tbuckley/cabot-search huggingface dataset:
CD44s Regulates the TGF-β–Mediated Mesenchymal Phenotype and Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma
Authors: Kosuke Mima, Hirohisa Okabe, Takatsugu Ishimoto, Hiromitsu Hayashi, Shigeki Nakagawa, Hideyuki Kuroki, Masayuki Watanabe, Toru Beppu, Mayumi Tamada, Osamu Nagano, Hideyuki Saya, Hideo Baba
Journal: Cancer Research (2012)

The prognosis for individuals diagnosed with hepatocellular carcinoma (HCC) remains poor because of the high frequency of invasive tumor growth, intrahepatic spread, and extrahepatic metastasis. Here, we investigated the role of the standard isoform of CD44 (CD44s), a major adhesion molecule of the extracellular matrix and a cancer stem cell marker, in the TGF-β-mediated mesenchymal phenotype of HCC. We found that CD44s was the dominant form of CD44 mRNA expressed in HCC cells. Overexpression of CD44s promoted tumor invasiveness and increased the expression of vimentin, a mesenchymal marker, in HCC cells. Loss of CD44s abrogated these changes. Also in the setting of CD44s overexpression, treatment with TGF-β1 induced the mesenchymal phenotype of HCC cells, which was characterized by low E-cadherin and high vimentin expression. Loss of CD44s inhibited TGF-β-mediated vimentin expression, mesenchymal spindle-like morphology, and tumor invasiveness. Clinically, overexpression of CD44s was associated with low expression of E-cadherin, high expression of vimentin, a high percentage of phospho-Smad2-positive nuclei, and poor prognosis in HCC patients, including reduced disease-free and overall survival. Together, our findings suggest that CD44s plays a critical role in the TGF-β-mediated mesenchymal phenotype and therefore represents a potential therapeutic target for HCC.
Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab: implications for molecular targeted therapy
Authors: Naoshi Nishina, Jun Kikuchi, Misato Hashizume, Keiko Yoshimoto, Hideto Kameda, Tsutomu Takeuchi
Journal: Annals of the Rheumatic Diseases (2013)

Interleukin-6 (IL-6) is a monomeric protein that binds to either soluble or membrane-bound IL-6 receptors (IL-6R)1 ,2 Tocilizumab, a humanised anti-IL-6R monoclonal antibody, binds to soluble IL-6R (sIL-6R) and membrane-bound IL-6R, blocking signal transduction pathways through competitive inhibition of IL-6 binding.3 We have previously demonstrated that baseline plasma tumour necrosis factor (TNF) levels are associated with the clinical response to infliximab, anti-TNF monoclonal antibody binding to soluble and membrane-bound TNF.4 Therefore, it is tempting to speculate that baseline serum levels of sIL-6R, rather than those of IL-6, are associated with clinical response to tocilizumab in patients with rheumatoid arthritis (RA). To test this hypothesis, we analysed serum levels of IL-6 and sIL-6R before tocilizumab treatment in our institution and evaluated their association with clinical remission.

Consecutive patients with RA in our institution who commenced 8 mg/kg tocilizumab treatment every 4 weeks as the first biologic agent between March 2010 and April 2012 were included. At baseline, serum levels of IL-6 and sIL-6R were measured by electrochemiluminescence assay with the Ultra-Sensitive Kit (Meso Scale …
Non-invasive investigation of gastrointestinal functions with magnetic resonance imaging: towards an "ideal" investigation of gastrointestinal function
Authors: W Schwizer
Journal: Gut (2003)

Gastrointestinal (GI) function is complex and physiological measurements are subject to a variety of technical difficulties and practical limitations. The ideal technique would be non-invasive, widely available, convenient, and reliable and would not expose the subject to ionising radiation. It would permit direct assessment of GI function in the postprandial as well as the resting state, and be able to differentiate between food, secretion, and air in the lumen. GI structure and function are interdependent and the ideal technique would permit simultaneous assessment of these factors. Finally, the bowel operates as a functional whole and assessment of the GI tract proximal and distal to the area of interest is desirable. In this article the authors summarise the development and validation of magnetic resonance imaging techniques that overcome many of the deficiencies of existing methods, and have many characteristics of the "ideal" investigation of GI function.
P63 Patients’ and healthcare professionals’ perceptions of oxygen therapy? A qualitative study
Authors: CA Kelly
Journal: Thorax (2013)

