tbuckley/cabot-search huggingface dataset:
Tumour-educated circulating monocytes are powerful candidate biomarkers for diagnosis and disease follow-up of colorectal cancer
Authors: Alexander Hamm, Hans Prenen, Wouter Van Delm, Mario Di Matteo, Mathias Wenes, Estelle Delamarre, Thomas Schmidt, Jürgen Weitz, Roberta Sarmiento, Angelo Dezi, Giampietro Gasparini, Françoise Rothé, Robin Schmitz, André D'Hoore, Hannes Iserentant, Alain Hendlisz, Massimiliano Mazzone
Journal: Gut (2015)

<h3>Objective</h3> Cancer immunology is a growing field of research whose aim is to develop innovative therapies and diagnostic tests. Starting from the hypothesis that immune cells promptly respond to harmful stimuli, we used peripheral blood monocytes in order to characterise a distinct gene expression profile and to evaluate its potential as a candidate diagnostic biomarker in patients with colorectal cancer (CRC), a still unmet clinical need. <h3>Design</h3> We performed a case-control study including 360 peripheral blood monocyte samples from four European oncological centres and defined a gene expression profile specific to CRC. The robustness of the genetic profile and disease specificity were assessed in an independent setting. <h3>Results</h3> This screen returned 43 putative diagnostic markers, which we refined and validated in the confirmative multicentric analysis to 23 genes with outstanding diagnostic accuracy (area under the curve (AUC)=0.99 (0.99 to 1.00), Se=100.0% (100.0% to 100.0%), Sp=92.9% (78.6% to 100.0%) in multiple-gene receiver operating characteristic analysis). The diagnostic accuracy was robustly maintained in prospectively collected independent samples (AUC=0.95 (0.85 to 1.00), Se=92.6% (81.5% to 100.0%), Sp=92.3% (76.9% to 100.0%). This monocyte signature was expressed at early disease onset, remained robust over the course of disease progression, and was specific for the monocytic fraction of mononuclear cells. The gene modulation was induced specifically by soluble factors derived from transformed colon epithelium in comparison to normal colon or other cancer histotypes. Moreover, expression changes were plastic and reversible, as they were abrogated upon withdrawal of these tumour-released factors. Consistently, the modified set of genes reverted to normal expression upon curative treatment and was specific for CRC. <h3>Conclusions</h3> Our study is the first to demonstrate monocyte plasticity in response to tumour-released soluble factors. The identified distinct signature in tumour-educated monocytes might be used as a candidate biomarker in CRC diagnosis and harbours the potential for disease follow-up and therapeutic monitoring.
Inhibition of plasmacytoma development in BALB/c mice by indomethacin.
Authors: M Potter, J S Wax, A O Anderson, R P Nordan
Journal: The Journal of Experimental Medicine (1985)

Indomethacin given continuously in the drinking water (20 micrograms/ml) to BALB/cAn pi mice during the latent period of pristane-induced plasmacytoma development dramatically reduced the plasmacytoma incidence from 34.9 to 2.2%. Additionally, indomethacin given from day 0 to 120 or begun as late as 60 d after a single injection of 1.0 ml pristane was also highly effective in reducing the development of plasmacytomas. Indomethacin treatment did not prevent the formation of a peritoneal inflammatory exudate or peritoneal oil granulomatous tissue, although it had a mild inhibitory effect on the intensity of the cellular inflammation, particularly after extensive treatment of greater than 100 d. Indomethacin treatment reduced the incidence of arthritis by 50%. A major effect of indomethacin treatment was a reduction in the appearance of microscopic plasmacytomas that appear in the oil granuloma before plasmacytomas can be detected by routine sampling of the peritoneal exudate. Between days 116 and 181, 16 of 20 mice given 0.5 ml pristane were found to have foci of plasmacytoma cells, while only 2 of 20 indomethacin-treated mice had foci-containing plasmacytoma cells. The number of mice with microscopic foci in the pristane-treated group greatly exceeded the expected incidence of plasmacytomas (22%) at this dose of pristane. The growth of primary plasmacytomas in transplant that is dependent on the pristane-conditioned peritoneal environment was not inhibited by indomethacin treatment. The role of indomethacin in inhibiting plasmacytoma development was not established; two possibilities are that it inhibits production of mutagenic and tissue destructive oxidants by inflammatory cells, and it inhibits prostaglandin synthesis and intracellular production of oxidant biproducts.
Decision making, evidence, audit, and education: case study of antibiotic prescribing in general practice Commentary: What can we learn from narratives of implementing evidence?
Authors: T. Lipman
Journal: BMJ (2000)

