tbuckley/cabot-search huggingface dataset:
704. RNA Interference of Stat3 Using Adenovirus Vector Inhibits Pancreatic Cancer Growth In Vitro and In Vivo
Authors: Chen Huang, Ju Feng Zhang, Zheng Jun Qiu, Fang Zhang
Journal: Molecular Therapy (2006)

Purpose/Objective: One member of the family of Signal Transducer and Activator of Transcription(STAT) proteins, Stat3, is a central cytoplasmic transcription factor activated by tyrosine kinase growth factor and cytokine receptors and is constitutively activated in a wide variety of human tumors, including pancreatic ccancer. Previous studies demonstrated that constitutively activated Stat3 plays a key role in the development and progression of pancreatic cancer by promoting cell proliferation and protecting against apoptosis.The objective of this study was to evaluate the potential use of adenovirus-mediated RNA interference(RNAi) to silence Stat3 expression and the effect on the growth of human pancreatic cancer cells in vitro and in vivo. Materials/Methods: Double-strand oligonucleotide for transcription of short hairpin RNA(shRNA) toward stat3 was constructed into the adenoviral vector. PANC-1 and SW1990 cell lines with constitutively activated Stat3 were infected with the shRNA-containing adenovirus. Stable suppression of Stat3 was confirmed by RT-PCR and Western blot. Cell proliferation and cell apoptosis were performed by MTT assay and flow cytometry, respectively. Expression of CyclinD1,Bcl-xL,Mcl-1and vascular endothelial growth factor (VEGF) were studied using RT-PCR and Western blot. RNAi effects on tumor growth in vivo were studied with pancreatic cancer xenograft tumor model in nude mice. Results: Using RNAi directed toward stat3 with adenovirus vector, we achieved specific inhibition of stat3. Furthermore, RNAi for stat3 inhibited cell proliferation, induced cell apoptosis and significantly reduced the levels of CyclinD1,Bcl-xL ,Mcl-1 and VEGF when compared with parental and empty vector/scrambled vector- transfected cells. In vivo experiments showed that RNAi for stat3 inhibited the tumorigenicity of PANC-1 and SW1990 cells and significantly suppressed tumor growth when injected directly into tumors. Conclusions: This study shows that Stat3 signaling is a novel therapeutic target for pancreatic cancer and that adenovirus vector- based Stat3 siRNA may be useful as a therapeutic agent for treatment of pancreatic cancer expressing constitutively activated Stat3.
Mechanisms of Quinidine Action on the Circulation and Therapeutic Reversal of Toxic Effects.
Authors: H. L. Conn
Journal: Annals of Internal Medicine (1961)

s1 May 1961Mechanisms of Quinidine Action on the Circulation and Therapeutic Reversal of Toxic Effects.H. L. Conn Jr., M.D., F.A.C.P., R. J. Luchi, M.D., T. H. Helwig Jr., M.D.H. L. Conn Jr., M.D., F.A.C.P.Search for more papers by this author, R. J. Luchi, M.D.Search for more papers by this author, T. H. Helwig Jr., M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-54-5-1032_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptDespite wide recognition of the electromechanical cardiac depressant and vasodilating effects of quinidine, the basic mechanisms responsible are obscure. Equally obscure are the mechanisms responsible by which the commonly used therapeutic agents reverse these effects. Even the usefulness of some recommended therapeutic agents is in doubt. Our data and those of others, derived from perfused heart experiments, have indicated that cardiac depression may in great part be due to derangement in cation movements and distribution. Subsequent in vitro dialysis studies of quinidine-protein binding led us to suggest that there is a specific binding at the cell surface between quinidine, cell... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Philadelphia, Pa. (CI) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 May 1961Volume 54, Issue 5Page: 1032-1033KeywordsCationsCell bindingHeartMedical dialysis ePublished: 1 December 2008 Issue Published: 1 May 1961 PDF downloadLoading ...
Abstract 552: Targeting brain tumors with PLX3397, an inhibitor of the CSF-1 receptor kinase
Authors: Brian L. West, James Tsai, Theodore Nicolaides, Bernice Wong, Hoa Nguyen, Adhirai Marimuthu, Prabha Ibrahim, Peter Hirth, Gideon Bollag
Journal: Cancer Research (2011)

Abstract Cancer growth in the brain incites a neuroinflammatory response that becomes a defining feature of the brain tumor microenvironment. Microglia and macrophages provide important functions that support the invasiveness of glioblastoma. Other cancer types that become metastatic to brain also rely on the microenvironment to support angiogenesis. PLX3397 is a potent inhibitor of the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). The CSF-1R is required for the differentiation and activation of microglia and macrophages. Oral administration of PLX3397 to mice at 20 mg/kg qd significantly reduces the microglia/macrophage marker, Iba1, as determined by western blotting. PLX3397 penetrates the blood-brain barrier, as determined through pharmacokinetic analysis, with brain levels reaching substantial fractions of the concurrent plasma levels. PLX3397 is highly bound to plasma albumin, and therefore the levels attained in the brain likely affect Iba1 levels through a local inhibition of brain microglia and macrophages, although a peripheral effect may also contribute. Culture of glioblastoma cell lines including U87, and treatment with chemotherapeutic agents or radiation, was found to cause a 4-fold elevation of the two CSF-1R ligands, CSF-1 and IL-34, as quantified by QPCR. This indicates that glioma cells can recruit and stimulate microglia and macrophages, and that current standard therapies likely exacerbate this stimulation. Other cancer types that are known to form metastases to brain, including melanoma and breast cancer, show similar abilities to produce these cytokines in response to standard therapies. The rat 9L glioblastoma line forms an aggressive tumor when tested as an orthotopic model in syngeneic Fisher rats. Seven days after implantation, PLX3397 was administered via rodent chow for 14 days, reducing the tumor growth by 44% as determined by MRI. These results provide preclinical evidence that PLX3397 may show a clinical benefit in brain cancers, either as a single agent or in combination with standard chemo- or radiation therapies. PLX3397 is nearing completion of a successful Phase 1 dose-escalation safety trial in solid tumor cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 552. doi:10.1158/1538-7445.AM2011-552
India to consider raft of new compulsory licences
Authors: S. Bagcchi
Journal: BMJ (2014)

A government appointed panel is set to review over 20 drug patents in India and recommend compulsory licensing so that the country’s generic drug manufacturers can produce the drugs at low cost, the magazine Bloomberg Businessweek has reported.1

The BMJ has found Indian media and the government silent on this issue. To date no announcement or document on this initiative has officially emerged. However, the Bloomberg Businessweek article quoted two anonymous sources who acknowledged the plans.

The article said, “The panel is looking beyond the cancer treatments it studied last year to areas such as HIV and diabetes, according to two people with knowledge of the matter, …
Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3
Authors: Yoshinori Seko, Nobuhiko Kayagaki, Ken-ichiro Seino, Hideo Yagita, K.o Okumura, Ryozo Nagai
Journal: Journal of the American College of Cardiology (2002)
Functional foods: the case for closer evaluation
Authors: Nynke de Jong, Olaf H Klungel, Hans Verhagen, Marion C J Wolfs, Marga C Ocké, Hubert G M Leufkens
Journal: BMJ (2007)

Current regulations focus on the mandatory safety evaluation of functional foods before they come to market, but<b> Nynke de Jong</b><b>and colleagues</b> argue that the effects of such foods should also be evaluated after they have been launched
In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1.
Authors: L Guedez, W G Stetler-Stevenson, L Wolff, J Wang, P Fukushima, A Mansoor, M Stetler-Stevenson
Journal: Journal of Clinical Investigation (1998)

Cellular pathways for induction of programmed cell death (PCD) have been identified, but little is known about specific extracellular matrix processes that may affect apoptosis along those pathways. In this study, a series of Burkitt's lymphoma (BL) cell lines were assayed for their expression of tissue inhibitor of metalloproteinases (TIMP)-1. Results indicate that TIMP-1-positive BL lines show resistance to cold-shock-induced apoptosis. Furthermore, recombinant TIMP-1, but not TIMP-2 or a synthetic metalloproteinase inhibitor (BB-94), confers resistance to apoptosis induced by both CD95-dependent and -independent (cold shock, serum deprivation, and gamma-radiation) pathways in TIMP-1-negative BL lines. TIMP-1 suppression of PCD is not due to metalloproteinase inhibition, as reduction and alkylation of the TIMP-1 did not abolish this activity. Retroviral induction of TIMP-1 not only resulted in cell survival but also in continued DNA synthesis for up to 5 d in the absence of serum, while controls underwent apoptosis. This resistance to apoptosis is reversed by anti-TIMP-1 antibodies, demonstrating that secreted TIMP-1 is active in blocking apoptosis. Furthermore, TIMP-1 upregulation induced expression of Bcl-XL but not Bcl-2 as well as decreased NF-kappaB activity as compared with controls. These results demonstrate that TIMP-1 suppresses apoptosis in B cells and suggests a novel activity for TIMP-1 in tissue homeostasis.
Schizophrenia: A benign trait
Authors: Valerie Gray Hardcastle
Journal: Behavioral and Brain Sciences (2004)

While schizophrenia may be genetically determined up to a point, neither it nor its nearest relatives offer any sort of reproductive advantage to its sufferers. Instead, from an evolutionary point of view, schizophrenia is benign – it neither promotes nor inhibits survival to reproduction. Because it is benign, its rate of occurrence should remain fairly constant over time.
Quantitative Evaluation of Renal Excretion on the Dynamic DTP A Renal Scan
Authors: KAZUO KUBOTA, HAROLD L. ATKINS, DAVID ANAISE, ZVI H. OSTER, WILLIAM POLLACK
Journal: Clinical Nuclear Medicine (1989)

In order to evaluate the renal excretion quantitatively, the authors analyzed the Tc-99m DTPA renogram using mean transit time (MTT) with deconvolution analysis and compared it to the perfusion index. One hundred thirteen studies consisting of 25 normal, 11 obstruction, 35 transplant-norm, 12 transplant-obstruction, and 30 transplant-rejection were evaluated. In the non-transplant obstruction, MTT is significantly long (3.40 +/- 0.85 minutes vs 2.02 +/- 0.42 minutes) and has high sensitivity (100%) and specificity (93%, 23/25) for the diagnosis of obstruction. In the transplant-obstruction, if the field of view includes both transplant and liver or spleen as a blood pool image, MTT has high sensitivity for the diagnosis (10/11) and for the follow up of obstruction (12/12), with the same specificity, but low sensitivity for rejection (25%). Perfusion index is of value in the diagnosis of rejection (73% specificity, 77% sensitivity) but is useless for the detection of obstruction (25% specificity, 75% sensitivity). The authors conclude that MTT is a useful marker for diagnosis and serial quantitative evaluation of renal obstruction. Also, they suggest the use of multiple techniques based on different principles for the complete evaluation of the renal scan.
Outcome of wheeze in childhood. Symptoms and pulmonary function 25 years later.
Authors: D J Godden, S Ross, M Abdalla, D McMurray, A Douglas, D Oldman, J A Friend, J S Legge, J G Douglas
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The outcome after 25 yr was studied for three groups of children classified in a random community survey in 1964 as having asthma (121 subjects), wheeze in the presence of infection (167 subjects), or no respiratory symptoms (167 comparison subjects). Approximately 80% of the subjects in each group, now aged 34 to 40 yr, were successfully traced. Current symptoms and smoking habit were recorded by questionnaire, and ventilatory function, peak flow variability, and bronchial reactivity to inhaled methacholine were measured. Subjects who had asthma in childhood were more likely to wheeze (odds ratio [OR] 14.4) or produce phlegm (OR 3.3) than comparison subjects. They also had significantly lower FEV1 values and greater bronchial reactivity than comparison subjects. Adult FEV1 correlated with childhood FEV1 (both expressed as % of predicted) (r = 0.44, p < 0.01). The prognosis for those children who were classed as having wheeze in the presence of infection in 1964 was better than for those who had asthma. Although they also were more likely to report wheeze (OR 3.8) or phlegm (OR 4.4) than comparison subjects, the wheezy symptoms were unlikely to interfere with activities and the ventilatory function and bronchial reactivity to methacholine did not differ from those of comparison subjects. Smokers were more likely to report wheeze (OR 2.0), cough (OR 7.2), and phlegm (OR 3.1) than never-smokers, and current smokers with current wheezy symptoms had significantly reduced FEV1 values, although smoking was not associated with increased methacholine reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
PHYSICIANS IN FICTION.PHYSICIANS AS SEEN BY HENRY FIELDING.
Authors: C. D. SPIVAK
Journal: JAMA (1905)

We deem it appropriate to begin the study of the types of physicians in fiction with an author who, according to Sir Walter Scott, was "the father of the English novel" and whose "Tom Jones" is considered by the foremost critics to be the greatest novel that was ever written. Although many of the libraries here and abroad have placed Fielding's works in<i>the index expurgatorium</i>, yet the observation made by Burrow<sup>1</sup>some sixty years ago holds good even in our generation. He calls Fielding "the most singular genius their island produced, whose works it had been the fashion to abuse in public and to read in private." In "Joseph Andrews," "Tom Jones" and "Amelia" no physician appears as a prominent character, but a number of medical men, surgeons and apothecaries make their appearance, and, with the exception of two, they offer excellent material for the formation of an opinion of the prevailing tendencies, foibles, shortcomings and petty jealousies among the physicians of the Eighteenth Century. We say "prevailing tendencies" advisedly.
Clinical application of coronary sinus retroperfusion during high risk percutaneous transluminal coronary angioplasty
Authors: Robert L. Incorvati, Stuart G. Tauberg, Michael J. Pecora, Robin S. Macherey, Sinda B. Dianzumba, Bryan C. Donohue, Mitchell W. Krucoff
Journal: Journal of the American College of Cardiology (1993)
A British Medical Association Lecture ON THE PATHOLOGY OF GASTRIC ULCER: Delivered to the Derby Division, May 18th, 1923
Authors: M. J. Stewart
Journal: BMJ (1923)

ETIOLOGY OF PEPTIC ULCER.IT iS now generally believed, on str'onlg clinical and pathological evidence (Bolton, 19131), that all chronic gastric ulcers arise in and from acute ulcers-that is, that all ulcers are rapidly formed in the first instance, a chronic ulcer being merely one which has been in existence for a certain length of time.Two etiological problems are thus presented- (A) the cause or causes of acute ulcer, anid (B) the factors which lead to the persistence or non-healing of such an ulcer. A. ETIOLOGY OF ACUTE ULCER.The various factors, clinical and experimental, concerned in the production of acute ulcers fall into two categories:(1) those which act by producing injury (malnutrition, devitalization, etc.) of the gastric mucosa, and (2) the digestive action of the gastric juice.
The power of stories
Authors: T. Groves
Journal: BMJ (2009)

“The brains of human beings seem built to process stories better than other forms of input . . . they seem to offer a solution—a way to extract some meaning and redemption from tragedy by preventing its reoccurrence.” So said Thomas B Newman, professor of epidemiology and biostatistics at the University of San Francisco, in the Christmas BMJ six years ago, in a plea for a broad perspective when making public health decisions ( BMJ 2003;327:1424-7, doi:10.1136/bmj.327.7429.1424).

Introducing a new BMJ series this week, called Safety Alerts, Tara Lamont and colleagues from the National Patient Safety Agency (NPSA) quote Newman …
Oxidation of DNA bases by tumor promoter-activated processes.
Authors: K Frenkel
Journal: Environmental Health Perspectives (1989)

Evidence has accumulated showing that active oxygen species participate in at least one stage of tumor promotion. Tumor promoters can induce various types of cells to undergo processes that result in formation of active oxygen species. They stimulate polymorphonuclear leukocytes (PMNs) to undergo an oxidative burst that is characterized by rapid formation of .O2- and H2O2. We find that in vitro formation of H2O2 by tumor promoter-activated PMNs correlates with their in vivo first-stage promoting activity. Moreover, two thymidine derivatives are formed in DNA coincubated with tumor promoter-stimulated PMNs: 5-hydroxymethyl-2'-deoxyuridine (HMdU) and thymidine glycol (dTG). The amounts of HMdU and dTG formed correlate with the first-stage tumor-promoting potencies of the agents used for PMN stimulation and with the amount of H2O2 generated. We find that HMdU is also formed in the DNA of HeLa cells coincubated with 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated PMNs, with the amount of HMdU being proportional to that of TPA used. Even in the absence of PMNs, HMdU is increasingly formed in cellular DNA with increased TPA concentration, although at much lower levels than in the presence of PMNs. When rat liver microsomes are incubated with benzo[a]pyrene (BaP), a complete carcinogen, H2O2 is also generated. Production of H2O2 increases linearly with increasing concentrations of BaP. Furthermore, HMdU is formed in DNA exposed to BaP-treated microsomes, and its formation is inhibited by catalase. These results suggest that carcinogen-induced processes generating H2O2 are associated with the first-stage promoting activity of complete carcinogens.
Mitochondrial Dysfunction in NnaD Mutant Flies and Purkinje Cell Degeneration Mice Reveals a Role for Nna Proteins in Neuronal Bioenergetics
Authors: Lisa Chakrabarti, Rabaab Zahra, Stephen M. Jackson, Parsa Kazemi-Esfarjani, Bryce L. Sopher, Amanda G. Mason, Thomas Toneff, Soyoung Ryu, Scott Shaffer, Janice W. Kansy, Jeremiah Eng, Gennifer Merrihew, Michael J. MacCoss, Anne Murphy, David R. Goodlett, Vivian Hook, Craig L. Bennett, Leo J. Pallanck, Albert R. La Spada
Journal: Neuron (2010)
Pharmacological agents currently in clinical trials for disorders in neurogastroenterology
Authors: Michael Camilleri
Journal: Journal of Clinical Investigation (2013)

Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in understanding the mechanisms of these disorders, through basic and translational research, and in targeting the receptors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients' symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastroparesis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain.
Zinc, copper, and iron content of pleural fluid in benign and neoplastic disease
Authors: D. E. Dines, L. R. Elveback, J. T. McCall
Journal: Thorax (1972)

Zinc, copper, and iron were measured in the pleural fluid of 86 patients with benign conditions (including congestive heart failure, pulmonary embolus, collagen disease, pneumonitis, non-specific pleuritis, and tuberculosis) and in 116 patients with malignant disease (including lymphoma, breast carcinoma, primary lung cancer, and metastatic lung cancer). Though a positive correlation was found between zinc and copper in the benign group and not in the malignant group, the test was not specific enough to differentiate benign from malignant disease, because of the wide scatter of results. A positive regression for serum copper on pleural fluid copper was found in the benign, lymphoma, and malignant groups, but the differences between these three were not sufficient to help in the differential diagnosis. These findings suggest that pleural fluid heavy metals do not have the specificity that has been reported for serum heavy metals in benign and malignant disease and in malignant lymphoma.
Effect of Aerosolized Anti-IgE (E25) on Airway Responses to Inhaled Allergen in Asthmatic Subjects
Authors: JOHN V. FAHY, DONALD W. COCKCROFT, LOUIS-PHILIPPE BOULET, HOFER H. WONG, FRANCINE DESCHESNES, ELIZABETH E. DAVIS, JANE RUPPEL, JOHN Q. SU, DANIEL C. ADELMAN
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Intravenous administration of a humanized monoclonal antibody of IgE (E25) attenuates the early and late phase response to inhaled allergen in allergic asthmatic subjects. To test whether direct delivery of E25 to the airway might have the same effect, we conducted a randomized, double-blind, three group study in 33 subjects with mild allergic asthma (20 to 46 yr of age, 21 men, FEV1 > 70% predicted). The airway responses to aerosolized allergen were determined at baseline, after 2 and 8 wk of once daily treatment with aerosolized placebo (n = 11), aerosolized E25 1 mg (n = 12), or aerosolized E25 10 mg (n = 10), and after 4 wk of treatment withdrawal. We found that E25 was detectable in the serum during aerosol treatment, although serum IgE did not change significantly in any of the three groups during treatment. In addition, both doses of E25 were no more effective than placebo in attenuating the early phase responses to allergen at both times during treatment. Although aerosolized E25 was generally well tolerated, one subject receiving aerosolized E25 10 mg daily was found to have serum IgG and IgA antibodies to E25. We conclude that aerosol administration of an anti-IgE monoclonal antibody does not inhibit the airway responses to inhaled allergen in allergic asthmatic subjects. We speculate that the observed lack of efficacy may be due to the inability of aerosol route of delivery to result in high enough concentrations of E25 in the tissue compartments surrounding IgE effector cells to neutralize IgE arising from local airway and pulmonary sources and IgE arising from the vascular space. Additionally, the aerosol route of delivery of monoclonal antibodies may be more immunogenic than the parenteral route.