tbuckley/cabot-search huggingface dataset:
DARPin-targeting of Measles Virus: Unique Bispecificity, Effective Oncolysis, and Enhanced Safety
Authors: Katrin Friedrich, Jan RH Hanauer, Steffen Prüfer, Robert C Münch, Iris Völker, Christodoulos Filippis, Christian Jost, Kay-Martin Hanschmann, Roberto Cattaneo, Kah-Whye Peng, Andreas Plückthun, Christian J Buchholz, Klaus Cichutek, Michael D Mühlebach
Journal: Molecular Therapy (2013)

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Many naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. In addition, specific targeting of cancer cells can be achieved at the virus entry level. We optimized retargeting of cell entry by elongating the measles virus attachment protein with designed ankyrin repeat proteins (DARPins), while simultaneously ablating entry through the natural receptors. DARPin-targeted viruses were strongly attenuated in off-target tissue, thereby enhancing safety, but completely eliminated tumor xenografts. Taking advantage of the unique properties of DARPins of being fused without generating folding problems, we generated a virus simultaneous targeting two different tumor markers. The bispecific virus retained the original oncolytic efficacy, while providing proof of concept for a strategy to counteract issues of resistance development. Thus, DARPin-targeting opens new prospects for the development of personalized, targeted therapeutics. Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Many naturally occurring viruses have a preferential, although nonexclusive, tropism for tumors and tumor cells. In addition, specific targeting of cancer cells can be achieved at the virus entry level. We optimized retargeting of cell entry by elongating the measles virus attachment protein with designed ankyrin repeat proteins (DARPins), while simultaneously ablating entry through the natural receptors. DARPin-targeted viruses were strongly attenuated in off-target tissue, thereby enhancing safety, but completely eliminated tumor xenografts. Taking advantage of the unique properties of DARPins of being fused without generating folding problems, we generated a virus simultaneous targeting two different tumor markers. The bispecific virus retained the original oncolytic efficacy, while providing proof of concept for a strategy to counteract issues of resistance development. Thus, DARPin-targeting opens new prospects for the development of personalized, targeted therapeutics.
Saphenous vein bypass for direct coronary revascularization
Authors: D. N. Ross, L. Gonzalez-Lavin, T. Frazier
Journal: Thorax (1972)

The surgical approach to myocardial revascularization has been undertaken on the same basis as in peripheral vascular surgery. Aorta to coronary saphenous vein bypass has been found to be one of the best methods of providing immediate augmentation of coronary blood flow. Thirty-eight patients have been operated upon. The hospital mortality was 5.3% and the total mortality has been 13.2% in a follow-up extending one month to two years. Among the survivors, 90% had excellent initial results with complete disappearance of symptoms and marked improvement in exercise tolerance. The authors advocate the saphenous vein bypass as the procedure of choice for elective coronary revascularization.
Former GP is new chair of House of Commons Health Committee
Authors: A. O'Dowd
Journal: BMJ (2014)

The former GP Sarah Wollaston has been elected as the new chair of the parliamentary health select committee.

Wollaston, the Conservative MP for Totnes, won the position by a strong majority in the House of Commons election held on 18 June, beating four other candidates. In the final of four rounds of counting in a transferable vote election, Wollaston received 226 votes, followed by Philip Lee, also a GP, who received 195 votes. The other nominations (all Conservative) were David Tredinnick, MP for Bosworth, Charlotte Leslie, MP for Bristol North West, and Caroline Spelman, MP for Meriden.