Objectives: To describe a group general practice's implementation of a decision to prescribe 3 day courses of 200 mg trimethoprim twice daily for urinary tract infections in women and to compare 3 day courses with 5 and 7 day courses. Design: Record review, audit of trimethoprim prescribing for urinary tract infections, and critical appraisal of evidence originally presented in support of 3 day course. Setting: Group general practice in Newcastle upon Tyne. Data sources: The records of all female patients aged 12years and older who were prescribed trimethoprim for uncomplicated urinary tract infections during a 12 month period were reviewed. 271 valid records were identified. Data extraction: Prescribing rates for different courses of trimethoprim, rates of patients returning for second consultations, rates of urine cultures, results of cultures, results of critical appraisal of evidence. Results: 114 of 271 (42%) prescriptions written at the first visit were for 3 day courses. 16 of 114 (14%) patients who had had a 3 day course of treatment returned for a second consultation compared with 6/83 (7.2%) of those who had had a 5 day course and 8/74 (11%) who had had a 7 day course. The difference between 3 day and 5 day courses in rates of returning for second consultations was 6.8% (95% CI −1.7% to 12.6%) and between 3 day and 7 day courses was 3.2% (−3.6% to 10.0%). Appraisal of the original evidence on which the practice based its recommendations showed that it was flawed. Additional evidence was found in the Cochrane Library . Conclusions: Our original decision, made by consensus at a meeting of the practice's partners, had not led to a consistent change in practice. We did not find a significant increase in treatment failures among patients treated with the 3 day regimen. # Commentary: What can we learn from narratives of implementing evidence? {#article-title-21}
Identification of a Novel Mammary-Restricted Cytochrome P450, CYP4Z1, with Overexpression in Breast Carcinoma
Authors: Michael A. Rieger, Reinhard Ebner, David R. Bell, Andrea Kiessling, Jacques Rohayem, Marc Schmitz, Achim Temme, E. Peter Rieber, Bernd Weigle
Journal: Cancer Research (2004)

Abstract By screening a transcriptome database for expressed sequence tags that are specifically expressed in mammary gland and breast carcinoma, we identified a new human cytochrome P450 (CYP), termed CYP4Z1. The cDNA was cloned from the breast carcinoma line SK-BR-3 and codes for a protein of 505 amino acids. Moreover, a transcribed pseudogene CYP4Z2P that codes for a truncated CYP protein (340 amino acids) with 96% identity to CYP4Z1 was found in SK-BR-3. CYP4Z1 and CYP4Z2P genes consisting of 12 exons are localized in head-to-head orientation on chromosome 1p33. Tissue-specific expression was investigated using real-time reverse transcription PCR with normalized cDNA from 18 different human tissues. CYP4Z1 mRNA was preferentially detected in breast carcinoma tissue and mammary gland, whereas only marginal expression was found in all other tested tissues. Investigation of cDNA pairs from tumor/normal tissues obtained from 241 patients, including 50 breast carcinomas, confirmed the breast-restricted expression and showed a clear overexpression in 52% of breast cancer samples. The expression profile of CYP4Z2P was similar to that of CYP4Z1 with preference in breast carcinoma and mammary gland but a lower expression level in general. Immunoblot analyses with a specific antiserum for CYP4Z1 clearly demonstrated protein expression in mammary gland and breast carcinoma tissue specimens as well as in CYP4Z1-transduced cell lines. Confocal laser-scanning microscopy of MCF-7 cells transfected with a fluorescent fusion protein CYP4Z1-enhanced green fluorescent protein and a subcellular fractionation showed localization to the endoplasmic reticulum as an integral membrane protein concordant for microsomal CYP enzymes.
In Vivo Eradication of Human BCR/ABL-Positive Leukemia Cells With an ABL Kinase Inhibitor
Authors: Philipp le Coutre, Luca Mologni, Loredana Cleris, Edoardo Marchesi, Elisabeth Buchdunger, Roberto Giardini, Franca Formelli, Carlo Gambacorti-Passerini
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: The leukemia cells of approximately 95% of patients with chronic myeloid leukemia and 30%-50% of adult patients with acute lymphoblastic leukemia express the Bcr/Abl oncoprotein, which is the product of a fusion gene created by a chromosomal translocation [(9:22) (q34;q11)]. This oncoprotein expresses a constitutive tyrosine kinase activity that is crucial for its cellular transforming activity. In this study, we evaluated the antineoplastic activity of CGP57148B, which is a competitive inhibitor of the Bcr/Abl tyrosine kinase. METHODS: Nude mice were given an injection of the Bcr/Abl-positive human leukemia cell lines KU812 or MC3. Tumor-bearing mice were treated intraperitoneally or orally with CGP57148B according to three different schedules. In vitro drug wash-out experiments and in vivo molecular pharmacokinetic experiments were performed to optimize the in vivo treatment schedule. RESULTS: Treatment schedules administering CGP57148B once or twice per day produced some inhibition of tumor growth, but no tumor-bearing mouse was cured. A single administration of CGP57148B caused substantial (>50%) but short-lived (2-5 hours) inhibition of Bcr/Abl kinase activity. On the basis of the results from in vitro wash-out experiments, 20-21 hours was defined as the duration of continuous exposure needed to block cell proliferation and to induce apoptosis in these two leukemia cell lines. A treatment regimen assuring the continuous block of the Bcr/Abl phosphorylating activity that was administered over an 11-day period cured 87%-100% of treated mice. CONCLUSION: These data indicate that the continuous block of the oncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in vivo.
Look Ma, no fingers! Are children numerical solipsists?
Authors: Peter Gordon
Journal: Behavioral and Brain Sciences (2008)

