tbuckley/cabot-search huggingface dataset:
Gene Therapy by Targeted Adenovirus-mediated Knockdown of Pulmonary Endothelial Tph1 Attenuates Hypoxia-induced Pulmonary Hypertension
Authors: Ian Morecroft, Katie White, Paola Caruso, Margaret Nilsen, Lynn Loughlin, Raul Alba, Paul N Reynolds, Sergei M Danilov, Andrew H Baker, Margaret R MacLean
Journal: Molecular Therapy (2012)

Serotonin is produced by pulmonary arterial endothelial cells (PAEC) via tryptophan hydroxylase-1 (Tph1). Pathologically, serotonin acts on underlying pulmonary arterial cells, contributing to vascular remodeling associated with pulmonary arterial hypertension (PAH). The effects of hypoxia on PAEC-Tph1 activity are unknown. We investigated the potential of a gene therapy approach to PAH using selective inhibition of PAEC-Tph1 in vivo in a hypoxic model of PAH. We exposed cultured bovine pulmonary arterial smooth muscle cells (bPASMCs) to conditioned media from human PAECs (hPAECs) before and after hypoxic exposure. Serotonin levels were increased in hypoxic PAEC media. Conditioned media evoked bPASMC proliferation, which was greater with hypoxic PAEC media, via a serotonin-dependent mechanism. In vivo, adenoviral vectors targeted to PAECs (utilizing bispecific antibody to angiotensin-converting enzyme (ACE) as the selective targeting system) were used to deliver small hairpin Tph1 RNA sequences in rats. Hypoxic rats developed PAH and increased lung Tph1. PAEC-Tph1 expression and development of PAH were attenuated by our PAEC-Tph1 gene knockdown strategy. These results demonstrate that hypoxia induces Tph1 activity and selective knockdown of PAEC-Tph1 attenuates hypoxia-induced PAH in rats. Further investigation of pulmonary endothelial-specific Tph1 inhibition via gene interventions is warranted.
Leukoclastic Vasculitis From Cimetidine
Authors: W. K. Dernbach
Journal: JAMA (1981)

<h3>To the Editor.—</h3> Toxic effects attributable to cimetidine (Tagamet) have included transient diarrhea, muscle pains, dizziness, and rashes. In addition, confusional states in elderly patients have been recorded. We wish to report another toxic effect that we have seen. <h3>Report of a Case.—</h3> A 72-year-old man was examined for dyspepsia in early 1978. A large benign gastric ulcer was seen on endoscopy. He was treated with cimetidine and became symptom free, and repeated endoscopy demonstrated healing. He remained well until symptoms recurred 1 1/2 years later, and cimetidine therapy was recommended. At that time he was receiving no other medications. His condition improved, but eight days after the start of therapy a rash developed. This consisted of purpuric, raised red areas, most severely present on the arms and legs but also to a limited extent on the trunk. There was edema of both hands and feet. Notable laboratory values were as follows: lactic dehydrogenase
Abstract 1531: Reactive astrocytes promote the growth of cancer stem-like cells of metastatic breast tumor by activating Notch signaling in brain
Authors: Fei Xing, Aya Kobayashi, Hiroshi Okuda, Misako Watabe, Puspa R. Pandey, Sudha K. Pai, Koji Fukuda, Megumi Iiizumi, Kounosuke Watabe
Journal: Cancer Research (2012)

