tbuckley/cabot-search huggingface dataset:
Cytotoxic effects, mitochondrial damage and mutagenesis of Benzazolo[3,2-a]quinolinium Chlorides (BQs) on treated A431 tumor cells
Authors: Luz Arroyo, Christian Velez, Maria Terron, Sujey Carro, Wigberto Hernandez, Osvaldo Cox, Beatriz Zayas
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3231 

The purpose of this investigation is to establish the potentially cytotoxic effects, mitochondrial damage and mutagenesis of nitro or amine substituted benzazolo[3,2- a ]quinolinium chlorides (BQs); NBQ-38, NBQ-95, ABQ-115 and ABQ-117 on A431 epithelioid cancer cells. Cytotoxic effects, mitochondrial damage and mutagenesis were evaluated by growth inhibition, fluorescent microscopy and HPRT gene analysis respectively. The drug’s cationic nature could cause preferential mitochondrial retention, permitting the selective death of cancer cells. A431 cells were exposed to each NBQ and ABQ to levels between 0 and 150μM and incubated for 48 hrs at 37°C, 5%CO2, in a DMEM modified culture media. Assays were performed in triplicates. After 48 hr exposure period, cell cultures were photographed to observe morphological changes and cellular viability was determined by Trypan Blue exclusion. IC50 results per BQs were as follow: NBQ-38 (IC50=36μM) ; ABQ-115 (IC50=32μM) ; NBQ-95 (IC50=28μM) and ABQ-117 (IC50=36μM) . For evidence of BQs interaction with mitochondrial DNA, fluorescence microscopy analysis with JC-1 dye was performed. By fluorescence microscopy JC-1 is observed red or yellow (λ=590nm) when the mitochondrial membrane is intact and fluorescent green (λ=530nm) when membrane is broken indicating an apoptotic event. A431 cells were separately exposed to NBQ-38, ABQ-115, at their IC50 concentration and incubated for 48 hrs. The mitochondrial fluorescent assay results indicate mitochondrial damage in cells exposed to NBQ-38 and ABQ-115 in comparison to control cultures. Mutagenesis analyses at the HPRT gene are being performed. This assay will provide additional evidence of the drugs DNA interaction capability.
CCN1 (Cyr61) Is Overexpressed in Human Osteoarthritic Cartilage and Inhibits ADAMTS‐4 (Aggrecanase 1) Activity
Authors: Miyuki Chijiiwa, Satsuki Mochizuki, Tokuhiro Kimura, Hitoshi Abe, Yukie Tanaka, Yutaka Fujii, Hidenori Shimizu, Hiroyuki Enomoto, Yoshiaki Toyama, Yasunori Okada
Journal: Arthritis & Rheumatology (2015)

Objective ADAMTS‐4, also called aggrecanase 1, is considered to play a key role in aggrecan degradation in human osteoarthritic (OA) cartilage, but information about regulators of ADAMTS‐4 aggrecanase activity remains limited. We undertook this study to search for molecules that modulate ADAMTS‐4 activity. Methods Molecules copurified with ADAMTS‐4 from ADAMTS‐4–transfected chondrocytic cells were sequenced by nanoscale liquid chromatography tandem mass spectrometry. Binding activity was determined by immunoprecipitation and solid‐phase binding assay. Effects on ADAMTS‐4 activity were examined by aggrecan digestion assay. Expression of the binding molecule in OA cartilage and chondrocytes was examined by immunohistochemistry and reverse transcription–polymerase chain reaction. Results We identified CCN1 (Cyr61) as an ADAMTS‐4–binding protein and showed specific binding to the ADAMTS‐4 cysteine‐rich domain. Aggrecanase activity of ADAMTS‐4 was inhibited by interaction with CCN1. Expression of messenger RNA for CCN1 was significantly higher in human OA cartilage than in normal cartilage. CCN1 was immunolocalized to chondrocytes in OA cartilage, showing direct correlations of immunoreactivity with the Mankin score of cartilage lesions and chondrocyte cloning. CCN1 and ADAMTS‐4 were commonly coexpressed in clustered chondrocytes. CCN1 expression in OA chondrocytes was down‐regulated by interleukin‐1α (IL‐1α) and up‐regulated by transforming growth factor β (TGFβ). ADAMTS‐4 expression was induced by treatment with IL‐1α or TGFβ, but aggrecanase activity was detected only under stimulation with IL‐1α. TGFβ‐treated chondrocytes exhibited aggrecanase activity when CCN1 expression was knocked down. Conclusion Our findings provide the first evidence that CCN1 suppresses ADAMTS‐4 activity and that CCN1 overexpression is directly correlated with chondrocyte cloning in OA cartilage. Our results suggest that the TGFβ/CCN1 axis plays a role in chondrocyte cluster formation through inhibition of ADAMTS‐4.
Endovascular Edge-to-Edge Mitral Valve Repair
Authors: Frederick G. St. Goar, James I. Fann, Jan Komtebedde, Elyse Foster, Mehmet C. Oz, Thomas J. Fogarty, Ted Feldman, Peter C. Block
Journal: Circulation (2003)

