tbuckley/cabot-search huggingface dataset:
The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism
Authors: R. P. M. Steegers-Theunissen, J. Twigt, V. Pestinger, K. D. Sinclair
Journal: Human Reproduction Update (2013)

BACKGROUNDMost reproductive failures originate during the periconceptional period and are influenced by the age and the lifestyle of parents-to-be. We advance the hypothesis that these failures can arise as a partial consequence of derangements to one-carbon (1-C) metabolism (i.e. metabolic pathways that utilize substrates/cofactors such as methionine, vitamin B12, folate). 1-C metabolic pathways drive the synthesis of proteins, biogenic amines and lipids required for early growth, together with the synthesis and methylation of DNA and histones essential for the regulation of gene expression. We review how deficiencies in periconceptional 1-C metabolism affect fertility and development together with underlying mechanisms derived from animal studies.
Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome
Authors: Rainer G. Ruf, Michael Schultheiss, Anne Lichtenberger, Stephanie M. Karle, Isabella Zalewski, Bettina Mucha, Anne Schulze Everding, Thomas Neuhaus, Ludwig Patzer, Christian Plank, Johannes P. Haas, Fatih Ozaltin, Anita Imm, Arno Fuchshuber, Aysin Bakkaloglu, Friedhelm Hildebrandt
Journal: Kidney International (2004)
Altered Ventricular and Myocyte Response to Angiotensin II in Pacing-Induced Heart Failure
Authors: Che-Ping Cheng, Makoto Suzuki, Nobuyuki Ohte, Michiya Ohno, Zhong-Min Wang, William C. Little
Journal: Circulation Research (1996)

Alterations in the cardiac response to angiotensin II (Ang II) may contribute to the functional impairment in tachycardia-induced heart failure (congestive heart failure [CHF]). Accordingly, we studied the response to Ang II in eight conscious instrumented dogs before and after inducing CHF. Left ventricular (LV) performance was assessed by measuring LV pressure and LV volume. Isolated myocyte function was evaluated using computer-assessed videomicroscopy. In conscious animals before CHF, Ang II produced a load-dependent slowing of the time constant of LV relaxation (tau) and did not depress intact LV contractile function. After CHF, although Ang II produced a similar increase in LV systolic pressure, the increases in LV diastolic pressure and time constant tau were much greater, and contractile performance was depressed. These changes persisted when the elevation of end-systolic pressure was prevented by nitroprusside. Similar changes were also present after autonomic blockade. In isolated myocytes, before CHF, Ang II (10(-6) mol/L) produced a slight positive inotropic effect. In contrast, after CHF, Ang II produced a negative inotropic effect and slowed the rate of relengthening. The effects in the intact LV and myocytes were reversed by an Ang II AT1 receptor blocker (losartan). We conclude that pacing-induced CHF alters the LV and myocyte response to Ang II, so that Ang II produces direct depressions in intact LV contraction, relaxation, and filling and exacerbates myocyte contractile dysfunction. These effects are mediated through the activation of AT1 receptors.
Retrotransposon-Gene Associations Are Widespread Among D. melanogaster Populations
Authors: Lucia F. Franchini, Eric W. Ganko, John F. McDonald
Journal: Molecular Biology and Evolution (2004)

We have surveyed 18 natural populations of Drosophila melanogaster for the presence of 23 retrotransposon-gene–association alleles (i.e., the presence of an LTR retrotransposon sequence in or within 1,000 bp of a gene) recently identified in the sequenced D. melanogaster genome. The identified associations were detected only in the D. melanogaster populations. The majority (61%) of the identified retrotransposon-gene associations were present only in the sequenced strain in which they were first identified. Thirty percent of the associations were detected in at least one of the natural populations, and 9% of the associations were detected in all of the D. melanogaster populations surveyed. Sequence analysis of an association allele present in all populations indicates that selection is a significant factor in the spread and/or maintenance of at least some of retroelement-gene associations in D. melanogaster.
Dysfunctional Endothelial Nitric Oxide Biosynthesis in Healthy Smokers With Impaired Endothelium-Dependent Vasodilatation
Authors: Rajat S. Barua, John A. Ambrose, Lesley-Jane Eales-Reynolds, Mary C. DeVoe, John G. Zervas, Dhanonjoy C. Saha
Journal: Circulation (2001)

