tbuckley/cabot-search huggingface dataset:
Soluble Notch ligand and receptor peptides act antagonistically during angiogenesis
Authors: Ralph Klose, Caroline Berger, Iris Moll, M. Gordian Adam, Frank Schwarz, Kerstin Mohr, Hellmut G. Augustin, Andreas Fischer
Journal: Cardiovascular Research (2015)

Notch signalling is essential for blood vessel formation. During angiogenesis, the Notch ligand DLL4 on the leading tip cell activates Notch receptors on the adjacent stalk cells. DLL4-Notch signalling is impaired by the Notch ligand JAG1 in endothelial cells. The Delta/Serrate/Lag2 (DSL) domain of the Notch ligands binds to the EGF-like repeats 11–13 of the Notch receptor. This study aimed to elucidate how soluble proteins containing these short domains interfere with Notch signalling during angiogenesis. Adenoviral vectors were generated to express the DSL domains of DLL1, DLL4, JAG1, and the Notch1 EGF-like repeats 11–13 fused to immunoglobulin-G heavy chain. These soluble ligand peptides inhibited Notch signalling in endothelial cells and this caused hyperbranching in cellular angiogenesis assays and in the neonatal mouse retina. The soluble Notch receptor peptides bound stronger to JAG1 than DLL4 ligands, resulting in increased signalling activity. This led to impaired tip cell formation and less vessel sprouting in the retina. The minimal binding domains of Notch ligands are sufficient to interfere with Notch signalling. The corresponding soluble Notch1 EGF11-13 peptide binds stronger to inhibitory Notch ligands and thereby promotes Notch signalling in endothelial cells.
The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells
Authors: J MARTINEZGONZALEZ, L BADIMON
Journal: Cardiovascular Research (2004)

The molecular mechanisms regulating endothelial cell activation and vascular smooth muscle cell proliferation are critical in the pathological processes underlying atherosclerosis. Numerous growth factors and cytokines trigger the complex and redundant signaling pathways that regulate cell cycle entry; however, the genes controlling these processes are not fully known. Applying techniques for differential gene expression analysis, new transcription factors have been identified in these mechanisms, among them the three members of the NR4A subfamily of nuclear receptors (NRs). These transcription factors (NOR-1, Nur77 and Nurr1) are products of immediate–early genes whose expression and activity is regulated in a cell-specific manner by a variety of extracellular mitogenic, apoptotic and differentiation stimuli. Unlike most NRs whose transcriptional activity is regulated by direct modulatory ligands, NR4A genes do not appear to require ligand binding for activation, and in vascular cells they are highly responsive to growth factors, cytokines, lipoproteins and thrombin. In this review, we discuss our present knowledge on the role of this subfamily of NRs in vascular cell function.
The efficacy of pirfenidone in scleroderma related interstitial lung disease
Authors: Yukiko Miura, Yoshiya Tsunoda, Toru Tanaka, Hiroyuki Takoi, Yohei Yatagai, Shigen Rin, Akimasa Sekine, Kenji Hayashihara, Takefumi Saito, Akihiko Gemma, Arata Azuma
Journal: European Respiratory Journal (2012)