Abstract Metastatic diseases are responsible for the majority of deaths in breast cancer patients, and brain is one of the most common metastatic sites. The metastatic tumor in the brain profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the one year survival rate among these patients remains less than 20%. However, little is known about the pathogenesis of brain metastasis, and therefore, it is of paramount importance to elucidate the molecular mechanism of metastatic process in order to define a specific therapeutic target. Our analysis of existing microarray database indicate that interleukin-1α (IL-1α) is highly expressed in MDA-MB231BrM2a (231BrM) cell line which is capable of preferentially metastasizing to the brain. IL-1α is known to have an ability of “activating” astrocytes that are often found in the metastatic niche, and therefore, it is speculated that the reactive astrocytes can promote growth and invasion of metastasized cells in the brain. To explore this possibility, we examined the effect of IL-1α and the conditioned medium of 231BrM cells on rat primary astrocytes in vitro. Our results of qRT-PCR and Western blot analysis indicate that IL-1α and the conditioned medium significantly up-regulated the Notch ligand, JAG1, in astrocytes, and that this up-regulation was abrogated by the NF-κB inhibitor, PDTC. We also found that the interaction between CSCs and astrocytes significantly enhances the self-renewal ability of CSCs. To further examine the interaction of astrocytes and tumor cells in the brain, we intracardially injected 231BrM cells in nude mice, and tumor growth was monitored by Xenogen bioimager. After 4 weeks, metastatic tumor growth was observed at multiple sites of the brain, and the results of immunohistochemical analysis indicated that astrocytes adjacent to the metastatic lesions strongly expressed JAG1 and the reactive astrocyte marker, GFAP (Glial fibrillary acidic protein). Finally, we found that a BBB-permeable Notch inhibitor was able to significantly suppress metastatic growth of breast cancer in the brain in our animal model. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1531. doi:1538-7445.AM2012-1531
The Birth of the Blues: I. Blue Christmas
Authors: Meyer P. Schwartz
Journal: JAMA (1987)

<h3>To the Editor.—</h3> Of the many presenting signs a physician sees, skin discoloration is one of the most obvious. We are familiar with the cherry red of carbon monoxide poisoning or the orange of carotene, but what of blue? <h3>Report of a Case.—</h3> A 43-year-old man, presented to our freestanding clinic at 10:15 AM on Dec 29, a Sunday. He complained only of blueness to his face of one hour's duration. He denied trauma, heart disease, or a personal or familial history of bleeding disorders as well as any discomfort, itching, shortness of breath, dizziness, or other neurologic deficits. His only daily activity was showering, shaving, and dressing. Physical examination revealed a well-developed, well-nourished male not in acute distress, but concerned. His face, cephalad to the zygomatic arches bilaterally, was blue. There was no obvious edema or tenderness. Sclerae were white. The rest of his skin was of normal color,
An Obesity-Associated<i>FTO</i>Gene Variant and Increased Energy Intake in Children
Authors: Joanne E. Cecil, Roger Tavendale, Peter Watt, Marion M. Hetherington, Colin N.A. Palmer
Journal: New England Journal of Medicine (2008)

Variation in the fat mass and obesity–associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown.
Zones of Excess Mortality in Massachusetts
Authors: C. David Jenkins, Robert W. Tuthill, Saul I. Tannenbaum, Craig R. Kirby
Journal: New England Journal of Medicine (1977)

In the Report of the Sanitary Commission of Massachusetts, 1850, Lemuel Shattuck compared mortality rates for earlier years in urban Boston and in country towns with those reported from England. Shattuck's detailed report showed that the country towns had mortality rates comparable to the healthiest districts in England. Boston, however, had rates comparable to those of London, where the average life expectancy was shorter by eight years than that of England overall.*The study reported below addressed the same issues for the early 1970's with particular reference to the social and demographic correlates of excess mortality by selected causes . . .
Nonuniform cardiac sympathetic nerve discharge: mechanism for coronary occlusion and digitalis-induced arrhythmia.
Authors: C M Lathers, G J Kelliher, J Roberts, A B Beasley
Journal: Circulation (1978)

This study examined nonuniform postganglionic cardiac sympathetic neural discharge as a possible mechanism involved in the production of coronary occlusion or ouabain-induced arrhythmias. After acute occlusion of the left anterior descending coronary artery in 12 cats, anesthetized with alpha-chloralose and pretreated with atropine, arrhythmia occurred within 3 min in eight animals; three of these died in ventricular fibrillation. In recordings from 15 nerves in the eight animals with arrhythmia, spontaneous discharge increased in nine nerves, decreased in five nerves, and showed no change in one nerve. This nonuniform neural discharge was associated with the development of arrhythmia after occlusion. In four of the cats, neural discharge did not change within the first 3 min after coronary artery occlusion and arrhythmia did not occur. Development of ouabain-induced arrhythmia was accompanied by a nonuniform pattern in the neural discharge (13 cats). This discharge may alter ventricular excitation and conduction to produce arrhythmia.
Pancreatic noradrenergic nerves are activated by neuroglucopenia but not by hypotension or hypoxia in the dog. Evidence for stress-specific and regionally selective activation of the sympathetic nervous system.
Authors: P J Havel, R C Veith, B E Dunning, G J Taborsky
Journal: Journal of Clinical Investigation (1988)

