tbuckley/cabot-search huggingface dataset:
Gene signatures to prediction rheumatoid arthritis development
Authors: Joyce Lubbers, Mikael Brink, Lotte A van de Stadt, Saskia Vosslamber, John G Wesseling, Dirkjan van Schaardenburg, Solbritt M Rantapaa-Dahlqvist, Cornelis L Verweij
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background/purpose</h3> Early recognition of development of rheumatoid arthritis (RA) allows timely start of treatment. Recently, the authors reported gene signatures in the peripheral blood (PB), involving interferon (IFN) activity and B cell related genes, which are associated with the development of arthritis. The objective of this study is to validate these findings in independent cohorts. <h3>Method</h3> The authors analysed IFN-response gene expression in PB samples from 40 anticitrullinated protein antibodies (ACPA)+/rheumatoid factor (RF)+arthralgia patients from the Amsterdam Reade cohort who are clinically followed for RA development. In addition, PB mononuclear cells (MCs) of 22 preonset RA, 25 RA patients, and 48 healthy controls (HC) from the Northern Sweden Population Repository (Umeå University) were studied. Fluorescence-activated cell sorting (FACS)-analysis for B cell marker expression was performed on PB from 87 ACPA+/RF+ arthralgia patients and 30 HC from the Amsterdam Reade cohort. Quantitative PCR (qPCR) for B cell marker was performed of 45 ACPA+/RF+ arthralgia patients and six HC from the Amsterdam Reade cohort. <h3>Results</h3> The IFN-score (average of seven IFN-response genes) was measured at inclusion in an independent group of ACPA+/RF+ arthralgia patients at risk for RA (n=40). A total of 19 patients developed arthritis within a median period of 11 months (IQR 9–28). Comparative analysis of IFN-score high and low patients confirmed that the high IFN-score is associated with conversion to RA (p=0.025). In addition, the authors measured the IFN-score in PBMC from RA and preonset RA patients, and HC from the Northern Swedish Repository. Comparative analyses between the groups revealed that both preonset RA patients as well as RA patients had significantly increased IFN-scores compared to HC (Mann–Whitney U test p=0.0064 and p=0.0075, respectively). For the analysis of the role of B cells in development of RA the authors analysed the FACS profile of 87 ACPA+/RF+ at risk patients at inclusion, of who 22 developed RA within a median period to conversion of 10.5 months (IQR 4.5–13). The results confirmed that low B cell marker expression is significantly associated with RA conversion (p=0.01). An interim analysis with qPCR showed a trend towards the association between decreased B cell transcript marker and RA conversion (p=0.0714). <h3>Conclusion</h3> These results provide evidence for a role of IFN-activity and B cell abundance in the preclinical phase of RA. Further studies are aimed to demonstrate the diagnostic value of these markers.
Prodrugs—from Serendipity to Rational Design
Authors: Kristiina M. Huttunen, Hannu Raunio, Jarkko Rautio
Journal: Pharmacological Reviews (2011)

The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term <i>prodrug</i> was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.
Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials
Authors: Giulio G Stefanini, Usman Baber, Stephan Windecker, Marie-Claude Morice, Samantha Sartori, Martin B Leon, Gregg W Stone, Patrick W Serruys, William Wijns, Giora Weisz, Edoardo Camenzind, Philippe G Steg, Pieter C Smits, David Kandzari, Clemens Von Birgelen, Søren Galatius, Raban V Jeger, Takeshi Kimura, Ghada W Mikhail, Dipti Itchhaporia, Laxmi Mehta, Rebecca Ortega, Hyo-Soo Kim, Marco Valgimigli, Adnan Kastrati, Alaide Chieffo, Roxana Mehran
Journal: The Lancet (2013)
IMPACTED CYST IN THIRD VENTRICLE OF BRAIN
Authors: A. M. Drennan
Journal: BMJ (1929)

DURING a period of ten years two most unusual cases of cyst of the, choroid plexus in the t tird ventricle hvave come to neci-opsy.Both patients died rapidly and formed the suibjects of coroners' inquests, so that it seemued desirable to place the cases on record.-In searching the literature at my disposal I have bee-iAble to find butfew records of similar cases.It is true that
Regulation of ATP-sensitive K+ channels by caveolin-enriched microdomains in cardiac myocytes
Authors: Vivek Garg, Jundong Jiao, Keli Hu
Journal: Cardiovascular Research (2009)

