tbuckley/cabot-search huggingface dataset:
Selective LOXL2 inhibition: potent antifibrotic effects in ongoing fibrosis and fibrosis regression
Authors: Fernando Magdaleno, Jonel Trebicka
Journal: Gut (2017)

The study by Ikenaga et al 1 represents a significant step forward in the understanding and in the treatment approaches of hepatic fibrosis. Fibrosis is a general repair mechanism of tissue injury resulting from increased extracellular matrix (ECM) synthesis and deposition, followed by contraction of the scar, remodelling and degradation of the ECM when the tissue defect is covered and bridged. In chronic liver injury, this important protective process is altered to a morbid situation with excessive ECM accumulation, which maintains inflammation and contributes to the progression to cirrhosis and which in turn is associated with high morbidity and mortality.

Remodelling of ECM in fibrosis and cirrhosis is important for the regression of fibrosis, but also for its progression. Remodelling might even predict progression of fibrosis.2 ,3 In this context, collagen crosslinking is a key process that increases the persistence of fibrosis, in which lysyl oxidase/lysyl oxidase-like protein (LOX/LOXL) family members are crucial. The LOX/lysyl oxidase-like protein-2 (LOXL2) family is characterised by highly conserved C-terminal lysyl oxidase domain integrated by the …
Provider-Induced Demand in the Treatment of Carotid Artery Stenosis
Authors: Louis L. Nguyen, Ann D. Smith, Rebecca E. Scully, Wei Jiang, Peter A. Learn, Stuart R. Lipsitz, Joel S. Weissman, Lorens A. Helmchen, Tracey Koehlmoos, Andrew Hoburg, Linda G. Kimsey
Journal: JAMA Surgery (2017)

Although many factors influence the management of carotid artery stenosis, it is not well understood whether a preference toward procedural management exists when procedural volume and physician compensation are linked in the fee-for-service environment.To explore evidence for provider-induced demand in the management of carotid artery stenosis.The Department of Defense Military Health System Data Repository was queried for individuals diagnosed with carotid artery stenosis between October 1, 2006, and September 30, 2010. A hierarchical multivariable model evaluated the association of the treatment system (fee-for-service physicians in the private sector vs salary-based military physicians) with the odds of procedural intervention (carotid endarterectomy or carotid artery stenting) compared with medical management. Subanalysis was performed by symptom status at the time of presentation. The association of treatment system and of management strategy with clinical outcomes, including stroke and death, was also evaluated. Data analysis was conducted from August 15, 2015, to August 2, 2016.The odds of procedural intervention based on treatment system was the primary outcome used to indicate the presence and effect of provider-induced demand.Of 10 579 individuals with a diagnosis of carotid artery stenosis (4615 women and 5964 men; mean [SD] age, 65.6 [11.4] years), 1307 (12.4%) underwent at least 1 procedure. After adjusting for demographic and clinical factors, the odds of undergoing procedural management were significantly higher for patients in the fee-for-service system compared with those in the salary-based setting (odds ratio, 1.629; 95% CI, 1.285-2.063; P < .001). This finding remained true when patients were stratified by symptom status at presentation (symptomatic: odds ratio, 2.074; 95% CI, 1.302-3.303; P = .002; and asymptomatic: odds ratio, 1.534; 95% CI, 1.186-1.984; P = .001).Individuals treated in a fee-for-service system were significantly more likely to undergo procedural management for carotid stenosis compared with those in the salary-based setting. These findings remained consistent for individuals with and without symptomatic disease.
Independent radiologic review of AURELIA, a phase 3 trial of bevacizumab (BV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC).
Authors: Amreen Husain, Yan V. Wang, Rikke Frederiksen, David T. Bollag, Lars Christian Hanker, Belen Ojeda, Maarit Anttila, Enrico Breda, Peter Vuylsteke, Eric Pujade-Lauraine
Journal: Journal of Clinical Oncology (2014)

