tbuckley/cabot-search huggingface dataset:
Sunitinib and sorafenib exert direct effects on neuroblastoma cells and inhibit hypoxia-induced increases in HIF-1α and VEGF
Authors: Monique Nilsson, Hua-Kang Wu, Lizhi Zeng, Peter Zage, Patrick Zweidler-McKay, John Heymach
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4404 

Novel therapeutic strategies are needed to improve long-term survival of patients with neuroblastoma. Because expansive tumor growth is dependent on an adequate supply of oxygen, therapeutic regimens with direct activity against tumor cells as well as the associated vasculature and the will likely provide the greatest clinical benefit. Small-molecule inhibitors sunitinb, which has activity against VEGFR-1,2,3, PDGFR, Kit, RET, and sorafenib, which inhibits VEGFR-2,3, PDGFR, RET, and Kit have been shown to restrict tumor angiogenesis in multiple tumor models. We investigated whether these receptor tyrosine kinase inhibitors (RTKIs) have direct effects against neuroblastoma cells. We evaluated 7 neuroblastoma cell lines for expression of receptor tyrosine kinases. While neuroblastoma cell lines were heterogeneous in the expression of VEGFR-1, cKit, and RET, the majority of tumor cells expressed PDGFR-α and PDGFR-β. In vitro cell viability studies revealed that sunitinib and sorafenib have direct anti-tumor cell activity with IC50s below 1μM and 10μM respectively. In contrast, the majority of neuroblastoma cell lines were resistant to imatinib with IC50 values above 10μM. Flow cytometry was utilized to evaluate the effect of sunitinib and sorafenib on cell cycle progression and apoptosis on three neuroblastoma cell lines, SH-EP, CHP-134, and SK-N-AS. Both sunitinib and sorafenib effectively decreased the number of cycling cells, whereas only sunitinib induced apoptosis in all cell lines tested. Additionally, sunitinib significantly inhibited VEGFB-mediated migration of SK-N-AS cells while sorafenib did not, suggesting that the effect of sunitinib on cell migration is mediated through inhibition of VEGFR-1. Recently, RTKs such as VEGFR-1 have been shown to be part of a hypoxia-driven autocrine loop involving HIF-1α. To determine the effect of RTKIs on tumor cell response to hypoxia, neuroblastoma cells were incubated in hypoxic conditions with or without sunitinib or sorafinib, and HIF-1α expression was evaluated. Our results indicate that sunitinib and sorafenib diminish hypoxia-induced elevation of HIF-1α. Moreover, sunitinib and sorafenib significantly reduced hypoxia-induced VEGF expression in SY5Y neuroblastoma cells. These findings suggest that these agents may exert antiangiogenic effects by blockade of VEGF signaling as well as by inhibition of hypoxia-induced upregulation of proangiogenic factors in tumors.
549. Nonconserved Sequence Motifs outside the Catalytic Core Improve the Trans-Splicing Efficiency of Anti-HIV Hammerhead Ribozymes
Authors: Marc Weinberg, John J. Rossi
Journal: Molecular Therapy (2004)

Trans-cleaving hammerhead ribozymes (hhRzs), where stem-loops I and III are open-ended (I/III), have been widely used for the endonucleolytic cleavage of any specific RNA substrate. However, the application of hhRzs for use in gene therapy, especially for use in the targeted knockdown of HIV gene expression and replication, has been hampered by a low intracellular catalytic efficiency. As a result, therapeutic applications that exploit the RNA Interference (RNAi) pathway are presently more attractive than ribozymes. Recent studies have shown that the catalytic efficiency of naturally-derived cis-cleaving hhRzs is several orders of magnitude higher when compared to trans-cleaving counterparts. Moreover, changes made to stem-loops I and II, which are nonconserved sequence elements peripheral to the minimal essential catalytic core, greatly affect the catalytic turnover of cis-acting hhRzs. In this study, we designed two hhRzs variants with alterations intended to mimic stem-loop interactions found in the hhRz derived from satellite RNA of tobacco ringspot virus (sTRSV) to generate trans-cleaving hhRzs targeted to an accessible region within the HIV-1 rev sequence. Kinetic analyses were performed under multiple turnover conditions using an 18-mer synthetic RNA substrate at submillimolar levels. Under standard conditions (pH 7, 37°C, 10 mM MgCl2) the rate of cleavage (kobs) for hhRz variant sII-RV2 was significantly better than that of the conventional I/III hhRz, sII-RV3, with kobs of 0.24 min-1 and 0.094 min-1 respectively. HhRz variant sII-RV1, which differed from sII-RV2 only in the position of the peripheral stem, but with an identical loop, showed almost no substrate cleavage. These results may reflect the presence of a tertiary interaction between stem-loops I and 2 that facilitate cleavage. Alternatively, the addition of a mimicked stem-loop I possibly stabilizes active hhRz conformers.
THE RECRUIT'S FIRST YEAR
Authors: P. S. Madigan
Journal: Annals of Internal Medicine (1941)

