tbuckley/cabot-search huggingface dataset:
S91 Liver function tests during tuberculosis treatment and the implications on monitoring for hepatotoxicity
Authors: CD Tweed, G Wills, AM Crook, SK Meredith, AJ Nunn, CM Mendel, SR Murray, TD McHugh, SH Gillespie
Journal: Thorax (2016)

<h3>Introduction and objectives</h3> Drug-induced hepatotoxicity is a common complication of tuberculosis treatment.<sup>1</sup> Guidelines based on expert opinion are available, but the natural history of liver enzyme measurements over the course of treatment and the most effective approach to monitoring on treatment remains unclear. We investigated the pattern of liver enzyme levels in the REMoxTB trial to describe the magnitude and timing of elevations, along with factors that could influence enzyme patterns, and related this to liver function monitoring. <h3>Methods</h3> Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a four-month regimen with moxifloxacin substituted for ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Liver function tests were performed at weeks 0, 2, 4, 8, 12, 17, and during adverse events. The Chi Square or Fisher’s exact test was used for testing proportions among groups, log rank test for comparison of time, and Students t test for comparison of means. <h3>Results</h3> 639 patients were allocated to receive standard therapy as controls, 654 to the isoniazid arm, and 635 to the ethambutol arm (see Table 1). 60 patients (9.4%) taking standard therapy developed a peak ALT/AST ≥ 3 × ULN at median time 28 days (IQR 14–56). The mean difference in time to reach peak ALT was 7 days between isoniazid-containing regimens and the ethambutol arm, and a higher proportion of Asian patients elevated ALT/AST ≥ 3 × ULN in isoniazid-containing arms (51.0% vs 26.3%, (p &lt; 0.001)). Of the 40/421 (9.5%) HIV positive in Africa, 24/421 elevated ALT/AST ≥ 3 × ULN compared to 25/121 (5.7% vs 20.7%, (p &lt; 0.001)) in India elevating ALT/AST ≥ 3 × ULN where 2/121 (1.7%) were HIV-positive. <h3>Discussion</h3> Monitoring liver function routinely for the first two months of HRZE therapy would have detected approximately 75% of patients with a peak enzyme elevation of ≥3 × ULN, and we would recommend this as a standard of care based on these results. However, there is reassurance that over 90% of patients completed therapy without an ALT/AST result ≥3 xULN. HIV positive and Asian patients were at higher risk of liver enzyme elevation and there was a shorter time to peak ALT/AST for those receiving isoniazid. <h3>Reference</h3> Thompson N, Caplin M, Hamilton M, <i>et al</i>. Anti-tuberculosis medication and the liver: dangers and recommendations in management. <i>Eur Respir J</i> 1995;<b>8</b>:1384–1388.
518. Tumor Associated Macrophages Mitigate Oncolytic Herpes Simplex Virus Efficacy in Part Through TGF-β Signaling
Authors: Nicholas Denton, Chun-Yu Chen, Brian Hutzen, Jennifer Leddon, Pin-Yi Wang, Thomas Scott, Mark Currier, Tim Eubank, Timothy P. Cripe
Journal: Molecular Therapy (2016)

Introduction: Ewing sarcoma is a highly aggressive bone tumor that is often lethal following recurrence or metastasis. Oncolytic viruses (OVs), such as the rRp450 herpes simplex virus, are promising anticancer therapeutics designed to selectively replicate in cancer cells. While OV anti-tumor efficacy is partially caused by direct infection and lysis of cancer cells, stimulation of an anti-cancer immune response also contributes to virus-mediated efficacy. Immunologic responses to infections are known to be modulated by macrophages via various cytokines and chemokines and it is now appreciated that tumor associated macrophages (TAMs). M2 alternatively activated macrophages in particular express pro-tumor immunosuppressive cytokines, such as IL-10 and TGF-β. We hypothesize that TAMs reduce therapeutic efficacy by producing an immunosuppressive tumor microenvironment via IL-10 and TGF-β signaling. Research methods: Human Ewing sarcoma xenografts were implanted into athymic nude mice and macrophages were depleted using liposomal clodronate (encapsula) prior to intratumoral injection of rRp450 oncolytic HSV. Tumors were allowed to grow for tumor progression. In vitro cytotoxicity was determined using MTS assay. In vitro and in vivo virus replication was determined through plaque assay. Bone marrow derived macrophages were cocultured with Ewing sarcoma cell lines and harvested for flow cytometry and PCR analysis of tumor inflammatory signaling and M1/M2 macrophage gene profiles. F4/80+ tumor associated macrophages were extracted from tumors using magnetic bead separation. TGF-β cytokine superfamily receptor signaling was inhibited with A83-01 (Sigma-Aldrich) small molecule treatment prior to intratumoral injection of rRp450. Results: Macrophage depletion significantly inhibited tumorigenesis and enhanced rRp450 anti-tumor efficacy in A673, but not 5838 Ewing sarcoma xenografts. No change in virus titer was observed in the macrophage depleted tumors, suggesting the effect isn't due to enhanced virus replication. Macrophages cocultured with A673 cells had higher expression of M2 pro-tumor macrophage genes than macrophages cocultured with 5838 cells. Macrophages in A673 tumors also demonstrated higher expression of IL-10 and TGF-β than 5838 tumor associated macrophages. Inhibition of TGF-β signaling enhanced rRp450 oncolytic virus anti-tumor efficacy in A673 tumors. Conclusions: Macrophages play a significant role in mitigating OV anti-tumor efficacy. Specifically, our tumor models that promote M2 macrophage polarization are significantly more resistant to oncolytic virus therapy, in part due to TGF-β signaling. Our results suggest that the combination of oncolytic virus therapy with a macrophage modulatory therapy will improve OV anti-tumor efficacy in patients with highly immunosuppressive tumors.
