tbuckley/cabot-search huggingface dataset:
Pharmacokinetics of PF-00562271, a focal adhesion kinase inhibitor, in patients with advanced non-hematologic malignancies
Authors: Huiping Xu, Donghua Yin, Barbara Duncan, Howard Fingert, Amarnath Sharma
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

231 

Focal adhesion kinase (FAK) transduces signaling from integrins and growth factors to modulate tumor cell invasion, proliferation and survival. PF-00562271, a potent FAK inhibitor, is under development as an anticancer agent. In the first-in-human, dose escalation trial, serial serum samples were collected to characterize single dose and steady-state pharmacokinetics (PK) of PF-00562271 after BID or QD oral dosing in patients with non-hematologic malignancies. Clinical safety and other outcome data from this study have been described previously (Siu L et al, Proc. ASCO, 2007). Serum PF-00562271 concentrations were determined using a validated HPLC-MA/MS method. The concentration-time data were analyzed by non-compartmental methods using WinNonlin (Pharsight®, CA). After the lead-in single dose, PF-562,271 was readily absorbed with the maximum serum concentration (Cmax) achieved between 0.5 to 5 hr; the increase in systemic exposure (AUCinf) was dose proportional at doses from 5 mg to 25 mg, but was more than dose proportional at higher doses. After repeated oral dosing, there was a more than proportional accumulation in the PF-00562271 steady-state exposure. The mean ratio of AUC during a dose interval at steady state (AUC0-τ,ss) to AUC0-inf after the lead-in dose ranged from 1.5 to 5.72,    indicating a non-linear PK following repeated oral dosing. At the highest doses tolerated on an empty stomach of 80 mg BID and 175 mg QD, the average steady-state serum PF-00562271 concentrations were 29-fold and 46-fold, respectively, higher than the predicted efficacious concentration based on preclinical xenograft models. (W.G. Roberts, Cancer Res, 2008) In summary, the PK results demonstrated that PF-00562271 displayed a time- and dose-dependent non-linear PK, which is consistent with the in vitro observation of mechanism-based inhibition of the primary metabolic enzyme CYP 3A4 by PF-00562271. The PK results support both BID and QD regimens as viable options for further evaluation of PF-00562271 in Phase 2 studies.    #
Clues to the Etiology, Pathology, and Therapy of Cancer Provided by Analogies With Transplantation Disease&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;3&lt;/xref&gt;
Authors: Albert Tyler
Journal: JNCI Journal of the National Cancer Institute (1960)

Journal Article Clues to the Etiology, Pathology, and Therapy of Cancer Provided by Analogies With Transplantation Disease Get access Albert Tyler Albert Tyler Division of Biology, California Institute of Technology, Pasadena, California Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 25, Issue 6, December 1960, Pages 1197–1229, https://doi.org/10.1093/jnci/25.6.1197 Published: 01 December 1960 Article history Received: 12 July 1960 Published: 01 December 1960
Modulation of Cyclic Nucleotides in Isolated Rat Glomeruli
Authors: Vicente E. Torres, Thomas E. Northrup, Richard M. Edwards, Sudhir V. Shah, Thomas P. Dousa
Journal: Journal of Clinical Investigation (1978)

Because glomerular functions are modulated by numerous humoral agents, probably acting through cyclic nucleotides, the effects of some polypeptide hormones and biogenic amines on cyclic AMP (cAMP) and cyclic 3',5'-guanosine monophosphate (cGMP) were studied in glomeruli isolated from rat renal cortex. Glomeruli and cortical tubules were prepared by a combination of sieving and density-gradient centrifugation. Under basal conditions, the contents of cAMP and cGMP in glomeruli were significantly higher than in tubules and unfractionated renal cortical tissue.Histamine caused a striking increase in cAMP in glomeruli (+Delta% 675+/-87) and, to a lesser degree, increased cAMP in tubules (+Delta% 103+/-25) or in tissue slices. This stimulation was dose-dependent in the range of 1 muM-1 mM histamine. Metiamide (an H(2)-antagonist), but not pyrilamine (an H(1)-antagonist) blocked the effect of histamine on cAMP, which indicates that histamine causes its effect via interaction with H(2) receptors. Histamine caused less extensive increases in cGMP in both glomeruli and tubules. Carbamylcholine caused a marked increase in cGMP in glomeruli (+Delta 295+/-7) and a much lower increase in tubules (+Delta% 70+/-20); these effects were blocked by atropine. Parathyroid hormone (1 mug/ml) increased cAMP and, to a much lesser degree, also cGMP in glomeruli. In tubules, parathyroid hormone caused much more extensive increases in cAMP than in glomeruli; no changes, or rather a small decline in cGMP, was observed. Angiotensin-II (2 muM) markedly lowered cAMP in glomeruli (-Delta% -45+/-8) and in tubules (-Delta% 33+/-7) but had no effect on cGMP. Bradykinin (20 muM) did not consistently influence either cAMP or cGMP in glomeruli or tubules. Present results demonstrate that cAMP and cGMP metabolism in glomeruli are controlled independently by humoral agents known to alter glomerular functions in vivo. Our findings are consistent with the view that histamine and cholinergic agents generated and (or) released locally in glomeruli or in their vicinity may play important roles as mediators of immunopathological injury of glomeruli, and that these effects are mediated by cAMP and (or) cGMP through interaction with H(2) receptors and muscarinic receptors. Likewise, our results suggest that the effects of angiotensin-II and parathyroid hormone on glomerular dynamics may be mediated by cyclic nucleotides.Thus, we surmise that extrarenal as well as intrarenal humoral agents may play an important role in the pathology and physiology of glomeruli through mediation of either cAMP, cGMP, or both.
Heat Delivery Session: Summary of Discussion
Authors: James R. Oleson
Journal: Cancer Research (1984)

