tbuckley/cabot-search huggingface dataset:
Standardised assessment of membrane proteinase 3 expression. Analysis in ANCA-associated vasculitis and controls
Authors: A. P van Rossum, M. G Huitema, C. A Stegeman, M. Bijl, K. de Leeuw, M. A Van Leeuwen, P. C Limburg, C. G M Kallenberg
Journal: Annals of the Rheumatic Diseases (2007)

Increased numbers of neutrophils expressing proteinase 3 on their membrane (mPR3) have been reported in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and are suggested to be involved in AAV immunopathogenesis. In most studies, neutrophils were analysed for mPR3 expression without priming with TNFalpha, suggesting that mPR3 expression on neutrophils is dependent on other priming events, such as isolation procedures . These priming events can be variable. Therefore, we analysed mPR3 expression on neutrophils before and after priming with TNFalpha to assess whether standardised assessment of mPR3 expression requires priming. Using neutrophils before and after priming with TNFalpha, we assessed percentages of mPR3(+) neutrophils in patients with AAV and in disease and healthy controls.Neutrophils from patients with PR3-AAV and MPO-AAV, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and from healthy controls were analysed before and after priming with TNFalpha for mPR3 expression.42% of all individuals analysed showed minimal expression for mPR3 on all neutrophils before priming with TNFalpha, whereas after priming a clear mPR3(+) subset was observed next to mPR3(-) neutrophils, corresponding to bimodal mPR3 expression. In patients with PR3-AAV or MPO-AAV, the percentage of mPR3(+) neutrophils after priming with TNFalpha was significantly increased (p<0.01 and p<0.05, respectively) compared with healthy controls. Percentages of mPR3(+) PMN were also increased in patients with SLE (p<0.01) but not in RA.Standardised assessment of proteinase 3 on the membrane of neutrophils requires priming with TNFalpha. Percentages of mPR3(+) PMN are increased in AAV and SLE, but not in RA.
The Interleukin-2 Receptor γ Chain: Its Role in the Multiple Cytokine Receptor Complexes and T Cell Development in XSCID
Authors: Kazuo Sugamura, Hironobu Asao, Motonari Kondo, Nobuyuki Tanaka, Naoto Ishii, Kazuyuki Ohbo, Masataka Nakamura, Toshikazu Takeshita
Journal: Annual Review of Immunology (1996)

Interleukin 2 (IL-2), a T cell–derived cytokine, targets a variety of cells to induce their growth, differentiation, and functional activation. IL-2 inserts signals into the cells through IL-2 receptors expressed on cell surfaces to induce such actions. In humans, the functional IL-2 receptor consists of the subunit complexes of the α, β, and γ chains, or the β and γ chains. The third component, the γ chain, of IL-2 receptor plays a pivotal role in formation of the full-fledged IL-2 receptor; together with the β chain, the γ chain participates in increasing the IL-2 binding affinity and intracellular signal transduction. Moreover, the cytokine receptors for at least IL-2, IL-4, IL-7, IL-9, and IL-15 utilize the same γ chain as an essential subunit. Interestingly, mutations of the γ chain gene cause human X-linked severe combined immunodeficiency (XSCID) characterized by a complete or profound T cell defect. Among the cytokines sharing the γ chain, at least IL-7 is essentially involved in early T cell development in the mouse organ culture system. The molecular identification of the γ chain brought a grasp of the structures and functions of the cytokine receptor and an in-depth understanding of the cause of human XSCID. To investigate the mechanism of XSCID and development of gene therapy for XSCID, knockout mice for the γ chain gene were produced that showed similar but not exactly the same phenotypes as human XSCID.
A role for IRF3-dependent RXRα repression in hepatotoxicity associated with viral infections
Authors: Edward K. Chow, Antonio Castrillo, Arash Shahangian, Liming Pei, Ryan M. O'Connell, Robert L. Modlin, Peter Tontonoz, Genhong Cheng
Journal: The Journal of Experimental Medicine (2006)

