tbuckley/cabot-search huggingface dataset:
Structural, functional, and idiotypic characteristics of a phosphorylcholine-binding IgA myeloma protein of C57BL/ka allotype.
Authors: J L Claflin, S Rudikoff, M Potter, J M Davie
Journal: The Journal of Experimental Medicine (1975)

An IgA phosphorylcholine (PC)-binding myeloma protein with IgCH allotypic determinants different from those of BALB/c mice is characterized. The myeloma, CBPC 2, was induced in the CB-20 strain of mice which is congenic to BALB/c but differs from it by carrying the A15 allotypic determinant of C57BL/ka mice. Sequence analysis of the CBPC 2 light chain through the first hypervariable region, as well as isoelectric point analysis, show that this chain is indistinguishable from that of T15, a PC-binding myeloma protein of BALB/c origin. The heavy chains of CBPC 2 and T15 differ by only two amino acids (positions 14 and 16) through the first hypervariable region. As measured by inhibition of precipitation, both CBPC 2 and T15 have the same specificity for PC, glycerophosphorylcholine, acetylcholine, and choline. In addition, CBPC 2 possesses the binding site-associated idiotypic determinant which is present on T15. However, like normal or induced C57BL/6 anti-PC antibody, it does not possess the nonbinding site idiotypic determinant.
Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC
Authors: Annette O. Walter, Robert Tjin Tham Sjin, Henry J. Haringsma, Kadoaki Ohashi, Jing Sun, Kwangho Lee, Aleksandr Dubrovskiy, Matthew Labenski, Zhendong Zhu, Zhigang Wang, Michael Sheets, Thia St Martin, Russell Karp, Dan van Kalken, Prasoon Chaturvedi, Deqiang Niu, Mariana Nacht, Russell C. Petter, William Westlin, Kevin Lin, Sarah Jaw-Tsai, Mitch Raponi, Terry Van Dyke, Jeff Etter, Zoe Weaver, William Pao, Juswinder Singh, Andrew D. Simmons, Thomas C. Harding, Andrew Allen
Journal: Cancer Discovery (2013)

Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.
Surgery Versus Epilation for the Treatment of Minor Trichiasis in Ethiopia: A Randomised Controlled Noninferiority Trial
Authors: Saul N. Rajak, Esmael Habtamu, Helen A. Weiss, Amir Bedri Kello, Teshome Gebre, Asrat Genet, Robin L. Bailey, David C. W. Mabey, Peng T. Khaw, Clare E. Gilbert, Paul M. Emerson, Matthew J. Burton
Journal: PLoS Medicine (2011)

In this randomized, non-inferiority trial, Saul Rajak et al compare epilation and surgery for the management of minor trichiasis in Ethiopia, the country with the most cases of trachomatous trichiasis.
The Pathology of Enlargement of the Prostate
Authors: C. M. Moullin
Journal: BMJ (1896)

<h3>Summary</h3> Transgenic reporters allow the measurement of regulatory DNA activity <i>in vivo</i> and consequently have long been useful tools in the study of enhancers. Despite the utility of transgenic reporters, few studies have investigated the potential effects these reporters have on the expression of other transgenic reporters or endogenous genes. A full understanding of the impacts transgenic reporters have on expression is required for accurate interpretation of transgenic reporter data and characterization of gene regulatory mechanisms. Here, we investigate the impact transgenic reporters have on the expression of other transgenic reporters and endogenous genes. By measuring the expression of <i>Kruppel</i> (<i>Kr</i>) enhancer reporters in live <i>Drosophila</i> embryos that contain either one or two copies of identical reporters, we find reporters have an inhibitory effect on one another’s expression. Further, expression of a nearby endogenous gene is decreased in the presence of a <i>Kr</i> enhancer reporter. Through the use of competitor binding site arrays, we present evidence that reporters, and potentially endogenous genes, are competing for transcription factors (TFs). Increasing the number of competitor Bcd binding sites decreases the peak levels and spatial extent of Bcd-regulated enhancer reporters’ expression. To understand how small numbers of added TF binding sites could impact gene expression to the extent we observe, we develop a simple thermodynamic model of our system. Our model predicts competition of the measured magnitude specifically if TF binding is restricted to distinct nuclear subregions, underlining the importance of the non-homogenous nature of the nucleus in regulating gene expression.
Relief from IL-1
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The cytokine interleukin-1 (IL-1) is primarily to blame for a severe type of juvenile arthritis, according to Pascual and colleagues on page 1479. Blocking IL-1 activity in children with systemic onset juvenile idiopathic arthritis (SoJIA) completely resolved disease symptoms in a majority of children who had failed to respond to conventional treatments.

