tbuckley/cabot-search huggingface dataset:
Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib
Authors: Axel Bex, Peter Mulders, Michael Jewett, John Wagstaff, Johannes V. van Thienen, Christian U. Blank, Roland van Velthoven, Maria del Pilar Laguna, Lori Wood, Harm H. E. van Melick, Maureen J. Aarts, J. B. Lattouf, Thomas Powles, Igle Jan de Jong, MD, PhD, Sylvie Rottey, Bertrand Tombal, Sandrine Marreaud, Sandra Collette, Laurence Collette, John Haanen
Journal: JAMA Oncology (2018)

In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown.To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib.This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied.Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy.Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points.The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%).Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib.ClinicalTrials.gov identifier: NCT01099423.
A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1
Authors: Naifei Chen, Gang Zhao, Xu Yan, Zheng Lv, Hongmei Yin, Shilin Zhang, Wei Song, Xueli Li, Lingyu Li, Zhonghua Du, Lin Jia, Lei Zhou, Wei Li, Andrew R. Hoffman, Ji-Fan Hu, Jiuwei Cui
Journal: Genome biology (2018)

Friend leukemia virus integration 1 (FLI1), an ETS transcription factor family member, acts as an oncogenic driver in hematological malignancies and promotes tumor growth in solid tumors. However, little is known about the mechanisms underlying the activation of this proto-oncogene in tumors. Immunohistochemical staining showed that FLI1 is aberrantly overexpressed in advanced stage and metastatic breast cancers. Using a CRISPR Cas9-guided immunoprecipitation assay, we identify a circular RNA in the FLI1 promoter chromatin complex, consisting of FLI1 exons 4-2-3, referred to as FECR1.Overexpression of FECR1 enhances invasiveness of MDA-MB231 breast cancer cells. Notably, FECR1 utilizes a positive feedback mechanism to activate FLI1 by inducing DNA hypomethylation in CpG islands of the promoter. FECR1 binds to the FLI1 promoter in cis and recruits TET1, a demethylase that is actively involved in DNA demethylation. FECR1 also binds to and downregulates in trans DNMT1, a methyltransferase that is essential for the maintenance of DNA methylation. These data suggest that FECR1 circular RNA acts as an upstream regulator to control breast cancer tumor growth by coordinating the regulation of DNA methylating and demethylating enzymes. Thus, FLI1 drives tumor metastasis not only through the canonical oncoprotein pathway, but also by using epigenetic mechanisms mediated by its exonic circular RNA.
Dendritic Cell Membrane Vesicles for Activation and Maintenance of Antigen‐Specific T Cells
Authors: Lukasz J. Ochyl, James J. Moon
Journal: Advanced Healthcare Materials (2018)

Cell membranes have recently gained attention as a promising drug delivery system. Here, dendritic cell membrane vesicles (DC-MVs) are examined as a platform to promote T cell responses. Nanosized DC-MVs are derived from DCs pretreated with monophosphoryl lipid A (MPLA), a FDA-approved immunostimulatory adjuvant. These "mature" DC-MVs activate DCs in vitro and increase their expression of costimulatory markers. DC-MVs also promote cross-priming of antigen-specific T cells in vitro, increasing their survival and CD25 expression. In addition, these mature DC-MVs potently augment the expansion of adoptively transferred CD8+ T cells in vivo, generating twofold to fourfold higher frequency of antigen-specific T cells, compared with other control formulations, including "immature" DC-MVs obtained without the MPLA pretreatment. Taken together, these results suggest that DC-MVs are an effective delivery platform for T cell activation and may serve as a potential delivery system for improving adoptive T cell therapy.
Early Single-Site Experience With Transcatheter Tricuspid Valve Replacement
Authors: Rebecca T. Hahn, Isaac George, Susheel K. Kodali, Tamim Nazif, Omar K. Khalique, Deniz Akkoc, Alex Kantor, Torsten P. Vahl, Amisha Patel, Elliott Elias, Vivian Ng, Roberto Spina, Krzysztof Bartus, Poonam Velagapudi, Isaac Wu, Martin Leon, Vinayak Bapat
Journal: JACC. Cardiovascular imaging (2018)
Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expression to hepatocellular iron load
Authors: Carine Fillebeen, Edouard Charlebois, John Wagner, Angeliki Katsarou, Jeannie Mui, Hojatollah Vali, Daniel Garcia-Santos, Prem Ponka, John Presley, Kostas Pantopoulos
Journal: Blood (2018)
Can solid-phase assays replace immunofluorescence for ANA screening?
Authors: Nicola Bizzaro
Journal: Annals of the Rheumatic Diseases (2018)

