tbuckley/cabot-search huggingface dataset:
Abstract 2754: Cinnamoyl quinolines are novel autophagy inhibitors and enhance antitumor activity of 2-deoxyglucose
Authors: Ling-Huei Yih, Rajesh Kakadiya, Yi-Chen Wu, Hsiao-Hui Kuo, Tsann-Long Su
Journal: Cancer Research (2012)

Abstract Cinnamides exhibit a variety of biological properties including antineoplastic, antiallergic, and anti-infective activities etc. Modifications of the amide function of cinnamides by linking with aliphatic or heterocyclic moieties results in the formation of cinnamoyl derivatives with anticancer activities. In the present study, we prepared a series of cinnamoyl quinolines and evaluated their antitumor activity in a panel of cancer cell lines. These derivatives reduced cancer cell viability by inducing apoptosis and showed little to no cross-resistance to vinblastine- or cisplatin-induced multidrug resistance. Interestingly, the cinnamoyl-quinoline-6-yl derivatives (BO-2110 and BO-2112) induced cytoplasmic vacuolization and the processing and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes. However, these agents caused the accumulation and aggregation of p62/SQSTM1. Co-treatment of cinnamoyl-quinoline-6-yl derivatives with bafilomycin A1 did not induced a further increase in p62/SQSTM1 accumulation. These results indicated that cinnamoyl-quinoline-6-yl derivatives blocked autophagy. Since autophagy enables cancer cells to temporarily avoid cell death when nutrient deprivation or exposing to chemotherapeutic agents, cinnamoyl quinolines may sensitize cancer cells to death and augment chemotherapy-induced apoptosis. Co-treatment of these derivatives with 2-deoxyglucose (2DG, glycolysis inhibitor), but not cisplatin (DNA alkylating agent), camptothecin (Topo I inhibitor), doxorubicin or etoposide (Topo II inhibitor), significantly enhanced cell death in the tested tumor cell lines. Collectively, these results suggest that BO-2110 and BO-2112 are effective autophagy inhibitors and promising candidates that may be used in combination with 2DG for treating cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2754. doi:1538-7445.AM2012-2754
The Neisseria meningitidis CRISPR-Cas9 System Enables Specific Genome Editing in Mammalian Cells
Authors: Ciaran M Lee, Thomas J Cradick, Gang Bao
Journal: Molecular Therapy (2016)

The clustered regularly-interspaced short palindromic repeats (CRISPR)—CRISPR-associated (Cas) system from Streptococcus pyogenes (Spy) has been successfully adapted for RNA-guided genome editing in a wide range of organisms. However, numerous reports have indicated that Spy CRISPR-Cas9 systems may have significant off-target cleavage of genomic DNA sequences differing from the intended on-target site. Here, we report the performance of the Neisseria meningitidis (Nme) CRISPR-Cas9 system that requires a longer protospacer-adjacent motif for site-specific cleavage, and present a comparison between the Spy and Nme CRISPR-Cas9 systems targeting the same protospacer sequence. The results with the native crRNA and tracrRNA as well as a chimeric single guide RNA for the Nme CRISPR-Cas9 system were also compared. Our results suggest that, compared with the Spy system, the Nme CRISPR-Cas9 system has similar or lower on-target cleavage activity but a reduced overall off-target effect on a genomic level when sites containing three or fewer mismatches are considered. Thus, the Nme CRISPR-Cas9 system may represent a safer alternative for precision genome engineering applications. The clustered regularly-interspaced short palindromic repeats (CRISPR)—CRISPR-associated (Cas) system from Streptococcus pyogenes (Spy) has been successfully adapted for RNA-guided genome editing in a wide range of organisms. However, numerous reports have indicated that Spy CRISPR-Cas9 systems may have significant off-target cleavage of genomic DNA sequences differing from the intended on-target site. Here, we report the performance of the Neisseria meningitidis (Nme) CRISPR-Cas9 system that requires a longer protospacer-adjacent motif for site-specific cleavage, and present a comparison between the Spy and Nme CRISPR-Cas9 systems targeting the same protospacer sequence. The results with the native crRNA and tracrRNA as well as a chimeric single guide RNA for the Nme CRISPR-Cas9 system were also compared. Our results suggest that, compared with the Spy system, the Nme CRISPR-Cas9 system has similar or lower on-target cleavage activity but a reduced overall off-target effect on a genomic level when sites containing three or fewer mismatches are considered. Thus, the Nme CRISPR-Cas9 system may represent a safer alternative for precision genome engineering applications.
SP0001 Finding your Way Around Eular Hot Tips for a Successful Conference
Authors: P. Cornell
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> This year we've decided to present a preliminary session on getting the best out of EULAR for health professionals. This will be a short introduction to the logistics in Madrid, provide details of the health professional programme and the various study groups. This introductory session will include a presentation from the new EULAR president Maurizio Cutolo who will give a presidents perspective for the future of health professionals in EULAR. <h3>Disclosure of Interest</h3> None Declared
P45 Natural killer cell cytotoxicity is enhanced in injection drug users with apparent resistance to hepatitis C virus infection
Authors: U. Warshow, C. Sieberhagen, D. Hegazy, E. Kaminski, S. Knapp, S. Khakoo, M. E. Cramp
Journal: Gut (2011)

<h3>Introduction</h3> We have identified a cohort of injection drug users (IDU) who, despite long-term high risk sharing of drug injection equipment, remain seronegative and aviraemic for HCV. These exposed uninfected (EU) IDU appear resistant to HCV infection. This resistance is associated with the same Natural Killer (NK) immunoglobulin-like receptor (KIR)/HLA genotype known to favour spontaneous HCV clearance. Whether there is a functional alteration in NK cell cytotoxicity in these individuals is unknown. <h3>Aim</h3> To investigate cytotoxic function of NK cells in EU. <h3>Method</h3> Peripheral blood mononuclear cells (PBMC) were isolated from 16 EU (HCV-Ab positive and HCV-RNA negative), 10 IDU with untreated chronic HCV (cHCV) and five IDU with spontaneous resolution (SR) of HCV (HCV-Ab positive but HCV RNA negative). NK cytotoxicity was assessed against the NK-sensitive K562 cell line. PBMC incubated for 48 h with or without interleukin-2 (IL-2) were co-cultured with K562 for 4 h at an E:T ratio of 10:1. Flow cytometry was used to assess the frequency of NK cells [CD56(+) CD3(−)] in PBMC and cytotoxicity quantified by CFSE/7-AAD co-staining and expressed as the percentage of cells lysed. <h3>Results</h3> Natural killer cell cytotoxicity, in the absence of IL-2 stimulation, was no different between the groups. With IL-2 stimulation, EU demonstrated significantly higher cytotoxicity compared to cHCV (32.8±4.4% vs 17.6±3.2%, p=0.023), with similar levels to SR (27.7±9.9%, p=0.50). The proportion of NK cells in PBMC was not significantly different between the groups. <h3>Conclusion</h3> The current findings point to enhanced NK cytotoxicity in EU cases compared to those with chronic infection and suggests a role for NK cells in early viral clearance and resistance to HCV infection.
Comparison of Amphotericin B with Fluconazole in the Treatment of Acute AIDS-Associated Cryptococcal Meningitis
Authors: Michael S. Saag, William G. Powderly, Gretchen A. Cloud, Patrick Robinson, Michael H. Grieco, Patricia K. Sharkey, Sumner E. Thompson, Alan M. Sugar, Carmelita U. Tuazon, John F. Fisher, Newton Hyslop, Jeffrey M. Jacobson, Richard Hafner, William E. Dismukes
Journal: New England Journal of Medicine (1992)

Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease.
P17 The Accuracy of a Diagnosis of Pneumonia in a UK Teaching Hospital
Authors: KL Pink, I Mitchell, HE Davies
Journal: Thorax (2012)