ATP-sensitive potassium (KATP) channels in the heart are critical regulators of cellular excitability and action potentials during ischaemia. However, little is known about subcellular localization of these channels and their regulation. The present study was designed to explore the potential role of caveolae in the regulation of KATP channels in cardiac ventricular myocytes. Both adult and neonatal rat cardiomyocytes were used. Subcellular fractionation by density gradient centrifugation, western blotting, co-immunoprecipitation, and immunofluorescence confocal microscopy were employed in combination with whole-cell voltage clamp recordings and siRNA gene silencing. We detected that the majority of KATP channels on the plasma membrane of cardiac myocytes were localized in caveolin-3-enriched microdomains by cell fractionation and ultracentrifugation followed by western blotting. Immunofluorescence confocal microscopy revealed extensive colocalization of KATP channel pore-forming subunit Kir6.2 and caveolin-3 along the plasma membrane. Co-immunoprecipitation of cardiac myocytes showed significant association of Kir6.2, adenosine A1 receptors, and caveolin-3. Furthermore, whole-cell voltage clamp studies suggested that adenosine A1 receptor-mediated activation of KATP channels was largely eliminated by disrupting caveolae with methyl-β-cyclodextrin or by small interfering RNA, whereas pinacidil-induced KATP activation was not altered. We demonstrate that KATP channels are localized to caveolin-enriched microdomains. This microdomain association is essential for adenosine receptor-mediated regulation of KATP channels in cardiac myocytes.
Tamoxifen for the Prevention of Breast Cancer: Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study
Authors: Bernard Fisher, Joseph P Costantino, D Lawrence Wickerham, Reena S Cecchini, Walter M Cronin, Andre Robidoux, Therese B Bevers, Maureen T Kavanah, James N Atkins, Richard G Margolese, Carolyn D Runowicz, Joan M James, Leslie G Ford, Norman Wolmark
Journal: JNCI Journal of the National Cancer Institute (2005)

Initial findings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor-positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical significance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial findings.Women (n = 13,388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). Estimates of the net benefit from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided.After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically significant. The net benefit achieved with tamoxifen varied according to age, race, and level of breast cancer risk.Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer. Readily identifiable subsets of individuals comprising 2.5 million women could derive a net benefit from the drug.
A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state.
Authors: H Weiler-Guettler, P D Christie, D L Beeler, A M Healy, W W Hancock, H Rayburn, J M Edelberg, R D Rosenberg
Journal: Journal of Clinical Investigation (1998)

The activity of the coagulation system is regulated, in part, by the interaction of thrombin with the endothelial cell receptor thrombomodulin with subsequent generation of activated protein C and suppression of thrombin production. Our previous investigation demonstrated that ablation of the thrombomodulin gene in mice causes embryonic lethality before the assembly of a functional cardiovascular system, indicating a critical role for the receptor in early development. In the current study, we show that a single amino acid substitution in thrombomodulin dissociates the developmental function of the receptor from its role as a regulator of blood coagulation. Homozygous mutant mice with severely reduced capacity to generate activated protein C or inhibit thrombin develop to term, and possess normal reproductive performance. The above animals exhibit increased fibrin deposition in selected organs, which implies tissue specific regulation of the coagulation system that is supported by further evidence from the examination of mice with defects in fibrinolysis. The thrombomodulin-deficient animals provide a murine model to examine known or identify unknown genetic and environmental factors that lead to the development of thrombosis.
The Canadian Assisted Human Reproduction Act: Protecting Women's Health While Potentially Allowing Human Somatic Cell Nuclear Transfer into Non-Human Oocytes
Authors: Roxanne Mykitiuk, Jeff Nisker, Robyn Bluhm
Journal: The American Journal of Bioethics (2007)

Caulfield and Bubela (2007) argue that the Canadian Assisted Human Reproduction Act (An Act Respecting Assisted Human Reproduction and Related Research (S.C. 2004, c.2) imposes a complete “criminal...
FEV6 as a surrogate for FVC in detecting airways obstruction and restriction in the workplace
Authors: M Akpinar-Elci, K B Fedan, P L Enright
Journal: European Respiratory Journal (2006)

