tbuckley/cabot-search huggingface dataset:
Extracellular vesicles and intercellular communication within the nervous system
Authors: Valentina Zappulli, Kristina Pagh Friis, Zachary Fitzpatrick, Casey A. Maguire, Xandra O. Breakefield
Journal: Journal of Clinical Investigation (2016)

Extracellular vesicles (EVs, including exosomes) are implicated in many aspects of nervous system development and function, including regulation of synaptic communication, synaptic strength, and nerve regeneration. They mediate the transfer of packets of information in the form of nonsecreted proteins and DNA/RNA protected within a membrane compartment. EVs are essential for the packaging and transport of many cell-fate proteins during development as well as many neurotoxic misfolded proteins during pathogenesis. This form of communication provides another dimension of cellular crosstalk, with the ability to assemble a "kit" of directional instructions made up of different molecular entities and address it to specific recipient cells. This multidimensional form of communication has special significance in the nervous system. How EVs help to orchestrate the wiring of the brain while allowing for plasticity associated with learning and memory and contribute to regeneration and degeneration are all under investigation. Because they carry specific disease-related RNAs and proteins, practical applications of EVs include potential uses as biomarkers and therapeutics. This Review describes our current understanding of EVs and serves as a springboard for future advances, which may reveal new important mechanisms by which EVs in coordinate brain and body function and dysfunction.
P392 ANTI-SLA/LP ALONE OR IN COMBINATION WITH ANTI-Ro52 AND FINE SPECIFICITY OF ANTI-Ro52 ANTIBODIES IN PATIENTS WITH AUTOIMMUNE HEPATITIS
Authors: K. Zachou, S. Gabeta, N.K. Gatselis, K. Oikonomou, I. Goulis, M.N. Manoussakis, Y. Renaudineau, D.P. Bogdanos, G.N. Dalekos
Journal: Journal of Hepatology (2014)
P132 Lack of change in outcomes accompanying significant improvement in clinical parameters of care of patients admitted with community acquired pneumonia
Authors: IJ Maxwell, S Merritt, OK Kankam, DL Maxwell
Journal: Thorax (2013)

<h3>Background</h3> Significant improvements in quality of inpatient care would be expected to improve objective outcomes, such as length of stay (LOS) and mortality. The management of community acquired pneumonia was reviewed on both sites of this Trust over a 33 month period during which time training and feedback was provided on management, monitoring 5 aspects of clinical care:- documentation of oxygenation; documentation of CURB65 scores; blood cultures (if obtained) taken before antibiotics; antibiotics given in accordance with Trust guidelines; antibiotics given within 6 hrs. <h3>Methods</h3> 4922 patients discharged between July 2010 and March 2013 had been coded as being admitted with pneumonia. The notes of 52 patients were unobtainable. Patients were excluded where there was no evidence of pneumonia on admission CXR, where the admitting clinicians had not diagnosed pneumonia or when the pneumonia was not considered to be community acquired. A monthly ‘composite quality score’ (CQS) score was derived by averaging the percentage of the 5 parameters that were achieved for each patient/admission. <h3>Results</h3> 2842 (58%) patients remained for analysis. Significant improvements were noted in all the parameters being monitored with quarterly CQS scores rising from 68% to 93% and, more specifically, quarterly scores for antibiotic delivery within 6 hrs increasing from 40% to 78%. Despite this no improvement at all was seen in LOS (quarterly LOS range: 10.8–13.4 days; no time trend). A gradual fall in mortality occurred, but only at one of the two sites (absolute fall of 2.8% per yr cf. no change). Of note was an unexpected and progressive increase in quarterly admissions (35% per year) at the site with falling mortality, but no change at the other. <h3>Conclusions</h3> Demonstrable improvement in parameters of clinical care result from education and feedback. However, a subsequent lack of change in outcomes (LOS, and, at one site, in mortality) despite such clear improvements would be unexpected. There may either be more appropriate clinical parameters on which to focus or these outcomes may have multifactorial influences amongst which improvements in current levels of clinical care may actually have a minor role.
Coccidioidomycosis in New England
Authors: Edward R. H. Kurz, Norman W. Loud
Journal: New England Journal of Medicine (1947)

COCCIDIOIDOMYCOSIS, probably the most infectious of the systemic mycoses, is rarely found along the Atlantic Seaboard. Owing to the tremendous displacement of people from their native areas that occurred during the war, however, clinicians must be aware that these infections may occur among the population, particularly in persons who have seen service in endemic coccidioidomycotic areas. A carefully taken history in patients who present granulomatous conditions of the skin and bizarre pulmonary lesions, either of cavitation without surrounding exudation or of ring-like apical formations with negative tuberculins, as well as a period of residence in areas where coccidioidomycosis is present, . . .
Abstract 674: Novel combinatorial quinacrine cancer therapies for advanced colon cancer
Authors: Jean-Nicolas Gallant, Wenge Wang, Nathan G. Dolloff, Joshua E. Allen, Wafik S. El-Deiry
Journal: Cancer Research (2011)

Abstract BACKGROUND: Although treatments have improved patient prognosis in early stages of colorectal cancer, new effective drugs with improved safety profiles are needed for improving the treatment of patients with advanced colon cancer. Quinacrine, a small molecule anti-malarial agent that has activity in giardiasis, lupus, prion disease, and used as a means of non-surgical sterilization, has shown cytotoxic activity across a broad range of cancers. The well characterized safety profile of quinacrine and its anticancer activity hold promise in novel combinatorial cancer therapies. OBJECTIVES: To evaluate the potential of adding quinacrine to anticancer chemotherapeutics and targeted agents as a potential novel combinatorial therapy for advanced colon cancer and to detail the mechanism of action of quinacrine when combined with cancer chemotherapy and targeted agents. METHODS: In vitro dose-response curves and isobolograms were constructed for single agent and dual agent therapies using quinacrine, 5-fluorouracil, gemcitabine, and sorafenib using the following colon cancer cell lines: HT-29, HT-29-luc, HCT-15, HCT-116, HCT-116 p53−/−, HCT-116 bax−/−, RKO, DLD-1, SW-480, and SW-620. Western blot analysis and flow cytometry were used to investigate potential mechanisms of action and to examine cell death. In vivo experiments were carried out to investigate toxicity and efficacy of combinatorial quinacrine chemotherapy in an athymic nu/nu mouse tumor xenograft model with human HT-29-luc cells. RESULTS: Single-agent quinacrine demonstrates potent anticancer activity with an average IC50 of 5.79 ± 0.83 μM across all ten colon cancer cell lines screened. In combination, quinacrine enhanced the anticancer activity of 5-fluorouracil and gemcitabine while significantly synergizing with sorafenib. Western blot analysis revealed that quinacrine's anticancer activity partially arises from its ability to stabilize p53, elevate death receptor levels, and lower anti-apoptotic protein levels. Quinacrine, when combined with sorafenib, dramatically lowers levels of the anti-apoptotic protein MCL-1. In vivo studies have shown that quinacrine monotherapy at a daily dose of 150 mg/kg significantly lowers the tumor load of nu/nu mice. CONCLUSIONS: Quinacrine is cytotoxic to a broad range of colon cancer cells lines and enhances the anticancer activity of chemotherapies such as 5-fluorouracil, gemcitabine, and sorafenib. The administration of quinacrine in combination with chemotherapy agents and targeted agents in patients with advanced colon cancer should be further explored in the clinic. 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 674. doi:10.1158/1538-7445.AM2011-674
Abstract 5206: VEGF-A/VEGFR-2 signaling might be a promising target for the tumor invasion of pancreatic cancer
Authors: Yosuke Doi, Masakazu Yashiro, Nobuya Yamada, Ryosuke Amano, Yukihiro Kato, Shinichiro Kashiwagi, Satoru Noda, Yuhiko Fuyuhiro, Masahiro Komoto, Junko Matsuoka, Naoshi Kubo, Kazuya Muguruma, Hiroaki Tanaka, Toru Inoue, Tetsuji Sawada, Masaichi Ohira, Bunzo Nakata, Kosei Hirakawa
Journal: Cancer Research (2010)

