tbuckley/cabot-search huggingface dataset:
An immunological algorithm to predict risk of high-grade rejection in cardiac transplant recipients
Authors: Silviu Itescu, Thomas CM Tung, Elizabeth M Burke, Alan D Weinberg, Donna Mancini, Robert E Michler, Nicole M Suciu-Foca, Eric A Rose
Journal: The Lancet (1998)

Transplant-related coronary-artery disease (TCAD) develops frequently in cardiac-allograft recipients, and limits long-term survival. We examined the relation between this disorder and cumulative frequency of high-grade rejection, and investigated whether concomitant use of three immunological factors at the time of a low-grade endomyocardial biopsy can predict progression to high-grade rejection.We investigated the relation between the cumulative annual frequency of high-grade rejection and TCAD in 198 recipients of cardiac transplantation between 1992 and 1996 by means of Kaplan-Meier actuarial life-tables. Endomyocardial biopsy, lymphocyte-growth assays, and anti-HLA antibody measurements were compiled over 12 months in 102 patients during their first post-transplant year. We calculated predictive values for high-grade rejection within 90 days by chi2, Kaplan Meier survival curves, and by multivariable logistic regression analyses.We found a direct correlation between cumulative annual frequency of rejection and TCAD onset with highest risk in those with more than 0.75 rejections per year (p=0.0002). After a low-grade endomyocardial biopsy (0 or 1A), one or more donor-recipient HLA-DR matches protected against high-grade rejections (p<0.001). Among individuals with one or two DR matches, the negative predictive value for progression from a low-grade biopsy to a high-grade rejection was 87% in the presence of a negative lymphocyte-growth assay. Among individuals with no DR matches, the presence of either a positive lymphocyte-growth assay or IgG anti-major-histocompatibility complex (MHC) class II antibodies was independently associated with high probability of progression to rejection (64% and 66%, respectively, p<0.0005). When both assays were positive, concomitantly with a low-grade endomyocardial biopsy, the positive predictive value for progression to a high-grade rejection was 86% (p<0.0001). For endomyocardial-biopsy grades 1B or 2, a positive lymphocyte-growth assay alone was associated with high-grade rejection in 100% of cases.Use of an algorithm combining three immunological factors at the time of a low-grade endomyocardial biopsy enables prospective stratification of cardiac transplant recipients into risk categories for progression to high-grade rejection. Low-risk individuals require fewer biopsies, moderate-risk individuals require an ongoing schedule of surveillance biopsies, and high-risk individuals require rational organisation of interventional strategies aimed at preventing rejection. Additional predictive factors are needed to identify moderate-risk individuals who will progress to rejection. Ultimately, successful intervention may have an impact on the subsequent complication of TCAD.
STUDIES IN FOCAL INFECTION: ITS PRESENCE AND ELIMINATION IN THE FUNCTIONAL PSYCHOSES
Authors: Nicholas Kopeloff, Clarence O. Cheney
Journal: American Journal of Psychiatry (1922)

The conclusions resulting from this study of the relation of focal infections to functional psychoses may be summarized as follows: 1. The removal of infected teeth and tonsils from 27 cases showing manic-depressive, dementia præcox, and psychoneurotic reactions has been followed by no more mental benefit than was shown by a comparable group of 33 patients from whom such supposed foci of infection were not removed. There were no recoveries or distinct improvements other than those prognosticated irrespective of focal infection. 2. The Rehfuss method of fractional gastric analysis is not to be relied upon as a means for determining gastric infection. The bacteria found in the stomach contents by this method may be derived for the greatest part or entirely from the swallowed saliva. These studies are being continued, not only for the purpose of obtaining further facts regarding focal infection in the psychoses, but as a part of a general plan to afford psychotic patients all available opportunities for benefit.
The knowledge system underpinning healthcare is not fit for purpose and must change
Authors: I. Roberts, K. Ker, P. Edwards, D. Beecher, D. Manno, E. Sydenham
Journal: BMJ (2015)

