tbuckley/cabot-search huggingface dataset:
Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases
Authors: Daniel I. Perez, Carmen Gil, Ana Martinez
Journal: Medicinal Research Reviews (2010)

Following the discovery of the human kinome, protein kinases have become the second most important group of drug targets as they can be modulated by small ligand molecules. Moreover, orally active protein kinase inhibitors have recently reached the market and there are many more in clinical trials. The lack of treatments for neurodegenerative diseases has increased human and financial efforts in the search for new therapeutic targets that could provide new effective drug candidates. The importance of kinases in the molecular pathway of neuronal survival is under study, but different key pathways have been described. New roles for the old casein kinases 1 and 2, currently known as protein kinases CK1 and CK2, have recently been discovered in the molecular pathology of different neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. The search for specific inhibitors of these enzymes has become an important challenge for the treatment of these devastating diseases. The role of these two kinases in the molecular pathology of different neurodegenerative diseases together with different chemical families that are able to more or less specifically inhibit CK1 and CK2 are discussed in this review.
The Use of Angiotensin in the Assessment of Left Ventricular Function in Fixed Orifice Aortic Stenosis
Authors: JOSEPH K. PERLOFF, PETER F. BINNION, WALTER H. CAULFIELD, ANTONIO C. DELEON
Journal: Circulation (1967)

Catheterization of the left heart permits sophisticated assessment of the mechanical problem in aortic stenosis. Selection of patients for surgical repair requires an additional judgment regarding the contractile state of the left ventricle. Angiotensin has recently been used to study the function of the unobstructed left ventricle by imposing controlled pressure loads on both compensated and failing human hearts. The present study was designed to determine whether angiotensin might be of value in characterizing left ventricular function in the presence of aortic stenosis. Accordingly, controlled amounts of the drug were infused during transseptal left heart catheterization in 12 patients in whom fixed obstruction to left ventricular outflow was the sole mechanical fault. Observations were made before and during a series of stepwise increments in systemic systolic pressure. The following information was obtained: cardiac rate, stroke volume, peripheral vascular resistance, left ventricular systolic and end-diastolic pressures, brachial arterial systolic and diastolic pressures, aortic gradient, left ventricular stroke work, systolic ejection period, and aortic valve area. Left ventricular function curves were constructed by relating stroke work to diastolic filling pressure. Rises in brachial systolic pressure exceeded rises in left ventricular systolic, regularly diminishing the gradients. Elevations in systemic arterial pressure consistently elevated left ventricular end-diastolic pressure, indicating that angiotensin can be used to impose a pressure load on the left ventricle despite the interposition of fixed obstruction. In an attempt to gain further information on the mechanical and myocardial factors that coexist in aortic stenosis, three types of observations were made regarding the hemodynamic response of the left ventricle to the graded pressure loads: (1) the directional changes in stroke volume accompanying the increments in ventricular stress, (2) the magnitude of the increase in left ventricular systolic pressure accompanying a given increment in diastolic filling pressure, and (3) the relation between ventricular end-diastolic pressure and stroke work (ventricular function curves). Although the individual responses did not uniformly distinguish mechanical from myocardial influences, when stroke volume, left ventricular end-diastolic pressure, and ventricular function curves were taken together, a clearer impression of the behavior of the left ventricle emerged. Such information may prove useful in view of the practical need to assess ventricular adequacy in aortic stenotic patients considered for corrective surgery.
Abstract 5025: Regulation of miR-145 expression by Foxo3a, C/EBP-β and p53 in cancer cells
Authors: Nanjiang Zhou, Yin-Yuan Mo
Journal: Cancer Research (2012)