Introduction: The major cause of death in Systemic Sclerosis (SSc) is interstitial lung disease, and cyclophosphamide is an only agent which significantly demonstrated a beneficial effect on lung function in patients with scleroderma-related interstitial lung disease (SSc-ILD), however the effect was quite modest, and it is necessary to identify a reasonable alternative.  Objectives: TGF-beta1 plays a critical role in the pathophysiology of pulmonary fibrogenesis. Pirfenidone exerts its antifibrotic effect through regulation of lung TGF-beta1 levels. This raises the possibility that agents targeting TGF-beta1 may be beneficial for SSc-ILD.  Methods: We administered pirfenidone to 3 patients with SSc-ILD and evaluated pulmonary function.  Results:  Case 1 is a 62 year-old female. Vital capacity (VC) improved by pirfenidone. The change rate was +27.3% (+0.51L) for 5 months.  Case2 is a 75 year-old female. VC improved remarkably, at the change rate of +44.4% (+0.32L) for 25 months.  Case 3 is a 66 year-old female. VC improved at the rate of +8.3% (+0.17L) for 26 months.  Conclusion: All of 3 patients with SSc-ILD demonstrated the favorable efficacy of VC by pirfenidone without severe adverse events. The previous studies documented that deteriorating lung function was associated with increased mortality in SSc-ILD. Therefore, it is necessary to identify and treat early stages of patients with SSc-ILD for the prevention of pulmonary function impairment. Pirfenidone exerts its antifibrotic effect through regulation of TGF-beta1, which is one of the important inducers of fibrogenesis in SSc. We suggest pirfenidone may be a possible option for SSc-ILD.
Synthetic peroxides as antimalarials
Authors: Yuanqing Tang, Yuxiang Dong, Jonathan L. Vennerstrom
Journal: Medicinal Research Reviews (2004)

Abstract The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half‐lives and must be administered over a period of 5–7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4‐trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable “drug‐like” physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 4, 425–448, 2004
Redox‐Mediated Angiogenesis in the Hypoxic Joint of Inflammatory Arthritis
Authors: Monika Biniecka, Mary Connolly, Wei Gao, Chin T. Ng, Emese Balogh, Martina Gogarty, Lelani Santos, Evelyn Murphy, David Brayden, Douglas J. Veale, Ursula Fearon
Journal: Arthritis & Rheumatology (2014)

Objective Inflammatory arthritis is associated with joint inflammation, synovial tissue proliferation, and degradation of articular cartilage and bone. Angiogenesis is an early and fundamental component of synovial inflammation. Oxygen metabolism is recognized as an important mediator of joint vascular remodeling. The aim of this study was to determine whether in vivo synovial hypoxia (tissue P O 2 [tP O 2 ]) and tumor necrosis factor (TNF) blocking therapy alter synovial vascular expression of NADPH oxidase (NOX) and how this action regulates angiogenic mechanisms. Methods NOX‐2 protein and messenger RNA expression was examined in patients with inflammatory arthritis before and after receiving TNF inhibitor (TNFi) therapy and in mice with collagen‐induced arthritis (CIA). Proangiogenic processes were assessed in human microvascular endothelial cells (HMVECs) following culture with NOX‐2 activators (TNFα and 4‐hydroxynonenal), small interfering RNA (siRNA) for NOX, and the inhibitor diphenyleneiodonium (DPI) under conditions of normoxia or 3% hypoxia. Results We demonstrated significantly increased NOX‐2 expression in the joints of patients with inflammatory arthritis and the joints of mice with CIA as compared to controls. NOX‐2 expression was higher in patients with synovial tP O 2 levels &lt;3% than in those with tP O 2 levels &gt;3% ( P &lt; 0.05), and correlated with in vivo macroscopic/microscopic measures of angiogenesis, such as vascularity and levels of vascular endothelial growth factor, angiopoietin 2, factor VIII, neural cell adhesion molecule, and α‐smooth muscle actin ( P &lt; 0.05 for all). A decrease in NOX‐2 expression was paralleled by an increase in in vivo tP O 2 levels only in those patients who were defined as TNFi responders. In vitro NOX‐2 activators and 3% hypoxia significantly promoted HMVEC migration, angiogenic tube formation, and secretion of proangiogenic mediators, effects that were blocked by siRNA for NOX‐2 or the NOX‐2 inhibitor DPI. Conclusion We demonstrated that hypoxia activates NOX‐2 protein expression, and NOX‐2–induced oxidative stress may be an initiating factor in driving angiogenesis.
Health Care–Associated Infections
Authors: Eyal Zimlichman, Daniel Henderson, Orly Tamir, Calvin Franz, Peter Song, Cyrus K. Yamin, Carol Keohane, Charles R. Denham, David W. Bates
Journal: JAMA Internal Medicine (2013)