Compared with measurements of forced vital capacity (FVC), using the forced expiratory volume in six seconds (FEV(6)) reduces test time and frustration. It was hypothesised that using FEV(6) in the workplace setting would result in an acceptably low misclassification rate for detecting airways obstruction and spirometry-defined restriction when compared with using the traditional FVC. Experienced technicians from the National Institute for Occupational Safety and Health performed spirometry using dry rolling-seal spirometers as per American Thoracic Society guidelines in four workplace investigations. Airways obstruction was defined as an FEV(1)/FVC % below the lower limit of normal (LLN) using National Health and Nutrition Examination Survey III reference equations. Restriction was defined as an FVC below the LLN with a normal FEV(1)/FVC %. These "gold standard" definitions were compared with definitions based on FEV(6) (obstruction: FEV(1)/FEV(6) below the LLN; restriction: FEV(6) below the LLN with a normal FEV(1)/FEV(6)). The median (range) age of the 1,139 workers was 37 yrs (18-71 yrs) and 51.4% were male. A significantly high overall agreement was obtained between the two definitions. In conclusion, the current results confirm that forced expiratory volume in six seconds can be used as a surrogate for forced vital capacity in detecting airways obstruction and restriction in workers, although with some misclassification when compared to obtaining American Thoracic Society-acceptable manoeuvres of longer duration.
SUCCESSFUL TERMINATION OF PROLONGED INSULIN COMA OF TWENTY DAYS WITH ONE YEAR FOLLOW-UP
Authors: JAMES F. SUESS, EUGENE A. CEASE
Journal: American Journal of Psychiatry (1959)

In the treatment of prolonged insulin coma it is important that definitive measures are begun immediately and continued as long as necessary. Such measures, as indicated above, in our experience have brought all prolonged comas to a satisfactory termination.
Genetic Correction of Human Induced Pluripotent Stem Cells from Patients with Spinal Muscular Atrophy
Authors: Stefania Corti, Monica Nizzardo, Chiara Simone, Marianna Falcone, Martina Nardini, Dario Ronchi, Chiara Donadoni, Sabrina Salani, Giulietta Riboldi, Francesca Magri, Giorgia Menozzi, Clara Bonaglia, Federica Rizzo, Nereo Bresolin, Giacomo P. Comi
Journal: Science Translational Medicine (2012)

Motor neurons generated from genetically corrected iPSCs derived from patients with spinal muscular atrophy show rescue of the disease phenotype.
The effect of changes in the score on injury incidence during three FIFA World Cups
Authors: Jaakko Ryynänen, Astrid Junge, Jiri Dvorak, Lars Peterson, Jón Karlsson, Mats Börjesson
Journal: British Journal of Sports Medicine (2013)

Objective To study the effect of changes in the score and of different playing positions, as well as the effect of recovery time on injury incidence during Fédération Internationale de Football Association (FIFA) World Cups. Design Prospective injury surveillance at three international championships in 2002, 2006 and 2010. Official match statistics were obtained for all the games played in the three championships. Setting 2002, 2006 and 2010 FIFA World Cups. Participants National team players as well as the team doctors reporting all the injuries at the 2002, 2006 and 2010 FIFA World Cups. Main outcome measures Injury incidence and incidence rate ratios. Results There were statistically significant differences in injury incidence related to changes in the score (p=0.026) and to the teams’ current drawing/losing/winning status (p=0.008). Injury incidence was lowest (54.8/1000 match-hours (mh), 95% CI 46.4 to 64.3) during the initial 0–0 score and highest (81.2/1000 mh, 60.5 to 106.8) when the score was even but goals had been scored. Winning teams had a tendency towards a higher injury incidence (81.0/1000 mh, 67.5 to 96.4) than losing or drawing teams (55.5/1000 mh, 44.4 to 68.4 and 59.7/1000 mh, 51.8 to 68.6, respectively). There were also statistically significant differences in injury incidence between the playing positions (p&lt;0.001), with forwards having the highest injury incidence (85.7/1000 mh, 69.8 to 104.2). There was a linear relationship (p=0.043) between an increasing number of recovery days between matches and a higher injury incidence. Conclusions There is a considerable variation in injury incidence during a match in international men's football related to changes in the score. Players in a winning team run a higher risk of suffering an injury than players in a drawing or losing team. Identifying time periods with a high injury incidence may be of major importance to players and team personnel, as it may enable them to take precautions.
Binding of major histocompatibility complex class II to the invariant chain-derived peptide, CLIP, is regulated by allelic polymorphism in class II.
Authors: A Sette, S Southwood, J Miller, E Appella
Journal: The Journal of Experimental Medicine (1995)