Abstract Introduction: Pancreatic cancer is one of the most lethal solid tumors. Vascular endothelial growth factor receptors (VEGFRs) are expressed not only by endothelial cells but also by some types of cancer cells, including pancreatic cancer cells. VEGFRs might play an important role for the development of cancer cells. The purpose of this study was to evaluate the efficacy of VEGF/VEGFR-2 targeted therapy in pancreatic carcinoma. We here demonstrated that VEGFR-2 signaling on pancreatic cancer cells might be a promising therapeutic target for the invasion of pancreatic cancer. Materials &amp; Methods: Three pancreatic carcinoma cell lines, MiaPaCa-2, OCUP-AT and Panc-1, were used. The effect of anti-VEGF antibody, bevacitumab, a tyrosine kinase inhibitor against VEGFRs, sunitinib, and VEGF-R2 siRNA on cancer invasion was examined by invasion assay. The expression level of VEGFR mRNA of cancer cells was examined by RT-PCR. The effect of VEGF, bevacitumab and sunitinib on MAPK and PI3K signaling pathway was examined. Result: VEGF-A significantly increased the number of migration cells of MiaPaCa-2 and OCUP-AT, but not that of Panc-1. Bevacitumab and sunitinib significantly decreased the migration ability of MiaPaCa-2 and OCUP-AT cells. The expression levels of VEGF-R2 were high in MiaPaCa-2 and OCUP-AT cells, in compared with Panc-1 cells. Invasion and migration ability of MiaPaCa-2 cells significantly (p&amp;lt;0.05) decreased by VEGFR-2 siRNA treatment. The level of VEGFR-2 autophosphorylation, p-ERK and p-Akt expression was increased by VEGF-A, and decreased by bevacitumab and sunitinib. Conclusion: The invasion of pancreatic cancer cells was closely associated with VEGF-A/VEGFR-2 signaling. VEGF-A/VEGFR-2 inhibition by bevacitumab or sunitinib appears therapeutically promising in pancreatic cancer with VEGFR-2 expression. 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 5206.
Tobacco Smoking, Coffee Drinking, and Occupation as Risk Factors for Bladder Cancer in Greece&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: A Rebelakos, D Trichopoulos, A Tzonou, X Zavitsanos, E Velonakis, A Trichopoulos
Journal: JNCI Journal of the National Cancer Institute (1985)

Patients with bladder cancer (250 males and 50 females), consecutively admitted during a 2-year period in the major cancer hospital of Athens, and an equal number of age- and gender-matched comparison patients with orthopedic conditions were interviewed regarding demographic, socioeconomic, and biomedical characteristics, including their occupations and their use of coffee and tobacco prior to the onset of their present disease or condition. Analyses of the data showed that 1) cigarette smoking is an important, statistically significant and dose-dependent risk factor for bladder cancer, particularly in males (tobacco smoking is rare among older Greek women); 2) drinking 2 or more cups of Greek coffee per day appears to be a risk factor for bladder cancer, independent of tobacco smoking, although the association is neither strong nor dose dependent; and 3) a priori specified “high-risk” occupations were associated with an increased rate ratio for bladder cancer among men less than 65 years and among women in general but not among older men. The overall results of this study indicate that the established risk factors for bladder cancer in the United States and in other developed countries are, apparently, equally important for bladder cancer in Greece, despite the differences in composition and conditions of use of Oriental tobacco and Greek coffee and in the activities and exposures to carcinogens in the Greek work place.
Abstract 4513: IND-enabling studies for CEQ508 targeting β-catenin of GI polyps: First oral RNAi drug
Authors: Natalya Bodyak, Alex Borrelli, Johannes H. Fruehauf, Jens Harborth, F. Stephen Laroux, Moru Vaze, Catherine Grillot-Courvalin, Alison D. Silva
Journal: Cancer Research (2010)

Abstract Targeted delivery remains one of the biggest challenges in the development of RNAi-based therapeutics. Cequent has developed a proprietary delivery technique for RNA interference, transkingdom RNAi (tkRNAi), in which non-pathogenic bacteria are engineered to invade specific target cells, produce and release short hairpin RNA (shRNA). We have previously shown tkRNAi to be successful in cell culture assays, in a mouse model for human colon cancer (APCmin), and in non-human primates (cynomolgus monkeys), by suppressing the oncogene, β-catenin. β-catenin is the key oncogene implicated in Colorectal Cancer (CRC) and Familial Adenomatous Polyposis (FAP); the latter being an orphan hereditary disease resulting in the formation of hundreds of polyps in the gastrointestinal tract and ultimately leads to the development of colon cancer without surgical intervention. No pharmaceutical treatment is available for patients with FAP. The non-human primate studies designed to evaluate on-target toxicities were conducted with a precursor (CEQ501) to our clinical candidate, CEQ508. Following optimization, which most importantly included platform engineering to improve hairpin production and processing, we conducted a large GLP mouse bridging toxicity study comparing off-target effects of CEQ508 and CEQ501. No CEQ508 or CEQ501-related adverse responses were identified in the following study parameters analyzed: clinical observations, body weights, serum chemistry, hematology, cytokines, gross or histopathology. As no test article-related changes were identified under the conditions of this study at the highest dose evaluated, the No Observed Effect Level (NOEL) for daily oral administration of either CEQ508 or CEQ501 was 5×109 cfu/day, or 2×1011 cfu/kg/day. (CEQ501 in non-human primates showed a similar safety profile with the No Observed Adverse Effect Level (NOAEL) determined to be 1×1012 cfu/day, or 2×1011 cfu/kg/day). Together with multiple internally conducted pharmacology and pharmacokinetic experiments, Cequent used this data in the nonclinical section of an IND filed in late 2009. In addition to presenting detailed in vivo data from our filing, an update on further development will be presented on CEQ508 for the proposed daily dosing of FAP patients with this oral tkRNAi therapeutic targeting β-catenin. 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 4513.
EUS-FNA as the initial diagnostic modality in centrally located primary lung cancers
Authors: A Hernandez, M Kahaleh, J Olazagasti, D Jones, T Daniel, G White, E Stelow, V Shami
Journal: Endoscopy (2006)

Introduction: The need to safely and accurately diagnose lung neoplasms is crucial as the only prospect for a cure is surgical resection. A small amount of data exists on the use of EUS-FNA as the initial diagnostic modality of primary lung cancer.
Faisabilité de la microscopie confocale intra-tumorale guidée par échoendoscopie (MCEE)
Authors: M Giovannini, F Caillol, G Monges, E Bories, C Pesenti, O Turrini, JR Delpero
Journal: Endoscopy (2011)

Introduction: L'endomicroscopie confocale est une technique émergeante. Le but de cette étude a été d'évaluer la faisabilité de la microscopie confocale intra-tumorale guidée par échoendoscopie (EMCEE) chez des patients ayant donnés leur consentement éclairé et présentant soit des lésions kystiques ou solides du pancréas ou des adénopathies sus et sous mésocoliques.
Imaging of gliomas at 1.5 and 3 Tesla - A comparative study
Authors: L. Tselikas, R. Souillard-Scemama, O. Naggara, C. Mellerio, P. Varlet, E. Dezamis, J. Domont, F. Dhermain, B. Devaux, F. Chretien, J.-F. Meder, J. Pallud, C. Oppenheim
Journal: Neuro-Oncology (2014)

Glioma follow-up is based on MRI parameters, which are correlated with survival. Although established criteria are used to evaluate tumor response, radiological markers may be confounded by differences in instrumentation including the magnetic field strength. We assessed whether MRIs obtained at 3 Tesla (T) and 1.5T provided similar information. We retrospectively compared imaging features of 30 consecutive patients with WHO grades II and III gliomas who underwent MRI at 1.5T and 3T within a month of each other, without any clinical changes during the same period. We compared lesion volumes on fluid attenuation inversion recovery (FLAIR), ratio of cerebral blood volume (rCBV) on perfusion-weighted imaging, contrast-to-noise ratio (CNR) on FLAIR, and on post-gadolinium 3D T1-weighted sequences between 1.5T and 3T using intraclass correlation coefficient (ICC). Concordance between observers within and between modalities was evaluated using weighted-kappa coefficient (wκ). The mean ± SD delay between modalities (1.5T and 3T MRI) was 8.6 ± 5.6 days. Interobserver/intraobserver concordance for lesion volume was almost perfect for 1.5T (ICC = 0.96/0.97) and 3T (ICC = 0.99/0.98). Agreement between observers for contrast enhancement was excellent at 1.5T (wκ = 0.92) and 3T (wκ = 0.92). The tumor CNR was significantly higher for FLAIR at 1.5T (P < .001), but it was higher at 3T (P = .012) for contrast enhancement. Correlations between modalities for lesion volume (ICC = 0.97) and for rCBV values (ICC = 0.92) were almost perfect. In the follow-up of WHO grades II and III gliomas, 1.5T and 3T provide similar MRI features, suggesting that monitoring could be performed on either a 1.5 or a 3T MR magnet.
Mild High-Renin Essential Hypertension
Authors: Murray Esler, Stevo Julius, Andrew Zweifler, Otelio Randall, Ernest Harburg, Hermsworth Gardiner, Vincent DeQuattro
Journal: New England Journal of Medicine (1977)