Background— The edge-to-edge technique is an accepted method for the surgical repair of a regurgitant mitral valve. This study reports the initial use of an endovascular technology that enables a double-orifice edge-to-edge mitral valve repair without cardiopulmonary bypass in an animal model. Methods and Results— Adult pigs (n=14) were anesthetized, and left thoracotomy was performed for epicardial echo imaging. Using femoral vein access, a steerable guide catheter was placed transseptally into the left atrium. An implantable clip designed to grasp and approximate the middle scallops of the anterior and posterior mitral leaflets was introduced through the guide catheter. The clip was opened in the left atrium, advanced through the mitral orifice, and retracted to grasp the leaflet edges. When a functional double-orifice valve was confirmed by echo, the clip was closed to coapt the leaflets and detached from the delivery catheter. Before final clip detachment, echo demonstrated a double orifice in all 14 animals. In 2 studies, the clip released from the anterior mitral leaflet. Retrospective analysis of echo images indicated an incomplete grasp of the anterior leaflet. Immediate postmortem examination revealed that the clip successfully approximated the middle scallops of the anterior and posterior leaflets in all 12 double-orifice studies. Conclusions— This study demonstrates for the first time that an endovascular system can be successfully used to perform the edge-to-edge repair technique in a nondiseased porcine model. This technique is potentially applicable as a percutaneous catheterization laboratory procedure for the treatment of mitral regurgitation in humans.
Temporal Changes in DNA and RNA Synthesis in the Regenerating Liver of Hydrocortisone-treated Rats
Authors: Arturo J. Rizzo, Paul Heilpern, Thomas E. Webb
Journal: Cancer Research (1971)

The initial rise in DNA synthesis in the regenerating liver of young adult rats is reversibly inhibited by the administration of hydrocortisone, 50 mg/kg, at the beginning of the S phase, i.e. , 19 hr after partial hepatectomy. DNA synthesis is reinitiated approximately 31 hr postoperatively in the regenerating liver of the hydrocortisone-treated rat, with peak synthesis then occurring 36 hr after partial hepatectomy, compared to after 26 hr in the controls. Despite the inhibition of DNA synthesis, the rate of ribosome formation is increased 150 to 200% at 26 hr in the hydrocortisone-treated rats; similarly, following release of DNA synthesis at 36 hr ribosome formation is elevated 120 to 200% over controls. An analysis of the rates of synthesis and processing of the rRNA in the nucleus and of the accumulation of the products in the cytoplasm suggests that most of the increase in the hydrocortisone-treated rats is due to increased transport of the ribosomal subunits to the cytoplasm.
Abstract 9703: Factors of Atrial Fibrillation in Patients with History of Paroxysmal Supraventricular Tachycardia
Authors: Beátrice Brembilla-Perrot, Hadi Khachab, Etienne Aliot, Pierre Yves Zinzius, Jean Marc Sellal
Journal: Circulation (2011)

