tbuckley/cabot-search huggingface dataset:
Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung
Authors: Katharina Jandl, Elvira Stacher, Zoltán Bálint, Eva Maria Sturm, Jovana Maric, Miriam Peinhaupt, Petra Luschnig, Ida Aringer, Alexander Fauland, Viktoria Konya, Sven-Erik Dahlen, Craig E. Wheelock, Dagmar Kratky, Andrea Olschewski, Gunther Marsche, Rufina Schuligoi, Akos Heinemann
Journal: Journal of Allergy and Clinical Immunology (2016)

Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor-homologous molecule expressed on T(H)2 cells) in regulating macrophages have not been elucidated to date.We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo.In vitro studies, including migration, Ca(2+) flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice.Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca(2+) flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis.For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation.
P-283 Impact of second-line cetuximab-containing therapy in patients with KRAS wild type metastatic colorectal cancer: results from ITACa trial
Authors: A. Passardi, E. Scarpi, A. Fontana, L. Cavanna, S. Ruscelli, D. Turci, V. Lorusso, C. Mucciarini, D. Tassinari, A. Ragazzini, M. Valgiusti, P. Ulivi, G.L. Frassineti, D. Amadori
Journal: Annals of Oncology (2015)
Effect of aprepitant (AP) on cyclophosphamide (CPA) pharmacokinetics (PK) in early breast cancer patients
Authors: C. M. Walko, Y. A. Yu, S. Bhushan, I. Spasojevic, L. Carey, F. Collichio, D. Armstrong, E. C. Dees
Journal: Journal of Clinical Oncology (2009)

588 Background: AP, a moderate inhibitor of CYP3A4, is a selective neurokinin 1 receptor antagonist recommended by the ASCO guidelines for prevention of high and some moderately emetogenic chemotherapy regimens, including doxorubicin and CPA (AC). CPA is converted to the active 4-OH metabolite primarily by CYP2B6 (48–57%) and by CYP3A4 (12–18%). CYP3A4 also converts 10% of CPA to the N-dechloroethyl metabolite (DCE), which is responsible for neurotoxicity and nephrotoxicity. Because AP is utilized concurrently with CPA, this creates the potential for drug-drug interaction between AP and CPA. The objective of this study was to evaluate the effect of AP on the PK of CPA, 4-OH, and DCE in patients receiving AC. Methods: This double-blinded, placebo controlled, two-period, crossover study included breast cancer patients receiving regimens containing CPA 600 mg/m2 IV for at least two sequential cycles. Prior to each CPA cycle, patients were randomized to receive either oral AP (125 mg on d 1 prior to chemotherapy and 80 mg on d 2 and 3) or placebo for 3 d. During both cycles, patients were also pretreated with ondansetron 24 mg PO and dex 12 mg PO on d 1 and dex 8 mg PO once on d 2 and 3. Rescue anti-emetic medications were permitted. Serial plasma samples were obtained from 0 to 24 h after administration of CPA in combination with AP or placebo in each patient. CPA, 4-OH, and DCE plasma concentrations were determined using HPLC. Area under the plasma versus conc time curve (AUC) was calculated using WinNonlin. Results: 17 patients completed 2 cycles and were evaluated for PK. Geometric mean AUC data for CPA in combination with AP and placebo are summarized in the table. Conclusions: Based on geometric mean ratios ± 90% CI, concurrent administration of AP with CPA did not result in any significant changes in the 4-OH metabolite AUC, but did result in increased parent CPA and decreased DCE drug exposure levels. Based on these results, it is unlikely that aprepitant has a clinically significant effect on the efficacy of CPA. [Table: see text] [Table: see text]
Carcinoma of unknown primary site with unfavorable characteristics: Survival of 396 patients after treatment with five consecutive phase II trials by the Minnie Pearl Cancer Research Network
Authors: F. A. Greco, S. Litchy, C. Dannaher, R. C. Hermann, A. Pati, J. Hon, D. S. Thompson, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2004)