<h3>Background</h3> High C reactive protein (CRP) levels have been reported to be associated with a poor clinical outcome in a number of malignancies and with programmed cell death protein 1 immune checkpoint blockade in patients with advanced cancer. Little is known about the direct effects of CRP on adaptive immunity in cancer. Therefore, we investigated how CRP impacted the function of T cells and dendritic cells (DCs) from patients with melanoma. <h3>Methods</h3> The effects of CRP on proliferation, function, gene expression and phenotype of patient T cells and DCs, and expansion of MART-1 antigen-specific T cells were analyzed by multicolor flow cytometry and RNA-seq. Additionally, serum CRP levels at baseline from patients with metastatic melanoma treated on the Checkmate-064 clinical trial were assessed by a Luminex assay. <h3>Results</h3> In vitro, CRP inhibited proliferation, activation-associated phenotypes and the effector function of activated CD4+ and CD8+ T cells from patients with melanoma. CRP-treated T cells expressed high levels of interleukin-1β, which is known to enhance CRP production from the liver. CRP also suppressed formation of the immune synapse and inhibited early events in T-cell receptor engagement. In addition, CRP downregulated the expression of costimulatory molecules on mature DCs and suppressed expansion of MART-1-specific CD8+ T cells in a dose-dependent manner by impacting on both T cells and antigen-presenting cells. High-serum CRP levels at baseline were significantly associated with a shorter survival in both nivolumab-treated and ipilimumab-treated patients. <h3>Conclusions</h3> These findings suggest that high levels of CRP induce an immunosuppressive <i>milieu</i> in melanoma and support the blockade of CRP as a therapeutic strategy to enhance immune checkpoint therapies in cancer. <h3>Trial registration number</h3> NCT01783938 and NCT02983006.
PTU-234 Endoscopic ultrasound guided fine needle aspiration for the diagnosis of pancreatic cystic neoplasms: a meta-analysis
Authors: G D Thornton, M J McPhail, S Nayagam, M J Hewitt, P Vlavianos, K J Monahan
Journal: Gut (2012)

<h3>Introduction</h3> Pancreatic cystic neoplasms consist of mucinous cystic neoplasms (MCNs) and serous cystic neoplasms (SCNs). MCNs have significantly greater malignant potential, and if resected early the prognosis is excellent, although mortality is 2%–3%. Endoscopic ultrasound is a minimally invasive and well tolerated procedure. EUS with fine-needle aspiration (EUS-FNA) provides samples for cytology and fluid analysis, a major advantage over other techniques. However the diagnostic accuracy of EUS-FNA is highly variable in published studies. <h3>Aim</h3> To determine the diagnostic accuracy of EUS-FNA to differentiate mucinous vs non-mucinous cystic lesions with morphology, and cyst fluid analysis for cytology and carcinoembryonic antigen (CEA) via a meta-analysis of published studies. <h3>Methods</h3> Relevant studies were identified using MEDLINE and included if they used a reference standard of definitive surgical pathology or clinical follow-up (≥6 months). Study quality was assessed using the STARD (STAndards for the Reporting of Diagnostic Accuracy) initiative criteria. Data were analysed using Meta-DiSc© v.1.4, which generated pooled estimates for sensitivity, specificity and summary ROC curve. Subgroups, determined a priori, were used to assess heterogeneity: prospective vs retrospective, location, number of centres and patients, 19G or 22G needle and STARD score. <h3>Results</h3> 24 studies published between 2001 and 2011 were included, a total of 1703 patients. The median number of patients in each study was 53 (range 18–197) and the median study length was 54 (12–144) months. The pooled sensitivities (95% CI) and specificities (95% CI) and area under the sROC curve (SE), respectively, were: EUS morphology 55 (49–61)%, 65 (57–72)% and 0.74 (0.095); Cytology 54 (50–59)%, 93 (90–95)% and 0.95 (0.040); and CEA 63 (59–67)%, 88 (83–91)% and 0.79 (0.034). Subgroup analysis indicated that retrospective design, low STARD score and study location outside Europe were significant sources of heterogeneity. <h3>Conclusion</h3> Fine-needle aspiration has moderate sensitivity but high specificity resulting in good overall diagnostic accuracy for MCNs. Morphology alone is inadequate for distinguishing cystic lesions but may contribute to the assessment of more advanced lesions. The moderate sensitivity of FNA (54%) means a significant proportion of MCNs will not be detected. However, the high specificity (93%) means that a positive result is strongly indicative of a MCN. Thus, EUS-FNA is a useful diagnostic tool for correct identification of MCNs and may be the gold standard for pre-operative assessment. <h3>Competing interests</h3> None declared.
Effect of drugs on the pulmonary changes in experimental acute pancreatitis in the rat.
Authors: A R Berry, T V Taylor
Journal: Gut (1982)