Several discussants raised questions about F. A. Gibbs' com parison of thermometric and patient tolerance end points achieved with magnetic induction versus the annular phased array system. The possibility of bias resulting from the order in which the 2 methods were used seemed slight in view of the close reproducibility of temperature distributions from day to day achieved in a given patient with each device. F. K. Storm argued that systematic differences could result from differences in ther mometric approaches, but Dr. Gibbs pointed out that the same catheters were used for temperature monitoring with each device and that the mean duration of treatment with both devices was similar. The potential for injury with regional hyperthermia devices was recognized by many discussants to be significant if devices were used without understanding of physical characteristics of the device, measurement of temperatures, and attention to patient discomforts. Regional hyperthermia, particularly with microwave devices producing significant power deposition in deep sites, was felt at this time to be unsafe to administer to patients under general anesthesia. In view of increasing evidence that treatment efficacy with hyperthermia is related to minimum intratumoral temperature and in view of the difficulty in achieving and measuring such minimum temperatures near 42Â°with external devices, the use of whole-body hyperthermia appeared to several discussants to have advantages over local and regional hyperthermia. This issue was to be considered further in the session on whole-body hyperthermia.
Abstract 18172: Rhythm Control with Catheter Ablation Improves Ejection Fraction Compared to Rate Control: A Meta-Analysis of Randomized Controlled Studies
Authors: Ajay Vallakati, Arun Kanmantha Reddy, Mark Dunlap, William Lewis
Journal: Circulation (2014)

Background: Atrial fibrillation (AF) can exacerbate/worsen heart failure. A randomized study showed that rhythm control with anti-arrhythmic drugs (AADs) is not superior to rate control for heart failure patients who develop AF. However, a recent study revealed catheter ablation can improve the ejection fraction (EF) compared to medical rate control. Hypothesis: We performed a meta-analysis to compare the effect of rhythm control and medical rate control on EF in heart failure patients with AF. Methods: We searched PubMed, Embase, Google Scholar and Cochrane databases for all randomized controlled trials (RCTs) comparing rhythm control versus rate control for AF in heart failure. Primary outcome was change in EF. Random effects model was used to pool and analyze data across the studies. Results: Of a total of 7 RCTs (4 - AADs, 3 - catheter ablation) which compared rhythm control and medical rate control, 4 studies (n=202) reported quantitative data on EF. There was significant heterogeneity between the studies (I2=82%, p &lt;0.001). Compared to rate control, the mean improvement in EF with rhythm control was 5.94% (95% CI 0.63- 11.26, p=0.03). Sub-group analysis revealed catheter ablation improved the EF by 6.67% (95% CI 0.23 -13.11, p=0.04) whereas rhythm control with AADs did not significantly change EF (3.50, -1.76 -8.76). Conclusion: Rhythm control is associated with greater improvement in EF compared to rate control therapy in heart failure patients with AF. Catheter ablation of AF significantly improves the EF in these patients. Further studies are needed to determine if this improvement in EF is associated with decreased morbidity and mortality.
STUDIES ON THE VELOCITY OF BLOOD FLOW
Authors: Herrmann L. Blumgart, Soma Weiss
Journal: Journal of Clinical Investigation (1927)

In establishing a satisfactory method for measuring the velocity of blood flow by means of the intravenous injections of radium C, the collection of the active deposit of radium from radium emanation (radon) and the preparation of the active deposit for intravenous injection became problems of the utmost importance.
C-Reactive Protein and Risk of Colon Cancer
Authors: Moutasim H. Al-Shaer
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Heart-lung Bypass. Principles and Techniques of Extracorporeal Circulation.
Authors: John J. Osborn
Journal: Annals of Internal Medicine (1963)

The current edition attempts to bring the material more up to date with new chapters on drug therapy, psychodynamics, personality disorders, and mental deficiency.The chapter on classification of mental diseases has also been revised in keeping with the more current classification of mental disorders.A separate chapter is devoted to each major subdivision of mental illness as these are outlined in the American Psychiatric Association classification of mental disorders.There are, in addition, chapters on The Nurse and the Psychiatric Patient, Organic Therapy, Psychotherapy, and Psychiatry in War.Unfortunately missing were chapters on Psychiatry and the Law, Social Psychiatry, and Child Psychiatry.The extensive revision from the previous text, which appeared in 1952, is evidence of the many changes which have occurred in psychiatry.This volume presents a broad, and rather general, view of the field of psychiatry.Although it does not attempt to present original data or concepts, it should prove of interest to physicians in fields other than psychiatry, who are interested in current psychiatric concepts and treatment approaches.
Class IA PI3-kinase isoforms in signaling and cancer
Authors: Jean Zhao
Journal: Cancer Research (2008)

SY37-02   Class 1A phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptor tyrosine kinases (RTKs) and Ras to generate the primary intracellular lipid signal, phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is essential for multiple cellular processes. The tumor suppressor PTEN, a lipid phosphatase, dephosphorylates PIP3 and therefore opposes the action of PI3Ks. Constitutive activation of the class 1A PI3K signaling pathway, via direct or indirect mutagenic events is common in many types of human cancer. Thus, class 1A PI3Ks are attractive targets for therapeutic intervention in cancer. In mammals, there are two class 1A PI3K isoforms, p110α and p110β, broadly expressed in epithelial tissues/organs, among others. These two isoforms of PI3K are very similar in their catalytic and regulatory domains. They utilize the same substrates and generate the same lipid products. The structural and enzymatic overlap of these two PI3K isoforms suggests that they may function redundantly with each other. Recently, however, we have constructed conditional knockout mice via the Cre-LoxP (floxed) mediated recombination system for PIK3CA and PIK3CB encoding p110α and p110β, respectively. We found that the two isoforms have markedly different roles in cellular signaling and oncogenic transformation. Ablation of p110α in cells led to deficient cellular signaling in response to various growth factors and insulin. Interestingly, loss of p110β had little effect on growth factor signaling but impaired LPA (lisophosphatidic acid) elicited Akt activation and downstream signal events. However, cells lacking either p110α or p110β are resistant to oncogenic transformation induced by various oncogenes.  In vivo  tissue-specific deletion of p110α or p110β studies begin to reveal distinct roles of these two isoforms in development and tumorigenesis in breast and prostate tissues. Finally, a kinome-wide screen for kinases that are able to transform cells lacking p110α or p110β will also be discussed.
Abstract 573: Relation between Admission Plasma Glucose and In-Hospital Mortality is Different between Diabetic and Non-Diabetic Patients with Acute Myocardial Infarction
Authors: Masaharu Ishihara, Sunao Kojima, Masami Kosuge, Kazuo Kimura, Hisao Ogawa
Journal: Circulation (2008)

It has been well demonstrated that acute hyperglycemia is associated with high mortality after acute myocardial infarction (AMI). However, optimal plasma glucose (PG) level is not known. The relation between PG and mortality may be different between diabetic and non-diabetic patients. This study consisted of 3,750 patients who were admitted to the 35 hospitals participating to the Japanese Acute Coronary Syndrome Study (JACSS) group within 48 hours after the onset of AMI. PG was measured at the time of hospital admission. In non-diabetic patients, there was a linear relation between PG and in-hospital mortality. Non-diabetic patients with PG &lt;6 mmol/L had the lowest mortality (2.5%). As PG increased by 1 mmol/L, mortality increased by 17% (13%–21%, p&lt;0.001). However, in diabetic patients, there was a U-shape relation between PG and mortality (Figure ). Diabetic patients with PG 9–10 mmol/L had the lowest mortality (1.9%); both diabetic patients with PG &lt;7 mmol/L (9.4%, p=0.009) and those with PG ≥11 mmol/L (9.1%, p&lt;0.001) had significantly higher mortality than those with PG 7–11 mmol/L (3.2%). Diabetic patients with PG 9–10 mmol/L had the lowest mortality, whereas lower PG was better in non-diabetic patients. Optimal PG level may be different between diabetic and non-diabetic patients with AMI.
Sustained high prevalence of pneumococcal serotype 1 in paediatric parapneumonic empyema in southern Spain from 2005 to 2009
Authors: I. Obando, M.S. Camacho-Lovillo, A. Porras, M.A. Gandía-González, A. Molinos, I. Vazquez-Barba, B. Morillo-Gutierrez, O.W. Neth, D. Tarrago
Journal: Clinical Microbiology and Infection (2011)
81. Modification of HEK 293 Cell Integrin Expression Profile Allows Convenient Large-Scale Roller Bottle Production of Lentiviral Vectors
Authors: Manij Patel, David A. Wilcox, Angela M. Giddings, Tristan R. McKay, John C. Olsen
Journal: Molecular Therapy (2004)

