tbuckley/cabot-search huggingface dataset:
Identification of a novel microrna-gene circuit in human lupus nephritis: evidence for modulation of kallikrein genes by MIR-422A
Authors: E Krasoudaki, E Stagakis, K Loupasakis, A Papagianni, E Alexopoulos, G Bertsias, D Iliopoulos, D T Boumpas
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> The authors have previously used miRNA analysis in the peripheral blood of patients with SLE to identify novel molecular pathways contributing to immune response deregulation. As disease phenotype results from gene expression changes not only in the immune effector cells but also in the target organs, the authors sought to identify novel genes within the kidney in lupus nephritis. <h3>Materials and methods</h3> The authors isolated RNA from renal biopsy samples of 12 subjects with proliferative or membranous lupus nephritis and five healthy controls. MiRNA expression was analysed by TaqMan Low Density Arrays (TLDA human miRNA v1.0). Two different bioinformatic algorithms (TargetScan, PicTar) were used for the prediction of the gene targets of selected differentially expressed microRNAs. Experimental validation of the miRNA-gene target interaction was performed by luciferase assay and real-time PCR analysis. MicroRNA expression levels were monitored in kidney extracts from 2 months and 6 months lupus-prone (NZB/W F1) mice by real-time PCR. <h3>Results</h3> A 24-microRNA signature defines human lupus nephritis with 9 microRNAs up-regulated and 15 microRNAs down-regulated compared to normal tissue. Among them, miR-422a exhibited the highest up-regulation (17.2-fold) relative to control tissues. Bioinformatic analysis predicted that miR-422a has a binding site in the 39UTR of kallikrein 4 (KLK4) gene. Overexpression of miR-422a suppressed by 65% KLK4 luciferase activity and by 82% KLK4 mRNA levels in 293 cells. In order to monitor miR-422a/KLK4 expression during lupus nephritis progression, the authors used NZB/W F1 lupus prone mice. During early stages (2 months old NZB/W F1 mice) miR-422a was 4.1-fold up-regulated, while KLK4 mRNA levels were 3.4-fold down-regulated while at later stages (6 months) miR-422a was 9.4-fold up-regulated and KLK4 mRNA levels were 7.6-fold down-regulated. Experiments using antagomirs for miR-422 to further define its contribution to nephritis together with the construction of gene networks -by combining peripheral blood and renal microRNA data, are in progress. <h3>Conclusions</h3> The kallikrein family of genes has an important role in regulating inflammation, apoptosis, coagulation and fibrosis in the kidneys. Our data implicate regulation of KLK4 by miR-422a as a key pathogenetic event in lupus nephritis and suggest a potentially protective role of these genes in immune-mediated renal disease.
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles
Authors: David Cunningham, Eliza A Hawkes, Andrew Jack, Wendi Qian, Paul Smith, Paul Mouncey, Christopher Pocock, Kirit M Ardeshna, John A Radford, Andrew McMillan, John Davies, Deborah Turner, Anton Kruger, Peter Johnson, Joanna Gambell, David Linch
Journal: The Lancet (2013)
Clinical course and progression-free survival of adult intracranial and spinal ependymoma patients
Authors: Elizabeth Vera-Bolanos, Kenneth Aldape, Ying Yuan, Jimin Wu, Khalida Wani, Mary Jo Necesito-Reyes, Howard Colman, Girish Dhall, Frank S. Lieberman, Philippe Metellus, Tom Mikkelsen, Antonio Omuro, Sonia Partap, Michael Prados, H. Ian Robins, Riccardo Soffietti, Jing Wu, Mark R. Gilbert, Terri S. Armstrong
Journal: Neuro-Oncology (2014)

Ependymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution. Clinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival. The 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18–80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% (n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location (P < .01), grade III (anaplastic; P < .01), and subtotal resection, followed or not by radiation (P < .01), as significantly increasing risk of early progression. We report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.
NGEP, a Prostate-Specific Plasma Membrane Protein that Promotes the Association of LNCaP Cells
Authors: Sudipto Das, Yoonsoo Hahn, Satoshi Nagata, Mark C. Willingham, Tapan K. Bera, Byungkook Lee, Ira Pastan
Journal: Cancer Research (2007)

Abstract NGEP is a prostate-specific gene identified by analysis of expressed sequence tag databases. RNA analysis revealed two spliced forms of NGEP mRNA: a short form encoding a soluble protein (NGEP-S) and a long form encoding a polytopic membrane protein (NGEP-L). Transient expression of myc epitope–tagged NGEP-L showed that it was localized to the plasma membrane. We have now produced a specific antibody to the COOH terminus of NGEP-L and showed that it detects an ∼100-kDa protein in extracts of normal prostate and prostate cancers that contain high levels of NGEP mRNA. The antibody detects a protein that is highly expressed on the apical and the lateral surfaces of normal prostate and prostate cancer cells by immunohistochemistry. The antibody does not detect a protein in the prostate cancer cell line LNCaP, which has very low NGEP mRNA levels. To study NGEP function, two stable LNCaP cell lines were prepared by transfection with NGEP-L and shown to contain similar amounts of NGEP-L protein as human prostate. Confocal immunofluorescence showed that NGEP-L is present on the plasma membrane of the transfected LNCaP cells and is highly concentrated at cell:cell contact regions. Furthermore, as the cell density increased, the cells formed large aggregates. A specific RNA interference that lowered NGEP-L levels prevented formation of cell aggregates. Our results suggest that NGEP-L has a role in promoting cell contact–dependent interactions of LNCaP prostate cancer cells and also that NGEP is a promising immunotherapy target for prostate cancer. [Cancer Res 2007;67(4):1594–601]
Plasma DNA level in predicting therapeutic efficacy in advanced nonsmall cell lung cancer
Authors: S. Kumar, R. Guleria, V. Singh, A.C. Bharti, A. Mohan, B.C. Das
Journal: European Respiratory Journal (2010)

Assessment of total plasma DNA can be a promising noninvasive tool for monitoring the effect of cytotoxic therapies in order to predict therapeutic efficacy at an early stage. Cell-free plasma DNA levels were quantified before the first, second and third cycle of chemotherapy in 42 patients with advanced nonsmall cell lung cancer and correlated with response to therapy, as assessed by computed tomography following the third chemotherapy cycle. A significantly lower plasma DNA level, measured before various treatment cycles, was found in patients with remission or stable disease than in those with progression. Higher levels and insufficient decrease in plasma DNA levels during the course of chemotherapy indicated poor outcome. For predicting insufficient therapy response, a sensitivity of 26.9% was achieved at 100% specificity using plasma DNA levels before the first therapy cycle. Prediction of disease progression was achieved with a sensitivity of 35.7% at 100% specificity using plasma DNA levels before the first therapy cycle. Monitoring of plasma DNA levels during the course of chemotherapy could identify patients who are likely to exhibit an insufficient therapeutic response and disease progression at an early stage. This may help in individualising treatment, and could lead to better management of advanced-stage lung cancer.
Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of a New AHI-1–BCR-ABL–JAK2 Complex
Authors: Min Chen, Paolo Gallipoli, Donna DeGeer, Ivan Sloma, Donna L. Forrest, Matthew Chan, Damian Lai, Heather Jorgensen, Ashley Ringrose, Hui Mi Wang, Karen Lambie, Helen Nakamoto, Kyi Min Saw, Ali Turhan, Ralph Arlinghaus, James Paul, Jon Stobo, Michael J. Barnett, Allen Eaves, Connie J Eaves, Tessa L. Holyoake, Xiaoyan Jiang
Journal: JNCI Journal of the National Cancer Institute (2013)

Imatinib mesylate (IM) induces clinical remission of chronic myeloid leukemia (CML). The Abelson helper integration site 1 (AHI-1) oncoprotein interacts with BCR-ABL and Janus kinase 2 (JAK2) to mediate IM response of primitive CML cells, but the effect of the interaction complex on the response to ABL and JAK2 inhibitors is unknown. The AHI-1–BCR-ABL–JAK2 interaction complex was analyzed by mutational analysis and coimmunoprecipitation. Roles of the complex in regulation of response or resistance to ABL and JAK2 inhibitors were investigated in BCR-ABL+ cells and primary CML stem/progenitor cells and in immunodeficient NSG mice. All statistical tests were two-sided. The WD40-repeat domain of AHI-1 interacts with BCR-ABL, whereas the N-terminal region interacts with JAK2; loss of these interactions statistically significantly increased the IM sensitivity of CML cells. Disrupting this complex with a combination of IM and an orally bioavailable selective JAK2 inhibitor (TG101209 [TG]) statistically significantly induced death of AHI-1–overexpressing and IM-resistant cells in vitro and enhanced survival of leukemic mice, compared with single agents (combination vs TG alone: 63 vs 53 days, ratio = 0.84, 95% confidence interval [CI] = 0.6 to 1.1, P = .004; vs IM: 57 days, ratio = 0.9, 95% CI = 0.61 to 1.2, P = .003). Combination treatment also statistically significantly enhanced apoptosis of CD34+ leukemic stem/progenitor cells and eliminated their long-term leukemia-initiating activity in NSG mice. Importantly, this approach was effective against treatment-naive CML stem cells from patients who subsequently proved to be resistant to IM therapy. Simultaneously targeting BCR-ABL and JAK2 activities in CML stem/progenitor cells may improve outcomes in patients destined to develop IM resistance.
Sex differences in hip osteoarthritis: results of a longitudinal study in 508 patients
Authors: J F Maillefert
Journal: Annals of the Rheumatic Diseases (2003)

To evaluate sex differences in the clinical and structural presentation, and natural history of hip OA.A multicentre, prospective, longitudinal, five year follow up study of 508 patients (302 women, 206 men, mean age 63 (7) years) with painful hip OA. Data collected were baseline demographics, symptomatic, therapeutic, and structural variables; symptomatic variables and changes in joint space width (JSW) during the first year's follow up; requirement for total hip arthroplasty (THA) between the end of the first and fifth years.evaluation of sex differences (a) at baseline, in the main characteristics of hip OA using multivariate logistic regression; (b) during the first year of follow up, in the radiological progression of the disease; (c) during the five years of follow up, in the requirement for THA using Kaplan-Meier curves and the log rank test, and of the parameters related to THA, using a multivariate Cox analysis.At entry, women presented more frequently than men with polyarticular OA (mean (SD) articular score 306 (162) v 235 (127)), and superomedial migration of the femoral head (40% v 19%), and had more severe symptomatic disease (patient's overall assessment 46 (23) v 40 (26)). The change in JSW did not differ between women and men after one year, but a greater proportion of women had rapid structural progression (OR=2.34, 95% CI 1.1 to 5.2). THA was performed more often in women. Multivariate analysis suggested that the decision to perform surgery was related more closely to the symptomatic and structural severity of the disease than to the sex of the patient.Hip OA in women is more frequently part of a polyarticular OA, and displays greater symptomatic and structural severity.
Hyperdiploidy Is a Common Finding in Monoclonal Gammopathy of Undetermined Significance and Monosomy 13 Is Restricted to These Hyperdiploid Patients
Authors: Maud Brousseau, Xavier Leleu, Jérémie Gerard, Thomas Gastinne, Alban Godon, Franck Genevieve, Mamoun Dib, Jean-Luc Lai, Thierry Facon, Marc Zandecki
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Two pathways, hyperdiploid and nonhyperdiploid, are proposed for progression to plasma cell neoplasia. Implication of monosomy 13 (Δ13) is unclear in monoclonal gammopathy of undetermined significance (MGUS), and data on DNA content of plasma cells [DNA index (DI)] are rare. Experimental Design: We ascertained DI in 169 multiple myeloma (MM) and 96 MGUS patients. Interphase fluorescence in situ hybridization (FISH) coupled to cytoplasmic staining of specific Ig (cIg-FISH) was done to look for trisomies and to ascertain Δ13. Results: Hyperdiploidy and hypodiploidy were found in 54% and 11.5% of MGUS patients and in 59.5% and 25% of MM patients, respectively. In MGUS patients tested using probes for odd chromosomes, cIg-FISH showed association between trisomies for chromosomes 3, 7, 9, 11, or 15 and hyperdiploidy. Δ13 was found in 45.3% and 24.6% of MM and MGUS patients, respectively. Most Δ13 cases observed in MGUS were found within hyperdiploid clones, 38% versus 11% in hypodiploid cases, in sharp contrast with the occurrence of Δ13 in MM patients, 31.9% and 76.3%, respectively. That peculiar distribution of Δ13 according to DI persisted with other thresholds used to ascertain hyperdiploidy, such as DI ≥ 1.05. A strong relationship between IgA peak and hypodiploidy (P = 0.007) was only observed in MM, whereas λ light chain was significantly associated with hypodiploidy in MGUS (P = 0.001) and MM (P = 0.05). Hyperdiploidy shows similar pattern in MGUS and MM. Conclusion: This fits well a hyperdiploid pathway leading to MM after a preceding MGUS stage. Yet-to-be-determined secondary event(s) needs to occur for the transition to MM, unrelated to changes in chromosome number or to loss of chromosome 13. In contrast, the “nonhyperdiploid” pathway needs to be clarified further because hypodiploidy is less common in MGUS than in MM and Δ13 is rare in hypodiploid MGUS patients compared with hypodiploid MM patients.
Skin irritability to sodium lauryl sulfate is associated with increased positive patch test reactions
Authors: J. Schwitulla, J. Brasch, H. Löffler, A. Schnuch, J. Geier, W. Uter
Journal: British Journal of Dermatology (2014)

As previous observations have indicated an inter-relationship between irritant and allergic skin reactions we analysed data of synchronous allergen and sodium lauryl sulfate (SLS) patch tests in terms of a relationship between SLS responsiveness and allergic patch test reactions.To analyse differences in terms of allergen-specific and overall reaction profiles between patients with vs. those without an irritant reaction to SLS.Clinical data of 26 879 patients patch tested from 2008 to 2011 by members of the Information Network of Departments of Dermatology were analysed. After descriptive analyses, including the MOAHLFA index, the positivity ratio and the reaction index, a negative binomial hurdle model was adopted to investigate the correlation between SLS reactivity and positive patch test reactions.Men, patients aged ≥ 40 years and patients with an occupational dermatitis background were over-represented in the SLS-reactive group. Patients with an irritant reaction to SLS showed a higher proportion of weak positive reactions, as well as more questionable and irritant reactions to contact allergens than patients not reactive to SLS. The risk of an additional positive patch test reaction increased by 22% for SLS-reactive patients compared with those who were SLS negative.The marked association between SLS reactivity and the number of positive reactions in patch test patients may be due to nonspecific increased skin reactivity at the moment of patch testing only. However, increased SLS reactivity could also be due to longer-lasting enhanced skin irritability, which may have promoted (poly-)sensitization. Further studies, for example with longitudinal data on patients repeatedly patch tested with SLS and contact allergens, are necessary.
Enhanced Plasmonic Resonance Energy Transfer in Mesoporous Silica-Encased Gold Nanorod for Two-Photon-Activated Photodynamic Therapy
Authors: Nai-Tzu Chen, Kuo-Chun Tang, Ming-Fang Chung, Shih-Hsun Cheng, Ching-Mao Huang, Chia-Hui Chu, Pi-Tai Chou, Jeffrey S. Souris, Chin-Tu Chen, Chung-Yuan Mou, Leu-Wei Lo
Journal: Theranostics (2014)

The unique optical properties of gold nanorods (GNRs) have recently drawn considerable interest from those working in in vivo biomolecular sensing and bioimaging.Especially appealing in these applications is the plasmon-enhanced photoluminescence of GNRs induced by two-photon excitation at infrared wavelengths, owing to the significant penetration depth of infrared light in tissue.Unfortunately, many studies have also shown that often the intensity of pulsed coherent irradiation of GNRs needed results in irreversible deformation of GNRs, greatly reducing their two-photon luminescence (TPL) emission intensity.In this work we report the design, synthesis, and evaluation of mesoporous silica-encased gold nanorods (MS-GNRs) that incorporate photosensitizers (PSs) for two-photon-activated photodynamic therapy (TPA-PDT).The PSs, doped into the nano-channels of the mesoporous silica shell, can be efficiently excited via intra-particle plasmonic resonance energy transfer from the encased two-photon excited gold nanorod and further generates cytotoxic singlet oxygen for cancer eradication.In addition, due to the mechanical support provided by encapsulating mesoporous silica matrix against thermal deformation, the two-photon luminescence stability of GNRs was significantly improved; after 100 seconds of 800 nm repetitive laser pulse with the 30 times higher than average power for imaging acquisition, MS-GNR luminescence intensity exhibited ~260% better resistance to deformation than that of the uncoated gold nanorods.These results strongly suggest that MS-GNRs with embedded PSs might provide a promising photodynamic therapy for the treatment of deeply situated cancers via plasmonic resonance energy transfer.
Host-response biomarkers for diagnosis of late-onset septicemia and necrotizing enterocolitis in preterm infants
Authors: Pak Cheung Ng, Irene Ling Ang, Rossa Wai Kwun Chiu, Karen Li, Hugh Simon Lam, Raymond Pui On Wong, Kit Man Chui, Hon Ming Cheung, Eddy Wing Yin Ng, Tai Fai Fok, Joseph Jao Yiu Sung, Yuk Ming Dennis Lo, Terence Chuen Wai Poon
Journal: Journal of Clinical Investigation (2010)

Preterm infants are highly susceptible to life-threatening infections that are clinically difficult to detect, such as late-onset septicemia and necrotizing enterocolitis (NEC). Here, we used a proteomic approach to identify biomarkers for diagnosis of these devastating conditions. In a case-control study comprising 77 sepsis/NEC and 77 nonsepsis cases (10 in each group being monitored longitudinally), plasma samples collected at clinical presentation were assessed in the biomarker discovery and independent validation phases. We validated the discovered biomarkers in a prospective cohort study with 104 consecutively suspected sepsis/NEC episodes. Proapolipoprotein CII (Pro-apoC2) and a des-arginine variant of serum amyloid A (SAA) were identified as the most promising biomarkers. The ApoSAA score computed from plasma apoC2 and SAA concentrations was effective in identifying sepsis/NEC cases in the case-control and cohort studies. Stratification of infants into different risk categories by the ApoSAA score enabled neonatologists to withhold treatment in 45% and enact early stoppage of antibiotics in 16% of nonsepsis infants. The negative predictive value of this antibiotic policy was 100%. The ApoSAA score could potentially allow early and accurate diagnosis of sepsis/NEC. Upon confirmation by further multicenter trials, the score would facilitate rational prescription of antibiotics and target infants who require urgent treatment.
Dexamethasone: Effects on neointimal hyperplasia and vessel integrity
Authors: J FISCHER
Journal: Cardiovascular Research (2005)

See article by Pires et al. [11] (pages 415–424) in this issue. 

The clinical success of balloon angioplasty is limited by restenosis, which occurs in up to 50% of patients. Lumen compromise and restenosis are caused by acute elastic recoil and late constrictive remodeling and to a lesser degree by neointimal hyperplasia [1,2]. The application of bare metal stents (BMS) has revolutionized percutaneous coronary interventions by reducing the rate of clinical complications and the need for target vessel revascularization. Although BMS mechanically prevent the decrease of total vessel area caused by constrictive remodeling, in-stent restenosis still reduces the clinical success rate of BMS substantially. In contrast to restenosis after balloon angioplasty, after stent implantation restenosis is caused exclusively by ingrowth of a thickened neointima as the result of increased migration and proliferation of vascular smooth muscle cells (SMC) [3,4]. The invasion of inflammatory blood cells with the concomitant release of cytokines and growth factors positively correlates with the degree of in-stent stenosis [5]. In addition to the cellular component of the stent neointima, the accumulation of extracellular matrix (ECM) components such as proteoglycans and collagens has been recognized to be a key factor, since the ECM determines SMC phenotype, thrombogenic properties, and volume expansion [6,7].

Since in-stent restenosis is determined by the extent of neointimal hyperplasia, the application of anti-proliferative, anti-migratory, or anti-inflammatory drugs locally at the target lesion has become an attractive possibility to further enhance the long-term patency of stented vessels. Indeed, the introduction of drug-eluting stents … 

*Tel.: +49 211 81 12513x12500; fax: +49 211 81 14781. Email address: jens.fischer{at}uni-duesseldorf.de