tbuckley/cabot-search huggingface dataset:
Effects of Lysophosphatidic Acid, a Novel Lipid Mediator, on Cytosolic Ca <sup>2+</sup> and Contractility in Cultured Rat Mesangial Cells
Authors: Chiyoko N. Inoue, Hayley G. Forster, Murray Epstein
Journal: Circulation Research (1995)

Abstract Lysophosphatidic acid (LPA), the smallest and structurally simplest phospholipid, has the potential to modulate cellular signaling in diverse tissues and cell types, including fibroblasts. In the present study, we assessed the effects of LPA on cultured rat glomerular mesangial cells. Quantitative changes of [Ca 2+ ] i in response to LPA were measured in monolayers of mesangial cells loaded with the fluorescent Ca 2+ indicator fura 2. LPA (10 nmol/L to 100 μmol/L) increased [Ca 2+ ] i in a dose-dependent manner and evoked inositol trisphosphate formation. LPA (1 μmol/L to 30 μmol/L) also elicited a marked, albeit transient, contractile response in mesangial cells cultured on collagen gel, as assessed by a decrease in cell surface area (CSA). The contraction persisted for 5 minutes (CSA decreased by 31%), whereupon the mesangial cells gradually relaxed with a consequent increase in CSA. Pretreatment of mesangial cells with isradipine (1 μmol/L), a dihydropyridine-sensitive Ca 2+ channel blocker, completely blocked LPA-induced contraction. Isradipine also decreased resting [Ca 2+ ] i levels as well as the peak and the subsequently sustained [Ca 2+ ] i levels induced by LPA, suggesting that the contractile effects of LPA are dependent on Ca 2+ entry through voltage-gated Ca 2+ channels. Finally, LPA stimulated an increase in both prostaglandin E 2 synthesis and cAMP accumulation, indicating that these mediators may modulate the contractile effects of LPA. Our study is the first demonstration that exogenous LPA induces mesangial cell contraction and suggests that the contraction is mediated by mobilization of intracellular Ca 2+ by activation of the phosphoinositide cascade as well as by promotion of Ca 2+ entry across the plasma membrane.
P47 The impact of comorbid ischaemic heart disease on exercise capacity in COPD patients
Authors: A. R. C. Patel, A. D. Alahmari, G. C. Donaldson, B. Kowlessar, A. J. Mackay, R. Singh, J. R. Hurst, J. A. Wedzicha
Journal: Thorax (2011)

<h3>Introduction</h3> Comorbid ischaemic heart disease (IHD) is associated with an adverse impact on health status, symptoms (<i>ARJCCM</i> 2011;183:A2614) and exacerbation recovery in COPD patients (<i>ERJ</i> 2010;954s:E5209). Any impact on exercise capacity is poorly understood. We aimed to assess and quantify differences in exercise capacity in stable COPD patients with and without IHD. <h3>Methods</h3> We assessed 6-min walking distance (6MWD) in accordance with ATS guidance (<i>AJRCCM</i> 2002;166:111–117) in patients from the London COPD cohort. All assessments were performed in the stable state with no symptom-defined exacerbations recorded on daily diary cards for 6 weeks prior and 2 weeks following the visit. Dyspnoea and fatigue were measured before and after the test using the Borg scale, as were saturations from a pulse oximeter. Data were analysed using unpaired t-tests, Mann–Whitney U, χ<sup>2</sup> tests and multiple regression techniques. <h3>Results</h3> 115 patients had a 6MWD assessment, 19 (17%) had IHD (Abstract P47 table 1). COPD patients with IHD had a lower mean ± SD 6MWD than those without (310±138 vs 354±107 m) although this was not statistically significant (p=0.119). Following adjustment for age, gender, FEV<sub>1</sub> % predicted, BMI and smoking pack year history, IHD was found to be independently related with a 66 m reduction in 6MWD (95% CI 5 to 127 m), p=0.035. Median (IQR) dyspnoea on the Borg scale before the test was not higher in those with IHD (1(1,2) vs 1(0,3), p=0.135), this increased more in those with IHD compared to those without during the test (2(1,3) vs 1(0,3), p=0.043). Fatigue measured on the Borg scale was higher at the start of the test in those with IHD (1.5(0,3) vs 0(0,2), p=0.038), however, the increase after the test was not different between the groups (0(0,2) vs 0(0,2), p=0.831). The mean ± SD pre-test oxygen saturations and post-test change were similar in those with and without IHD (93.8±2.6% vs 94.1±2.4%, p=0.684; −0.9±4.4% vs −1.4±3.2%, p=0.595). <h3>Conclusions</h3> Comorbid IHD is independently associated with a clinically significant lower exercise capacity in COPD patients. Such patients may have a higher level of fatigue before exercise and develop more dyspnoea during exercise. Such patients may be an appropriate target for further intervention such as tailored pulmonary rehabilitation.
A Pitfall of Propidium Iodide Staining in Fluorescence-Activated Cell Sorting Cell Cycle Analysis?
Authors: Jennifer A. Fischer, Susan Muller-Weeks, Salvatore Caradonna
Journal: Cancer Research (2007)

