (NR; P < 0.001) and median overall survival (OS) of 41 months vs. NR vs. NR (P < 0.001). Five-year PFS and OS-rates were 5/31/54% and 25/68/98%, respectively. Survival prediction by HM metascore (Brier score 0.132, P < 0.001) is superior compared with the current gold standard, i.e., revised ISS score (0.137, P = 0.005).Prospective assessment and reporting of targets and risk by GEP-R in clinical routine are feasible in ≥ 80% of patients within the first cycle of induction chemotherapy, simultaneously allowing superior survival prediction.
Activated protein C ameliorates chronic graft-versus-host disease by PAR1-dependent biased cell signaling on T cells
Authors: Ranjeet K. Sinha, Ryan Flynn, Michael Zaiken, Katelyn Paz, Amanda L. Gavin, David Nemazee, José A. Fernández, Xiao Xu, John H. Griffin, Bruce R. Blazar
Journal: Blood (2019)
Abstract 3658: Characterization of the role of L3MBTL3 in medulloblastoma tumorigenesis
Authors: Honglai Zhang, Ester Calvo Fernandez, Claire Peabody, Rork Kuick, Sung-Soo Park, Thomas Saunders, Sandra Camelo-Piragua, Jean-Francois M. Rual
Journal: Cancer Research (2019)

Abstract Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements but are achieved at a high cost to quality of life. The Notch pathway governs cell proliferation in many biological contexts, including medulloblastoma tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of Notch for the mediation of Notch signals, and L3MBTL3, a methyllysine reader for which deletions are observed in medulloblastoma. We demonstrated that L3MBTL3 is part of a molecular mechanism linking the KDM1A demethylase to Notch signal modulation. We hypothesize that malfunction of this molecular mechanism may contribute to the previously suggested tumor suppressor role of L3MBTL3 in medulloblastoma. In a survival analysis using our L3mbtl3 KO mouse in combination with a genetically engineered mouse model of medulloblastoma, we validated our hypothesis that L3mbtl3 is a tumor suppressor in this disease context. Our discovery provides insights into the role of the L3MBTL3 in medulloblastoma that could be harnessed in the future for the therapeutic benefit of medulloblastoma patients. Citation Format: Honglai Zhang, Ester Calvo Fernandez, Claire Peabody, Rork Kuick, Sung-Soo Park, Thomas Saunders, Sandra Camelo-Piragua, Jean-Francois M. Rual. Characterization of the role of L3MBTL3 in medulloblastoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3658.
Abstract 10009: Aortic Hemodynamic and Mechanical Properties are Concomitantly Reduced in Pulmonary Arterial Hypertension
Authors: Michal Schafer, Omid Jazaeri, Vitaly O Kheyfets, Kendall S Hunter, Robin Shandas, Kern Buckner, Brett E Fenster
Journal: Circulation (2015)

Introduction: Although pulmonary arterial hypertension (PAH) has significant impact on flow and tissue remodeling in the pulmonary vasculature, previous studies indicate that PAH is also associated with increased stiffness and endothelial dysfunction in the systemic circulation. Alterations in vascular properties of the systemic circulation may have hemodynamic relevance for left ventricular adaptation to PAH. Reduced wall shear stress (WSS) and vascular elastic markers are known manifestations of vascular disease and may provide insight into the vascular behavior of the systemic circulation in PAH. Hypothesis: We hypothesized that WSS and mechanical elasticity are altered in the thoracic aorta in PAH, and that these measures correlate with pulmonary hemodynamics. Methods: As part of a prospective study, 18 patients with PAH and 5 age-matched controls underwent the same day right heart catheterization (RHC) and 4 dimensional flow cardiac magnetic resonance (4D CMR) for computation of WSS in four aortic regions (endovascular landing zones 1 to 4). The aortic capacitance was calculated as the ratio of stroke volume (SV) and pulse pressure (PP). The elastic modulus was defined as the inverse aortic strain divided by PP. The difference in median values was assessed via Wilcoxon ranked sum method and Spearman rho was used for linear regression analysis. Results: The WSS (N/m2) was significantly reduced in all four aortic zones (zone 1: 0.540 vs. 0.800, p = 0.0325; zone 2: 0.424 vs. 0.615, p = 0.0402; zone 3: 0.419 vs. 0.625, p = 0.0250; zone 4: 0.513 vs. 0.794, p = 0.0046). While aortic capacitance (mL/mmHg) was significantly reduced in the PAH subjects (1.82 vs. 5.97, p = 0.008), the elastic modulus (mmHg) was higher (3.52 vs. 8.25, p = &lt; 0.001). The most significant correlation was between the WSS in zone 4 and pulmonary vascular resistance (rho = -0.70, p = 0.006) and mean pulmonary artery pressure (rho = -0.62, p = 0.002). Conclusions: PAH is associated with reduced WSS in the thoracic aorta, suggesting reduced systemic flow conduction in PAH. WSS and mechanical vascular markers may aid in the understanding of the impact of PAH on systemic hemodynamics and tissue mechanics.
Abstract 12144: Quantifying Myocardial Fibrosis in Hypertensive Left Ventricular Hypertrophy Using T1 Mapping
Authors: Sujith Kuruvilla, Rajesh Janardhanan, Ellen Keeley, Yang Yang, Christopher Kramer, Michael Salerno
Journal: Circulation (2013)

