tbuckley/cabot-search huggingface dataset:
Abstract 9921: Angiotensin II Receptor Blocker Improves Exercise Capacity and Mitochondrial Function of Skeletal Muscle via Inhibiting Oxidative Stress in High Fat Diet-Induced Diabetic Mice
Authors: Shingo Takada, Shintaro Kinugawa, Takashi Yokota, Tadashi Suga, Masashige Takahashi, Arata Fukushima, Tsuneaki Homma, Sobirin A Mochamad, Taisuke Ono, Yoshihiro Masaki, Tomoyasu Kadoguchi, Koichi Okita, Hiroyuki Tsutsui
Journal: Circulation (2011)

Background We have previously reported that the exercise capacity is reduced and mitochondrial function is impaired in high fat diet (HFD)-induced diabetic mice, which is due to NAD(P)H oxidase-induced oxidative stress. NAD(P)H oxidase can be activated by angiotensin II. Hypothesis We thus hypothesized that angiotensin II receptor blocker can ameliorate the reduced exercise capacity in diabetic mice. Methods C57BL/6J mice were fed on normal diet (ND) or HFD, and each group of mice was divided into 2 groups of the treatment with or without olmesartan (OLM, 3mg/kg/day) in the drinking water. Four groups of mice, ND (n=10), ND+OLM (n=10), HFD (n=15), and HFD+OLM (n=15), were studied. After 8 weeks, treadmill tests were performed to determine the work and oxygen uptake (VO 2 ). ADP-dependent (state 3) respiration in mitochondria was determined, and NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence method were measured in isolated skeletal muscle. Results HFD significantly increased body weight, adipose tissue weight, plasma glucose and insulin compared to ND, and OLM did not affect these parameters in either group. The work and peak VO 2 were significantly reduced in HFD compared to ND (work; 14±1 vs 28±2 J, peak VO 2 ; 111±2 vs 145±3 mL/kg/min), and these reductions were ameliorated in HFD+OLM (work; 18±1 J, peak VO 2 ; 122±3 mL/kg/min). State 3 respiration was significantly decreased, and NAD(P)H oxidase activity and superoxide production were significantly increased in HFD compared with ND (state 3 respiration; 58±3 vs 39±3 nmol/min/mg protein, NAD(P)H oxidase activity; 403±70 vs 1771±326 RLU/min/100µg protein, superoxide; 61±11 vs 181±27 RLU/min/mg), which was attenuated by OLM (state 3 respiration; 56±3 nmol/min/mg protein, NAD(P)H oxidase activity; 646±51 RLU/min/100µg protein, superoxide; 81±20 RLU/min/mg). There were no such effects by OLM in ND mice. Conclusions Olmesartan ameliorated the reduced aerobic capacity in HFD-induced diabetic mice via the improvement of impaired mitochondrial function and attenuation of oxidative stress in the skeletal muscle. The improvement of aerobic capacity by angiotensin II receptor blocker may have a clinical impact in the treatment of patients with diabetes mellitus.
PTH-028 Real world surveillance of barrett’s oesophagus – does it make a difference using the prague classification or following seattle biopsy protocol?: Abstract PTH-028 Table 1
Authors: S Ghuman, K Asghar, J Evans, S Kakhi, N Hawkes
Journal: Gut (2015)

<h3>Introduction</h3> BSG Barrett’s Surveillance guidance recommends that the Prague Classification (PC) should be used to describe a Barrett’s segment and Seattle Protocol (SP) be used when taking biopsies. Previous studies have reported poor compliance with such protocols. We sought to investigate the extent to which adherence to advice affected outcomes in our patient cohort. We aimed to investigate the impact of 1) reported use of the Prague classification and 2) adherence to the Seattle protocol, on the detection of all dysplasia and advanced dysplasia (HGD, or in-situ adenocarcinoma). <h3>Method</h3> HICCS Endoscopic Reporting System was searched for all detected Barrett’s oesophagus between Oct 2010–Oct 2014 (n = 587 procedures). Only specific surveillance cases were included (index and specific recall cases excluded). Endoscopy reports were checked and histology results retrieved from the Welsh Clinical Portal system. Differences in dysplasia detection rates for 1) PC used versus PC not used, and 2) SP followed versus SP not followed were tested using the Chi-squared test. Numbers of biopsies in each SP group were compared using two-tailed t-test. Significance level set at p &lt; 0.05. <h3>Results</h3> In the 4 year study period, 367 Barrett’s surveillance procedures were performed in 220 patients. PC was reported in 106 (28.9%) and SP followed in 116 (31.6%) of procedures. The dysplasia rates are shown in the Table. There was a significant increase in detection rate of all types of dysplasia and advanced dysplasia (AD) when PC was used and where SP was followed. Significantly more biopsies were taken in the SP followed group, both for short (p = 0.037) and longer (&gt;3 cm) segments (p &lt; 0.00001). <h3>Conclusion</h3> Adherence to recommended reporting and biopsy protocols may just reflect deeper interest in Barrett’s surveillance or greater experience level. Even if only surrogate markers for ‘quality’ of examination, their use marked clinically relevant differences in dysplasia detection, which in turn is linked to numbers of patients who may require endotherapy or radiofrequency ablation. <h3>Disclosure of interest</h3> None Declared.
Abstract 2690: A novel antibody-drug conjugate directed to the ALK receptor tyrosine kinase demonstrates efficacy in models of neuroblastoma
Authors: Renata Sano, Kateryna Krytska, Colleen Larmour, Gwenda F. Ligon, Jay S. Lillquist, Ulisse Cucchi, Paolo Orsini, Simona Rizzi, Gerald McMahon, Diego Alvarado, Yael P. Mosse
Journal: Cancer Research (2016)