SoJIA is a systemic inflammatory disease of unknown etiology that can cause long-term arthritis in children. The pathogenesis of the disease is unclear, although increases in the inflammatory cytokine IL-6 have been reported in the blood of these patients. Currently the most effective therapy for SoJIA is long-term treatment with steroids, which carries with it the risk of growth retardation, osteoporosis, and obesity.

Pascual and colleagues now reveal a central role for IL-1—a cytokine that plays a major role in many inflammatory and autoimmune diseases—in the pathology of SoJIA. They show that serum from SoJIA patients provokes healthy cells to increase expression of IL-1, but no other cytokines. In addition, stimulated peripheral blood cells from children with SoJIA produced more IL-1, but not IL-6 or TNF, compared with cells from healthy children.

These results prompted Pascual and colleagues to treat these patients with an IL-1 receptor antagonist (Anakinra). The results were remarkable—symptoms were completely resolved or significantly improved in all children with active arthritis, with only one later case of reversion.

The mechanism behind the increased IL-1 production in SoJIA is unknown. As SoJIA is not an inherited disease, the defect is likely to be different from familial IL-1–triggered inflammatory diseases in which a mutated NALP3 can no longer control the activation of caspase-1, which cleaves the IL-1β precursor into the active cytokine. The authors are now looking for the serum component that turns on IL-1.
THE CARDIAC OUTPUT IN PATIENTS WITH CIRRHOSIS OF THE LIVER AND TENSE ASCITES WITH OBSERVATIONS ON THE EFFECT OF PARACENTESIS
Authors: Henry J. Kowalski, Walter H. Abelmann, William F. McNeely
Journal: Journal of Clinical Investigation (1954)

Previous studies in this laboratory (1) have in- dicated that the cardiac output may be elevated in patients with Laennec's cirrhosis.The question arose as to what role distention of the abdomen by ascites might play in determining the level of sys- temic blood flow.In the previously reported pa- tients, elevation of cardiac output did not appear to be related to the presence or degree of ascites, but this aspect of the problem required further investigation.Few studies of the effect of ascites on cardiac output in man have come to our attention.Res- nik, Friedman, and Harrison (2) estimated cardiac output in patients with congestive heart failure by means of the acetylene method and noted slight decreases during the accumulation of ascites in four patients.Six hours after paracentesis, per-
ACCF/ASE/ACEP/AHA/ASNC/SCAI/SCCT/SCMR 2008 Appropriateness Criteria for Stress Echocardiography
Authors: Pamela S. Douglas, Bijoy Khandheria, Raymond F. Stainback, Neil J. Weissman, Eric D. Peterson, Robert C. Hendel, Raymond F. Stainback, Michael Blaivas, Roger D. Des Prez, Linda D. Gillam, Terry Golash, Loren F. Hiratzka, William G. Kussmaul, Arthur J. Labovitz, JoAnn Lindenfeld, Frederick A. Masoudi, Paul H. Mayo, David Porembka, John A. Spertus, L. Samuel Wann, Susan E. Wiegers, Ralph G. Brindis, Pamela S. Douglas, Robert C. Hendel, Manesh R. Patel, Eric D. Peterson, Michael J. Wolk, Joseph M. Allen
Journal: Circulation (2008)