112. Potent Antifibrotic Effect on Human Dermal Fibroblasts and Keloid Spheroids by Adenovirus-Mediated Inhibition of Wnt and TGF-β Signaling
Authors: Hyo Min Ahn, Won Jai Lee, Youjin Na, Jinwoo Hong, Chae-Ok Yun
Journal: Molecular Therapy (2016)

Aberrant activation of the canonical Wingless type (Wnt) signaling pathway plays a key role in the development of hypertrophic scars and keloids. This aberrant activation of the canonical Wnt pathway and its potent profibrotic effects suggest that Wnt pathway can be a potential target for the development of novel anti-fibrotic agents. In this study, we evaluated the anti-fibrotic potential of a soluble Wnt decoy receptor (sLRP6E1E2)-expressing non-replicating adenovirus (Ad; dE1-k35/sLRP6E1E2) on human dermal fibroblasts (HDFs) and keloid spheroid. Wnt family member 3a and its effector β-catenin expression in keloid tissues were analyzed by hematoxylin and eosin and immunohistochemical staining. HDFs were transduced with dE1-k35/sLRP6E1E2 or control Ad vector (dEl-k35/LacZ), and then luciferase reporter assay for β-catenin activity was performed. Furthermore, change in type-I and -III collagen mRNA levels in HDFs were measured by quantitative real time PCR. Wnt intracellular signaling and secreted transforming growth factor-β1 (TGF-β1) protein expression were examined by western blot and the enzyme-linked immunosorbent assay, respectively. The effect of sLRP6E1E2 on the nuclear localization of β-catenin and Smad 2/3 complex was evaluated by immunofluorescence staining. Lastly, the expression levels of major extracellular matrix components were investigated by immunohistochemistry in keloid spheroids after transduction with dEl-k35/LacZ or dE1-k35/sLRP6E1E2. Higher Wnt3a and β-catenin expression was observed in the keloid region compared to the adjacent normal tissues. The activity of β-catenin and mRNA expression of type-I and -III collagen were significantly decreased following treatment with dE1-k35/sLRP6E1E2. The expression of LRP6, β-catenin, phosphorylated glycogen synthase kinase 3 beta, Smad 2/3 complex, and TGF-β1 were decreased in Wnt3a- or TGF-β1-activated HDFs, following administration of dE1-k35/sLRP6E1E2. Moreover, dE1-k35/sLRP6E1E2 markedly inhibited nuclear translocation of both β-catenin and Smad 2/3 complex. The expression levels of type-I and -III collagen, fibronectin, and elastin were also significantly reduced in keloid spheroids after treatment with dE1-k35/sLRP6E1E2. These results indicate that Wnt decoy receptor-expressing Ad can degrade extracellular matrix in HDFs and primary keloid spheroids, and thus it could be highly beneficial for treatment of keloids.
Patients with Relapsed CLL and 17p Deletion by FISH Have Very Poor Survival Outcomes.
Authors: Xavier C. Badoux, Michael Keating, Susan O'Brien, Alessandra Ferrajoli, Jan A. Burger, Stefan Faderl, Guillermo Garcia-Manero, Tapan Kadia, Lynne V Abruzzo, William G. Wierda
Journal: Blood (2009)
Circulating endothelial cells, endothelial progenitor cells, microparticles, and markers of inflammation and coagulation in advanced non-small cell lung cancer.