<h3>Importance</h3> Health care–associated infections (HAIs) account for a large proportion of the harms caused by health care and are associated with high costs. Better evaluation of the costs of these infections could help providers and payers to justify investing in prevention. <h3>Objective</h3> To estimate costs associated with the most significant and targetable HAIs. <h3>Data Sources</h3> For estimation of attributable costs, we conducted a systematic review of the literature using PubMed for the years 1986 through April 2013. For HAI incidence estimates, we used the National Healthcare Safety Network of the Centers for Disease Control and Prevention (CDC). <h3>Study Selection</h3> Studies performed outside the United States were excluded. Inclusion criteria included a robust method of comparison using a matched control group or an appropriate regression strategy, generalizable populations typical of inpatient wards and critical care units, methodologic consistency with CDC definitions, and soundness of handling economic outcomes. <h3>Data Extraction and Synthesis</h3> Three review cycles were completed, with the final iteration carried out from July 2011 to April 2013. Selected publications underwent a secondary review by the research team. <h3>Main Outcomes and Measures</h3> Costs, inflated to 2012 US dollars. <h3>Results</h3> Using Monte Carlo simulation, we generated point estimates and 95% CIs for attributable costs and length of hospital stay. On a per-case basis, central line–associated bloodstream infections were found to be the most costly HAIs at $45 814 (95% CI, $30 919-$65 245), followed by ventilator-associated pneumonia at $40 144 (95% CI, $36 286-$44 220), surgical site infections at $20 785 (95% CI, $18 902-$22 667),<i>Clostridium difficile</i>infection at $11 285 (95% CI, $9118-$13 574), and catheter-associated urinary tract infections at $896 (95% CI, $603-$1189). The total annual costs for the 5 major infections were $9.8 billion (95% CI, $8.3-$11.5 billion), with surgical site infections contributing the most to overall costs (33.7% of the total), followed by ventilator-associated pneumonia (31.6%), central line–associated bloodstream infections (18.9%),<i>C difficile</i>infections (15.4%), and catheter-associated urinary tract infections (&lt;1%). <h3>Conclusions and Relevance</h3> While quality improvement initiatives have decreased HAI incidence and costs, much more remains to be done. As hospitals realize savings from prevention of these complications under payment reforms, they may be more likely to invest in such strategies.
Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma
Authors: María-Victoria Mateos, Miguel-Teodoro Hernández, Pilar Giraldo, Javier de la Rubia, Felipe de Arriba, Lucía López Corral, Laura Rosiñol, Bruno Paiva, Luis Palomera, Joan Bargay, Albert Oriol, Felipe Prosper, Javier López, Eduardo Olavarría, Nuria Quintana, José-Luis García, Joan Bladé, Juan-José Lahuerta, Jesús-F San Miguel
Journal: New England Journal of Medicine (2013)

For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention.In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety.After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower.Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00480363.).
Investigation of residual hepatitis C virus in presumed recovered subjects
Authors: Kei Fujiwara, Robert D. Allison, Richard Y. Wang, Patricia Bare, Kentaro Matsuura, Cathy Schechterly, Krishna Murthy, Francesco M. Marincola, Harvey J. Alter
Journal: Hepatology (2012)

Recent studies have found hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) of the majority of presumed recovered subjects. We investigated this unexpected finding using samples from patients whose HCV RNA and anti-HCV status had been serially confirmed. HCV RNA was detected in PBMCs from 66 of 67 chronic HCV carriers. Subpopulation analysis revealed that the viral load (log copies/106 cells) in B cells (4.14 ± 0.71) was higher than in total PBMCs (3.62 ± 0.71; P &lt; 0.05), T cells (1.67 ± 0.88; P &lt; 0.05), and non-B/T cells (2.48 ± 1.15; P &lt; 0.05). HCV negative-strand RNA was not detected in PBMCs from any of 25 chronically infected patients. No residual viral RNA was detected in total PBMCs or plasma of 59 presumed recovered subjects (11 spontaneous and 48 treatment induced) using nested real-time polymerase chain reaction with a detection limit of 2 copies/μg RNA (from ˜1 × 106 cells). PBMCs from 2 healthy HCV-negative blood donors became HCV RNA positive, with B-cell predominance, when mixed in vitro with HCV RNA–positive plasma, thus passively mimicking cells from chronic HCV carriers. No residual HCV was detected in liver or other tissues from 2 spontaneously recovered chimpanzees. Conclusion: (1) HCV RNA was detected in PBMCs of most chronic HCV carriers and was predominant in the B-cell subpopulation; (2) HCV detected in PBMCs was in a nonreplicative form; (3) HCV passively adsorbed to PBMCs of healthy controls in vitro , becoming indistinguishable from PBMCs of chronic HCV carriers; and (4) residual HCV was not detected in plasma or PBMCs of any spontaneous or treatment-recovered subjects or in chimpanzee liver, suggesting that the classic pattern of recovery from HCV infection is generally equivalent to viral eradication.
HCV carriers with normal alt: healthy people or patients with chronic hepatitis? The Italian study of the asymptomatic C carriers (ISACC)
Authors: C. Puoti, M. Puoti, E. Minola, G. Gaeta, R. Castellacci, F. Montagnese, T. Zaltron, G. Stomaiuolo, M. Pace, C. Lo Iacono, N. Bergarni
Journal: Journal of Hepatology (2001)
Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis)
Authors: D Kerjaschki, T J Neale
Journal: Journal of the American Society of Nephrology (1996)

The molecular pathogenesis of human membranous nephropathy (MN) is unknown, despite the relatively high incidence and severity of this glomerular immune disease. Heymann nephritis (HN) in rats is considered an instructive experimental model of MN. This study summarizes current molecular aspects of two key events common to both MN and HN, i.e., formation of characteristic subepithelial immune deposits in the glomerular basement membrane (GBM), and development of glomerular capillary wall damage resulting in proteinuria. In HN, the antigenic targets of immune deposit-forming antibodies were identified in cell membranes of glomerular epithelial cells as a 515-kd glycoprotein (megalin, or gp330), which is a polyspecific receptor related to the low-density lipoprotein receptor family, and an associated 44-kd protein (receptor associated protein, RAP). One epitope was recently narrowed to 14 amino acids in RAP, and several others on megalin/gp330 are under investigation. Proteinuria requires formation of the complement C5b-9 membrane attack complex, which is presumably triggered by antibodies directed against lipid antigens that associate with immune deposit-forming megalin/gp330 immune complexes. Sublytic C5b-9 attack on glomerular epithelial cells causes upregulation of expression of the NADPH oxidoreductase enzyme complex by glomerular cells, which is translocated to their cell surfaces, similar to activated neutrophil granulocytes in the respiratory burst reaction. Subsequently, reactive oxygen species (ROS) are produced locally, which reach the GBM matrix. Here formation of lipid peroxidation (LPO) adducts is found, preferentially on monomeric and dimerized NCl domains of covalently crosslinked Type IV collagen. These structural changes within the GBM could be of functional relevance because treatment with the potent LPO-antagonist probucol reduces proteinuria by < 80%. Intact or fragmented apoprotein E-containing lipoproteins were identified as potential sources of the polyunsaturated lipids required for the production of LPO adducts. Lipoproteins accumulate within immune deposits and show signs of oxidative damage, similar to oxidized LDL within atherosclerotic lesions. Collectively, the results obtained so far in HN permit the compilation of a sequence of events, linking formation of immune deposits with proteinuria. However, despite this relatively detailed knowledge of pathogenic events in HN, the bridge to human NM remains to be built.
The Treatment of Syphilis
Authors: J. M. Sims
Journal: BMJ (1883)

sx or eight days, and sometimes more.G. Cuvier fixed even at fifteen days the duration of the flow in a female mandrill which he made the subject of repeated observations."Cuvier observed menstruation in carnivora, among others, in the genets; and Lesson and Garnot recognised it in the flying-fox (pteropus), which Saint-Hilaire says is periodical.Haller quotes many authors who thought monkeys, cows, deer and bitches offered evident traces of menstruation.Numann and Rainard made similar observations, while Pouchet had himself observed it in bitches, sows, cats, rabbits, and guinea-pigs, especially in the first.(Mr. Bartlett, the able superintendent of the Zoological Gardens, tells me that the discharge may be abundant in the bitch, and that the heat is sometimes long sustained in the carnivora).The wild pigeon produces only once or twice a year, while the varieties whichit ,has given us through care, breed ten times a year, as Aristotle, Buffon, and Blumenbach have observed.Kuhlemann says sheep come to heat every fortnight; sows every fifteen to eighteen days.Kahleis and Numann, that cows come every month or three weeks; Greve, that mares come monthly; and Cuvier, that buffaloes, zebras, and monkeys, come also monthly.Courty also recognised the graduated relation of menstruation in the zoological series.From his observations on sows, Pouchet concludes that the men- strual phenomena ordinarily precede the rupture of the Graafian follicles.(P.262 :) " During menstruation the vagina of the sow offers a rosy tint, and the mucous fluid which it contains is slightly abundant.Microscopical examination showed me that the latter is composed of fragments of epithelium, cylindrical and pavement; mucus-globules, and blood-corpuscles in small number....The womb, before its bifurcation, is reddened, and its capillaries are highly injected with blood. . .The cornua are excessively in- jected with blood.Their mucosa is considerably thickened and spongy, and of a deep red, and, in certain parts, the abundance of blood wherewith it is engorged gives it even a violet coloration.Thus, then, menstruation in the sow is a demonstrated fact.As in the human species, there is an emission of blood; but if this is not abundant, it is because this fluid is found in great part poured out in the immense extent of the internal generative apparatus."During the intermenstrual period, the vaginal and uterine mucous membranes are pale.Pouchet says that the appearances are absolutely similar in the rabbit, but that there is even more blood; and his observations upon bitches, cats, and other mammalia were equally confirmatory.At p. 266, Pouchet says:-" In a work on the physical and moral system of woman, Roussel (Syst.mePhysique et MVoral de la Femme,
The Novel Expanded Porphyrin, Motexafin Gadolinium, Combined with [90Y]Ibritumomab Tiuxetan for Relapsed/Refractory Non-Hodgkin's Lymphoma: Preclinical Findings and Results of a Phase I Trial
Authors: Andrew M. Evens, William G. Spies, Irene B. Helenowski, David Patton, Stewart Spies, Borko D. Jovanovic, Sarah Miyata, Elizabeth Hamilton, Daina Variakojis, Jun Chen, Louie Naumovski, Steven T. Rosen, Jane N. Winter, Richard A. Miller, Leo I. Gordon
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation. Experimental Design: We did preclinical studies examining motexafin gadolinium combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of motexafin gadolinium concurrently with standard [90Y]ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin's lymphoma. Results: In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through a mitochondrial-mediated caspase-dependent pathway, whereas cell death in Ramos and SUDHL4 cells was additive. Motexafin gadolinium/rituximab combined with radiation (1-3 Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47-87 years), and histologies were marginal-zone (n = 1), mantle-cell (n = 3), diffuse large cell (n = 6), and follicular lymphoma (n = 18). Of all patients, 86% were rituximab refractory. Therapy was well tolerated, and no dose-limiting toxicity was seen. Overall response rate was 57% [complete remission (CR), 43%], with median time–to–treatment failure of 10 months (1-48+ months) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n = 14), overall response rate was 86% (CR, 64%), with a median time–to–treatment failure of 14 months (2-48+ months). Conclusions: This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Furthermore, tumor responses with [90Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma. (Clin Cancer Res 2009;15(20):6462–71)