The position became free after the former chair, Stephen …
Leukemia inhibitory factor levels are elevated in septic shock and various inflammatory body fluids.
Authors: P Waring, K Wycherley, D Cary, N Nicola, D Metcalf
Journal: Journal of Clinical Investigation (1992)

Leukemia inhibitory factor (LIF) has many biological actions which parallel those of IL-1, IL-6 and tumor necrosis factor-alpha, but its role in the pathogenesis of human disease is unknown. A specific radioreceptor competition assay capable of detecting LIF at concentrations above 1 ng/ml (45 pM) was developed. To identify disease states in which LIF might be involved, a cross-sectional survey of serum and body fluids from approximately 1,500 subjects with a variety of diseases was performed using the LIF radioreceptor competition assay. Serum LIF concentrations were transiently elevated (2-200 ng/ml) in six subjects with meningococcal or Gram-negative septic shock, and in a subject with idiopathic fulminant hepatic failure. Moderately elevated LIF concentrations (> 10 ng/ml) were detected in cerebrospinal fluid from subjects with bacterial meningitis, in effusions associated with pneumonia and peritonitis, and in amniotic fluid from a woman with chorioamnionitis. Low LIF concentrations (1-10 ng/ml) were present in synovial fluid from subjects with inflammatory arthritis, amniotic fluid from women in labor, and some reactive, chronic inflammatory and malignant effusions and cyst fluids, but rarely in transudates. These initial findings suggest that LIF might be involved in the pathogenesis of inflammation and septic shock.
Sorafenib or Placebo with Either Gemcitabine or Capecitabine in Patients with HER-2–Negative Advanced Breast Cancer That Progressed during or after Bevacizumab
Authors: Lee S. Schwartzberg, Kurt W. Tauer, Robert C. Hermann, Grace Makari-Judson, Claudine Isaacs, J. Thaddeus Beck, Virginia Kaklamani, Edward J. Stepanski, Hope S. Rugo, Wei Wang, Katherine Bell-McGuinn, Jeffrey J. Kirshner, Peter Eisenberg, Richard Emanuelson, Mark Keaton, Ellis Levine, Diana C. Medgyesy, Rubina Qamar, Alexander Starr, Sunhee Kwon Ro, Nathalie A. Lokker, Clifford A. Hudis
Journal: Clinical Cancer Research (2013)

We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab.This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS).One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%).The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions.
HOSPITALS AND CLUBS
Authors: W. Martin
Journal: BMJ (1907)

The empirical observation is well documented that currency exposure can add risk to an unhedged international equity portfolio. Extending that work, this article uses three manipulations of the standard portfolio risk equation to show (1) why currency acts as implicit leverage in a portfolio and can therefore increase risk, even under the assumption of zero correlation; (2) how, under an additional assumption, the portfolio risk equation reduces to the Pythagorean equation and that, by using that result, a simple proof can show that an unhedged international equity portfolio is always riskier than a hedged one; and (3) how the risk equation can be rearranged to give the “correlation breakeven” that an investor requires to be indifferent to hedging (or not hedging). <b>TOPICS:</b>Currency, developed markets, portfolio construction, risk management
A 41-Year-Old African American Man With Poorly Controlled Hypertension
Authors: Lisa A. Cooper
Journal: JAMA (2009)

Mr R is an African American man with a long history of poorly controlled hypertension and difficulties with adherence to recommended treatments. Despite serious complications such as hypertensive emergency requiring hospitalization and awareness of the seriousness of his illness, Mr R says at times he has ignored his high blood pressure and his physicians' recommendations. African Americans are disproportionately affected by hypertension and its complications. Although most pharmacological and dietary therapies for hypertension are similarly efficacious for African Americans and whites, disparities in hypertension treatment persist. Like many patients, Mr R faces several barriers to effective blood pressure control: societal, health system, individual, and interactions with health professionals. Moreover, evidence indicates that patients' cognitive, affective, and attitudinal factors and the patient-physician relationship play critical roles in improving outcomes and reducing racial disparities in hypertension control.
Attenuation of oxidant/antioxidant imbalance during treatment of exacerbations of chronic obstructive pulmonary disease
Authors: I. Rahman, E. Skwarska, W. MacNee
Journal: Thorax (1997)