Abstract I ask whether it is necessary that principles of number be mentally represented and point to the role of language in determining cultural variation. Some cultures possess extensive counting systems that are finite. I suggest that learning number principles is similar to learning conservation and, as such, might be derived from learning about the empirical properties of objects and other individuals in combinations.
Chitin Activates Parallel Immune Modules that Direct Distinct Inflammatory Responses via Innate Lymphoid Type 2 and γδ T Cells
Authors: Steven J. Van Dyken, Alexander Mohapatra, Jesse C. Nussbaum, Ari B. Molofsky, Emily E. Thornton, Steven F. Ziegler, Andrew N.J. McKenzie, Matthew F. Krummel, Hong-Erh Liang, Richard M. Locksley
Journal: Immunity (2014)
Validation of the English Severe Respiratory Insufficiency Questionnaire
Authors: Dipansu Ghosh, Peter Rzehak, Mark W. Elliott, Wolfram Windisch
Journal: European Respiratory Journal (2011)

Assessment of health-related quality of life in patients with respiratory failure on home ventilation requires appropriate and highly specific measurement tools. We attempt to validate the English version of the Severe Respiratory Insufficiency Questionnaire (SRI). Psychometric properties of the SRI in 152 patients established on home ventilation were assessed. Cronbach's alpha ranged between 0.77 and 0.89 for the seven subscales and and was 0.93 for the summary scale. Principal components analysis revealed a one-factor solution for four and two factors for three subscales. Confirmatory factor analysis revealed a two-factor solution for six subscales, but these factors were dependent on each other. One factor was extracted out of the subscales confirming one summary scale accounting for 70% of the total variance. Correlation analysis between scales of the SRI and the Medical Outcome Study 36-item short-form health survey demonstrated highest correlations between comparable subscales. Chronic obstructive pulmonary disease patients had lower summary scale scores than patients with restrictive chest wall diseases, neuromuscular disorders and obesity hypoventilation syndrome. The English SRI has high internal consistency reliability, clearly established construct and concurrent validity, and is capable of differentiating between different diseases. It is now validated for use in research involving patients receiving home ventilation.
Role of microtubules in the rapid regulation of renal phosphate transport in response to acute alterations in dietary phosphate content.
Authors: M Lötscher, B Kaissling, J Biber, H Murer, M Levi
Journal: Journal of Clinical Investigation (1997)