5540^ Background: AURELIA is a phase 3, randomized, open-label trial in patients (pts) with PT-resistant, recurrent OC (NCT00976911). Based on investigator (INV) assessment of radiographic data, CT + BV showed significant improvement vs CT alone in the primary end point of progression-free survival (PFS) (Pujade-Lauraine, JCO in press). Median PFS was 3.4 months for CT vs 6.8 months for CT + BV (stratified hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.30–0.49; P<.001). As this was an open-label trial, an independent review committee (IRC) assessment of radiologic data was conducted retrospectively to confirm these results. Methods: Radiologic images were provided to the IRC for 92.2% of randomized pts; 82.5% of pts were IRC-evaluable. Data were reviewed in a blinded manner according to a prespecified charter following modified RECIST v.1.0. PFS analysis was based on the intent-to-treat population. Results: IRC results were consistent with those from the INV, demonstrating a statistically significant and clinically meaningful improvement in PFS with BV (Table). The concordance rate for progression status (yes, no) was similar across arms (CT, 69.9%; CT + BV, 68.2%), as was agreement on the date of progressive disease (PD; CT, 69.1%; CT + BV, 67.2%). The early discrepancy rates (INV-determined PD earlier than IRC-determined PD) were similar in the 2 arms (CT, 0.372; CT + BV, 0.364), whereas the late discrepancy rate was higher in the CT + BV arm (CT, 0.329, CT + BV, 0.463). The differential discordance of 0.134 suggests some degree of INV bias toward the CT + BV arm. Conclusions: The PFS analysis results from the IRC assessment were consistent with those from the primary INV-led PFS analysis, despite a trend for INV assessment of PD at a later date in the CT + BV arm in this trial. The results provided further evidence that INV-determined PFS based on RECIST is reliable and reproducible in OC clinical trials. Clinical trial information: NCT00976911. IRC-assessed PFS INV-assessed PFS CT (n=182) CT + BV (n=179) CT (n=182) CT + BV (n=179) Median PFS, mo (95% CI) 3.9 (3.4–5.2) 8.1 (6.9–9.6) 3.4 (2.10–3.75) 6.8 (5.62–7.79) Stratified HR (95% CI) 0.484 (0.370–0.632) 0.384 (0.300–0.491) Log-rank p value <.0001 <.0001
Clinical Outcomes of Patients with Recurrent/Refractory Hodgkin Disease Receiving Cyclosporine, Interferon-γ, and Interleukin-2 Immunotherapy To Induce Autoreactivity after Autologous Stem Cell Transplantation with BEAM: A COG Study.
Authors: Allen R. Chen, Robert Hutchison, Allan Hess, Sharon Gardner, Tanya Trippett, Pedro de Alarcon, Shirley Hogan, Joy Mitchell, Vickie Massey, Louis S. Constine, Lu Chen, Cindy L. Schwartz
Journal: Blood (2007)
TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives
Authors: Alessandra Tammaro, Marc Derive, Sebastien Gibot, Jaklien C. Leemans, Sandrine Florquin, Mark C. Dessing
Journal: Pharmacology & Therapeutics (2017)

Triggering receptor expressed on myeloid cells-1 (TREM-1) is expressed on the majority of innate immune cells and to a lesser extent on parenchymal cells. Upon activation, TREM-1 can directly amplify an inflammatory response. Although it was initially demonstrated that TREM-1 was predominantly associated with infectious diseases, recent evidences shed new light into its role in sterile inflammatory diseases. Indeed, TREM-1 receptor and its signaling pathways contribute to the pathology of several non-infectious acute and chronic inflammatory diseases, including atherosclerosis, ischemia reperfusion-induced tissue injury, colitis, fibrosis and cancer. This review, aims to give an extensive overview of TREM-1 in non-infectious diseases, with the focus on the therapeutic potential of TREM-1 intervention strategies herein. In addition, we provide the reader with a functional enrichment analysis of TREM-1 signaling pathway and potential TREM-1 ligands in these diseases, obtained via in silico approach. We discuss pre-clinical studies which show that TREM-1 inhibition, via synthetic soluble TREM-1 protein mimickers, is effective in treating (preventing) specific inflammatory disorders, without significant effects on antibacterial response. Further research aimed at identifying specific TREM-1 ligands, in different inflammatory disorders, is required to further unravel the role of this receptor, and explore new avenues to modulate its function.
Phase I and pharmacokinetic (PK)/pharmacodynamic (PD) study of LY2334737, an oral gemcitabine prodrug, in patients (pts) with advanced solid tumors.
Authors: Sandrine J. Faivre, Anthony J. Olszanski, Karin Weigang-Koehler, Hanno Riess, Guangbin Peng, Sophie Callies, Karim Adnane Benhadji, Eric Raymond
Journal: Journal of Clinical Oncology (2012)

2554 Background: LY2334737 is a valproic acid-bound carboxylesterase-substrate prodrug of gemcitabine that can be given orally. The primary objective was to define the recommended phase II doses and schedules (sch) of administration of LY2334737 in 28-day cycles. Methods: Eligible pts (ECOG&lt;2) had adequate hematologic, renal, and hepatic functions. In sch-A, LY2334737 was given every other day for 21 days. In sch-B, LY2334737 was given daily every other week. Dose escalation (3+3) was based on CTCAE V3 toxicities. Secondary objectives were PKs (LY2334737, dFdC, dFdU), PD biomarkers (dFdC DNA incorporation, Cytokeratin 18 - M30), and antitumor activity. Results: 57 pts (38 males, 19 females, median age 60 yrs) were treated using 7 dose-levels (40–100 mg/day). Pts received a median of 2 cycles. Dose limiting toxicities (DLTs) at cycle 1 (any dose level) consisted of diarrhea (2pt), AST elevation (1pt), lower extremity edema (1pt), QTC prolongation (1pt), and general deterioration (1pt). A total of 2/7pts treated with 100mg in sch-A and 1/4pts treated with 90mg in sch-B had DLTs. During dose escalation most frequent toxicities were 1) Sch-A (28 pts): nausea (10pts), pyrexia (9pts), vomiting (8pts), mucositis (6pts), anorexia (6pts), ALT elevation (5pts), asthenia (5pts), anemia (5pts), fatigue (4pts), chills (4pts), and lymphopenia (4pts). 2) Sch-B (29 pts): pyrexia (13pts), nausea (8pts), diarrhea (6pts), vomiting (5pts), chills (6pts), anemia (5pts), asthenia (6pts), AST elevation (6pts), ALT elevation (5pts), and fatigue (4pts). Nine pts had stable disease (3pts completed &gt;6 cycles). PKs showed a dose-proportional increase in exposure of LY2334737 and dFdC with no accumulation after repeated dosing. dFdC is detected in the DNA of peripheral blood mononuclear cells (increasing amount with dose and over time after repeated cycle). In sch-A, we observed a significant increase in cytokeratin 18 M30 relative to baseline. Conclusions: LY2334737 displayed linear PK and acceptable safety profile in both schedules. The dose of 90mg given every other day is the recommended dose for phase II trials with LY2334737 (dose expansion is ongoing).
A quick, simple method for detecting circulating fluorescent advanced glycation end-products: Correlation with in vitro and in vivo non-enzymatic glycation
Authors: Marika Villa, Mariacristina Parravano, Arianna Micheli, Lucia Gaddini, Andrea Matteucci, Cinzia Mallozzi, Francesco Facchiano, Fiorella Malchiodi-Albedi, Flavia Pricci
Journal: Metabolism (2017)
A Dose-Escalation Study of Venetoclax (ABT-199/GDC-0199) in Combination with Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma
Authors: Sven de Vos, Lode Swinnen, Mark Kozloff, Ding Wang, Erin Reid, Loretta Nastoupil, Nathan Fowler, Jaclyn Cordero, Diane D'Amico, Susan Diehl, Martin Dunbar, Ming Zhu, Shekman Wong, Sari Heitner Enschede, David Chien, Rod A. Humerickhouse, Christopher Flowers
Journal: Blood (2015)
Application of CRISPR/Cas9 in plant biology
Authors: Xuan Liu, Surui Wu, Jiao Xu, Chun Sui, Jianhe Wei
Journal: Acta Pharmaceutica Sinica B (2017)

The CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) system was first identified in bacteria and archaea and can degrade exogenous substrates. It was developed as a gene editing technology in 2013. Over the subsequent years, it has received extensive attention owing to its easy manipulation, high efficiency, and wide application in gene mutation and transcriptional regulation in mammals and plants. The process of CRISPR/Cas is optimized constantly and its application has also expanded dramatically. Therefore, CRISPR/Cas is considered a revolutionary technology in plant biology. Here, we introduce the mechanism of the type II CRISPR/Cas called CRISPR/Cas9, update its recent advances in various applications in plants, and discuss its future prospects to provide an argument for its use in the study of medicinal plants.
A phase II study of a temozolomide-based chemoradiotherapy regimen for high-risk low-grade gliomas: Preliminary results of RTOG 0424.
Authors: Barbara Jean Fisher, Jeff Lui, David R. Macdonald, Glenn Jay Lesser, Stephen Coons, David Brachman, Samuel Ryu, Maria Werner-Wasik, Jean-Paul Bahary, Chen Hu, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2013)