4186 Background: Most patients with carcinoma of unknown primary site cannot be assigned to a favorable prognostic subgroup associated with an improved survival. In the past 8 years, several new cytotoxic agents with a broad spectrum of activity have been introduced including the taxanes, gemcitabine (G), and irinotecan (I). Methods: The Minnie Pearl Cancer Research Network has performed 5 consecutive phase II trials in a total of 396 patients from 1995 through 2002. Favorable subsets of patients were excluded. Study 1 included paclitaxel, carboplatin, and oral etoposide (PCE) (N=71), study 2 docetaxel and cisplatin (N=26), study 3 docetaxel and carboplatin (N=47), study 4 gemcitabine, carboplatin, and paclitaxel (N=120), and study 5 sequential PCE with GI (N=132). Results: The response rate in all 5 studies was 30% (107 of 353 evaluable patients), with 85 (24%) partial responders and 22 (6%) complete responders. With a minimum follow-up of 1 year, the median survival (MS) is 9.1 months and the 1-, 2-, 3-, 5-, and 8-year survivals are 38%, 19%, 12%, 8%, and 6%, respectively. The median progression-free survival (PFS) is 5 months and the 1-, 2-, 3-, 5-, and 8-year PFS are 17%, 7%, 5%, 4%, and 3%, respectively. The first 144 patients on the first 3 trials have a minimum follow-up of 4.8 years (range 4.8–8 years) and the MS is 10 months with a 1-, 2-, 3-, 5-, and 8-year survival of 42%, 22%, 18%, 12%, and 10%, respectively. The toxicity of these 5 regimens was moderate and primarily myelosuppression. There were 8 (2%) treatment-related deaths. When comparing these results to historical data from 45 prospective trials (since 1964) including 1,515 patients, and in retrospective reviews including 31,419 patients, the 1- and 2-year survival is significantly prolonged (40% versus 20% at 1 year and 22% versus 5% at 2 years). Conclusions: The newer chemotherapy regimens as reported here produce a prolongation of survival for these patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb; Eli Lilly; Pfizer-Pharmacia; Novartis; GlaxoSmithKline; Aventis; Genentech; Sanofi
Possible Roles of an Adult T-Cell Leukemia (ATL)-Derived Factor/Thioredoxin in the Drug Resistance of ATL to Adriamycin
Authors: Jingxin Wang, Masanobu Kobayashi, Keisuke Sakurada, Masahiro Imamura, Tetsuya Moriuchi, Masuo Hosokawa
Journal: Blood (1997)
Abstract 19374: A Collagen Matrix for Endothelial Progenitor Cell Therapy Improves Myocardial Function through Enhanced Cell Retention and Phenotype in a Mouse Model of Myocardial Infarction
Authors: Ali Ahmadi, Hadi Toeg, Jean N DaSilva, Myra Kordos, Stephanie Thorn, Jennifer Renaud, Thierry G Mesana, Robert S Beanlands, Rob A deKemp, Erik J Suuronen, Marc Ruel
Journal: Circulation (2010)

Background: To improve cell therapy, we tested the echo-guided intramyocardial delivery of Endothelial Progenitor Cells (EPCs), with and without a collagen matrix, in a mouse model of myocardial in...
Utility of Nontraditional Risk Markers in Atherosclerotic Cardiovascular Disease Risk Assessment
Authors: Joseph Yeboah, Rebekah Young, Robyn L. McClelland, Joseph C. Delaney, Tamar S. Polonsky, Farah Z. Dawood, Michael J. Blaha, Michael D. Miedema, Christopher T. Sibley, J. Jeffrey Carr, Gregory L. Burke, David C. Goff, Bruce M. Psaty, Philip Greenland, David M. Herrington
Journal: Journal of the American College of Cardiology (2016)
Abstract #2220: BMP2-induced EMT and invasion are mediated through activating PI-3 kinase /Akt and NF-\#954;B signaling
Authors: Young A Yoo, Myoung Hee Kang, Jung Lim Kim, Han Na Kang, Jae Hong Seo, Jun Suk Kim, Sang Cheul Oh
Journal: Cancer Research (2009)

