tbuckley/cabot-search huggingface dataset:
The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008
Authors: C. Verslype, E. Van Cutsem, M. Dicato, N. Arber, J.D. Berlin, D. Cunningham, A. De Gramont, E. Diaz-Rubio, M. Ducreux, T. Gruenberger, D. Haller, K. Haustermans, P. Hoff, D. Kerr, R. Labianca, M. Moore, B. Nordlinger, A. Ohtsu, P. Rougier, W. Scheithauer, H.-J. Schmoll, A. Sobrero, J. Tabernero, C. van de Velde
Journal: Annals of Oncology (2009)
Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator.
Authors: J P Cooke, E Rossitch, N A Andon, J Loscalzo, V J Dzau
Journal: Journal of Clinical Investigation (1991)

Flow-mediated vasodilation is endothelium dependent. We hypothesized that flow activates a potassium channel on the endothelium, and that activation of this channel leads to the release of the endogenous nitrovasodilator, nitric oxide. To test this hypothesis, rabbit iliac arteries were perfused at varying flow rates, at a constant pressure of 60 mm Hg. Increments in flow induced proportional increases in vessel diameter, which were abolished by L,N-mono-methylarginine (the antagonist of nitric-oxide synthesis). Barium chloride, depolarizing solutions of potassium, verapamil, calcium-free medium, and antagonists of the KCa channel (charybdotoxin, iberiotoxin) also blocked flow-mediated vasodilation. Conversely, responses to other agonists of endothelium-dependent and independent vasodilation were unaffected by charybdotoxin or iberiotoxin. To confirm that flow activated a specific potassium channel to induce the release of nitric oxide, endothelial cells cultured on micro-carrier beads were added to a flow chamber containing a vascular ring without endothelium. Flow-stimulated endothelial cells released a diffusible vasodilator; the degree of vasorelaxation was dependent upon the flow rate. Relaxation was abrogated by barium, tetraethylammonium ion, or charybdotoxin, but was not affected by apamin, glybenclamide, tetrodotoxin, or ouabain. The data suggest that transmission of a hyperpolarizing current from endothelium to the vascular smooth muscle is not necessary for flow-mediated vasodilation. Flow activates a potassium channel (possibly the KCa channel) on the endothelial cell membrane that leads to the release of nitric oxide.
Short Hairpin RNA Knockdown of the Androgen Receptor Attenuates Ligand-Independent Activation and Delays Tumor Progression
Authors: Helen Cheng, Rob Snoek, Fariba Ghaidi, Michael E. Cox, Paul S. Rennie
Journal: Cancer Research (2006)