Authors: T. Fleitas, G. Reynes, V. Martinez-Sales, V. Vila, E. Reganon, D. Mesado, M. Martin, J. Gómez-Codina, J. Montalar
Journal: Journal of Clinical Oncology (2011)

7583 Background: Circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), and microparticles (MPs) have prognostic value in cancer, and might be predictors of response to chemotherapy and antiangiogenic treatments. We investigated the pre- and post-treatment levels of CECs, EPCs MPs and inflammation and coagulation markers in patients with stage IIIB and IV non-small cell lung cancer (NSCLC). Methods: We studied 60 patients, before first line taxane and platinum chemotherapy +/- bevacizumab and sixty controls. Quantification of CECs was carried out by an immunomagnetic technique. The number of EPCs (CD34/CD133/CD309) and MPs-phosphatidylserine-positive (0.5-1μm) in blood was evaluated by flow cytometry. Markers of inflammation: interleukin-6 (IL-6), coagulation: tissue factor (TF) and angiogenesis vascular endothelial growth factor (VEGF) and their receptors VEGFR1 and VEGFR2 were quantified by ELISA. Results: Mean number of CECs was significantly increased in patients before and after treatment as compared to controls p<0.0001 and p=0.01 respectively). Levels of EPCs before treatment were similar to those of controls (p=0.05) but they were significantly higher after treatment (p=0.01). Levels of MPs were significantly higher in patients before and after treatment than in controls (p< 0.0001). Levels of IL-6, TF were significantly higher in patients before and after treatment than in controls (p<0.0001 and p<0.001 respectively). Levels of VEGF and their receptors were significantly higher in patients before treatment and after treatment than in controls (p<0.001). The Pearson correlation between VEGF and MPs was positive and statistically significant (r=0.40, p<0.001). There was an association between increased levels of MPs before treatment and survival >15 months (p<0.05), as well as an increased levels of IL6 and TF in stage IIIB patients (p<0.01). Conclusions: CECs, EPCs and MPs, as well as a set of markers of inflammation and coagulation, are strongly elevated in patients with advanced NSCLC and still elevated after treatment. The influence of treatment on CEC, EPC and MP levels is unclear and needs further study.
A Bone Glue with Sustained Adhesion under Wet Conditions
Authors: Laura Wistlich, Anja Rücker, Martha Schamel, Alexander C. Kübler, Uwe Gbureck, Jürgen Groll
Journal: Advanced Healthcare Materials (2016)

Bone glues often suffer from low adhesion to bone under wet conditions. This study aims to improve wet adhesiveness of a bone glue based on a photocurable poly(ethylene glycol) dimethacrylate matrix through in situ interpenetrating network formation by addition of six-armed isocyanate functional star-shaped prepolymers (NCO-sP(EO-stat-PO)). Biodegradable ceramic fillers are added to adjust the paste workability. The 3-point bending strength of the bone glues is in the range of 3.5-5.5 MPa and not significantly affected by the addition of NCO-sP(EO-stat-PO). Storage in phosphate buffered saline (PBS) decreases the bending strength of all formulations to approximately 1 MPa but the adhesion to cortical bone increases from 0.15-0.2 to 0.3-0.5 MPa after adding 20-40 wt% NCO-sP(EO-stat-PO) to the matrix. Bone glues without the NCO-sP(EO-stat-PO) additive lose their adhesiveness to bone after aging in PBS for 7 days, whereas modified glues maintain a shear strength of 0.18-0.25 MPa demonstrating the efficacy of the approach. Scanning electron microscopy and energy-dispersive X-ray spectroscopy investigations of the fracture surfaces prove a high amount of residual adhesive on the bone surface indicating that adhesion to the bone under wet conditions is stronger than cohesion.