The paper by Pisetsky et al 1 has stimulated a timely and interesting debate on a focal point in the diagnosis of autoimmune rheumatic diseases, that is, the accuracy of the antinuclear antibody (ANA) test and the reliability of the results provided by this test. The data produced by Pisetsky et al once more demonstrate the poor standardisation of the ANA assay when performed by the indirect immunofluorescence (IIF) method and the enormous difference that exists between different ANA-IIF kits. However, issues are related to intermethods variability and to the intrinsic limitations of the IIF method. Whatever title is chosen, it entails either a relevant loss of diagnostic specificity or sensitivity. This raises the question of whether IIF on HEp-2 cell substrates should be still considered the gold standard for ANA detection as stated almost 10 years ago by the American College of Rheumatology (ACR). The reasons that led the ACR to take this position were related to the insufficient diagnostic sensitivity of emerging alternative methods to IIF. These alternative methods, which were then almost exclusively made up of immunoenzymatic assays (ELISA), were spreading in clinical laboratories as substitutes of the manual IIF method to overcome known IIF limitations and for their higher throughput. …
Abstract 11581: Longer Receptor Residence Times Improve the Effectiveness of CCR2 Antagonists in the Prevention of Atherosclerosis
Authors: Ilze Bot, Natalia V Ortiz Zacarias, Henk de Vries, Peter J van Santbrink, Daniel van der Velden, Johan Kuiper, Dean Stamos, Adriaan P IJzerman, Laura H Heitman
Journal: Circulation (2015)

The chemokine receptor CCR2 is known to be critically involved in atherosclerosis development, rendering blockade of the CCL2-CCR2 axis of therapeutic interest. CCR2 antagonists have, however, limited clinical success. Interestingly, it was shown for other drug targets that a measure for the dissociation of the drug-receptor complex, the so-called residence time (RT), can have a crucial impact on a drug’s efficacy. In this study, we thus aimed to determine whether an increased RT improves the therapeutic effectiveness of CCR2 antagonists. Carotid artery atherosclerosis was induced by collar placement in apoE -/- mice, followed by treatment with the short RT CCR2 antagonist 15b (RT=15 min, 150 μg/day), the long RT CCR2 antagonist 15a (RT=714 min, 150 μg/day) or vehicle control. After four weeks, atherosclerotic plaques were analyzed. Treatment with the CCR2 antagonists did not affect body weight or plasma cholesterol levels. At sacrifice, circulating CCR2 + monocyte numbers were only significantly reduced in the long RT 15a-treated mice (controls: 14.9±3.2*10 3 , 15b: 9.1±3.1*10 3 and 15a: 4.5±1.0*10 3 cells/mL, *P&lt;0.05). Atherosclerotic plaque size was reduced from 64.4±11.8*10 3 μm 2 in control mice to 33.2±6.8*10 3 μm 2 in 15b-treated mice (-49%, *P&lt;0.05), and even up to 17.6±4.1*10 3 μm 2 in 15a-treated mice (-73%, **P&lt;0.01). Interestingly, relative plaque macrophage content was only decreased in 15a-treated mice compared to both control and 15b-treated mice (controls: 46±4%, 15b: 45±6%, 15a: 25±8%, *P&lt;0.05), while neutrophil and mast cell numbers were not affected. In the aortic root, 15b did not significantly affect plaque size (controls: 252±25*10 3 μm 2 vs 15b: 196±17*10 3 μm 2 ), while the long RT CCR2 antagonist 15a inhibited plaque development to 157±15*10 3 μm 2 (-38%, **P&lt;0.01). Also at that site of lesion development, macrophage area was only significantly reduced in the 15a-treated mice (controls: 35±4%, 15b: 32±3%, 15a: 23±4%, *P&lt;0.05 compared to controls). In conclusion, our data demonstrate that the CCR2 antagonist with a long residence time was more effective in inhibiting atherosclerotic plaque development compared to the short RT antagonist, which implies that receptor residence time is an important parameter in drug development.
Parvovirus B19 Infection
Authors: Marika Mende, Katja Sockel
Journal: New England Journal of Medicine (2018)