Background: Patients with history of paroxysmal supraventricular tachycardia (PSVT) have a higher risk of atrial fibrillation (AF) than patients without PSVT. The purpose of the study was to evaluate the incidence of AF in patients seen for PSVT and to look for the factors that could favour AF. Population: 1187 patients, 458 males (39%), 729 females (61%), mean age was 50±19 years were studied between 1980 and 2010 for PSVT confirmed by electrophysiological study (EPS). Patients with anterograde conduction through an accessory pathway (AP) were excluded. Methods: History of spontaneous AF was noted. Clinical factors and electrophysiological factors were collected. Patients with AF (group I) and without AF (group II) were compared. PSVT ablation was performed in 648 patients. Mean follow-up was 4.48±4.9 years. Results: 61 patients developed documented paroxysmal or permanent AF or atrial flutter (5%). They were older than patients without AF (59±13 vs 49±19 years, p&lt; 0.0005), were more frequently men (59% vs 37%) (p&lt;0.002), had more frequently prior AF (24.5% vs 0.5%)(&lt; 0.00000) and associated heart disease (18% vs 5%) (p&lt;0.004). There were no differences at EPS concerning the mechanism of re-entry: 13% of the group I patients and 18 % from the group II had a concealed AP (NS); 87 % of the group I patients and 82 % of the group II patients had typical or atypical AV nodal re-entrant tachycardia (NS). AF induction or occurrence during EPS was more frequent in group I patients (31%) than in group II patients (9%) (p&lt;0.00000). Multivariate analysis showed age, male gender, prior AF, heart disease and atrial vulnerability during EPS were independent predictors of AF. 52.4% of the group I patients and 54.7% from the group II underwent a successful procedure of radiofrequency ablation after EPS. Univariate comparison between both groups suggests no effect of PSVT ablation on the incidence of AF. Conclusions: The incidence of AF was 5% in 1187 patients consecutively admitted for PSVT and electrophysiological study. The risk of AF was correlated with the classical factors of AF: male gender, age, prior AF and the presence of heart disease. AF induction was a risk factor of AF. There was no correlation between the mechanism of reentry and the risk of AF. PSVT ablation did not prevent AF.
Abstract 4195: GNASR201H and KrasG12D cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm
Authors: Toru Furukawa, Etsuko Tanji, Masaki Ohmuraya, Katsunobu Taki, Kimi Araki
Journal: Cancer Research (2015)

Abstract Intraductal papillary mucinous neoplasm (IPMN) is the most common pancreatic cystic neoplasm, which is a precursor of the invasive ductal adenocarcinoma. IPMNs recurrently harbor activating somatic mutations in GNAS and KRAS, mostly GNASR201H and KRASG12D. GNAS encodes the stimulatory G-protein α subunit (Gsα) that mediates a stimulatory signal to adenylyl cyclase to produce cyclic AMP (cAMP), a second messenger activating cAMP dependent protein kinase (PKA). The GNASR201H mutation is known to result in constitutive activation of Gsα and its downstream signaling molecules, which induces expression of various genes including mucin genes. To study a role of GNAS in pancreatic tumourigenesis in vivo, we generated transgenic mice lines of which transgene is consisted of Lox-STOP-Lox (LSL)- GNASR201H under the control of the CAG promoter (Tg(CAG-LSL-GNAS)). The transgene contains genetic elements that inhibit transcription and translation of GNASR201H flanked by functional LoxP sites. These mice lines were crossed to pancreatic transcription factor 1 a (Ptf1a)-cre mice, and generated Tg(CAG-LSL-GNAS);Ptf1a-cre mice. This mouse line showed elevated cAMP levels and a compensatory upregulation of PKA in the pancreas. GNASR201H alone was not sufficient to induce tumourigenesis by 2 months of age, but small dilated tubular complex formation, loss of acinar cells, and fibrosis, which could be a very early phenotype of IPMN. To know a cooperative effect of GNASR201H and KRASG12D in pancreatic tumorigenesis, we crossed Tg(CAG-LSL-GNAS);Ptf1a-cre mice with LSL-KrasG12D mice. Tg(CAG-LSL-GNAS);LSL-KrasG12D;Ptf1a-cre mice developed multiple cysts consisting of marked dilated ducts lined with papillary dysplastic epithelia in the pancreas within 5 weeks, which recapitulated human IPMNs. Our data strongly suggest that mutated GNAS cooperating with mutated KRAS may sufficiently cause to develop IPMN. Citation Format: Toru Furukawa, Etsuko Tanji, Masaki Ohmuraya, Katsunobu Taki, Kimi Araki. GNASR201H and KrasG12D cooperate to promote murine pancreatic tumorigenesis recapitulating human intraductal papillary mucinous neoplasm. [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 4195. doi:10.1158/1538-7445.AM2015-4195
Abstract 2487: The antitumor efficacy of anti-BST2 antibody is significantly increased in combination with CpG oligodeoxynucleotide in endometrial cancer
Authors: Yusuke Takahashi, Satoshi Serada, Kosuke Hiramatsu, Kouji Kobiyama, Minoru Fujimoto, Ken Ishii, Tetsuji Naka
Journal: Cancer Research (2015)

Abstract Background: CpG oligodeoxynucleotides (ODN) has been shown to exhibit a potent immunostimulatory activity. Therefore, CpG ODN has been considered to be a promising material for enhancing the therapeutic effect of anticancer monoclonal antibody with antibody-dependent cell-mediated cytotoxicity (ADCC) activity. We have previously identified bone marrow stromal antigen 2 (BST2) as a therapeutic target of endometrial cancer cells and also demonstrated that an anti-BST2 antibody showed a potent anti-tumor effect by ADCC and complement-dependent cytotoxicity (CDC) activities against BST2 positive cells. The aim of this study was to evaluate the synergistic anti-tumor effect by combination of anti-BST2 antibody and CpG ODN, and to clarify the mechanisms of its anti-tumor effect, using xenograft model of BST2 positive endometrial cancer cells. Material and Method: We implanted 7-8 week-old female SCID mice with 5×106 HEC-88 nu endometrial cancer cells subcutaneously. Mice with tumor were treated by intra-peritoneal injection of an anti-BST2 mAb alone (12.5 and 200 μg/mouse, twice a week for four weeks), intra-tumoral injection of CpG ODN alone (10 μg/mouse, twice a week for four weeks) or combination therapy (12.5 μg/mouse of anti-BST2 mAb and 10 μg/mouse of CpG ODN). Anti-tumor effect was evaluated by monitoring the changes of tumor volume. Finally, population of NK cells and macrophages infiltrated into the tumor were analyzed by the FACS analysis, how CpG ODN induces immunopotentiative action. Results: Intraperitoneal treatment by anti-BST2 antibody showed a significant anti-tumor effect, dose dependently. The combination therapy of anti-BST2 antibody and CpG ODN was more effective than the single-agent therapy (p = 0.0002). In addition, the combination therapy also resulted high population of NK cells and macrophages in tumor significantly (p = 0.00018). Conclusion: We showed that CpG ODN increases the efficacy of anti-tumor effect of anti-BST2 mAb induced ADCC activity via potentiating NK cells and macrophages mediated cancer cell injury. Combination of GpG ODN would be a promising approach for enhancing the activity of ADCC based monoclonal antibodies, which targeting anti-tumor antigen. Citation Format: Yusuke Takahashi, Satoshi Serada, Kosuke Hiramatsu, Kouji Kobiyama, Minoru Fujimoto, Ken Ishii, Tetsuji Naka. The antitumor efficacy of anti-BST2 antibody is significantly increased in combination with CpG oligodeoxynucleotide in endometrial cancer. [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 2487. doi:10.1158/1538-7445.AM2015-2487
Double-blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal
Authors: R Malcolm, J C Ballenger, E T Sturgis, R Anton
Journal: American Journal of Psychiatry (1989)