BACKGROUND: An oxidant/antioxidant imbalance is thought to occur in patients with chronic obstructive pulmonary disease (COPD). It has recently been shown that during exacerbations of COPD the antioxidant capacity and protein sulfhydryls of plasma are lower and the levels of products of lipid peroxidation are higher than in age matched healthy subjects. The aims of this study were to confirm these data and to measure the time course of these changes. METHODS: The plasma Trolox equivalent antioxidant capacity (TEAC), protein sulfhydryls, and products of lipid peroxidation were measured throughout the course of treatment in 13 patients who presented with an acute exacerbation of COPD. RESULTS: TEAC values (mmol/l) were low on admission (mean 0.67, 95% confidence interval (CI) 0.32 to 0.88; p &lt; 0.05) and had increased by discharge (0.98, 95% CI 0.88 to 1.2; p &lt; 0.05) but still remained lower than in healthy subjects (1.33, 95% CI 1.11 to 1.65). There was also restoration of plasma protein sulfhydryl levels (mmol/l) from admission (0.32, 95% CI 0.20 to 0.43) to discharge (0.49, 95% CI 0.42 to 0.62, p &lt; 0.001) to levels similar to those in healthy subjects (0.52, 95% CI 0.43 to 0.65). Products of lipid peroxidation, measured as thiobarbituric acid-malondialdehyde adducts (mumol/l), were significantly higher (2.08, 95% CI 1.8 to 2.5) than in control subjects (1.3, 95% CI 0.85 to 1.32; p &lt; 0.01) and returned to normal values by the time of discharge (1.2, 95% CI 0.88 to 1.29). CONCLUSIONS: These data confirm the presence of a profound oxidant/antioxidant imbalance in the blood of patients with acute exacerbations of COPD which returns towards normal values during the course of treatment.
Prognostic Factors and Outcome of Core Binding Factor Acute Myeloid Leukemia Patients With t(8;21) Differ From Those of Patients With inv(16): A Cancer and Leukemia Group B Study
Authors: Guido Marcucci, Krzysztof Mrózek, Amy S. Ruppert, Kati Maharry, Jonathan E. Kolitz, Joseph O. Moore, Robert J. Mayer, Mark J. Pettenati, Bayard L. Powell, Colin G. Edwards, Lisa J. Sterling, James W. Vardiman, Charles A. Schiffer, Andrew J. Carroll, Richard A. Larson, Clara D. Bloomfield
Journal: Journal of Clinical Oncology (2005)

Purpose Because both t(8;21) and inv(16) disrupt core binding factor (CBF) in acute myeloid leukemia (AML) and confer relatively favorable prognoses, these cytogenetic groups are often treated similarly. Recent studies, however, have shown different gene profiling for the two groups, underscoring potential biologic differences. Therefore, we sought to determine whether these two cytogenetic groups should also be considered separate entities from a clinical standpoint. Patients and Methods We analyzed 144 consecutive adults with t(8;21) and 168 with inv(16) treated on Cancer and Leukemia Group B front-line studies. We compared pretreatment features, probability of achieving complete remission (CR), overall survival (OS) and cumulative incidence of relapse (CIR) between the two groups. Results With a median follow-up of 6.4 years, for CBF AML as a whole, the CR rate was 88%, 5-year OS was 50% and CIR was 53%. After adjusting for covariates, patients with t(8;21) had shorter OS (hazard ratio [HR] = 1.5; P = .045) and survival after first relapse (HR = 1.7; P = .009) than patients with inv(16). Unexpectedly, race was an important predictor for t(8;21) AML, in that nonwhites failed induction more often (odds ratio = 5.7; P = .006) and had shorter OS than whites when certain secondary cytogenetic abnormalities were present. In patients with t(8;21) younger than 60 years, type of induction also correlated with relapse risk. For inv(16) AML, secondary cytogenetic abnormalities (especially +22) and male sex predicted better outcome. Conclusion When the prognostic impact of race, secondary cytogenetic abnormalities, sex, and response to salvage treatment is considered, t(8;21) and inv(16) AMLs seem to be distinct clinical entities and should be stratified and reported separately.
Amifostine reduces lung vascular permeability<i>via</i>suppression of inflammatory signalling
Authors: P. Fu, A. A. Birukova, J. Xing, S. Sammani, J. S. Murley, J. G. N. Garcia, D. J. Grdina, K. G. Birukov
Journal: European Respiratory Journal (2008)