To determine if acute stress activates pancreatic noradrenergic nerves, pancreatic norepinephrine (NE) output (spillover) was measured in halothane-anesthetized dogs. Central neuroglucopenia, induced by intravenous 2-deoxy-D-glucose [( 2-DG] 600 mg/kg + 13.5 mg/kg-1 per min-1) increased pancreatic NE output from a baseline of 380 +/- 100 to 1,490 +/- 340 pg/min (delta = +1,110 +/- 290 pg/min, P less than 0.01). Surgical denervation of the pancreas reduced this response by 90% (delta = +120 +/- 50 pg/min, P less than 0.01 vs. intact innervation), suggesting that 2-DG activated pancreatic nerves by increasing the central sympathetic outflow to the pancreas rather than by acting directly on nerves within the pancreas itself. These experiments provide the first direct evidence of stress-induced activation of pancreatic noradrenergic nerves in vivo. In contrast, neither hemorrhagic hypotension (50 mmHg) nor hypoxia (6-8% O2) increased pancreatic NE output (delta = +80 +/- 110 and -20 +/- 60 pg/min, respectively, P less than 0.01 vs. neuroglucopenia) despite both producing increases of arterial plasma NE and epinephrine similar to glucopenia. The activation of pancreatic noradrenergic nerves is thus stress specific. Furthermore, because both glucopenia and hypotension increased arterial NE, yet only glucopenia activated pancreatic nerves, it is suggested that a regionally selective pattern of sympathetic activation can be elicited by acute stress, a condition in which sympathetic activation has traditionally been thought to be generalized and nondiscrete.
Gallium nitrate inhibits calcium resorption from bone and is effective treatment for cancer-related hypercalcemia.
Authors: R P Warrell, R S Bockman, C J Coonley, M Isaacs, H Staszewski
Journal: Journal of Clinical Investigation (1984)

Approximately two-thirds of patients who receive the anticancer drug gallium nitrate develop mild hypocalcemia. To evaluate the mechanism of drug-induced hypocalcemia, we tested the effects of gallium nitrate upon in vitro release of 45Ca++ from explanted fetal rat bones. The drug significantly inhibited 45Ca++ release in response to stimulation with both parathyroid hormone and a lymphokine preparation with osteoclast activating factor activity. The inhibitory effects on bone resorption were both time- and dose-dependent. Later, in a pilot study, we treated 10 patients who had cancer-related hypercalcemia with gallium nitrate administered by continuous infusion. All patients responded by a reduction of total serum calcium to normal or subnormal concentrations (13.8 +/- 1.05 mg/dl, mean +/- SD pretreatment, to 8.03 +/- 1.03 mg/dl, mean posttreatment nadir). Our results indicate that gallium nitrate effectively treats cancer-related hypercalcemia and that it probably acts by inhibiting calcium release from bone.
Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vasorum in injured rat arteries.
Authors: E R Edelman, M A Nugent, L T Smith, M J Karnovsky
Journal: Journal of Clinical Investigation (1992)

Basic fibroblast growth factor (bFGF) is mitogenic for smooth muscle cells (SMC) and angiogenic. We examined the in vivo effects of bFGF in balloon denuded carotid arteries of laboratory rats. bFGF was administered continuously from polymer-based devices at 34 ng/d into the periadventitial space of rat carotid arteries for 2 wk. Intimal hyperplasia was not observed in the absence of injury or with lipopolysaccharide induced endothelial dysfunction. Different degrees of vascular injury produced proportionally more intimal hyperplasia. bFGF increased the intimal hyperplastic response 1.3-fold with severe vascular injury, and 2.4-fold with more mild injury. Increased cell proliferation, not extracellular matrix production, accounted for these effects. Cell density was unchanged for the control and bFGF-treated groups, and the number of proliferating intimal cells at 2 wk rose to an amount equivalent to the increase in mass; 1.9- and 4.0-fold for severe and lesser injury, respectively. The relative ability of heparin to reduce SMC proliferation was not altered by the presence of bFGF.bFGF also induced profound angiogenesis within and surrounding the polymeric releasing device, and in the vasa vasorum immediately around the injured arteries. bFGF's effect on vasa was linearly related to the amount of SMC proliferation within the blood vessel. Thus, the in vivo mitogenic and angiogenic potential of bFGF are coupled, and may be similarly modulated by the products of local injury and/or factors in the vessel wall.
COARCTATION OF THE AORTA
Authors: Wilmot F. Pierce
Journal: JAMA (1934)

Death from coarctation of the aorta occurs sometimes from rupture of a mycotic aneurysm in the aortic wall. Hamilton and Abbott<sup>1</sup>mention four such deaths in 200 persons with coarctated aorta, and Evans<sup>2</sup>mentions two in twenty-eight. In the case reported here the aorta also broke, but it was involved from without by suppurative mediastinitis. Part of the abscess wall was formed by the aorta and esophagus. <h3>REPORT OF CASE</h3><h3>Clinical History.</h3> B. P., an Italian laborer, aged 35, a patient of Dr. F. H. Straus, was admitted to the Presbyterian Hospital on three occasions. The first was Sept. 26, 1927, when he came in with bronchopneumonia. He had worked in coal mines at hard manual labor for many years and there had never been any symptoms referable to the cardiovascular system. Physical examination revealed, besides the bronchopneumonia, an enlarged heart, palpable and visible pulsations in both suprascapular
The Influence of a Family History of Asthma and Parental Smoking on Airway Responsiveness in Early Infancy
Authors: Young S, Le Souëf Pn, Geelhoed Gc, Stick Sm, Turner Kj, Landau Li
Journal: New England Journal of Medicine (1991)

Airway responsiveness to inhaled nonspecific bronchoconstrictive agents has been demonstrated in normal, healthy infants. However, it is unknown whether airway responsiveness is present from birth or if it develops as a result of subsequent insults to the respiratory tract. To investigate this question, we assessed airway responsiveness in 63 normal infants at a mean age of 4 1/2 weeks.
Comparative Therapeutic Studies with Tilavist
Authors: Michael Alexander
Journal: Allergy (1995)

Summary Comparative clinical trials which include known therapies as well as placebos are essential in constructing a solid basis from which to ‘launch’ any new drug. This applies especially to eye drops for treatment of seasonal allergic conjunctivitis, where the symptomatology, already dependent on the vagaries of the natural pollen challenge season, is further influenced by a positive washing action of the placebo eye drops. Tilavist (2% nedocromil sodium ophthalmic solution) has therefore been compared with sodium cromoglycate eye drops and non‐sedating antihistamine tablets, both mainstays in the treatment of seasonal allergy, in a series of double‐masked, placebo‐controlled, mainly multicentre studies. Nedocromil sodium, twice or four times daily, proved as effective overall as sodium cromoglycate (2% or 4% four times daily) in three seasonal trials, and was the more effective treatment in a study of patients with vernal keratoconjunctivitis. Its efficacy was most evident during peak periods of pollen challenge, when neither placebo nor sodium cromoglycate eye drops controlled breakthrough symptoms. Three further seasonal studies showed nedocromil sodium eye drops to be as effective as standard oral doses of astemizole and terfenadine, whilst a faster onset of action than terfenadine was reported in one multicentre study.
Greater Velocity and Magnitude of Airway Narrowing in Immature Than in Mature Rabbit Lung Explants
Authors: ALEXANDRE DUGUET, CHONG-GANG WANG, RUTE GOMES, HEBERTO GHEZZO, DAVID H. EIDELMAN, ROBERT S. TEPPER
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Methacholine (MCh)-induced bronchoconstriction in vivo produces greater maximal increases in pulmonary and airway resistances in immature than in mature rabbits. Our recent findings of lower shear modulus and greater airway distensibility suggest a lower elastic load limiting airway smooth muscle (ASM) shortening in immature rabbit lungs. We hypothesized that a lower elastic load should result in greater velocity of airway narrowing. Lung explants were prepared from three immature and five mature rabbits. Dynamic narrowing of intraparenchymal airways after maximal MCh stimulation was assessed by video microscopy. Immature airways (n = 80) compared with mature airways (n = 110) demonstrated greater peak velocity of shortening (6.98 ± 0.32 versus 4.22 ± 0.18% of baseline perimeter/s) and greater maximal airway narrowing, expressed as percentage of baseline area (31.9 ± 1.6 versus 42.2 ± 1.8%). For both groups, a greater velocity of shortening resulted in greater airway narrowing. As available data do not support maturational differences in rabbit ASM, our results are consistent with a lower elastic load limiting ASM shortening in the immature rabbit.
Ganetespib and HSP90: Translating Preclinical Hypotheses into Clinical Promise
Authors: David A. Proia, Richard C. Bates
Journal: Cancer Research (2014)