Abstract Progression to androgen independence is the lethal end stage of prostate cancer. We used expression of androgen receptor (AR)-targeted short hairpin RNAs (shRNA) to directly test the requirement for AR in ligand-independent activation of androgen-regulated genes and hormone-independent tumor progression. Transient transfection of LNCaP human prostate cancer cells showed that AR shRNA decreased R1881 induction of the prostate-specific antigen (PSA)-luciferase reporter by 96%, whereas activation by forskolin, interleukin-6, or epidermal growth factor was inhibited 48% to 75%. Whereas the antiandrogen bicalutamide provided no further suppression, treatment with the mitogen-activated protein kinase (MAPK) inhibitor U0126 completely abrogated the residual activity, indicating a MAPK-dependent, AR-independent pathway for regulating the PSA promoter. Expression of doxycycline-inducible AR shRNA expression in LNCaP cells resulted in decreased levels of AR and PSA as well as reduced proliferation in vitro. When these cells were grown as xenografts in immunocompromised mice, induction of AR shRNA decreased serum PSA to below castration nadir levels and significantly retarded tumor growth over the entire 55-day experimental period. This is the first demonstration that, by inducibly suppressing AR expression in vivo, there is an extensive delay in progression to androgen independence as well as a dramatic inhibition of tumor growth and decrease in serum PSA, which exceeds that seen with castration alone. Based on these findings, we propose that suppressing AR expression may provide superior therapeutic benefit in reducing tumor growth rate than castration and may additionally be very effective in delaying progression to androgen independence. (Cancer Res 2006; 66(21): 10613-20)
Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells
Authors: Daisuke Tokita, Tina L. Sumpter, Giorgio Raimondi, Alan F. Zahorchak, Zhiliang Wang, Atsunori Nakao, George V. Mazariegos, Masanori Abe, Angus W. Thomson
Journal: Journal of Hepatology (2008)
Reproducibility of Blind Protected Bronchoalveolar Lavage in Mechanically Ventilated Children
Authors: France Gauvin, Jacques Lacroix, Marie-Claude Guertin, François Proulx, Catherine Ann Farrell, Albert Moghrabi, Pierre Lebel, Clément Dassa
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Blind protected bronchoalveolar lavage (BAL) could be an interesting tool in the diagnosis of ventilator-associated pneumonia in intubated children, but its reproducibility has never been evaluated. This study evaluates the reproducibility, feasibility, and safety of blind protected BAL in mechanically ventilated children. Two blind protected BAL were done, at a 2-hour interval, in 30 patients. The reproducibility of microbiologic and cytologic results was studied. A total of 60 BALs was analyzed. Bacterial growth was present in 26 of 60 BAL (43%). Reproducibility for the presence of bacteria on quantitative cultures was excellent (concordance, 93%; kappa [κ], 0.86). Concordance for the type of bacteria isolated was 86% and for the number of bacteria was 79%. Reproducibility for the presence of neutrophils containing bacteria was perfect (concordance, 100%; κ, 1) although only a few BALs had a positive result (8/60). Blind protected BAL was feasible in all patients and all samples were considered adequate for analysis. Complications were mostly benign and transitory except in two cases: one pneumothorax and one significant increase in intracranial pressure. Overall, blind protected BAL is a reproducible test in mechanically ventilated children, is easily feasible, and is usually well tolerated.
Should we be pursuing the earlier diagnosis of lung cancer in symptomatic patients?
Authors: Michael D Peake
Journal: Thorax (2012)

Three papers published in this issue of Thorax address the issue of the late diagnosis of lung cancer.1–3 The most recent international population-based survival data for lung cancer again show the UK at the bottom of the scale with a predicted 8.8% of those diagnosed between 2005 and 2007 being alive at 5 years compared with 14.4% in Norway, 16.3% in Sweden and 15–20% in areas of Australia and Canada.4 It has been estimated that, in England, around 1300 lives per year would be saved if our survival matched the best in Europe.5 It is well known that late diagnosis is the major reason why lung cancer outcomes are generally so poor and this is illustrated by the fact that, in the UK, more than 70% of patients have advanced stage (IIIB or IV) disease at the time of diagnosis.6 Huge attention has therefore been focused on the possibility of screening asymptomatic individuals and the most recent findings of the National Lung Cancer Screening Trial7 would appear promising.

In considering reasons underlying the consistent finding of poor UK survival rates, most attention has been given to shortcomings in treatment in secondary care and there is no doubt that there are wide variations in treatment and survival within the UK itself.6 What is not yet known is the extent to which later stage at diagnosis in the UK may explain these survival differences. Some have proposed that at least part of the explanation may be a higher rate of comorbidities in the UK,8 although the evidence for this is limited. One recent study, however, suggests that late diagnosis in the UK is a major factor. Holmberg et al 9 …
Pooled Analysis of Prognostic Impact of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in 8377 Breast Cancer Patients
Authors: Maxime P Look, Wim L J van Putten, Michael J Duffy, Nadia Harbeck, Ib Jarle Christensen, Christoph Thomssen, Ronald Kates, Frédérique Spyratos, Mårten Fernö, Serenella Eppenberger-Castori, C G J Fred Sweep, Kurt Ulm, Jean-Philippe Peyrat, Pierre-Marie Martin, Henri Magdelenat, Nils Brünner, Catherine Duggan, Björn W Lisboa, Pär-Ola Bendahl, Véronique Quillien, Alain Daver, Gabriel Ricolleau, Marion E Meijer-van Gelder, Peggy Manders, W Edward Fiets, Marinus A Blankenstein, Philippe Broët, Sylvie Romain, Günter Daxenbichler, Gudrun Windbichler, Tanja Cufer, Simona Borstnar, Willy Kueng, Louk V A M Beex, Jan G M Klijn, Niall O'Higgins, Urs Eppenberger, Fritz Jänicke, Manfred Schmitt, John A Foekens
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer–Receptor and Biomarker Group (EORTC-RBG). Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). Conclusions: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategies.
Effects of diffuse pleural thickening on respiratory mechanics
Authors: PA Corris, JJ Best, GJ Gibson
Journal: European Respiratory Journal (1988)