<h3>Background</h3> Obtaining an accurate diagnosis of pneumonia is an essential part of optimal patient care. Analysis of patients' hospital records allows clinical coding (ICD-10) of admission events which assist development of clinical decision algorithms, assessment of quality of care and public health evaluation. We sought to evaluate the reliability of applied clinical codes and the accuracy of a diagnosis of pneumonia in our institution. <h3>Methods</h3> A retrospective case note review of all patients admitted to University Hospital Llandough in 2011 with a final clinical code diagnosis of pneumonia. Pneumonia was defined as the presence of new radiographic infiltrate in patients with symptoms consistent with an acute lower respiratory tract infection.1 The chest radiographs of each patient were reviewed by a respiratory physician (KP, HED) and the formal radiology report was independently scrutinised (IM). <h3>Results</h3> 710 patient episodes of ICD-10 coded pneumonia were identified in a 1 year period at our hospital. Ten patients had no chest x-ray performed and one x-ray had no report. Radiological confirmation of pneumonia (by radiology reporting) occurred in 69.8% (488/699); a radiological diagnosis of pneumonia was made by a respiratory physician (KP, HED) in 71.8% (502/699) of patients. There was 85% agreement between the Respiratory and Radiology reports (592/699 cases) with a kappa of 0.66 (95% CI 0.57 to 0.69). The accuracy of a pneumonia diagnosis differed little between patients cared for by a respiratory physician (72.3% agreement with radiology report) and those admitted to a non-respiratory ward (68.1%). In 27.0% and 31.9% of patients respectively there was no radiological evidence of pneumonia. <h3>Conclusions</h3> A clinical coding diagnosis of pneumonia is unreliable with 30.2% of patients not having compatible radiograph change. This has implications for the validity of any research performed on data selected on the basis of clinically coded information. Misdiagnosis by clinicians is the most likely reason for this discrepancy. <h3>Reference</h3> BTS Guidelines for the Management of Community Acquired Pneumonia in Adults Update 2009.
Abstract 4270: Targeting cancer cells resistant to hypoxia and nutrient starvation double-deprivation stress as a novel cancer therapy
Authors: Tsuyoshi Osawa, Masashi Muramatsu, Rika Tsuchida, Feng Wang, Yasuhito Yuasa, Masabumi Shibuya
Journal: Cancer Research (2011)

Abstract Anti-angiogenesis is an effective cancer treatment, however, tumor progression and refractoriness to anti-angiogenesis are observed in both clinical and preclinical cancer models. Stress under hypoxia and nutrition deprivation might play an important role in the tumor aggressiveness and refractoriness. Here we show that a long term hypoxia and nutrient starvation double-deprivation stress (DDS) stimulates migration, invasion and anchorage independent growth of tumor cells in vitro and an increased tumor progression and angiogenesis in vivo associated with an increase in blood vessels and infiltration of CD11b+ cells. We also observed up-regulation of DDS-responsive genes including VEGF-A, FGF18, and JHDM2A. We found that histone demethylase JHDM2A is commonly up-regulated under DDS in human and mouse cancer cell lines in vitro and in vivo at the phase of pre-angiogenic switch and refractory phase of anti-angiogenic treatments. Specific inhibition of JHDM2A by siRNAs significantly suppressed tumor growth in vivo. Importantly, suppression of JHDM2A demonstrated synergetic effects in treatment with anti-VEGF neutralizing antibody (bevacizumab) or small molecular inhibitor for VEGF receptors (sunitinib), and improved an efficacy of anti-angiogenesis. Collectively, our results indicate that minor population of cancer cells resistant to both hypoxia and low nutrition acquires tumor aggressiveness through specific mechanisms upon the DDS responses. Our observations suggest that the targeting of cancer cells resistant to hypoxia and nutrient starvation by inhibition of DDS-responsible genes such as JHDM2A can be utilized for a novel treatment to overcome the refractoriness to anti-angiogenic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4270. doi:10.1158/1538-7445.AM2011-4270
Abstract 2642: Identification and characterization of selective inhibitors of ubiquitin specific protease 7
Authors: Céline Reverdy, Susan Conrath, Roman Lopez, Cécile Planquette, Vincent Collura, Philippe Guedat, Rémi Delansorne, Laurent Daviet, Frédéric Colland
Journal: Cancer Research (2010)

Abstract Regulated protein turnover is primarily controlled by the ubiquitin-proteasome system. The only marketed drug related to the ubiquitin-proteasome system, bortezomib, is acting as a proteasome inhibitor and has been approved for the treatment of some hematological cancers. Targeting the upstream ubiquitin conjugation/deconjugation system carries out promises of therapeutics with increased specificity and selectivity. Ubiquitin-specific proteases (USP) are involved in the deubiquitination of specific target substrates regulating their stability, subcellular localization and/or activation status. USP represent a drugable target class due to their thiol-protease catalytic core which is amenable to pharmacological inhibition by small molecules. A genome-wide RNAi screen of the catalytically active human USPs in cancer-relevant cellular models and phenotypic assays allowed us to identify USP7/HAUSP as promising cancer target. Fluorescence-based screening assays using optimized USP substrates including various ubiquitin derivatives (ubiquitin precursor, branched ubiquitin chains) as well as specific, physiological substrates were developed. High-throughput screening performed on our chemically diverse library followed by different optimization programs resulted in the discovery of several series as novel USP7 inhibitors. Our progress made towards the specificity issue will be presented here with the identification of the first USP7-specific series. These will help further validate this novel class of molecular targets and may provide a structural basis for the development of new anticancer drugs. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2642.
Malignant Argentaffinoma Associated with Cardiovascular Abnormalities
Authors: W. R. Eyler, H. Tesluk, E. H. Drake
Journal: New England Journal of Medicine (1956)

THERE has recently been considerable interest in the association of argentaffin tumors with valvular lesions of the heart.1 2 3 4 5 The unusual character of this association was first recognized by Biorck, Axen and Thorson,1 although they were able to find a few cases previously reported. In general these patients all had argentaffin tumors, which had often extensively metastasized to the liver. However, in a case reported by Arnett and Long6 the tumor was thought to be a carcinoma of the pancreas, and in 1 of the cases of Rosenbaum et al.,7 the neoplasm was interpreted as a bile-duct carcinoma. The cardiac component . . .
Use of Radiolabeled Antibodies to Carcinoembryonic Antigen for the Detection and Localization of Diverse Cancers by External Photoscanning
Authors: David M. Goldenberg, Frank DeLand, Euishin Kim, Sidney Bennett, F. James Primus, John R. van Nagell, Norman Estes, Philip DeSimone, Pam Rayburn
Journal: New England Journal of Medicine (1978)

To determine whether tumors containing carcinoembryonic antigen could be detected by administration of a radiolabeled, affinity-purified, goat lgG having 70 per cent immunoreactivity against carcinoembryonic antigen, 18 patients with a history of cancer of diverse histopathology received an average total dose of 1.0 mCi of 131l-labeled lgG. Total-body photoscans were performed with a gamma scintillation camera at various intervals after administration of the radioactive antibody. Ordinary photoscans proved difficult to interpret because of blood-pool background radioactivity, thus necessitating the computer subtraction of radioactive blood-pool agents from the antibody's 131l activity. Tumor location could be demonstrated at 48 hours after injection in almost all cases studied. The scans were negative in patients without demonstrable tumors or with tumors apparently devoid of carcinoembryonic antigen. Circulating antigen levels of up to 350 ng per milliliter did not prevent successful tumor imaging after injection of the radioantibody.
P246 Airway and systemic inflammation in stable and exacerbated bronchiectasis: a pilot study
Authors: R. Chitkara, H. Batchelor, R. J. Sapsford, S. Workman, A. R. C. Patel, A. J. Mackay, B. Grimbacher, J. R. Hurst
Journal: Thorax (2011)

<h3>Introduction</h3> It is not known whether systemic inflammation reflects lower airway inflammation in non-CF bronchiectasis. If confirmed, blood biomarkers may provide useful information on pulmonary disease burden in both stable and exacerbated states. Serum C reactive protein (CRP) is readily measurable in many clinical settings, including at point-of-care, and procalcitonin (PCT) has a potential role with documented utility in other respiratory diseases. This study explored the relationship between airway and systemic inflammatory biomarkers in adult patients with non-CF bronchiectasis. <h3>Method</h3> Serum CRP (for systemic inflammation) and PCT, and sputum interleukin (IL)-6 (for airway inflammation) were measured in 31 well-phenotyped stable patients from The London Bronchiectasis Cohort. Six exacerbation samples were obtained from patients who had been previously sampled at baseline, with the exacerbation sample obtained at exacerbation onset, prior to initiation of additional antibiotic therapy. Sputum IL-6 was measured using ELISA, serum PCT using TRACE, and CRP using immunoturbidimetry techniques. Data were analysed using SPSS V.14.0. <h3>Results</h3> Of the 31 patients, 23 (74.2%) patients were female, with a mean (SD) age of 54.7 (14.9) years, FEV<sub>1</sub> 2.09 (0.90) l (75.71% predicted), and FVC 3.12 (1.01) l. The predominant aetiologies were primary immunodeficiency (mostly CVID, n=13, 42%), post-infectious (10, 32%) and idiopathic (4, 13%). The median (IQR) baseline sputum IL-6 was 101 (30–701) pg/ml, baseline serum PCT was 0.030 (0.021–0.040) μg/ml and CRP 3.0 (1.0–6.0) mg/l. The degree of systemic inflammation in stable bronchiectasis reflected that occurring in the airways as evidenced by a significant correlation between sputum IL-6 and serum CRP in the 31 stable samples (r=0.43, p=0.027). There was also a correlation between the two systemic markers (PCT and CRP: r=0.42, p=0.029), but the relationship between serum PCT and sputum IL-6 concentration was not statistically significant (r=0.28, p=0.127). In the six patients with paired samples, serum PCT increased significantly from baseline to exacerbation (0.031 vs 0.147 μg/ml p=0.043). Changes in sputum IL-6 and blood serum CRP did not reach statistical significance. <h3>Conclusion</h3> We report a direct relationship between airway and systemic inflammation in stable patients with non-CF bronchiectasis. This suggests that systemic biomarkers may be useful for monitoring local disease activity in this neglected condition.
When I use a word: Historian
Authors: H. Lucas
Journal: BMJ (2001)

Patients are sometimes referred to as “bad historians.” But who is the historian? “Historian” refers to the one taking and interpreting history, not the subject (whether a person or a topic). If a history is contradictory, lacking evidence, or irrelevant this could well represent part of the intrinsic problem rather than be a deliberate attempt to mislead. If you attribute blame to the historian you rightly (albeit inadvertently) blame yourself.
Remission of Bone Metastases After Combined Chemotherapy and Radionuclide Therapy With Re-186 HEDP
Authors: H Palmedo, F Grünwald, U Wagner, S Köhler, D Krebs, H J Biersack
Journal: Clinical Nuclear Medicine (1998)

A patient with disseminated osseous metastases due to breast cancer reported multifocal pain. Because of persisting pain after a first cycle of chemotherapy, 1,295 MBq Re-186 HEDP was administered intravenously. Excellent pain relief was observed. Subsequently, the patient received further combined chemotherapy and Re-186 HEDP therapy and remained pain free. Tc-99m MDP bone imaging showed a significant regression of osseous metastases. It may be speculated that the combination of Re-186 HEDP and chemotherapy results in significantly increased palliation of metastatic bone disease.
Letter to the editor: Early transmission dynamics of Ebola virus disease (EVD), West Africa, March to August 2014 – Eurosurveillance 17 September 2014
Authors: D Plachouras, B Sudre, M Testa, E Robesyn, D Coulombier
Journal: Eurosurveillance (2014)

Preview this article: Letter to the editor: Early transmission dynamics of Ebola virus disease (EVD), West Africa, March to August 2014 – Eurosurveillance 17 September 2014, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/19/37/art20907-en-1.gif
P135 Prevalence Of Sensitisation To Soya Flour In The Baking Industry Within The Uk
Authors: J. Cannon, M. Jones, J. Welch, B. Fitzgerald, J. Szram, P. Cullinan
Journal: Thorax (2014)

<h3>Introduction</h3> Soya flour is routinely used as a baking additive to increase shelf life, improve colour and introduce a nutty flavour to bread. Although a large number of bakers are exposed to soya flour, there is little information as to the prevalence of sensitisation to soya flour in the baking industry. One study reports sensitisation to soya flour in four bakers who were sensitised to flour and alpha amylase and a bronchial challenge to soya flour elicited an immediate or dual asthmatic response. Studies in soy processing plant (slightly different to bakeries) report soy-specific IgE in 21% of soy processing workers compared with only 4% in health care workers, suggesting soya is an important occupational allergen in the soy processing industry. <h3>Methods</h3> To determine prevalence of sensitisation to soya flour in bakery workers, we carried out skin prick testing to soya flour (Allergopharma 598) in bakery workers exposed to soya flour (n = 196) and in non-bakery controls (n = 50), who attended an occupational lung disease clinic. Skin tests were categorised as positive if they induced a wheal with a mean diameter of ≥2 mm greater than the response to a negative (saline) control and histamine was used as a positive control. <h3>Results</h3> In a total of one hundred and ninety five bakery workers exposed to soya, forty two bakers were sensitised to soya flour (21%), and forty of those bakers were also sensitised to either flour and or alpha amylase (95%) In comparison, none of the control group (n = 50) were sensitised to soya flour. <h3>Conclusion</h3> In our preliminary study of bakery workers exposed to soya flour, we found that around a fifth of the population were sensitised to soya flour. The clinical significance of soya flour need further investigation, although it seems prudent to include soya flour in the diagnostic tests for bakers asthma.