Respiratory complications of acute pancreatitis are well recognised and are closely related to a poor prognosis. Using an experimental model in the rat, a decrease in lung compliance and an increase in lung weight were produced in acute pancreatitis. The effects of dexamethasone, heparin, and aspirin on these changes were studied. The mean specific lung compliance was reduced by 16% in the pancreatitis group compared with the control group (p less than 0.05) and this change was abolished by dexamethasone (p less than 0.02), heparin (p less than 0.01), and aspirin (p less than 0.001). Percentage lung weight (as percentage of total body weight) was raised by 22% in the pancreatitis group compared with the sham operation group (p less than 0.01) and this change was abolished by heparin (p less than 0.01) and aspirin (p less than 0.05), but not affected by dexamethasone (p less than 0.5). The results indicate that 9stiff9 and heavy lungs occur in experimental acute pancreatitis. The fact that these changes are abolished by heparin and improved by aspirin suggests that intrapulmonary fibrin deposition is a factor in the pathogenesis of the important respiratory complications of this condition.
Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides
Authors: Milla Koistinaho, Suizhen Lin, Xin Wu, Michail Esterman, Deanna Koger, Jeffrey Hanson, Richard Higgs, Feng Liu, Seema Malkani, Kelly R Bales, Steven M Paul
Journal: Nature Medicine (2004)
Signaling via β2 Integrins Triggers Neutrophil-Dependent Alteration in Endothelial Barrier Function
Authors: Narinder Gautam, Heiko Herwald, Per Hedqvist, Lennart Lindbom
Journal: The Journal of Experimental Medicine (2000)

Activation of polymorphonuclear leukocytes (PMNs) and adhesion to the endothelial lining is a major cause of edema formation. Although known to be dependent on the function of β2 integrins (CD11/CD18), the precise mechanisms by which adherent PMNs may impair endothelial barrier capacity remain unclear. Here, the role of transmembrane signaling by β2 integrins in PMN-induced alterations in tight junctional permeability of cultured endothelial cell (EC) monolayers was investigated. PMN activation, in the absence of proinflammatory stimuli, was accomplished through antibody cross-linking of CD11b/CD18, mimicking adhesion-dependent receptor engagement. CD18 cross-linking in PMNs added to the EC monolayer provoked a prompt increase in EC permeability that coincided with a rise in EC cytosolic free Ca2+ and rearrangement of actin filaments, events similar to those evoked by chemoattractant PMN activation. Cell-free supernatant obtained after CD18 cross-linking in suspended PMNs triggered an EC response indistinguishable from that induced by direct PMN activation, and caused clear-cut venular plasma leakage when added to the hamster cheek pouch in vivo preparation. The PMN-evoked EC response was specific to β2 integrin engagement inasmuch as antibody cross-linking of l-selectin or CD44 was without effect on EC function. Our data demonstrate a causal link between outside-in signaling by β2 integrins and the capacity of PMNs to induce alterations in vascular permeability, and suggest a paracrine mechanism that involves PMN-derived cationic protein(s) in the cellular crosstalk between PMNs and ECs.
Decreased hypothalamic growth hormone-releasing hormone content and pituitary responsiveness in hypothyroidism.
Authors: H Katakami, T R Downs, L A Frohman
Journal: Journal of Clinical Investigation (1986)

The effects of thyroidectomy (Tx) and thyroxine replacement (T4Rx) on pituitary growth hormone (GH) secretion and hypothalamic GH-releasing hormone (GRH) concentration were compared to define the mechanism of hypothyroid-associated GH deficiency. Thyroidectomized rats exhibited a complete loss of pulsatile GH secretion with extensive reduction in GRH responsiveness and pituitary GH content. Cultured pituitary cells from Tx rats exhibited reduced GRH sensitivity, maximal GH responsiveness, and intracellular cyclic AMP accumulation to GRH, while somatostatin (SRIF) suppressive effects on GH secretion were increased. Hypothalamic GRH content was also markedly reduced. T4Rx completely restored hypothalamic GRH content and spontaneous GH secretion despite only partial recovery of pituitary GH content, GRH and SRIF sensitivity, and intracellular cyclic AMP response to GRH. The results indicate multiple effects of hypothyroidism on GH secretion and suggest that a critical role of T4 in maintaining normal GH secretion, in addition to restoring GH synthesis, is related to its effect on hypothalamic GRH.
The Secondary Structure of Human Hageman Factor (Factor XII) and its Alteration by Activating Agents
Authors: Carl R. McMillin, Hidehiko Saito, Oscar D. Ratnoff, Alan G. Walton
Journal: Journal of Clinical Investigation (1974)