Up-regulation of BMPs and their receptors by tumor is an important hallmark in cancer progression, as it contributes through autocrine and paracrine mechanisms to tumor development, invasion, and metastasis. Generally, increased motility and invasion are positively correlated with epithelial-mesenchymal transition (EMT). The present study aims to determine whether the BMP-2 signaling for inducing gastric cancer cells to undergo EMT-mediated invasion might possibly pass through the phosphatidylinositol 3-Kinase (PI-3 Kinase)/Akt and NF-\#954;B signaling pathway. Here we showed that the mean serum BMP-2 level from patients with metastatic gastric cancer was significantly higher than that from control groups and patients without bone metastasis. Moreover, an increased concentration of BMP2strongly enhanced motility and invasiveness in gastric cancer cells, whereas no increase was observed in cells treated with either Noggin (a BMP2 inhibitor) or BMP2 neutralization antibodies. The stimulation of BMP2 in gastric cancer cells induces a full EMT characterized by Snail induction, E-cadherin delocalization and down-regulation, and up-regulation of mesenchymal and invasiveness markers. Furthermore, blockade of BMP2 signaling by Noggin or BMP2 neutralization antibodies also restored these changes of EMT markers. In addition, phosphorylation of Akt and of I\#954;B\#945;, I\#954;B\#945; degradation, and the nuclear translocation of NF-\#954;B was also enhanced by treatment with BMP2, but not Noggin or BMP2 neutralization antibodies. Pretreated of gastric cancer cells with either PI-3 Kinase/Akt kinase inhibitor (kinase-dead Akt (AktK179M) or LY294002) or NF-\#954;B inhibitor significantly inhibited the BMP2-induced EMT and invasiveness. Furthermore, the BMP2-mediated increasing of I\#954;B\#945; phosphorylation and the nuclear translocation of NF-\#954;B were inhibited by AktK179M or LY294002. Overall, our studies suggest that BMP2 promote motility and invasion of gastric cancer cells by activating PI-3 Kinase/Akt and NF-\#954;B signaling and that targeting for these signaling may provide therapeutic opportunities in preventing metastasis mediated by BMP2.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2220.
P47 Recording of hospitalisations for acute exacerbations of COPD in UK electronic healthcare records databases
Authors: KJ Rothnie, H Mullerova, JR Hurst, L Smeeth, J Chandan, K Davis, S Thomas, JK Quint
Journal: Thorax (2015)

<h3>Background</h3> The Clinical Practice Research Datalink (CPRD) is a UK database of primary care health records covering 11 million residents of England and Wales, including at least 200,000 COPD patients. We have recently validated both the recording of COPD and algorithms to identify acute exacerbations of COPD (AECOPD) treated in primary care. It is unclear if primary care records alone can be used to identify hospitalisations for AECOPD. We aimed to validate strategies for identifying hospitalisations for acute exacerbations of COPD (AECOPD) using CPRD. <h3>Methods</h3> We identified 22,599 patients with a validated diagnosis<sup>1</sup> of COPD who had HES data linked to CPRD. We assessed the positive predictive value (PPV) and sensitivity of four strategies to identify hospitalisations for AECOPD using CPRD: 1) AECOPD hospitalisation code; 2) AECOPD identified using our validated algorithm; 3) generic hospitalisation code; or 4) AECOPD identified using our validated algorithm and generic hospitalisation code on the same day. We identified hospitalisations for AECOPD in HES using ICD codes, and used HES identified AECOPD hospitalisation as the reference standard. We used ICD-10 codes J44.0 and J44.1 in any position and J44.9 in first position to identify hospitalisations for AECOPD in HES. We searched primary care records over a 30 day window after a record for hospitalisation for AECOPD for recording consistent with AECOPD hospitalisation defined by the four strategies. Patients were followed up between January 2004 and July 2013. As a sensitivity analysis, we repeated the analysis using a more specific definition of hospitalisation for AECOPD (J44.0 or J44.1 in first position only). <h3>Results</h3> 19,507 hospitalisations for AECOPD were identified based on HES during the study period. The PPV and sensitivity of the various strategies to identify hospitalisations for AECOPD from CPRD alone are presented in Table 1. Sensitivity analysis did not significantly change the results. <h3>Conclusions</h3> Primary care electronic healthcare databases are not sufficient to accurately identify hospitalisations for AECOPD. Future studies should use HES data linked with primary care records to study AECOPD which result in hospitalisation. <i>Sponsored by MRC and GSK.</i> <h3>Reference</h3> 1 Quint JK, Müllerova H, DiSantostefano RL. <i>et al.</i> Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD).<i> BMJ Open</i>. 2014;<b>4</b>:e005540
Sustained release donepezil loaded PLGA microspheres for injection: Preparation, in vitro and in vivo study
Authors: Wenjia Guo, Peng Quan, Liang Fang, Dongmei Cun, Mingshi Yang
Journal: Asian Journal of Pharmaceutical Sciences (2015)