Five patients with radiographic and computed tomography (CT) evidence of extensive pleural thickening were studied. All had a restrictive ventilatory defect. The single breath carbon monoxide transfer factor (TLCO) was reduced in each case (mean 76% predicted) but in four patients the transfer coefficient (KCO) was increased (mean 116% predicted), which is consistent with lung 'en cuirasse'. Static pressure-volume curves of the lungs showed that the maximum transpulmonary pressure was greater than normal and pulmonary compliance was reduced; the curves were therefore indistinguishable from those obtained in patients with pulmonary fibrosis. Transdiaphragmatic pressures during maximal inspiratory efforts were moderately impaired and the proportions of each tidal breath contributed by anterposterior (AP) motion of rib cage and abdomen were similar to normal in both erect and supine postures, suggesting that diaphragmatic mobility was well preserved.
Intra-tumoral dendritic cells increase efficacy of peripheral vaccination by modulation of glioma microenvironment
Authors: Serena Pellegatta, Pietro Luigi Poliani, Elena Stucchi, Daniela Corno, Chiara Agnese Colombo, Francesca Orzan, Maria Ravanini, Gaetano Finocchiaro
Journal: Neuro-Oncology (2010)

Pilot data showed that adding intratumoral (IT) injection of dendritic cells (DCs) prolongs survival of patients affected by glioblastoma multiforme (GBM) treated by subcutaneous (SC) delivery of DCs. Using a murine model resembling GBM, we investigated the immunological mechanisms underlying this effect. C57BL6/N mice received brain injections of GL261 glioma cells. Seven days later, mice were treated by 3 SC injections of DCs with or without 1 IT injection of DCs. DC maturation, induced by pulsing with GL261 lysates, was necessary to develop effective immune responses. IT injection of pulsed (pDC), but not unpulsed DCs (uDC), increased significantly the survival, either per se or in combination with SC-pDC (P < .001 vs controls). Mice treated by IT-pDC plus SC-pDC survived longer than mice treated by SC-pDC only (P = .03). Injected pDC were detectable in tumor parenchyma, but not in cervical lymph nodes. In gliomas injected with IT-pDC, CD8+ cells were significantly more abundant and Foxp3+ cells were significantly less abundant than in other groups. Using real-time polymerase chain reaction, we also found enhanced expression of IFN-γ and TNF-α and decreased expression of transforming growth factor-beta (TGF-β) and Foxp3 in mice treated with SC-pDC and IT-pDC. In vitro, pDC produced more TNF-α than uDC: addition of TNF-α to the medium decreased the proliferation of glioma cells. Overall, the results suggest that IT-pDC potentiates the anti-tumor immune response elicited by SC-pDC by pro-immune modulation of cytokines in the tumor microenvironment, decrease of Treg cells, and direct inhibition of tumor proliferation by TNF-α.
Mutational Heterogeneity in Human Cancers: Origin and Consequences
Authors: Jesse J. Salk, Edward J. Fox, Lawrence A. Loeb
Journal: Annual Review of Pathology Mechanisms of Disease (2009)

Cancer recapitulates Darwinian evolution. Mutations acquired during life that provide cells with a growth or survival advantage will preferentially multiply to form a tumor. As a result of The Cancer Genome Atlas Project, we have gathered detailed information on the nucleotide sequence changes in a number of human cancers. The sources of mutations in cancer are diverse, and the complexity of those found to be clonally present in tumors has increasingly made it difficult to identify key rate-limiting genes for tumor growth that could serve as potential targets for directed therapies. The impact of DNA sequencing on future cancer research and personalized therapy is likely to be profound and merits critical evaluation.
Pringle's manoeuvre in living donors
Authors: Hiroshi Imamura, Tadatoshi Takayama, Yasuhiko Sugawara, Norihiko Kokudo, Taku Aoki, Jun-ichi Kaneko, Yutaka Matsuyama, Keiji Sano, Atsushi Maema, Masatoshi Makuuchi
Journal: The Lancet (2002)
CDK2 Inhibition Causes Anaphase Catastrophe in Lung Cancer through the Centrosomal Protein CP110
Authors: Shanhu Hu, Alexey V. Danilov, Kristina Godek, Bernardo Orr, Laura J. Tafe, Jaime Rodriguez-Canales, Carmen Behrens, Barbara Mino, Cesar A. Moran, Vincent A. Memoli, Lisa Maria Mustachio, Fabrizio Galimberti, Saranya Ravi, Andrew DeCastro, Yun Lu, David Sekula, Angeline S. Andrew, Ignacio I. Wistuba, Sarah Freemantle, Duane A. Compton, Ethan Dmitrovsky
Journal: Cancer Research (2015)

Aneuploidy is frequently detected in human cancers and is implicated in carcinogenesis. Pharmacologic targeting of aneuploidy is an attractive therapeutic strategy, as this would preferentially eliminate malignant over normal cells. We previously discovered that CDK2 inhibition causes lung cancer cells with more than two centrosomes to undergo multipolar cell division leading to apoptosis, defined as anaphase catastrophe. Cells with activating KRAS mutations were especially sensitive to CDK2 inhibition. Mechanisms of CDK2-mediated anaphase catastrophe and how activated KRAS enhances this effect were investigated. Live-cell imaging provided direct evidence that following CDK2 inhibition, lung cancer cells develop multipolar anaphase and undergo multipolar cell division with the resulting progeny apoptotic. The siRNA-mediated repression of the CDK2 target and centrosome protein CP110 induced anaphase catastrophe of lung cancer cells. In contrast, CP110 overexpression antagonized CDK2 inhibitor-mediated anaphase catastrophe. Furthermore, activated KRAS mutations sensitized lung cancer cells to CDK2 inhibition by deregulating CP110 expression. Thus, CP110 is a critical mediator of CDK2 inhibition-driven anaphase catastrophe. Independent examination of murine and human paired normal-malignant lung tissues revealed marked upregulation of CP110 in malignant versus normal lung. Human lung cancers with KRAS mutations had significantly lower CP110 expression as compared with KRAS wild-type cancers. Thus, a direct link was found between CP110 and CDK2 inhibitor antineoplastic response. CP110 plays a mechanistic role in response of lung cancer cells to CDK2 inhibition, especially in the presence of activated KRAS mutations.
Radiographic joint destruction in postmenopausal rheumatoid arthritis is strongly associated with generalised osteoporosis
Authors: H Forsblad d'Elia
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objectives:</b> To investigate determinants of joint destruction and reduced bone mineral density (BMD) in postmenopausal women with active rheumatoid arthritis (RA) not treated with bisphosphonates or hormone replacement therapy and to evaluate if there are common markers of erosive disease and bone loss. <b>Methods:</b> BMD was measured using dual <i>x</i> ray absorptiometry and joint damage was examined by <i>x</i> ray examination according to the Larsen method in 88 patients with RA. Associations between BMD and Larsen score, and between demographic and disease related variables, including proinflammatory cytokines, HLA-DR4 epitopes, and markers of bone and cartilage turnover, were examined bivariately by simple and multiple linear regression analyses. <b>Results:</b> 49/88 (56%) patients had osteoporosis in at least one site. Reduced BMD and increased joint destruction were associated with: at the forearm and femoral neck, high Larsen score, low weight, and old age (<i>R</i><sup>2</sup>=0.381, p&lt;0.001; <i>R</i><sup>2</sup>=0.372, p&lt;0.001, respectively); at the total hip, low weight, high Larsen score, and dose of injected glucocorticosteroids (<i>R</i><sup>2</sup>=0.435, p&lt;0.001); at the lumbar spine, low weight, reduced cartilage oligomeric matrix protein, and increased carboxyterminal propeptide of type I procollagen (<i>R</i><sup>2</sup>=0.248, p&lt;0.001). Larsen score was associated with long disease duration and increased C reactive protein (CRP) (<i>R</i><sup>2</sup>=0.545, p&lt;0.001). <b>Conclusions:</b> Osteoporosis is common in postmenopausal patients with RA. Low weight and high Larsen score were strongly associated with BMD reduction. Increased CRP and long disease duration were determinants of erosive disease in postmenopausal women with RA. These findings indicate common mechanisms of local and generalised bone loss in RA.
Recurrent insertion and duplication generate networks of transposable element sequences in the Drosophila melanogaster genome.
Authors: Casey M Bergman, Hadi Quesneville, Dominique Anxolabéhère, Michael Ashburner
Journal: Genome biology (2006)