Hageman factor (factor XII) is activated by exposure to surfaces such as glass or by solutions of certain compounds, notably ellagic acid. Changes in the structure of Hageman factor accompanying activation have been examined in this study by circular dichroism spectroscopy. The spectrum of unactivated Hageman factor in aqueous solutions suggests that its conformation is mainly aperiodic. Various perturbants altered the conformation of Hageman factor in differing ways, demonstrating the sensitivity of Hageman factor to its environment. After activation of Hageman factor with solutions of ellagic acid, a negative trough appeared in the region of the circular dichroism spectrum commonly assigned to tyrosine residues, along with other minor changes in the peptide spectral region. Some of these changes are similar to changes that occurred upon partial neutralization of the basic residues at alkali pH. Activation of Hageman factor by adsorption to quartz surfaces (in an aqueous environment) also produced changes similar to those in the ellagic acid-activated Hageman factor, including the negative ellipticity in the tyrosine region. These observations suggest that the activation process may be related to a change in status of some of the basic amino acid residues, coupled with a specific change in the environment of some tyrosine residues. The importance of these changes during the activation process remains to be determined. The sensitivity of Hageman factor to its environment is consistent with the view that the initiation of clotting by exposure of plasma to appropriate agents is brought about by alterations in the conformation of Hageman factor that occur in the apparent absence of Fletcher factor or other recognized clotting factors.
Increased nuclear β-catenin in suprabasal involved psoriatic epidermis
Authors: P.J. Hampton, O.K. Ross, N.J. Reynolds
Journal: British Journal of Dermatology (2007)

Background Psoriasis is a common inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation, increased angiogenesis and inflammation. There is evidence that some keratinocyte differentiation events are controlled by changes in cell–cell adhesion. β-catenin is a 94-kDa protein which has a dual function as a component of intercellular adherens junctions and also as a transcription factor as part of the Wnt signalling pathway. β-catenin is not required for keratinocyte proliferation but has been shown to regulate keratinocyte stem cells and hair follicle morphogenesis. Objectives To investigate the distribution and function of β-catenin in involved psoriatic epidermis and in epidermal keratinocytes. Methods Biopsies were obtained from patients with psoriasis and from normal controls. The distribution of β-catenin was investigated using antibodies to both total and unphosphorylated active β-catenin. Luciferase assays were used to measure transcriptional activation of transglutaminase 1 (TGase 1) and involucrin and to investigate the functional role of β-catenin in interfollicular keratinocytes. Results Increased nuclear β-catenin was seen in lesional suprabasal psoriatic epidermis compared with uninvolved or normal skin. Increased active unphosphorylated β-catenin was also detected within the differentiating compartment of involved psoriatic epidermis. Expression of TGase 1 overlapped with β-catenin in suprabasal lesional psoriasis. The TGase 1 promoter was positively regulated by activated β-catenin and by the glycogen synthase kinase binding protein, suggesting that β-catenin and glycogen synthase kinase 3β may regulate TGase 1 expression. Conclusions This is the first report to convincingly demonstrate increased β-catenin in involved psoriasis and to implicate β-catenin in the regulation of TGase 1. This evidence suggests a role for β-catenin signalling in regulating keratinocyte differentiation in interfollicular skin in addition to previously reported functions in stem cell fate determination, hair follicle regulation and skin tumorigenesis.
Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins
Authors: Marta Guix, Anthony C. Faber, Shizhen Emily Wang, Maria Graciela Olivares, Youngchul Song, Sherman Qu, Cammie Rinehart, Brenda Seidel, Douglas Yee, Carlos L. Arteaga, Jeffrey A. Engelman
Journal: Journal of Clinical Investigation (2008)

Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation.
Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study
Authors: Gianpiero L Cavalleri, Michael E Weale, Kevin V Shianna, Rinki Singh, John M Lynch, Bronwyn Grinton, Cassandra Szoeke, Kevin Murphy, Peter Kinirons, Deirdre O'Rourke, Dongliang Ge, Chantal Depondt, Kristl G Claeys, Massimo Pandolfo, Curtis Gumbs, Nicole Walley, James McNamara, John C Mulley, Kristen N Linney, Leslie J Sheffield, Rodney A Radtke, Sarah K Tate, Stephanie L Chissoe, Rachel A Gibson, David Hosford, Alice Stanton, Tracey D Graves, Michael G Hanna, Kai Eriksson, Anne-Mari Kantanen, Reetta Kalviainen, Terence J O'Brien, Josemir W Sander, John S Duncan, Ingrid E Scheffer, Samuel F Berkovic, Nicholas W Wood, Colin P Doherty, Norman Delanty, Sanjay M Sisodiya, David B Goldstein
Journal: The Lancet Neurology (2007)
Nucleolar organiser regions in small cell carcinoma of the bronchus.
Authors: J Crocker, J Ayres, J McGovern
Journal: Thorax (1987)

An argyrophil technique for the demonstration of nucleolar organiser regions has been applied to routinely processed paraffin sections of 15 specimens of small cell carcinoma and 15 biopsy specimens infiltrated by lymphocytes. To avoid tautological problems, the nature of the specimens was confirmed by means of immunohistochemical staining for neurone specific enolase and leucocyte common antigen. The specimens of small cell carcinoma were readily differentiated from those containing lymphocytes by the argyrophil method, the range of mean number of nucleolar organiser regions per nucleus being 4.2-7.3 for small cell carcinoma cells and 0.9-1.7 for lymphocytes. This method separates malignant epithelial cells from benign lymphocytic cells and has potential in both clinical and research investigation of respiratory tumours.
Genome-wide association study of kidney function decline in individuals of European descent
Authors: Mathias Gorski, Adrienne Tin, Maija Garnaas, Gearoid M. McMahon, Audrey Y. Chu, Bamidele O. Tayo, Cristian Pattaro, Alexander Teumer, Daniel I. Chasman, John Chalmers, Pavel Hamet, Johanne Tremblay, Marc Woodward, Thor Aspelund, Gudny Eiriksdottir, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Braxton D. Mitchell, Jeffrey R. O'Connell, Alan R. Shuldiner, Josef Coresh, Man Li, Paul Freudenberger, Edith Hofer, Helena Schmidt, Reinhold Schmidt, Elizabeth G. Holliday, Paul Mitchell, Jie Jin Wang, Ian H. de Boer, Guo Li, David S. Siscovick, Zoltan Kutalik, Tanguy Corre, Peter Vollenweider, Gérard Waeber, Jayanta Gupta, Peter A. Kanetsky, Shih-Jen Hwang, Matthias Olden, Qiong Yang, Mariza de Andrade, Elizabeth J. Atkinson, Sharon L.R. Kardia, Stephen T. Turner, Jeanette M. Stafford, Jingzhong Ding, Yongmei Liu, Cristina Barlassina, Daniele Cusi, Erika Salvi, Jan A. Staessen, Paul M. Ridker, Harald Grallert, Christa Meisinger, Martina Müller-Nurasyid, Bernhard K. Krämer, Holly Kramer, Sylvia E. Rosas, Ilja M. Nolte, Brenda W. Penninx, Harold Snieder, M. Fabiola Del Greco, Andre Franke, Ute Nöthlings, Wolfgang Lieb, Stephan J.L. Bakker, Ron T. Gansevoort, Pim van der Harst, Abbas Dehghan, Oscar H. Franco, Albert Hofman, Fernando Rivadeneira, Sanaz Sedaghat, André G. Uitterlinden, Stefan Coassin, Margot Haun, Barbara Kollerits, Florian Kronenberg, Bernhard Paulweber, Nicole Aumann, Karlhans Endlich, Mike Pietzner, Uwe Völker, Rainer Rettig, Vincent Chouraki, Catherine Helmer, Jean-Charles Lambert, Marie Metzger, Benedicte Stengel, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Olli Raitakari, Andrew Johnson, Afshin Parsa, Murielle Bochud, Iris M. Heid, Wolfram Goessling, Anna Köttgen, W.H. Linda Kao, Caroline S. Fox, Carsten A. Böger
Journal: Kidney International (2014)