In Response:We thank Franz Buchegger and coworkers for their interest in our article. They raise a valid point about the pitfalls of propidium iodide staining in fluorescence-activated cell sorting (FACS) cell cycle analysis. Fortunately, we provide a control cell line that does not show 5-fluoro-2′-deoxyuridine (FdUrd)–induced turnover but does show a cell cycle–induced turnover of the nuclear isoform of uracil-DNA glycosylase (nUDG). In previous work, we show that nUDG from HeLa S3 cells turns over in a cell cycle–dependent manner (1). In contrast, nUDG remains stable when HeLa S3 cells are treated with FdUrd. Therefore, similar cell cycle–dependent mechanisms seem to exist for nUDG turnover in both HeLa S3 and HT29 cell lines. In contrast, different mechanisms seem to be at work in these cell lines in relation to FdUrd-induced nUDG instability. Both cell lines reveal nearly identical cell cycle patterns as a function of time post-FdUrd treatment. FACS analyses of both cell lines, as a function of FdUrd treatment, are shown in Fig. 2 of our recent publication (2). Taking our published results in their entirety tends to indicate that there is a distinct FdUrd-associated trigger that induces nUDG instability in certain cell lines (e.g., HT29) but not in others (e.g., HeLa S3).
Pituitary-testicular responsiveness in male hypogonadotropic hypogonadism.
Authors: R L Weinstein, R E Reitz
Journal: Journal of Clinical Investigation (1974)

An isolated deficiency of pituitary gonadotropins was demonstrated in six 46 XY males, 22 to 36 years of age, with and without anosmia. Undetectable or low levels of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) clearly separated hypogonadotropic from normal adult males. Chronic (8-12 wk) administration of clomiphene citrate caused no increase in serum FSH or LH in gonadotropin-deficient subjects. However, the administration of synthetic luteinizing hormone releasing factor (LRF) resulted in the appearance of serum LH and, to a lesser degree, serum FSH in three subjects tested. While levels of plasma testosterone were significantly lower in gonadotropin-deficient subjects, plasma androstenedione and dehydroepiandrosterone were in a range similar to that of age-matched normal men. Treatment with human chorionic gonadotropin (HCG) increased levels of plasma testosterone to normal adult male values in all gonadotropin-deficient subjects. Cessation of treatment with HCG resulted in the return of plasma testosterone to low, pretreatment levels. That HCG therapy with resultant normal levels of plasma testosterone may somehow stimulate endogenous gonadotropin secretion in gonadotropin-deficient subjects was not evident. The adult male levels of serum FSH and LH after LRF, and plasma testosterone after HCG, confirm pituitary and Leydig cell responsiveness in these subjects.
Inflammation Amplifier, a New Paradigm in Cancer Biology
Authors: Toru Atsumi, Rajeev Singh, Lavannya Sabharwal, Hidenori Bando, Jie Meng, Yasunobu Arima, Moe Yamada, Masaya Harada, Jing-Jing Jiang, Daisuke Kamimura, Hideki Ogura, Toshio Hirano, Masaaki Murakami
Journal: Cancer Research (2013)

Tumor-associated inflammation can induce various molecules expressed from the tumors themselves or surrounding cells to create a microenvironment that potentially promotes cancer development. Inflammation, particularly chronic inflammation, is often linked to cancer development, even though its evolutionary role should impair nonself objects including tumors. The inflammation amplifier, a hyperinducer of chemokines in nonimmune cells, is the principal machinery for inflammation and is activated by the simultaneous stimulation of NF-κB and STAT3. We have redefined inflammation as local activation of the inflammation amplifier, which causes an accumulation of various immune cells followed by dysregulation of local homeostasis. Genes related to the inflammation amplifier have been genetically associated with various human inflammatory diseases. Here, we describe how cancer-associated genes, including interleukin (IL)-6, Ptgs2, ErbB1, Gas1, Serpine1, cMyc, and Vegf-α, are strongly enriched in genes related to the amplifier. The inflammation amplifier is activated by the stimulation of cytokines, such as TNF-α, IL-17, and IL-6, resulting in the subsequent expression of various target genes for chemokines and tumor-related genes like BCL2L11, CPNE7, FAS, HIF1-α, IL-1RAP, and SOD2. Thus, we conclude that inflammation does indeed associate with the development of cancer. The identified genes associated with the inflammation amplifier may thus make potential therapeutic targets of cancers.
A class of DNA-binding peptides from wheat bud causes growth inhibition, G2 cell cycle arrest and apoptosis induction in HeLa cells
Authors: Loretta Mancinelli, Paula M De Angelis, Lucia Annulli, Valentina Padovini, Kjell Elgjo, Gian Luigi Gianfranceschi
Journal: Molecular Cancer (2009)

Abstract Background Deproteinized DNA from eukaryotic and prokaryotic cells still contains a low-molecular weight peptidic fraction which can be dissociated by alkalinization of the medium. This fraction inhibits RNA transcription and tumor cell growth. Removal from DNA of normal cells causes amplification of DNA template activity. This effect is lower or absent in several cancer cell lines. Likewise, the amount of active peptides in cancer cell DNA extracts is lower than in DNA preparation of the corresponding normal cells. Such evidence, and their ubiquitous presence, suggests that they are a regulatory, conserved factor involved in the control of normal cell growth and gene expression. Results We report that peptides extracted from wheat bud chromatin induce growth inhibition, G 2 arrest and caspase-dependent apoptosis in HeLa cells. The growth rate is decreased in cells treated during the S phase only and it is accompanied by DNA damage and DNA synthesis inhibition. In G 2 cells, this treatment induces inactivation of the CDK1-cyclin B1 complex and an increase of active chk1 kinase expression. Conclusion The data indicate that the chromatin peptidic pool inhibits HeLa cell growth by causing defective DNA replication which, in turn, arrests cell cycle progression to mitosis via G 2 checkpoint pathway activation.
More Questions Than Answers Surrounding E-Cigarette Debate
Authors: N. Nelson
Journal: JNCI Journal of the National Cancer Institute (2014)

nicotine was detected in cartridges labeled as having the same amount, suggesting imperfect quality control in their manufac- ture. Also, tobacco-specific nitrosamines, known human carcinogens, were found in half the samples, and tobacco-specific impurities suspected of being harmful to humans—anabasine, myosmine, and β-nicotyrine—were found in most samples. One sample had diethylene glycol. In a similar study, Maciej Goniewicz, Ph.D., of the Roswell Park Cancer Institute in Buffalo, N.Y., and colleagues analyzed vapors from 12 brands of e-cigarettes for the presence of carcinogens found in tobacco smoke, focusing on four groups: carbonyl compounds, volatile organic com-
Targeted Noninvasive Imaging of EGFR-Expressing Orthotopic Pancreatic Cancer Using Multispectral Optoacoustic Tomography
Authors: Shanice V. Hudson, Justin S. Huang, Wenyuan Yin, Sabrin Albeituni, Jamie Rush, Anil Khanal, Jun Yan, Brian P. Ceresa, Hermann B. Frieboes, Lacey R. McNally
Journal: Cancer Research (2014)

Abstract Detection of orthotopic xenograft tumors is difficult due to poor spatial resolution and reduced image fidelity with traditional optical imaging modalities. In particular, light scattering and attenuation in tissue at depths beyond subcutaneous implantation hinder adequate visualization. We evaluate the use of multispectral optoacoustic tomography (MSOT) to detect upregulated epidermal growth factor (EGF) receptor in orthotopic pancreatic xenografts using a near-infrared EGF-conjugated CF-750 fluorescent probe. MSOT is based on the photoacoustic effect and thus not limited by photon scattering, resulting in high-resolution tomographic images. Pancreatic tumor-bearing mice with luciferase-transduced S2VP10L tumors were intravenously injected with EGF-750 probe before MSOT imaging. We characterized probe specificity and bioactivity via immunoblotting, immunocytochemistry, and flow cytometric analysis. In vitro data along with optical bioluminescence/fluorescence imaging were used to validate acquired MSOT in vivo images of probe biodistribution. Indocyanine green dye was used as a nonspecific control to define specificity of EGF-probe accumulation. Maximum accumulation occurred at 6 hours postinjection, demonstrating specific intratumoral probe uptake and minimal liver and kidney off-target accumulation. Optical bioluminescence and fluorescence imaging confirmed tumor-specific probe accumulation consistent with MSOT images. These studies demonstrate the utility of MSOT to obtain volumetric images of ligand probe biodistribution in vivo to detect orthotopic pancreatic tumor lesions through active targeting of the EGF receptor. Cancer Res; 74(21); 6271–9. ©2014 AACR.
Yin Yang 1 Is a Novel Regulator of Pulmonary Fibrosis
Authors: Xin Lin, Patricia J. Sime, Haodong Xu, Marc A. Williams, Larry LaRussa, Steve N. Georas, Jia Guo
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known.
Should computed tomography be the modality of choice for imaging Crohn's disease in children? The radiation risk perspective
Authors: D. J Brenner
Journal: Gut (2008)

Computed tomography (CT) and, more recently, CT enterography are excellent non-invasive tools for diagnosing Crohn’s disease, and for subsequent assessment of the disease, before and after therapy.1 In this light, and given the general availability and ease of use of CT machines, it is not surprising that CT is steadily replacing barium small-bowel follow-through as the radiological modality of choice for imaging Crohn’s disease.

There is, however, a potential downside, which is the radiation exposure produced by the CT scan. By their nature, CT scans result in radiation doses which are very much at the high end of those produced in diagnostic radiology, simply because a CT scan is effectively a large number of individual images that are electronically combined to produce a three-dimensional image. The effective dose involved in a CT scan is not large, but it is typically two to six times larger than that from barium small-bowel follow-through. Because of the typical long-term remission/relapse pattern of Crohn’s disease, together with the fact that is predominantly a disease of young people, Crohn’s disease patients are often imaged multiple times which, of course, correspondingly multiplies the radiation dose.

In this light, the report by Desmond et al 2 in this issue of the journal ( see page 1524 ) surveying trends in radiation exposure as a result of imaging …
Developmental changes in the effects of lidocaine on the electrophysiological properties of canine Purkinje fibers.
Authors: Y Morikawa, M R Rosen
Journal: Circulation Research (1984)

Developmental changes in the cardiac effects of antiarrhythmic drugs have been noted in the clinical setting. To study whether these might in part be based on developmental differences in drug effects on the transmembrane potential, we used standard microelectrode techniques to study the effects of lidocaine on the transmembrane potentials of Purkinje fibers from adult and young dogs. Control studies of membrane responsiveness and steady state recovery kinetics of Vmax showed no age-related differences in these variables. Lidocaine reduced Vmax of adult fibers to a greater extent than that of young fibers at basic drive cycle lengths of 1000 and 400 msec. The number of beats to reach steady state Vmax at basic drive cycle length of 400 msec was smaller in adult than in young fibers. Both tonic and use-dependent block appeared to be greater and to develop more rapidly in the adult than the young fibers. Moreover, fibers from young dogs recovered more rapidly from the effects of lidocaine than did adult fibers. These data suggest there are developmental changes in the tonic and use-dependent effects of lidocaine that may contribute to age-related differences in drug effect.
TLR4-induced IFN-γ production increases TLR2 sensitivity and drives Gram-negative sepsis in mice
Authors: Stephan Spiller, Greg Elson, Ruth Ferstl, Stefan Dreher, Thomas Mueller, Marina Freudenberg, Bruno Daubeuf, Hermann Wagner, Carsten J. Kirschning
Journal: The Journal of Experimental Medicine (2008)

Gram-negative bacterial infection is a major cause of sepsis and septic shock. An important inducer of inflammation underlying both syndromes is the cellular recognition of bacterial products through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). We identified a novel antagonistic mAb (named 1A6) that recognizes the extracellular portion of the TLR4-MD-2 complex. If applied to mice before infection with clinical isolates of Salmonella enterica or Escherichia coli and subsequent antibiotic therapy, 1A6 prevented otherwise fatal shock, whereas application of 1A6 after infection was ineffective. In contrast, coapplication of 1A6 and an anti-TLR2 mAb up to 4 h after infection with Gram-negative bacteria, in combination with the start of antibiotic therapy (mimicking clinical conditions), provided robust protection. Consistent with our findings in mice, dual blockade of TLR2 and TLR4 inhibited TNF-alpha release from human peripheral blood mononuclear cells upon Gram-negative bacterial infection/antibiotic therapy. Both murine splenocytes and human PBMCs released IFN-gamma in a TLR4-dependent manner, leading to enhanced surface TLR2 expression and sensitivity for TLR2 ligands. Our results implicate TLR2 as an important, TLR4-driven sensor of Gram-negative bacterial infection and provide a rationale for blockade of both TLRs, in addition to antibiotic therapy for the treatment of Gram-negative bacterial infection.
Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy
Authors: Lina Nordquist, Malou Friederich-Persson, Angelica Fasching, Per Liss, Kumi Shoji, Masaomi Nangaku, Peter Hansell, Fredrik Palm
Journal: Journal of the American Society of Nephrology (2014)

Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.
Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult
Authors: Shaefali P Rodgers, Heather A Born, Pritam Das, Joanna L Jankowsky
Journal: Molecular Neurodegeneration (2012)

Abstract Background Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two-year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder. Results We show that overexpression of the Alzheimer’s-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral. Conclusions Our findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer’s disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long-lasting effects on neuronal function in the adult. The tet-off APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the mice reach adulthood.
KPC-2 producing Klebsiella pneumoniae and Escherichia coli co-infection in a catheter-related infection
Authors: R.S. Leão, A. P. D' A. Carvalho-Assef, J.C.D. Correal, R.V. Silva, D.C. Goldemberg, M.D. Asensi, E.A. Marques
Journal: Clinical Microbiology and Infection (2010)