Background The mechanisms involved in the dysfunction of both endothelium-dependent vasodilatation (EDV) and NO biosynthesis related to smoking are unclear. In this study, EDV was assessed in healthy smokers and nonsmokers in vivo and, using serum from the same individuals, was related to the NO biosynthetic pathway in vitro. Methods and Results Flow-mediated EDV of the brachial artery was measured in 23 male patients (8 nonsmokers and 15 smokers). Serum was collected, added to confluent (≈85%) monolayers of human umbilical vein endothelial cells (HUVECs), and incubated for 12 hours. Basal and substance P–stimulated NO production was measured. The HUVECs used for measuring basal NO production were lysed, and both endothelial NO synthase (eNOS) protein expression and eNOS activity were determined. EDV was lower in smokers compared with nonsmokers ( P &lt;0.001). HUVECs treated with serum from smokers compared with nonsmokers showed significantly lower basal ( P &lt;0.0001) and stimulated ( P &lt;0.02) NO production, higher eNOS expression ( P &lt;0.0001), but lower eNOS activity ( P &lt;0.004). There was a significant positive correlation between in vivo EDV and in vitro substance P–stimulated NO production (rho=0.57, P &lt;0.01) and between basal NO production and eNOS activity ( r =0.54, P &lt;0.008) and a negative correlation between basal NO production and eNOS protein expression ( r =−0.60, P &lt;0.003). Conclusions This is the first study to combine an in vivo model with a near-physiological in vitro model to demonstrate an association between decreased NO production and reduced EDV. Cigarette smoking was associated with reduced EDV, NO generation, and eNOS activity in the presence of increased eNOS protein expression.
Suppressive effects of Aspergillus fumigatus culture filtrates on human alveolar macrophages and polymorphonuclear leucocytes
Authors: T Murayama, R Amitani, Y Ikegami, R Nawada, WJ Lee, F Kuze
Journal: European Respiratory Journal (1996)

Aspergillus spp., especially A. fumigatus (Af) can colonize the airways and the lungs with localized underlying conditions and further invade the surrounding lung tissues, even in subjects without systemic predisposing factors, presumably by escaping the local host defences. To clarify the mechanisms of colonization and invasion of Af, we investigated the in vitro effects of Af culture filtrates (ACFs) on the functions of human alveolar macrophages (AMs), and polymorphonuclear leucocytes (PMNs). ACFs were obtained by culturing clinically isolated Af in Medium-199 at 37 degrees C for 5 days. In the study of phagocytosis of Af conidia by human AMs, 52% of AMs ingested conidia during a 60 min incubation period in Medium-199. However, the percentage decreased to 24% when incubated with a final concentration of 30% ACF in Medium-199. With respect to the antichemotactic activity on human PMNs, 3% ACF was sufficient for significant suppression, and 30% ACF completely inhibited the migration of PMNs. In addition, phorbol myristate acetate (PMA)-induced O2- release from PMNs was significantly suppressed in Medium-199 which included 12.5% ACF or more. The antichemotactic activity of ACF was partially abolished by trypsin or chicken egg ovomacroglobulin. When ACF was separated into two fractions (molecular weight &gt; 10 and &lt; 10 kDa) by dialysis and centrifugation through CL-LGC filters, both fractions retained the antichemotactic activity. We conclude that Af produce several antiphagocytic factors, which can be responsible for the colonization of Af in the bronchopulmonary tissues and allow this species to invade surrounding lung tissues in pulmonary aspergillosis by suppressing local host defences.
Integrating drug concentrations and minimum inhibitory concentrations with Bayesian-dose optimisation for multidrug-resistant tuberculosis
Authors: Shashikant Srivastava, Tawanda Gumbo
Journal: European Respiratory Journal (2013)

To the Editor :

The problems of multidrug-resistant (MDR) tuberculosis (TB), extensively drug-resistant (XDR) TB, and even “totally drug-resistant” TB (a term that is still debated), have exposed two important clinical issues [1, 2]. The first issue involves figuring out a way to prevent these difficult-to-treat diseases. The second issue is treating patients with drug-resistant TB [3]. In the meantime even the current susceptibility breakpoints have been challenged as being too high, so that potentially more drug-resistant TB exists than anticipated [4]. This latter aspect suggests that we need a better idea of the minimum inhibitory concentrations (MICs) to both first-line drugs and second-line drugs. Here we propose the use of MICs and drug concentrations to calculate pharmacokinetic/pharmacodynamics (PK/PD) target exposures and then to use Bayesian-feedback dosing as an integrated solution that could improve treatment outcomes.

PK/PD relationships are deterministic, which means that the PK/PD parameters and exposures associated with certain degrees of microbial responses can be …
The specificity of DNA recognition by the RAGE receptor
Authors: Laure Yatime, Gregers Rom Andersen
Journal: The Journal of Experimental Medicine (2014)

A recent paper by Sirois et al. in The Journal of Experimental Medicine reports that the receptor for advanced glycation end-products (RAGE) promotes uptake of DNA into endosomes and lowers the immune recognition threshold for the activation of Toll-like receptor 9. Two crystal structures suggested that the DNA phosphate-deoxyribose backbone is recognized by RAGE through well-defined interactions. However, the electron densities for the DNA molecules are weak enough that the presented modeling of DNA is questionable, and models only containing RAGE account for the observed diffraction data just as well as the RAGE–DNA complexes presented by the authors.
Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial
Authors: Robert J Motzer, Camillo Porta, Nicholas J Vogelzang, Cora N Sternberg, Cezary Szczylik, Jakub Zolnierek, Christian Kollmannsberger, Sun Young Rha, Georg A Bjarnason, Bohuslav Melichar, Ugo De Giorgi, Viktor Grünwald, Ian D Davis, Jae-Lyun Lee, Emilio Esteban, Gladys Urbanowitz, Can Cai, Matthew Squires, Mahtab Marker, Michael M Shi, Bernard Escudier
Journal: The Lancet Oncology (2014)
Antigen-specific Immunoglobulin-A Prevents Increased Airway Responsiveness and Lung Eosinophilia after Airway Challenge in Sensitized Mice
Authors: JÜRGEN SCHWARZE, GRZEGORZ CIESLEWICZ, ANTHONY JOETHAM, LEE K. SUN, WILLIAM N. SUN, TSE WEN CHANG, ECKARD HAMELMANN, ERWIN W. GELFAND
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Aeroallergens such as Amb a I from short ragweed are important in the development of allergic airway disease. We tested the ability of a human monoclonal immunoglobulin-A (IgA) antibody specific for Amb a I (A-IgA) to modulate airway responsiveness and lung eosinophilia after airway challenge with nebulized Amb a I or ragweed extract in mice sensitized to Amb a I or ragweed extract, respectively. A-IgA or nonspecific IgA (C-IgA) were given intranasally up to 8 h before each challenge. Allergen challenge resulted in increases in airway responsiveness, in numbers of lung eosinophils, and in Amb a I–specific IgE levels. These were prevented by pretreatment with A-IgA but not with C-IgA. Decreases in IFN- γ and increases in IL-4 and IL-5 production following challenge with Amb a I were also reduced by A-IgA treatment. In contrast, increases in total IgE and total IgG and in numbers of lung neutrophils after challenge were not significantly affected by A-IgA, which additionally induced increased levels of Amb a I–specific IgG2a antibodies. In mice sensitized and challenged with ovalbumin (OVA), A-IgA did not affect airway responsiveness, lung eosinophilia, cytokine production, or immunoglobulin levels. These data indicate that allergen-specific IgA can prevent airway hyperresponsiveness and reduce eosinophil influx into the lungs following allergen challenge via the airways in sensitized mice, and these effects are allergen-specific. Neutralization of allergen may contribute to the effects of IgA, but the induction of allergen-specific IgG2a in A-IgA-treated mice suggests an immunomodulatory action for A-IgA.
Sorafenib Induces Apoptosis Specifically in Cells Expressing BCR/ABL by Inhibiting Its Kinase Activity to Activate the Intrinsic Mitochondrial Pathway
Authors: Tetsuya Kurosu, Manabu Ohki, Nan Wu, Hiroyuki Kagechika, Osamu Miura
Journal: Cancer Research (2009)

Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, relapse with emerging imatinib resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we show that the multikinase inhibitor sorafenib inhibits proliferation and induces apoptosis at much lower concentrations in Ton.B210 cells when driven by inducibly expressed BCR/ABL than when driven by interleukin-3. The increased sensitivity to sorafenib was also observed in cells inducibly expressing BCR/ABL with the imatinib-resistant E255K or T315I mutation. Sorafenib-induced apoptosis in these cells and Ph+ leukemic cells was synergistically enhanced by rottlerin, bortezomib, or ABT-737 and inhibited by the pan-caspase inhibitor BOC-d-fmk or the overexpression of Bcl-XL. It was further revealed that sorafenib activates Bax and caspase-3 and reduces mitochondrial membrane potential specifically in BCR/ABL-driven cells. Sorafenib also inhibited BCR/ABL-induced tyrosine phosphorylation of its cellular substrates and its autophosphorylation in Ton.B210. It was finally shown that sorafenib inhibits the kinase activity of BCR/ABL as well as its E255K and T315I mutants in in vitro kinase assays. These results indicate that sorafenib induces apoptosis of BCR/ABL-expressing cells, at least partly, by inhibiting BCR/ABL to activate the mitochondria-mediated apoptotic pathway. Thus, sorafenib may provide an effective therapeutic measure to treat Ph+ leukemias, particularly those expressing the T315I mutant, which is totally resistant to imatinib and the second generation BCR/ABL inhibitors.
Interlobar differences in bronchoalveolar lavage fluid from children with cystic fibrosis
Authors: J.P. Gutierrez, K. Grimwood, D.S. Armstrong, J.B. Carlin, R. Carzino, A. Olinsky, C.F. Robertson, P.D. Phelan
Journal: European Respiratory Journal (2001)

Bronchoalveolar lavage (BAL) performed in specialist centres has improved the understanding of infant cystic fibrosis (CF) lung disease. As most researchers sample from a single lobe, it was determined whether BAL results could be generalized to other lung segments. Thirty-three CF children, aged 1.5–57 months, underwent in random order sequential BAL of their right middle and lingula lobes. Specimens from each lobe had separate quantitative bacteriology, cytology and cytokine analysis. Bacterial counts ≥1×10 5 colony forming units (cfu)·mL −1 were observed in nine (27%) subjects, including six involving only the right middle lobe. These six children had similar inflammatory indices in their right middle and lingula lobes, and interleukin (IL)-8 concentrations in the latter were significantly higher than that observed within the lingula lobes of the 24 CF children with bacterial counts &lt;1×10 5 cfu·mL −1 . Lingula neutrophil and IL-8 levels correlated best with right middle lobe bacteria numbers. This observational study in cystic fibrosis children suggests that while inflammation is detected in both lungs, bacterial distribution may be more inhomogeneous. Bronchoalveolar lavage microbiological findings from a single lobe may therefore, not be generalized to other lung segments. When performing bronchoalveolar lavage in cystic fibrosis children, it is important to sample from multiple sites.
Hepatocyte Growth Factor/Scatter Factor Differentially Regulates Expression of Proangiogenic Factors through Egr-1 in Head and Neck Squamous Cell Carcinoma
Authors: Brian Worden, Xin Ping Yang, Tin Lap Lee, Lorena Bagain, Ning T. Yeh, Joshua G. Cohen, Carter Van Waes, Zhong Chen
Journal: Cancer Research (2005)

Abstract Hepatocyte growth factor/scatter factor (HGF) and the angiogenesis factors platelet-derived growth factors (PDGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) are found in elevated concentrations in serum or tumor tissue of patients with head and neck squamous cell carcinomas (HNSCC), suggesting these factors may be coregulated. A cDNA microarray analysis for HGF-inducible genes revealed that HGF also modulates PDGFA expression, a gene recently shown to be inducible by the transcription factor, early growth response-1 (Egr-1). In the present study, we investigated the potential role of HGF-induced Egr-1 in expression of PDGF, VEGF, and IL-8. HGF induced expression of all three factors and Egr-1 expression and DNA-binding activity. The analysis of promoter sequences showed putative Egr-1 binding sites in the PDGFA or VEGF but not in the IL-8 promoter, and HGF-induced Egr-1–binding activity was confirmed by chromatin immunoprecipitation (ChIP) assay. The maximal basal and HGF-induced promoter activity for the PDGFA gene existed within −630 bp of the promoter region, and overexpression of Egr-1 significantly increased such activity. Consistent with this, expression of PDGFA and VEGF but not IL-8 showed corresponding differences with Egr-1 expression in HNSCC tumor specimens and were strongly suppressed by transfection of Egr-1–antisense or small interference RNA (siRNA) oligonucleotides. HGF-induced expression of Egr-1, PDGFA, and VEGF was suppressed by pharmacologic and siRNA inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and protein kinase C (PKC) pathways. We conclude that the HGF-induced activation of transcription factor Egr-1 by MEK1/2- and PKC-dependent mechanisms differentially contributes to expression of PDGF and VEGF, which are important angiogenesis factors and targets for HNSCC therapy.
CD80 (B7-1) Binds Both CD28 and CTLA-4 with a Low Affinity and Very Fast Kinetics
Authors: P.  Anton van der Merwe, Dale L. Bodian, Susan Daenke, Peter Linsley, Simon J. Davis
Journal: The Journal of Experimental Medicine (1997)

The structurally related T cell surface molecules CD28 and CTLA-4 interact with cell surface ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells (APC) and modulate T cell antigen recognition. Preliminary reports have suggested that CD80 binds CTLA-4 and CD28 with affinities (Kd values ∼12 and ∼200 nM, respectively) that are high when compared with other molecular interactions that contribute to T cell–APC recognition. In the present study, we use surface plasmon resonance to measure the affinity and kinetics of CD80 binding to CD28 and CTLA-4. At 37°C, soluble recombinant CD80 bound to CTLA-4 and CD28 with Kd values of 0.42 and 4 μM, respectively. Kinetic analysis indicated that these low affinities were the result of very fast dissociation rate constants (koff); sCD80 dissociated from CD28 and CTLA-4 with koff values of ⩾1.6 and ⩾0.43 s−1, respectively. Such rapid binding kinetics have also been reported for the T cell adhesion molecule CD2 and may be necessary to accommodate dynamic T cell–APC contacts and to facilitate scanning of APC for antigen.
Nitric oxide: a key factor behind the dysfunctionality of endothelial progenitor cells in diabetes mellitus type-2
Authors: Saher Hamed, Benjamin Brenner, Ariel Roguin
Journal: Cardiovascular Research (2010)

Diabetes mellitus type-2 (DM-2) contributes to atherogenesis by inducing endothelial cell injury and dysfunction. Endothelial progenitor cells (EPCs) are essential to blood vessel formation, can differentiate into mature endothelial cells, and promote the repair of damaged endothelium. In DM-2, the circulating EPC count is low and their functionality is impaired. The mechanisms that underlie this reduced count and impaired functionality are poorly understood. Nitric oxide (NO) is a short-lived signalling molecule that is produced by vascular endothelial cells and participates in the maintenance of vascular tone. NO is also known to participate in other physiological processes, such as cell survival, proliferation, and migration. The bioavailability of NO is reduced in EPCs from DM-2 patients. Interestingly, an inverse relationship exists between the reduction in NO bioavailability in EPCs and the patient's plasma glucose and glycated haemoglobin levels. In addition, NO bioavailability in EPCs correlates with plasma oxidized low-density lipoprotein levels in DM-2. Although this reduction in NO bioavailability could be attributed to oxidative stress in DM-2 patients, it also may be due to impairment of one or more members of the protein signalling cascades that are responsible for NO production. The stimulation of NO production or its signalling cascades in EPCs may increase their numbers and improve their function, thus attenuating endothelium damage, independent of the vasodilatory effects of NO. This review summarizes the metabolic alterations that underlie the molecular mechanisms that may be responsible for EPC decrease and dysfunction in DM-2 with emphasis on the involvement of the NO system.
The Transcription Factor E26 Transformation–Specific Sequence-1 Mediates Neointima Formation in Arteriovenous Fistula
Authors: Wenguang Feng, Phillip Chumley, Michael Allon, James George, David W. Scott, Rakesh P. Patel, Silvio Litovsky, Edgar A. Jaimes
Journal: Journal of the American Society of Nephrology (2013)

Hemodialysis vascular access dysfunction contributes to increased morbidity and mortality in hemodialysis patients. Arteriovenous fistula (AVF) is the preferred type of vascular access for hemodialysis but has high rates of dysfunction, in part because of excessive neointima formation. The transcription factor E26 transformation-specific sequence-1 (ETS-1) is a mediator of proinflammatory responses in hypertension and endovascular injury. We examined the role of ETS-1 in the formation of neointima in AVF. Right carotid artery to internal jugular vein fistulas were created in C57BL/6 mice and assigned to treatment with an ETS-1-dominant negative peptide (ETS-DN), an inactive mutant peptide (ETS-MU), or vehicle (n=6 per group). After 7 and 21 days, AVFs or contralateral internal jugular veins were processed for PCR, immunofluorescence, immunohistochemistry, and morphometry. In AVFs, ETS-1 mRNA increased 2.5-fold at 7 days and 4-fold at 21 days. By immunofluorescence, we confirmed increased expression of ETS-1 predominantly in the neointima and overlying endothelium. Similarly, ETS-1 expression increased in human AVFs compared with normal veins. In mice, ETS-DN, but not ETS-MU, reduced neointima formation at days 7 and 21 and reduced the expression of nitric oxide synthase 2, NADPH oxidase (NOX) 2, NOX4, E-selectin, and monocyte chemotactic protein-1. Shear stress increased ETS-1 phosphorylation in human umbilical vein cells in a NOX-dependent manner, demonstrating a role for reactive oxygen species in ETS-1 activation. These results unveil the role of ETS-1 as a mediator of neointima formation in AVF and may result in the development of novel strategies for the treatment of AVF dysfunction.