Despite an encouraging outcome of antioxidant therapy in animal models of acute lung injury, effective antioxidant agents for clinical application remain to be developed. The present study investigated the effect of pre-treatment with amifostine, a thiol antioxidant compound, on lung endothelial barrier dysfunction induced by Gram-negative bacteria wall-lipopolysaccharide (LPS). Endothelial permeability was monitored by changes in transendothelial electrical resistance. Cytoskeletal remodelling and reactive oxygen species (ROS) production was examined by immunofluorescence. Cell signalling was assessed by Western blot. Measurements of Evans blue extravasation, cell count and protein content in bronchoalveolar lavage fluid were used as in vivo parameters of lung vascular permeability. Hydrogen peroxide, LPS and interleukin-6 caused cytoskeletal reorganisation and increased permeability in the pulmonary endothelial cells, reflecting endothelial barrier dysfunction. These disruptive effects were inhibited by pre-treatment with amifostine and linked to the amifostine-mediated abrogation of ROS production and redox-sensitive signalling cascades, including p38, extracellular signal regulated kinase 1/2, mitogen-activated protein kinases and the nuclear factor-κB pathway. In vivo , concurrent amifostine administration inhibited LPS-induced oxidative stress and p38 mitogen-activated protein kinase activation, which was associated with reduced vascular leak and neutrophil recruitment to the lungs. The present study demonstrates, for the first time, protective effects of amifostine against lipopolysaccharide-induced lung vascular leak in vitro and in animal models of lipopolysaccharide-induced acute lung injury.
Low-Fat Diet and Cardiovascular Disease—Reply
Authors: Barbara V. Howard, Garnet L. Anderson, Bette Caan, Judith Hsia, Karen Johnson, Marian Limacher, JoAnn E. Manson, Ross L. Prentice, Marcia L. Stefanick, Sylvia Wassertheil-Smoller, Linda Van Horn, for the Writing Groups for the WHI Investigators
Journal: JAMA (2006)

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
THE MECHANISM OF ACTIVE CEREBRAL IMMUNITY TO EQUINE ENCEPHALOMYELITIS VIRUS
Authors: R. Walter Schlesinger
Journal: The Journal of Experimental Medicine (1949)

Continued serial brain-to-brain passage of strains of W.E.E. virus in mice has yielded variants which kill mice with increased rapidity. Their rate of multiplication in the mouse brain has been found to be correspondingly increased. At 1 hour after intracerebral inoculation of various amounts of W.E.E. virus, only 3.5 to 10 per cent of the expected amount of virus was recovered from the infected brains. In infected mouse brains, the period of active viral multiplication was preceded by a latent phase which lasted a considerably shorter time in the case of a "fast" than in that of a "slow" variant. In brains inoculated with various amounts in excess of minimal lethal doses the rates of multiplication tended to converge with the result that the maximum titer was reached after about the same period of time. After inoculation of smaller amounts, the rates of viral multiplication tended to parallel each other. Vaccinated mice may be fully resistant to maximal intracerebral doses of a slowly multiplying strain while they are not at all or only partly protected against a rapidly multiplying one derived from it. This difference is demonstrable even though fast and slow variants are, as far as can be tested, serologically identical. The difference in response may be masked if animals are immunized with relatively large doses of vaccine. The bearing of these findings on certain practical problems has been pointed out.
<i>In vivo</i> Dynamics and Distinct Functions of Hypoxia in Primary Tumor Growth and Organotropic Metastasis of Breast Cancer
Authors: Xin Lu, Carol H. Yan, Min Yuan, Yong Wei, Guohong Hu, Yibin Kang
Journal: Cancer Research (2010)