The American College of Cardiology Foundation (ACCF) and the American Society of Echocardiography (ASE) together with key specialty and subspecialty societies, conducted an appropriateness review for stress echocardiography. The review assessed the risks and benefits of stress echocardiography for several indications or clinical scenarios and scored them on a scale of 1 to 9 (based upon methodology developed by the ACCF to assess imaging appropriateness). The upper range (7 to 9) implies that the test is generally acceptable and is a reasonable approach, and the lower range (1 to 3) implies that the test is generally not acceptable and is not a reasonable approach. The midrange (4 to 6) indicates a clinical scenario for which the indication for a stress echocardiogram is uncertain. The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Use of stress echocardiography for risk assessment in patients with coronary artery disease (CAD) was viewed favorably, while routine repeat testing and general screening in certain clinical scenarios were viewed less favorably. It is anticipated that these results will have a significant impact on physician decision making and performance, reimbursement policy, and will help guide future research.
Organizing Diabetes Care: Identify, Monitor, Prioritize, Intensify
Authors: Patrick J. O’Connor
Journal: Diabetes Care (2001)

The need for radical and rapid improvement in diabetes care was clearly articulated by Williams in 1967 (1), but progress toward that laudable goal has been painfully slow. Only recently have population-based reports from primary care settings documented significant progress toward the goal of better diabetes care (2,3,4,5). In these and other studies (6), multiple interventions that address office systems, provider behavior, and patient behavior were usually needed to improve diabetes care (7,8). Successful interventions often used common strategies to improve care. These strategies included 1 ) accurately identifying patients with diabetes (9); 2 ) monitoring one or more important clinical parameters, such as glycosylated hemoglobin (HbA1c) or cholesterol levels; 3 ) prioritizing patients based on their clinical status and readiness to change (10); and 4 ) intensifying care through active outreach or visit planning.

Although identification of diabetic patients can be accomplished in most settings, stratification of patients by risk presents greater challenges. Risk information can be used to prioritize patients and to match interventions to level of risk, which may substantially increase the effectiveness of interventions (11). In this issue, Selby et al. (12) present an …
Good doctors doing nothing
Authors: L. Farrell
Journal: BMJ (1999)

Gaelic football is our national game, followed fanatically in every parish in the land. The climax of the year is in Croke Park in September, the All Ireland final, and exiles from all across the world tune in to feel the pulse of the heartland. The game is started by throwing in the ball; this function used to be performed by the Archbishop of Dublin, who would then have to hitch his skirts up and scurry …
Interchange of Apolipoproteins between Chylomicrons and High Density Lipoproteins during Alimentary Lipemia in Man
Authors: Richard J. Havel, John P. Kane, Moti L. Kashyap
Journal: Journal of Clinical Investigation (1973)

Apolipoproteins of the "C" group in human blood plasma, which contain the activator of the lipoprotein lipase-substrate interaction, were found to be transferred specifically from serum to phospholipid-stabilized fat emulsion. Content and distribution of apoprotein activator were measured in healthy men in the postabsorptive state and 4 h after ingestion of meals containing 100 g fat. Content of activator protein in whole serum did not change after ingestion of the fat-rich meals but that contained in triglyceride-rich lipoproteins of density (d) <1.006 approximately doubled whereas that of high density lipoproteins fell by half. The increased activator content of triglyceride-rich lipoproteins was virtually confined to chylomicrons and its concentration in chylomicron apoprotein was substantially greater than that in very low density lipoproteins. This difference could be ascribed largely to a higher content of C apoproteins in chylomicron protein since both the concentration of C apoproteins and of apoprotein activator were directly proportional to particle diameter while the pattern of fast-migrating C apoproteins in polyacrylamide gels was similar among chylomicrons and subfractions of very low density lipoproteins. Apparent concentration of activator protein was much greater in the high density lipoprotein subfraction of d 1.063-1.125 than in the subfraction of d 1.125-1.21. In the subfraction of d 1.063-1.125, the concentration of activator protein and of fast-migrating C apoproteins in polyacrylamide gels decreased after the fat-rich meal. Concentration of phospholipids in this fraction increased gradually to a peak 43% above the basal value 6 h after the meal. The results obtained demonstrate that high density lipoproteins contribute certain functionally important polar constituents to chylomicrons during alimentary lipemia in man and suggest that they also receive surface constituents from chylomicrons during the course of their metabolism.
Vitrectomy Surgery for Diabetic Retinopathy
Authors: G H Bresnick, F L Myers
Journal: Annual Review of Medicine (1979)