As with many physiologic processes that become subverted during tumorigenesis, the chaperoning activity of heat shock protein 90 (HSP90) is often exploited by cancer cells to confer aberrant proliferative, survival, and/or metastatic potential. Functional inhibition of HSP90 results in the degradation of its client proteins, in turn providing a means to concomitantly disrupt multiple oncogenic signaling cascades through one molecular target. Pharmacologic blockade of HSP90 has, therefore, emerged as an innovative and multifaceted approach for the development of new antineoplastic agents. However, no HSP90 inhibitors are currently approved for cancer therapy and the full promise of this class of agents is yet to be realized. This review focuses on the preclinical activity profile of ganetespib, a potent small-molecule inhibitor of HSP90, the characterization of which has provided important frameworks for the optimal design and application of HSP90 inhibitor-based strategies in a variety of cancer types. Beyond client protein-driven tumors, ganetespib can also potentiate the effects of other molecularly targeted and standard-of-care therapeutics while simultaneously overcoming drug resistance in multiple tumor types, thereby positioning this compound as the leading HSP90 inhibitor currently under clinical development.
Abstract 461: Modulation of estrogen receptor (ER) and androgen receptor (AR) by a modified CRISPR-Cas9 system
Authors: Nanjiang Zhou, Yin-Yuan Mo
Journal: Cancer Research (2014)

Abstract Clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated (Cas) system is a bacterial adaptive immune defense against foreign nucleic acids from viruses, plasmids, and other mobile genetic elements. There are three types of CRISPR systems; type II uses single effector enzyme, Cas9, to cleave double-stranded DNA (dsDNA). Because of this unique feature, CRISPR/Cas9 system has been widely used as a genetic engineering tool from bacteria to mammals. In this system, Cas9 nuclease can bind and cleave genome directed by sequence-specific guide RNA (gRNA). While the wild type Cas9 can cleave double stranded DNA, the mutant Cas9 at D10A and H804A can only bind to but cannot cleave the DNA. Given this unique feature, we tried to repurpose Cas9 as a gene activation or suppression tool. To achieve this, we generated DMCas9 (double-mutant Cas9), and fused it with VP16AD (VP16 activation domain) or VP64AD (VP64 activation domain) to explore its utility for gene activation. To generate a Cas9-based gene silencing tool, we fused DMCas9 with Krab, a well-known protein domain with suppression function. Using a reporter system carrying a specific sequence that was recognized by a given gRNA and mCherry as a readout, we demonstrated that co-expression of VP16AD-DMCas9 and specific gRNAs leads to a at least three-fold induction of mCherry signal; in contrast, DMhCas9-Krab along with the specific gRNA resulted in a significant suppression of mCherry activity. Furthermore, we showed that DMCas9-Krab combined with gRNAs suppressed endogenous expression of AR and ER in MCF-7 cells, causing cell growth inhibition. Together, these results demonstrate the feasibility of Cas9-based gene activation and gene suppression. Citation Format: Nanjiang Zhou, Yin-Yuan Mo. Modulation of estrogen receptor (ER) and androgen receptor (AR) by a modified CRISPR-Cas9 system. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 461. doi:10.1158/1538-7445.AM2014-461
The Survival Rate in Superior Sulcus Tumors Treated by Presurgical Irradiation
Authors: Donald L. Paulson
Journal: JAMA (1966)

Presurgical irradiation in moderate dosage has converted superior sulcus tumors to operable lesions with prolonged survival in some cases. Previous experience was poor whether the patient received no treatment, irradiation alone, or resection followed by irradiation.<sup>7</sup> Bronchogenic carcinomas developing peripherally in the upper lobe of either lung and invading the superior sulcus of the chest (Pancoast's tumor) are usually low-grade epidermoid carcinomas which grow slowly and metastasize late. Situated in the narrow confines of the apex of the chest, they invade early the lymphatics in the endothoracic fascia and involve the lower roots of the brachial plexus, the intercostal nerves, the stellate ganglion, the sympathetic chain, and adjacent ribs and vertebrae, producing severe pain and the Horner's syndrome. Generally such tumors have been considered as not accessible to complete surgical removal and to resist all efforts at irradiation treatment. The average expected time of survival reported in the literature