<h3>Background</h3> Despite common usage of oxygen as a therapeutic intervention, audit suggests poor prescribing and administration practices exist. Contemporary studies and guidelines propose an influencing culture whereby oxygen is given to alleviate breathlessness with disregard for potential harm; but there is no evidence supporting this claim. Further suggestions indicate confusion regarding the use of oxygen therapy, possibly as a consequence of conflicting information; again, there is no evidence. The problem may self-perpetuate as erroneous beliefs are passed to patients, their carers and the general public. <h3>Aim</h3> To explore healthcare professionals' (HCPs) and patients' perceptions of oxygen therapy and help direct future research, education and practice. <h3>Method</h3> Semi-structured interviews were undertaken with 28 patients and 33 HCPs, including doctors, nurses, paramedics and pharmacists. Self-reported beliefs and behaviours were recorded and transcribed verbatim and analysed iteratively using interpretative phenomenological analysis (IPA). Independent audit served to validate findings. <h3>Results</h3> Two overarching themes were identified: <i>oxygen as a panacea</i> and <i>antecedents to beliefs </i>(Figure 1). Sub-themes under these constants differed between HCPs and patients but fundamentally both groups viewed oxygen as an innocuous therapy with numerous benefits. HCPs use of oxygen stems from <i>entrenched culture</i>, <i>expectations</i> (of patients, families and other HCPs) and a need to '<i>to do something</i>'. Patients are influenced by <i>HCPs</i>, <i>past experiences</i> (of self and others) and <i>social media</i>. Knowledge, education and understanding predisposed both groups' perceptions, but without exception all HCPs believed that they had not received enough education about oxygen therapy and an approach of DIY education prevails. <h3>Conclusion</h3> These findings suggest that a set of fixed beliefs and practices regarding oxygen therapy exist, influenced by several factors. The overwhelming perception being that oxygen is a universal remedy. Patients rely on HCPs for education and information, yet HCPs' fixed beliefs regarding oxygen therapy can lead to ill-informed practice. As the gatekeepers to oxygen therapy, and a major influence on patients' education, HCPs would seem the logical catalyst to change these fundamental beliefs and practices. In order to achieve this, current educational curricula needs to be addressed.
Platelet Nitric Oxide and Superoxide Release During the Development of Nitrate Tolerance
Authors: Gary E. McVeigh, Paul Hamilton, Martin Wilson, Colm G. Hanratty, William J. Leahey, Adrian B. Devine, David G. Morgan, Lana J. Dixon, Lawrence T. McGrath
Journal: Circulation (2002)

Background — The therapeutic benefits that accompany the continuous administration of organic nitrates are attenuated by the development of tolerance to the compounds. Altered superoxide production and NO bioavailability have been implicated in contributing to the development of tolerance, an effect that may be ameliorated by the administration of antioxidants. Methods and Results — We studied the effect of 3 days of continuous transdermal administration of nitroglycerin (NTG) (10 mg/24 hours) on platelet free radical (NO and superoxide anion [O 2 ·− ] activity) with and without coadministration of supplemental ascorbate (2.4 g/24 hours). NAD(P)H oxidase activity, nitric oxide synthase (NOS) activity, and cyclic guanosine monophosphate (cGMP) content were also assessed. Radial artery pressure pulse waveforms were used to track the hemodynamic actions of NTG. Three days of NTG/placebo was associated with a significant increase in platelet NO and O 2 ·− production from 1.0±1.17 to 2.52±0.88 pmol/10 8 platelets and 13.2±4.8 to 72.5±34.4 pmol/10 8 platelets, respectively ( P &lt;0.01 for both). These changes were accompanied by increased platelet NADH oxidase activity from 47.9±11.0 to 65.3±13.6 pmol O 2 ·− min/mg protein and cGMP content from 0.60±0.10 to 0.89±0.16 pmol/10 9 platelets ( P &lt;0.05 for both). Administration of NTG/ascorbate attenuated both NO and O 2 ·− release in platelets. Conclusions — Three days of continuous transdermal administration of NTG was accompanied by increased platelet NO and O 2 ·− production and NADH oxidase activity that was suppressed by coadministration of oral ascorbate. Although a significant degree of tolerance would be expected during continuous nitrate administration, a residual hemodynamic action could be identified by arterial pulse contour analysis.
Risk Factors in Late Adolescence for Young-Onset Dementia in Men
Authors: Peter Nordström, Anna Nordström, Marie Eriksson, Lars-Olof Wahlund, Yngve Gustafson
Journal: JAMA Internal Medicine (2013)