Chronotherapy for hypertension in obstructive sleep apnoea (CHOSA): a randomised, double-blind, placebo-controlled crossover trial
Authors: Yasmina Serinel, Brendon J Yee, Ronald R Grunstein, Keith H Wong, Peter A Cistulli, Hisatomi Arima, Craig L Phillips
Journal: Thorax (2016)

<h3>Background</h3> Obstructive sleep apnoea (OSA) is an important cause of secondary hypertension. Nocturnal hypertension is particularly prevalent in OSA and is a strong predictor of cardiovascular mortality. Studies in patients with essential hypertension have suggested that nocturnal administration of antihypertensives improves nocturnal blood pressure (BP) without elevating daytime BP. We evaluated the efficacy of this technique in patients with OSA with stage I/II hypertension, both before and after the addition of CPAP. <h3>Methods</h3> In this double-blind randomised placebo-controlled crossover trial, patients with moderate-to-severe OSA and hypertension received 6 weeks each of evening or morning perindopril with opposing time-matched placebo. CPAP therapy was subsequently added for 8 weeks in addition to either morning or evening perindopril. The primary outcome was sleep systolic BP (SBP) using 24-hour BP monitoring, analysed using linear mixed models. <h3>Results</h3> Between March 2011 and January 2015, 85 patients were randomised, 79 completed both dosing times, 78 completed the CPAP phase. Sleep SBP reduced significantly from baseline with both evening (−6.9 mm Hg) and morning (−8.0 mm Hg) dosing, but there was no difference between dosing times (difference: 1.1 mm Hg, 95% CI −0.3 to 2.5). However, wake SBP reduced more with morning (−9.8 mm Hg) than evening (−8.0 mm Hg) dosing (difference: 1.8 mm Hg, 95% CI 1.1 to 2.5). Addition of CPAP to either evening or morning dosing further reduced sleep SBP, but by a similar amount (evening: −3.2 mm Hg, 95% CI −5.1 to −1.3; morning: −3.3 mm Hg, 95% CI −5.2 to 1.5). <h3>Conclusions</h3> Our findings support combining OSA treatment with morning administration of antihypertensives. Unlike in essential hypertension, our results do not support evening administration of antihypertensives, at least with perindopril. Further research is required before this strategy can be widely adopted into hypertension guidelines and clinical practice. <h3>Trial registration number</h3> ACTRN12611000216910, Results.
Trends in Perioperative Cardiovascular Events
Authors: Nicole M. Bhave, Kim A. Eagle
Journal: JAMA Cardiology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Targeted Alpha Radiation and Gamma Rays Induce Distinct and Mutation Status Specific Transcriptional Responses in Human Leukemic Lymphocytes.
Authors: Simona Martin, Ralf Kronenwett, Katia Vandenbulcke, Fritz Offner, Slawomir Kliszewski, Christos Apostolidis, Alfred Morgenstern, Ulrich Steidl, Sascha Raschke, Frank Neumann, Jan Philippe, Guido Slegers, Rainer Haas
Journal: Blood (2004)
Real-World Results on Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Data from 97 Swedish Patients Treated in a Compassionate Use Program
Authors: Lotta Hansson, Maria Winqvist, Anna Asklid, P-O Andersson, Karin Karlsson, Claes Karlsson, Birgitta Lauri, Jeanette Lundin, Mattias Mattsson, Stefan Norin, Anna Sandstedt, Anders Österborg
Journal: Blood (2015)
SNP-A Karyotyping Provides Clinically Relevant Results In Myeloid Hematologic Disorders with Unsuccessful Routine Cytogenetic Testing.
Authors: Kathryn M Guinta, Hideki Makishima, Christine L. O'Keefe, Simon Dujardin, Ramon V. Tiu, Mikkael A. Sekeres, Jaroslaw P Maciejewski
Journal: Blood (2010)
Retroviral Gene Transfer of T Cell Receptors (TCR) Specific for Minor Histocompatibility Antigens to Virus-Specific T Cells as Cellular Immunotherapy of Patients with Relapsed Hematological Malignancies after Allogeneic Stem Cell Transplantation.