Article1 July 1941THE RECRUIT'S FIRST YEARP. S. MADIGAN, F.A.C.P.P. S. MADIGAN, F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-15-1-18 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptSince the birth of our nation and the formation of a defensive army to protect our shores, it has forever been foremost in the minds of our military leaders to stress the point that the art of soldiering should be a vocation of life. Every vocation of necessity has its prerequisites, and the art of soldiering differs in no way from this general principle. Numerous writers throughout the history of our country have dilated upon this aspect in their description of military life.During the present emergency it is incumbent upon the Army to train a million and a half...Bibliography REYNOLDS A: The Life of an Enlisted Soldier in the United States Army, 1904. Google Scholar PEW WA: Making a Soldier, Massachusetts National Guard, 1917. Google Scholar HARBORD JG: The Officer's Guide, Produced for the Infantry, 1930. Google Scholar MOSLEY VH: Suggestions from a General to the Youngsters of His Command, January, 1933. Google Scholar Circular Letter No. 19, Surgeon General's Office, March 12, 1941. Google Scholar Medical Department, U. S. A., Training Program for 1940. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Medical Corps U. S. Army Washington, D. C.*Read at the Symposium of Military Medicine, Boston meeting of the American College of Physicians, April 24, 1941. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byThe Restriction of Activity in Coronary Occlusion with Particular Reference to the Extent of Myocardial Infarction 1 July 1941Volume 15, Issue 1Page: 18-24KeywordsArmed forcesBirthMilitary medicine ePublished: 1 December 2008 Issue Published: 1 July 1941 PDF downloadLoading ...
Abstract PR02: Identification of ERK1/2 mutations that confer resistance to MAPK pathway inhibitors
Authors: Eva M. Goetz, Mahmoud Ghandi, Daniel Treacy, Nikhil Wagle, Levi A. Garraway
Journal: Clinical Cancer Research (2015)

Abstract Recent treatment advances in metastatic BRAF mutant melanoma using targeted therapy have increased progression free survival by many months. However, resistance to these targeted agents is a common occurrence, with relapse occurring in almost every case. Many of the alterations that confer clinical resistance to RAF and MEK inhibitors in BRAF mutant melanoma reactivate the MAPK pathway, but remain sensitive to ERK inhibition in vitro. Prospectively determining mechanisms of resistance to MAPK pathway inhibitors, such as an ERK inhibitor, before clinical trials begin may inform which patients will respond to therapy, potential markers of resistance, or best therapy combinations. Previous studies have shown that in vitro random mutagenesis screens can select specific alleles seen in resistant patient populations. Since ERK inhibitors are entering clinical trials, we wanted to determine mutations in ERK1 and ERK2 that could confer resistance to ERK or RAF/MEK inhibition. Therefore, we expressed dox-inducible ERK1 or ERK2 mutant libraries in A375 cells, which were then treated with MAPK inhibitor(s) and doxycycline until resistant cells emerged. Exogenous ERK1 or ERK2 was analyzed in resistant cells by massively parallel DNA sequencing. We validated 15 alleles that conferred resistance to the ERK inhibitor, VX-11e, and 11 alleles that conferred resistance to RAF, MEK, or RAF+MEK inhibition (dabrafenib and trametinib). Some resistance alleles were analogous between ERK1 and ERK2, while others were specific to ERK1 or ERK2. ERK inhibitor resistant alleles were localized to areas surrounding the ATP/drug binding site, including the glycine-rich loop, c-helix, and activation loop. These alleles were also cross-resistant to another ERK inhibitor, SCH-772984, albeit some only at lower concentrations. The RAF/MEK inhibitor resistant residues were located in the c-helix, activation loop, and common docking domain. Only a single ERK1 allele was found to confer resistance to RAF + MEK and ERK inhibition, suggesting that resistance mutations in ERK might be suppressed if RAF, MEK, and ERK inhibitors are given in combination. In addition, an ERK mutation arising in a patient treated with an ERK inhibitor would still be sensitive to RAF/MEK inhibition and vice versa. Screening for these alleles before administering therapy or after relapse may help inform patient treatment. Citation Format: Eva M. Goetz, Mahmoud Ghandi, Daniel Treacy, Nikhil Wagle, Levi A. Garraway. Identification of ERK1/2 mutations that confer resistance to MAPK pathway inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr PR02.
The nature and identification of quantitative trait loci: a community's view
Authors: Oduola Abiola, Joe M. Angel, Philip Avner, Alexander A. Bachmanov, John K. Belknap, Beth Bennett, Elizabeth P. Blankenhorn, David A. Blizard, Valerie Bolivar, Gudrun A. Brockmann, Kari J. Buck, Jean Francois Bureau, William L. Casley, Elissa J. Chesler, James M. Cheverud, Gary A. Churchill, Melloni Cook, John C. Crabbe, Wim E. Crusio, Ariel Darvasi, Gerald de Haan, Peter Demant, R. W. Doerge, Rosemary W. Elliott, Charles R. Farber, Lorraine Flaherty, Jonathan Flint, Howard Gershenfeld, John P. Gibson, Jing Gu, Weikuan Gu, Heinz Himmelbauer, Robert Hitzemann, Hui Chen Hsu, Kent Hunter, Fuad A. Iraqi, Ritsert C. Jansen, Thomas E. Johnson, Byron C. Jones, Gerd Kempermann, Frank Lammert, Lu Lu, Kenneth F. Manly, Douglas B. Matthews, Juan F. Medrano, Margarete Mehrabian, Guy Mittleman, Beverly A. Mock, Jeffrey S. Mogil, Xavier Montagutelli, Grant Morahan, John D. Mountz, Hiroki Nagase, Richard S. Nowakowski, Bruce F. O'Hara, Alexander V. Osadchuk, Beverly Paigen, Abraham A. Palmer, Jeremy L. Peirce, Daniel Pomp, Michael Rosemann, Glenn D. Rosen, Leonard C. Schalkwyk, Ze'ev Seltzer, Stephen Holloway Settle, Kazuhiro Shimomura, Siming Shou, James M. Sikela, Linda D. Siracusa, Jimmy L. Spearow, Cory Teuscher, David W. Threadgill, Linda A. Toth, Ayo A. Toye, Csaba Vadasz, Gary Van Zant, Edward Wakeland, Robert W. Williams, Huang Ge Zhang, Fei Zou
Journal: Nature Reviews Genetics (2003)
Relationship between angiographic late loss and target lesion revascularization after coronary stent implantation
Authors: Stephen G. Ellis, Jeffrey J. Popma, John M. Lasala, Joerg J. Koglin, David A. Cox, James Hermiller, Charles O’Shaughnessy, James Tift Mann, Mark Turco, Ronald Caputo, Patrick Bergin, Joel Greenberg, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2005)
Abstract 18: Changes in Diet Quality Scores and Risk of Cardiovascular Disease Among Us Men and Women
Authors: Mercedes Sotos-Prieto, Shilpa N Bhupathiraju, Josiemer Mattei, Teresa T Fung, Yanping Li, An Pan, Walter C Willett, Eric B Rimm, Frank B Hu
Journal: Circulation (2015)

Background: While adherence to several diet quality scores, including the Alternative Healthy Eating Index (AHEI), Alternative Mediterranean diet score (AMED), and Dietary Approach to Stop Hypertension (DASH), has been associated with lower risk of cardiovascular disease (CVD), little is known about how changes in these scores over time influence subsequent CVD risk. Objective: To evaluate the association between 4-y changes in three diet quality scores (AHEI, AMED and DASH) and subsequent risk of CVD among women and men in the Nurses’ Health Study I and Health Professionals Follow-up Study. Methods: We followed up 50,195 women in the Nurses’ Health Study (1986-2010) and 29,547 men in the Health Professionals Follow-up Study (1986-2010). AHEI, AMED and DASH were defined using data obtained from validated food frequency questionnaires updated every 4-y. Time-dependent and baseline Cox proportional hazards regression models were used to calculate hazard ratios (HR) with adjustment for age, family history of CVD, race, baseline diet quality, changes in smoking status, and initial and changes in other lifestyle factors (physical activity, alcohol intake, total energy intake). Outcome was defined as the number of confirmed incident cases of CVD (total coronary heart disease and stroke). Results across cohorts were pooled by an inverse variance-weighted, random-effect meta-analysis. Results: During 1,397,871 person-years of follow-up, we documented 11,542 incident CVD cases. Compared with individuals whose diet quality remained relatively stable (no change) in each 4-y period, those with the greatest improvements (11-22%) in diet quality had a 7-8% lower risk of CVD in the subsequent 4-y period [pooled HR (95% CI): AHEI: 0.92(0.87, 0.99); AMED: 0.93 (0.85, 1.02); DASH: 0.93, (0.87, 0.99); all P-trend&lt;0.05]. A 20 % increase in diet scores was associated with 3-9% lower risk of CVD (AHEI: 0.91 (0.86, 0.97); AMED: 0.97 (0.94, 0.99); DASH: 0.94 (0.90, 0.98). Increasing the diet scores (12-22%) from baseline to the first 4-y follow-up was associated with a lower risk of CVD during the next 20 years of follow-up [7% (1%, 12%) for AHEI and 9% (3%, 14%) for AMED]. On the other hand, a decrease in DASH score (16%) was associated with 8% (2%, 15%) higher risk of CVD over 20 years. Conclusions: Improving adherence to diet quality scores over time is associated with significantly lower risk of CVD, both in the short-term and long-term. Our results provide novel evidence that modest improvement in diet quality over time confers benefits for CVD prevention.
Mechanisms of Disease. An Introduction to Pathology.
Authors: Ruy Pérez-Tamayo
Journal: Annals of Internal Medicine (1962)

This book is dedicated to the clear presentation of basic processes in disease, the nature of which is considered in a philosophical preface that clarifies the concept of "life under abnormal conditions."The author, a pathologist, makes use of the approach of conventional pathology in basing some discussions upon morphologic alterations in cells and tissues, but changes in gross or microscopic structure are used as indices, comparable to clinical or physiological measurements, which also are not disease per se but constitute evidence from which the nature of basic changes can be perceived more clearly.Appropriate consid- eration of all kinds of evidence has led to success in the synthesis of clear ideas of the mechanisms involved in disease.The discussions of mechanisms are penetrating but are reasonably concise, and do not obscure the broad ideas by enumeration of detail, which is available through abundant quoted references.No attempt is made to consider diseases as isolated entities, but rather as instances of the general mechanisms by which homeostasis is achieved.The result is practical and interesting.Illustrations are not numerous but are well selected to supplement the text.This book will provide a student of medicine with an authoritative and readable presentation of general pathology, and should also be of use to all specialists in medicine as a means of broadening their perspective, and so counteracting some of the undesirable results of the high degree of specialization that has occurred during the last century.
Degenerative Disease of the Temporomandibular Joint and Pain-Dysfunction Syndrome
Authors: Hugh Ogus
Journal: Journal of the Royal Society of Medicine (1978)

It is proposed that pain-dysfunction syndrome and degenerative disease ofthe temporomandibular joint may both be expressions of the same problem, i.e, repetitive overload of the joint system. Acceptance of this proposal will explain the contrasting, although often successful, methods of treatment.
21st Century Miracle Medicine, by Alexandra Wyke
Authors: B. Jennett
Journal: BMJ (1997)

Alexandra Wyke: Plenon, £16.33, pp 352 ISBN 0 306 45565 X

Dr Wyke is well placed to embark on this exercise in predicting the future of medicine, with a doctorate in biochemistry and 15 years as healthcare correspondent with the Economist . She began her task by setting out on a whirlwind tour, mainly in the United States, to talk to those at the growing edges of both technology and the organisation of health care for their views about how medicine would be in the year 2050.

She begins with the familiar litany of criticisms of medicine today—overuse of diagnostic and therapeutic interventions, halfway technologies prolonging disabled lives without curing, and iatrogenic ills from hospital infections and medical mishaps. These are associated with more healthcare staff and escalating costs, and the whole enterprise is compromised by poor communication between doctor and patient, doctor and doctor, and teacher and taught.

Communication technology is rightly identified as the key to change, leading to the death of distance. Patients, with a …
A CASE OF POLYCYTHEMIA VERA ASSOCIATED WITH THE WOLFF-PARKINSON-WHITE SYNDROME
Authors: G A WESTFALL, P J BURDON
Journal: Annals of Internal Medicine (1950)

Case Reports1 November 1950A CASE OF POLYCYTHEMIA VERA ASSOCIATED WITH THE WOLFF-PARKINSON-WHITE SYNDROMEGEORGE A. WESTFALL JR., M.D., PHYLLIS J. BURDON, M.D.GEORGE A. WESTFALL JR., M.D.Search for more papers by this author, PHYLLIS J. BURDON, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-33-5-1290 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptAlthough the etiology of polycythemia vera remains unknown, repeated attempts have been made to correlate the condition with some cardiovascular phenomenon. Gaisböck1 has described a syndrome characterized by polycythemia with an associated hypertension, and Reznikof, Foot and Bethea2 have suggested an anoxia of the bone marrow as an etiologic agent. An underlying congenital cardiac defect was considered as a possible explanation for a secondary polycythemia in this case, but our studies failed to substantiate this assumption.3The Wolff-Parkinson-White syndrome is characterized electrocardiographically by shortened P-R interval and aberrant QRS component. It has been shown that bouts of paroxysmal tachycardia may...Bibliography1. Gaisböck F: Die Polyzythämie, Ergebn d. inn. Med. u. Kinderh. 21: 210, 1922. (Quoted from Wintrobe, M. M.: Clinical hematology, 2nd ed., 1946, Lea & Febiger, Philadelphia, p. 592.) Google Scholar2. ReznikofFootBethea PNCJM: Etiology and pathologic factors in polycythemia vera, Am. J. M. Sc. 189: 753, 1935. CrossrefGoogle Scholar3. Stein MH: A Wolff-Parkinson-White syndrome in a case of congenital heart disease. Am. Heart J. 35: 140 (Jan.) 1948. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Topeka, Kansas*Presented before the Kansas State Heart Association meeting, Veterans Administration Hospital, Topeka, Kansas, on December 11, 1947. Received for publication May 8. 1948.From the Department of Medicine, Winter Veterans Administration Hospital, Topeka, Kansas.Sponsored by the V. A and published with the approval of the Chief Medical Director. The statements and conclusions published by the authors are a result of their own study and do not necessarily reflect the opinion or policy of the Veterans Administration.†From the Medical Department, Hertzler Clinic, formerly resident in medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 November 1950Volume 33, Issue 5Page: 1290-1294KeywordsBone marrowElectrocardiographyEtiologyHeartHospital medicineHypertensionPolycythemiaPolycythemia veraTachycardia ePublished: 1 December 2008 Issue Published: 1 November 1950 PDF downloadLoading ...
Molecular epidemiology of penicillin-resistant Streptococcus pneumoniae in a university hospital, Ankara, Turkey
Authors: A Pinar, Ö. Köseoğlu, G. Yenişehirli, B. Şener
Journal: Clinical Microbiology and Infection (2004)

Penicillin-resistant Streptococcus pneumoniae isolates (n = 76) from clinical samples of patients admitted to Hacettepe University Hospital between January 1997 and December 2001 were included in the study. MICs of penicillin G, erythromycin A, clindamycin, cefaclor, cefotaxime, vancomycin, chloramphenicol, tetracycline, ciprofloxacin and rifampicin were determined by agar dilution. The isolates were serogrouped on the basis of the Neufeld Quellung reaction and were typed by BOX-PCR. Genetic polymorphismof the penicillin resistance genes pbp2b and pbp2x was investigated by restriction fragment length polymorphism (RFLP) analysis. Of the 76 isolates tested, 64 (84.2%) showed intermediate resistance to penicillin, while 12 (15.8%) were resistant to higher levels of penicillin (MIC ≥ 2 mg/L). The resistance patterns of the isolates revealed six different resistance profiles. There were 22 different serotypes, with c. 55% of the isolates belonging to serotypes 23B, 19A, 19F, 14, 6 A and 9V. Five distinct patterns for pbp2b and 12 distinct patterns for pbp2x were obtained by RFLP analysis of penicillin-binding protein genes. The combination of these patterns allowed isolates to be classified into 22 fingerprint subgroups. BOX-PCR analysis showed that the isolates fell into 14 distinct BOX genotypes, with 33 subtypes. Serotype 9V isolates with pbp genotype 2–6 and BOX-PCR type 4, 4.1 or 4.2 were related to the pandemic clone Spain9V–3. No relatedness to other international clones was detected among the other study strains, but genetic relatedness was observed among some of the serotype 19A and 23B isolates. Overall, the results demonstrated that most of the penicillin-resistant pneumococcal isolates in Turkey, other than those belonging to serotypes 9V, 19A and 23B, were derived from several independent clones, possibly resulting from multiple importation of strains originating from outside the country. Differences in pbp patterns, serotypes and resistance profiles among isolates that showed similar BOX-PCR patterns supported the hypothesis that horizontal transfer of capsular genes, pbp genes and other genetic determinants between S. pneumoniae and viridans group streptococci may have occurred.