tbuckley/cabot-search huggingface dataset:
Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy
Authors: John C. Byrd, John G. Gribben, Bercedis L. Peterson, Michael R. Grever, Gerard Lozanski, David M. Lucas, Ben Lampson, Richard A. Larson, Michael A. Caligiuri, Nyla A. Heerema
Journal: Journal of Clinical Oncology (2005)

Purpose Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig V H mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy. Methods We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712. Results Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig V H mutational status to classify risk, there was no association between complete response rate with either unmutated Ig V H mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig V H unmutated patients as compared with the Ig V H mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk. Conclusion These data demonstrate that high-risk CLL patients characterized by Ig V H unmutated (≥ 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig V H mutational status and interphase cytogenetics on treatment outcome.
Age-related differences in perceived asthma control in childhood: guidelines and reality
Authors: C.E. Kuehni, U. Frey
Journal: European Respiratory Journal (2002)

Current guidelines specify the goals of asthma treatment in children and propose a stepwise approach to achieve them. The authors sought to determine whether these goals were attained in children of different age groups in the community and to assess treatment in those with unsatisfactory asthma control. A cross-sectional postal questionnaire survey was performed in 1998 in all members of the major Swiss parents organisation for childhood asthma. With a response rate of 85%, data from 572 Swiss-German children aged 4–16 yrs with wheeze were analysed. Asthma control was excellent in 18% of the children, satisfactory (only episodic symptoms) in 33%, and unsatisfactory in 49% with disturbed sleep, restricted activities and school absences. When stratified by age, excellent or satisfactory control was attained by 66% of children aged 13–16 yrs, but only by 56%, 44%, and 38% of those aged 10–12, 7–9 and 4–6 yrs, respectively. Although the majority were followed-up by a doctor (95%) and were receiving β 2 -agonists (82%) and inhaled corticosteroids (68%), intensity and duration of treatment were not sufficiently matched to asthma severity. In virtually all children there was scope to improve medical treatment, preventive measures and knowledge of asthma management, with very few if any children with therapy-resistant asthma. Even in children with poor asthma control, 89% of parents were satisfied with the results of treatment. The goals of asthma treatment were attained in one-half of the children, particularly in younger age groups. Although inhaler use was common, detailed assessment showed evidence for undertreatment, especially in the youngest age group, and insufficient adherence to preventive measures. Parental expectations of asthma control, which were lower than those outlined in guidelines, might be an important but underestimated factor in paediatric asthma management.
NAD(P)H Oxidase Mediates TGF-β1–Induced Activation of Kidney Myofibroblasts
Authors: Corry D. Bondi, Nagaraj Manickam, Duck Yoon Lee, Karen Block, Yves Gorin, Hanna E. Abboud, Jeffrey L. Barnes
Journal: Journal of the American Society of Nephrology (2009)

TGF-β1 expression closely associates with activation and conversion of fibroblasts to a myofibroblast phenotype and synthesis of an alternatively spliced cellular fibronectin variant, Fn-ED-A. Reactive oxygen species (ROS), such as superoxide, which is a product of NAD(P)H oxidase, also promote the transition of fibroblasts to myofibroblasts, but whether these two pathways are interrelated is unknown. Here, we examined a role for NAD(P)H oxidase–derived ROS in TGF-β1–induced activation of rat kidney fibroblasts and expression of α-smooth muscle actin (α-SMA) and Fn-ED-A. <i>In vitro</i>, TGF-β1 stimulated formation of abundant stress fibers and increased expression of both α-SMA and Fn-ED-A. In addition, TGF-β1 increased both the activity of NADPH oxidase and expression of Nox2 and Nox4, homologs of the NAD(P)H oxidase family, indicating that this growth factor induces production of ROS. Small interfering RNA targeted against Nox4 markedly inhibited TGF-β1–induced stimulation of NADPH oxidase activity and reduced α-SMA and Fn-ED-A expression. Inhibition of TGF-β1 receptor 1 blocked Smad3 phosphorylation; reduced TGF-β1–enhanced NADPH oxidase activity; and decreased expression of Nox4, α-SMA, and Fn-ED-A. Diphenyleneiodonium, an inhibitor of flavin-containing enzymes such as the Nox oxidases, had no effect on TGF-β1–induced Smad3 but reduced both α-SMA and Fn-ED-A protein expression. The Smad3 inhibitor SIS3 reduced NADPH oxidase activity, Nox4 expression, and blocked α-SMA and Fn-ED-A, indicating that stimulation of myofibroblast activation by ROS is downstream of Smad3. In addition, TGF-β1 stimulated phosphorylation of extracellular signal–regulated kinase (ERK1/2), and this was inhibited by blocking TGF-β1 receptor 1, Smad3, or the Nox oxidases; ERK1/2 activation increased α-SMA and Fn-ED-A. Taken together, these results suggest that TGF-β1–induced conversion of fibroblasts to a myofibroblast phenotype involves a signaling cascade through Smad3, NAD(P)H oxidase, and ERK1/2.
Identification of class II major histocompatibility complex and T cell receptor binding sites in the superantigen toxic shock syndrome toxin 1.
Authors: J M Hurley, R Shimonkevitz, A Hanagan, K Enney, E Boen, S Malmstrom, B L Kotzin, M Matsumura
Journal: The Journal of Experimental Medicine (1995)

Superantigens, in association with class II major histocompatibility complex (MHC) molecules, activate T cells bearing particular beta chain variable domains of the T cell receptor (TCR). Unlike conventional peptide antigens, superantigens bind as intact proteins to TCR and MHC molecules outside their peptide binding sites. To characterize these interactions at the molecular level, random point mutations were generated in the gene encoding toxic shock syndrome toxin 1, a bacterial superantigen associated with toxic shock syndrome. Functionally impaired mutants were identified based on their lack of murine and human T cell stimulatory activities, and experiments analyzing binding to human histocompatibility leukocyte antigen-DR molecules differentiated residues involved in MHC from TCR binding. The results showed that the great majority of mutations are clustered in two distinct regions of the toxic shock syndrome toxin 1 molecule. The class II MHC binding site is located in the hydrophobic region of the NH2-terminal domain, and the TCR binding site is primarily in the major central groove of the COOH-terminal domain. These studies provide insight into the interactions necessary for superantigen-mediated disease in humans.
Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial
Authors: Paolo Verdecchia, Jan A Staessen, Fabio Angeli, Giovanni de Simone, Augusto Achilli, Antonello Ganau, Gianfrancesco Mureddu, Sergio Pede, Aldo P Maggioni, Donata Lucci, Gianpaolo Reboldi
Journal: The Lancet (2009)
Impairment of Store-Operated Ca <sup>2+</sup> Entry in TRPC4 <sup>−/−</sup> Mice Interferes With Increase in Lung Microvascular Permeability
Authors: Chinnaswamy Tiruppathi, Marc Freichel, Stephen M. Vogel, Biman C. Paria, Dolly Mehta, Veit Flockerzi, Asrar B. Malik
Journal: Circulation Research (2002)

We investigated the possibility that the TRPC gene family of putative store-operated Ca 2+ entry channels contributes to the increase in microvascular endothelial permeability by prolonging the rise in intracellular Ca 2+ signaling. Studies were made in wild-type (wt) and TRPC4 knockout (TRPC4 −/− ) mice and lung vascular endothelial cells (LECs) isolated from these animals. RT-PCR showed expression of TRPC1, TRPC3, TRPC4, and TRPC6 mRNA in wt LECs, but TRPC4 mRNA expression was not detected in TRPC4 −/− LECs. We studied the response to thrombin because it is known to increase endothelial permeability by the activation of G protein-coupled proteinase-activated receptor-1 (PAR-1). In wt LECs, thrombin or PAR-1 agonist peptide (TFLLRNPNDK-NH 2 ) resulted in a prolonged Ca 2+ transient secondary to influx of Ca 2+ . Ca 2+ influx activated by thrombin was blocked by La 3+ (1 μmol/L). In TRPC4 −/− LECs, thrombin or TFLLRNPNDK-NH 2 produced a similar initial increase of intracellular Ca 2+ secondary to Ca 2+ store depletion, but Ca 2+ influx induced by these agonists was drastically reduced. The defect in Ca 2+ influx in TRPC4 −/− endothelial cells was associated with lack of thrombin-induced actin-stress fiber formation and a reduced endothelial cell retraction response. In isolated-perfused mouse lungs, the PAR-1 agonist peptide increased microvessel filtration coefficient (K f,c ), a measure of vascular permeability, by a factor of 2.8 in wt and 1.4 in TRPC4 −/− ; La 3+ (1 μmol/L) addition to wt lung perfusate reduced the agonist effect to that observed in TRPC4 −/− . These results show that TRPC4-dependent Ca 2+ entry in mouse LECs is a key determinant of increased microvascular permeability.
Early proliferation of CCR5+ CD38+++ antigen-specific CD4+ Th1 effector cells during primary HIV-1 infection
Authors: John J. Zaunders, Mee Ling Munier, Daniel E. Kaufmann, Susanna Ip, Pat Grey, Don Smith, Tim Ramacciotti, Dick Quan, Robert Finlayson, John Kaldor, Eric S. Rosenberg, Bruce D. Walker, David A. Cooper, Anthony D. Kelleher
Journal: Blood (2005)
Anticancer Effects of Niclosamide in Human Glioblastoma
Authors: Anja Wieland, Daniel Trageser, Sabine Gogolok, Roman Reinartz, Heike Höfer, Mihaela Keller, Anke Leinhaas, Ramona Schelle, Sabine Normann, Lil Klaas, Andreas Waha, Philipp Koch, Rolf Fimmers, Torsten Pietsch, Anthony T. Yachnis, David W. Pincus, Dennis A. Steindler, Oliver Brüstle, Matthias Simon, Martin Glas, Björn Scheffler
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Glioblastoma is a highly malignant, invariably fatal brain tumor for which effective pharmacotherapy remains an unmet medical need. Experimental Design: Screening of a compound library of 160 synthetic and natural toxic substances identified the antihelmintic niclosamide as a previously unrecognized candidate for clinical development. Considering the cellular and interindividual heterogeneity of glioblastoma, a portfolio of short-term expanded primary human glioblastoma cells (pGBM; n = 21), common glioma lines (n = 5), and noncancer human control cells (n = 3) was applied as a discovery platform and for preclinical validation. Pharmacodynamic analysis, study of cell-cycle progression, apoptosis, cell migration, proliferation, and on the frequency of multipotent/self-renewing pGBM cells were conducted in vitro, and orthotopic xenotransplantation was used to confirm anticancer effects in vivo. Results: Niclosamide led to cytostatic, cytotoxic, and antimigratory effects, strongly reduced the frequencies of multipotent/self-renewing cells in vitro, and after exposure significantly diminished the pGBMs' malignant potential in vivo. Mechanism of action analysis revealed that niclosamide simultaneously inhibited intracellular WNT/CTNNB1-, NOTCH-, mTOR-, and NF-κB signaling cascades. Furthermore, combinatorial drug testing established that a heterozygous deletion of the NFKBIA locus in glioblastoma samples could serve as a genomic biomarker for predicting a synergistic activity of niclosamide with temozolomide, the current standard in glioblastoma therapy. Conclusions: Together, our data advocate the use of pGBMs for exploration of compound libraries to reveal unexpected leads, for example, niclosamide that might be suited for further development toward personalized clinical application. Clin Cancer Res; 19(15); 4124–36. ©2013 AACR.
Aberrant Promoter Methylation in Human DAB2 Interactive Protein (<b> <i>hDAB2IP</i> </b>) Gene in Breast Cancer
Authors: Hideaki Dote, Shinichi Toyooka, Kazunori Tsukuda, Masaaki Yano, Mamoru Ouchida, Hiroyoshi Doihara, Makoto Suzuki, Hong Chen, Jer-Tsong Hsieh, Adi F. Gazdar, Nobuyoshi Shimizu
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumor suppressor gene inactivated by methylation in prostate cancer. We analyzed methylation and expression status of hDAB2IP in breast cancer. Experimental Design: The promoter region of hDAB2IP was divided into two regions (m2a and m2b) following our previous report on prostate cancer, and methylation status was determined in breast cancer cell lines with bisulfited DNA sequencing. Expression was semiquantified with real-time reverse transcription-PCR to find that aberrant methylation showed the inverse relationship with expression. On the basis of sequence data, we developed methylation-specific PCR for m2a and m2b regions and applied to samples. Results: Aberrant methylation was detected in 11 of 25 breast cancer cell lines (44%) and 15 of 39 primary tumors (38%) at the m2a region and in 12 of 25 cell lines (48%) and 13 of 39 tumors (33%) at the m2b region. In addition, gene expression was restored in methylated cell lines with 5-aza-2′-deoxycytidine, confirming that methylation caused gene down-regulation. We also examined the relationship between hDAB2IP methylation and clinicopathologic features in primary tumors and found that methylation in the m2b region was associated with progressive nodal status of tumors. Conclusions: We developed methylation-specific PCR for hDAB2IP and examined its methylation status in breast cancer. Our results demonstrate that hDAB2IP methylation frequently is present in breast cancer and plays a key role in hDAB2IP inactivation, suggesting the relationship between hDAB2IP methylation and lymph node metastasis of breast cancer.
Early Loss of Thrombomodulin Expression Impairs Vein Graft Thromboresistance
Authors: Antony Y. Kim, Peter L. Walinsky, Frank D. Kolodgie, Ce Bian, Jason L. Sperry, Clayton B. Deming, Eric A. Peck, Jay G. Shake, Gregory B. Ang, Richard H. Sohn, Charles T. Esmon, Renu Virmani, R. Scott Stuart, Jeffrey J. Rade
Journal: Circulation Research (2002)

Thrombosis is the major cause of early vein graft failure. Our aim was to determine whether alterations in the expression of the anticoagulant proteins, thrombomodulin (TM) and the endothelial cell protein C receptor (EPCR), impair endothelial thromboresistance that may contribute to vein graft failure. Immunohistochemical staining of autologous rabbit vein graft sections revealed that the expression of TM, but not EPCR, was reduced significantly early after graft implantation. Western blot analysis revealed that TM expression was reduced by &gt;95% during the first 2 weeks after implantation, with gradual but incomplete recovery by 42 days. This resulted in up to a 95% reduction in the capacity of the grafts to activate protein C and was associated with an increase in bound thrombin activity, which peaked on day 7 at 28.7±3.8 mU/cm 2 and remained elevated for more than 14 days. Restoration of TM expression using adenovirus vector-mediated gene transfer significantly enhanced the capacity of grafts to activate protein C and reduced bound thrombin activity on day 7 to levels comparable to that of normal veins (5.7±0.4 versus 5.2±1.1 mU/cm 2 , respectively, P =0.74). Surprisingly, neointima formation was not affected by this inhibition of local thrombin activity. These data suggest that the early loss of TM expression significantly impairs vein graft thromboresistance and results in enhanced local thrombin generation. Although enhanced local thrombin generation may predispose to early vein graft failure due to thrombosis, it does not seem to contribute significantly to late vein graft failure due to neointimal hyperplasia.
Updated Evidence-Based Treatment Algorithm in Pulmonary Arterial Hypertension
Authors: Robyn J. Barst, J. Simon R. Gibbs, Hossein A. Ghofrani, Marius M. Hoeper, Vallerie V. McLaughlin, Lewis J. Rubin, Olivier Sitbon, Victor F. Tapson, Nazzareno Galiè
Journal: Journal of the American College of Cardiology (2009)
Gene expression and metabolite profiling of Populus euphratica growing in the Negev desert.
Authors: Mikael Brosché, Basia Vinocur, Edward R Alatalo, Airi Lamminmäki, Thomas Teichmann, Eric A Ottow, Dimitar Djilianov, Dany Afif, Marie-Béatrice Bogeat-Triboulot, Arie Altman, Andrea Polle, Erwin Dreyer, Stephen Rudd, Lars Paulin, Petri Auvinen, Jaakko Kangasjärvi
Journal: Genome biology (2005)

Abstract Background Plants growing in their natural habitat represent a valuable resource for elucidating mechanisms of acclimation to environmental constraints. Populus euphratica is a salt-tolerant tree species growing in saline semi-arid areas. To identify genes involved in abiotic stress responses under natural conditions we constructed several normalized and subtracted cDNA libraries from control, stress-exposed and desert-grown P. euphratica trees. In addition, we identified several metabolites in desert-grown P. euphratica trees. Results About 14,000 expressed sequence tag (EST) sequences were obtained with a good representation of genes putatively involved in resistance and tolerance to salt and other abiotic stresses. A P. euphratica DNA microarray with a uni-gene set of ESTs representing approximately 6,340 different genes was constructed. The microarray was used to study gene expression in adult P. euphratica trees growing in the desert canyon of Ein Avdat in Israel. In parallel, 22 selected metabolites were profiled in the same trees. Conclusion Of the obtained ESTs, 98% were found in the sequenced P. trichocarpa genome and 74% in other Populus EST collections. This implies that the P. euphratica genome does not contain different genes per se , but that regulation of gene expression might be different and that P. euphratica expresses a different set of genes that contribute to adaptation to saline growth conditions. Also, all of the five measured amino acids show increased levels in trees growing in the more saline soil.
New Delhi Metallo-beta-lactamase around the world: An eReview using Google Maps
Authors: M Berrazeg, S M Diene, L Medjahed, P Parola, M Drissi, D Raoult, J M Rolain
Journal: Eurosurveillance (2014)

Gram-negative carbapenem-resistant bacteria, in particular those producing New Delhi Metallo-beta-lactamase-1 (NDM-1), are a major global health problem. To inform the scientific and medical community in real time about worldwide dissemination of isolates of NDM-1-producing bacteria, we used the PubMed database to review all available publications from the first description in 2009 up to 31 December 2012, and created a regularly updated worldwide dissemination map using a web-based mapping application. We retrieved 33 reviews, and 136 case reports describing 950 isolates of NDM-1-producing bacteria. Klebsiella pneumoniae (n= 359) and Escherichia coli (n=268) were the most commonly reported bacteria producing NDM-1 enzyme. Several case reports of infections due to imported NDM-1 producing bacteria have been reported in a number of countries, including the United Kingdom, Italy, and Oman. In most cases (132/153, 86.3%), patients had connections with the Indian subcontinent or Balkan countries. Those infected were originally from these areas, had either spent time and/or been hospitalised there, or were potentially linked to other patients who had been hospitalised in these regions. By using Google Maps, we were able to trace spread of NDM-1-producing bacteria. We strongly encourage epidemiologists to use these types of interactive tools for surveillance purposes and use the information to prevent the spread and outbreaks of such bacteria.
Association between low density lipoprotein and rheumatoid arthritis genetic factors with low density lipoprotein levels in rheumatoid arthritis and non-rheumatoid arthritis controls
Authors: Katherine P Liao, Dorothée Diogo, Jing Cui, Tianxi Cai, Yukinori Okada, Vivian S Gainer, Shawn N Murphy, Namrata Gupta, Daniel Mirel, Ashwin N Ananthakrishnan, Peter Szolovits, Stanley Y Shaw, Soumya Raychaudhuri, Susanne Churchill, Isaac Kohane, Elizabeth W Karlson, Robert M Plenge
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives:</h3> To describe the association between diabetes numeracy and diabetes self-management among Saudi adults with insulin-treated diabetes. <h3>Methods:</h3> From August 2018 to January 2019, a cross-sectional study was conducted in 3 diabetes centers in Riyadh, Buraydah, and Jeddah, Saudi Arabia. Systematic random sampling was used to include 290 Saudi adults with insulin-treated diabetes. The levels of diabetes numeracy and diabetes self-management were measured by using the Diabetes Numeracy Test tool (DNT-15) and Diabetes Self-Management Questionnaire tool (DSMQ). <h3>Results:</h3> The final analysis included 279 completed surveys. The mean total score of DSMQ was 6.47. The total DSMQ score was higher among patients who had a lower level of education (<i>p</i>=0.02), and patients who had a higher level of diabetes knowledge (<i>p</i>=0.01). The mean total score of DNT-15 was 41.3%. Patients who had lower diabetes numeracy scores tended to be younger, married, have fewer years of education, have a lower monthly income(<i>p</i>&lt;0.001), use insulin only, and have type 1 diabetes. Patients who achieved a total score of 82%, and higher in DNT-15 have also achieved the highest score in DSMQ (<i>p</i>=0.17). A linear regression analysis adjusted for level of education, diabetes knowledge, and other variables found a modest association between low diabetes numeracy and low diabetes self-management (<i>p</i>=0.08). <h3>Conclusion:</h3> Lower level of diabetes numeracy was associated with lower level of diabetes self-management.
The Nature of So-Called 'Parasites' of the Skin
Authors: W. T. Fox
Journal: BMJ (1864)

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