Renal proximal tubular response to acute administration of a low Pi diet is characterized by a rapid adaptive increase in apical brush border membrane (BBM) Na-Pi cotransport activity and Na-Pi cotransporter protein abundance, independent of a change in Na-Pi cotransporter mRNA levels (Levi, M., M. Lötscher, V. Sorribas, M. Custer, M. Arar, B. Kaissling, H. Murer, and J. Biber. 1994. Am. J. Physiol. 267: F900-F908). The purposes of the present study were to determine if the acute adaptive response occurs independent of de novo protein synthesis, and if microtubules play a role in the rapid upregulation of the Na-Pi cotransporters at the apical BBM. We found that inhibition of transcription by actinomycin D and translation by cycloheximide did not prevent the rapid adaptive response. In addition, in spite of a 3.3-fold increase in apical BBM Na-Pi cotransporter protein abundance, there was no change in cortical homogenate Na-Pi cotransporter protein abundance. Pretreatment with colchicine, which resulted in almost complete disruption of the microtubular network, abolished the adaptive increases in BBM Na-Pi cotransport activity and Na-Pi cotransporter protein abundance. In contrast, colchicine had no effect on the rapid downregulation of Na-Pi cotransport in response to acute administration of a high Pi diet. We conclude that the rapid adaptive increase in renal proximal tubular apical BBM Na-Pi cotransport activity and Na-Pi cotransporter abundance is independent of de novo protein synthesis, and is mediated by microtubule-dependent translocation of presynthesized Na-Pi cotransporter protein to the apical BBM.
Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia
Authors: Sven Asmussen, Hiroshi Ito, Daniel L Traber, Jae W Lee, Robert A Cox, Hal K Hawkins, Daniel F McAuley, David H McKenna, Lillian D Traber, Hanjing Zhuo, Jennifer Wilson, David N Herndon, Donald S Prough, Kathleen D Liu, Michael A Matthay, Perenlei Enkhbaatar
Journal: Thorax (2014)

<h3>Background</h3> Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with <i>Escherichia coli</i> bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. <h3>Methods</h3> Adult sheep (30–40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live <i>Pseudomonas aeruginosa</i> (2.5×10<sup>11</sup> CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer9s solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5×10<sup>6</sup> hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10×10<sup>6</sup> hMSCs/kg, n=4. <h3>Results</h3> By 24 h, the PaO<sub>2</sub>/FiO<sub>2</sub> ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO<sub>2</sub>/FiO<sub>2</sub> of 97±15 mm Hg; lower dose: 288±55 mm Hg (p=0.003); higher dose: 327±2 mm Hg (p=0.003)). The median lung water content was lower in the higher-dose hMSC-treated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9–5.8] vs control: 6.7 g wet/g dry [IQR 6.4–7.5] (p=0.01)). The hMSCs had no adverse effects. <h3>Conclusions</h3> Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS. <h3>Trail registration number:</h3> NCT01775774 for Phase 1. NCT02097641 for Phase 2.
Auscultation of the Heart by Machine and by Physicians
Authors: Aldo leri
Journal: JAMA (1967)

An automatic screening device for auscultatory evidence of heart disease was tested on 308 children and adolescents who had previously had rheumatic fever. The device correctly recognized as abnormal 88.5% of 131 patients with rheumatic heart disease (RHD), and correctly recognized as normal 83.6% of 177 patients with no RHD. For purposes of comparison a cardiologist, an internist, and a senior medical student each listened while blindfolded to the heart sounds of three 100-patient subsets of the above population. The auscultation was limited to the areas used for the automatic screening. They correctly recognized as abnormal 97.9%, 94.5%, and 91.9% of the patients with RHD, and correctly recognized as normal 81.1%, 84.4%, and 85.7% of the patients without RHD.
Lowering the Criterion for Impaired Fasting Glucose Will Not Provide Clinical Benefit
Authors: Mayer B. Davidson, Pamela B. Landsman, Charles M. Alexander
Journal: Diabetes Care (2003)

In 1997, the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus lowered the fasting criterion for diabetes from ≥140 (7.8 mmol/l) to ≥126 mg/dl (7.0 mmol/l) (1). This decision was made to allow the prevalence of diabetes diagnosed by fasting plasma glucose (FPG) concentrations to equal the prevalence of diabetes diagnosed by 2-h values on a glucose tolerance test. The fact that 60% of the new cohort of people with diabetes, i.e., those diagnosed by FPG concentrations of 126–139 mg/dl, would have normal A1C levels (2) did not seem to trouble the committee.

Using the same rationale of equalizing outcomes achieved by utilizing two different criteria, in last month’s issue of Diabetes Care (3) the Expert Committee decreased the lower limit of normal for FPG concentrations. The definition of impaired …
General Medical Care among Patients with Chronic Kidney Disease
Authors: Annamaria T. Kausz, Haifeng Guo, Brian J.G. Pereira, Allan J. Collins, David T. Gilbertson
Journal: Journal of the American Society of Nephrology (2005)

<h3>Introduction</h3> Acute exacerbations of COPD have a major impact on patients' health related quality of life (HRQoL), and the utilisation of health care resources. Current guidelines recommend oral corticosteroids and/or antibiotics for the treatment of acute exacerbations of COPD based on patients' symptoms. With increasing bacterial resistance to antibiotics and the rising costs of COPD treatment, further research into diagnostic tools to aid the management of COPD in its stable and exacerbating states is required. Sputum colour (SC) is an accessible marker of underlying bronchial inflammation. We investigated the contribution of objective measures of SC as a component of the clinical assessment of exacerbations and relationships with symptom severity. <h3>Methods</h3> Data from 36 patients with moderate to very severe COPD was assessed in this prospective observational cohort study (AERIS). There were 122 exacerbations in total over a year. Sputum and blood sampling were performed at enrolment, routine follow up and exacerbation visits. A five-point sputum colour chart was developed to objectively report the SC. Sputum samples from all visits were graded against this chart by the trained laboratory staff. Data from mild, moderate and severe exacerbations were included in the analysis. <h3>Results</h3> We found a correlation between SC at exacerbations and disease severity (FEV1%) at exacerbations. SC was also related to sputum neutrophilia at exacerbations. SC was significantly associated with systemic markers such as blood neutrophilia, CRP and fibrinogen. Interestingly, we observed no statistically significant correlation between SC and Procalcitonin levels. We also found no statistically significant relationship between SC and symptom scores (CAT and EXACT-PRO) at exacerbations. However, we found a significant association between CAT and EXACT-PRO scores (rho 0.46; p &lt; 0.01). <h3>Conclusion</h3> We observed that visual colour score of sputum at exacerbations is related to underlying airway and systemic inflammation but not to symptom scores. The use of a SC combined with other clinical and laboratory biomarkers, as part of a multicomponent diagnostic tool, may further improve its clinical utility to better guide effective exacerbation treatment. Further analysis of the full AERIS cohort will explore this.
Rheumatoid factor (RF) production during anamnestic immune responses in the mouse. III. Activation of RF precursor cells is induced by their interaction with immune complexes and carrier-specific helper T cells.
Authors: P G Coulie, J Van Snick
Journal: The Journal of Experimental Medicine (1985)

IgG1 immune complexes were identified as the humoral stimuli responsible for the synthesis of IgG1-specific IgM rheumatoid factor (RF), which occurs in the mouse during the early stages of secondary immune responses to protein antigens. The specificity of this phenomenon was illustrated by the fact that complexes made with IgG1 F(ab')2 fragments or with antibodies of a different isotype failed to induce significant anti-IgG1 RF synthesis. The importance of immune complexes in the induction of RF was further underscored by the substantial increase in the titers of isotype-specific RF observed in the serum of mice immunized with IgG1- or IgG2a-complexed antigen rather than with antigen alone. The RF-inducing capacity of the complexes varied with the antigen/antibody ratio: it was maximal in antibody excess or at equivalence, but dramatically reduced in large antigen excess. The importance of T cell priming in RF precursor cell activation by immune complexes was demonstrated by the failure of T cell-deprived spleen cells to reconstitute the capability of irradiated mice to produce RF, and by the optimal RF responses observed after reconstitution of irradiated recipients with primed T cells and naive B cells. The involvement of T cells in this process could not be explained by the release of nonspecific B cell activators, because antigenic stimulation of primed T cells failed to enhance the activation of RF precursor cells by immune complexes of unrelated antigen.