To determine whether the elevated plasma renin activity in some cases of mild essential hypertension expresses sympathetic-nervous-system over-activity, we compared indexes of sympathetic activity in 16 patients with mild high-renin essential hypertension, 15 hypertensive patients with normal plasma renin activity and 20 normal subjects. Patients with elevated activity exhibited a raised plasma norepinephrine concentration (P less than 0.05), a greater fall in cardiac output with cardiac beta-adrenergic blockade by intravenous propranolol (P less than 0.01), reduction in total peripheral vascular resistance with alpha-adrenergic blockade produced by intravenous phentolamine (P less than 0.01), and reduction to normal of blood pressure by "total" autonomic blockade (atropine, propranolol and phentolamine). On psychometric testing, patients with high-renin hypertension, but not those with normal plasma renin activity, exhibited suppressed hostility (P less than 0.01), a behavioral pattern linked to increased sympathetic activity. The hypertension in these patients with high renin activity is neurogenic and possibly psychosomatic in origin.
PWE-073 The Multidimensional Nature of Ibd Fatigue: A Systematic Review And Meta- Analysis
Authors: I Nathan, K C Fragos, A Forbes
Journal: Gut (2013)

<h3>Introduction</h3> Fatigue is recognised as a troublesome symptom for patients with IBD. There is no consensus regarding mechanisms driving fatigue or treatment. The aim of the present study is to assess the factors associated with IBD fatigue, using a systematic literature review and meta-analysis. <h3>Methods</h3> A systematic literature review was performed in PubMed and EMBASE and additional articles and abstracts were identified by a hand search. All studies reporting correlation coefﬁcients (CCs) of fatigue with disease activity were included. A random-effects model was employed to produce a pooled estimate of CCs, which was the effect size in the current analysis. Fisher’s Z transformation of the CCs was utilised for the analysis. Publication bias was assessed with funnel plots and Egger’s test. All computations were executed with Stata 10.0 and MetaWin. <h3>Results</h3> 23 studies were eligible for inclusion (total sample size = 5980). Fatigue was strongly correlated with IBD disease activity (pooled CC 0.386; 95% CI 0.335 to 0.435, range 0.165 to 0.540). Although there was no publication bias (failsafe N = 958), there was moderate heterogeneity (Q = 33.74, df = 14, p = 0.002; I² = 58.5%). Subgroup analysis showed a relationship between the correlation of fatigue and disease activity with population group (adult, paediatric) but not with country. Meta regression with percentage of males and mean age did not suggest that either were significant moderators of the particular correlation coefficient. Fatigue was also strongly correlated with quality of life (pooled CC –0.534; 95% CI –0.636 to –0.414), psychological distress (pooled CC 0.515; 95% CI 0.412 to 0.606) and daytime sleepiness (pooled CC 0.400; 95% CI 0.32 to 0.471), and was moderately correlated with anaemia (pooled CC 0.167; 95% CI 0.104 to 0.231) and social and functional impairment (pooled CC 0.288; 95% CI 0.133 to 0.424). Flare ups were not a significant predictor of fatigue (p &gt; 0.05). Heterogeneity was present in all analyses (p &lt; 0.05), except for the meta-analyses with anaemia, daytime sleepiness and social and functional impairment. Publication bias (assessed with the funnel plot) was more probable in the secondary factors compared with disease activity analyses in the initial correlation. <h3>Conclusion</h3> A number of factors were found to correlate with IBD fatigue. These include: psychological distress, daytime sleepiness, disease activity, anaemia and social and functional impairment. This suggests both cognitive and physical aspects of IBD fatigue and clearly highlights the multidimensional nature of this symptom. This is part of a larger study conducted in collaboration with Crohn’s and Colitis UK, King’s College London and Addenbrookes’ NHS Trust, funded by the Big Lottery Fund. <h3>Disclosure of Interest</h3> None Declared.