Of 86 alcoholic men with severe alcohol withdrawal who began a double-blind controlled study comparing carbamazepine, 800 mg/day, to oxazepam, 120 mg/day, 66 (carbamazepine, N = 32; oxazepam, N = 34) completed the 7-day trial. In general, the drugs were found to be equally efficacious in treating the withdrawal syndrome and not significantly different with respect to side effects. The subjects taking oxazepam had an increase in global psychological distress from day 3 to day 7, and those taking carbamazepine exhibited a decline. The study suggests that carbamazepine is as effective and safe as benzodiazepine treatment for alcohol withdrawal.
Abstract P096: Maternal Serum C-Reactive Protein Levels During Pregnancy and Risk for High C-Reactive Protein 7-13 Years Later
Authors: Bonny Rockette-Wagner, Claudia Holzman, Bertha L Bullen, Andrew D Althouse, Janet M Catov
Journal: Circulation (2014)

Introduction: Elevated serum C-reactive protein (CRP) can be a marker of disease activity involving inflammation, such as pregnancy complications and cardiovascular disease (CVD). Systemically high levels of CRP in women, including during pregnancy, may indicate higher risk for CVD. It is unknown if CRP measured during the pro-inflammatory state of pregnancy correlates with concentrations assessed 7-13 years after delivery. Hypothesis: Concentrations of CRP assessed during pregnancy will be related to CRP measured several years after pregnancy, independent of weight gain. Methods: We studied the first 252 women enrolled in the follow-up of the Pregnancy Outcomes and Community Health Study (POUCHmoms 2011-2013) with complete CRP data for the pregnancy (mean gestational age: 22.36 [2.22] weeks) and POUCHmoms visits (mean follow-up: 10.76 [1.38] years). The relative risk for high hsCRP (≥ 3.39 μg/ml) at the follow-up visit, related to quartiles of CRP during pregnancy, was examined using stepwise regression models. Results: Median (IQR) levels of pregnancy CRP and hsCRP at the follow-up visit were 5.68 [3.08, 9.76] and 3.39 [0.69, 9.73] μg/ml, respectively. Although absolute values of hsCRP at follow-up were generally lower than pregnancy CRP, 56% of women in the top and bottom quartiles of pregnancy CRP (71 of 126) were in the same quartile for hsCRP at follow-up (figure). The relative risk of having high hsCRP (≥ 3.39 μg/ml) at follow-up ranged from 2.7-5.2 for the 2 nd - 4 th quartiles of pregnancy CRP (vs. the 1st quartile). Controlling for pre-pregnancy BMI and follow-up weight change, the relative risk of having high hsCRP at follow-up was significantly higher for the 2 nd (1.15 [1.02-1.30]),3 rd (1.19 [1.05-1.35), and 4 th (1.22 [1.05-1.41]) quartiles of pregnancy CRP. Conclusions: Pregnancy CRP levels are related to hsCRP levels several years later in this cohort of women, even after adjusting for pre-pregnancy BMI and follow-up weight change. CRP assessed in pregnancy may reflect inflammatory status later in life.
Allergic rhinitis does it have an impact on controller asthma therapy choice
Authors: Guergana Petrova, Snezhina Lazova, Vera Papochieva, Dimitrinka Miteva, Penka Perenovska
Journal: European Respiratory Journal (2014)

Background: In the last decade there is a worldwide increase in prevalence of allergic rhinitis (AR) and asthma. After the relationship between both entities was clarified the latest guidelines recommend integrated management.

Method: The records of 882 children (324 girls and 558 boys, mean age 7,5 y) admitted for asthma attack in our department for a period of 4 years (Jan. 2010- Dec. 2013) were analyzed for gender, age, AR and controller.

Results: The total number of patients was not significantly different and there were no significant difference in gender and age distribution through the years. AR was documented in 499 children (average 55.79%) with increasing prevalence from 51.52% in 2010 to 58.76% in 2012. Excluding 2013 boys had higher AR prevalence 60-61% vs.51-56% in girls. All patients regardless their AR status received antihistamines as additional therapy and 18 didn't have controller therapy (14 in 2010 , 1 in 2011 and 3 in 2013). While in 2010 the children had as a controller therapy Inhaled corticosteroids (ICS) more often (>60%), in 2011, 2012 and 2013 leukotriene receptor antagonist (LTRA) alone or in combination with ICS prevailed(>60%). Combined therapy (ICS+LTRA ± long acting beta2 agonist) was mainly prescribed for children older than 10 years. Some (all of them with AR) of the patients were re-admitted in the studied period – all of them with poor asthma control and AR.