Abstract Background The recent availability of genome sequences has provided unparalleled insights into the broad-scale patterns of transposable element (TE) sequences in eukaryotic genomes. Nevertheless, the difficulties that TEs pose for genome assembly and annotation have prevented detailed, quantitative inferences about the contribution of TEs to genomes sequences. Results Using a high-resolution annotation of TEs in Release 4 genome sequence, we revise estimates of TE abundance in Drosophila melanogaster . We show that TEs are non-randomly distributed within regions of high and low TE abundance, and that pericentromeric regions with high TE abundance are mosaics of distinct regions of extreme and normal TE density. Comparative analysis revealed that this punctate pattern evolves jointly by transposition and duplication, but not by inversion of TE-rich regions from unsequenced heterochromatin. Analysis of genome-wide patterns of TE nesting revealed a 'nesting network' that includes virtually all of the known TE families in the genome. Numerous directed cycles exist among TE families in the nesting network, implying concurrent or overlapping periods of transpositional activity. Conclusion Rapid restructuring of the genomic landscape by transposition and duplication has recently added hundreds of kilobases of TE sequence to pericentromeric regions in D. melanogaster . These events create ragged transitions between unique and repetitive sequences in the zone between euchromatic and beta-heterochromatic regions. Complex relationships of TE nesting in beta-heterochromatic regions raise the possibility of a co-suppression network that may act as a global surveillance system against the majority of TE families in D. melanogaster .
Got Milk? Exploring the Evolutionary Connection between Milk Drinking, Lactose Digestion, and Sunlight
Authors: J. Caspermeyer
Journal: Molecular Biology and Evolution (2014)

Milk,as thepopularslogangoes,doesabodygood.Itcontains essential nutrients including fat, protein, sugar, as well as calcium, other minerals, and vitamin D needed for bones. Most people in the world lose the ability to digest lactose, the main sugar in milk, shortly after weaning. For these people, drinking fresh milk can lead to unpleasant bloating, flatulence, and cramps. However, about one-third of people in the world— mostly those whose ancestors originate in Europe, the Middle East, Africa, and southern Asia—continue to produce the enzyme lactase, which is responsible for lactose digestion, throughout adulthood. This trait is called lactase persistence, and recent genetic evidence has shown that it evolved independently in different parts of the world over the last 10,000 years as ar esult of strong natural selection. Why lactase persistence has evolved under such strong natural selection remains something of a mystery. The most widely cited explanation is that in the absence of dietary sources for vitamin D and with insufficient sunlight to make vitamin D in the skin, early northern European farmers were at risk of bone disease. Milk is an excellent source of calcium and an adequate source of vitamin D. So, as this “calcium assimilation hypothesis” proposes, having the ability to drink fresh milk into adulthood could have led to a major survival advantage. In a new article in Molecular Biology and Evolution journal,