Viral infections and antiviral responses have been linked to several metabolic diseases, including Reye's syndrome, which is aspirin-induced hepatotoxicity in the context of a viral infection. We identify an interferon regulatory factor 3 (IRF3)–dependent but type I interferon–independent pathway that strongly inhibits the expression of retinoid X receptor α (RXRα) and suppresses the induction of its downstream target genes, including those involved in hepatic detoxification. Activation of IRF3 by viral infection in vivo greatly enhances bile acid– and aspirin-induced hepatotoxicity. Our results provide a critical link between the innate immune response and host metabolism, identifying IRF3-mediated down-regulation of RXRα as a molecular mechanism for pathogen-associated metabolic diseases.
Chromosomal Instability and Copy Number Alterations in Barrett's Esophagus and Esophageal Adenocarcinoma
Authors: Thomas G. Paulson, Carlo C. Maley, Xiaohong Li, Hongzhe Li, Carissa A. Sanchez, Dennis L. Chao, Robert D. Odze, Thomas L. Vaughan, Patricia L. Blount, Brian J. Reid
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Chromosomal instability, as assessed by many techniques, including DNA content aneuploidy, loss of heterozygosity, and comparative genomic hybridization, has consistently been reported to be common in cancer and rare in normal tissues. Recently, a panel of chromosome instability biomarkers, including loss of heterozygosity and DNA content, has been reported to identify patients at high and low risk of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA), but required multiple platforms for implementation. Although chromosomal instability involving amplifications and deletions of chromosome regions have been observed in nearly all cancers, copy number alterations (CNA) in premalignant tissues have not been well characterized or evaluated in cohort studies as biomarkers of cancer risk. Experimental Design: We examined CNAs in 98 patients having either BE or EA using Bacterial Artificial Chromosome (BAC) array comparative genomic hybridization to characterize CNAs at different stages of progression ranging from early BE to advanced EA. Results: CNAs were rare in early stages (less than high-grade dysplasia) but were progressively more frequent and larger in later stages (high-grade dysplasia and EA), including high-level amplifications. The number of CNAs correlated highly with DNA content aneuploidy. Patients whose biopsies contained CNAs involving &amp;gt;70 Mbp were at increased risk of progression to DNA content abnormalities or EA (hazards ratio, 4.9; 95% confidence interval, 1.6-14.8; P = 0.0047), and the risk increased as more of the genome was affected. Conclusions: Genome-wide analysis of CNAs provides a common platform for the evaluation of chromosome instability for cancer risk assessment as well as for the identification of common regions of alteration that can be further studied for biomarker discovery.
Clotting linked to a memory maker
Authors: Hema Bashyam
Journal: The Journal of Experimental Medicine (2008)

![Graphic][1] 

Mice injected with glutamate receptor–blocking drugs (left) form fewer clots (spots). A chemical that boosts our ability to learn and remember also boosts blood clotting, say Morrell et al. (page 

[575][2]).

The learning chemical, glutamate, is released at neuronal
Activation of p53 in Cervical Cancer Cells by Human Papillomavirus E6 RNA Interference Is Transient, but Can Be Sustained by Inhibiting Endogenous Nuclear Export–Dependent p53 Antagonists
Authors: Riku Koivusalo, Antoine Mialon, Hanna Pitkänen, Jukka Westermarck, Sakari Hietanen
Journal: Cancer Research (2006)

Abstract p53 is degraded in cervical cancer cells by the human papillomavirus E6 and can be stabilized with short interfering RNA (siRNA) molecules targeting E6 mRNA. In this in vitro study, we show that E6 siRNA–induced p53 activation is transient in HeLa cervical cancer cells despite continuous suppression of E6 mRNA; activation can be sustained if the endogenous p53 antagonists COP1, MDM2, Pirh2, and c-Jun-NH2-kinase are also targeted by siRNAs or by inhibiting the nuclear export of p53 with leptomycin B. The direct targeting of any one of these four cellular p53 antagonists had no effect on p53 activity when E6 was intact, but inhibited the fading off of E6 siRNA–induced p53 activation in nonstress conditions. The effect was additive when multiple cellular antagonists were concomitantly inhibited, indicating that all these proteins degrade p53 when E6 is inactivated. The antiproliferative effect induced by E6 silencing was enhanced when the endogenous p53 antagonists were additionally targeted. In conclusion, if human papillomavirus E6 is inhibited under nonstress conditions, the subsequent p53 activation is quickly reversed by the endogenous p53 degenerative machinery. The present results indicate that several cellular p53 antagonists must be inhibited for sustained p53 activity if E6 siRNA therapy is attempted and if no combined genotoxic therapy is applied. (Cancer Res 2006; 66(24): 11817-24)
Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300).
Authors: A Rötig, V Cormier, P Chatelain, R Francois, J M Saudubray, P Rustin, A Munnich
Journal: Journal of Clinical Investigation (1993)

The Wolfram syndrome (MIM 222300) is a disease of unknown origin consisting of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Here we report on a generalized deficiency of the mitochondrial respiratory enzyme activities in skeletal muscle and lymphocyte homogenate of a girl suffering from the Wolfram syndrome. In addition, we provide evidence for a 7.6-kilobase pair heteroplasmic deletion (spanning nucleotides 6465-14135) of the mitochondrial DNA in the two tissues and show that directly repeated sequences (11 bp) were present in the wild-type mitochondrial genome at the boundaries of the deletion. Neither of the patient's parents was found to bear rearranged molecules. This study supports the view that a respiratory chain defect can present with insulin-dependent diabetes mellitus as the onset symptom. It also suggests that a defect of oxidative phosphorylation should be considered when investigating other cases of Wolfram syndrome, especially because this syndrome fulfills the criteria for a genetic defect of the mitochondrial energy supply: (a) an unexplained association of symptoms (b) with early onset and rapidly progressive course, (c) involving seemingly unrelated organs and tissues.
The responses of multiple cytokines following incubation of whole blood from TB patients, latently infected individuals, and controls with the TB antigens ESAT-6, CFP-10, and TB7.7
Authors: Sae Byol Kim, Song Yee Kim, Moo Suk Park, Yong Sam Kim, Se Kyu Kim, Joon Chang, Hye Jon Lee, Sang-Nae Cho, Young Ae Kang
Journal: European Respiratory Journal (2012)

Purpose : The development of clinically relevant biomarkers is important for diagnosing latent tuberculosis infection (LTBI) and active tuberculosis (TB) and predicting their prognoses. This study examined whether the responses of multiple cytokines can be used as a biomarker to distinguish the TB infection status and mycobacterial load.

Methods : We analyzed the responses of multiple cytokines (IFN-γ, IL-2, IL-10, IL-13, IL-17, and TNF-α) in the supernatant from the QuantiFERON- TB Gold In-Tube assay following stimulation of whole-blood from TB group (n = 32), LTBI group (n = 19), and healthy controls (n = 30) with TB antigens (ESAT-6, CFP-10, and TB7.7).

Results : The median responses of IFN-γ, IL-2, IL-10, and IL-13 were higher in the LTBI and active TB groups than in the non-TB control group (IFN-γ, p < 0.001; IL-2, p < 0.001; IL-10, p = 0.012; IL-13, p < 0.001). The median IL-2/IFN-γ ratio of the LTBI group was higher than that of the active TB group (p = 0.014) and differed significantly among LTBI, smear-negative TB, and smear-positive TB patients (p = 0.027). This difference was especially evident between the LTBI and smear-positive TB patients (p = 0.047).

Conclusions : IFN-γ, IL-2, IL-10, and IL-13 can serve as biomarkers for distinguishing TB infection. In addition, the IL-2/IFN-γ ratio appears to be a biomarker for diagnosing LTBI and may be useful as a prognostic factor and for evaluating treatment responses.
Predictive Value of Plasma Hepatocyte Growth Factor/Scatter Factor Levels in Patients with Clinically Localized Prostate Cancer
Authors: Amit Gupta, Pierre I. Karakiewicz, Claus G. Roehrborn, Yair Lotan, Alexandre R. Zlotta, Shahrokh F. Shariat
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine that is involved in cancer growth, motility, invasion, and angiogenesis. We assessed whether preoperative plasma levels of HGF can enhance the accuracy of standard models for predicting pathologic features and clinical outcomes. Experimental Design: The study comprised 421 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma. HGF/SF was measured using a commercially available immunoassay. Multivariate logistic regression was used to assess the relationship between plasma HGF/SF and pathologic features. Multivariate Cox regression was used to predict disease recurrence. One thousand bootstrap replicates were created for internal validation and predictive accuracies were estimated for each model. Results: Plasma HGF/SF levels were significantly elevated in patients with lymph node and/or seminal vesicle invasion (P &amp;lt; 0.0001 and P = 0.007, respectively). Preoperative plasma HGF/SF level was an independent predictor of lymph node invasion [odds ratio (OR) for every 100 pg/mL increase in HGF/SF, 1.82; 95% confidence interval (95% CI), 1.33-2.49] and seminal vesicle invasion (OR, 1.18; 95% CI, 1.06-1.3). Addition of HGF/SF increased the accuracy of a base model that included standard preoperative variables for prediction of lymph node invasion by 6.7% (predictive accuracy, 98.4%). HGF/SF also independently predicted disease recurrence after surgery (hazard ratio, 1.07; 95% CI, 1.0-1.15). Conclusions: Preoperative plasma level of HGF/SF is an independent predictor of prostate cancer metastasis to lymph nodes and disease recurrence after surgery. Use of HGF may help in therapeutic decision-making and enrollment into clinical trials.
Author's response to ‘Complete (EBUS and EUS) endosonographic staging of lung cancer’
Authors: Bin Hwangbo, Hyo Jae Kang
Journal: Thorax (2014)

s response to 'Complete (EBUS and EUS) endosonographic staging of lung cancer'We thank Dr Annema 1 for his thoughtful comments on our article published online in Thorax. 2 We observed a significant diagnostic benefit from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) following endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the mediastinal staging of potentially operable lung cancer.We believe that our finding is based on differences in EBUS-TBNA and EUS-FNA accessibility to the mediastinum.Additional benefits of EBUS-TBNA in the EUS-centred group were mainly obtained from targeting inaccessible nodes by EUS (2R or 4R).Subcarinal nodes are generally accessible by EUS; however, some parts may not be covered by EUS.Among four metastatic subcarinal nodes diagnosed only by EBUS in the EUS-centred group, the right sides of the subcarinal nodes were not well visualised by EUS in three cases (figure 1).In one patient, performing EUS-FNA on subcarinal nodes was difficult due to a haematoma that developed following the sampling of the 4 L nodes.Of the four cases, two cases were counted as having benefited from EBUS-TBNA in 'detecting' mediastinal metastasis.In the two other cases, metastases of the other nodes were diagnosed by EUS.As Dr Annema commented 1 , we missed three metastatic subcarinal nodes by endoscopic staging.We believe that this false-negative result is because these nodes had very small metastatic foci.Surgery identified microscopic metastatic foci in two cases (2.2 and 0.8 mm, respectively).In the third case, the size of the subcarinal node was 14×42 mm on chest CT scans; however, three metastatic foci diagnosed by surgery were relatively small (5.5, 2 and 2 mm).Two aspirations by each method missed these foci.To miss small metastatic foci is a limitation of endoscopic staging. 3 4 Secondary procedures were added for inaccessible locations or areas difficult to access by the first procedure.In the EBUS-centred group, common targets of EUS-FNA were nodal stations 4 L and 7. 2 However, large areas of the nodes were already covered by EBUS-TBNA, the mean aspiration number by EUS per target was 1.6 and the procedure time was short.The higher aspiration number by the first procedure in the EBUS-centred group compared with the EUS-centred group (mean 8.1 vs 4.1) 2 is due to a higher accessibility to the mediastinum by EBUS. 5 The number of nodal stations sampled by the first procedure was higher in the EBUS-centred group (mean 3.0 vs 1.9). 2 The number of aspirations per nodal station by the first procedure was slightly higher in the EBUS-centred group (2.7 (8.1/3.0)vs 2.2 (4.1/1.9)).This may be explained by the fact that larger areas are covered by EBUS-TBNA.Station 4R nodes were aspirated 2.9 times on average by EBUS-TBNA in order to cover the anterior-tracheal and right paratracheal
Alveolar haemorrhage as a presenting feature of myeloma
Authors: E Russi, B Odermatt, HI Joller-Jemelka, MA Spycher
Journal: European Respiratory Journal (1993)

An immunoglobulin A (IgA)-paraprotein secreting myeloma was found to be the underlying disease in a patient who presented with alveolar haemorrhage. The diffuse pulmonary bleeding stopped after initiation of treatment consisting of corticosteroids and melphalan. A paraprotein mediated lesion of the alveolar capillary membrane was suspected but could not be demonstrated.
Deleting the TGF-β Receptor Attenuates Acute Proximal Tubule Injury
Authors: Leslie Gewin, Sangeetha Vadivelu, Surekha Neelisetty, Manakan B. Srichai, Paisit Paueksakon, Ambra Pozzi, Raymond C. Harris, Roy Zent
Journal: Journal of the American Society of Nephrology (2012)

TGF-β is a profibrotic growth factor in CKD, but its role in modulating the kidney's response to AKI is not well understood. The proximal tubule epithelial cell, which is the main cellular target of AKI, expresses high levels of both TGF-β and its receptors. To determine how TGF-β signaling in this tubular segment affects the response to AKI, we selectively deleted the TGF-β type II receptor in the proximal tubules of mice. This deletion attenuated renal impairment and reduced tubular apoptosis in mercuric chloride–induced injury. In vitro, deficiency of the TGF-β type II receptor protected proximal tubule epithelial cells from hydrogen peroxide–induced apoptosis, which was mediated in part by Smad-dependent signaling. Taken together, these results suggest that TGF-β signaling in the proximal tubule has a detrimental effect on the response to AKI as a result of its proapoptotic effects.
Relationship between neuroendocrine features and prognostic parameters in human prostate adenocarcinoma
Authors: E. Bollito, A. Berruti, M. Bellina, A. Mosca, E. Leonardo, R. Tarabuzzi, S. Cappia, M. Mari, M. Tampellini, D. Fontana, L. Gubetta, A. Angeli, L. Dogliotti
Journal: Annals of Oncology (2001)
Relevance of animal models for chronic bacterial airway infections in humans.
Authors: T O'Reilly
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Animal models of chronic bacterial airway infections are limited in relevance to human infection, not only because of limitations present in all animal models (e.g., abnormal sequence of pathologic events, artificial imposition of infection involving large inocula, dissimilar host pharmacokinetic attributes), but especially because underlying disease (chronic obstructive pulmonary disease, or COPD) is usually absent. A major problem in establishing chronic lung infection models is the rapid clearance of bacteria instilled into the drugs; this can be overcome by encasing bacteria into agar beads to restrict phagocytosis. Despite these limitations, animal models based upon agar bead-encased inocula have provided persistent infections resulting in lung pathology and high humoral immune responses similar to that observed in patients with COPD. Such models have illuminated some aspects of the virulence of the bacteria, the involvement of bacterial exoenzymes in promoting lung damage, the potential of vaccination to restrict infectious exacerbations, and the activity of subminimal inhibitory concentrations of antibiotics in reducing lung damage by inhibiting exoenzyme release. Animal models have also shown that anti-inflammatory therapy may be effective in reducing inflammation-associated lung damage. Despite the limitations of chronic lung infection models, they may provide insight into pathologic events and positive therapeutic intervention for lung infections of patients with COPD.
Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs
Authors: J. Bousquet, H.J. Schünemann, B. Samolinski, P. Demoly, C.E. Baena-Cagnani, C. Bachert, S. Bonini, L.P. Boulet, P.J. Bousquet, J.L. Brozek, G.W. Canonica, T.B. Casale, A.A. Cruz, W.J. Fokkens, J.A. Fonseca, R. Gerth van Wijk, L. Grouse, T. Haahtela, N. Khaltaev, P. Kuna, R.F. Lockey, K.C. Lodrup Carlsen, J. Mullol, R. Naclerio, R.E. O'Hehir, K. Ohta, S. Palkonen, N.G. Papadopoulos, G. Passalacqua, R. Pawankar, D. Price, D. Ryan, F.E.R. Simons, A. Togias, D. Williams, A. Yorgancioglu, O.M. Yusuf, W. Aberer, M. Adachi, I. Agache, N. Aït-Khaled, C.A. Akdis, A. Andrianarisoa, I. Annesi-Maesano, I.J. Ansotegui, I. Baiardini, E.D. Bateman, A. Bedbrook, B. Beghé, M. Beji, E.H. Bel, A. Ben Kheder, K.S. Bennoor, K.C. Bergmann, F. Berrissoul, T. Bieber, C. Bindslev Jensen, M.S. Blaiss, A.L. Boner, J. Bouchard, F. Braido, C.E. Brightling, A. Bush, F. Caballero, M.A. Calderon, M.A. Calvo, P.A.M. Camargos, L.R. Caraballo, K.H. Carlsen, W. Carr, A.M. Cepeda, A. Cesario, N.H. Chavannes, Y.Z. Chen, A.M. Chiriac, T. Chivato Pérez, E. Chkhartishvili, G. Ciprandi, D.J. Costa, L. Cox, A. Custovic, R. Dahl, U. Darsow, F. De Blay, D. Deleanu, J.A. Denburg, P. Devillier, T. Didi, D. Dokic, W.K. Dolen, H. Douagui, R. Dubakiene, S.R. Durham, M.S. Dykewicz, Y. El-Gamal, A. El-Meziane, R. Emuzyte, A. Fiocchi, M. Fletcher, T. Fukuda, A. Gamkrelidze, J.E. Gereda, S. González Diaz, M. Gotua, M.A. Guzmán, P.W. Hellings, B. Hellquist-Dahl, F. Horak, J.O'B. Hourihane, P. Howarth, M. Humbert, J.C. Ivancevich, C. Jackson, J. Just, O. Kalayci, M.A. Kaliner, A.F. Kalyoncu, T. Keil, P.K. Keith, G. Khayat, Y.Y. Kim, B. Koffi N'Goran, G.H. Koppelman, M.L. Kowalski, I. Kull, V. Kvedariene, D. Larenas-Linnemann, L.T. Le, C. Lemière, J. Li, P. Lieberman, B. Lipworth, B. Mahboub, M.J. Makela, F. Martin, G.D. Marshall, F.D. Martinez, M.R. Masjedi, M. Maurer, S. Mavale-Manuel, A. Mazon, E. Melen, E.O. Meltzer, N.H. Mendez, H. Merk, F. Mihaltan, Y. Mohammad, M. Morais-Almeida, A. Muraro, S. Nafti, L. Namazova-Baranova, K. Nekam, A. Neou, B. Niggemann, E. Nizankowska-Mogilnicka, T.D. Nyembue, Y. Okamoto, K. Okubo, M.P. Orru, S. Ouedraogo, C. Ozdemir, P. Panzner, I. Pali-Schöll, H.S. Park, B. Pigearias, W. Pohl, T.A. Popov, D.S. Postma, P. Potter, K.F. Rabe, J. Ratomaharo, S. Reitamo, J. Ring, R. Roberts, B. Rogala, A. Romano, M. Roman Rodriguez, J. Rosado-Pinto, L. Rosenwasser, M. Rottem, M. Sanchez-Borges, G.K. Scadding, P. Schmid-Grendelmeier, A. Sheikh, J.C. Sisul, D. Solé, T. Sooronbaev, V. Spicak, O. Spranger, R.T. Stein, S.W. Stoloff, J. Sunyer, A. Szczeklik, A. Todo-Bom, E. Toskala, Y. Tremblay, R. Valenta, A.L. Valero, D. Valeyre, A. Valiulis, E. Valovirta, P. Van Cauwenberge, O. Vandenplas, C. van Weel, P. Vichyanond, G. Viegi, D.Y. Wang, M. Wickman, S. Wöhrl, J. Wright, B.P. Yawn, P.K. Yiallouros, H.J. Zar, M.E. Zernotti, N. Zhong, M. Zidarn, T. Zuberbier
Journal: Journal of Allergy and Clinical Immunology (2012)