Authors: Marieke Griffioen, H.M. Esther van Egmond, Menno A.W.G. van der Hoorn, Renate S. Hagedoorn, Michel Kester, J.H. Frederik Falkenburg, Mirjam H.M. Heemskerk
Journal: Blood (2005)
Abstract 3641: Identification of naphthyridines as potent inhibitors of fibroblast growth factor receptor kinase family
Authors: Patrick R. Angibaud, Michel Obringer, Julien Marin, Matthieu Jeanty, Norbert Esser, Ron Gilissen, Peter King, Lieven Meerpoel, Olivier Querolle, David C. Rees, Bruno Roux, Gordon Saxty, Tinne Verhulst, Berthold Wroblowski, Christopher C. Murray, Jorge Vialard
Journal: Cancer Research (2015)

Abstract The fibroblast growth factor receptor (FGFR) tyrosine kinase family members, FGFR1, 2, 3 and 4, have roles in a variety of key cellular processes, including proliferation, migration, survival, and differentiation1. Aberrant activation of FGFRs through mutation, amplification, chromosomal translocation, and ligand up-regulation being strongly implicated in oncogenic signalling in many tumour types, has triggered efforts to identify selective FGFR inhibitors. As a result, several potent FGFR kinase inhibitors are currently being evaluated in clinical studies across many tumor types, including non-small cell lung, breast and bladder cancers. We have designed novel 1,5 and 1,7-naphthyridine derivatives that are potent kinase inhibitors of all FGFR family members in enzymatic and cellular systems. Initial hits were further optimized to increase potency and ADME properties leading to identification of a novel 1,5-naphthyridine-based chemical series with nanomolar affinity for FGFR1, 2, 3, and 4, activity in cells, and selectivity with respect to VEGFR-2. In vivo screening using an FGFR3-driven xenograft model revealed efficacious compounds that could be explored further as antitumoral agents. This report represents the first disclosure of the structure-activity relationship and synthesis pathway of novel naphthyridine chemical series displaying nanomolar affinity for FGFRs1, 2, 3 and 4. 1 Dieci M. V., Ardenos M., Andre F., Soria J.C. Cancer Discovery. 2013, 3(3) 264-279. Citation Format: Patrick R. Angibaud, Michel Obringer, Julien Marin, Matthieu Jeanty, Norbert Esser, Ron Gilissen, Peter King, Lieven Meerpoel, Olivier Querolle, David C. Rees, Bruno Roux, Gordon Saxty, Tinne Verhulst, Berthold Wroblowski, Christopher C. Murray, Jorge Vialard. Identification of naphthyridines as potent inhibitors of fibroblast growth factor receptor kinase family. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3641. doi:10.1158/1538-7445.AM2015-3641
Abstract 3351: NF-κB signaling between stromal macrophages and breast cancer cells
Authors: Jennifer W. Bradford
Journal: Cancer Research (2015)

Abstract It has become increasingly clear that the tumor microenvironment directly interacts with tumor cells to promote tumor growth and progression. Tumor associated macrophages (TAMs) have emerged as key components of the tumor microenvironment, and their presence in breast cancer is associated with poor prognosis. There is evidence that nuclear factor -kappaB (NF-κB) is an important signaling pathway between cancer cells and the stromal compartment. Disruption of NF-κB communication between TAMs and breast tumors may weaken the pro-tumorigenic influences of TAMs, and therefore make the tumor more susceptible to standard treatments. Our work reveals that when breast cancer cells and bone marrow derived macrophages (BMDMs) are co-cultured in transwell plates, activated canonical NF-κB and STAT3 levels dramatically increase in both cell types. This signaling interaction was confirmed by co-culturing human blood derived macrophages with breast cancer cells. BMDMs co-cultured with breast cancer cells acquire a mixed M1/M2 activation phenotype, and also have skewed inflammatory cytokine production. In basal-like mouse tumors, active NF-κB levels are much higher in the CD11b+ (TAM) fraction compared to the CD11b- fraction. Even more so than BMDMs, TAMs isolated from mouse basal-like tumors have high NF-κB activity, and can promote elevated NF-κB and STAT3 activation and cytokine production in breast cancer cells when co-cultured in transwell plates. BMDMs genetically lacking p65 have altered inflammatory cytokine production when compared to wild type BMDMs, which remains skewed when the cells are co-cultured with breast cancer cells. Because the NF-κB pathway can be targeted therapeutically, understanding how NF-κB activation influences breast tumor-TAM communication is important for developing new treatment options for aggressive cancers. Citation Format: Jennifer W. Bradford. NF-κB signaling between stromal macrophages and breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3351. doi:10.1158/1538-7445.AM2015-3351
A New Pathogenomic Mechanism In FPD/AML by a Constitutional T(16;21) Involving 16p13 ATF7IP2 and 21q22 RUNX1 Loci
Authors: Arjan Buijs, Saskia van der Crabben, Bert van der Zwaag, Ellen van Binsbergen, Martin Poot, Okke de Weerdt, Marielle van Gijn, H. Karel Nieuwenhuis
Journal: Blood (2010)
Mesenchymal Stem Cells Improve Wound Healing Via Early Activation of the Matrix Metalloproteinase-9 and Vascular Endothelial Growth Factor: Using a 3-Dimensional Collagen Gel Model.
Authors: Jong-Ho Won, Cheol-Hann Kim, Moon-Kyun Cho, Sang-Cheol Lee, Chan-Kyu Kim, Nam-Su Lee, Dae-Sik Hong, Hee-Sook Park
Journal: Blood (2007)