tbuckley/cabot-search huggingface dataset:
Evaluation of Nuclear Factor-κB, Urokinase-Type Plasminogen Activator, and HBx and Their Clinicopathological Significance in Hepatocellular Carcinoma
Authors: Chun-Fung Chan, Tai-On Yau, Dong-Yan Jin, Chun-Ming Wong, Sheung-Tat Fan, Irene Oi-Lin Ng
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Nuclear factor κB (NF-κB) signaling pathway is an important regulating pathway in human diseases and cancers. One of its downstream target genes is urokinase plasminogen activator (uPA), which is involved in cancer invasion and metastasis. The purpose of this study was to evaluate NF-κB activation, uPA up-regulation, and hepatitis B viral X protein (HBx) expression in human hepatocellular carcinoma (HCC) and to assess their clinicopathological significance. Experimental Design: We evaluated NF-κB activation, expression of uPA, and presence of HBx in 32 human HCCs. Their clinicopathological significance was assessed by correlation with the clinicopathological features. Aberrant NF-κB signaling pathway and uPA up-regulation mediated by HBx were also analyzed in vitro. Results: We found that NF-κB activation and uPA up-regulation were frequently (56% and 59%, respectively) observed in HCCs, and particularly in HBx-positive HCCs. NF-κB activation and uPA overexpression were closely associated with one another (P &amp;lt; 0.0001). Furthermore, both activation of NF-κB and up-regulation of uPA were significantly associated with a more aggressive tumor behavior in terms of venous invasion, direct liver invasion, and absence of tumor encapsulation. In vitro, NF-κB activation was induced by HBx transfection in HepG2 cells through inhibitor of nuclear factor-κB kinase β (IKKβ). HBx also up-regulated uPA and enhanced cell invasion synergistically with IKKβ. Conclusions: The data indicate that NF-κB dysregulation and uPA overexpression may lead to a more aggressive tumor behavior in HCC. In addition, our data suggest that IKKβ plays a critical role in the HBx-activated NF-κB signaling pathway.
Plato's Socratic dialogues and the epistemology of modern medicine
Authors: James May, Michael Baum, Susan Bewley
Journal: Journal of the Royal Society of Medicine (2010)

Plato's recordings of the dialogues of Socrates, the greatest thinker of ancient Greece, are precious items in Western philosophy, culture and science. Socratic method still informs our teaching; wise medical instructors do not fill students' heads with ‘facts’ but adopt a feigned position of ignorance from which to ask probing questions so they arrive eventually at insights that are the true prerequisite for gaining knowledge. Furthermore, these dialogues represent the birth of scientific method; starting with the recognition of one's ignorance we learn that posing pertinent questions is halfway to solving them.
Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir
Authors: Romain Coriat, Jérôme Alexandre, Carole Nicco, Laurent Quinquis, Evelyne Benoit, Christiane Chéreau, Hervé Lemaréchal, Olivier Mir, Didier Borderie, Jean-Marc Tréluyer, Bernard Weill, Joel Coste, François Goldwasser, Frédéric Batteux
Journal: Journal of Clinical Investigation (2013)

Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer.
Serum levels of soluble interleukin-2 receptor alpha (sIL-2Rα) as a predictor of outcome in brucellosis
Authors: Alexandros C. Makis, Emmanouil Galanakis, Eleftheria C. Hatzimichael, Zoe L. Papadopoulou, Antigone Siamopoulou, Konstantinos L. Bourantas
Journal: Journal of Infection (2004)
A new correction technique for measuring respiratory impedance through an endotracheal tube
Authors: AM Lorino, L Beydon, C Mariette, E Dahan, H Lorino
Journal: European Respiratory Journal (1996)