<h3>Importance</h3> Young-onset dementia (YOD), that is, dementia diagnosed before 65 years of age, has been related to genetic mutations in affected families. The identification of other risk factors could improve the understanding of this heterogeneous group of syndromes. <h3>Objective</h3> To evaluate risk factors in late adolescence for the development of YOD later in life. <h3>Design</h3> We identified the study cohort from the Swedish Military Service Conscription Register from January 1, 1969, through December 31, 1979. Potential risk factors, such as cognitive function and different physical characteristics, were assessed at conscription. We collected other risk factors, including dementia in parents, through national register linkage. <h3>Participants</h3> All Swedish men conscripted for mandatory military service (n = 488 484) with a mean age of 18 years. <h3>Setting</h3> Predominantly Swedish men born from January 1, 1950, through December 31, 1960. <h3>Exposure</h3> Potential risk factors for dementia based on those found in previous studies, data available, and quality of register data. <h3>Main Outcomes and Measure</h3> All forms of YOD. <h3>Results</h3> During a median follow-up of 37 years, 487 men were diagnosed as having YOD at a median age of 54 years. In multivariate Cox regression analysis, significant risk factors (all<i>P</i> &lt; .05) for YOD included alcohol intoxication (hazard ratio, 4.82 [95% CI, 3.83-6.05]); population-attributable risk, 0.28), stroke (2.96 [2.02-4.35]; 0.04), use of antipsychotics (2.75 [2.09-3.60]; 0.12), depression (1.89 [1.53-2.34]; 0.28), father's dementia (1.65 [1.22-2.24]; 0.04), drug intoxication other than alcohol (1.54 [1.06-2.24]; 0.03), low cognitive function at conscription (1.26 per 1-SD decrease [1.14-1.40]; 0.29), low height at conscription (1.16 per 1-SD decrease [1.04-1.29]; 0.16), and high systolic blood pressure at conscription (0.90 per 1-SD decrease [0.82-0.99]; 0.06). The population-attributable risk associated with all 9 risk factors was 68%. Men with at least 2 of these risk factors and in the lowest third of overall cognitive function were found to have a 20-fold increased risk of YOD during follow-up (hazard ratio, 20.38 [95% CI, 13.64-30.44]). <h3>Conclusions and Relevance</h3> In this nationwide cohort, 9 independent risk factors were identified that accounted for most cases of YOD in men. These risk factors were multiplicative, most were potentially modifiable, and most could be traced to adolescence, suggesting excellent opportunities for early prevention.
Circulating T cells and subclinical atherosclerosis in obstructive sleep apnea
Authors: Jose M. Marin, Jorge Artal, Maria Tª Martin, Javier Godino, Marta Marin-Oto, Victoria Gil
Journal: European Respiratory Journal (2014)

Background . Because of intermittent hypoxia, Obstructive Sleep Apnoea (OSA) may cause endothelial dysfunction and a shift towards a more pro-inflammatory lymphocyte phenotype. This may contribute to premature atherosclerosis.   Aim . To determine the phenotype of circulating T-Cell populations and their relationship with carotid intima-media thickness (IMT) in OSA.   Methods . At our sleep clinic we consecutively enrolled 132 adults (age: 20 to 55 year). Exclusion criteria were: history of tobacco or alcohol consumption, and any chronic disease. OSA diagnosis was made on the basis of an apnea/hypopnea index (AHI) g 5. IMT was assessed in carotid arteries by high-resolution ultrasonography. On fresh samples we performed immunophenotyping of peripheral blood mononuclear cells using flow cytometry. Cells were stained for CD3, CD4, CD8, CD25 and Foxp3 + . Regulatory T cells (Treg) are defined as CD4 + CD25 + FOXP3 + .   Results . Non-OSA subjects (n = 40) were younger (42 vs 45 years, p = 0.03) and had a lower BMI (27.2 vs 30.1 kg/m 2 , p l 0.001) than OSA patients (n = 93). IMT was 0.57 ± 0.2 (95 percentile: 0.65 mm) and 0.67 ± 0.15 mm respectively (pl0.001). Abnormal IMT (g 0.65 mm) was identified in 48% of OSA group. There was no difference between groups of T cells except for Treg (7.9 ± 1.8% of all CD4+ in non-OSA vs 6.7 ± 1.4 % in OSA patients). IMT and Treg cells were related (r = -0.29, p =0.007). In multivariate regression analyses, age, systolic blood pressure and Treg, but not AHI were related with IMT.   Conclusions . In OSA there are non-uniform changes in lymphocytic phenotypes that may contribute to subclinical atherosclerosis suggesting different epigenetic adaptation to apnea episodes  (supported by FIS 12/02175).
Evolutionary distances for protein-coding sequences: modeling site- specific residue frequencies
Authors: A. L. Halpern, W. J. Bruno
Journal: Molecular Biology and Evolution (1998)

Estimation of evolutionary distances from coding sequences must take into account protein-level selection to avoid relative underestimation of longer evolutionary distances. Current modeling of selection via site-to-site rate heterogeneity generally neglects another aspect of selection, namely position-specific amino acid frequencies. These frequencies determine the maximum dissimilarity expected for highly diverged but functionally and structurally conserved sequences, and hence are crucial for estimating long distances. We introduce a codon-level model of coding sequence evolution in which position-specific amino acid frequencies are free parameters. In our implementation, these are estimated from an alignment using methods described previously. We use simulations to demonstrate the importance and feasibility of modeling such behavior; our model produces linear distance estimates over a wide range of distances, while several alternative models underestimate long distances relative to short distances. Site-to-site differences in rates, as well as synonymous/nonsynonymous and first/second/third-codon-position differences, arise as a natural consequence of the site-to-site differences in amino acid frequencies.
Influence of Body Mass Index on Lung Function in Korean Children With No Asthma Symptoms Residing in Urban Area
Authors: Y.H. Shin, K.W. Kim, K.E. Kim, H.Y. Yum, K.E. Lee, T.W. Song, E.S. Kim, M.H. Sohn, K.E. Kim
Journal: Journal of Allergy and Clinical Immunology (2007)
Cross-linking of major histocompatibility complex class II molecules by staphylococcal enterotoxin A superantigen is a requirement for inflammatory cytokine gene expression.
Authors: K Mehindate, J Thibodeau, M Dohlsten, T Kalland, R P Sékaly, W Mourad
Journal: The Journal of Experimental Medicine (1995)

Staphylococcal enterotoxin A (SEA) has two distinct binding sites for major histocompatibility complex (MHC) class II molecules. The aspartic acid located at position 227 (D227) in the COOH terminus of SEA is one of the three residues involved in its interaction with the DR beta chain, whereas the phenylalanine 47 (F47) of the NH2 terminus is critical for its binding to the DR alpha chain. Upon interaction with MHC class II molecules, SEA triggers several cellular events leading to cytokine gene expression. In the present study, we have demonstrated that, contrary to wild-type SEA, stimulation of the THP1 monocytic cell line with SEA mutated at position 47 (SEAF47A) or at position 227 (SEAD227A) failed to induce interleukin 1 beta and tumor necrosis factor-alpha messenger RNA expression. Pretreatment of the cells with a 10-fold excess of either SEAF47A or SEAD227A prevented the increase in cytokine messenger RNA induced by wild-type SEA. However, cross-linking of SEAF47A or SEAD227A bound to MHC class II molecules with F(ab')2 anti-SEA mAb leads to cytokine gene expression, whereas cross-linking with F(ab) fragments had no effect. Taken together, these results indicate that cross-linking of two MHC class II molecules by one single SEA molecule is a requirement for cytokine gene expression.
Abstract 3435: NM23-H1 suppresses melanoma cell motility by promoting strong adhesions between fibronectin and α4α1 integrin
Authors: Marian Novak, Xiuwei H. Yang, Stuart G. Jarrett, David M. Kaetzel
Journal: Cancer Research (2012)

Abstract The metastasis suppressor NM23-H1 has a prominent role in melanoma and other leading malignancies, where loss of NM23-H1 expression is associated with onset of aggressive phenotypes and metastasis. NM23-H1 blocks multiple facets of the metastatic cascade, with autonomous cell motility being perhaps the most scrutinized across multiple cancer types. However, the molecular mechanisms through which NM23-H1 suppresses cellular motility in melanoma are poorly understood. Herein, we report a novel mechanism of motility suppression by NM23-H1 in melanoma via upregulation of the extracellular matrix (ECM) component fibronectin. In agreement with previous reports, forced expression of NM23-H1 in metastatic melanoma cell lines 1205LU and MDA-MB-435s/M14 led to a significant decrease in random cell motility. The resultant sedentary phenotype was associated with pronounced changes in cell morphology, including a highly flattened appearance and marked increases in actin stress fiber formation and the size of focal adhesions. In light of the known roles of cell adhesion in conveying such phenotypic changes, we measured the effect of NM23-H1 on expression and localization of fibronectin, a major component of focal adhesion complexes. Forced expression of NM23-H1 resulted in significantly increased expression of endogenous fibronectin protein, which was concentrated at focal adhesion sites. To assess the contribution of NM23-induced expression of fibronectin to formation of immobilizing adhesions, blocking antibodies directed against α4α1 and Δ5α1 integrins, the dominant fibronectin receptors on melanoma cells, were applied. Antibodies directed against integrin α4, but not Δ5, reversed the suppressing effect of forced NM23-H1 expression on cellular motility. These findings indicate a novel role of NM-23-H1 in regulating endogenous fibronectin-mediated cell movement, a critical aspect of melanoma metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3435. doi:1538-7445.AM2012-3435
Septic Shock
Authors: Christopher W. Seymour, Matthew R. Rosengart
Journal: JAMA (2015)

Septic shock is a clinical emergency that occurs in more than 230,000 US patients each year. OBSERVATIONS AND ADVANCES: In the setting of suspected or documented infection, septic shock is typically defined in a clinical setting by low systolic (≤90 mm Hg) or mean arterial blood pressure (≤65 mm Hg) accompanied by signs of hypoperfusion (eg, oliguria, hyperlactemia, poor peripheral perfusion, or altered mental status). Focused ultrasonography is recommended for the prompt recognition of complicating physiology (eg, hypovolemia or cardiogenic shock), while invasive hemodynamic monitoring is recommended only for select patients. In septic shock, 3 randomized clinical trials demonstrate that protocolized care offers little advantage compared with management without a protocol. Hydroxyethyl starch is no longer recommended, and debate continues about the role of various crystalloid solutions and albumin.The prompt diagnosis of septic shock begins with obtainment of medical history and performance of a physical examination for signs and symptoms of infection and may require focused ultrasonography to recognize more complex physiologic manifestations of shock. Clinicians should understand the importance of prompt administration of intravenous fluids and vasoactive medications aimed at restoring adequate circulation, and the limitations of protocol-based therapy, as guided by recent evidence.
Computer tomography lung density in smokers is correlated to measures of local inflammation in the lung
Authors: Reza Karimi, Sven Nyren, Åsa Weelock, Göran Tornling, Magnus Skold
Journal: European Respiratory Journal (2012)

Cigarette smoking causes an inflammatory response in the lungs. CT imaging provides means of quantifying pulmonary structure and function. We hypothesized that the inflammation in smokers may be mirrored both by an altered attenuation on CT and by measures inflammation in the lungs.

Materials: 

Healty smokers (20 men, 20 women, mean age 54, 35±12 pack years, 40 healthy neversmokers, age 57 and 40 COPD, age 59 (38±11 PY, 31 current smokers, 9 exsmokers) performed inspiratory CT scans .Values between -500 and- 750 HU were considered as high attenuation area. BAL, was performed. Cell concentration were mesured.

Result: 

Attenuation for smokers (44% ± 5.7) and neversmokers (38% ± 5.6), COPD exsmokers (33% ± 4.5)(p<0.001 and p<0.05 respectively). COPD smokers (41% ± 5.0) did not differ from that of healthy smokers. Both smoker groups (healthy smokers: 556±259 x 106/L (mean±SD); COPD smokers: 458±263) had higher cell concentration in BAL compared to neversmokers (121±50) and COPD exsmokers (100±29). The difference between the smoking and nonsmoking groups were significant (p<0.001). There was a significant correlation (p<0.0001) between cell concentration in BAL and CT attenuation, There was no significant correlation between cell concentrations in BAL and CT attenuation in neversmokers and COPD exsmokers.

Conclusion: 

The increased lung density in smokers compared to nonsmokers may mirror an inflammatory response induced by cigarette smoke. This hypothesis is strengthened by a positive correlation between lung attenuation and cell concentration in the lower respiratory tract. Our results provide a quantitative approach for measuring smoke-related structural changes in the lung.