The vitrectomy operation is a new ophthalmic surgical procedure for the treatment of diabetic retinopathy. Since vitrectomy is a major intraocular surgical procedure with the potential for serious ocular complications, its use is reserved for certain advanced stages of proliferative diabetic retinopa­ thy (PDR) where safer alternative modes of therapy (e.g. photocoagulation) are ineffective. With this in mind one may consider vitrectomy surgery for two aspects of severe diabetic retinopathy: (a) severe vitreous hemorrhage, and (b) retinal detachment affecting or threatening central vision. This review article delineates the current techniques, indications, and results of vitrectomy surgery in the treatment of diabetic retinopathy. The natural history and a description of other modes of treatment of diabetic retinopathy introduce the discussion of the surgical procedure. Since new developments in this area of ophthalmic surgery are occurring rapidly, the potential of future advances is also discussed. The medical problems en­ countered in caring for the diabetic patient undergoing vitrectomy may be considerable, and therefore this aspect is also reviewed.
Nuclear Factor-κB p65/relA Silencing Induces Apoptosis and Increases Gemcitabine Effectiveness in a Subset of Pancreatic Cancer Cells
Authors: Xue Pan, Thiruvengadam Arumugam, Tameyoshi Yamamoto, Pavel A. Levin, Vijaya Ramachandran, Baoan Ji, Gabriel Lopez-Berestein, Pablo E. Vivas-Mejia, Anil K. Sood, David J. McConkey, Craig D. Logsdon
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Nuclear factor κB (NFκB) activity may increase survival and protect cancer cells from chemotherapy. Therefore, NFκB activity may be prognostic, and inhibition of NFκB may be useful for pancreatic cancer therapy. To test these hypotheses, we examined NFκB activity and the effects of inhibiting NFκB in several pancreatic cancer cell lines with differing sensitivities to gemcitabine. Experimental Design: The gemcitabine sensitivity of pancreatic cancer cell lines BxPC-3, L3.6pl, CFPAC-1, MPanc-96, PANC-1, and MIA PaCa-2 were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and fluorescence-activated cell sorting assays. NFκB levels were determined by electrophoretic mobility shift assay and reporter assays. The effects of gemcitabine on NFκB activity were determined in vitro and in vivo. NFκB was inhibited by silencing of the p65/relA subunit using small interfering RNA in vitro and by neutral liposomal delivery of small interfering RNA in vivo, and the effects were evaluated on gemcitabine sensitivity. Results: The cell lines L3.6pl, BxPC-3, and CFPAC-1 were sensitive, whereas MPanc-96, PANC-1, and MIA PaCa-2 were resistant to gemcitabine. No significant correlation was observed between basal NFκB activity and gemcitabine sensitivity. Gemcitabine treatment did not activate NFκB either in vitro or in vivo. Silencing of p65/relA induced apoptosis and increased gemcitabine killing of all gemcitabine-sensitive pancreatic cancer cells. No significant effects, however, were observed on gemcitabine-resistant pancreatic cancer cell lines either in vitro or in vivo. Conclusions: NFκB activity did not correlate with sensitivity to gemcitabine. Silencing of p65/relA was effective alone and in combination with gemcitabine in gemcitabine-sensitive but not gemcitabine-resistant pancreatic cancer cells. Thus, NFκB may be a useful therapeutic target for a subset of pancreatic cancers.
Directed Membrane Transport Is Involved in Process Formation in Cultured Podocytes
Authors: MATIAS SIMONS, RAINER SAFFRICH, JOCHEN REISER, PETER MUNDEL
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Mature glomerular visceral epithelial cells, or podocytes, are unique cells with a complex cell architecture. Characteristically, they possess a highly branched array of major processes and foot processes, which are essential for glomerular filtration in the kidney. A podocyte cell line with the potential to exhibit many features of differentiated podocytes, particularly the formation of cell processes, was recently established. In this study, it is shown that directed membrane transport is involved in process formation in cultured podocytes. The well-characterized vesicular stomatitis virus G was used as a marker protein for the biosynthetic pathway in these cells. It seems that newly synthesized vesicular stomatitis virus G is preferentially delivered into the cell processes of the podocytes, where it is colocalized with known regulators of vesicular transport from the Golgi apparatus to the plasma membrane, such as the small GTPase rab8 and the sec6/sec8 complex. To determine the role of vesicular transport in process formation, cells were treated with brefeldin A, a drug that disrupts the trafficking of post-Golgi transport vesicles. As a result, the podocytes reversibly lost their ability to form processes. These findings suggest that podocytes are dependent on a constant fresh source of lipids and proteins to form their processes.
Drug-resistance - a challenge for tuberculosis control in the European Union and European Economic Area
Authors: M J van der Werf, M Sprenger
Journal: Eurosurveillance (2014)

