tbuckley/cabot-search huggingface dataset:
Enhanced Therapeutic Angiogenesis by Cotransfection of Prostacyclin Synthase Gene or Optimization of Intramuscular Injection of Naked Plasmid DNA
Authors: Kazuya Hiraoka, Hiromi Koike, Seiji Yamamoto, Naruya Tomita, Chieko Yokoyama, Tadashi Tanabe, Takashi Aikou, Toshio Ogihara, Yasufumi Kaneda, Ryuichi Morishita
Journal: Circulation (2003)

Although clinical trials of therapeutic angiogenesis by angiogenic growth factors with intramuscular injection of naked plasmid DNA have been successful, there are still unresolved problems such as low transfection efficiency. From this viewpoint, we performed the following modifications: (1) combination with vasodilation using prostacyclin and (2) changing the agents or volume of naked plasmid DNA in vivo.First, we examined cotransfection of the VEGF gene with the prostacyclin synthase gene in a mouse hindlimb ischemia model. Cotransfection of the VEGF gene with the prostacyclin synthase gene resulted in a further increase in blood flow and capillary density compared with single VEGF gene. Similar results were obtained with other angiogenic growth factors, such as hepatocyte growth factor (HGF). Alternatively, we changed the injection volume of the solution of plasmid DNA. Luciferase activity was increased in a volume-dependent manner. An increase in injection volume at 1 site rather than separate injections at multiple sites resulted in high transfection efficiency, which suggests that transfection of naked plasmid DNA is mediated by pressure. Interestingly, treatment with hyperbaric oxygen increased the transfection efficiency. Finally, we also examined the effects of different solutions. Saline and PBS, but not water, achieved high transfection efficiency. In addition, sucrose solution but not glucose solution resulted in high luciferase activity.Overall, angiogenesis might be enhanced by cotransfection of prostacyclin synthase gene or an increase in injection volume and osmotic pressure. These data provide important information for the clinical application of therapeutic angiogenesis to treat peripheral arterial disease.
Calcitonin gene related peptide (CGRP) activates adenylate cyclase of bovine aortic endothelial cells: guanosine 5' triphosphate dependence and partial agonist activity of a tyrosinated analogue
Authors: J R Mcewan, J M Ritter, J Macdermot
Journal: Cardiovascular Research (1989)

Journal Article Calcitonin gene related peptide (CGRP) activates adenylate cyclase of bovine aortic endothelial cells: guanosine 5′ triphosphate dependence and partial agonist activity of a tyrosinated analogue Get access J R MCEWAN, J R MCEWAN From the Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W12 Search for other works by this author on: Oxford Academic PubMed Google Scholar J M RITTER, J M RITTER * From the Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W12 *Present address: Department of Clinical Pharmacology, United Medical and Dental Schools of Guy's & St Thomas's Hospitals, London Bridge SE1 9RT. Search for other works by this author on: Oxford Academic PubMed Google Scholar J MACDERMOT J MACDERMOT From the Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W12 Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 23, Issue 11, November 1989, Pages 921–927, https://doi.org/10.1093/cvr/23.11.921 Published: 01 November 1989 Article history Accepted: 11 May 1989 Published: 01 November 1989
MODULATION OF FUNCTION OF THE ACTIVATED FIRST COMPONENT OF COMPLEMENT BY A FRAGMENT DERIVED FROM SERUM
Authors: Irma Gigli, Allen P. Kaplan, K. Frank Austen
Journal: The Journal of Experimental Medicine (1971)

An activity designated Kf can be separated from human serum and shown to give a 100–300% enhancement in the hemolytic activity of fully activated, fractionated C1. The enhancement of C1 activity is not because of activation of precursor C1 and it is not attributable to an effect on C1 binding. EAC42 or EAC4 intermediates interacted with C1Kf exhibit a greater Tmax and shorter Zmax than when such intermediates are reacted with the same number of hemolytic units of C1. C3 consumption by the EAC1Kf42 intermediate greatly exceeds that of the EAC142 intermediate produced from the same EAC4 cells by comparable inputs of the other two complement components. Taken together, these findings suggest that Kf-treated C1 achieves more efficient utilization of C4 and C2 to create a larger number of 42 sites as appreciated on the intermediates by shorter Tmax and a greater Zmax, and an increased capacity to utilize C3. The capacity of Kf to enhance C1 upon introduction into whole serum of a patient with hereditary angioedema (HAE) in a manner comparable to its effect on fractionated C1 suggests that the effect of Kf may be pertinent to certain pathophysiologic conditions of man.
Prevalence of elevated antithyroid antibodies and antinuclear antibodies in children with immune thrombocytopenic purpura
Authors: Ellen L. Pratt, Michael D. Tarantino, Debra Wagner, Ora Hirsch Pescovitz, Suzanne Bowyer, Amy D. Shapiro
Journal: American Journal of Hematology (2005)

Abstract The prevalence and significance of autoantibodies found at the time of diagnosis of childhood ITP were studied to correlate their presence with risk for development of chronic ITP. Children presenting with acute or chronic ITP to The James Whitcomb Riley Hospital for Children between July 1993 and September 1994 were tested at study entry and followed for the presence of antithyroid antibodies (ATA), antinuclear antibodies (ANA), Coombs' reactivity, and anti‐human immunodeficiency virus (HIV) antibodies. Grouped data were evaluated for significance using Fisher's exact t ‐test. Thirty‐one patients were enrolled in the study with a median age of 8 years (range 17 months–16 years) and male‐to‐female ratio of 1:1.8. Forty‐two percent of these children had an acute course of ITP, and 58% of children had a chronic course of ITP. Of children with acute ITP, three (23%) of the patients had an acute nonplatelet autoantibody detected. Of the children with chronic ITP, six (33%) of the children had at least one abnormal antibody value. Five children (16%) tested positive for ATA: 2 children with acute ITP and 3 with chronic ITP. Five children had positive ANA, and of these children, 4 (80%) had chronic ITP. Sixty‐seven percent of patients testing positive for autoantibodies were female, and 67% of all patients were 12 years of age or older. Three patients, 1 with acute ITP and 1 with chronic ITP, had insignificant abnormal thyroid function tests (these children had minimally elevated T3 with otherwise normal thyroid function, and none of these children had autoantibodies). No patients included in the study tested positive for HIV. Our results suggest that patients with acute ITP who also have other autoantibodies may be more likely to develop chronic ITP than those lacking these autoantibodies. Larger studies are needed to determine whether the presence of ATA or ANA is predictive of clinically significant autoimmune disease. Am. J. Hematol. 79:175–179, 2005. © 2005 Wiley‐Liss, Inc.
Lysophosphatidylcholine Activates p38 and p42/44 Mitogen-Activated Protein Kinases in Monocytic THP-1 Cells, but Only p38 Activation Is Involved in Its Stimulated Chemotaxis
Authors: Qing Jing, Sun-Mei Xin, Wen-Bo Zhang, Ping Wang, Yong-Wen Qin, Gang Pei
Journal: Circulation Research (2000)

Abstract —Oxidized LDLs (OxLDLs) have been shown to be involved in recruitment of blood monocytes into the arterial subendothelial space, which is the earliest step in atherogenesis, but the underlying molecular mechanisms are poorly understood. The present study demonstrated that lysophosphatidylcholine (LPC), a major phospholipid component of OxLDL, strongly evoked phosphorylation and activation of p38 and p42/44 mitogen-activated protein kinases in monocytic cells. The stimulation of p38 and p42/44 occurred in a dose- and time-dependent manner, reaching the maximal activation at 25 μg/mL LPC within 5 minutes. Interestingly, inhibition of p38 activation by OxLDL or LPC, using its selective inhibitors (SB203580 and SKF86002 ), completely blocked OxLDL- or LPC-stimulated chemotaxis of THP-1 cells, which was measured in a transwell chemotaxis assay. In contrast, inhibition of p42/44 activation by its potent inhibitor (PD98059) did not block OxLDL- or LPC-stimulated chemotaxis. Moreover, expression of a p38 dominant-negative mutant (p38AF) reduced cell chemotaxis significantly. In addition, activation of p38 by LPC was apparently mediated neither by scavenger receptors nor by tyrosine kinase receptors. It was, however, effectively blocked by pertussis toxin and substantially reduced by phospholipase C inhibitor (U73122) and phosphatidylinositol 3-kinase inhibitors (wortmannin and LY294002). LPC also inhibited forskolin-stimulated cAMP accumulation in a pertussis toxin–sensitive manner, indicating that Gi/Go proteins likely mediated the effects of LPC. Our results suggested that OxLDL/LPC efficiently activated both p38 and p42/44, but only the activation of p38 was functionally associated with OxLDL-/LPC-induced chemotaxis in THP-1 cells. ( Circ Res. 2000;87:52-59.)
Eugenics and Family Allowances
Authors: J. A. F. Roberts
Journal: BMJ (1965)

Britain.This is not so, since Wales was not taken into consideration by the " investi- gators."Need I say that there is a vast difference between the green pastures of Beckenham and the coal-tips of the Rhondda Valley.The situation in general practice in this area is critical.Recently a practice with a five figure gross income failed to attract one British doctor and neither of the two foreign applicants had had any experience in general practice.Several senior practitioners are long overdue for retirement but cannot do so because no replacements can be found.Every month conditions are worsening.Is it any wonder that we doctors in the Rhondda, who have read this report, think it is the biggest laugh of the century.I sincerely hope that the Minister thinks the same.-Iam; etc.,
Protection from Respiratory Virus Infections Can Be Mediated by Antigen-Specific Cd4+ T Cells That Persist in the Lungs
Authors: Robert J. Hogan, Weimin Zhong, Edward J. Usherwood, Tres Cookenham, Alan D. Roberts, David L. Woodland
Journal: The Journal of Experimental Medicine (2001)

Although CD4+ T cells have been shown to mediate protective cellular immunity against respiratory virus infections, the underlying mechanisms are poorly understood. For example, although phenotypically distinct populations of memory CD4+ T cells have been identified in different secondary lymphoid tissues, it is not known which subpopulations mediate protective cellular immunity. In this report, we demonstrate that virus-specific CD4+ T cells persist in the lung tissues and airways for several months after Sendai virus infection of C57BL/6 mice. A large proportion of these cells possess a highly activated phenotype (CD44hi, CD62Llo, CD43hi, and CD25hi) and express immediate effector function as indicated by the production of interferon γ after a 5-h restimulation in vitro. Furthermore, intratracheal adoptive transfer of lung memory cells into β2m-deficient mice demonstrated that lung-resident virus-specific CD4+ T cells mediated a substantial degree of protection against secondary virus infection. Taken together, these data demonstrate that activated memory CD4+ T cells persisting at mucosal sites play a critical role in mediating protective cellular immunity.
Cardiac Energy Metabolism in Obesity
Authors: Gary D. Lopaschuk, Clifford D.L. Folmes, William C. Stanley
Journal: Circulation Research (2007)

Obesity results in marked alterations in cardiac energy metabolism, with a prominent effect being an increase in fatty acid uptake and oxidation by the heart. Obesity also results in dramatic changes in the release of adipokines, such as leptin and adiponectin, both of which have emerged as important regulators of cardiac energy metabolism. The link among obesity, cardiovascular disease, lipid metabolism, and adipokine signaling is complex and not well understood. However, optimizing cardiac energy metabolism in obese subjects may be one approach to preventing and treating cardiac dysfunction that can develop in this population. This review discusses what is presently known about the effects of obesity and the impact adipokines have on cardiac energy metabolism and insulin signaling. The clinical implications of obesity and energy metabolism on cardiac disease are also discussed.
Intrapulmonary gas mixing and the sloping alveolar plateau in COPD patients with macroscopic emphysema
Authors: F.A. Wilschut, C.P.M. van der Grinten, R.J.s Lamers, E.F.M. Wouters, S.C.M. Luijendijk
Journal: European Respiratory Journal (1999)

Chronic obstructive pulmonary disease patients, especially those with emphysema, show steep slopes of the alveolar plateau (S). This study tested the hypothesis that continued gas exchange between poorly and well-ventilated lung units by means of collateral ventilation would contribute to S in these patients. Nine young volunteers, nine older volunteers and 11 patients with macroscopic emphysema performed wash-out tests with helium (He) and sulphur hexafluoride (SF6). S was determined for breaths 1-5 (range 1), and for breaths between 95% and 98% of complete wash-out (range 2). An unequal ventilation index (UVI) was defined as the ratio between the estimated mean alveolar pressure and the end tidal pressure (PET) of each tracer gas, calculated over range 2. Over the same range, a phase III ratio was calculated by dividing PET by the estimated pressure at Fowler dead space. In all groups of subjects, the S for He and SF6 were greater for range 2 than for range 1 (p< or =0.012). In the emphysema patients, the correlations between S and UVI were 0.72 for He (p=0.012) and 0.81 for SF6 (p=0.002), while the mean phase III ratios were 1.7 for He and 2.4 for SF6, much less than their theoretical maxima. It was concluded that in patients collateral ventilation may account for only a small part of the increase in the alveolar plateau slope between ranges 1 and 2, and that this increase was mainly caused by unequal ventilation in combination with sequential emptying of lung units. The degree of sequential emptying, however, was modest compared with its full potential.
TGFβ1 Inhibition Increases the Radiosensitivity of Breast Cancer Cells<i>In Vitro</i>and Promotes Tumor Control by Radiation<i>In Vivo</i>
Authors: Fanny Bouquet, Anupama Pal, Karsten A. Pilones, Sandra Demaria, Byron Hann, Rosemary J. Akhurst, Jim S. Babb, Scott M. Lonning, J. Keith DeWyngaert, Silvia C. Formenti, Mary Helen Barcellos-Hoff
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To determine whether inhibition of TGFβ signaling prior to irradiation sensitizes human and murine cancer cells in vitro and in vivo. Experimental Design: TGFβ-mediated growth and Smad phosphorylation of MCF7, Hs578T, MDA-MB-231, and T47D human breast cancer cell lines were examined and correlated with clonogenic survival following graded radiation doses with and without pretreatment with LY364947, a small molecule inhibitor of the TGFβ type I receptor kinase. The DNA damage response was assessed in irradiated MDA-MB-231 cells pretreated with LY364947 in vitro and LY2109761, a pharmacokinetically stable inhibitor of TGFβ signaling, in vivo. The in vitro response of a syngeneic murine tumor, 4T1, was tested using a TGFβ neutralizing antibody, 1D11, with single or fractionated radiation doses in vivo. Results: Human breast cancer cell lines pretreated with TGFβ small molecule inhibitor were radiosensitized, irrespective of sensitivity to TGFβ growth inhibition. Consistent with increased clonogenic cell death, radiation-induced phosphorylation of H2AX and p53 was significantly reduced in MDA-MB-231 triple-negative breast cancer cells when pretreated in vitro or in vivo with a TGFβ type I receptor kinase inhibitor. Moreover, TGFβ neutralizing antibodies increased radiation sensitivity, blocked γH2AX foci formation, and significantly increased tumor growth delay in 4T1 murine mammary tumors in response to single and fractionated radiation exposures. Conclusion: These results show that TGFβ inhibition prior to radiation attenuated DNA damage responses, increased clonogenic cell death, and promoted tumor growth delay, and thus may be an effective adjunct in cancer radiotherapy. Clin Cancer Res; 17(21); 6754–65. ©2011 AACR.
Smoking and depression
Authors: J Flanagan, I Maany
Journal: American Journal of Psychiatry (1982)

be related to the sleep alterations observed. Hallucinations are known to be produced by drugs that are thought to block the actions of serotonin, such as ergot derivatives and LSD, by catecholamine agonists, and by cholinergic blocking agents, among others. Dopamine receptor blockers can often eliminate visual hallucinations whether they are caused by schizophrenia or are drug induced. Anatomic lesions in the temporal-parietal region seem to produce formed hallucinations more frequently than lesions elsewhere (5), yet in most cases ofhallucinations no anatomic site can be found. It seems likely that the mechanism of hallucinatory toxicity with propranolol may be related to complex neurotransmitter-related psychotomimetic effects, although a more exact understanding is not currently available.
Effect of Digitalis on Carotid Sinus Baroreceptor Activity
Authors: JOHN A. QUEST, RICHARD A. GILLIS
Journal: Circulation Research (1974)

The effect of intracarotid injections of ouabain (25.0 µg) or acetylstrophanthidin (1.56 µg) on feline carotid sinus baroreceptors was evaluated using an isolated perfused carotid sinus preparation. The effects of the drugs on baroreceptor activity were determined by monitoring carotid sinus nerve activity and systemic arterial blood pressure. Administration of either drug to the isolated carotid sinus region altered the relationship between the change in carotid sinus pressure and the fall in systemic arterial blood pressure. Raising the carotid sinus pressure produced a greater depressor response when digitalis was present (-29.6 ± 3.8 mm Hg) than it did when digitalis was absent (-15.3 ± 2.6 mm Hg). Digitalis administration also resulted in a greater increase in carotid sinus nerve discharge when carotid sinus pressure was increased. At a constant carotid sinus pressure, digitalis increased the spontaneous firing of the carotid sinus nerve; the drug-induced augmentation in nerve firing was identical to that produced by raising carotid sinus pressure. These changes in baroreceptor activity in the presence of digitalis occurred without drug-induced changes in the pressure in the isolated carotid sinus region. The results demonstrate that the digitalis preparations studied can directly alter the sensitivity of baroreceptors and produce significant changes in carotid sinus nerve activity and cardiovascular function.
A novel subset of putative stem/progenitor CD34+Oct-4+ cells is the major target for SARS coronavirus in human lung
Authors: Yongxiong Chen, Vera Sau-Fong Chan, Bojian Zheng, Kelvin Yuen-Kwong Chan, Xiaoning Xu, Leo Yuk-Fai To, Fang-Ping Huang, Ui-Soon Khoo, Chen-Lung Steve Lin
Journal: The Journal of Experimental Medicine (2007)

Identification of the nature of severe acute respiratory syndrome (SARS)-infected cells is crucial toward understanding the pathogenesis. Using multicolor colocalization techniques, we previously reported that SARS+ cells in the lung of fatally infected patients expressed the only known functional receptor, angiotensin-converting enzyme 2, and also a binding receptor, liver/lymph node–specific ICAM-3–grabbing non-integrin (CD209L). In this study, we show that SARS-infected cells also express the stem/progenitor cell markers CD34 and Oct-4, and do not express cytokeratin or surfactant. These putative lung stem/progenitor cells can also be identified in some non-SARS individuals and can be infected by SARS-coronavirus ex vivo. Infection of these cells may contribute to the loss of lung repair capacity that leads to respiratory failure as clinically observed.
Survival Benefit From Up-Front Fluorouracil, Leucovorin, and Irinotecan/Cetuximab in Metastatic Colorectal Cancer: Is It Just a Now-or-Never Result?
Authors: Mark J. Rother
Journal: Journal of Clinical Oncology (2011)

TO THE EDITOR: I read with interest the updated analysis of the overall survival results according to tumor KRAS and BRAF mutational status from the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial. 1 Thestudydemonstratedastatisticallysignificantandclinicallymeaningful increase of 3.5 months of life in patients with KRAS wild-type tumorstreatedwithinitialfluorouracil,leucovorin,andirinotecan(FOLFIRI)/cetuximab.However,wasthisafunctionoftheuseofcetuximab in first-line therapy or simply a result of the use of anti‐epidermal growthfactorreceptor(EGFR)monoclonalantibodiessomewherein the course of the disease? Earlier trials in metastatic colorectal cancer clearly demonstrated that the initial use of multiple drugs in combination was no better from a survival perspective than the sequential useofthesamedrugs. 2,3 Also,theNationalCancerInstituteofCanada CO17trial 4 revealedthatsingle-agentcetuximabadded4.7monthsof survival benefit in individuals with KRAS wild-type tumors when given after all standard chemotherapy failed. Because only approximately30%ofpatientsintheFOLFIRIcontrolarminthecurrenttrial ever received an anti-EGFR drug in the course of their illness, it is difficult to attribute the survival gain to the addition of cetuximab to first-line FOLFIRI chemotherapy. It is equally plausible that the survival benefit was simply a function of the fact that all patients in the
Primary Chemotherapy for Intracranial Nongerminomatous Germ Cell Tumors: Results of the Second International CNS Germ Cell Study Group Protocol
Authors: Stewart J Kellie, Hayden Boyce, Ira J Dunkel, Blanca Diez, Marc Rosenblum, Lynette Brualdi, Jonathan L Finlay
Journal: Journal of Clinical Oncology (2004)

Purpose The optimum therapy for intracranial nongerminomatous germ cell tumors (NGGCT) remains controversial. The primary objective of this study was to determine whether intensive cisplatin and cyclophosphamide-based combination chemotherapy was effective in patients with intracranial NGGCT. Patients and Methods Twenty patients were enrolled, aged 5 to 41 years (median, 13 years). Initial therapy included two courses of Regimen A (cisplatin, etoposide, cyclophosphamide, and bleomycin). Patients achieving a complete remission (CR) then received two courses of Regimen B (carboplatin, etoposide, and bleomycin). Those in CR after four courses of treatment received one additional course of Regimen A and Regimen B, while those not in CR after four treatment courses underwent second-look surgery and/or irradiation. Results Sixteen of 17 patients assessable for response after two courses of treatment achieved a CR or partial response (CR + partial response, 0.94; 95% CI, 0.73 to 1.0). With a median follow-up of 6.3 years, 14 of 20 patients are alive without disease; eight patients were without relapse or progression, of whom three received local irradiation in first complete remission in violation of protocol, and six patients were in durable second or third complete remission after further chemotherapy and/or irradiation. The 5-year overall survival and event-free survival were 0.75 (95% CI, 0.56 to 0.94) and 0.36 (95% CI, 0.13 to 0.59), respectively. Conclusion Intensive chemotherapy was effective in one-third of patients in this study. Salvage therapy, including irradiation, was feasible in patients with recurrent disease.