The purpose of this study was to develop a PLGA microspheres-based donepezil (DP) formulation which was expected to sustain release of DP for one week with high encapsulation efficiency (EE). DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method. The optimized formulation which avoided the crushing of microspheres during the preparation process was characterized in terms of particle size, morphology, drug loading and EE, physical state of DP in the matrix and in vitro and in vivo release behavior. DP microspheres were prepared successfully with average diameter of 30 µm, drug loading of 15.92 ± 0.31% and EE up to 78.79 ± 2.56%. Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface. Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres. The Tg of PLGA was increased with the addition of DP. The release profile in vitro was characterized with slow but continuous release that lasted for about one week and fitted well with first-order model, which suggested the diffusion governing release mechanism. After single-dose administration of DP microspheres via subcutaneous injection in rats, the plasma concentration of DP reached peak concentration at 0.50 d, and then declined gradually, but was still detectable at 15 d. A good correlation between in vitro and in vivo data was obtained. The results suggest the potential use of DP microspheres for treatment of Alzheimer's disease over long periods.
Abstract 1729: Discovery of a synthetic small molecule inhibitor of HSP90 for cancer therapy
Authors: Rudi Bao, Zhongzong Pan, Zhiming Zhao, Hongping Yu, Yaochang Xu
Journal: Cancer Research (2015)

Abstract HSP90 is a major heat shock protein involved in the proper folding of its client proteins including many onco-proteins. HSP90 is elevated in tumor cells with a more active configuration, making it a potential target for cancer drug development. Utilizing structure-base design, we discovered a small molecule compound that inhibits HSP90 activity with an IC50 at low- nanomolar concentration. Cell proliferation was inhibited by this compound at a IC50 of single-digit nanomolar concentration across many different cancer cell lines. Mechanism of action studies demonstrated that this compound could induce HER-2 degradation in the breast cancer cell line BT-474 in vitro at concentrations between 100-300 nM. The compound showed an ideal pharmacological kinetic feature of less exposure and fast clearance in rat retina after intravenous administration, thus reducing the possibility of ocular toxicity as demonstrated by some other earlier HSP90 inhibitors. The compound also caused tumor growth inhibition in the xenograft tumor models, correlating with its target inhibition activity in these tumors. These data supports further development of this compound as a cancer therapeutic agent. Citation Format: Rudi Bao, Zhongzong Pan, Zhiming Zhao, Hongping Yu, Yaochang Xu. Discovery of a synthetic small molecule inhibitor of HSP90 for cancer therapy. [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 1729. doi:10.1158/1538-7445.AM2015-1729
Forced Activation of Notch in Macrophages Represses Tumor Growth by Upregulating miR-125a and Disabling Tumor-Associated Macrophages
Authors: Jun-Long Zhao, Fei Huang, Fei He, Chun-Chen Gao, Shi-Qian Liang, Peng-Fei Ma, Guang-Ying Dong, Hua Han, Hong-Yan Qin
Journal: Cancer Research (2016)

