tbuckley/cabot-search huggingface dataset:
A human tumor necrosis factor (TNF) alpha mutant that binds exclusively to the p55 TNF receptor produces toxicity in the baboon.
Authors: K J Van Zee, S A Stackpole, W J Montegut, M A Rogy, S E Calvano, K C Hsu, M Chao, C L Meschter, H Loetscher, D Stüber
Journal: The Journal of Experimental Medicine (1994)

A number of recent studies have demonstrated that cellular responses to tumor necrosis factor (TNF) mediated by the p55 and the p75 TNF receptors are distinct. To evaluate the relative in vivo toxicities of wild-type TNF alpha (wtTNF alpha) and a novel p55 TNF selective receptor agonist, healthy, anesthetized baboons (Papio sp.) were infused with a near-lethal dose of either wtTNF alpha or a TNF alpha double mutant (dmTNF alpha) that binds specifically to the p55, but not to the p75, TNF receptor. Both wtTNF alpha and dmTNF alpha produced comparable acute hypotension, tachycardia, increased plasma lactate, and organ dysfunction in Papio. However, administration of wtTNF alpha produced a marked granulocytosis and loss of granulocyte TNF receptors, whereas little if any changes in neutrophil number or cell surface TNF receptor density were seen after dmTNF alpha mutant administration. Infusion of dmTNF alpha resulted in a plasma endogenous TNF alpha response that peaked after 90-120 min. We conclude that selective p55 TNF receptor activation is associated with early hemodynamic changes and the autocrine release of endogenous TNF alpha. Significant systemic toxicity results from p55 TNF receptor activation, but the role of the p75 TNF receptor in systemic TNF toxicity requires further study.
A1.7 Interferon and B-Cell Gene Signatures Contribute to Diagnosis of Pre-Clinical Rheumatoid Arthritis
Authors: Joyce Lubbers, Lotte A van de Stadt, Saskia Vosslamber, John G Wesseling, Senay Oztürk, Dirkjan van Schaardenburg, Cornelis L Verweij
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background/Objective</h3> Early diagnosis of the preclinical phase of rheumatoid arthritis (pre-RA) allows timely start of treatment with the potential to prevent disease progression. It is known that antibodies against citrullinated proteins (ACPA) and rheumatoid factor (RF) have diagnostic value to identify pre-RA. However, since only 20–40% of ACPA<sup>+</sup>/RF<sup>+</sup> arthralgia patients develop arthritis within 5 years, better prognostic markers are needed. Recently, we demonstrated involvement of interferon (IFN) response and B-cell gene signatures in pre-RA. The objective is to demonstrate the value of these signatures to diagnose pre-RA. <h3>Methods</h3> Peripheral blood (Paxgene) was collected from 115 ACPA<sup>+</sup>/RF<sup>+</sup> arthralgia patients who were clinically followed for arthritis development, one or more swollen joints, with a mean follow-up time of 23 months (IQR 12–30). An IFN and B-cell score was calculated based on 7 Type I IFN response genes and 3 B-cell related genes, respectively, measured by multiplex qPCR. Cox regression analysis and Receiver Operating Characteristic (ROC)-curve analysis were used to demonstrate prognostic and diagnostic significance. <h3>Results</h3> Out of 115 arthralgia patients 44 developed arthritis after a median time of 8 months (IQR 5–13). Stratification of these individuals based on the IFN score revealed that 60% of the IFN<sup>high</sup> patients converted to arthritis compared to 32% in IFN<sup>low</sup> patients (P = 0.011). For the B-cell signature, 58% in B-cell<sup>low</sup> patients developed arthritis, compared to 33% of B-cell<sup>high</sup> patients (P = 0.020). Combined analysis revealed a significant high risk for arthritis development in IFN<sup>high</sup>/B-cell<sup>low</sup> patients (80%, hazard ratio (HR) 6.22, P = 0.003) and a low risk for IFN<sup>low</sup>/B-cell<sup>high</sup> patients (26%, HR 0.16, P = 0.003). To demonstrate clinical utility a ROC-curve was constructed of ACPA<sup>+</sup>/RF<sup>+</sup> alone and in combination with both signatures. The area under the curve reached 0.619 (P = 0.032, CI 0.514–0.724) for ACPA<sup>+</sup>/RF<sup>+</sup> and increased to 0.803 (P = 0.0001, CI 0.718–0.888) with IFN and B-cell signatures included. The sensitivity to diagnose pre-RA increased from 16% to 52% when both signatures are included, with a cut-off of 94% specificity. <h3>Conclusions</h3> These findings demonstrate the clinical value of IFN and B-cell gene signatures as biomarkers for the diagnosis of pre-RA. This research was supported by the Center for Translational Molecular Medicine (CTMM) consortium "TRACER".
Does breast milk unleash gonadotropins?
Authors: Elizabeth Rasche González
Journal: JAMA (1980)