Measurement of respiratory impedance (Zrs) in intubated patients requires corrections for flow-dependent resistance and air compression inside the endotracheal tube (ET). The purpose of this study was to test a new correction technique for these effects. We therefore studied 110 patients in two conditions: breathing normally (C1), or breathing through an ET placed at the mouth (C2). In C1, we measured pressure and flow signals at the mouth, and in C2, at the ET inlet, during application of a pseudorandom forced excitation (4-32 Hz). In C1, respiratory impedance was calculated directly as Z1. In C2, pressure data were first corrected for the flow-dependent resistance of the ET, and respiratory impedance was then corrected both for gas compression inside the set-up and ET inertance (impedance Z2). Strong linear relationships were found between the reference and corrected estimates of the resistance at 6 Hz, the frequency dependence of resistance and the resonant frequency. The mean normalized distance between Z1 and Z2 observed in the patients over the 4-32 Hz frequency range was about 14% for resistance and 12% for reactance (-9% and -4%, respectively, when considering the algebraic value of the distance). This slight underestimation of both components of impedance might be due to an overcorrection of pressure for the flow-dependent resistance of the ET. We conclude that, in intubated patients, newly tested corrections for the mechanical contribution of the endotracheal tube may yield a fair estimate of respiratory impedance when pressure is measured at the inlet of the endotracheal tube.
Aetiology of colorectal cancer and relevance of monogenic inheritance
Authors: M Ponz de Leon
Journal: Gut (2003)

Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors.Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing.Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected.The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.
Pharmacogenetic Analyses of a Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma With Fluorouracil and Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie
Authors: Eray Goekkurt, Salah-Eddin Al-Batran, Jörg T. Hartmann, Ulrike Mogck, Gunter Schuch, Michael Kramer, Elke Jaeger, Carsten Bokemeyer, Gerhard Ehninger, Jan Stoehlmacher
Journal: Journal of Clinical Oncology (2009)

To evaluate the association of germ-line polymorphisms of genes that may impact treatment outcome of platinum and fluorouracil combination chemotherapy in advanced gastric cancer (AGC).Blood samples of 156 patients enrolled onto a phase III study comparing fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin were collected. Polymorphisms within genes of TS, MTHFR, MTR, OPRT, XPD, ERCC1, XRCC1, XPA, GSTP1, GSTT1, and GSTM1 were genotyped using polymerase chain reaction-based techniques.Median overall survival (OS) was 11.8 months (95% CI, 9.75 to 13.79 months) and median progression-free survival (PFS) was 5.8 months (95% CI, 4.99 to 6.61 months). The TS-3R/+6 haplotype (P = .004), the GSTT1 deletion polymorphism (P = .015), and genotypes of OPRT-Gly213Ala (P = .003) and XRCC1-Arg399Gln (P = .023) could be identified as independent predictors of OS. For PFS analyses, the TS-3R/+6 haplotye (P = .003) and MTR-A2756G (P = .01) were identified as independent positive predictors. The association between the GSTT1 deletion polymorphism and PFS showed only borderline significance (P = .053). Treatment related hematotoxicity in terms of grade 3/4 leukopenia was lowest among TS-3R/+6 haplotype carriers (P = .037). Grade 3/4 neutropenia was directly associated with the MTR-2756G/G genotype (P = .011), GSTP1-105Ile/Ile genotype (P = .02), and with the ERCC1-118T/8092C-haplotype (P = .042). In addition, significant associations between GSTP1-105Ile/Ile genotype and neurotoxicity and between the XPD-Asn312/751Gln haplotype and nephrotoxicity could be identified (P = .028 and P = .005, respectively).These findings underline the hypothesis that germ-line polymorphisms may play an important role in individualizing chemotherapy in AGC and deserve further prospective evaluation in AGC patients.
Autoimmune Disease–Associated Haplotypes of <i>BLK</i> Exhibit Lowered Thresholds for B Cell Activation and Expansion of Ig Class‐Switched B Cells
Authors: Kim R. Simpfendorfer, Brandon E. Armstead, Andrew Shih, Wentian Li, Mark Curran, Nataly Manjarrez‐Orduño, Annette T. Lee, Betty Diamond, Peter K. Gregersen
Journal: Arthritis & Rheumatology (2015)

