tbuckley/cabot-search huggingface dataset:
Does the order of second-line treatment in rheumatoid arthritis matter?
Authors: M M Steven, J A Hunter, R M Murdoch, H A Capell
Journal: BMJ (1982)

In a prospective study 88 patients, with rheumatoid arthritis who had stopped taking gold, penicillamine, or levamisole were randomly allocated to one of the alternative drugs and followed up for a minimum of one year. Concurrent studies of the effects of gold, penicillamine, and levamisole prescribed in 123 patients as the first second-line drug were used for comparison. No difference in toxicity or efficacy between primary and secondary use of gold or penicillamine was identified. Variation in the toxicity of levamisole could in part be accounted for by changes in the dose regimen over the four years of study. The length of the treatment-free interval between drugs did not influence subsequent development of toxicity. These results suggest that an adverse reaction to one of the three second-line drugs studied should not prejudice the selection of another.
SPINAL REPOSITIONING DEFICIT. THE EFFECT OF PROLONGED FLEXED POSTURE
Authors: Vasileios Korakakis, Giannis Giakas
Journal: British Journal of Sports Medicine (2013)

Flexed sitting posture is commonly adopted in daily sitting activities and when sustained has been proposed to affect biological properties of spinal tissues and act detrimentally on proprioception. The objective of this study by using an optoelectronic motion analysis system was to assess sitting posture regarding the head, spine and pelvis, in healthy individuals; the time effect of flexed posture (FSP) on proprioception and the impact of an MDT (Mechanical Diagnosis and Therapy) procedure on proprioceptive deficit. Using a cross sectional repeated measures design (N=47) physically active subjects were assessed regarding their habitual sitting posture (HSP), perception of optimal posture (SPOP), ability to adopt an instructed sitting posture (IOSP) and accuracy to reproduce the criterion posture immediately, after 10 and 30 minutes in FSP and after the “slouch-overcorrect” procedure (SOP). Dependent variables were nine sagittal upper body angles. Results revealed that HSP was more flexed than SPOP and IOSP (p&lt;.05) and SPOP was significantly more flexed than IOSP (p&lt;.05) in most measured angles. There was no significant difference in immediate repositioning to IOSP, while significant differences were identified in the lumbar angle (LU) after 10 minutes in FSP and in LU, head (HE) and cervico-thoracic (CT) angles after 30 minutes in FSP. Repositioning to IOSP after SOP abolished proprioceptive deficit in head and spine. Postural repositioning error showed significant differences for LU and HE angles. The findings suggest that healthy individuals habitually sit in more flexed posture than SPOP and IOSP. Postural education can be actualized in a reliable way and subjects can adopt an educated posture. Furthermore FSP challenged postural proprioception, but SOP increased proprioceptive accuracy.
Cooperation: The Foundation of Improvement
Authors: Terry P. Clemmer
Journal: Annals of Internal Medicine (1998)

Cooperation--working together to produce mutual benefit or attain a common purpose--is almost inseparable from the quest for improvement. Although the case for cooperation can be made on ethical grounds, neither the motivation for nor the effects of cooperation need to be interpreted solely in terms of altruism. Cooperation can be a shrewd and pragmatic strategy for accomplishing personal goals in an interdependent system. Earlier papers in this series have explored the conceptual roots of modern approaches to improvement, which lie in systems theory. To improve systems, we must usually attend first and foremost to interactions. Among humans, "better interaction" is almost synonymous with "better cooperation." Physicians have ample opportunities and, indeed, an obligation to cooperate with other physicians in the same or different specialties, with nurses and other clinical workers, with administrators, and with patients and families. Many intellectual disciplines have made cooperation an object of study. These include anthropology; social psychology; genetics; biology; mathematics; game theory; linguistics; operations research; economics; and, of course, moral and rational philosophy. Scientifically grounded methods to enhance cooperation include developing a shared purpose; creating an open, safe environment; including all who share a common purpose and encouraging diverse viewpoints; negotiating agreement; and insisting on fairness and equity in the application of rules. These methods apply at the organizational level and at the level of the individual physician. This paper describes the application of these methods at the organizational level and focuses on one especially successful example of system-level cooperation in a care delivery site where interactions matter a great deal: the modern intensive care unit.
MicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis
Authors: Junchao Cai, Hongyu Guan, Lishan Fang, Yi Yang, Xun Zhu, Jie Yuan, Jueheng Wu, Mengfeng Li
Journal: Journal of Clinical Investigation (2013)