2008 Background: The primary endpoint of RTOG 0424 was to compare the 3-year survival (OS) of a regimen of concurrent and adjuvant temozolomide (TMZ) and radiotherapy (RT) in a high-risk low-grade glioma (LGG) population to the 3 year (yr) OS rate of the high risk EORTC LGG patients (pts) reported by Pignatti et al (J Clin Oncol 2002;20(8):2076-84). Secondary endpoints were: progression-free survival (PFS), toxicity, neurocognitive and quality of life data and molecular analysis. Methods: Pts with LGG's and &gt;=3 high risk factors (age&gt; = 40, astrocytoma dominant histology, tumor crossing midline, tumor &gt; = 6 cm or preoperative neurological function status &gt;1) were eligible and treated with conformal RT (54 Gy/30 fractions) plus concurrent TMZ 75 mg/m 2 /day for 6 weeks and post-RT TMZ 150-200 mg/m 2 /day days 1-5 q28 days for up to 12 cycles. The study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months, and a 20% improvement in 3 yr OS rate from 54% to 65%, at a 10% significance level (1 sided) and 96% power. Results: Between January 2005-August 2009 136 pts were accrued, 129 (75 males, 54 females) were evaluable. Median age was 49 years, 91% had a Zubrod score 0-1 and 69%, 25% and 6% of pts had 3,4 and 5 high risk factors respectively. With a median follow-up time of 4.1 yrs, minimum follow-up of 3 yrs, MST has not yet been reached. Three year OS rate was 73.1% (95%CI:65.3-80.8%), significantly improved from historical control with a p-value &lt;0.0001. No difference in OS rates for pts with 3, 4 or 5 high risk factors was seen. 3 year PFS was 59.2% (95% CI:50.7-67.8%). Grade 3 adverse events (AE) occurred in 43% of pts and grade 4 AE in 10%, primarily hematologic, constitutional or gastrointestinal (nausea, anorexia) toxicity. One patient died of herpes encephalitis. Secondary analyses are ongoing. Radiation Quality Assurance was per protocol/ acceptable in 95% and 74% of pts completed chemotherapy per protocol. Conclusions: The 3 year OS rate of 73.1% for these high risk LGG pts is significantly higher than those reported for historical controls (54%, p &lt; 0.0001, one-sided) and the study-hypothesized 65%. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI and Merck Clinical trial information: NCT00114140.
Antenatal Determinants of Bronchopulmonary Dysplasia and Late Respiratory Disease in Preterm Infants
Authors: Lindsey A. Morrow, Brandie D. Wagner, David A. Ingram, Brenda B. Poindexter, Kurt Schibler, C. Michael Cotten, John Dagle, Marci K. Sontag, Peter M. Mourani, Steven H. Abman
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Mechanisms contributing to chronic lung disease after preterm birth are incompletely understood.To identify antenatal risk factors associated with increased risk for bronchopulmonary dysplasia (BPD) and respiratory disease during early childhood after preterm birth, we performed a prospective, longitudinal study of 587 preterm infants with gestational age less than 34 weeks and birth weights between 500 and 1,250 g.Data collected included perinatal information and assessments during the neonatal intensive care unit admission and longitudinal follow-up by questionnaire until 2 years of age.After adjusting for covariates, we found that maternal smoking prior to preterm birth increased the odds of having an infant with BPD by twofold (P = 0.02). Maternal smoking was associated with prolonged mechanical ventilation and respiratory support during the neonatal intensive care unit admission. Preexisting hypertension was associated with a twofold (P = 0.04) increase in odds for BPD. Lower gestational age and birth weight z-scores were associated with BPD. Preterm infants who were exposed to maternal smoking had higher rates of late respiratory disease during childhood. Twenty-two percent of infants diagnosed with BPD and 34% of preterm infants without BPD had no clinical signs of late respiratory disease during early childhood.We conclude that maternal smoking and hypertension increase the odds for developing BPD after preterm birth, and that maternal smoking is strongly associated with increased odds for late respiratory morbidities during early childhood. These findings suggest that in addition to the BPD diagnosis at 36 weeks, other factors modulate late respiratory outcomes during childhood. We speculate that measures to reduce maternal smoking not only will lower the risk for preterm birth but also will improve late respiratory morbidities after preterm birth.
Cytokine Gene Polymorphisms and Overall Survival in Follicular Lymphoma: Results from a Large Population-Based Study.
Authors: James R. Cerhan, Sophia Wang, Matthew J. Maurer, Stephen M. Ansell, Susan M. Geyer, Wendy Cozen, Lindsay M. Morton, Scott Davis, Richard K. Severson, Nathaniel Rothman, Charles F. Lynch, Stephen Chanock, Thomas M. Habermann, Patricia Hartge
Journal: Blood (2006)
Abstract 075: Novel Role for GRK2 in Cardiac Hypertrophy and Heart Failure
Authors: Sarah M Schumacher-Bass, Erhe Gao, Kurt Chuprun, Jessica I Gold, Walter J Koch
Journal: Circulation Research (2013)