Major histocompatibility complex class II-associated invariant chain (Ii) provides several important functions that regulate class II expression and function. One of these is the ability to inhibit class II peptide loading early in biosynthesis. This allows for efficient class II folding and egress from the endoplasmic reticulum, and protects the class II peptide binding site from loading with peptides before entry into endosomal compartments. The ability of Ii to interact with class II and interfere with peptide loading has been mapped to Ii exon 3, which encodes amino acids 82-107. This same region of Ii has been described as a nested set of class II-associated Ii peptides (CLIPs) that are transiently associated with class II in normal cells and accumulate in human histocompatibility leukocyte antigen-DM-negative cell lines. Currently it is not clear how CLIP and the CLIP region of Ii blocks peptide binding. CLIP may bind directly to the class II peptide binding site, or may bind elsewhere on class II and modulate class II peptide binding allosterically. In this report, we show that CLIP can interact with many different murine and human class II molecules, but that the affinity of this interaction is controlled by polymorphic residues in the class II chains. Likewise, structural changes in CLIP also modulate class II binding in an allele-dependent manner. Finally, the specificity and kinetics of CLIP binding to class II molecule is similar to antigenic peptide binding to class II. These data indicate that CLIP binds to class II in an analogous fashion as conventional antigenic peptides, suggesting that the CLIP segment of Ii may actually occupy the class II peptide binding site.
Proteomics-Based Identification of Proteins Secreted in Apical Surface Fluid of Squamous Metaplastic Human Tracheobronchial Epithelial Cells Cultured by Three-Dimensional Organotypic Air-Liquid Interface Method
Authors: Seung-Wook Kim, Kyounga Cheon, Chang-Hoon Kim, Joo-Heon Yoon, David H. Hawke, Ryuji Kobayashi, Ludmila Prudkin, Ignacio I. Wistuba, Reuben Lotan, Waun Ki Hong, Ja Seok Koo
Journal: Cancer Research (2007)

Squamous cell carcinoma in the lung originates from bronchial epithelial cells that acquire increasingly abnormal phenotypes. Currently, no known biomarkers are clinically efficient for the early detection of premalignant lesions and lung cancer. We sought to identify secreted molecules produced from squamous bronchial epithelial cells cultured with organotypic culture methods. We analyzed protein expression patterns in the apical surface fluid (ASF) from aberrantly differentiated squamous metaplastic normal human tracheobronchial epithelial (NHTBE) and mucous NHTBE cells. Comparative two-dimensional PAGE analysis revealed 174 unique proteins in the ASF of squamous NHTBE cells compared with normal mucociliary differentiated NHTBE cells. Among them, 64 well-separated protein spots were identified by liquid chromatography-tandem mass spectrometry, revealing 22 different proteins in the ASF from squamous NHTBE cells. Expression of six of these proteins [SCC antigen 1 (SCCA1), SCC antigen 2 (SCCA2), S100A8, S100A9, Annexin I, and Annexin II] in the squamous NHTBE cells was further confirmed with immunoblot analysis. Notably, SCCA1 and SCCA2 were verified as being expressed in squamous metaplastic NHTBE cells but not in normal mucous NHTBE or normal bronchial epithelium. Moreover, SCCA1 and SCCA2 expression increased in in vitro lung carcinogenesis model cell lines with increasing malignancy. In summary, we identified proteins that are uniquely secreted from squamous metaplastic primary human bronchial epithelial cells cultured by the organotypic air-liquid interface method. These ASF proteins may be used to detect abnormal lesions in the lung without collecting invasive biopsy specimens.
Inhibition of SET Domain–Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis
Authors: Kensuke Sasaki, Shigehiro Doi, Ayumu Nakashima, Taisuke Irifuku, Kyoko Yamada, Keiko Kokoroishi, Toshinori Ueno, Toshiki Doi, Eisuke Hida, Koji Arihiro, Nobuoki Kohno, Takao Masaki
Journal: Journal of the American Society of Nephrology (2015)

TGF-β1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain–containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-β1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-β1 neutralizing antibody. TGF-β1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P<0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-methylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-β1-induced α-smooth muscle actin expression and H3K4me1 in both NRK-52E and NRK-49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent.