101,295 research outputs found
Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer
No full textThis work was supported by the Chief Scientist Office, Scotland (ETM37; to G.D. Stewart, A.C.P. Riddick, M. Aitchison, and D.J. Harrison), Cancer Research UK (Experimental Cancer Medicine Centre; to T. Powles, London and D.J. Harrison, Edinburgh), Medical Research Council (to A. Laird and D.J. Harrison), Royal College of Surgeons of Edinburgh (to A. Laird), Melville Trust (to A. Laird), Medical Research Council (MC_UU_12018/25; to I.M. Overton), Royal Society of Edinburgh Scottish Government Fellowship cofunded by Marie Curie Actions (to I.M. Overton), Renal Cancer Research Fund (to G.D. Stewart), Kidney Cancer Scotland (to G.D. Stewart) and an educational grant from Pfizer (to T. Powles).Purpose: The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC). Experimental design: Multiple tumor samples (n=187 samples) were taken from the primary renal tumors of mccRCC patients who were sunitinib treated (n=23, SuMR clinical trial) or untreated (n=23, SCOTRRCC study). ITH of pathological grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia and stromal related genes). ITH was analysed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene expression clustering. Results: Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and transcript changes to key targets of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples. Conclusions: These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy.Peer reviewe
Anti-Programmed Cell Death 1/Ligand 1 (PD-1/PD-L1) Antibodies for the Treatment of Urothelial Carcinoma: State of the Art and Future Development
No full textA phase II study investigating the re-induction of endocrine sensitivity following chemotherapy in androgen-independent prostate cancer
No full textWhen chemotherapy is used in androgen-independent prostate cancer (AIPC), androgen deprivation is continued despite its failure. In this study, we investigated whether it was possible to re-induce hormone sensitivity in previously castrate patients by stopping endocrine therapy during chemotherapy. A phase II prospective study investigated the effects of reintroduction of endocrine therapy after oral chemotherapy in 56 patients with AIPC, which was given without concurrent androgen deprivation. After chemotherapy, patients were given maximum androgen blockade until failure when treatment was switched to diethylstilbestrol and dexamethasone. Patients had already received these endocrine treatments in the same sequence before chemotherapy. All patients were castrate at the start of chemotherapy. Forty-three subsequently restarted endocrine therapy after the completion of chemotherapy. The median overall survival for these 43 patients from the time of restarting endocrine therapy was 7.7 months (95% confidence interval (CI): 3.7–10.9 months). Sixteen (37%) patients had a 50% PSA response to treatment, which was associated with improved overall survival (14.0 months vs 3.7 months P=0.003). Eight out of 12 patients who did not respond to diethylstilbestrol before chemotherapy did so post chemotherapy. Re-induction of hormone sensitivity can occur after chemotherapy in AIP
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Inheritance of evolved glyphosate resistance in Lolium rigidum (Gaud.)
No full textThe original publication can be found at www.springerlink.comResistance to the non-selective herbicide, glyphosate, has evolved recently in several populations of Lolium rigidum (Gaud.). Based upon the observed pattern of inheritance, glyphosate resistant and susceptible populations are most probably homozygous for glyphosate resistance and susceptibility, respectively. When these populations were crossed and the F1 progeny treated with glyphosate, the dose response behavior was intermediate to that of the parental populations. This observation, coupled with an absence of a difference between reciprocal F1 populations, suggests that glyphosate resistance is inherited as an incompletely dominant nuclear-encoded trait. The segregation of resistance in F12S backcrosses suggests that the major part of the observed resistance is conferred by a single gene, although at low glyphosate treatments other genes may also contribute to plant survival. It appears from this study that a single nuclear gene confers resistance to glyphosate in one population of L. rigidum.D. F. Lorraine-Colwill, S. B. Powles, T. R. Hawkes and C. Presto
Handwritten biographical information on Paulina T. McClung Merritt
No full textA handwritten biography of Paulina T. McClung Merritt by an unknown author, 1892.
Heterogeneous and tissue-specific regulation of effector T cell responses by IFN-gamma during Plasmodium berghei ANKA infection.
No full textIFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses in wild-type and IFN-γ(-/-) mice during P. berghei ANKA infection. The expansion of splenic CD4(+) and CD8(+) T cells during P. berghei ANKA infection was unaffected by the absence of IFN-γ, but the contraction phase of the T cell response was significantly attenuated. Splenic T cell activation and effector function were essentially normal in IFN-γ(-/-) mice; however, the migration to, and accumulation of, effector CD4(+) and CD8(+) T cells in the lung, liver, and brain was altered in IFN-γ(-/-) mice. Interestingly, activation and accumulation of T cells in various nonlymphoid organs was differently affected by lack of IFN-γ, suggesting that IFN-γ influences T cell effector function to varying levels in different anatomical locations. Importantly, control of splenic T cell numbers during P. berghei ANKA infection depended on active IFN-γ-dependent environmental signals--leading to T cell apoptosis--rather than upon intrinsic alterations in T cell programming. To our knowledge, this is the first study to fully investigate the role of IFN-γ in modulating T cell function during P. berghei ANKA infection and reveals that IFN-γ is required for efficient contraction of the pool of activated T cells
The reorientation of t-butyl groups in butylated hydroxytoluene: A deuterium nuclear magnetic resonance spectral and relaxation time study
No full textDeuterium nuclear magnetic resonance (NMR) spectra and spin-lattice relaxation times were determined in order to study the dynamics of t-butyl groups in butylated hydroxytoluene. The results are consistent with a model first proposed by Beckmann et al. [J. Magn. Reson. 36, 199 (1979)], where there is an inequivalence between the methyl groups within each t-butyl group. While two methyl groups reorient rapidly relative to the whole t-butyl rotation, the remaining methyl group is more restricted in its motion, reorienting at a rate comparable to that of the t-butyl group itself. The spin-lattice relaxation data show two T1 minima, the high temperature minimum (40-degrees-C) corresponding to the combined t-butyl and "slow" methyl rotations, and the low temperature minimum corresponding to "fast" methyl group rotation. Using an explicitly defined T1 fitting function, the T1 data yield activation energies of 2.2 and 6.0 kcal/mol for the fast methyl and t-butyl rotations, respectively, both in agreement with Beckmann's values obtained from proton T1 experiments. It was also possible to simulate the low temperature deuterium NMR spectra from T = - 160-degrees-C to T = - 80-degrees-C using the aforementioned dynamical inequivalence between the t-butyl methyl groups. While the fast methyl group rotation was in the motional narrowing region for T > - 160-degrees-C, it was possible, from the simulations, to determine the t-butyl exchange rates to within 10%. The jump rates are remarkably close to the values predicted from the T1 results. Above - 80-degrees-C, the spectra could not be simulated, implying that a third motion must be present to further alter the high temperature line shapes. The effective axial asymmetry of the T > - 20-degrees spectra indicates that the additional motion involves a two site exchange.PT: J; CR: ABRAGAM A, 1961, PRINCIPLES NUCLEAR M, P451 ALBERT S, 1972, J CHEM PHYS, V56, P1332 ALBERT S, 1976, J CHEM PHYS, V6, P3277 ALBERT S, 1976, J CHEM PHYS, V64, P3277 ARONSON M, 1981, CHEM PHYS, V63, P349 BECKMANN P, 1978, J MAGN RESON, V32, P391 BECKMANN P, 1979, J MAGN RESON, V36, P199 BECKMANN P, 1981, CHEM PHYS, V63, P359 BECKMANN PA, 1984, J MAGN RESON, V59, P63 BEVINGTON PR, 1969, DATA REDUCTION ERROR, CH11 BLOEMBERGEN N, 1948, PHYS REV, V73, P679 BLOOM M, 1980, CAN J PHYS, V58, P1510 DAVIS JH, 1976, CHEM PHYS LETT, V42, P390 DAVIS JH, 1983, BIOCHIM BIOPHYS ACTA, V737, P117 DRUYAN ME, 1976, J AM CHEM SOC, V98, P4801 ELSAFFAR ZM, 1972, J CHEM PHYS, V56, P1477 FABER DH, 1974, ACTA CRYSTALLOGR B, V30, P449 FROST JC, 1980, PHILOS T ROY SOC B, V290, P567 FROST JC, 1982, J CHEM SOC FARAD T 2, V78, P2139 GALL CM, 1981, J AM CHEM SOC, V103, P5039 GOLDBERG I, 1975, ACTA CRYSTALLOGR B, V31, P2592 GRIFFIN RG, 1981, METHOD ENZYMOL, V72, P108 HASEBE T, 1985, J CHEM SOC FARAD T 2, V81, P735 HASEBE T, 1985, J CHEM SOC FARAD T 2, V81, P749 HURT CJ, 1975, ACTA CRYSTALLGR, V91, P273 LEADBETTER AJ, 1985, J CHEM SOC FARAD T 2, V81, P1067 MAZEBAUDET M, 1973, ACTA CRYSTALLOGR B, V29, P602 MCKENZIE TC, 1975, ACTA CRYSTALLOGR B, V31, P1778 MOOIBROEK S, 1985, CAN J CHEM, V63, P2926 MOOIBROEK S, 1988, CAN J CHEM, V66, P734 OREILLY DE, 1973, J CHEM PHYS, V59, P3576 OWEN NL, 1974, INTERNAL ROTATIONS M, P157 POWLES JG, 1953, J CHEM PHYS, V21, P1695 POWLES JG, 1953, J CHEM PHYS, V21, P1704 RIPMEESTER JA, 1985, J CHEM PHYS, V82, P1053 SPIESS HW, 1981, J MAGN RESON, V42, P381 STEJSKAL EO, 1958, J CHEM PHYS, V28, P388 STEJSKAL EO, 1959, J CHEM PHYS, V31, P55 TORCHIA DA, 1982, J MAGN RESON, V49, P107 VEGA AJ, 1987, J CHEM PHYS, V86, P1803 WITTEBORT RJ, 1987, J CHEM PHYS, V86, P5411; NR: 41; TC: 13; J9: J CHEM PHYS; PG: 8; GA: FA778Source type: Electronic(1
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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