Abstract Activated ALK by mutation or amplification is a validated therapeutic target in a subset of patients with high-risk neuroblastoma, and tyrosine kinase inhibitors are being developed to abrogate ALK signaling (Bresler et al, 2014). Native ALK is expressed on the surface of the majority of neuroblastoma tumors, but not on normal tissue, giving it properties of a tumor antigen. We hypothesized that ALK-targeted antibodies may be useful in neuroblastoma as single-agent immunotherapy or in combination with small-molecule ALK inhibitors - especially where mutations reduce kinase inhibitor sensitivity. In this work, an anti-ALK monoclonal antibody (anti-ALK2) was conjugated to a cytotoxic agent (ALK2-ADC) and its anti-tumor activity was investigated in a panel of extensively characterized human neuroblastoma cell lines (n = 10) harboring wild type and mutant ALK. Cell surface ALK was quantified using flow cytometry and revealed differential antigen expression. Using in vitro growth inhibition assays, there was evidence for a dose-dependent cytotoxicity to neuroblastoma cells at subnanomolar concentrations that correlated with ALK expression and was independent of underlying mutation status. In order to evaluate the therapeutic potential of ALK2-ADC in vivo, mice bearing Felix-patient-derived xenograft (PDX) tumors, containing the third most common ALK mutation (R1245C), were used to demonstrate that ALK2-ADC led to a significant reduction in tumor growth compared to unconjugated antibody and a control ADC (p&amp;lt;0.0001). Although ALK2-ADC binds potently to mouse ALK as well as human ALK, doses of up to 10 mg/kg in the rodent model appeared to be well tolerated with no overt toxicity noted. Additional in vivo studies are ongoing to assess the antitumor potential of the ADC in a broader range of ALK-expressing neuroblastoma models. Thus, targeting human ALK-expressing with an ALK antibody-drug conjugate demonstrated early signs of favorable efficacy and tolerability supporting future development of this approach as a potential novel therapeutic for patients with neuroblastoma. Citation Format: Renata Sano, Kateryna Krytska, Colleen Larmour, Gwenda F. Ligon, Jay S. Lillquist, Ulisse Cucchi, Paolo Orsini, Simona Rizzi, Gerald McMahon, Diego Alvarado, Yael P. Mosse. A novel antibody-drug conjugate directed to the ALK receptor tyrosine kinase demonstrates efficacy in models of neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2690.
Abstract 3014: ONC201 anti-cancer effects against solid tumors are mediated through eIF2α kinases HRI and PKR but are PERK-independent
Authors: Christina Leah B. Kline, Wafik S. El-Deiry
Journal: Cancer Research (2016)