A 67-year-old woman with a history of a lung transplantation presented with dyspnea on exertion and a hemoglobin level of 6.7 g per deciliter. Bone marrow aspiration revealed giant proerythroblasts. PCR testing confirmed parvovirus B19 infection.
Fair Governance of Biotechnology: Patents, Private Governance, and Procedural Justice
Authors: Nienke de Graeff, Léon E. Dijkman, Karin R. Jongsma, Annelien L. Bredenoord
Journal: The American Journal of Bioethics (2018)

This article refers to:Patenting Foundational Technologies: Lessons From CRISPR and Other Core Biotechnologies
Clinical Features of Immune Checkpoint Inhibitor-Associated Autoimmune Hemolytic Anemia: A Series of 14 Cases
Authors: Rebecca Karp Leaf, Christopher Ferreri, Kerry Lynn Reynolds, Deepa Rangachari, James Mier, Wesley Witteles, George Ansstas, Theodora Anagnostou, Leyre Zubiri, Zofia Piotrowska, Thein H. Oo, David Iberri, Mark Yarchoan, April Salama, Osama Rahma, David Leaf
Journal: Blood (2018)
Abstract 16450: The Impact of Left Ventricular versus Simultaneous Biventricular Pacing on Structural and Biochemical Reverse Remodeling in Patients With Heart Failure: Insights From the EvAluation of Resynchronization Therapy for Heart Failure (EARTH) Trial
Authors: Sabah Skaf, Bernard Thibault, Eileen O’Meara, Paul Khairy, Annik Fortier, Halyna Prylutska, Céline Pitre, Michel White, Anique Ducharme
Journal: Circulation (2015)

Introduction: Cardiac Resynchronization Therapy (CRT) with simultaneous biventricular pacing (BiVP) is recommended for patients with heart failure and wide QRS, however up to a third of patients do not respond. GREATER-EARTH has demonstrated similar benefits with BiVP or LV pacing (LVP). Herein, we evaluate the effects of these two CRT modes on cardiac remodeling, evaluated by echocardiography and circulating biomarkers. Methods: 121 patients (LVEF≤35% and QRS≥120ms) referred for defibrillator implantation were randomized to BiVP or LVP for consecutive 6-month periods with cross-over. The primary endpoint was the change in LV end-systolic volume (LVESV) between patients with BiVP vs LVP from baseline to 6 months. Secondary endpoints included changes in LVEF, mitral regurgitation, RV and diastolic function. Changes in levels of markers of cardiac remodeling were also compared. Results: Both CRT pacing modes led to remodeling benefits after 6-months of therapy: LVESV decreased from 162±57mL at baseline to 130±63mL with BiVP vs 130±60 mL with LVP (p=0.68 between CRTs), with a positive response (≥15% LVESV reduction) being observed in 49% of patients with BiVP and 33% of LVP, p=0.09. Similarly, RV remodeling (dimension and RV-MPI) was equally improved with both pacing strategies (p=0.69 and p=0.38 respectively, between CRTs). Interestingly, estimated systolic PAP (from 43±14 to 37±10 and 41±14, p=0.008), selected indices of LV diastolic function such as indexed LA volume (p=0.045) and diastolic dysfunction grade (p=0.019), as well as changes in MR grade (p=0.004) were significantly improved only with BiVP. In parallel, there was a non-statistically significant decrease in NT-proBNP, from 2559±3296 to 1554±2092 and 1630±1950 ng/L, with BiVP and LVP respectively (p=0.093) as well as a trend in decreasing PIIINP levels, from 8.3±3.0 to 7.5±2.7 and 7.6±2.3 with BiVP and LVP respectively, p=0.097. Conclusions: In this prospective, multicenter, randomized, double-blind study, both BiVP and LVP resulted in improvements in LV remodelling assessed by echocardiography, while more patients responded to BiVP. BiVP may be superior to LVP to improve multiple aspects of myocardial remodeling and should remain the preferred mode of CRT in patients with advanced HF.
<i>KIF5B-RET</i>: Discovery of a novel fusion oncogene in lung adenocarcinomas by a systematic screen for tyrosine kinase fusions and identification of patients for a RET targeted therapy trial.
Authors: Yoshiyuki Suehara, Maria E. Arcila, Alexander Edward Dela Cruz Drilon, Tatsuo Ito, Lu Wang, Adnan Hasanovic, Raya Khanin, Naiyer A. Rizvi, Marc Ladanyi
Journal: Journal of Clinical Oncology (2012)