Abstract Background: MicroRNAs are master gene regulators that control gene expression through the posttranscriptional repression mechanism. Accumulating evidence indicates that microRNAs are often dysregulated in human cancers, and they may function as oncogenes or tumor suppressors. Our laboratory and other groups have previously shown that miR-145 is a tumor suppressor that is downregulated in a variety of tumors. However, it is not fully understood about the underlying mechanism of miR-145 regulation. In this study, we characterized miR-145 regulation involving transcription factors FoxO3a, C/EBP-β and p53 in cancer cells. Methods: We previously constructed the miR-145 promoter luciferase reporter in pGL3-basic, which was used in this study to determine the effect of FoxO3a, C/EBP-β or p53 on miR-145 promoter activity. p53 expression vector was constructed in pEGFP; C/EBP-β and FoxO3a were cloned into pCDH lentiviral vector carrying copGFP. Western blot and fluorescence microscope were used to determine expression of exogenous genes. Endogenous miR-145 levels were determined by TaqMan real time PCR after reverse transcription as well as by in situ hybridization. The expression vectors or luciferase reporter were introduced into cells by either transfection or infection. Results: We showed that miR-145 functions a downstream effector of Akt, and impacts tumor growth and invasion. For example, suppression of Akt by serum starvation or PI3K inhibitor LY29 significantly activates p53, which in turn binds to the miR-145 promoter and induces miR-145 expression. Furthermore, we showed that in addition to p53, FoxO3a also functions a positive regulator of miR-145. Of considerable interest, FoxO3a induces miR-145 expression in the mutant p53 background; however, in the wild type p53 background, p53 suppresses the ability of FoxO3a to induce miR-145. On the other hand, C/EBP-β serves as a negative regulator of miR-145 in both wild type p53 and mutant p53 backgrounds, which is likely in part through regulation of Akt activity. Experiments are underway to further dissect the regulation of miR-145. Conclusion: Together, these results suggest a sophisticated regulatory system controlling miR-145 expression in cancer cells. Thus, a better understanding of this regulatory network will aid in the identification of novel cancer biomarkers and therapeutic targets, and improve cancer diagnosis and treatment. 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 5025. doi:1538-7445.AM2012-5025
Lung lymphocyte elimination by apoptosis in the murine response to intratracheal particulate antigen.
Authors: A M Milik, V A Buechner-Maxwell, J Sonstein, S Kim, G D Seitzman, T F Beals, J L Curtis
Journal: Journal of Clinical Investigation (1997)

Pulmonary immune responses are suited to determine mechanisms of lymphocyte elimination, as lung inflammation must be regulated tightly to preserve gas exchange. The self-terminating response of primed C57BL/6 mice to intratracheal challenge with the T cell-dependent Ag sheep erythrocytes (SRBC) was used to test the importance of lung lymphocyte apoptosis in pulmonary immunoregulation. Apoptosis of alveolar and interstitial lymphocytes was demonstrated morphologically, by three independent methods to detect DNA fragmentation, and by surface expression of phosphatidylserine. Apoptotic lymphocytes were exclusively CD4-, CD8-, B220-, but many were CD3+ and Thy 1+. Inhibiting apoptosis by in vivo cyclosporine treatment prolonged lung lymphocyte accumulation following SRBC challenge. Experiments using mice homozygous for the lpr or gld mutations showed that pulmonary lymphocyte apoptosis depended on expression of Fas (CD95) and its ligand (Fas-L). Pulmonary inflammation increased on repeated intratracheal SRBC challenge of lpr/lpr mice, in contrast to the waning response in normal mice. These results confirm that in situ lymphocyte apoptosis contributes to termination of immune responses in nonlymphoid organs, probably because of activation-induced cell death, and may be important in inducing tolerance to repeated antigen exposure.
Pigmentation and Vitamin-B12 Deficiency
Authors: S. J. Baker, M. Ignatius, S. Johnson, S. K. Vaish
Journal: BMJ (1963)

MEDICA.L JOURNA~L origin and symptomless unless they become accidentally infected or very large.Symptoms arising in a previously quiescent diverticulum as a result of infection due to trauma, either from catheterization or the passage of the foetal head, would explain the high incidence of parous women in the series so far recorded.Urethral diverticula, while apparently not so common in Great Britain as in some parts of the United States of America and the West Indies, are by no means very rare.I have personally encountered two in London in the past four years, and Mr. Geoffrey Dixon has recently drawn my attention to a third example which, like Dr. Phillips's case, contained calculi.It is likely that if looked for carefully by British gynaecologists and urologists urethral diverticula would be found more often.This has certainly been the case elsewhere.-Iam, etc.,
Bicarbonate Therapy in Severe Acidosis
Authors: Robert G. Narins, Jordan J. Cohen
Journal: Annals of Internal Medicine (1988)

Letters and Corrections1 February 1988Bicarbonate Therapy in Severe AcidosisROBERT G. NARINS, M.D., JORDAN J. COHEN, M.D.ROBERT G. NARINS, M.D.Search for more papers by this author, JORDAN J. COHEN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-108-2-311_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: We wish to address recent objections (1, 2) raised to our advocacy of bicarbonate therapy in severe organic acidosis. The salutary effect of infused alkali may be offset by two countervailing forces. Untreated lactic acid overproduction may prevent correction of hypobicarbonatemia while titration of infused alkali generates CO2causing local or systemic hypercapnia. Failure to control these issues has rendered animal models of lactic acidosis poorly reflective of the human condition (3). Fixed ventilation in experimental animals artificially impairs their removal of additional CO2, thereby sustaining relative or absolute hypercapnia while their acidosis is allowed to continue...References1. JAESCHKE R. Bicarbonate in severe lactic acidosis [Letter]. Ann Intern Med. 1987;107:258-9. LinkGoogle Scholar2. WEIL M, GAZMURI R, VON PLANTA M, and RACKOW E. Bicarbonate in severe lactic acidosis [Letter]. Ann Intern Med. 1987;107:259. MedlineGoogle Scholar3. PARK R and ARIEFF A. Lactic acidosis: current concepts. Clin Endocrinol Metab. 1983;12:339-58. CrossrefMedlineGoogle Scholar4. WEIL M, RACKOW E, TREVINO R, GRUNDLER L, FALK J, and GRIFFEL M. Difference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation. N Engl J Med. 1986;315:153-6. CrossrefMedlineGoogle Scholar5. CLANCY R, CINGOLANI H, TAYLOR R, GRAHAM T, and GILMORE J. Influence of sodium bicarbonate on myocardial performance. Am J Physiol. 1967;212:917-23. CrossrefMedlineGoogle Scholar6. MORRIS L, MURPHY M, and KITABCHI A. Bicarbonate therapy in severe diabetic ketoacidosis. 1986;105:836-40. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: ROBERT G. NARINS, M.D.; JORDAN J. COHEN, M.D. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byMetabolic Acidosis and Alkalosis 1 February 1988Volume 108, Issue 2 Page: 311-311 Keywords Animal models Bicarbonates Hypercapnia Lactic acid Lactic acidosis ePublished: 1 December 2008 Issue Published: 1 February 1988 PDF downloadLoading ...
Heart Bypass: What Every Patient Must Know
Authors: Samuel Zoneraich
Journal: JAMA (1982)

This book is unique in that it provides broad, unbiased data on controversial issues. In this highly informative volume, the author reviews all the options the patient is entitled to know when he decides to undergo heart surgery. Modern cardiology has become a realm of spectacular diagnostic and surgical techniques. Impressive surgical suites, replete with expensive and sophisticated equipment including blinking monitors and artificial heart pumps, have become widely familiar. The patient's expectations for total cure are very high indeed. In separate chapters, this book tries to answer basic questions: What is angina pectoris? What is the bypass operation, and why is it so controversial? Am I a candidate for bypass surgery? What is the operation like, and what are the risks? Can angina be treated without surgery? How is life after surgery? Are there alternatives to surgery? The real advantages and limitations offered by modern cardiology are thus placed
Abstract 1264: <i>BRCA1</i> induces reversion of “Warburg effect” in a breast cancer cell model
Authors: Maud Privat, Daniel Morvan, Abderrahim El Guerrab, Corinne Aubel, Yves-Jean Bignon
Journal: Cancer Research (2011)