Abstract ONC201 is a first-in-class small molecule inducer of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway. We recently reported that ONC201-mediated induction of the TRAIL pathway is largely promoted by a preceding early activation of the integrated stress response pathway (ISR) (Kline et al., Sci. Sig., in press, 2015). ONC201 engages the ISR to exert its broad-spectrum anti-cancer effects through pro-apoptotic and anti-proliferative activities. ONC201 upregulates ATF4, the key indicator of ISR activation, in a manner that is dependent on two eIF2α kinases: heme-regulated inhibitor (HRI) and double-stranded RNA activated protein kinase (PKR). Of note, the activation of ATF4 and downstream cell death signaling by ONC201 is PERK-independent. We now further elucidate how the novel dual engagement of HRI and PKR by ONC201 contributes to the anti-cancer effects of ONC201. ONC201 treatment results in early phosphorylation of eIF2α in a manner that is dependent on HRI. On the other hand, we have shown that ONC201-induced downregulation of cyclin D1 is dependent, at least in part, on PKR, but not on eIF2 α phosphorylation per se. This occurs potentially via PKR-mediated ubiquitination and subsequent proteasome degradation of cyclin D1. Treating cells with ONC201 and the proteasome inhibitor MG132 prevents ONC201-induced decrease of cyclin D1. Despite distinctions in their regulatory protein domains, HRI and PKR have both been shown to respond to oxidative stress. Treating cells with ONC201 in the presence of the antioxidant N-acetylcysteine abrogated ATF4 induction. Our findings document a unique activity of ONC201 on protein translation, via activation of HRI and PKR, as well as effects on protein stability through the proteasome leading to anti-cancer effects. Citation Format: Christina Leah B. Kline, Wafik S. El-Deiry. ONC201 anti-cancer effects against solid tumors are mediated through eIF2α kinases HRI and PKR but are PERK-independent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3014.
Clinical Benefit Of Anticoagulation In Treatment Of Catheter-Related Deep Vein Thrombosis In Patients With Acute Leukemia
Authors: Nora Oliver, Mya S Thein, Vu H. Duong, Michael L. Tidwell, Edward A. Sausville, Farin Kamangar, Maria R. Baer, Ashkan Emadi
Journal: Blood (2013)
ESEN : une comparaison des programmes de vaccination - Troisième partie : rougeole, oreillons et rubéole
Authors: D Lévy-Bruhl, R G Pebody, I Veldhuijzen, M Valenciano, K Osborne
Journal: Eurosurveillance (1998)

Cet article est le dernier d’une serie de trois articles portant sur la comparaison, dans huit pays (Danemark, Angleterre et Pays de Galles, Finlande, France, Allemagne, Italie, Suede et Pays-Bas), des programmes vaccinaux et de l’impact epidemiologique de la vaccination contre la diphterie, la coqueluche, la rougeole, les oreillons et la rubeole. Cette etude a ete realisee par le Reseau Europeen de Surveillance serologique (ESEN), projet finance par l’Union Europeenne (1). La methodologie de l’analyse, les caracteristiques des differents programmes de vaccination ainsi que les resultats de la vaccination contre la diphterie et la coqueluche ont ete decrits (2, 3). Cet article presente les resultats concernant la vaccination contre la rougeole, les oreillons et la rubeole (ROR).
Novel Fusion Transcripts PVT1-NSMCE2 and BF104016-NSMCE2 Resulting In Depletion Of NSMCE2 Protein In Acute Myeloid Leukemia Harboring 8q24 Amplicons
Authors: Yoshiaki Chinen, Natsumi Sakamoto, Hisao Nagoshi, Tomohiko Taki, Satoru Kobayashi, Kazuhiro Nishida, Saori Maegawa, Ryuko Nakayama, Miki Kiyota, Shinsuke Mizutani, Yuji Shimura, Mio Yamamoto-Sugitani, Tsutomu Kobayashi, Yosuke Matsumoto, Shohei Yokota, Shigeo Horiike, Junya Kuroda, Masafumi Taniwaki
Journal: Blood (2013)
Reply
Authors: Andreas Drolz, Valentin Fuhrmann
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. REPLY: We thank Dr. Qi and colleagues for their interest in our article.1 They suggest that anticoagulation with unfractionated heparin (UFH) may be associated with higher bleeding risk compared with low molecular weight heparin. This assumption is based on the following aspects, to which we would like to respond. In our study, we identified activated partial thromboplastin time (aPTT) values >100 s as a strong predictor of major bleeding in critically ill patients with cirrhosis. Dr. Qi and colleagues assume that the use of UFH may be responsible for prolonged aPTT. Because aPTT values at admission were predictive of new onset of major bleeding, and because no patient was treated with UFH before admission to the intensive care unit, UFH‐associated prolongation of aPTT seems unlikely. The mechanisms behind the increase in aPTT values in critically ill patients with cirrhosis require further investigation. A superimposed disseminated intravascular coagulation‐like process as well as accumulation of endogenous heparin‐like compounds may contribute to prolongation of aPTT values in these patients.2 Notably, there was no significant difference in the proportion of use of therapeutic anticoagulation between cirrhosis patients with and without major bleeding. Furthermore, Qi et al. note that the bleeding rate in our patients appears to be higher than that found in other studies on anticoagulation in cirrhosis.3 This finding may be attributable to the fact that most previous studies were performed in stable patients in a normal ward or in outclinic patients rather than in critically ill patients with cirrhosis who had multiorgan failure (87% of our patients fulfilled the criteria of acute‐on‐chronic liver failure, with a median sequential organ failure assessment score of 13). In accordance with our results, Cholongitas et al.4 reported an incidence of 20% for gastrointestinal bleeding in another cohort of critically ill patients with cirrhosis. However, data on the type of anticoagulation and its relation to bleeding complications in critically ill patients with cirrhosis are still lacking, so further studies in this field are definitely required.
Abstract 4652: Effects of anti-DLL4 treatment on non-small cell lung cancer (NSCLC) human xenograft tumors
Authors: Alayne Brunner, Fiore Cattaruzza, Wan-Ching Yen, Pete Yeung, Marcus Fischer, Belinda Cancilla, Gilbert O’Young, Raymond Tam, Yu-Wang Liu, Austin Gurney, John Lewicki, Tim Hoey, Min Wang, Ann M. Kapoun
Journal: Cancer Research (2016)

Abstract Background: Non-small cell lung cancer (NSCLC) accounts for the vast majority of lung cancers, the leading cause of cancer-related deaths. Notch signaling has been shown to play an important role in lung cancer initiation and progression. Delta-like ligand 4 (DLL4) activates the Notch pathway and is important for cancer stem cell (CSC) survival. Demcizumab (OMP-21M18) is a humanized IgG2 anti-DLL4 antibody currently being tested in a Phase 2 trial in combination with pemetrexed and carboplatin for first-line treatment of patients with NSCLC. Previously, OMP-21M18 in combination with its mouse anti-DLL4 surrogate has been shown to inhibit tumor growth, decrease cancer stem cell frequency, and cause dysfunctional sprouting of new vessels resulting in an anti-angiogenic effect in patient-derived tumor xenograft (PDX) models in breast, colon, ovarian, and pancreatic cancers. Here we show results from NSCLC PDX models. Methods and Results: Anti-DLL4 treatment was tested in a series of NSCLC PDX models. Because DLL4 inhibition has been shown to have effects on the tumor as well as the vasculature, the combination of OMP-21M18 (targeting human DLL4) and 21R30 (antibody targeting mouse DLL4) treatment in the PDX models was used to model demcizumab treatment in humans. Treatment with anti-DLL4 in combination with chemotherapy inhibited tumor growth in a series of NSCLC PDX models. Additionally, a tumorigenicity assay showed a decrease in the frequency of tumor-initiating cells following treatment with anti-DLL4 and chemotherapy. Gene expression analysis of tumor samples provided insights into the mechanism of action. Conclusions: Anti-DLL4 treatment in a panel of NSCLC PDX tumor models in vivo showed inhibition of tumor growth and a decrease in the frequency of tumor-initiating cells. Mechanism of action and gene expression analysis of these models treated with anti-DLL4 will be presented. These findings provide additional evidence supporting demcizumab as an effective treatment for NSCLC patients. Citation Format: Alayne Brunner, Fiore Cattaruzza, Wan-Ching Yen, Pete Yeung, Marcus Fischer, Belinda Cancilla, Gilbert O’Young, Raymond Tam, Yu-Wang Liu, Austin Gurney, John Lewicki, Tim Hoey, Min Wang, Ann M. Kapoun. Effects of anti-DLL4 treatment on non-small cell lung cancer (NSCLC) human xenograft tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4652.
Abstract LB-315: Bone marrow adipocytes alter the metabolic phenotype of metastatic prostate cancer cells through the activation of HIF-1a
Authors: Jonathan Diedrich, Erandi Rajagurubandara, Mackenzie Herroon, Izabela Podgorski
Journal: Cancer Research (2016)

Abstract Bone is a preferential site of metastasis from prostate cancer (PCa). Age and obesity, conditions that increase adipocyte numbers in bone marrow, are risk factors for skeletal metastases from PCa. Research in our laboratory focuses on understanding the interactions between adipocytes and tumor cells that have infiltrated the bone marrow. Specifically, we are examining how the secretion, transport, and uptake of adipocyte-supplied factors promote metastatic progression in bone. We have previously shown that bone marrow adipocytes enhance a glycolytic phenotype in PCa cells through paracrine activation of glycolytic enzymes GLUT1, HK2, PDK1, ENO2, and LDHa at both the mRNA and protein levels. This correlated with an increase in glycolytic activity as measured by higher levels of lactate secretion and decreases in oxidative phosphorylation, indicative of an enhanced Warburg-like metabolic signature. We then assessed HIF-1a activity through mRNA analysis of HIF-1a target genes carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF). We found that CA9 and VEGF had elevated expression levels in tumor cells exposed to adipocytes, indicative of enhanced HIF-1a activity. Notably, PCa cells exposed to bone marrow adipocytes had significantly enhanced presence of HIF-1a in the nucleus, result further confirming HIF-1α, activation in tumor cells exposed to marrow adipocytes. Hypoxia chamber experiments revealed that these effects were observable regardless of the presence or absence of oxygen, indicating the presence of oxygen-independent HIF-1a signaling or a state of pseudohypoxia in tumor cells. These results were further validated in multiple in vitro cell culture and in vivo mouse models, where an increased production of both glycolytic genes and HIF-1α target genes was shown to correlate with marrow adiposity. Our overall hypothesis is that bone marrow adipocyte-supplied lipids within the bone microenvironment cause HIF-1a activation and metabolic switch to glycolysis in metastatic PCa cells in bone, leading to their increased aggressiveness and resistance to therapy. Citation Format: Jonathan Diedrich, Erandi Rajagurubandara, Mackenzie Herroon, Izabela Podgorski. Bone marrow adipocytes alter the metabolic phenotype of metastatic prostate cancer cells through the activation of HIF-1a. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-315.
The 2016 Guidelines for Hospital-acquired and Ventilator-associated Pneumonia. A Selection Correction?
Authors: Sushant Govindan, Robert C. Hyzy
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

neurocognitive function.However, we still need more information.In particular, we need to confirm a causal relationship between OSA and clinically significant diminished neurocognitive function, and we need to be confident that the risks associated with treatment of OSA in children are appropriately balanced against the risks of untreated OSA.Anyone who has worked with children who are struggling as a result of sleep-disordered breathing can attest to the benefits of successful treatment, and there is an abundance of evidence demonstrating the benefits of adenotonsillectomy on patient quality of life (12).However, we must continue to exercise our clinical judgment in our approach to these patients, maintaining awareness of both the risks of action as well as inaction while we await more data.After all, in some cases, the cure may be worse than the disease.
Effect of NVP-BEZ235, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, on radiosensitivity of oral cancer cell line through G2/M phase checkpoint regulation.
Authors: Yu-Chieh Su, Chih-Chia Yu, Shih-Kai Hung, Hon-Yi Lin, Michael Wing-Yan Chan, Hsien-Bin Huang, Ching-Chih Lee
Journal: Journal of Clinical Oncology (2014)

e13558 Background: Radioresistance is a major challenge in head and neck cancer radiotherapy (RT). PI3K/mTOR signal pathway has been considered an important regulatory mechanism of resistance to radiation therapy on OSCC. Here, we generated radiation-resistance OML-1R subline derived from OML-1, the certain oral cancer patient in Taiwan. We hypothesized that G2/M checkpoint are involved in radiation-resistance OML-1R and correlated with the PI3K/mTOR signal pathway; Specifically blocking the PI3K and mTOR signal pathway by NVP-BEZ235 improve OML-1R cells to radiosensitivity via disruption of the G2/M checkpoint. Methods: Clonogenic assays were performed to determine the radiosensitizing effect of RAD001 and NVP-BEZ235 on OML-1 and OML-1R cells. Target protein phosphorylation, apoptosis, and G2/M Checkpoint were assessed after treatment of OML-1 and OML-1R cells with NVP-BEZ235 and/or ionizing radiation. Results: We show that NVP-BEZ235 was more effective than RAD001 in reducing cell viability of OML-1R sensitivity to radiation using clonogenic survival assay. Resistance is characterized by altered G2/M checkpoint and PI3K/mTOR pathway proteins using western blotting. Specifically, we discover that activation of Chk2 checkpoint protein , which leads to phosphorylation of Cdc25c at Ser216, destruction of the cyclin B-cdc2 complex, disruption of the G2/M checkpoint after after treatment with NVP-BEZ235 and radiation of OML-1R cells, but not in OML-1 cells. However, we find the cytotoxic effect of NVP-BEZ235 enhanced the effect of radiation on OML-1R cells, independently of apoptotic and autophagic cell death pathways. Conclusions: Our findings indicate that OSCC radioresistance is associated with G2/M checkpoint and activation of the PI3K/mTOR signaling pathway, and that the combination of NVP-BEZ235 with RT effectively reduces the radiation-induced mTOR substrates S6 and 4E-BP1 and abrogates the G2 checkpoint to overcome radiosistance in the treatment of OSCC.