87,597 research outputs found
Unusual oxygen binding behavior of a 24-meric crustacean hemocyanin
No full textHemocyanins from Crustacea usually are found as 1 × 6 or 2 × 6-meric assemblies. An exception is the hemocyanin isolated from thalassinidean shrimps where the main component is a 24-meric structure. Our analysis of oxygen binding data of the thalassinidean shrimp Upogebia pusilla based on a three-state MWC-model revealed that despite the 24-meric structure the functional properties can be described very well based on the hexamer as allosteric unit. In contrast to the hemocyanins from other thalassinidean shrimps the oxygen affinity of hemocyanin from U. pusilla is increased upon addition of l-lactate. A particular feature of this hemocyanin seems to be that l-lactate already enhances oxygen affinity under resting conditions which possibly compensates the rather low intrinsic affinity observed in absence of l-lactate. The fast rate of oxygen dissociation might indicate that in this hemocyanin a higher cooperativity is less important than a fast response of saturation level to changes in oxygen concentration. © 2010 Elsevier Inc. All rights reserved
The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells
No full textBackground/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel
The molecular heterogeneity of hemocyanin: structural and functional properties of the 4x6-meric protein of Crustacea.
No full textThe structural properties of the hemocyanin isolated from the Mediterranean mud shrimp, Upogebia pusilla (Decapoda: Thalassinidea), were investigated. Our intent was to make use of the U. pusilla case to perform a structural comparison between crustacean and chelicerate 4 x 6-meric hemocyanins. The thalassinidean hemocyanin appears similar in size but different in structural organization compared to the chelicerate 4 x 6-mer. Ultracentrifiage analyses on the purified protein revealed a sedimentation coefficient of 39S, typical of 4 x 6 hemocyanins. Electron micrographs are in agreement with a model in which four 2 x 6-meric building blocks are arranged in a tetrahedron-like quaternary structure and not in the quasi-square-planar orientation characteristic of the chelicerate protein. Size-exclusion chromatography-fast protein chromatography analysis showed elevated instability of the protein in absence of divalent ions or at pH values higher than 8.0. This analysis also shows that the dissociation of the U. pusilla 4 x 6-meric hemocyanin into hexamers occurs without any intermediate 2 x 6-meric state, in contrast with the dissociation profile of the chelicerate protein exhibiting several dissociation intermediates. The oxygen-binding properties of U. pusilla hemocyanin were studied to disclose possible effects by the typical allosteric effectors that modulate the functional properties of crustacean hemocyanin. A marked Bohr and lactate effect, but no significant influence of urate, on the oxygen affinity of U. pusilla hernocyanin were found
Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study
No full textAbstractObjectivesCyclin D–cyclin-dependent kinase (CDK) 4/6–inhibitor of CDK4/6–retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting.Materials and methodsPostmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2–) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling.ResultsMean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38–100%; n = 2), Arm 2 96% (range 78–100%; n = 6), Arm 3 92% (range 75–100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment.ConclusionThe results suggest absence of a drug–drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2– BC (NCT01919229)
Abstract P3-07-04: EphA2: An emerging target in triple-negative breast cancer
No full textAbstract
Purpose: Breast tumors classified as 'triple negative' (TNBC) lack defining markers ER/PR/HER2 and do not have clinically-approved targeted therapy. This heterogeneous classification of breast cancers, while immediately responsive to standard chemotherapy, commonly develop resistance and have a poor five-year survival rate. As such, the identification of new therapeutic targets are warranted. As part of our drug discovery platform, we have identified EphA2, as a synthetic-lethal gene that enhances the therapeutic action of FDA-approved, anti-inflammatory compounds. Thus we sought to ascertain the relevance of EphA2-targeted therapy in TNBC, through the evaluation of the marker in preclinical and clinical specimens.
Methods: Sixty-one human and murine breast cancer cell lines or patient-derived xenografts were collated. Protein lysates were created from cells in vitro or from respective tumors established from cells implanted into NSG mice. Forty-nine tumors established (minimum 500mm3) and were surgically removed, fixed in formalin and paraffin embedded. A TMA was constructed with tumor specimens represented twice on the array and reflected all molecular subtypes including; ER-positive (n=5), PR-positive (n=3), HER2-positive (n=9) and TNBC (n=31). Immunostaining for EphA2 was performed with the rabbit monoclonal antibody EphA2 (D4A2) XP (Cell Signaling, #6997) using manufacturer's instructions. Immunostaining was evaluated using the H-score method (score between 0-300), with positive staining for EphA2 reflecting a score of 100 or greater. Analysis of breast cancer lysates by western blot was analyzed by absolute and relative quantitation methods; gene expression data was assessed through Oncomine or using the BreastMark algorithm (http://glados.ucd.ie/BreastMark/). This algorithm integrates gene expression and survival data from 26 datasets on 12 different microarray platforms corresponding to ˜17,000 genes in up to 4,738 samples.
Results: In an integrated gene expression platform (BreastMark), we observed that elevated EphA2 expression was associated with poor prognosis in a cohort of TNBC patient tumor samples. Western blot analysis of EphA2 protein on breast cancer cell lines, identified a greater percentage of TNBC cells expressing EphA2 compared to non-TNBC cell lines. EphA2 immunostaining was observed in the majority of tumor tissues. When present on cancer cells, EphA2 localized to the cell surface; while displaying ubiquitous localization within stromal populations. Cell surface expression of EphA2 on cancer cells was largely restricted to TNBC tumors (11/31 tumors, 35.5%) compared to other molecular subtypes (1/13 non-TNBC tumors, 7.7%; p = 0.0294). Expression of EphA2 in stromal cell populations was similar between groups (TNBC = 22/31, non-TNBC = 11/13; p = 0.1711).
Conclusions: Our analysis determined that EphA2 was specifically expressed on cancer cells derived from tumors with a 'triple-negative' molecular subtype. Collectively our data suggests that EphA2 is an emerging target in TNBC and that therapies directed against EphA2 may provide a significant benefit for a majority of patients that express this marker.
Citation Format: Eckhardt BL, Torres AM, Woodward WA, Krishnamurthy S, Meric-Bernstam F, Ueno NT. EphA2: An emerging target in triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-04.</jats:p
A comparative ecotoxicity investigation on fungicides using marine and freshwater species.
No full textVariations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the neo-tango trial
No full textBackground: Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response.
Methods: A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion.
Results: In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes.
Conclusion: We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials
[Newspaper Clipping: Author Claims Evidence of Second JFK Assassin #1]
No full textNewspaper article titled "Author Claims Evidence of Second JFK Assassin." The article states that author Richard J. Whalen concluded "that there is circumstantial evidence to support the theory of a second assassin in the shooting of President John F. Kennedy.
Also By The Same Author: AKTiveAuthor, a Citation Graph Approach to Name Disambiguation
No full textThe desire for definitive data and the semantic web drive for inference over heterogeneous data sources requires co-reference resolution to be performed on those data. In particular, name disambiguation is required to allow accurate publication lists, citation counts and impact measures to be determined. This paper describes a graph-based approach to author disambiguation on large-scale citation networks. Using self-citation, co-authorship and document source analyses, AKTiveAuthor clusters papers, achieving precision of 0.997 and recall of 0.818 over a test group of eight surname clusters
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