B lymphoid kinase (BLK) is associated with rheumatoid arthritis (RA) and several other B cell-associated autoimmune disorders. BLK risk variants are consistently associated with reduced BLK expression, but the mechanisms by which reduced expression alters human B cell function to confer autoimmune disease susceptibility are unknown. This study was undertaken to characterize the BLK risk haplotype and to determine associated B cell functional phenotypes involved in autoimmunity.The BLK risk haplotype association with RA (determined using whole-genome sequencing data) was confirmed in 2,526 RA cases and 2,134 controls. Peripheral blood mononuclear cells (PBMCs) from RA patients, healthy adults, and umbilical cord blood were used to study B cell functional phenotypes associated with the BLK risk genotype. Association of the BLK haplotype with B cell phenotypes was analyzed using cell culture and flow cytometry.Two insertion/deletions were found on the RA risk haplotype in BLK, and the reduction in BLK expression associated with the risk haplotype was confirmed in primary B lymphocytes. Carriers of the RA-associated haplotype had evidence of lower basal B cell receptor (BCR) signaling activity, yet their B cells were hyperactivatable, with enhanced up-regulation of CD86 after BCR crosslinking and greater T cell stimulatory capacity. The number of isotype-switched memory B cells was also significantly increased in subjects carrying the risk haplotype.A major mechanism underlying the BLK association with autoimmune disease involves lowered thresholds for BCR signaling, enhanced B cell-T cell interactions, and altered patterns of isotype switching.
Reply to M.-H. Tan et al
Authors: Hyeong-Gon Moon, Wonshik Han, Dong-Young Noh
Journal: Journal of Clinical Oncology (2010)

We are grateful for the interesting and constructive comments on our article by Tan et al. 1 The correspondents have raised several alternative explanations regarding the poor prognosis for underweight breast cancer patients shown in our study. 2Considering the retrospective nature of our study, it is imperative to adjust for potential biases and to clarify the method of statistic analysis as the correspondents have requested.First, Tan et al 1 raised the possibility that the prognostic effect of underweight may have resulted from study length and lead time bias, because age and body mass index are positively correlated and the
PI3K Pathway Activation in High-Grade Ductal Carcinoma<i>In Situ</i>—Implications for Progression to Invasive Breast Carcinoma
Authors: Rita A. Sakr, Britta Weigelt, Sarat Chandarlapaty, Victor P. Andrade, Elena Guerini-Rocco, Dilip Giri, Charlotte K.Y. Ng, Catherine F. Cowell, Neal Rosen, Jorge S. Reis-Filho, Tari A. King
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To assess the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in pure high-grade ductal carcinoma in situ (DCIS) and DCIS associated with invasive breast cancer (IBC), and to determine whether DCIS and adjacent IBCs harbor distinct PI3K pathway aberrations. Experimental Design: Eighty-nine cases of pure high-grade DCIS and 119 cases of high-grade DCIS associated with IBC were characterized according to estrogen receptor (ER) and HER2 status, subjected to immunohistochemical analysis of PTEN, INPP4B, phosphorylated (p)AKT and pS6 expression, and to microdissection followed by Sequenom genotyping of PIK3CA and AKT1 hotspot mutations. Results: Alterations affecting the PI3K pathway were found in a subset of pure DCIS and DCIS adjacent to IBC. A subtype-matched comparison of pure DCIS and DCIS adjacent to IBC revealed that PIK3CA hotspot mutations and pAKT expression were significantly more prevalent in ER-positive/HER2-negative DCIS adjacent to IBC (P values, 0.005 and 0.043, respectively), and that in ER-negative/HER2-positive cases INPP4B loss of expression was more frequently observed in pure DCIS (a P value of 0.013). No differences in the parameters analyzed were observed in a pairwise comparison of the in situ and invasive components of cases of DCIS and adjacent IBC. Analysis of the PIK3CA-mutant allelic frequencies in DCIS and synchronous IBC revealed cases in which PIK3CA mutations were either restricted to the DCIS or to the invasive components. Conclusion: Molecular aberrations affecting the PI3K pathway may play a role in the progression from high-grade DCIS to IBC in a subset of cases (e.g., a subgroup of ER-positive/HER2-negative lesions). Clin Cancer Res; 20(9); 2326–37. ©2014 AACR.
IFN-α–Induced Apoptosis in Hepatocellular Carcinoma Involves Promyelocytic Leukemia Protein and TRAIL Independently of p53
Authors: Kerstin Herzer, Thomas G. Hofmann, Andreas Teufel, Christoph C. Schimanski, Markus Moehler, Stephan Kanzler, Henning Schulze-Bergkamen, Peter R. Galle
Journal: Cancer Research (2009)

IFNs are pleiotropic cytokines that have been shown to be important regulators of cell growth. IFN-alpha has recently been recognized to harbor therapeutic potential in prevention and treatment of hepatocellular carcinoma (HCC). However, HCC cells respond differentially to IFN treatment, the mechanism of which is largely unknown. To address this issue, we analyzed the effect of IFN-alpha on different liver tumor cell lines. We found that growth inhibiting effects of IFN-alpha in hepatoma cells require PML-NB induction and, moreover, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on the mRNA and protein level. RNAi silencing of PML down-regulates TRAIL expression in hepatoma cells and correspondingly blocks IFN-alpha-induced apoptosis. In addition, PML-deficient primary hepatocytes fail to up-regulate TRAIL upon IFN-alpha-treatment in contrast to their wild-type counterparts. These data identify TRAIL as a novel downstream transcriptional target of PML-mediated apoptosis in hepatomas and suggest that PML and TRAIL play important roles in IFN-regulated apoptosis in HCC. Furthermore, the mechanism is independent of the p53 status of the tumor cells. In summary, our results identify central molecules mediating IFN-alpha induced apoptosis in liver tumors, shed light on the differential response of hepatoma cells to IFN exposure and, thus, may contribute to an efficient application of this substance in the treatment of liver cancer.
Comorbidity of Attention Deficit Hyperactivity Disorder With Early- and Late-Onset Bipolar Disorder
Authors: Gary S. Sachs, Claudia F. Baldassano, Christine J. Truman, Constance Guille
Journal: American Journal of Psychiatry (2000)

The relationship between attention deficit hyperactivity disorder (ADHD) and earlier age at onset of affective illness was examined in probands with a history of bipolar disorder.The authors assessed 56 adult bipolar subjects. Those with a history of childhood ADHD (N=8) were age and sex matched with bipolar subjects without a history of childhood ADHD (N=8).The age at onset of the first affective episode was lower for the subjects with bipolar disorder and a history of childhood ADHD (mean=12.1 years, SD=4.6) than for those without a history of childhood ADHD (mean=20. 0 years, SD=11.3).ADHD in children of bipolar probands might identify children at highest risk for development of bipolar disorder.
B-type natriuretic peptide adds to clinical judgement in the diagnosis of heart failure: a bayesian analysis from the BNP multinational study
Authors: Peter A. McCullough, Richard M. Nowak, James McCord, Judd E. Hollander, Gabriel Steg, Phillipe Duc, Arne Westheim, Torbjorn Omland, Alan B. Storrow, William T. Abraham, Alan H. Wu, Paul Clopton, Leslie Lenert, Alan S. Maisel
Journal: Journal of the American College of Cardiology (2002)
Real-Time Improvement of Continuous Glucose Monitoring Accuracy
Authors: Andrea Facchinetti, Giovanni Sparacino, Stefania Guerra, Yoeri M. Luijf, J. Hans DeVries, Julia K. Mader, Martin Ellmerer, Carsten Benesch, Lutz Heinemann, Daniela Bruttomesso, Angelo Avogaro, Claudio Cobelli
Journal: Diabetes Care (2012)

Reliability of continuous glucose monitoring (CGM) sensors is key in several applications. In this work we demonstrate that real-time algorithms can render CGM sensors smarter by reducing their uncertainty and inaccuracy and improving their ability to alert for hypo- and hyperglycemic events.The smart CGM (sCGM) sensor concept consists of a commercial CGM sensor whose output enters three software modules, able to work in real time, for denoising, enhancement, and prediction. These three software modules were recently presented in the CGM literature, and here we apply them to the Dexcom SEVEN Plus continuous glucose monitor. We assessed the performance of the sCGM on data collected in two trials, each containing 12 patients with type 1 diabetes.The denoising module improves the smoothness of the CGM time series by an average of ∼57%, the enhancement module reduces the mean absolute relative difference from 15.1 to 10.3%, increases by 12.6% the pairs of values falling in the A-zone of the Clarke error grid, and finally, the prediction module forecasts hypo- and hyperglycemic events an average of 14 min ahead of time.We have introduced and implemented the sCGM sensor concept. Analysis of data from 24 patients demonstrates that incorporation of suitable real-time signal processing algorithms for denoising, enhancement, and prediction can significantly improve the performance of CGM applications. This can be of great clinical impact for hypo- and hyperglycemic alert generation as well in artificial pancreas devices.
Monitoring childhood asthma: Web-based diaries and the asthma control test
Authors: Sandra Voorend-van Bergen, Anja A. Vaessen-Verberne, Anneke M. Landstra, Hein J. Brackel, Norbert J. van den Berg, Daan Caudri, Johan C. de Jongste, Peter J. Merkus, Mariëlle W. Pijnenburg
Journal: Journal of Allergy and Clinical Immunology (2013)
Cost effectiveness of treatment for gastro-oesophageal reflux
Authors: R J F LAHEIJ, J B M J JANSEN, J L SEVERENS, A L M VERBEEK
Journal: Gut (1998)

Editor,—Eggleston et al ( Gut 1998; 42 :13–16) concluded from their observational study that the “step up” approach, starting with a prokinetic or H2 receptor antagonist, represents the most cost effective initial therapeutic strategy for the treatment of patients with a diagnosis of uncomplicated gastro-oesophageal reflux disease (GORD). In studies of the effects of treatments, non-randomised comparisons can be affected by confounding factors1 and in our opinion this has resulted in the wrong conclusions being drawn from this study. Therapeutic interventions are commonly prompted by an indication. Primary care physicians selectively treat patients exhibiting more severe GORD with omeprazole and less severe symptoms …
Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis.
Authors: D M van der Heijde, M A van't Hof, P L van Riel, M A van Leeuwen, M H van Rijswijk, L B van de Putte
Journal: Annals of the Rheumatic Diseases (1992)

There is no agreement as to which variable best mirrors disease activity in rheumatoid arthritis (RA) and no studies have been performed on the validity of disease activity variables. In this study the validity of 10 commonly used single variables and three composite indices was tested. All patients participated in a large follow up study in two clinics. The patients (n = 233) had classical or definite RA and a disease duration of less than one year at entry. The mean follow up time was 30 months; the follow up frequency was once every four weeks; 6011 records were used in the analysis. The validation criteria included correlations with the other variables (correlational validity), with the physical disability (criterion validity I), and with the radiographically determined damage of hands and feet (construct validity). The judgment of a group of rheumatologists in clinical practice was also used as a model of criterion validity (II). In this comparison the disease activity score and Mallya index showed the best validity. The best single variable was the number of swollen joints. The validity of most single variables was poor and these variables were not suitable as single endpoint measures in clinical trials.