Human embryonic kidney cells (HEK 293) are the most widely used cell type for production of viral gene transfer vectors. They are highly transfectable with plasmid DNAs encoding viral proteins using a number of transfection reagents and protocols to transiently express recombinant viruses. A variety of stable 293-based packaging cell lines have also been generated for virus production. We have developed a gene transfer system based on the non-primate lentivirus equine infectious anemia virus (EIAV), that utilizes a stable 293 based inducible packaging cell line (BiG 45) for high-titer virus production. Large-scale production of vectors using 293 cells is often difficult since they easily detach from regular tissue culture plates. This can be overcome by adapting the cells to grow in suspension cultures, however this can result in a significant loss in viral titer. Alternately, cultures can be grown in vessels that are treated with cell attachment substrates such as fibronectin or poly-lysine. Both strategies, however, significantly increase the cost of large-scale vector production. In this study, we tested a new strategy of increasing the adhesion properties of 293 cells by modifying their integrin expression profile. First, we tested the effects of over-expressing the integrin beta-3 subunit alone or in combination with its known binding partners, alpha-v or alpha-IIb. The cell adhesion assay involved transiently expressing integrin sub-units in 293-based EIAV packaging cells expressing green fluorescent protein. The cells were plated at a density of 2–4×105 cells/well on untreated multi-well plates. The plating efficiency of the cells was determined 1 hr after plating by measuring the fluorescence of the cells before and after washing the cells. We found that over-expression of the beta-3 integrin subunit in 293 cells resulted in a significant increase in adhesion of the cells to untreated tissue culture plates as compared to unmodified cells. Co-expression of alpha-v, but not alpha-IIb further increased 293 cell adherence. We next investigated production of both HIV and EIAV-based lentiviral vectors from integrin-modified 293 cells. Vector titers and reporter gene expression in target cells were not compromised as a result of this modification and this led us to scale up vector production in roller bottles for generating vectors for in vivo experiments. In summary, over-expression of alpha-v and beta-3 in 293 cells increases adhesion to regular untreated tissue culture dishes without compromising viral vector production. This modification should be of use in other applications that require the use of poorly adherent cell lines.
318. Cationic Lipids/Ligands Induce DNA Helix Denaturation and Alter Transcriptional Activity
Authors: K. T. Prasad, Madhusudhana N. Rao, Vijaya Gopal
Journal: Molecular Therapy (2004)

Top of pageAbstract
Cationic lipid-based formulations are promising gene delivery agents owing to their simplicity and self organizing properties. Although the physical properties of cationic lipids have been extensively worked out, the resultant low transfection efficiency observed in gene therapy protocols is ambiguous. We have investigated the effect of several cationic liposomes, namely 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), on transcription by Escherichia coli RNA polymerase at DNA templates complexed with the cationic lipid. The observed stimulation in transcription at excess DNA negative charges over lipid positive charge prompted us to investigate in detail the basic nature of Cationic Lipid DNA Complexes (CLDC) by absorbance spectroscopy and circular dichroism. Cetyl tri-methyl ammonium bromide (CTAB), a single chain cationic amphiphile and polyethylenimine (PEI), a cationic polymer, and other cationic lipids also bring about similar changes albeit to a lesser extent. The observed stimulation in transcription motivated us to explore in detail the molecular nature of CLDC by KMnO4 probing. Interestingly, thymidines followed by a purine showed higher susceptibility to cationic lipid/ligand-mediated melting of DNA. Other water-soluble cationic ligands such as polylysine, protamine and polyethyleneimine also demonstrated melting of the DNA but with variations. Similarly small cations such as spermine, spermidine and CTAB also rendered the DNA susceptible to modification by KMnO4. We present direct proof for melting of DNA upon interaction with cationic lipids/ligands. Structural changes subsequent to binding of cationic lipids/ligands to DNA may lead to instability and formation of DNA bubbles in double-stranded DNA. These observations would help in describing the CLDC completely.
Comparison of Copeptin, B-Type Natriuretic Peptide, and Amino-Terminal Pro-B-Type Natriuretic Peptide in Patients With Chronic Heart Failure
Authors: Stephanie Neuhold, Martin Huelsmann, Guido Strunk, Brigitte Stoiser, Joachim Struck, Nils G. Morgenthaler, Andreas Bergmann, Deddo Moertl, Rudolf Berger, Richard Pacher
Journal: Journal of the American College of Cardiology (2008)
Four Directions Summer Program Guides Native Americans Toward Medical Careers
Authors: M J Friedrich
Journal: JAMA (2001)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal