tbuckley/cabot-search huggingface dataset:
C-Type Lectin DC-SIGN Modulates Toll-like Receptor Signaling via Raf-1 Kinase-Dependent Acetylation of Transcription Factor NF-κB
Authors: Sonja I. Gringhuis, Jeroen den Dunnen, Manja Litjens, Bert van het Hof, Yvette van Kooyk, Teunis B.H. Geijtenbeek
Journal: Immunity (2007)
Uric acid promotes an acute inflammatory response to sterile cell death in mice
Authors: Hajime Kono, Chun-Jen Chen, Fernando Ontiveros, Kenneth L. Rock
Journal: Journal of Clinical Investigation (2010)

Necrosis stimulates inflammation, and this response is medically relevant because it contributes to the pathogenesis of a number of diseases. It is thought that necrosis stimulates inflammation because dying cells release proinflammatory molecules that are recognized by the immune system. However, relatively little is known about the molecular identity of these molecules and their contribution to responses in vivo. Here, we investigated the role of uric acid in the inflammatory response to necrotic cells in mice. We found that dead cells not only released intracellular stores of uric acid but also produced it in large amounts postmortem as nucleic acids were degraded. Using newly developed Tg mice that have reduced levels of uric acid either intracellularly and/or extracellularly, we found that uric acid depletion substantially reduces the cell death-induced inflammatory response. Similar results were obtained with pharmacological treatments that reduced uric acid levels either by blocking its synthesis or hydrolyzing it in the extracellular fluids. Importantly, uric acid depletion selectively inhibited the inflammatory response to dying cells but not to microbial molecules or sterile irritant particles. Collectively, our data identify uric acid as a proinflammatory molecule released from dying cells that contributes significantly to the cell death-induced inflammatory responses in vivo.
Mesenchymal Stem Cell Delivery of TRAIL Can Eliminate Metastatic Cancer
Authors: Michael R. Loebinger, Ayad Eddaoudi, Derek Davies, Sam M. Janes
Journal: Cancer Research (2009)

Cancer is a leading cause of mortality throughout the world and new treatments are urgently needed. Recent studies suggest that bone marrow-derived mesenchymal stem cells (MSC) home to and incorporate within tumor tissue. We hypothesized that MSCs engineered to produce and deliver tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a transmembrane protein that causes selective apoptosis of tumor cells, would home to and kill cancer cells in a lung metastatic cancer model. Human MSCs were transduced with TRAIL and the IRES-eGFP reporter gene under the control of a tetracycline promoter using a lentiviral vector. Transduced and activated MSCs caused lung (A549), breast (MDAMB231), squamous (H357), and cervical (Hela) cancer cell apoptosis and death in coculture experiments. Subcutaneous xenograft experiments confirmed that directly delivered TRAIL-expressing MSCs were able to significantly reduce tumor growth [0.12 cm(3) (0.04-0.21) versus 0.66 cm(3) (0.21-1.11); P < 0.001]. We then found, using a pulmonary metastasis model, systemically delivered MSCs localized to lung metastases and the controlled local delivery of TRAIL completely cleared the metastatic disease in 38% of mice compared with 0% of controls (P < 0.05). This is the first study to show a significant reduction in metastatic tumor burden with frequent eradication of metastases using inducible TRAIL-expressing MSCs. This has a wide potential therapeutic role, which includes the treatment of both primary tumors and their metastases, possibly as an adjuvant therapy in clearing micrometastatic disease following primary tumor resection.
Postvaccinial Meningo-Encephalitis
Authors: Juan J. Angulo, Evandro Pimenta-de-Campos, Luis F. de Salles-Gomes
Journal: JAMA (1964)

THE ETIOLOGY, pathogenesis, and pathology of postvaccinial encephalitis are subjects of much controversy.<sup>1-4</sup>Since isolation of vaccinia virus is not difficult, the reports of failures are impressive. Greenberg and Applebaum, for example, were unsuccessful in attempts to isolate the virus from the brain in three fatal cases of postvaccinial encephalitis,<sup>2</sup>and Verlinde failed in six cases.<sup>4</sup>On the other hand, vaccinia virus was isolated from the brain in three fatal cases by Blaxall,<sup>5</sup>and in two cases by Turnbull and McIntosh.<sup>6</sup>Blaxall recovered the virus from the brain, liver, and blood of calves up to the 13th day after vaccination, in rabbits up to the 10th day, and in monkeys up to the 8th day.<sup>5</sup>The present communication reports the case of a patient with postvaccinial meningo-encephalitis from whose brain vaccinia virus was isolated and identified. <h3>Report of a Case</h3> This case was studied
Reply to Dr Nuhoğlu et al.'s Letter to the Editor re: Miroslav L. Djordjevic, Sava V. Perovic, Zoran Slavkovic and Nenad Djakovic. Longitudinal Dorsal Dartos Flap for Prevention of Fistula after a Snodgrass Hypospadias Procedure. Eur Urol 2006;50:53–57
Authors: Miroslav Djordjevic
Journal: European Urology (2006)
Release of osmolytes from perfused rat liver on perivascular nerve stimulation: α-adrenergic control of osmolyte efflux from parenchymal and nonparenchymal liver cells
Authors: Stephan Vom Dahl, Johannes Georg Bode, Roland Michael Reinehr, Irmhild Mönnighoff, Ralf Kubitz, Dieter Häussinger
Journal: Hepatology (1999)

The effects of perivascular nerve stimulation and phenylephrine on osmolyte release were studied in the intact perfused rat liver and isolated liver parenchymal cells (PC) and nonparenchymal cells. In the perfused liver, electrical stimulation of perivascular nerves (20 Hz/2 ms/20 V) led to a phentolamine–sensitive increase of cell hydration by 6.5% ± 1.2% (n = 3) and a transient phentolamine–sensitive stimulation of taurine and inositol, but not betaine, release. These nerve effects were mimicked by phenylephrine, but not prostaglandin F 2α , and were not affected by sodium nitroprusside (SNP) or ibuprofen. Nerve stimulation-induced taurine, but not inositol, release was inhibited by 4,4′–di–isothiocyanatostilbene–2,2′–disulphonic acid (DIDS) (50 μmol/L). Single–cell fluorescence studies with isolated liver PC, Kupffer cells (KC), sinusoidal endothelial cells (SEC), and hepatic stellate cells (HSC) revealed that phenylephrine induced an increase in cytosolic free Ca 2+ only in PC and HSC, but not in KC and SEC, whereas extracellular uridine triphosphate (UTP) produced Ca 2+ transients/oscillations in all liver cell types studied. Phenylephrine had no effect on osmolyte release from isolated KC and SEC, but increased taurine (but not inositol) release from PC and inositol (but not taurine) efflux from HSC. The data suggest that: 1) liver cell hydration and—consecutively—osmolyte content are modulated by hepatic nerves via an α–adrenergic mechanism, which does not involve eicosanoids or hemodynamic changes; 2) that PC and HSC are the primary targets for nerve–dependent α–adrenergic activation, whereas 3) KC and SEC probably do not express α–adrenoceptors coupled to Ca 2+ mobilization or osmolyte efflux.
Comparison of Intake and Systemic Relative Effect Potencies of Dioxin-like Compounds in Female Mice after a Single Oral Dose
Authors: Karin I. van Ede, Patrik L. Andersson, Konrad P.J. Gaisch, Martin van den Berg, Majorie B.M. van Duursen
Journal: Environmental Health Perspectives (2013)

Background: Risk assessment for mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) is performed using the toxic equivalency factor (TEF) approach. These TEF values are derived mainly from relative effect potencies (REPs) linking an administered dose to an in vivo toxic or biological effect, resulting in “intake” TEFs. At present, there is insufficient data available to conclude that intake TEFs are also applicable for systemic concentrations (e.g., blood and tissues).Objective: We compared intake and systemic REPs of 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3´,4,4´,5-pentachlorobiphenyl (PCB-126), 2,3´,4,4´,5-pentachlorobiphenyl (PCB-118), and 2,3,3´,4,4´,5-hexachlorobiphenyl (PCB-156) in female C57BL/6 mice 3 days after a single oral dose.Methods: We calculated intake REPs and systemic REPs based on administered dose and liver, adipose, or plasma concentrations relative to TCDD. Hepatic cytochrome P450 1A1–associated ethoxyresorufin-O-deethylase (EROD) activity and gene expression of Cyp1a1, 1a2 and 1b1 in the liver and peripheral blood lymphocytes (PBLs) were used as biological end points.Results: We observed up to one order of magnitude difference between intake REPs and systemic REPs. Two different patterns were discerned. Compared with intake REPs, systemic REPs based on plasma or adipose levels were higher for PeCDD, 4-PeCDF, and PCB-126 but lower for the mono-ortho PCBs 118 and 156.Conclusions: Based on these mouse data, the comparison between intake REPs and systemic REPs reveals significant congener-specific differences that warrants the development of systemic TEFs to calculate toxic equivalents (TEQs) in blood and body tissues.
Antineoplastons: The Controversy Continues
Authors: Robert G. Houston
Journal: JAMA (1993)

<h3>To the Editor.</h3> —As a medical writer who has investigated antineoplastons, I found that numerous assertions in the article by Dr Green<sup>1</sup>appear to be at odds with the documentation. He claims, for example, that "none of the independent tests... have shown anticancer activity." Yet his article cites three independent animal studies (references 18 through 20) from Japan and the United States regarding tumor inhibition by antineoplastons. Focusing on letters, Green ignores these published results. Also ignored were the results of published clinical studies by Dr Burzynski (references 7 and 33). Green repeatedly misstates the work of Burzynski. Contrary to Green, I found Burzynki's 1968 doctoral dissertation in biochemistry listed in the bibliography that Green claims omits it. The article concludes that phenylacetic acid, a component of the therapy, is not active against cancer. Yet scientists at the NCI have reported that phenylacetate is a "nontoxic inducer of tumor
Withdrawing the Critical but Not the Care-Reply
Authors: David K. Lee
Journal: JAMA (1994)

In Reply.  —We appreciate Dr Orr's bringing us up short on the careless use of jargon. We used the catchwords withdrawing  because the phrase has become part of common usage. We agree that after intensive care interventions are withdrawn, we have left to offer only our humanity, compassion, and care. May we learn to use our human skills as well as we use our technical ones.
Angioedema induced by angiotensin II blocker telmisartan
Authors: A. Borazan, H. Üstün, A. Yılmaz
Journal: Allergy (2003)

Telmisartan (Pritor, Glaxo-Smith-Kline, Boehringer Ingelheim Pharma KG, Germany) is an orally effective blocker of the angiotensin II (AII) receptor. Angioedema is a rare side effect of AII-receptor blockers (1, 2). We describe a case of angioedema caused by telmisartan, which rarely causes allergic reactions. A 66-year-old woman was admitted to the outpatient clinic with occipital headache. The patient had 1 year hypertension history and had not used any antihypertensive medication. The blood pressure was 160/100 mmHg. All physical examination findings of the patient was normal. Telmisartan was started at a dose of 80 mg/day per oral. The patient was admitted to hospital with dyspnea after 12 h of telmisartan medication. Physical examination of the patient revealed 140/100 mmHg of blood pressure, edema of mucosal surfaces and uvula and edema-like anasarca pattern especially in right-sided hemilateral, wheezing and ronchus. Methyl-prednisolone and antihistaminic were administered intravenously to the patient. Symptomatic relief was achieved after 2 h of medication. Oral methyl-prednisolone and antihistaminic were continued for 5 days. A calcium channel blocker, amlodipin, 10 mg/day was started as antihypertensive agent. The patient was reported to Glaxo-Smith-Kline Centre because of angioedema development after telmisartan therapy. Telmisartan is an AII-receptor blocker and effective in patients with mild-to-moderate hypertension with daily doses of 20–160 mg (1). The frequency of cough in patients taking losartan or telmisartan was low (3, 4). Acetylcholinesterase (ACE) inhibitor-induced cough is thought to result from the inhibition of bradykinin degradation by ACE inhibitors. If bradykinin causes ACE inhibitor-induced cough or anaphylaxis, AII-receptor blockers should be free of these side effects (1, 5). Recent case reports, however document angioedema following therapy with A II-receptor blockers; 32% of the reported patients experienced a prior episode of angioedema attributed to ACE inhibitor therapy (6). In our case, the patient had no ACE inhibitor medication previously. Sharma and coworkers (7) reported the case of a hemodialysis patient who previously had angioedema after therapy with ACE inhibitors and again had angioedema while taking losartan. Acker et al. (8) reported a case of losartan-induced angioedema in a patient with renal insufficiency and allergic to radiographic contrast material. The patient previously used ACE inhibitor without any side effect or angioedema history. Alternative therapy is necessary for patients who experience angioedema which is a potential life-threatening adverse effect. Our patient's blood pressure was controlled with a calcium channel blocker, amlodipin. We recommend that telmisartan and other AII-receptor blockers should be used cautiously in patients with a history of sensitivity to ACE inhibitors or other agents and the patients should be informed about the allergicreactions.
Abstract 1048: Targeted BRAF therapy attenuates the promotional activity of estrogen in thyroid cancer.
Authors: Elyse K. Hanly, Shilpi Rajoria, Andrea L. George, Robert Suriano, Jan Geliebter, Harry Pantelides, Edward J. Shin, Raj K. Tiwari
Journal: Cancer Research (2013)

Abstract Thyroid cancer, which is three to four times more prevalent in women than men, is the most common endocrine-related cancer in the United States and its incidence has increased in the past three decades. Among various genetic lesions identified in thyroid cancer, the BRAF V600E mutation is found in 50% of papillary thyroid cancers and affords an opportunity for targeted drug therapy. Our laboratory identified estrogen as a promotional factor in thyroid cancer, as estrogen enhances proliferation, migration, and invasion of thyroid cancer cells in vitro. Since the mitotic activity of estrogen is partially mediated by the mitogen-activated protein kinase (MAPK) pathway, we hypothesized that a targeted BRAF V600E inhibitor, PLX4032, would inhibit estrogen-mediated tumor-promoting activity. Results demonstrate that PLX4032 abrogates estrogen-induced increases in proliferation and invasion of BRAF V600E-mutated BCPAP papillary thyroid cancer cells in a dose-dependent manner. In contrast, this phenomenon was not observed in Nthy-ori 3-1 thyroid cells, which are wild-type immortalized thyroid cells without the BRAF V600E mutation. Expression of estrogen receptor is not modulated by PLX4032 treatment, indicating that PLX4032 targets signal transduction pathways in estrogen-responsive thyroid cells. PLX4032 down-regulates the expression of key signaling molecules of the BRAF pathway, including mitogen-activated protein kinase kinase (p-MEK), extracellular-signal regulated kinases (p-ERK), and mammalian target of rapamycin (p-mTOR) in BRAF-mutated BCPAP cells and does not alter the expression of these signaling molecules in wild-type Nthy-ori 3-1 cells. These results demonstrate a direct interlinking of a genetic lesion amenable to drug therapy with the promotional activity of estrogen. These findings will lead to an evaluation of combinational therapy including anti-estrogens and PLX4032 in preclinical animal models and a subset of patients harboring the BRAF V600E mutation. Targeting growth-promoting signal transduction pathways constitutively activated by genetic lesions will ultimately aid in overcoming resistance to traditional radioactive iodine therapy in patients with specific mutations such as BRAF V600E. Citation Format: Elyse K. Hanly, Shilpi Rajoria, Andrea L. George, Robert Suriano, Jan Geliebter, Harry Pantelides, Edward J. Shin, Raj K. Tiwari. Targeted BRAF therapy attenuates the promotional activity of estrogen in thyroid cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1048. doi:10.1158/1538-7445.AM2013-1048
Simultaneous Noncontact Mapping of Left Atrium in Patients With Paroxysmal Atrial Fibrillation
Authors: Gerhard Hindricks, Hans Kottkamp
Journal: Circulation (2001)

Background Catheter ablation of pulmonary vein ectopic foci is a potentially curative treatment strategy for patients with atrial fibrillation. However, identification of arrhythmogenic pulmonary veins with conventional mapping is difficult, especially in patients with rare focal activity, multiple active foci, or extrapulmonary foci. The present study was designed to investigate use of simultaneous noncontact mapping in this setting. Methods and Results In 17 consecutive patients with paroxysmal atrial fibrillation, a catheter-mounted noncontact multielectrode array positioned in the left atrium was used to reconstruct 3300 electrograms simultaneously from a single beat. Isopotential maps were generated during sinus rhythm and focal activity. After ectopic foci were identified, radiofrequency catheter ablation was performed in patients with 1 or 2 foci. However, in patients who had multiple foci, intraoperative ablation of atrial fibrillation was advised. A total of 28 ectopic foci (25 pulmonary vein foci and 3 extrapulmonary vein foci) were identified by use of isopotential maps generated from a single beat of focal activity. Radiofrequency catheter ablation guided by noncontact mapping was attempted in 12 patients with 1 or 2 ectopic foci. Successful ablation of atrial fibrillation was achieved in 9 of 12 patients (75%). Conclusions Noncontact mapping allows rapid and precise identification of arrhythmogenic pulmonary veins in addition to extrapulmonary vein foci. Thus, the present study shows that the technology may be used not only to guide radiofrequency catheter ablation, but also as a diagnostic tool to develop individual treatment strategies.
Treatment of Status Epilepticus
Authors: Harold A. Wilkinson
Journal: JAMA (1977)

To the Editor.—  I read with interest the article by Dr Celesia entitled, Modern Concepts of Status Epilepticus (235:1571, 1976), but was disturbed to find two omissions that I consider significant. Although Dr Celesia correctly identifies diazepam given intravenously as an effective agent for termination of status epilepticus, he fails to carefully document the potential dangers of intravenous administration of this agent. He specifically included no reference to cardiac arrest, which can follow use of this drug, especially if it is administered rapidly. The dose required to cause cardiac arrest is at times surprisingly small, especially in older or debilitated patients or in patients whose myocardium is exhausted by prolonged seizure activity. I have personally seen a cardiac death (from a series of five such cardiac deaths) in an elderly man after only 7 or 8 mg diazepam was administered intravenously.  The second omission was that Dr Celesia made no
Using Multilocus Sequence Data to Assess Population Structure, Natural Selection, and Linkage Disequilibrium in Wild Tomatoes
Authors: Uraiwan Arunyawat, Wolfgang Stephan, Thomas Städler
Journal: Molecular Biology and Evolution (2007)

We employed a multilocus approach to examine the effects of population subdivision and natural selection on DNA polymorphism in 2 closely related wild tomato species (Solanum peruvianum and Solanum chilense), using sequence data for 8 nuclear loci from populations across much of the species' range. Both species exhibit substantial levels of nucleotide variation. The species-wide level of silent nucleotide diversity is 18% higher in S. peruvianum (πsil ≈ 2.50%) than in S. chilense (πsil ≈ 2.12%). One of the loci deviates from neutral expectations, showing a clinal pattern of nucleotide diversity and haplotype structure in S. chilense. This geographic pattern of variation is suggestive of an incomplete (ongoing) selective sweep, but neutral explanations cannot be entirely dismissed. Both wild tomato species exhibit moderate levels of population differentiation (average FST ≈ 0.20). Interestingly, the pooled samples (across different demes) exhibit more negative Tajima's D and Fu and Li's D values; this marked excess of low-frequency polymorphism can only be explained by population (or range) expansion and is unlikely to be due to population structure per se. We thus propose that population structure and population/range expansion are among the most important evolutionary forces shaping patterns of nucleotide diversity within and among demes in these wild tomatoes. Patterns of population differentiation may also be impacted by soil seed banks and historical associations mediated by climatic cycles. Intragenic linkage disequilibrium (LD) decays very rapidly with physical distance, suggesting high recombination rates and effective population sizes in both species. The rapid decline of LD seems very promising for future association studies with the purpose of mapping functional variation in wild tomatoes.
T5 KCa3.1 ion channel blockers restore corticosteroid sensitivity in cytokine-treated airway smooth muscle (ASM) cells from both COPD and asthmatic patients
Authors: L. Chachi, A. Shikotra, A. Sutcliffe, C. Brightling, P. Bradding, Y. Amrani
Journal: Thorax (2010)

<h3>Background</h3> The K<sup>+</sup> channel KCa3.1 is expressed by several inflammatory and structural airway cells including mast cells and airway smooth muscle (ASM). We have proposed that this channel may play roles in the development of both airway inflammation and remodelling in asthma and COPD. The role of KCa3.1 channels in chemokine secretion by ASM is not known. <h3>Aims</h3> To investigate the expression of KCa3.1 in ASM in the airways of healthy and asthmatic subjects, and its function in <i>ex vivo</i> cultured primary human ASM cells. <h3>Methods</h3> Tissue was collected at bronchoscopy from subjects with asthma and healthy controls, and either processed into GMA for immunohistochemistry, or dissected for the culture of ASM. Further ASM samples were cultured from patients with COPD undergoing lung resection for carcinoma. To examine ASM chemokine production, we used our well-established cellular model of corticosteroid resistance (TNFα/IFNgamma-treated ASM cells). <h3>Results</h3> KCa3.1 immunostaining was evident in the ASM in healthy subjects and patients with asthma. There was no difference in the level of expression between healthy subjects (n=7), and those with moderate (n=5) and severe (n=6) asthma. In cultured ASM cells exposed to TNFα/IFNgamma, both ELISA and RT-PCR demonstrated expression of CX3CL1 or CCL5 which were (1) synergistically produced at 24 h and (2) completely resistant to fluticasone pre-treatment (100 nM). We found that KCa3.1 block alone did not inhibit the secretion of CX3CL1 or CCL5. Interestingly, the failure of fluticasone to suppress CX3CL1 and CCL5 expression in response to TNFα/IFNgamma combination was reversed by TRAM-34, a selective inhibitor of KCa3.1 channels. The increased anti-inflammatory action induced by the TRAM-34-fluticasone combination was observed in cells derived from healthy (n=3), asthmatic (n=3) and COPD (n=3) patients. In addition, restoration of corticosteroid sensitivity by KCa3.1 blockers was associated with an increased GR phosphorylation on serine 211 residues. <h3>Conclusions</h3> Together, these data suggest that targeting KCa3.1 channels could serve as a novel approach to enhancing/restoring steroid sensitivity in pulmonary disease.