7578 Background: The mutually exclusive pattern of major targetable driver oncogenes in lung adenocarcinomas (ADC) suggests that other similar driver oncogenes may exist. We therefore performed a systematic screen for tyrosine kinase (TK) fusions in cases without known driver oncogenes by measuring aberrantly high RNA expression of kinase domain (KD) exons relative to more 5’ exons. Methods: We studied 74 patients whose lung ADC lacked mutations in KRAS, EGFR, BRAF, HER2, and ALK fusions. A NanoString-based assay was designed to query the transcripts of 90 TKs at two points: 5’ to the KD and within or 3’ to the KD. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 3’ to 5’ expression ratios. The assay was validated on samples with known ALK and ROS fusions. Presumed novel fusion events were followed up by rapid amplification of cDNA ends (RACE) and confirmatory RT-PCR. Results: The NanoString assay identified aberrant 5’ to 3’ ratios in ROS and RET in 2 cases, respectively, out of 74. RACE analysis isolated a novel GOPC-ROS fusion in the former and a novel KIF5B-RET fusion in the latter, both confirmed by RT-PCR. Further screening by RT-PCR for KIF5B-RET identified one more positive sample in the study set that had not been detected by NanoString. At the RNA level, both fusions joined exon 15 of KIF5B to exon 12 of RET, thus retaining a portion of the dimerization domain of KIF5B and the entire KD of RET, analogous to RET fusions in papillary thyroid carcinoma (TC). One KIF5B-RET patient was a 60 y.o. female never smoker, the other, a 73 y.o. male former smoker. Conclusions: The novel KIF5B-RET fusion described here and also recently reported by Ju YS et al. (Genome Res, Dec 22, 2011) defines a new subset of lung ADC with a potentially targetable driver oncogene. Based on these genetic data and the preclinical activity of the RET inhibitor XL184 (Exelixis) in papillary TC and its known activity in medullary TC with RET mutations, we have initiated prospective testing for KIF5B-RET as part of our lung ADC screening panel in anticipation of a planned phase 2 trial with XL184 in patients with KIF5B-RET or related variant RET fusions.
Abstract 15893: Mediators of the Improvement in Heart Failure Outcomes With Empagliflozin in the EMPA-REG OUTCOME Trial
Authors: David Fitchett, Silvio E Inzucchi, Bernard Zinman, Christoph Wanner, Faiez Zannad, Martin Schumacher, Claudia Schmoor, Kristin Ohneberg, Afshin Salsali, Jyothis T George, Stefan Hantel, Erich Bluhmki, John M Lachin
Journal: Circulation (2017)