During heart failure (HF), cardiac levels and activity of the G protein-coupled receptor (GPCR) kinase (GRK) GRK2 are elevated, increasing phosphorylation, desensitization and down-regulation of β-adrenergic receptors (βARs) and other cardiac GPCRs. Increased GRK2 has been shown to participate in adverse remodeling and contractile dysfunction during HF, while GRK2 inhibition via a carboxy-terminal peptide, βARKct, enhances heart function and can prevent HF development. Mounting evidence supports the idea of a dynamic GRK2 “interactome” in which GRK2 can uncouple GPCRs via novel protein-protein interactions. Several novel GRK2 interacting partners are important for adaptive and maladaptive myocyte growth including Gq, the signaling trigger for maladaptive cardiac hypertrophy, leading to HF. Importantly, GRK2 contains a putative amino-terminal Regulator of G protein Signaling (RGS) domain (termed βARK-RGS). This domain directly interacts with Gq and appears to inhibit signaling without altering Gq enzymatic activity. Therefore, this domain of GRK2 may alter hypertrophic responses in the heart and represent a novel role for GRK2 and also a potential therapeutic target to limit maladaptive cardiac hypertrophy. We have begun to address this by generation of novel transgenic mice with cardiac-specific expression of the RGS domain of GRK2. Data from mice with cardiac expression of βARK-RGS demonstrate anti-hypertrophic effects in a trans-aortic constriction (TAC) model of pressure overload hypertrophy. Echocardiographic analysis post-TAC revealed reduced left ventricular posterior wall thickness in βARK-RGS compared to non-transgenic littermate controls (1.34 vs 1.57 mm LVPWd at 4 weeks). RT-PCR analysis found decreased hypertrophic factor transcripts, such as ANF for which the nearly 18-fold increase post TAC was completely inhibited in βARK-RGS mice. Other hypertrophic phenotypic markers have been studied and mechanistic characterization is underway. These data support our hypothesis that the RGS domain of GRK2 may serve as a non-canonical inhibitor of Gq-mediated hypertrophic signaling in the heart and highlight how this research may pave the way for novel GRK2-based therapeutic approaches to prevent hypertrophy and HF.
Genome-Wide Analysis Reveals Conserved and Divergent Features of Notch1/RBPJ Binding in Human and Murine T Lymphoblastic Leukemia Cells
Authors: Jon C Aster, Hongfang Wang, James Zou, Yumi Yashiro-Ohtani, Bo Zhao, Eric Johannsen, Jonathan Schug, Stephen C. Blacklow, Elliott Kieff, Warren S. Pear
Journal: Blood (2011)
Abstract P1-05-30: Genomic and microenvironmental intra-tumor heterogeneity in DCIS
Authors: A Fortunato, L King, D Mallo, V Kovacheva, Y Yuan, A Boddy, T Graham, A Aktipis, ER Mardis, A Hall, JR Marks, S Hwang, CC Maley
Journal: Cancer Research (2017)

Abstract Intra-tumor heterogeneity drives neoplastic progression by supplying the fuel for natural selection among neoplastic cells. It also complicates screening and treatment of neoplasms. We hypothesize that the degree of intra-tumor heterogeneity in DCIS should predict which tumors are likely to become invasive and metastatic. We initiated a pilot project to test this hypothesis by comparing 9 cases of pure DCIS to 9 cases of DCIS with adjacent invasive disease. For each case, we sequenced the exome from two spatially distinct regions of DCIS as well as normal tissue taken from a lymph node with no tumor involvement. This required the development of new methods to extract high quality sequencing data from small amounts of DNA extracted from FFPE samples. We calculated the genetic divergence between the two tumor regions, defined as percent of the sequenced regions of the genome showing differences between the two samples that had sufficient sequencing coverage and quality scores for confident scoring. We also employed automated imaging analysis to score microenvironmental differences between the two tumor regions. These microenvironmental measures are based on ecological methods for measuring organismal interactions and habitats. We will present initial data on differences in phenotypic and genotypic intra-tumor heterogeneity comparing pure DCIS to DCIS associated with invasive breast cancer. Our methods can be readily translated to large tissue banks of FFPE samples from DCIS. Citation Format: Fortunato A, King L, Mallo D, Kovacheva V, Yuan Y, Boddy A, Graham T, Aktipis A, Mardis ER, Hall A, Marks JR, Hwang S, Maley CC. Genomic and microenvironmental intra-tumor heterogeneity in DCIS [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-30.