Tumor hypoxia is known to activate angiogenesis, anaerobic glycolysis, invasion, and metastasis. However, a comparative analysis of the potentially distinct functions of hypoxia in primary tumor growth and organ-specific metastasis has not been reported. Here, we show distinct hypoxia kinetics in tumors generated by the MDA-MB-231 breast cancer sublines with characteristically different primary tumor growth rates and organotropic metastasis potentials. Hypoxia-induced angiogenesis promotes both primary tumor growth and lung metastasis but is nonessential for bone metastasis. Microarray profiling revealed that hypoxia enhances the expression of a significant number of genes in the lung metastasis signature, but only activates a few bone metastasis genes, among which DUSP1 was functionally validated in this study. Despite the different mechanisms by which hypoxia promotes organ-specific metastasis, inhibition of HIF-1alpha with a dominant-negative form of HIF-1alpha or 2-methoxyestradiol reduced metastasis to both lung and bone. Consistent with the extensive functional overlap of hypoxia in promoting primary tumor growth and lung metastasis, a 45-gene hypoxia response signature efficiently stratifies breast cancer patients with low or high risks of lung metastasis, but not for bone metastasis. Our study shows distinct functions of hypoxia in regulating angiogenesis and metastasis in different organ microenvironments and establishes HIF-1alpha as a promising target for controlling organotropic metastasis of breast cancer.
Glucocorticoid receptor isoform expression does not predict steroid treatment response in IBD
Authors: M Hausmann, H Herfarth, J Scholmerich, G Rogler
Journal: Gut (2007)

The occurrence of glucocorticoid dependent or refractory disease courses is a major clinical problem not only in inflammatory bowel disease (IBD) but also in other chronic inflammatory conditions such as asthma and rheumatoid arthritis.1 It would be of great value if the responsiveness of patients to glucocorticoids could be evaluated before their administration to avoid ineffective treatment.

The response to steroids is mediated by the glucocorticoid receptor (hGR) of which two isoforms exist, hGRα and hGRβ. Both are products of alternative splicing of the primary transcript of GR messenger RNA (mRNA).2 The hGR isoforms differ in their carboxyl termini: whereas hGRα is ligand activated, modulating the expression of glucocorticoid responsive genes by binding to specific glucocorticoid response elements (GREs), hGRβ does not bind glucocorticoids and is transcriptionally inactive. Therefore it has been suggested that hGRβ might be an endogenous inhibitor of glucocorticoid action and a negative regulator determining glucocorticoid sensitivity in the target tissues.3

In 2000 Honda and coworkers published a study indicating that hGRβ mRNA was detectable in peripheral blood …
Quantitative Method for the In Vivo Testing of Fibrinolytic Agents: Effect of Intravenous Trypsin on Radioactive Thrombi and Emboli
Authors: J. L. AMBRUS, N. BACK, E. MIHALYI, CLARA M. AMBRUS
Journal: Circulation Research (1956)

Quantitative methods for testing fibrinolytic agents in vivo are described. Methods based on the incorporation into the clot of P 32 labeled blood cells or Cr 51 labeled erythrocytes were found to be unsatisfactory. Clots were produced with I 131 labeled fibrinogen. Dissolution of a clot resulted in decrease of radioactivity. This was recorded by placing segments of blood vessels in a special lead shield containing a scintillation detector head, connected to a radiation rate meter and an Esterline recorder. Pulmonary, peripheral and coronary emboli were produced by injecting radioactive clots produced and ground, in vitro. Using these methods it was found that maximal tolerated doses of trypsin showed no significant fibrinolytic effect.