tbuckley/cabot-search huggingface dataset:
Hepatitis C virus non-structural 3/4A protein interferes with intrahepatic interferon-γ production
Authors: Erwin Daniel Brenndörfer, Anette Brass, Jonas Söderholm, Lars Frelin, Soo Aleman, Johannes Georg Bode, Matti Sällberg
Journal: Gut (2011)

<h3>Background</h3> The non-structural (NS) 3/4A protease/helicase of the hepatitis C virus is known to modulate signalling pathways in the infected hepatocyte by cleaving CARD adaptor inducing IFNβ (Cardif), T-cell protein tyrosine phosphatase (TC-PTP) and TIR domain-containing adaptor inducing IFNβ (TRIF), but the effects of NS3/4A in vivo still remain unclear. <h3>Aim</h3> To investigate the influence of NS3/4A on intracellular and intercellular signalling in vivo by analysing the intrahepatic inflammatory response of naïve, lipopolysaccharide (LPS)/d-galactosamine (d-galN) or tumour necrosis factor-α (TNFα)/d-galN-treated NS3/4A-transgenic (Tg) mice. <h3>Methods</h3> The intrahepatic immunity of naïve and LPS/d-galN- or TNFα/d-galN-treated NS3/4A-Tg mice was determined using western blot, ELISA, real-time PCR, flow cytometry and survival monitoring. The injection of cytokines or antibodies against signalling components was performed to analyse the relevance of the respective pathways for the investigated issues. A Tg mouse lineage expressing an inactivated NS3/4A protease (NS3/4A<sup>Ile1073Ala</sup>-Tgs) was generated to examine if protective effects were NS3/4A protease dependent. <h3>Results</h3> The activation of hepatic signal transducer and activator of transcription 1 and 2 was impaired in NS3/4A-Tg mice after treatment with LPS/d-galN or TNFα/d-galN. This was paralleled by a reduction in hepatic interferon-γ (IFNγ). Reconstitution of IFNγ reverted the resistance to LPS/TNFα in NS3/4A-Tg mice. Subsequently, blocking IFNγ in vivo rendered wild-type mice resistant against treatment with LPS/TNFα. A new Tg mouse expressing an inactivated NS3/4A protease had the same phenotype as wild-type mice with respect to hepatic IFNγ levels and sensitivity to LPS/d-galN. Finally, the chemokine profile was altered in the NS3/4A-Tg mice towards an anti-inflammatory state, which helps to explain the altered immune cell subsets and reduction in hepatic IFNγ production. <h3>Conclusions</h3> Our data demonstrate that the NS3/4A protease reduces the intrahepatic production of IFNγ and alters TNFα-mediated effects, thereby impairing the hepatic inflammatory response. This may contribute to viral persistence.
TYPES OF ALCOHOLIC INSANITY, WITH ANALYSIS OF CASES
Authors: H. W. Mitchell
Journal: American Journal of Psychiatry (1904)

obtained less than six hours' sleep during this period.On the fifth day, he slept 15 hours without hypnotics, and from that time was oriented, and had clear insight.He had a dreamy recollection of recent experiences, but could not give the details of actual occurrences.He remained in the hospital for three months.He was discharged, recovered, and two years later was reported to be abstinent, working steadily.
Treatment of Early Cancer of the Prostate
Authors: Hugh J. Jewett
Journal: JAMA (1963)

RADICAL PERINEAL PROSTATECTOMY for clinically localized prostatic cancer was first advocated and performed by the late Dr. Hugh H. Young in 1904. Although 444 patients had been operated on at the Johns Hopkins Hospital as of May 1, 1962, this number represented only a small percentage of patients with this disease who were suitable subjects for the operation. Nevertheless, general interest in radical perineal prostatectomy has increased, partly because in the last 15 years there has been a sharp reduction in mortality rates and complications, and partly because most cases of prostatic cancer, when too far advanced for this operation, have not been effectively controlled over the long term by endocrine manipulation. The purpose of this study is to compare the results of radical perineal prostatectomy after 15 years with those results obtained simply by endocrine treatment of a group of roughly comparable cases, thereby showing that this increased interest
Early Signals in Cardiac Development
Authors: Stéphane Zaffran, Manfred Frasch
Journal: Circulation Research (2002)

The heart is the first organ to form during embryogenesis and its circulatory function is critical from early on for the viability of the mammalian embryo. Developmental abnormalities of the heart have also been widely recognized as the underlying cause of many congenital heart malformations. Hence, the developmental mechanisms that orchestrate the formation and morphogenesis of this organ have received much attention among classical and molecular embryologists. Due to the evolutionary conservation of many of these processes, major insights have been gained from the studies of a number of vertebrate and invertebrate models, including mouse, chick, amphibians, zebrafish, and Drosophila . In all of these systems, the heart precursors are generated within bilateral fields in the lateral mesoderm and then converge toward the midline to form a beating linear heart tube. The specification of heart precursors is a result of multiple tissue and cell-cell interactions that involve temporally and spatially integrated programs of inductive signaling events. In the present review, we focus on the molecular and developmental functions of signaling processes during early cardiogenesis that have been defined in both vertebrate and invertebrate models. We discuss the current knowledge on the mechanisms through which signals induce the expression of cardiogenic transcription factors and the relationships between signaling pathways and transcriptional regulators that cooperate to control cardiac induction and the formation of a linear heart tube.
How Long Have I Got? Estimating Typical, Best-Case, and Worst-Case Scenarios for Patients Starting First-Line Chemotherapy for Metastatic Breast Cancer: A Systematic Review of Recent Randomized Trials
Authors: Belinda E. Kiely, Yu Yang Soon, Martin H.N. Tattersall, Martin R. Stockler
Journal: Journal of Clinical Oncology (2010)

To estimate scenarios for survival for women with metastatic breast cancer (MBC) who are starting chemotherapy.We sought randomized, first-line chemotherapy trials for MBC published from 1999 to 2009. We recorded median progression-free survival (PFS) and median overall survival (OS) and extracted the following percentiles (represented scenario) from each OS curve: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We also estimated these scenarios for each OS curve by multiplying its median by four simple multiples: 0.25 (worst-case), 0.5 (lower-typical), 2 (upper-typical), and 3 (best-case). Estimates were deemed accurate if they were within 0.75 to 1.33 times the actual value.From 36 trials (13,083 women), the mean for median PFS was 7.6 months (interquartile range [IQR], 6.0 to 9.0 months), the mean for median OS was 21.7 months (IQR,18.2 to 24.0 months), and the mean for the ratio of median OS to median PFS was 3.0 (IQR, 2.4 to 3.5). The mean for each OS scenario was worst-case, 6.3 months (IQR, 4.8 to 7.5 months); lower-typical, 11.9 months (IQR, 9.9 to 13.2 months); upper-typical, 36.2 months (IQR, 31.1 to 41.3 months); and best-case, 55.8 months (IQR, 47.5 to 60.2 months). Simple multiples of the median gave accurate estimates of the worst-case scenario in 73% of OS curves, lower-typical in 97%, upper-typical in 95%, and best-case in 96%. OS was longer in trials with higher proportions of estrogen receptor-positive tumors (P = .001) and in trials of trastuzumab-treated human epidermal growth factor receptor 2-positive tumors (P = .001).Simple multiples of an OS curve's median can accurately estimate typical (half to double the median), best-case (triple the median), and worst-case (one quarter of the median) scenarios for survival.
Pathophysiology and Therapeutic Potential of Purinergic Signaling
Authors: Geoffrey Burnstock
Journal: Pharmacological Reviews (2006)

The concept of a purinergic signaling system, using purine nucleotides and nucleosides as extracellular messengers, was first proposed over 30 years ago. After a brief introduction and update of purinoceptor subtypes, this article focuses on the diverse pathophysiological roles of purines and pyrimidines as signaling molecules. These molecules mediate short-term (acute) signaling functions in neurotransmission, mechanosensory transduction, secretion and vasodilatation, and long-term (chronic) signaling functions in cell proliferation, differentiation, and death involved in development and regeneration. Plasticity of purinoceptor expression in pathological conditions is frequently observed, including an increase in the purinergic component of autonomic cotransmission. Recent advances in therapies using purinergic-related drugs in a wide range of pathological conditions will be addressed with speculation on future developments in the field.
FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination
Authors: Alabbas Alkhatib, Markus Werner, Eva Hug, Sebastian Herzog, Cathrin Eschbach, Hemin Faraidun, Fabian Köhler, Thomas Wossning, Hassan Jumaa
Journal: The Journal of Experimental Medicine (2012)

Somatic rearrangement of immunoglobulin (Ig) genes is a key step during B cell development. Using pro–B cells lacking the phosphatase Pten (phosphatase and tensin homolog), which negatively regulates phosphoinositide-3-kinase (PI3K) signaling, we show that PI3K signaling inhibits Ig gene rearrangement by suppressing the expression of the transcription factor Ikaros. Further analysis revealed that the transcription factor FoxO1 is crucial for Ikaros expression and that PI3K-mediated down-regulation of FoxO1 suppresses Ikaros expression. Interestingly, FoxO1 did not influence Ikaros transcription; instead, FoxO1 is essential for proper Ikaros mRNA splicing, as FoxO1-deficient cells contain aberrantly processed Ikaros transcripts. Moreover, FoxO1-induced Ikaros expression was sufficient only for proximal VH to DJH gene rearrangement. Simultaneous expression of the transcription factor Pax5 was needed for the activation of distal VH genes; however, Pax5 did not induce any Ig gene rearrangement in the absence of Ikaros. Together, our results suggest that ordered Ig gene rearrangement is regulated by distinct activities of Ikaros, which mediates proximal VH to DJH gene rearrangement downstream of FoxO1 and cooperates with Pax5 to activate the rearrangement of distal VH genes.
Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation
Authors: Sophia Bardehle, Martin Krüger, Felix Buggenthin, Julia Schwausch, Jovica Ninkovic, Hans Clevers, Hugo J Snippert, Fabian J Theis, Melanie Meyer-Luehmann, Ingo Bechmann, Leda Dimou, Magdalena Götz
Journal: Nature Neuroscience (2013)
Can we deliver randomized trials of focal therapy in prostate cancer?
Authors: Hashim U. Ahmed, Viktor Berge, David Bottomley, William Cross, Rakesh Heer, Richard Kaplan, Tom Leslie, Chris Parker, Clare Relton, Richard Stephens, Matthew R. Sydes, Lindsay Turnbull, Jan van der Meulen, Andrew Vickers, Timothy Wilt, Mark Emberton
Journal: Nature Reviews Clinical Oncology (2014)
Reactive Nitrogen Species and Tyrosine Nitration in the Respiratory Tract
Authors: ALBERT van der VLIET, JASON P. EISERICH, MARK K. SHIGENAGA, CARROLL E. CROSS
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Since its discovery as a biologic messenger molecule just over a decade ago, nitric oxide (NO · ) has become well recognized for its participation in diverse biologic processes in nearly all aspects of life, including vasodilation, bronchodilation, neurotransmission, inhibition of phagocyte and platelet aggregation, and antimicrobial activity (1–3). Excessive production of NO · during inflammatory–immune processes of the respiratory tract is thought to provide a host defense mechanism, although this comes with a price, since high levels of NO · can also cause respiratory tract injury and thus contribute to the pathobiology of respiratory tract disease. These detrimental effects of NO · are generally assumed to be related to the formation of more reactive nitrogen intermediates via interactions of NO · with partially reduced oxygen species, a common hallmark of inflammatory processes. Conversely, NO · has in some cases been shown to also attenuate oxidant-induced lung injury, and NO · inhalation has been proposed as a therapeutic strategy in the management of pulmonary hypertension and in some forms of adult respiratory distress syndrome (ARDS). This dual property of NO · has been the subject of intense recent investigation, which has uncovered multifaceted biochemical pathways of NO · that are highly dependent on dose and on local redox status. NO · -derived reactive nitrogen intermediates can induce a number of covalent modifications in various biomolecules, such as nitrosoand nitroadducts, that result in functional and/or structural changes. One such modification yields 3-nitrotyrosine, and detection of this adduct in proteins is now commonly used as a diagnostic tool to identify involvement of NO · -derived oxidants in many disease states (4–6). Furthermore, a number of in vitro studies have established changes in enzyme activity upon nitration of critical tyrosine residues, which has raised suggestions that protein nitration in vivo may be causally linked to inflammation-related forms of lung injury. In this Pulmonary Perspective we will briefly summarize the involvement of NO · in the pathophysiology of inflammatory diseases of the respiratory tract, and will address characteristic diagnostic modifications in proteins or in other biomolecules, with special emphasis on 3-nitrotyrosine and related modifications in other aromatic substrates. We will examine the scope of bioreactive mechanisms known to contribute to aromatic nitration during inflammatory–immune processes, and will critically evaluate analytical procedures that have been developed and used to detect such modifications. We will also discuss the potential pathophysiologic consequences of tyrosine nitration and related modifications.
hMSC-mediated Concurrent Delivery of Endostatin and Carboxylesterase to Mouse Xenografts Suppresses Glioma Initiation and Recurrence
Authors: Jinlong Yin, Jun-Kyum Kim, Jai-Hee Moon, Samuel Beck, Dachuan Piao, Xun Jin, Sung-Hak Kim, Young Chang Lim, Do-Hyun Nam, Seungkwon You, Hyunggee Kim, Yun-Jaie Choi
Journal: Molecular Therapy (2011)

Glioma stem cells (GSCs) are known to be maintained within a "vascular niche"; thereby, disruption of this microenvironment using antiangiogenesis agents is a promising therapeutic modality. However, this regimen leads to treatment failure and tumor recurrence in patients with glioblastoma multiforme (GBM). Therefore, more effective therapeutic approaches that can eradicate GSCs and the bulk tumors are needed. Toward this goal, we examined the antitumor effects of an antiangiogenesis approach combined with conventional chemotherapy on suppressing glioma xenograft growth. We established three genetically engineered mesenchymal stem cell (MSC) lines (GE-AF-MSCs) by stably transducing the gene encoding endostatin (an antiangiogenesis factor), the gene encoding secretable form of carboxylesterase 2 (sCE2, a prodrug-activating enzyme), or a mixture of both genes. Among the three GE-AF-MSC cell lines, injection of amniotic fluid (AF)-MSCs-endostatin-sCE2 cells into U87MG-EGFRvIII-driven orthotopic brain tumor and postsurgery tumor recurrence models, and subsequent CPT11 treatment yielded the strongest antitumor responses, including diminished angiogenesis, increased cell death, and a reduced Nestin-positive GSC population. Therefore, our antitumor strategy provides a novel basis for designing stem cell-mediated therapeutic approaches to target and eradicate GSCs and the bulk tumors.
A Novel Mouse Model of Atherosclerotic Plaque Instability for Drug Testing and Mechanistic/Therapeutic Discoveries Using Gene and MicroRNA Expression Profiling
Authors: Yung-Chih Chen, Anh Viet Bui, Jeannine Diesch, Richard Manasseh, Christian Hausding, Jennifer Rivera, Izhak Haviv, Alex Agrotis, Nay Min Htun, Jeremy Jowett, Christoph Eugen Hagemeyer, Ross D. Hannan, Alex Bobik, Karlheinz Peter
Journal: Circulation Research (2013)

The high morbidity/mortality of atherosclerosis is typically precipitated by plaque rupture and consequent thrombosis. However, research on underlying mechanisms and therapeutic approaches is limited by the lack of animal models that reproduce plaque instability observed in humans.Development and use of a mouse model of plaque rupture that reflects the end stage of human atherosclerosis.On the basis of flow measurements and computational fluid dynamics, we applied a tandem stenosis to the carotid artery of apolipoprotein E-deficient mice on high-fat diet. At 7 weeks postoperatively, we observed intraplaque hemorrhage in ≈50% of mice, as well as disruption of fibrous caps, intraluminal thrombosis, neovascularization, and further characteristics typically seen in human unstable plaques. Administration of atorvastatin was associated with plaque stabilization and downregulation of monocyte chemoattractant protein-1 and ubiquitin. Microarray profiling of mRNA and microRNA (miR) and, in particular, its combined analysis demonstrated major differences in the hierarchical clustering of genes and miRs among nonatherosclerotic arteries, stable, and unstable plaques and allows the identification of distinct genes/miRs, potentially representing novel therapeutic targets for plaque stabilization. The feasibility of the described animal model as a discovery tool was established in a pilot approach, identifying a disintegrin and metalloprotease with thrombospondin motifs 4 (ADAMTS4) and miR-322 as potential pathogenic factors of plaque instability in mice and validated in human plaques.The newly described mouse model reflects human atherosclerotic plaque instability and represents a discovery tool toward the development and testing of therapeutic strategies aimed at preventing plaque rupture. Distinctly expressed genes and miRs can be linked to plaque instability.
Infecting academic conferences: brands linked to ill health
Authors: Stuart W Flint
Journal: The Lancet Global Health (2015)

Empirical evidence shows the links between sweetened soft drinks1Brownell KD Farley T Willett WC et al.The public health and economic benefit of taxing sugar-sweetened beverages.N Eng J Med. 2009; 361: 1599-1605Crossref PubMed Scopus (551) Google Scholar, 2Vartanian LR Schwartz MB Brownell KD Effects of soft drink consumption on nutrition and health: a systematic review and meta-analysis.Am J Public Health. 2007; 97: 667-675Crossref PubMed Scopus (1321) Google Scholar or fast food3Prentice AM Jebb SA Fast foods, energy density ad obesity: a possible mechanistic link.Obes Rev. 2003; 4: 187-194Crossref PubMed Scopus (503) Google Scholar and chronic illness such as obesity and diabetes. However, as a researcher investigating the causes of obesity, I have become disappointed at the presence of brands of unhealthy products at major conferences relating to obesity, physical activity, and nutrition. In recent years, brands such as Coca Cola Inc and McDonalds Corp have sponsored several conference events. At Obesity Week 2013—the annual scientific meeting of the Obesity Society—not only were Coca Cola products available, but the company also sponsored one of the keynote presentations. Meanwhile another keynote address highlighted the risks of consuming sweetened soft drinks. Last year Coca Cola Inc also sponsored the Congress of the European College of Sport Sciences in Amsterdam, Netherlands; the International Congress on Physical Activity and Public Health in Rio de Janeiro, Brazil; and the Childhood Obesity and Public Health Conference in Baton Rouge, LA, USA. Similarly, McDonalds Corp sponsored the California Dietetic Association Conference in Pomona, CA, USA, and both Coca Cola Inc and McDonalds Corp sponsored the Dietitians Association of Australia Conference in Brisbane, QLD, Australia, and the Canadian Obesity Summit in Vancouver, BC, Canada. It is time for academics and professionals to take a stand against these global companies, whose products have been linked with ill health, and for conference organisers to refrain from these conflicting and confusing partnerships. There is no place for brands of unhealthy consumption at health, physical activity, or nutrition conferences, and organising committees of such events should select sponsors that do not conflict with empirical evidence that might well be disseminated at the conference or in the journals they are aligned with. I declare no competing interests.
A Double-Blind Randomized Placebo-Controlled Trial of Orlistat for the Treatment of Nonalcoholic Fatty Liver Disease
Authors: Shira Zelber–Sagi, Ada Kessler, Eli Brazowsky, Muriel Webb, Yoav Lurie, Moshe Santo, Moshe Leshno, Laurence Blendis, Zamir Halpern, Ran Oren
Journal: Clinical Gastroenterology and Hepatology (2006)
Novel Agents in the Treatment of Lung Cancer: Fourth Cambridge Conference
Authors: Thomas J. Lynch, Philip D. Bonomi, Charles Butts, Angela M. Davies, Jeffrey Engelman, Ramaswamy Govindan, Roy S. Herbst, John V. Heymach, Bruce E. Johnson, Renato G. Martins, Roman Perez-Soler, Gregory J. Riely, Alan B. Sandler, Lecia V. Sequist, Mark A. Socinski, Kwok-Kin Wong, Carol S. Hart
Journal: Clinical Cancer Research (2007)

Abstract The Fourth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts on September 29 to 30, 2006, to discuss ongoing clinical research of novel targeted agents for the treatment of non–small cell lung cancer, along with supportive basic and translational research into the molecular pathways implicated in cancer growth and resistance. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized below and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings.
Intratumoral CD8+ T Lymphocytes as a Prognostic Factor of Survival in Endometrial Carcinoma
Authors: Svetlana Kondratiev, Edmond Sabo, Evgeny Yakirevich, Ofer Lavie, Murray B. Resnick
Journal: Clinical Cancer Research (2004)

Abstract Purpose: CTLs are a prominent immune component infiltrating many solid tumors. These cells are considered to be a manifestation of host-immune response to the tumor; however, their prognostic significance remains a subject of considerable debate. The objective of this study was to evaluate the distribution pattern and prognostic value of CD8+ T cells in endometrial carcinoma. Experimental Design: We studied 90 cases of endometrial carcinoma, including 75 endometrioid and 15 papillary serous carcinomas. Immunohistochemical staining for CD8 and granzyme B was performed on paraffin-embedded sections. The number of immunohistochemically staining CD8+ T cells was enumerated in the following four regions: lymphocytes infiltrating the tumor epithelium at the invasive border, within the underlying tumor stroma, within the superficial tumor epithelium, and in the perivascular areas of the myometrium. Results: Patients with &amp;gt;10 CD8+ T lymphocytes/high-power field within the tumor epithelium at the invasive border displayed improved overall survival compared with patients with fewer intraepithelial CD8+ T lymphocytes (87 and 50%, respectively; P = 0.027). Multivariate analysis revealed that stage, vascular invasion, grade, and the number of intraepithelial CD8+ T lymphocytes at the invasive border were the only independent predictors of survival (P &amp;lt; 0.0001, P = 0.001, P = 0.011, and P = 0.025, respectively). Granzyme B+ cytoplasmatic granules were detected in a high proportion of CTLs, confirming their activated cytotoxic phenotype. Conclusions: Our study demonstrates for the first time that increased numbers of CTLs at the invasive border may be a reliable independent prognostic factor of survival in patients with endometrial carcinoma.