Abstract BRCA1 is a major tumor suppressor in breast cancer and it was implicated in numerous pathways resulting in anticarcinogene functions. Likewise, the hypermetabolic nature of cancer cells and their increased reliance on “aerobic glycolysis”, as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. The objective of our study was to address specific contributions of BRCA1 to the signature metabolic features of cancer cells, including the so-called “Warburg effect”. The breast cancer cell line carrying the 185delAG mutation of the BRCA1 gene, SUM1315MO2 cells, was stably transfected with a wild type BRCA1 plasmid. In this cell model, we combined analysis of cell metabolism major enzymes transcriptional expression by TaqMan low density array with the investigation of metabolites by 1H-NMR spectroscopy. We demonstrated that BRCA1 transfection in mutant cells induced strong decrease of glycolysis metabolites and enzymes while TCA cycle and oxidative phosphorylation tended to be activated. Glucose assay confirmed that BRCA1-mutated cells consumed more glucose than cells expressing wild-type BRCA1. Preliminary results seem to show that BRCA1 could act on glycolysis via inhibition of the HIF1α pathway. Our study showed a new function for BRCA1 in cell metabolic regulation, globally resulting in reversion of the Warburg effect in our breast cancer cell model. 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 1264. doi:10.1158/1538-7445.AM2011-1264
Natalizumab and progressive multifocal leucoencephalopathy
Authors: J R Berger
Journal: Annals of the Rheumatic Diseases (2006)

Current data suggest that as many as 1 in 1000 treated individuals may develop progressive multifocal leucoencephalopathy (PML) in concert with the use of natalizumab. Natalizumab was withdrawn in early 2005. The present paper provides a comprehensive description of PML and reviews the role of natalizumab in the pathogenesis of PML. It is likely that use of drugs which cause specific perturbations of the immune system will be accompanied by similar rare infections. Thus researchers should be on the alert when using such agents in clinical trials.
Primary Cellulitis due to Serratia marcescens
Authors: Mary Jo Bonner
Journal: JAMA (1983)

CELLULITIS secondary to a gram-negative organism is uncommon, usually occurring in an immunosuppressed host. Rarely, cellulitis may occur via the bacteremic route. Unusual causes of cellulitis can occur by this mechanism. We report a case of<i>Serratia marcescens</i>cellulitis occurring as a primary infection in an immunosuppressed host. <h3>Report of a Case</h3> A 60-year-old man with a history of peripheral neuropathy of unknown etiology came to the emergency room with pain and swelling in his left leg. One day earlier, he had tripped and bumped the toes and calf of his left leg, not breaking the skin. Several hours before admission, he first noticed redness and pain at the site of a muscle-and-nerve biopsy of the left calf that had been performed three months earlier. The patient had no history of fever, chills, sweating, or recent infections. He was admitted to the hospital with a presumptive diagnosis of cellulitis. At
Angiogenesis Inhibition by an Oncolytic Herpes Virus Expressing Interleukin 12
Authors: Richard J. Wong, Mei-Ki Chan, Zhenkun Yu, Ronald A. Ghossein, Ivan Ngai, Prasad S. Adusumilli, Brendon M. Stiles, Jatin P. Shah, Bhuvanesh Singh, Yuman Fong
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Oncolytic herpes simplex viruses (HSVs) may have significant antitumor effects resulting from the direct lysis of cancer cells. HSVs may also be used to express inserted transgenes to exploit additional therapeutic strategies. The ability of an interleukin (IL)-12-expressing HSV to treat squamous cell carcinoma (SCC) by inhibition of tumor angiogenesis is investigated in this study. Experimental Design: A replication-competent, attenuated, oncolytic HSV carrying the murine IL-12 gene (NV1042), its non-cytokine-carrying analog (NV1023), or saline was used to treat established murine SCC flank tumors by intratumoral injection. The expression of secondary antiangiogenic mediators was measured. Angiogenesis inhibition was assessed by in vivo Matrigel plug assays, flank tumor subdermal vascularity, and in vitro endothelial cell tubule formation assay. Results: Intratumoral injections of NV1042 (2 × 107 plaque-forming units) into murine SCC VII flank tumors resulted in smaller tumor volumes as compared with NV1023 or saline. IL-12 and IFN-γ expression in tumors was 440 and 2.2 pg/mg, respectively, at 24 h after NV1042 injection, but both IL-12 and IFN-γ were undetectable (&amp;lt;0.2 pg/mg) after NV1023 or saline injections. Expression of two antiangiogenesis mediators, monokine induced by IFN-γ and IFN-inducible protein 10, was elevated after NV1042 treatment. Matrigel plug assays of NV1042-transfected SCC VII tumor cells demonstrated significantly decreased hemoglobin content and microvessel density as compared with NV1023 and PBS. Excised murine flank tumors treated with NV1042 had decreased subdermal vascularity as compared with NV1023 and PBS. Both splenocytes and IL-12 expression by NV1042 were required for in vitro inhibition of endothelial tubule formation. Conclusions: IL-12 expression by an oncolytic herpes virus enhances therapy of SCC through antiangiogenic mechanisms. Strategies combining HSV oncolysis with angiogenesis inhibition merit further investigation for potential clinical application.
The fate of mesenchymal stem cells transplanted into immunocompetent neonatal mice: implications for skeletal gene therapy via stem cells
Authors: Christopher Niyibizi, Sujing Wang, Zhibao Mi, Paul D Robbins
Journal: Molecular Therapy (2004)

To explore the feasibility of skeletal gene and cell therapies, we transduced murine bone marrow-derived mesenchymal stem cells (MSCs) with a retrovirus carrying the enhanced green fluorescent protein and zeocin-resistance genes prior to transplantation into 2-day-old immunocompetent neonatal mice. Whole-body imaging of the recipient mice at 7 days post-systemic cell injection demonstrated a wide distribution of the cells in vivo. Twenty-five days posttransplantation, most of the infused cells were present in the lung as assessed by examination of the cells cultured from the lungs of the recipient mice. The cells persisted in lung and maintained a high level of gene expression and could be recovered from the recipient mice at 150 days after cell transplantation. A significant number of GFP-positive cells were also present in the bones of the recipient mice at 35 days post-cell transplantation. Recycling of the cells recovered from femurs of the recipient mice at 25 days posttransplantation by repeated injections into different neonatal mice resulted in the isolation of a clone of cells that was detected in bone and cartilage, but not in lung and liver after systemic injection. These data demonstrate that MSCs persist in immunocompetent neonatal mice, maintain a high level of gene expression, and may participate in skeletal growth and development of the recipient animals.
Mental health should have same priority as physical health
Authors: Zosia Kmietowicz
Journal: BMJ (2005)

Staying mentally well should be given the same priority by NHS policymakers as keeping physically fit, says an independent think tank based in the United kingdom, the Institute for Public Policy Research. In a report published this week, the institute set out its vision of what mental health services should look like in 2025. It suggests that by then, people with mental health problems will have access to local drop-in services and that public stigma around mental health will have declined. In addition, every neighbourhood will have access workers, …
Portal Hypertension, 1979
Authors: Ronad A. Malt, Donald C. Nabseth, Marshall J. Orloff, Sergio Stipa
Journal: New England Journal of Medicine (1979)

Would anyone have guessed that the two issues in portal hypertension most hotly debated during the last quarter century would have been settled without argument among the 60 surgeons and internists at a recent international meeting in Rome? Pending publication of the detailed proceedings by Academic Press next year, this article summarizes the consensus. For brevity, specific attributions are not given.*Studies from three continents agreed, first, that the results of end-to-side portacaval shunts and traditional splenorenal shunts ("proximal" shunts, with splenectomy) are identical. This conclusion holds whether the patients have alcoholic cirrhosis or postnecrotic cirrhosis and whether results are . . .
Report on the American Cancer Society Workshop on Community Cancer Detection, Education, and Prevention Demonstration Projects for Underserved Populations
Authors: B. L. Black, R. Schweitzer, T. Dezelsky
Journal: CA A Cancer Journal for Clinicians (1993)

The American Cancer Society has been funding six pilot projects organized with the stated purpose of demonstrating how to implement cancer prevention and control projects for socioeconomically disadvantaged and underserved populations. This article reports on the results of a workshop held to evaluate project experiences and develop recommendations for the future.