Tumor metastasis involves a series of biological steps during which the tumor cells acquire the ability to invade surrounding tissues and survive outside the original tumor site. During the early stages, the cancer cells undergo an epithelial-mesenchymal transition (EMT). Wnt/β-catenin signaling is known to drive EMT and metastasis. Here we report that Wnt/β-catenin signaling is hyperactivated in metastatic breast cancer cells that express microRNA 374a (miR-374a). In breast cancer cell lines, ectopic overexpression of miR-374a promoted EMT and metastasis both in vitro and in vivo. Furthermore, miR-374a directly targeted and suppressed multiple negative regulators of the Wnt/β-catenin signaling cascade, including WIF1, PTEN, and WNT5A. Notably, miR-374a was markedly upregulated in primary tumor samples from patients with distant metastases and was associated with poor metastasis-free survival. These results demonstrate that miR-374a maintains constitutively activated Wnt/β-catenin signaling and may represent a therapeutic target for early metastatic breast cancer.
Combined Tbet and IL12 Gene Therapy Elicits and Recruits Superior Antitumor Immunity In Vivo
Authors: Yanyan Qu, Lu Chen, Devin B Lowe, Walter J Storkus, Jennifer L Taylor
Journal: Molecular Therapy (2012)

We have recently shown that intratumor (i.t.) injection of syngenic dendritic cells (DC) engineered to express the transcription factor Tbet (TBX21) promotes protective type-1 T cell-mediated immunity via a mechanism that is largely interleukin (IL)-12p70-independent. Since IL-12 is a classical promoter of type-1 immunity, the current study was undertaken to determine whether gene therapy using combined Tbet and IL-12 complementary DNA (cDNA) would yield improved antitumor efficacy based on the complementary/synergistic action of these biologic modifiers. Mice bearing established subcutaneous (s.c.) tumors injected with DC concomitantly expressing ectopic Tbet and IL12 (i.e., DC.Tbet/IL12) displayed superior (i) rates of tumor rejection and extended overall survival, (ii) cross-priming of Tc1 reactive against antigens expressed within the tumor microenvironment, and (iii) infiltration of CD8(+) T cells into treated tumors in association with elevated locoregional production of CXCR3 ligand chemokines. In established bilateral tumor models, i.t. delivery of DC.Tbet/IL12 into a single lesion led to slowed growth or regression at both tumor sites. Furthermore, DC.Tbet/IL12 pulsed with tumor antigen-derived peptides and injected as a therapy distal to the tumor site prevented tumor growth and activated robust antigen-specific Tc1 responses. These data support the translation use of combined Tbet and IL-12p70 gene therapy in the cancer setting.
Color nominalism, pluralistic realism, and color science
Authors: Mohan Matthen
Journal: Behavioral and Brain Sciences (2003)

Abstract Byrne &amp; Hilbert are right that it might be an objective fact that a particular tomato is unique red, but wrong that it cannot simultaneously be yellowish-red (not only objectively, but from somebody else's point of view). Sensory categorization varies among organisms, slightly among conspecifics, and sharply across taxa. There is no question of truth or falsity concerning choice of categories, only of utility and disutility. The appropriate framework for color categories is Nominalism and Pluralistic Realism.
The Warnings on Cigarette Packages Are Ineffective
Authors: John W. Richards
Journal: JAMA (1989)

<h3>To the Editor. —</h3> Both smokers and non-smokers regularly encounter the Surgeon General's warnings about the health hazards of tobacco. The presence of these warnings has become a basis for tobacco companies' defense in product liability cases. They have argued that because of these health messages, the public is adequately warned about the "alleged" hazards of tobacco use. Yet, at the same time, they contend that smoking does not cause disease. There is growing concern that the Surgeon General's warnings may be ineffective. Recent evidence<sup>1,2</sup>has demonstrated that the warnings are often not seen when they appear on magazine advertisements, billboards, and taxi signs. We conducted a pilot study to examine the public's knowledge of the current Surgeon General's warnings on cigarette packages. In particular, we were interested in the level of knowledge that smokers had about the warnings. <h3>Study.—</h3> Using a typical "market survey" format, adults in a
Abstract P4-15-09: An exploratory analysis of inactivation of PI3K/AKT/mTOR signaling pathway using neoadjuvant BKM120 in PI3KCA mutated early breast cancer
Authors: LG Estevez, A Suarez, I Calvo, M Fernandez-Abad, S Perea, M Hidalgo
Journal: Cancer Research (2013)

Abstract Background: The PI3K/AKT/mTOR signaling pathway plays a key role for the growth and survival of breast cancer cells and aberrations such as phosphatidylinositol-3-kinase (PI3KCA) mutations are common. BKM120 is an oral pan-class I PI3KCA inhibitor. The aim of this study was to evaluate neoadjuvant treatment with BKM120 in PI3KCA mutated early breast cancer in order to assess the effect in PI3K/Akt/mTOR signalling pathway. Methods: Patients (pts) with previously untreated invasive, non-metastatic histologically confirmed breast cancer, with a tumor size ≥ 1,5cm and non-urgent surgical treatment were enrolled. Only women with ER+ / HER2- and PI3KCA gene mutated were eligible. Patients received treatment with BKM120 (100mg/day; administered orally) during 4 weeks. Subsequently, surgery was performed. Inmunohistochemical analysis of pAkt and pS6 (the H-score intensity x%) as well as KRAS mutation were evaluated on tumor tissue at surgery. H score &amp;lt; 150 was related with inactivation of PI3K signalling pathway. Results: To date 24 patients has been included in the study (median age, 52,5 years; range 38-69 years;). 13 out of 24 (54%) had PI3KCA mutated and 8 have completed BKM120 treatment. PI3KCA mutation: Exon 20, 4 pts; exon 9, 2 pts; exon 4, 1 pts and exon 20 and 9, 1 pts. One patient discontinued treatment due to adverse event (nausea grade 2). The most relevant adverse events included transitory increase of transaminases. No serious or grade 4 adverse events were observed. Preliminary results of 7 pts showed inactivation of pAkt (H score &amp;lt; 150) in 2 pts with no change in the reminder 5 pts (median H score 300). Conclusion: Our preliminary data shown that four weeks of BKM120 treatment do not inactivate PI3K/Akt/mTOR signalling pathway, measured throughout pAkt in ER+/HER2-/PI3KCA mutated breast cancer pts. However, we cannot draw any conclusion because the small number of pts included so far. KRAS mutation and pS6 analysis will be presented along with updated results. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-09.
WHO backs further probes into possible link between H1N1 vaccine and narcolepsy in children
Authors: J. Zarocostas
Journal: BMJ (2011)

A World Health Organization’s expert panel on vaccine safety has called for more investigations after examining new evidence that indicates children and adolescents faced an increased risk of narcolepsy after being vaccinated against H1N1 influenza with Pandemrix manufactured by GlaxoSmithKline.

The recommendation from WHO’s independent Global Advisory Committee on Vaccine Safety was made after reviewing data from at least 12 countries where Pandemrix has been used, including …
Stem Cells of Aging Donors—Insufficient Capacity to Repair Causes Progression of Atherosclerosis in the Recipient
Authors: R. Karra, S. Vemullapalli, C. Dong, E.E. Herderick, X. Song, K. Slosek, J.R. Nevins, M. West, P.J. Goldschmidt-Clermont, D. Seo
Journal: Journal of the American Society of Nephrology (2006)

Both clinical ([1][1]) and experimental ([2][2]–[4][3]) observations indicate that in renal disease atherosclerosis is accelerated—and this not only in end-stage renal disease, but even in early stages of renal dysfunction ([2][2]). The clinical importance is illustrated by the finding that the
Effects of acute myocardial ischemia on QT dispersion: evaluation by dipyridamole-stress echocardiography
Authors: Erberto Carluccio, Paolo Biagioli, Maurizio Bentivoglio, Myriam Mariotti, Massimo Politano, Ketty Savino, Mariagrazia Sardone, Emanuela H. Locati, Giuseppe Ambrosio
Journal: Journal of the American College of Cardiology (2002)
Glycemic Effect of a Single High Oral Dose of the Novel Sweetener Sucralose in Patients With Diabetes
Authors: Nicholas H E Mezitis, Carol A Maggio, Pamela Koch, Arshad Quddoos, David B Allison, F Xavier Pi-Sunyer
Journal: Diabetes Care (1996)

OBJECTIVE To examine the effect of a single high oral dose of the novel noncaloric sweetener sucralose on short-term glucose homeostasis in patients with IDDM or NIDDM. RESEARCH DESIGN AND METHODS A total of 13 IDDM and 13 NIDDM patients with glycosylated hemoglobin levels &amp;lt; 10% completed this double-blind cross-over study. After an overnight fast, patients were administered opaque capsules containing either 1,000 mg sucralose or cellulose placebo, followed by a standardized 360-kcal liquid breakfast. Plasma glucose and serum C-peptide levels were measured over the next 4 h. RESULTS Regardless of the type of diabetes, areas under the curves for changes of plasma glucose and serum C-peptide levels after sucralose administration were not significantly different from those after placebo. During test meals with sucralose, one episode of symptomatic hypoglycemia occurred in each of three IDDM patients, but these episodes were not considered the result of sucralose administration. CONCLUSIONS The present results support the conclusion that sucralose consumption does not adversely affect short-term blood glucose control in patients with diabetes.
Management of chronic lymphocytic leukemia (<scp>CLL</scp>) in the era of <scp>B</scp>‐cell receptor signal transduction inhibitors
Authors: Anthony Mato, Shekeab Jauhari, Stephen J. Schuster
Journal: American Journal of Hematology (2015)

The treatment of patients with chronic lymphocytic leukemia (CLL), an indolent B-cell lymphoma is in the midst of a transformation. There are a large number of promising new therapeutic agents and cellular therapies being studied which exhibit remarkable activity, favorable toxicity profiles, convenient administration schedules, and treatment options are rapidly expanding. The recent advances in the management of CLL exemplify the value of translational medicine. This review highlights key aspects of B-cell receptor (BCR) signaling in relation to novel inhibitors of the BCR signaling pathway, currently at various stages of preclinical and clinical development.
Teenage Pregnancy and Educational Opportunity-Reply
Authors: Herman A. Hein
Journal: JAMA (1991)

<h3>In Reply.</h3> —I have read Dr Devitt's letter and find little to refute. I disagree only on his assertion that I assumed all unplanned pregnancies were undesired. I stand unreproved about my remarks in the Commentary. I join with Devitt in urging the best possible general education for all young Americans.
Hepatocyte-specific NEMO deletion promotes NK/NKT cell– and TRAIL-dependent liver damage
Authors: Naiara Beraza, Yann Malato, Leif E. Sander, Malika Al-Masaoudi, Julia Freimuth, Dieter Riethmacher, Gregory J. Gores, Tania Roskams, Christian Liedtke, Christian Trautwein
Journal: The Journal of Experimental Medicine (2009)

Nuclear factor κB (NF-κB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-κB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMOΔhepa) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMOΔhepa mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMOΔhepa livers. Interestingly, depletion of the NK1.1+ cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMOΔhepa mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)–mediated injury. The critical role of the NK cell/TRAIL axis in NEMOΔhepa livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient−/− mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMOΔhepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.
MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes
Authors: Chiara Braconi, Nianyuan Huang, Tushar Patel
Journal: Hepatology (2009)

Although the inflammation-associated cytokine interleukin-6 (IL-6) has been implicated in cholangiocarcinoma growth, the relationship between IL-6 and oncogenic changes is unknown. IL-6 can increase expression of DNA methyltransferase-1 (DNMT-1) and epigenetically regulate the expression of several genes, including microRNAs (miRNAs). DNMT-1 up-regulation occurs in hepatobiliary cancers and is associated with a poor prognosis. To understand the potential regulation of DNMT-1 by IL-6–dependent miRNAs, we examined the expression of a group of miRNAs which have sequence complementarity to the 3'-untranslated region of DNMT-1, namely miR-148a, miR-152, and miR-301. The expression of these miRNAs was decreased in cholangiocarcinoma cells. Moreover, the expression of all three miRNAs was decreased in IL-6–overexpressing malignant cholangiocytes in vitro and in tumor cell xenografts. There was a concomitant decrease in expression of the methylation-sensitive tumor suppressor genes Rassf1a and p16INK4a. Using luciferase reporter constructs, DNMT-1 was verified as a target for miR-148a and miR-152. Precursors to miR-148a and miR-152 decreased DNMT-1 protein expression, increased Rassf1a and p16INK4a expression, and reduced cell proliferation. Conclusion: These data indicate that IL-6 can regulate the activity of DNMT-1 and expression of methylation-dependent tumor suppressor genes by modulation of miR-148a and miR-152, and provide a link between this inflammation-associated cytokine and oncogenesis in cholangiocarcinoma. (Hepatology 2010.)
John ("Jock") Burgess Metcalfe
Authors: R. Metcalfe
Journal: BMJ (2002)

Former general practitioner Telford (b Leeds 1921; q King's College Hospital 1945), d 5 May 2002.

In 1951, he and his wife, Marion, were jointly appointed principals in general practice in Madeley, Staffordshire. When Telford New Town began to take shape, they moved the centre of the practice to the first of the new estates, and began to take in partners to cope with the new population. Jock retired from full time practice in 1973 and was ordained as an Anglican minister in 1976. He officiated in Telford parishes until 1984, when, after he left home to live with Mrs Ronwyn Walker, his licence was revoked. He leaves his first wife, Marion; four children; seven grandchildren; and his second wife, Ronwyn.
Anti-nucleosome antibodies complexed to nucleosomal antigens show anti-DNA reactivity and bind to rat glomerular basement membrane in vivo.
Authors: C Kramers, M N Hylkema, M C van Bruggen, R van de Lagemaat, H B Dijkman, K J Assmann, R J Smeenk, J H Berden
Journal: Journal of Clinical Investigation (1994)

Histones can mediate the binding of DNA and anti-DNA to the glomerular basement membrane (GBM). In ELISA histone/DNA/anti-DNA complexes are able to bind to heparan sulfate (HS), an intrinsic constituent of the GBM. We questioned whether histone containing immune complexes are able to bind to the GBM, and if so, whether the ligand in the GBM is HS. Monoclonal antibodies (mAbs) complexed to nucleosomal antigens and noncomplexed mAbs were isolated from culture supernatants of four IgG anti-nuclear mAbs. All noncomplexed mAbs showed strong anti-nucleosome reactivity in ELISA. One of them showed in addition anti-DNA reactivity in noncomplexed form. The other three mAbs only showed anti-DNA reactivity when they were complexed to nucleosomal antigens. After renal perfusion a fine granular binding of complexed mAbs to the glomerular capillary wall and activation of complement was observed in immunofluorescence, whereas noncomplexed mAbs did not bind. Immuno-electron microscopy showed binding of complexes to the whole width of the GBM. When HS in the GBM was removed by renal heparinase perfusion the binding of complexed mAb decreased, but did not disappear completely. We conclude that anti-nucleosome mAbs, which do not bind DNA, become DNA reactive once complexed to nucleosomal antigens. These complexed mAbs can bind to the GBM. The binding ligand in the GBM is partly, but not solely, HS. Binding to the GBM of immune complexes containing nucleosomal material might be an important event in the pathogenesis of lupus nephritis.
Trolox protects rat hepatocytes against oxyradical damage and the ischemic rat liver from reperfusion injury
Authors: Tai-Wing Wu, Noriaki Hashimoto, Jian-Xun Au, Jun Wu, Donald A. G. Mickle, Doug Carey
Journal: Hepatology (1991)

Trolox, a hydrophilic analog of vitamin E, was reported to scavenge peroxyl radicals from artificial systems better than its parent compound. Here we examined the possible cytoprotective effect of Trolox in cultured hepatocytes and in the rat liver. In cultured rat hepatocytes, 0.5 to 16 mmol/L Trolox (with optimum between 1 to 2 mmol/L) was observed to prolong the survival of cells exposed to oxyradicals generated with xanthine oxidase-hypoxanthine. The protection by 1 mmol/L Trolox surpassed that provided by either ascorbate, mannitol, superoxide dismutase and/or catalase--each at a level giving its maximal protection in the same system. In both a global and partial model of hepatic ischemia-reperfusion in rats, infusion of Trolox (7.5 to 10 mumol/kg body weight) just before reflow reduced by greater than 80% the liver necrosis sustained in untreated (no Trolox) control rats. Such organ salvage was apparently accompanied by approximately 50% reduction in the amount of hepatic conjugated dienes, which were quantified by a highly specific radiochemical assay. Since conjugated dienes are presumed to be good "markers" of oxyradical damage, our data may have provided a semiquantitative link between free radical-induced necrosis and its chemical imprint in vivo. The data also indicated a relatively rapid and potent antioxidant-like action by Trolox on rat hepatocytes and on the postischemic reperfused rat liver.