Hormones continue to crop up in unexpected places. The detection of these powerful substances far from their presumed sites of origin is raising heretofore undreamed-of questions: How do catechol estrogens in the brain interact with biogenic amines, and could this interaction be implicated in the pathogenesis of disorders ranging from premenstrual tension to psychosis? What business do neurotransmitters have in the gastrointestinal tract? Is extrapancreatic insulin actually synthesized outside the pancreas (<i>JAMA</i>[MEDICAL NEWS] 242:1345, 1979), and if so, why? One of the "far-flung" hormones now under study is luteinizing hormone-releasing hormone (LH-RH), formerly thought to originate only in the hypothalamus and to act only on the anterior pituitary where it induces the production and release of these gonadotropins: LH, follicle-stimulating hormone (FSH), and human chorionic gonadotropin (HCG). This year, G. S. Khodr, MD, and T. M. Siler-Khodr, MD, of the Department of Obstetrics and Gynecology, University of Texas Health
Keratins of the human occipital hair medulla: androgenic regulation of<i>in vitro</i>hair keratin K37 expression
Authors: H. Yoshida, H. Taguchi, T. Kitahara, Y. Takema, M.O. Visscher, J. Schweizer, L. Langbein
Journal: British Journal of Dermatology (2013)

Journal Article Keratins of the human occipital hair medulla: androgenic regulation of in vitro hair keratin K37 expression Get access H. Yoshida, H. Yoshida Biological Science Laboratories Kao Corporation 2606 Akabane Ichikai‐Machi Haga‐Gun Tochigi 321‐3497 Japan Search for other works by this author on: Oxford Academic Google Scholar H. Taguchi, H. Taguchi Biological Science Laboratories Kao Corporation 2606 Akabane Ichikai‐Machi Haga‐Gun Tochigi 321‐3497 Japan Search for other works by this author on: Oxford Academic Google Scholar T. Kitahara, T. Kitahara Biological Science Laboratories Kao Corporation 2606 Akabane Ichikai‐Machi Haga‐Gun Tochigi 321‐3497 Japan Search for other works by this author on: Oxford Academic Google Scholar Y. Takema, Y. Takema Biological Science Laboratories Kao Corporation 2606 Akabane Ichikai‐Machi Haga‐Gun Tochigi 321‐3497 Japan Search for other works by this author on: Oxford Academic Google Scholar M.O. Visscher, M.O. Visscher The Skin Sciences Institute Cincinnati Children's Hospital Medical Center Cincinnati OH U.S.A Search for other works by this author on: Oxford Academic Google Scholar J. Schweizer, J. Schweizer German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany Search for other works by this author on: Oxford Academic Google Scholar L. Langbein L. Langbein Department of Genetics of Skin Carcinogenesis A110 Im Neuenheimer Feld 280 69120 Heidelberg Germany Correspondence: Lutz Langbein. E‐mail: Langbein@dkfz.de Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 169, Issue 1, 1 July 2013, Pages 218–221, https://doi.org/10.1111/bjd.12278 Published: 01 July 2013
cGMP Signals Modulate cAMP Levels in a Compartment-Specific Manner to Regulate Catecholamine-Dependent Signaling in Cardiac Myocytes
Authors: Alessandra Stangherlin, Frank Gesellchen, Anna Zoccarato, Anna Terrin, Laura Ashley Fields, Marco Berrera, Nicoletta Concetta Surdo, Margaret Anne Craig, Godfrey Smith, Graham Hamilton, Manuela Zaccolo
Journal: Circulation Research (2011)

cAMP and cGMP are intracellular second messengers involved in heart pathophysiology. cGMP can potentially affect cAMP signals via cGMP-regulated phosphodiesterases (PDEs).To study the effect of cGMP signals on the local cAMP response to catecholamines in specific subcellular compartments.We used real-time FRET imaging of living rat ventriculocytes expressing targeted cAMP and cGMP biosensors to detect cyclic nucleotides levels in specific locales. We found that the compartmentalized, but not the global, cAMP response to isoproterenol is profoundly affected by cGMP signals. The effect of cGMP is to increase cAMP levels in the compartment where the protein kinase (PK)A-RI isoforms reside but to decrease cAMP in the compartment where the PKA-RII isoforms reside. These opposing effects are determined by the cGMP-regulated PDEs, namely PDE2 and PDE3, with the local activity of these PDEs being critically important. The cGMP-mediated modulation of cAMP also affects the phosphorylation of PKA targets and myocyte contractility.cGMP signals exert opposing effects on local cAMP levels via different PDEs the activity of which is exerted in spatially distinct subcellular domains. Inhibition of PDE2 selectively abolishes the negative effects of cGMP on cAMP and may have therapeutic potential.
Early neonatal mortality, asphyxia related deaths, and timing of low risk births in Hesse, Germany, 1990-8: observational study
Authors: G. Heller
Journal: BMJ (2000)

coronary artery disease in men.This may partly explain differences between individuals in the development of coronary artery disease.Of the three other polymorphisms in this gene, the most extensively studied, intronic PvuII polymorphism, showed no association with coronary artery stenosis as measured by angiography. 5 Although the biochemical evidence is presently lacking, we speculate that carriers of the long repeat variants have lower expression of the oestrogen receptor gene and benefit less from the cardiovascular protective effect of oestrogen receptors.We thank Outi Lumme and Mervi Niittylahti for their skilful technical assistance, Seppo Tyynelä for planimetric measurements, and Markus Perola for DNA isolation.
JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders
Authors: Isabelle Plo, Mayuka Nakatake, Laurent Malivert, Jean-Pierre de Villartay, Stéphane Giraudier, Jean-Luc Villeval, Lisa Wiesmuller, William Vainchenker
Journal: Blood (2008)
EFFECTS OF ANTICELLULAR SERUM ON PHAGOCYTOSIS AND THE UPTAKE OF TRITIATED THYMIDINE AND URIDINE BY HELA CELLS
Authors: Francis J. Carey, Nobuko O. Kuhn, Carl G. Harford
Journal: The Journal of Experimental Medicine (1965)

Anticellular serum inhibited phagocytosis of colloidal gold and staphylococci by HeLa cells. This inhibition of phagocytosis was reversed by conditions which allowed the antibody to elute from the cell. Concentrations of antiserum that inhibited phagocytosis did not interfere with the transport of tritiated thymidine and uridine across the cell membrane, and their incorporation into cell nucleic acids was unaltered as evaluated by autoradiography. These results indicate that thymidine and uridine were taken into cells independently of phagocytosis. Morphologic changes induced in the cells by antibody suggest that the antibody agglutinates adjacent portions of the cell membrane. This agglutination of the cell membrane by antibody would be expected to interfere with the continuous evagination and invagination of the cell membrane associated with phagocytosis. The inhibition of virus infection by anticellular antibody may be a result of the effect of the antiserum upon phagocytosis.
Vitamin D and Calcium Intake in Relation to Type 2 Diabetes in Women
Authors: Anastassios G. Pittas, Bess Dawson-Hughes, Tricia Li, Rob M. Van Dam, Walter C. Willett, Joann E. Manson, Frank B. Hu
Journal: Diabetes Care (2006)

OBJECTIVE—The purpose of this study was to prospectively examine the association between vitamin D and calcium intake and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS—In the Nurses’ Health Study, we followed 83,779 women who had no history of diabetes, cardiovascular disease, or cancer at baseline for the development of type 2 diabetes. Vitamin D and calcium intake from diet and supplements was assessed every 2–4 years. During 20 years of follow-up, we documented 4,843 incident cases of type 2 diabetes. RESULTS—After adjusting for multiple potential confounders, there was no association between total vitamin D intake and type 2 diabetes. However, the relative risk (RR) of type 2 diabetes was 0.87 (95% CI 0.75–1.00; P for trend = 0.04) comparing the highest with the lowest category of vitamin D intake from supplements. The multivariate RRs of type 2 diabetes were 0.79 (0.70–0.90; P for trend &amp;lt;0.001) comparing the highest with the lowest category of calcium intake from all sources and 0.82 (0.72–0.92; P for trend &amp;lt;0.001) comparing the highest with the lowest category of calcium intake from supplements. A combined daily intake of &amp;gt;1,200 mg calcium and &amp;gt;800 IU vitamin D was associated with a 33% lower risk of type 2 diabetes with RR of 0.67 (0.49–0.90) compared with an intake of &amp;lt;600 mg and 400 IU calcium and vitamin D, respectively. CONCLUSIONS— The results of this large prospective study suggest a potential beneficial role for both vitamin D and calcium intake in reducing the risk of type 2 diabetes.
Cigarette smoke extract (CSE) alters the secretion profile of the Pseudomonas aeruginosa strain PA14
Authors: Naseem Mushtaq, Richard Waite, Joe Aduse-Opoku, Jonathan Grigg
Journal: European Respiratory Journal (2012)

Background: In North America, a major cause of morbidity and mortality is due to chronic obstructive pulmonary disease (COPD), an emerging epidemic that requires a better understanding of the pathobiology of the disease1. The single most important factor in the development of COPD is cigarette smoke; where the mechanisms and pathogenesis of the disease remain unclear. The airways of COPD patients are colonized with potential pathogens, including Pseudomonas aeruginosa (Ps)2. However, the effect of cigarette smoke on the cellular physiology of Ps is not known. Since Ps utilizes a variety of secreted virulence factors during infection, we sought to assess whether CSE affects protein secretion in the Ps strain PA14.  Methods: An overnight growth of Ps strain PA14 (Ps) was inoculated into cell culture media 1) Ps only 2) Ps +0.1% CSE 3) Ps+0.5% CSE and 4) Ps+1% CSE and harvested (OD 0.8). The cultures were then filter sterilised and the proteins precipitated by acetone; culture secreted profiles were then determined by SDS-PAGE.  Results: CSE increased the production of low molecular weight proteins in a dose dependent manner by the virulent Ps strain PA14 when stimulated with 0.1, 0.5 and 1% CSE as observed on an acrylamide gel.  Conclusion: We have shown that CSE causes a significant physiological response in PA14 by up-regulating the production of it9s secreted proteins. Enhanced production of these proteins can potentially cause severe damage to the upper and lower airways of smokers which can therefore influence the development of progressive COPD.  1. Yoshida T et al. Physiol Rev. 2007 Jul;87(3):1047-82.  2. Laan M et al. J Immunol. 2004 Sep 15;173(6):4164-70.
Characterization and species distribution of high affinity GTP-coupled receptors for human rantes and monocyte chemoattractant protein 1.
Authors: G Van Riper, S Siciliano, P A Fischer, R Meurer, M S Springer, H Rosen
Journal: The Journal of Experimental Medicine (1993)

Equilibrium binding studies with recombinant human chemoattractant cytokines Rantes and monocyte chemoattractant protein 1 (MCP-1) on monocytic THP-1 cells have allowed the functional identification of two distinct receptors for C-C chemokines. One is a novel oligospecific receptor with high affinity for Rantes (50% maximal inhibitory concentration [IC50], 0.68 nM) and low affinity (IC50, 35 nM) for MCP-1, while the other is the previously described specific receptor for MCP-1 (IC50, 0.5 nM). Receptor affinity for Rantes is enhanced on preparation of isolated membranes with a 12-fold decrease in receptor Kd. The basis of this enhancement is not understood. The Rantes receptor appears to be G protein linked, as binding activity is abolished by guanosine 5'-O-(3-thiotriphosphate) (IC50, 7.3 nM). In contrast to the consequences of MCP-1 binding, we were unable to demonstrate ligand-dependent calcium fluxes on binding of Rantes to human monocytes or THP-1 cells. The binding of Rantes and MCP-1 to mononuclear cells from dog, rabbit, and rat were tested. While high affinity binding could be demonstrated in dog and rabbit, differences in ligand-induced Ca2+ fluxes could be shown between species. This suggests that receptor-ligand interactions and receptor coupling is best examined with autologous receptors and cytokine.
The Pathology of Mesotheliomata and an Analysis of their Association with Asbestos Exposure
Authors: D. OB. Hourihane
Journal: Thorax (1964)

Primary tumours of serosal membranes are un- common and their diagnosis is difficult.Several authorities deny that they are more than rare curiosities (Willis, 1960;Smart and Hinson, 1957).The pathology of pleural tumours was defined by Klemperer and Rabin (1931), and their general division into localized (usually fibrous) and diffuse (usually epithelial) tumours still obtains.Since
P201 Rituximab as rescue therapy in interstitial lung disease refractory to conventional immunosuppression
Authors: RR Abdullah, D Ming, GJ Keir, TM Maher, AU Wells, EA Renzoni
Journal: Thorax (2013)

<h3>Background</h3> Rituximab, a B cell-depleting monoclonal antibody, may offer an effective rescue therapy in a subgroup of patients with severe interstitial lung disease (ILD), progressing despite conventional immunosuppression. <h3>Methods</h3> Retrospective assessment of 50 patients with severe, progressive ILD treated with rituximab between 2010 and 2012. This included 33 with connective tissue disease-associated ILD (CTD-ILD), 6 with fibrotic hypersensitivity pneumonitis, 3 with likely drug-induced ILD, 2 with desquamative interstitial pneumonia (DIP) and the rest with miscellaneous ILD patterns, excluding idiopathic pulmonary fibrosis. At the time of rituximab treatment, mean FVC was 49.1% ( + 17.6) and DLco 25.5% ( + 9.9). Four patients were mechanically ventilated. Prior to rituximab, all patients except one had received immunosuppressive treatment, including IV cyclophosphamide in 44 patients. Change in pulmonary function tests, as compared to pre-rituximab levels, was assessed at six to twelve months post-treatment and analysed by Wilcoxon signed rank test. Categorical trends (improvement, stability, deterioration) before and after treatment were defined using either ≥10% change in forced vital capacity (FVC) or ≥15% change in diffusing capacity for carbon monoxide (DLco) as threshold values. <h3>Results</h3> In the six to twelve months following rituximab treatment, a median improvement in FVC of 5.7% (p &lt; 0.01) and stability of DLco (p &lt; 0.01) was observed. This was in contrast to a median decline in FVC and DLco of 14.6% and 18.8% respectively, in the six to twelve months prior to rituximab therapy (p &lt; 0.01). Patients with CTD-ILD were most represented in this cohort and were more likely to improve or stabilise following Rituximab (28/33), than those with non CTD-related ILD (8/17) (p = 0.008, Fisher exact test). However, of the four patients requiring invasive ventilation, improvement to extubation was observed in three patients with non CTD-ILD (one DIP, one acute interstitial pneumonia, one unclassifiable ILD). Two patients developed serious infections (pneumonia) requiring hospitalisation following rituximab, and ten patients died, all from progression of underlying ILD, a median of 5.1 months after treatment. <h3>Conclusions</h3> Rituximab may offer a safe and effective therapeutic intervention in a subgroup of patients with severe, progressive ILD unresponsive to conventional immunosuppression. Future prospective, controlled trials are warranted to validate these findings.
Exercise Single-Photon Emission Computed Tomography Provides Effective Risk Stratification of Elderly Men and Elderly Women
Authors: Uma S. Valeti, Todd D. Miller, David O. Hodge, Raymond J. Gibbons
Journal: Circulation (2005)

Background— In a recent study, we reported that the Duke treadmill score was unable to effectively stratify elderly patients according to risk. The purpose of this study was to evaluate the prognostic value of exercise single-photon emission computed tomography (SPECT) in this same population and to examine results by gender. Methods and Results— A cohort of 247 elderly (age ≥75 years) patients (108 women, 139 men, age 77±3 years) who underwent exercise thallium-201 SPECT were followed up for a median duration of 6.4 years. SPECT variables were significantly associated with cardiac death: summed stress score (SSS) χ 2 =19.5, P &lt;0.001; summed difference score χ 2 =12.3, P &lt;0.001; increased lung uptake χ 2 =9.6, P =0.002; and left ventricular enlargement χ 2 =8.3, P =0.004. The Duke score was not significantly associated with cardiac death (χ 2 &lt;1, P =NS). The SSS classified most patients as low risk (49%) or high risk (35%); the Duke score classified the majority (68%) as intermediate risk. Annual cardiac mortality rates for patients categorized by SSS as low risk and high risk were 0.8% and 5.8%, respectively. Cardiac survival rates according to SSS risk categories were significantly different for both women ( P =0.012) and men ( P =0.003). Conclusions— SPECT classified most elderly patients into clinically useful low- and high-risk categories and accurately predicted outcomes in both genders. If these results can be validated in future studies, exercise SPECT rather than standard treadmill testing may emerge as the initial noninvasive testing strategy in elderly patients who are able to exercise.