Background: Diffuse myocardial fibrosis contributes to increased cardiovascular risk in hypertensive heart disease (HHD) and left ventricular hypertrophy (LVH). We hypothesize that T1 mapping by ca...
Production of Anti-CD19 CAR T Cells for ZUMA-3 and -4: Phase 1/2 Multicenter Studies Evaluating KTE-C19 in Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R ALL)
Authors: Marianna Sabatino, Kenny Choi, Vijay Chiruvolu, Marc Better
Journal: Blood (2016)
Abstract 3090: <i>In vivo</i> characterization of AMG 510 - a potent and selective KRASG12Ccovalent small molecule inhibitor in preclinical KRASG12Ccancer models
Authors: Karen Rex, Anne Y. Saiki, Ji-Rong Sun, Tyler Holt, Neelima Koppada, Brian A. Lanman, Laurie P. Volak, Robert S. Foti, Victor J. Cee, J. Russell Lipford, Jude Canon
Journal: Cancer Research (2019)

Abstract Somatic activating mutations of RAS family members are tumor driver mutations found in an estimated 21% of all cancers. Oncogenic KRAS mutations at residues G12, G13, and Q61 represent the most common RAS mutations found in solid malignancies. The prevalence of KRAS p.G12C tumors is ~13% of lung adenocarcinoma (including NSCLC), 3% of colorectal carcinoma (CRC), and 1% to 2% of numerous other solid tumors, representing an unmet medical need. We have developed AMG 510, an orally bioavailable, covalent inhibitor of KRASG12C with potent biochemical and cellular activity, and robust in vivo efficacy. AMG 510 inhibited SOS-catalyzed nucleotide exchange of recombinant mutant KRASG12C/C118A but had minimal effect on KRASC118A, which is wildtype at position 12. In cellular assays, AMG 510 covalently modified KRASG12C and inhibited KRASG12C signaling as measured by phosphorylation of ERK1/2 (p-ERK) in all KRAS p.G12C-mutant cell lines tested but did not inhibit p-ERK in cell lines with various other KRAS mutations. AMG 510 also selectively impaired viability of KRAS p.G12C mutant cell lines but did not affect cell lines with other KRAS mutations. In vivo pharmacodynamic assays demonstrated dose- and time-dependent inhibition of KRASG12Csignaling in human pancreatic and NSCLC tumor xenografts. Covalent modification of KRASG12C by AMG 510 was measured by mass spectrometry and correlated with p-ERK inhibition in tumors. AMG 510 significantly inhibited the growth of KRAS p.G12C xenografts and resulted in tumor regression. Combination treatment of AMG 510 with standard-of-care and targeted agents demonstrated enhanced tumor growth inhibition compared to either single agent. In a syngeneic model of KRAS p.G12C mutant cancer, AMG 510 treatment significantly inhibited tumor growth and caused regression. AMG 510 is currently in Phase 1, first-in-human clinical trials for patients with advanced solid tumors harboring a KRAS p.G12C mutation. Citation Format: Karen Rex, Anne Y. Saiki, Ji-Rong Sun, Tyler Holt, Neelima Koppada, Brian A. Lanman, Laurie P. Volak, Robert S. Foti, Victor J. Cee, J. Russell Lipford, Jude Canon. In vivo characterization of AMG 510 - a potent and selective KRASG12Ccovalent small molecule inhibitor in preclinical KRASG12Ccancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3090.
Neoadjuvant chemotherapy versus neoadjuvant hormonal therapy in postmenopausal women with ER-positive, HER2/neu negative locally advanced breast cancer.
Authors: Tadeu Frantz Ambros, Isildinha M. Reis, Dilprit Bagga, Jose Caetano Villasboas, Clifford Blieden, Victoria Sujoy, Jean L. Wright, Kunal Saigal, Carmen Gomez Fernandez, Judith Hurley
Journal: Journal of Clinical Oncology (2012)

595 Background: Postmenopausal women with large ER+/HER-2 negative tumors frequently receive neoadjuvant chemotherapy (NC), but pathological complete response (pCR) rates are low. Neoadjuvant hormonal therapy (NH) may offer benefit in this setting. Methods: Retrospective review of medical records from University of Miami/Jackson Memorial Hospital from 1998-2011. Primary outcomes: pCR (absence of invasive tumor in breast and lymph nodes at surgery), recurrence free survival (RFS) and tumor size reduction evaluated through comparison of palpable breast mass size at presentation with pathological tumor size in surgical specimen, and categorized as good response (GR) ≥ 30% reduction or no response (NR) &lt; 30%. The Kaplan-Meier method and the log-rank test were used in the analysis of RFS. Results: Data from 151 post-menopausal women with ER+/HER-2 negative BC who received NC (57%) or NH (43%) was analyzed. Median follow-up among alive patients with no evidence of disease was 5.4 years in NC and 2.9 years in NH. Mean age was higher in the NH group (63.3 vs 56.1, p&lt;0.0001). There were no racial or ethnic differences between the groups. Clinical stage was comparable in NC and NH (IIA 5.8% vs 9.2%, IIB 25.6% vs 20%, IIIA 37.2% vs 29.2%, IIIB/IIIC 31.4% vs 41.5%, p=0.775). Tumor histology was predominantly ductal in both groups (NC 85.7% and NH 78.5%, p=0.247). pCR was similar in NC and NH (4.7% vs 0%, p=0.078) along with RFS (median 8.5 yrs vs 6.0 yrs, p=0.946). In the NC group, GR was significantly more frequent (77.9% vs 60%, p=0.017). Among patients in the NH group, having GR was predictive of longer RFS (5-year rate 83.7% vs 50.5%, p=0.014). Breast only pCR occurred at equivalent rates between NC and NH (9.3% vs 3.1%, p=0.189) as did the absence of lymph node metastasis (29.1% vs 26.2%, p=0.606). In the NH cohort 38.5% received no adjuvant chemotherapy. Conclusions: NH provides an effective alternative to NC and, if there is a GR, may preclude the need for chemotherapy in over one third of postmenopausal women with large ER positive/HER-2 negative breast cancer.
A phase I study of 2-cyano-3, 12 dioxoolean-1, 9-dien-28-oic acid (CDDO) in advance solid tumors
Authors: B. Holkova, S. Kummar, P. Glauber, A. Chen, J. M. Strong, R. J. Parker, J. Collins, A. J. Murgo, J. H. Doroshow, M. E. Gutierrez
Journal: Journal of Clinical Oncology (2007)

14137 Background: CDDO, a synthetic triterpenoid, induces apoptosis through intrinsic and extrinsic pathways, and as a ligand for the transcription factor PPAR-? that controls cellular differentiation and growth inhibition. Methods: CDDO was given as a 5 day continuous infusion every 28 days; starting dose 0.6 mg/m 2 /hr. Accelerated titration design used, 1 patient (pt)/cohort entered until a single pt has dose-limiting toxicity (DLT) or 2 pts exhibit grade (gr) = 2 toxicity during the first cycle. The study then converts to a standard 3–6 pt/cohort design. Maximum tolerated dose (MTD): Dose at which no more than 1/6 pts have DLT and the dose below which at least 2/6 patients have DLT. Objectives: Determine toxicity profile, pharmacokinetics (PK), and MTD of CDDO. PK were determined by LC-MS/MS analysis of plasma collected pre, during and post CDDO infusion. Results: 6 pts have been accrued thus far up to dose level 6. (19.2 mg/m2). Diagnoses: colon -3, sarcoma-1, bladder -1 and ovary-1. Median age: 52. DLT and MTD have not yet been achieved. Gr 1–2 toxicities have been acceptable: anemia, thrombocytopenia, decreased Na+, Mg++ and albumin, elevated Ca++, transaminases and bilirubin, and anorexia, fatigue and constipation. Gr 4 pulmonary emboli (unrelated to CDDO) was seen in one pt. PK: Steady state CDDO plasma concentrations (C ss ) in the first 3 dose levels increased linearly (see table ). Post infusion CDDO plasma concentrations decreased in a bi- exponential manner for the first three dose levels. Data indicate that &lt; 1% of CDDO is excreted in the urine unchanged. No oxidative metabolism has been observed; however, we identified a CDDO glucuronide conjugate in urine and in human liver tissue incubations in vitro. Conclusions: The DLT and MTD have not been reached, and accelerated dose escalation continues. Since the CDDO C ss appears to increase linearly with dose, we anticipate achieving 1 μM plasma levels at dose level 5 (9.6mg/m2/hr), the effective concentration in preclinical models. [Table: see text] No significant financial relationships to disclose.
Abstract 16967: High Dose Beta-blocker Therapy Does Not Overcome Effects of Prolonged Cardiac Sympathetic Activation
Authors: Naoko Yamaguchi, Daigo Yagishita, Siamak Salavatian, Koji Yoshie, Jeffery L Ardell, Kalyanam Shivkmar, Marmar Vaseghi
Journal: Circulation (2017)

Background: β-adrenergic receptor blockers inhibit effects of sympathetic activation and reduce risk of ventricular arrhythmias (VT), but many patients experience recurrent VT despite maximal doses...
Abstract 224: Socioeconomic Disparities in Layperson CPR Training Within a Large U.S. City
Authors: Nabil M Abdulhay, Konstantinos Totolos, David G Buckler, Nicole Hewitt, Marion Leary, Benjamin S Abella
Journal: Circulation (2018)

Aim of the Study: Prompt bystander CPR is a crucial intervention to improve cardiac arrest survival. However, recent work suggests that the prevalence of layperson CPR training remains low. We sought to understand how individual factors and neighborhood characteristics influence an individual’s likelihood of being trained in CPR within a large U.S. city. We hypothesized that higher socioeconomic status (educational attainment, and median household income (MHI)) would be associated with a higher likelihood of having previously received CPR training. Methods: Through The Mobile CPR Project, a program providing hands-only CPR and AED education to underserved communities in the greater Philadelphia region, we surveyed participants regarding prior CPR training. Survey questions pertained to race, gender, education, prior CPR training, Automated External Defibrillator (AED) awareness, and nearest street intersection to their residence. MHI was extrapolated via census tract data. Results: From 7/2016 to 4/2018, 1665 subjects completed surveys prior to CPR training. Of these, 70% were female, 70% were non-white, median age was 41 [IQR 25-59] yrs, and MHI was $39,318 [IQR $27,708-$60,795]. Subjects residing in tracts with MHI below the cohort median were significantly less likely to have ever received CPR training (first quartile: OR 0.646, CI 0.491 -0.850, p=0.002; second quartile: OR 0.576, CI 0.437 - 0.759, p&lt;0.001). Gender was not significantly related to likelihood of being trained. Individuals who did not complete high school were less likely to ever receive training (Less than high school: OR 0.175, CI 0.089 - 0.344, p&lt;0.001; Some high school: OR 0.452 0.303 - 0.675, p&lt;0.001). In multiple logistic regression controlling for age, race, gender, MHI, and education, increasing educational attainment was associated with higher likelihoods of ever receiving trained (OR 7.96 Master’s or Doctoral compared to less than high school, CI 5.24 - 12.11, p &lt; 0.001). Conclusions: Among laypersons attending a free CPR training session, there is a strong association between socioeconomic factors (MHI, educational attainment) and likelihood of prior CPR training.
Abstract 14892: Impact of Past and Current Smoking on Mortality Risk in Angiographied Coronary Patients With Type 2 Diabetes
Authors: Christoph H Saely, Alexander Vonbank, Christine Heinzle, Daniela Zanolin, Barbara Larcher, Arthur Mader, Andreas Leiherer, Axel Muendlein, Heinz Drexel
Journal: Circulation (2018)

Introduction: Smoking is a major risk factor for heart disease. When combined with other risk factors (such as unhealthy blood cholesterol levels, high blood pressure, and overweight or obesity) sm...
Abstract 2312: Anti-CS1 x anti-CD3 bispecific antibody (BiAb)-armed anti-CD3 activated T cells (CS1-BATs) specifically kill CS1+ myeloma cells and release type-1 cytokines
Authors: Manley Huang, Archana Thakur, Lawrence G. Lum
Journal: Cancer Research (2019)

Abstract Although advances in multiple myeloma (MM) therapy such as stem cell transplantation and newly approved biological agents have shown promising results, MM remains a terminal disease. Thus, new strategies to eliminate or control MM cells are needed. Elotuzumab, a humanized monoclonal antibody approved for treatment of MM, targets myeloma cells expressing CS1/SLAMF7. We heteroconjugated anti-CD3 (OKT3) and elotuzumab to develop a BiAb, CS1Bi, to target activated T cells (ATC) to CS1+ MM cells. To examine the potential therapeutic activity of BATs against MM, we tested the ability of ATC armed with CS1Bi to bind to MM cell lines, specifically kill MM cells lines expressing different levels of CS1, and produce Th1 cytokines upon engaging MM tumor targets. Initial studies showed that CS1-BATs bound to MM cells by flow cytometry and specifically killed CS1+ targets as measured in a 6 hour 51Cr-release assay. Cytokine secretion by CS1-BATs vs. unarmed ATC (n=2) of interferon-γ (IFN- γ: 512 pg/mL vs. 260pg/mL), tumor necrosis factor-α (TNF- α: 450pg/mL vs. 110pg/mL), granulocyte-macrophage colony-stimulating factor (GM-CSF: 217 pg/mL vs. 135 pg/mL), macrophage inflammatory protein-1α (MIP-1α: 8250 pg/mL vs. 400 pg/mL), macrophage inflammatory protein-1β (MIP-1β: 14750 pg/mL vs. 600 pg/mL), and RANTES (3550 pg/mL vs. 2600 pg/mL) were induced when CS1-BATs were co-cultured with CS1+ cell line, L-363 for 24h at E:T of 25:1. A more sensitive quantitative flow cytometry-based cytotoxicity assay was developed based on comparing of the number of eFluor 450-labeled target cells pre- and post-incubation with either CS1Bi-BATs or unarmed ATC prepared from healthy donors, or culture media alone. The number of eFluor450+/7AAD- viable cells/unit volume post-incubation were compared to the number of viable cells in untreated wells to calculate the percent cytotoxicity. This assay reproducibly demonstrated significant killing of five MM cell lines by CS1-BATS (armed with 50ng CS1Bi/106 ATC at an E:T ratio of 1:1) ranging up to 60%, depending on the target line, (n=8). Between 78- 95% of MM.1S cells were eliminated at an E:T ratio of 3:1 (n=2). These data demonstrate the clinical relevance of this anti-MM strategy for use in a Ph1/II clinical trial in patients with relapsed and/or refractory MM. Citation Format: Manley Huang, Archana Thakur, Lawrence G. Lum. Anti-CS1 x anti-CD3 bispecific antibody (BiAb)-armed anti-CD3 activated T cells (CS1-BATs) specifically kill CS1+ myeloma cells and release type-1 cytokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2312.