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Endoscopic tri-modal imaging for surveillance in ulcerative colitis: randomised comparison of high-resolution endoscopy and autofluorescence imaging for neoplasia detection; and evaluation of narrow-band imaging for classification of lesions
Authors: F J C van den Broek, P Fockens, S van Eeden, J B Reitsma, J C H Hardwick, P C F Stokkers, E Dekker
Journal: Gut (2008)

<h3>Background:</h3> Endoscopic tri-modal imaging (ETMI) incorporates white light endoscopy (WLE), autofluorescence imaging (AFI) and narrow-band imaging (NBI). <h3>Aims:</h3> To assess the value of ETMI for the detection and classification of neoplasia in patients with longstanding ulcerative colitis. <h3>Design:</h3> Randomised comparative trial of tandem colonoscopies. <h3>Setting:</h3> Academic Medical Centre Amsterdam, Netherlands. <h3>Patients and methods:</h3> Fifty patients with ulcerative colitis underwent surveillance colonoscopy with ETMI. Each colonic segment was inspected twice, once with AFI and once with WLE, in random order. All detected lesions were inspected by NBI for Kudo pit pattern analysis and additional random biopsies were taken. <h3>Main outcome measures:</h3> Neoplasia miss-rates of AFI and WLE, and accuracy of the Kudo classification by NBI. <h3>Results:</h3> Among patients assigned to inspection with AFI first (n = 25), 10 neoplastic lesions were primarily detected. Subsequent WLE detected no additional neoplasia. Among patients examined with WLE first (n = 25), three neoplastic lesions were detected; subsequent inspection with AFI added three neoplastic lesions. Neoplasia miss-rates for AFI and WLE were 0% and 50% (p = 0.036). The Kudo classification by NBI had a sensitivity and specificity of 75% and 81%; however, all neoplasia was coloured purple on AFI (sensitivity 100%). No additional patients with neoplasia were detected by random biopsies. <h3>Conclusion:</h3> Autofluorescence imaging improves the detection of neoplasia in patients with ulcerative colitis and decreases the yield of random biopsies. Pit pattern analysis by NBI has a moderate accuracy for the prediction of histology, whereas AFI colour appears valuable in excluding the presence of neoplasia. <h3>Trial registration number:</h3> ISRCTN05272746