Introduction: In the EMPA-REG OUTCOME trial, empagliflozin (EMPA) given in addition to standard of care to patients with T2DM and established CV disease reduced the risk of hospitalization for hear...
Personalized Transcriptomics Reveals Heterogeneous Immunophenotypes in Children with Viral Bronchiolitis
Authors: Anya C. Jones, Denise Anderson, Sally Galbraith, Emmanuelle Fantino, Diana Gutierrez Cardenas, James F. Read, Michael Serralha, Barbara J. Holt, Deborah H. Strickland, Peter D. Sly, Anthony Bosco, Patrick G. Holt
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: A subset of infants are hypersusceptible to severe/acute viral bronchiolitis (AVB), for reasons incompletely understood. Objectives: To characterize the cellular/molecular mechanisms underlying infant AVB in circulating cells/local airway tissues. Methods: Peripheral blood mononuclear cells and nasal scrapings were obtained from infants (<18 mo) and children (≥18 mo to 5 yr) during AVB and after convalescence. Immune response patterns were profiled by multiplex analysis of plasma cytokines, flow cytometry, and transcriptomics (RNA-Seq). Molecular profiling of group-level data used a combination of upstream regulator and coexpression network analysis, followed by individual subject-level data analysis using personalized N-of-1-pathways methodology. Measurements and Main Results: Group-level analyses demonstrated that infant peripheral blood mononuclear cell responses were dominated by monocyte-associated hyperupregulated type 1 IFN signaling/proinflammatory pathways (drivers: TNF [tumor necrosis factor], IL-6, TREM1 [triggering receptor expressed on myeloid cells 1], and IL-1B), versus a combination of inflammation (PTGER2 [prostaglandin E receptor 2] and IL-6) plus growth/repair/remodeling pathways (ERBB2 [erbb-b2 receptor tyrosine kinase 2], TGFB1 [transforming growth factor-β1], AREG [amphiregulin], and HGF [hepatocyte growth factor]) coupled with T-helper cell type 2 and natural killer cell signaling in children. Age-related differences were not attributable to differential steroid usage or variations in underlying viral pathogens. Nasal mucosal responses were comparable qualitatively in infants/children, dominated by IFN types 1-3, but the magnitude of upregulation was higher in infants (range, 6- to 48-fold) than children (5- to 17-fold). N-of-1-pathways analysis confirmed differential upregulation of innate immunity in infants and natural killer cell networks in children, and additionally demonstrated covert AVB response subphenotypes that were independent of chronologic age. Conclusions: Dysregulated expression of IFN-dependent pathways after respiratory viral infections is a defining immunophenotypic feature of AVB-susceptible infants and a subset of children. Susceptible subjects seem to represent a discrete subgroup who cluster based on (slow) kinetics of postnatal maturation of innate immune competence.
Near-infrared light-regulated cancer theranostic nanoplatform based on aggregation-induced emission luminogen encapsulated upconversion nanoparticles
Authors: Guorui Jin, Rongyan He, Qian Liu, Min Lin, Yuqing Dong, Kai Li, Ben Zhong Tang, Bin Liu, Feng Xu
Journal: Theranostics (2018)

Photodynamic therapy (PDT) has been widely applied in the clinic for the treatment of various types of cancer due to its precise controllability, minimally invasive approach and high spatiotemporal accuracy as compared with conventional chemotherapy. However, the porphyrin-based photosensitizers (PSs) used in clinics generally suffer from aggregation-caused reductions in the generation of reactive oxygen species (ROS) and limited tissue penetration because of visible light activation, which greatly hampers their applications for the treatment of deep-seated tumors. Methods: We present a facile strategy for constructing a NIR-regulated cancer theranostic nanoplatform by encapsulating upconversion nanoparticles (UCNPs) and a luminogen (2-(2,6-bis((E)-4-(phenyl(40-(1,2,2-triphenylvinyl)-[1,10-biphenyl]-4-yl)amino)styryl)-4H-pyran-4-ylidene)malononitrile, TTD) with aggregation-induced emission (AIEgen) characteristics using an amphiphilic polymer, and further conjugating cyclic arginine-glycine-aspartic acid (cRGD) peptide to yield UCNP@TTD-cRGD NPs. We then evaluated the bioimaging and anti-tumor capability of the UCNP@TTD-cRGD NPs under NIR light illumination in an in vitro three-dimensional (3D) cancer spheroid and in a murine tumor model, respectively. Results: With a close match between the UCNP emission and absorption of the AIEgen, the synthesized NPs could efficiently generate ROS, even under excitation through thick tissues. The NIR-regulated UCNP@TTD-cRGD NPs that were developed could selectively light up the targeted cancer cells and significantly inhibit tumor growth during the NIR-regulated PDT treatment as compared with the cells under white light excitation. Conclusion: In summary, the synthesized UCNP@TTD-cRGD NPs showed great potential in NIR light-regulated photodynamic therapy of deep-seated tumors. Our study will inspire further exploration of novel theranostic nanoplatforms that combine UCNPs and various AIEgen PSs for the advancement of deep-seated tumor treatments with potential clinical translations.