Conclusion: As all guidelines and research papers state the role of LTRA – there is increasing use of them in children with asthma even in cases without AR. Better understanding and control of AR is related with better asthma control and less emergency department visits and hospitalizations.
Treatment-Related Deaths and Second Cancer Risk After Autologous Stem-Cell Transplantation for Hodgkin's Disease
Authors: Marc André, Michel Henry-Amar, Didier Blaise, Philippe Colombat, Joël Fleury, Noël Milpied, Jean-Yves Cahn, José-Luis Pico, Yves Bastion, Mathieu Kuentz, Gérard Nedellec, Michel Attal, Christophe Fermé, Christian Gisselbrecht
Journal: Blood (1998)
Molecular Predictors for the Response to Nilotinib Treatment After Acquired Imatinib Failure In Ph+ Chronic Myeloid Leukemia
Authors: Mridul Agrawal, Philipp Erben, Benjamin Hanfstein, Armin Leitner, John Reynolds, Richard C. Woodman, Laura Robin, Wolf-Karsten Hofmann, Andreas Hochhaus, Martin C. Müller
Journal: Blood (2010)
Lectins improve efferocytosis via changes to cytoskeletal remodeling: Relevance to COPD
Authors: Violet Mukaro, Johan Byland, Jessica Ahern, Mark Holmes, Greg Hodge, Paul Reynolds, Sandra Hodge
Journal: European Respiratory Journal (2012)

We have shown that the defective ability of alveolar macrophages (AM) to phagocytose apoptotic cells (efferocytosis) in COPD could be therapeutically improved using mannose binding lectin (MBL) although the exact mechanisms are unknown. A further lectin ,  galectin-3, is also known to regulate macrophage phenotype and function, via interaction with its receptor CD98 (an 9M29 mediator). We hypothesized that defective expression of MBL and galectin/CD98 would be associated with defective efferocytosis in COPD via effects on cytoskeletal remodeling and macrophage phenotype.  Galectin-3 was measured by ELISA in BAL from controls, smokers and current/ex-smokers with COPD. CD98 was measured on AM using flow cytometry. We assessed the effects of MBL and galectin-3 on efferocytosis, CD98, actin polymerisation, rac activation, and the involvement of PI3K (using β-actin probing and wortmannin inhibition)  in vitro  using human AM.  A significant decrease in galectin-3 was observed in BAL from smokers and COPD subjects vs controls. Galectin 3 and MBL increased efferocytosis via an increase in active GTP bound Rac1. This was confirmed with β-actin probing and the role of PI3k was confirmed using wortmannin inhibition. The increased efferocytosis was associated with increases in available glutathione and expression of CD98.  We provide evidence for a role of airway lectins in the failed efferocytosis in COPD, supporting their further investigation as potential macrophage-targeted therapies.
Connecting the Dots: Health Information Technology Expansion and Health Disparities
Authors: Courtney Lyles, Dean Schillinger, Urmimala Sarkar
Journal: PLoS Medicine (2015)

Points• Meaningful use is an incentive program sponsored by the US federal government that has provided more than US$25 billion to date to incentivize US healthcare clinics and hospitals to implement electronic health records (EHRs).Healthcare systems receive incentives for reaching a wide range of EHR targets, including providing patient access to/use of EHR information through portal websites.• Early evidence links EHR and portal use to better healthcare processes and health outcomes.• Promoting patient engagement with health technology such as portals is challenging, and rapid expansion of portals could exacerbate existing healthcare disparities if only well-resourced individuals use these websites.• Improving the usability and accessibility of portals for diverse patients requires collaboration between health communication researchers, user-centered designers, healthcare systems, vendors, and government agencies.