Abstract Tumor-associated macrophages (TAM) contribute greatly to hallmarks of cancer. Notch blockade was shown to arrest TAM differentiation, but the precise role and underlying mechanisms require elucidation. In this study, we employed a transgenic mouse model in which the Notch1 intracellular domain (NIC) is activated conditionally to define the effects of active Notch1 signaling in macrophages. NIC overexpression had no effect on TAM differentiation, but it abrogated TAM function, leading to repressed growth of transplanted tumors. Macrophage miRNA profiling identified a novel downstream mediator of Notch signaling, miR-125a, which was upregulated through an RBP-J–binding site at the first intronic enhancer of the host gene Spaca6A. miR-125a functioned downstream of Notch signaling to reciprocally influence polarization of M1 and M2 macrophages by regulating factor inhibiting hypoxia inducible factor-1α and IRF4, respectively. Notably, macrophages transfected with miR-125a mimetics increased phagocytic activity and repressed tumor growth by remodeling the immune microenvironment. We also identified a positive feedback loop for miR-125a expression mediated by RYBP and YY1. Taken together, our results showed that Notch signaling not only supported the differentiation of TAM but also antagonized their protumorigenic function through miR-125a. Targeting this miRNA may reprogram macrophages in the tumor microenvironment and restore their antitumor potential. Cancer Res; 76(6); 1403–15. ©2016 AACR.
Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier
Authors: Kaijun Di, G. Kenneth Lloyd, Vivek Abraham, Ann MacLaren, Francis J. Burrows, Annick Desjardins, Mohit Trikha, Daniela A. Bota
Journal: Neuro-Oncology (2015)

The proteasome plays a vital role in the physiology of glioblastoma (GBM), and proteasome inhibition can be used as a strategy for treating GBM. Marizomib is a second-generation, irreversible proteasome inhibitor with a more lipophilic structure that suggests the potential for penetrating the blood-brain barrier. While bortezomib and carfilzomib, the 2 proteasome inhibitors approved for treatment of multiple myeloma, have little activity against malignant gliomas in vivo, marizomib could be a novel therapeutic strategy for primary brain tumors. The in-vitro antitumor activity of marizomib was studied in glioma cell lines U-251 and D-54. The ability of marizomib to cross the blood-brain barrier and regulate proteasome activities was evaluated in cynomolgus monkeys and rats. The antitumor effect of marizomib in vivo was tested in an orthotopic xenograft model of human GBM. Marizomib inhibited the proteasome activity, proliferation, and invasion of glioma cells. Meanwhile, free radical production and apoptosis induced by marizomib could be blocked by antioxidant N-acetyl cysteine. In animal studies, marizomib distributed into the brain at 30% of blood levels in rats and significantly inhibited (>30%) baseline chymotrypsin-like proteasome activity in brain tissue of monkeys. Encouragingly, the immunocompromised mice, intracranially implanted with glioma xenografts, survived significantly longer than the control animals (P < .05) when treated with marizomib. These preclinical studies demonstrated that marizomib can cross the blood-brain barrier and inhibit proteasome activity in rodent and nonhuman primate brain and elicit a significant antitumor effect in a rodent intracranial model of malignant glioma.
Expanding the clinicopathological spectrum of late cutaneous Lyme borreliosis (acrodermatitis chronica atrophicans [ACA]): A prospective study of 20 culture- and/or polymerase chain reaction (PCR)-documented cases
Authors: Cédric Lenormand, Benoît Jaulhac, Sébastien Debarbieux, Nicolas Dupin, Florence Granel-Brocard, Henri Adamski, Cathy Barthel, Bernard Cribier, Dan Lipsker
Journal: Journal of the American Academy of Dermatology (2016)
Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia
Authors: M M Patnaik, T L Lasho, P Vijayvargiya, C M Finke, C A Hanson, R P Ketterling, N Gangat, A Tefferi
Journal: Blood Cancer Journal (2016)

Abstract Mutations involving epigenetic regulators ( TET2 ~60% and ASXL1 ~40%) and splicing components ( SRSF2 ~50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had &gt;3 mutations. In a univariate analysis, the presence of ASXL1 mutations ( P =0.02) and the absence of TET2 mutations ( P =0.03), adversely impacted survival; while the number of concurrent mutations had no impact ( P =0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations ( P =0.01) and absence of TET2 mutations ( P =0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt ( n =56), ASXL1mut/TET2wt ( n =31), ASXL1mut/TET2mut ( n =50) and ASXL1wt/TET2mut ( n =38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P =0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) ( P =0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations.