tbuckley/cabot-search huggingface dataset:
Thrombus formation and platelet-vessel wall interaction in the nephrotic syndrome under flow conditions.
Authors: J J Zwaginga, H A Koomans, J J Sixma, T J Rabelink
Journal: Journal of Clinical Investigation (1994)

Increased in vitro platelet aggregability and hypercoagulability are generally held to be main determinants in the prethrombotic state in nephrosis. In vivo, however, thrombotic events depend on the dynamic interaction of flowing blood with the vessel wall. The present study confirms that aggregability of platelets of nephrotic patients is significantly increased by mere stirring or by exogenous stimuli as adenosine diphosphate and arachidonic acid. Moreover, the nephrotic patients have high von Willebrand factor and decreased red blood cell deformability, which normally increase platelet-vessel wall interaction. However, perfusion studies under well-defined flow conditions, in which anticoagulated nephrotic blood was exposed to deendothelialized human umbilical artery segments and sprayed collagen, showed normal platelet adhesion and only a modest increase in the deposition of platelet aggregates. This suggests that some factor counteracts platelet-vessel wall interaction under flow conditions in the nephrotic syndrome. When tissue factor associated with endothelial extracellular matrix (ECM) was allowed to generate thrombin, perfusions with nephrotic blood over this ECM resulted in a strong increase in fibrin generation. The capacity of patient blood to form increased amounts of fibrin appeared strongly correlated with the level of hyperfibrinogenemia. Platelet adhesion as well as aggregation in these experiments was even decreased below control values. This suggests that fibrin coverage may block the direct contact between blood platelets and matrix. We therefore also studied the isolated effect of high fibrinogen on platelet-vessel wall interaction by increasing fibrinogen concentrations in normal blood. Modulation of fibrinogen concentrations in normal blood could mimic all the observations in nephrotic blood: platelet aggregation in suspension increased with increasing concentrations of fibrinogen, while platelet adhesion and aggregate formation under flow conditions decreased. In perfusions over tissue factor-rich matrix, fibrin deposition increased. Therefore, our observations indicate that nephrotic hyperaggregability in suspension is not associated with increased platelet vessel wall-interaction under flow conditions. The latter is probably counteracted by high levels of fibrinogen. Our observations further suggest that hyperfibrinogenemia may be a major thrombotic risk factor in nephrosis by inducing more fibrin depositions.
Genome-wide patterns of carbon and nitrogen regulation of gene expression validate the combined carbon and nitrogen (CN)-signaling hypothesis in plants
Authors: Peter M Palenchar, Andrei Kouranov, Laurence V Lejay, Gloria M Coruzzi
Journal: Genome biology (2004)

Carbon and nitrogen are two signals that influence plant growth and development. It is known that carbon- and nitrogen-signaling pathways influence one another to affect gene expression, but little is known about which genes are regulated by interactions between carbon and nitrogen signaling or the mechanisms by which the different pathways interact. Microarray analysis was used to study global changes in mRNA levels due to carbon and nitrogen in Arabidopsis thaliana. An informatic analysis using InterAct Class enabled us to classify genes on the basis of their responses to carbon or nitrogen treatments. This analysis provides in vivo evidence supporting the hypothesis that plants have a carbon/nitrogen (CN)-sensing/regulatory mechanism, as we have identified over 300 genes whose response to combined CN treatment is different from that expected from expression values due to carbon and nitrogen treatments separately. Metabolism, energy and protein synthesis were found to be significantly affected by interactions between carbon and nitrogen signaling. Identified putative cis-acting regulatory elements involved in mediating CN-responsive gene expression suggest multiple mechanisms for CN responsiveness. One mechanism invokes the existence of a single CN-responsive cis element, while another invokes the existence of cis elements that promote nitrogen-responsive gene expression only when present in combination with a carbon-responsive cis element. This study has allowed us to identify genes and processes regulated by interactions between carbon and nitrogen signaling and take a first step in uncovering how carbon- and nitrogen-signaling pathways interact to regulate transcription.
Season of Birth Modifies the Risk of Food Allergy in Infants with Eczema and Food Sensitization in HealthNuts: a Population-based Study
Authors: P.E. Martin, N.J. Osborne, J.J. Koplin, L.C. Gurrin, M. Wake, M.L. Tang, M.C. Matheson, A.J. Lowe, T. Dang, T. Tan, D. Anderson, M. Sutherland, L. Thiele, L. Miles, A. Ponsonby, S.C. Dharmage, K.J. Allen
Journal: Journal of Allergy and Clinical Immunology (2011)
Detection of YMDD mutant using a novel sensitive method in chronic liver disease type B patients before and during lamivudine treatment
Authors: Toshihiko Kirishima, Takeshi Okanoue, Yukiko Daimon, Yoshito Itoh, Hideki Nakamura, Atsuhiro Morita, Tetsuya Toyama, Masahito Minami
Journal: Journal of Hepatology (2002)
Involvement of oxidative and nitrosative stress in the development of proteolytic pulmonary emphysema
Authors: Manuella Lanzetti, Cristiane Costa, Tatiana Victoni, Renata Nesi, Alan Lopes, Jackson Alves, Vanessa Martins, Angela Resende, Vincent Lagente, Luís Porto, Samuel Valenca
Journal: European Respiratory Journal (2012)

Our aim was to investigate the participation of oxidative stress in elastase-induced pulmonary emphysema. C57BL/6 mice were submitted to pancreatic porcine elastase (PPE) instillation (0.05U or 0.5U) per mouse (i.t.) to induce pulmonary emphysema. A separated group of mice were treated with aminoguanidine 1% (AMG). Lungs were collected on days 7, 14 and 21 after PPE instillation. Control group was sham-injected. We performed BAL, biochemical analyses of oxidative stress, and lung stereology and morphometry. Emphysema was histologically characterized at 21 days after 0.5 U of PPE, presenting increased alveolar linear intercept and volume density of airspaces in comparison with the control group. TNF-α was elevated at 7 and 14 days after PPE 0.5 U, concomitant with reduction in the IL-10 levels at the same time-points. Myeloperoxidase was elevated in all groups treated with 0.5 U of PPE. A contribution of oxidative stress at early stage of emphysema was observed with increased levels of nitrite, malondialdehyde and superoxide dismutase activity at 7 days after PPE 0.5 U. Glutathione peroxidase activity was increased in all groups treated with 0.5 U of PPE. With iNOS inhibition by AMG 1%, emphysema was attenuated. Furthermore, the proteolytic stimulus by PPE enhanced expression of nitrotyrosine and iNOS, while the group PPE+AMG showed low expression of iNOS and nitrotyrosine. PPE stimulus also induced eNOS expression, but AMG reduced it. Our results suggest a pathway of oxidative and nitrosative stress by nitric oxide production via iNOS expression in pulmonary emphysema.
Antibody-Enzyme Conjugates for Cancer Therapy
Authors: R. G. Melton, R. F. Sherwood
Journal: JNCI Journal of the National Cancer Institute (1996)

The use of antibody-enzyme conjugates directed at tumor-associated antigens to achieve site-specific activation of prodrugs to potent cytotoxic species, termed "antibody-directed enzyme prodrug therapy" (ADEPT), has attracted considerable interest since the concept was first described in 1987. Prodrug forms of both clinically used anticancer agents and novel cytotoxic compounds have been developed to take advantage of potential prodrug-generating technology employing a variety of enzymes with widely differing substrate specificities. A particular advantage of the ADEPT approach is that it may allow the use of extremely potent agents such as nitrogen mustards and palytoxin, which are too toxic to be readily used in conventional chemotherapy. Preliminary studies using an antibody-enzyme conjugate constructed with a bacterial enzyme and a murine monoclonal antibody not only have established the value of the ADEPT technique, but also have highlighted the potential problem of immunogenicity of proteins of nonhuman origin. This problem has been tackled in the first instance by the use of immunosuppressive agents, but long-term solutions are being investigated in the development of second-generation ADEPT systems, including the development of human antibody-human enzyme fusion proteins and catalytic antibodies. Such improvements, coupled with further refinement of the prodrug-drug element of the system and the wide variety of antibody-enzyme-drug combinations available, should mean that ADEPT-based approaches will form an important element of the search for the anticancer drugs of the future. [J Natl Cancer Inst 1996;88:153–65]
Guidelines for the management of alopecia areata
Authors: S.P. MacDonald Hull, M.L. Wood, P.E. Hutchinson, M. Sladden, A.G. Messenger
Journal: British Journal of Dermatology (2003)

These guidelines for management of alopecia areata have been prepared for dermatologists on behalf of the British Association of Dermatologists. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
Polysaccharide Krestin Is a Novel TLR2 Agonist that Mediates Inhibition of Tumor Growth via Stimulation of CD8 T Cells and NK Cells
Authors: Hailing Lu, Yi Yang, Ekram Gad, Cynthia A. Wenner, Amy Chang, Emily R. Larson, Yushe Dang, Mark Martzen, Leanna J. Standish, Mary L. Disis
Journal: Clinical Cancer Research (2010)

Polysaccharide krestin (PSK) is a mushroom extract that has been long used in Asia and recently in Western countries as a treatment for cancer due to its presumed immune potentiating effects. Although there have been reports of clinical responses after patients have ingested PSK, the mechanism of action of the agent remains undefined. The current study was undertaken to investigate the mechanism of the antitumor actions of PSK.The immunostimulatory effect of PSK was first evaluated in vitro using splenocytes from neu transgenic mice and Toll-like receptor (TLR) 2 knockout (TLR2(-/-)) mice. Then the immunostimualtory and antitumor effect of PSK was determined using tumor-bearing neu transgenic mice, TLR2(-/-), and wild-type C57BL/6 mice.We demonstrate that PSK is a selective TLR2 agonist, and the activation of dendritic cells (DC) and T cells by PSK is dependent on TLR2. Oral administration of PSK in neu transgenic mice significantly inhibits breast cancer growth. Selective depletion of specific cell populations suggests that the antitumor effect of PSK is dependent on both CD8(+) T cell and NK cells, but not CD4(+) T cells. PSK does not inhibit tumor growth in TLR2(-/-) mice suggesting that the antitumor effect is mediated by TLR2.These results demonstrate that PSK, a natural product commonly used for the treatment of cancer, is a specific TLR2 agonist and has potent antitumor effects via stimulation of both innate and adaptive immune pathways.
THE DETERMINATION OF THE LENGTH OF LIFE OF TRANSFUSED BLOOD CORPUSCLES IN MAN
Authors: Winifred Ashby
Journal: The Journal of Experimental Medicine (1919)

1. It is possible in mixtures of corpuscles of different groups to separate the corpuscles practically quantitatively by treating with a serum that agglutinates the corpuscles of one kind, leaving the others unagglutinated. 2. After a recipient has been transfused with blood of a group other than his own, specimens of his blood treated with a serum that will agglutinate his own corpuscles but not the transfused corpuscles show unagglutinated corpuscles in large numbers. 3. These unagglutinated corpuscles which appear in the recipien's blood after such a transfusion are the transfused corpuscles and their count is a quantitative indicator of the amount of transfused blood still in the recipient's circulation. 4. The life of the transfused corpuscle is long; it has been found to extend for 30 days and more. The beneficial results of transfusion are without doubt not due primarily to a stimulating effect on the bone marrow, but, it is reasonable to assume, to the functioning of the transfused blood corpuscles.
Presence of a Putative Tumor-Initiating Progenitor Cell Population Predicts Poor Prognosis in Smokers with Non–Small Cell Lung Cancer
Authors: Aik T. Ooi, Vei Mah, Derek W. Nickerson, Jennifer L. Gilbert, Vi Luan Ha, Ahmed E. Hegab, Steve Horvath, Mohammad Alavi, Erin L. Maresh, David Chia, Adam C. Gower, Marc E. Lenburg, Avrum Spira, Luisa M. Solis, Ignacio I. Wistuba, Tonya C. Walser, William D. Wallace, Steven M. Dubinett, Lee Goodglick, Brigitte N. Gomperts
Journal: Cancer Research (2010)

Abstract Smoking is the most important known risk factor for the development of lung cancer. Tobacco exposure results in chronic inflammation, tissue injury, and repair. A recent hypothesis argues for a stem/progenitor cell involved in airway epithelial repair that may be a tumor-initiating cell in lung cancer and which may be associated with recurrence and metastasis. We used immunostaining, quantitative real-time PCR, Western blots, and lung cancer tissue microarrays to identify subpopulations of airway epithelial stem/progenitor cells under steady-state conditions, normal repair, aberrant repair with premalignant lesions and lung cancer, and their correlation with injury and prognosis. We identified a population of keratin 14 (K14)–expressing progenitor epithelial cells that was involved in repair after injury. Dysregulated repair resulted in the persistence of K14+ cells in the airway epithelium in potentially premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis, and this predictive value was strongest in smokers, in which it also correlated with metastasis. This suggests that reparative K14+ progenitor cells may be tumor-initiating cells in this subgroup of smokers with NSCLC. Cancer Res; 70(16); 6639–48. ©2010 AACR.
Defining a Gene Promoter Methylation Signature in Sputum for Lung Cancer Risk Assessment
Authors: Shuguang Leng, Kieu Do, Christin M. Yingling, Maria A. Picchi, Holly J. Wolf, Timothy C. Kennedy, William J. Feser, Anna E. Baron, Wilbur A. Franklin, Malcolm V. Brock, James G. Herman, Stephen B. Baylin, Tim Byers, Christine A. Stidley, Steven A. Belinsky
Journal: Clinical Cancer Research (2012)

Abstract Purpose: To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case–control study from the Colorado cohort, and to assess the replication of results from the most promising genes in an independent case–control study of asymptomatic patients with stage I lung cancer from New Mexico. Experimental Design: Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation-specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling. Results: Seventeen genes with ORs of 1.4 to 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (ORs, 3.2–4.2) seen for the PAX5α, GATA5, and SULF2 genes. Receiver operating characteristic (ROC) curves generated from seven-gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel. Conclusions: These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the highest risk smokers for computed tomographic screening for early detection of lung cancer. Clin Cancer Res; 18(12); 3387–95. ©2012 AACR.
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies
Authors: Brian D. Lehmann, Joshua A. Bauer, Xi Chen, Melinda E. Sanders, A. Bapsi Chakravarthy, Yu Shyr, Jennifer A. Pietenpol
Journal: Journal of Clinical Investigation (2011)

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
Low specificity of cytokeratin 20 in the diagnosis of extramammary Paget’s disease
Authors: M.l-C. Wu, J. Guitart
Journal: British Journal of Dermatology (2000)

S ir, Ito et al. 1 recently discussed the utility of cytokeratin 20 (CK20) in evaluating perianal Paget’s disease based on the proposed high specificity of CK20 for gastrointestinal carcinoma. They state that according to Moll et al. 2 the expression of CK20 is confined to normal and carcinomatous gastrointestinal epithelium and that Merkel cells also express CK20. However, review of the literature including the study by Moll et al. 2 shows a wider distribution of CK20. Other normal cells besides gastrointestinal epithelial cells and Merkel cells that significantly express CK20 include urothelial umbrella cells, taste bud cells and thymic reticulum cells. 2 CK20 is expressed in Merkel cell carcinoma 2 and carcinomas of the liver, 3 pancreas, biliary system and alimentary canal. 2 CK20‐positive tumours outside the digestive system include: transitional cell carcinomas, 2 ovarian carcinomas, 2, 4 endometrial carcinomas, 5 Mullerian testicular papillary serous tumours 4 and small cell carcinoma of the salivary gland. 6 Rarely, small cell carcinomas of the lung and cervix; 6 adenocarcinomas of the lung, breast, prostate and paranasal sinuses; 2 and squamous cell carcinomas 2 express CK20. These immunohistochemical findings therefore considerably expand the list of primary tumours that should be sought as the possible underlying cause of CK20‐positive extramammary Paget’s disease. Weak expression of CK20 that escapes detection by immunohistochemistry may be detected by molecular methods. 5
Molecular Pathways: JAK/STAT Pathway: Mutations, Inhibitors, and Resistance
Authors: Alfonso Quintás-Cardama, Srdan Verstovsek
Journal: Clinical Cancer Research (2013)

Aberrant activation of the JAK/STAT pathway has been reported in a variety of disease states, including inflammatory conditions, hematologic malignancies, and solid tumors. For instance, a large proportion of patients with myeloproliferative neoplasms (MPN) carry the acquired gain-of-function JAK2 V617F somatic mutation. This knowledge has dramatically improved our understanding of the pathogenesis of MPNs and has facilitated the development of therapeutics capable of suppressing the constitutive activation of the JAK/STAT pathway, now recognized as a common underlying biologic abnormality in MPNs. Ruxolitinib is an oral JAK1 and JAK2 inhibitor that has recently been approved for the treatment of myelofibrosis and has been tested against other hematologic malignancies. A series of agents with different specificities against different members of the JAK family of proteins is currently undergoing evaluation in clinical trials for patients with MPNs, lymphoma, and solid tumors such as breast or pancreatic cancer. Despite the significant clinical activity exhibited by these agents in myelofibrosis, some patients fail to respond or progress during JAK kinase inhibitor therapy. Recent reports have shed light into the mechanisms of resistance to JAK inhibitor therapy. Several approaches hold promise to overcome such resistance.
Cardiovascular Risk Factors and Retinal Microvascular Signs in an Adult Japanese Population: The Funagata Study
Authors: Ryo Kawasaki, Jie Jin Wang, Elena Rochtchina, Bronwen Taylor, Tien Yin Wong, Makoto Tominaga, Takeo Kato, Makoto Daimon, Toshihide Oizumi, Sumio Kawata, Takamasa Kayama, Hidetoshi Yamashita, Paul Mitchell
Journal: Ophthalmology (2006)
Changes in active and passive smoking in the European Community Respiratory Health Survey
Authors: Christer Janson, N Künzli, R de Marco, S Chinn, D Jarvis, C Svanes, J Heinrich, R Jögi, T Gislason, J Sunyer, U Ackermann-Liebrich, J M Antó, I Cerveri, M Kerhof, B Leynaert, C Luczynska, F Neukirch, P Vermeire, M Wjst, P Burney
Journal: European Respiratory Journal (2006)

The aim of the present investigation was to study changes and determinants for changes in active and passive smoking. The present study included 9,053 adults from 14 countries that participated in the European Community Respiratory Health Survey II. The mean follow-up period was 8.8 yrs. Change in the prevalence of active and passive smoking was expressed as absolute net change (95% confidence interval) standardised to a 10-yr period. Determinants of change were analysed and the results expressed as adjusted hazard risk ratio (HRR) or odds ratio (OR). The prevalence of active smoking declined by 5.9% (5.1–6.8) and exposure to passive smoking in nonsmokers declined by 18.4% (16.8–20.0). Subjects with a lower educational level (HRR: 0.73 (0.54–0.98) and subjects living with a smoker (HRR: 0.45 (0.34–0.59)) or with workplace smoking (HRR: 0.69 (0.50–0.95)) were less likely to quit. Low socio-economic groups were more likely to become exposed (OR: 2.21 (1.61–3.03)) and less likely to cease being exposed to passive smoking (OR: 0.48 (0.37–0.61)). In conclusion, the quitting rate was lower and the risk of exposure to passive smoking higher among subjects with lower socio-economic status. Exposure to other peoples smoking decreased quitting rates and increased the risk of starting to smoke.