julilili42/papers huggingface dataset:
The CysLT1 Ligand Leukotriene D4 Supports α4β1- and α5β1-Mediated Adhesion and Proliferation of CD34+ Hematopoietic Progenitor Cells
2009-05-19

Abstract Cytokines and chemokines control hematopoietic stem and progenitor cell (HPC) proliferation and trafficking. However, the role of nonpeptide mediators in the bone marrow microenvironment has remained elusive. Particularly CysLT1, a G protein-coupled receptor recognizing inflammatory mediators of the cysteinyl leukotriene family, is highly expressed in HPCs. We therefore analyzed the effects of its ligands on human CD34+ HPCs. The most potent CysLT1 ligand, LTD4, rapidly and significantly up-regulated α4β1 and α5β1 integrin-dependent adhesion of both primitive and committed HPC. LTD4-triggered adhesion was inhibited by specific CysLT1 antagonists. The effects of other CysLT1 ligands were weak (LTC4) or absent (LTE4). In serum-free liquid cultures supplemented with various hematopoietic cytokines including IL-3, only LTD4 significantly augmented the expansion of HPCs in a dose-dependent manner comparable to that of peptide growth factors. LTC4 and LTE4 were less effective. In CD34+ cell lines and primary HPCs, LTD4 induced phosphorylation of p44/42 ERK/MAPK and focal adhesion kinase-related tyrosine kinase Pyk2, which is linked to integrin activation. Bone marrow stromal cells produced biologically significant amounts of cysteinyl leukotrienes only when hematopoietic cells were absent, suggesting a regulatory feedback mechanism in the hematopoietic microenvironment. In contrast to antagonists of the homing-related G protein-coupled receptor CXCR4, administration of a CysLT1 antagonist failed to induce human CD34+ HPC mobilization in vivo. Our results suggest that cysteinyl leukotriene may contribute to HPC retention and proliferation only when cysteinyl leukotriene levels are increased either systemically during inflammation or locally during marrow aplasia.
New Perspectives on Bone Marrow Contrast Agents and Molecular Imaging
2009-05-19

Magnetic resonance (MR) imaging of bone marrow provides a noninvasive diagnosis of the vascularity, cell quantity, and composition of the normal and pathological bone marrow. This article reviews new and evolving techniques for bone marrow MR imaging with a special focus on translational and clinical applications. Evaluations of bone marrow perfusion with standard small molecular contrast agents and, more recently, with macromolecular contrast agents are currently being applied for therapy monitoring. Cell-specific contrast agents are expected to improve the sensitivity and specificity of bone marrow MR imaging. Novel cellular and molecular imaging techniques for the depiction of cell metabolism and specific biochemical pathways are discussed. Cell tracking techniques may allow specific diagnoses of inflammatory processes as well as monitoring of novel therapies based on stem cells. Future developments of fusion imaging techniques and bifunctional contrast agents are directed to combine comprehensive information about bone marrow structure and function with targeted and image-guided therapies.
Unusual energy shifts in resonant photoemission spectra of organic model molecules
2009-05-19

We study the electronic structure of zinc phthalocyanine (ZnPc) and 1,4-octa-decyl substituted zinc phthalocyanine [(Dec)8PcZn] thin films (∼6–15 nm) using resonant photoemission spectroscopy and X-ray absorption spectroscopy (XAS) at room temperature and at liquid He temperature. From XAS we conclude that the probability amplitude of the lowest unoccupied molecular orbital is located predominantly at the inner C and N atoms of the molecules. Nonlinear energy shifts in resonant photoemission were observed; large shifts are explained by reduced electrical conductivity of inhomogeneously oriented molecules.
Mutations in theGUCA1Agene involved in hereditary cone dystrophies impair calcium-mediated regulation of guanylate cyclase
2009-05-20

The GUCA1A gene encodes the guanylate cyclase activating protein 1 (GCAP1) of mammalian rod and cone photoreceptor cells, which is involved in the Ca2+-dependent negative feedback regulation of membrane bound guanylate cyclases in the retina. Mutations in the GUCA1A gene have been associated with different forms of cone dystrophies leading to impaired cone vision and retinal degeneration. Here we report the identification of three novel and one previously detected GUCA1A mutations: c.265G>A (p.Glu89Lys), c.300T>A (p.Asp100Glu), c.476G>T (p.Gly159Val) and c.451C>T (p.Leu151Phe). The clinical data of the patients carrying these mutations were compared with the functional consequences of the mutant GCAP1 forms. For this purpose we purified the heterologously expressed GCAP1 forms and investigated whether the mutations affected the Ca2+-triggered conformational changes and the apparent interaction affinity with the membrane bound guanylate cyclase. Furthermore, we analyzed Ca2+-dependent regulatory modes of wildtype and mutant GCAP1 forms. Although all novel mutants were able to act as a Ca2+-sensor protein, they differed in their Ca2+-dependent activation profiles leading to a persistent stimulation of guanylate cyclase activities at physiological intracellular Ca2+ concentration.
Oscillations of dissipative superfluid neutron stars
2009-05-20

We investigate the oscillations of slowly rotating superfluid stars, taking into account the vortex-mediated mutual friction force that is expected to be the main damping mechanism in mature neutron star cores. Working to linear order in the rotation of the star, we consider both the fundamental f-modes and the inertial r-modes. In the case of the (polar) f-modes, we work out an analytic approximation of the mode which allows us to write down a closed expression for the mutual friction damping time scale. The analytic result is in good agreement with previous numerical results obtained using an energy integral argument. We extend previous work by considering the full range of permissible values for the vortex drag, e.g. the friction between each individual vortex and the electron fluid. This leads to the first ever results for the f-mode in the strong drag regime. Our estimates provide useful insight into the dependence on, and relevance of, various equation of state parameters. In the case of the (axial) r-modes, we confirm the existence of two classes of modes. However, we demonstrate that only one of these sets remains purely axial in more realistic neutron star models. Our analysis lays the foundation for companion studies of the mutual friction damping of the r-modes at second order in the slow-rotation approximation, the first time evolutions for superfluid neutron star perturbations and also the first detailed attempt at studying the dynamics of superfluid neutron stars with both a relative rotation between the components and mutual friction.
The do's and don'ts of p53 isoforms
2009-05-20

Abstract Upon DNA damage and other stresses, the transcription factor p53 elicits numerous responses including DNA repair, cell cycle arrest and apoptosis, properties that make p53 the prototype tumor suppressor. In addition, p53 also transactivates genes whose products act in an anti-apoptotic manner providing strong evidence that p53 exhibits both tumor suppressive and tumorigenic functions. Although several events were postulated to contribute to the p53-mediated decision process, the precise mechanism(s) that governs p53 activities is still elusive. Recently, it was found that the p53 gene allows expression of at least nine different isoforms that arise from multiple splicing events and the usage of alternative promoters. Several of these isoforms were shown to critically interfere with the function of the full-length p53 mainly by acting in a dominant-negative manner. However, an isoform-dependent selective activation of p53 target genes was also observed. Furthermore, certain p53 isoforms are aberrantly expressed in various tumors strongly implying their involvement in tumorigenic events. Thus, p53 isoforms may represent crucial determinants in p53-mediated decision processes whose precise functions (their do's and don'ts) are only beginning to emerge.
The value of PET/CT with 18F-FLT and 18F-FDG in the management of metastatic germ cell tumors (GCT): A pilot study
2009-05-20

e16142 Background: The purpose is to assess the ability of [F-18]-3’-Fluoro-3’-deoxythymidin (FLT), a cell proliferation marker, for early response monitoring and prediction of histology of residual tumor masses in patients (pts) with metastatic GCT in comparison to the standard tracer F-18-FDG, CT-scans and tumor markers. Methods: 11 male pts, age 23–48 yrs, with metastatic GCT were evaluated with both FDG- and FLT-PET/CT prior to chemotherapy (CTh), after the first cycle (early response) and 3 weeks after completion of induction CTh. PET was analyzed visually and quantitatively. The results were validated by histopathology of resected residual masses after CTh in 7 pts or by clinical follow-up for at least 6 mos in 4 pts. Presence of necrosis was judged as responder, as well as CR/PRm- within a minimum progression-free interval (PFI) of 6 mos. In case of multiple resections, the worse histology was taken into account. Regarding early tumor response EORTC criterias were used. Results: 8 out of 11 pts had a PFI &gt; 6 mos (range, 206–1337 days). Examination of resected masses revealed necrosis in 3/7, teratoma in 2/7 as well as 2/7 pts with viable tumors. Prior to CTh the reference lesions showed increased FDG uptake (SUVrange/mean, 2.9–15.0/8.8) in all pts but moderate FLT uptake (SUVrange/mean, 1.7–9.7/3.7) in 10 out of 11 pts. SUVavg decrease in early response FDG monitoring was 64% in responders and 60% in non-responders (p = 0.8), as well as 57% vs. 48% for FLT (p = 0.5), respectively, and 85% vs. 72% (FDG, p = 0.1) and 67% vs. 65% (FLT, p = 0.8) in the final monitoring. Results of early and final response were inconsistent in 6/11 pts in FDG and in 4/10 pts in FLT-PET. In 2 pts with teratoma false negative results in both FDG- and FLT-PET have been seen. The sensitivities, specificities, positive and negative predictive values (%) of FDG and FLT-PET for early and final response monitoring were 60/33/43/50, 60/80/75/67, 20/100/100/60, and 0/100/0/50, respectively. Conclusions: PET negative residual masses after CTh of metastatic GCT still require resection, since the low negative predictive value of FDG-PET cannot be improved by application of the proliferation marker FLT. No significant financial relationships to disclose.
HLA-associated multipeptide vaccination in biochemically relapsed prostate cancer patients
2009-05-20

5134 Background: We conduct a phase I/II monocenter clinical trial using multi peptide vaccination in patients with hormone naive, biochemically relapsed prostate cancer. The synthetic peptides applied are MHC-class I (HLA-A2) and -class II binders for activating CD4+ and CD8+ T- effector cells in vivo. Study endpoints are side effects as well as PSA- and T-cell response. Methods: Patients (pts) with rising PSA after primary curative surgical treatment without metastatic imageable lesions receive 14 peptides emulsified in Montanide ISA51 subcutaneously, combined with one of four T-cell stimulatory adjuvants versus no adjuvant for 18 months (mo) or until progression. PSA doubling time (DT) and clinical performance are monitored. T-cell activity and specifity are assessed with Elispot assay, tetramer staining and intracellular cytokine stainings. Results: 25 out of 35 pts have terminated the study treatment so far. During the vaccination period, geometric mean PSA DT increased from 7.8 mo (range 1.5 - 44.8 mo, 25 pts) to 11.8 months (range 2.2 - 571.3 mo, 24pts) whereas 1 pt showed a decreasing PSA value. Overall 8/25 pts (32%) had a mean rise of PSA DT of 81.6 mo and four of them did not receive any further treatment and were evaluable for follow-up (FU) after peptide vaccination (FU median 16 mo, range 5–33). These four pts raised their mean geometric PSA DT from 8.2 mo prior study treatment to 51.9 mo at treatment end and 52.5 mo at end of FU. PSA progressed unchanged in 10 patients (40%) or increased intermittently only in 4 pts. Two pts had PSA decline or DT increase during FU but not during the treatment period. Four patients (16%) exhibited an allergic reaction CTCAE II°. All pts reacted to at least one of the tumor antigen-derived HLA-class I epitopes after the fourth vaccine injection and up to six peptides were recognized simultaneously by CD8+ T cells in some individuals. Conclusions: Multi peptide vaccination stabilized or slowed down PSA progress in 11 of 25 cases. Stimulation of specific T-cell response is observed. Rise of PSA DT delaying standard treatment up to 33 mo and thus, delaying disease specific mortality is feasible. No significant financial relationships to disclose.
4-[3-(4-Fluorophenyl)quinoxalin-2-yl]-N-isopropylpyridin-2-amine
2009-05-20

In the crystal structure of the title compound, C 22 H 19 FN 4 , the quinoxaline system makes dihedral angles of 32.07 (13) and 69.64 (13)° with the 4-fluorophenyl and pyridine rings, respectively. The 4-fluorophenyl ring makes a dihedral angle of 71.77 (16)° with the pyridine ring. The crystal structure is stabilized by intermolecular N—H...N hydrogen bonding.
Expression profile of CTC and corresponding tumors in primary breast cancer patients
2009-05-20

538 Background: The target of adjuvant therapy in breast cancer is minimal residual disease (MRD). However, treatment decisions are based on expression of predictive markers (ER; PR, HER-2) of the primary tumor. Based on current studies, presence of MRD may be reflected by the detection of circulating tumor cells (CTC). Therefore, the aim of the study was to characterize CTC by multiplex-PCR for the expression of HER-2, ER, and PR and compare the expression profiles of CTCs with those of the corresponding primary tumors. Methods: CTC from blood of 431 patients with primary breast cancer were analyzed for EpCAM, MUC1, and HER-2 transcripts with the AdnaTest BreastCancer (AdnaGen AG, Germany). A blood samples was CTC positive when at least one of the markers was detected. Expression of the ER and PR receptor was assessed in an additional RT-PCR. The ER, PR and HER2 receptor status of the primary tumors was determined by immunohistochemistry. The DAKO-Score for the expression of HER-2 was determined with the HercepTest. Results: The overall detection rate for CTC was 13% (58/431 patients) with the expression rates of 38% for HER-2 (22/58 patients), 25% for ER (12/48) and 4% for PR (2/48), respectively. ER positivity of the primary tumor was demonstrated in 45/58 (78%) of these patients, PR positivity in 41/58 (71%) patients and HER-2 in 9/58 (16%) patients, respectively. The concordance rate between ER, PR, and HER-2 status of CTCs and the primary tumor was 29%, 25%, and 53%, respectively Interestingly, the spread of CTC was mostly found in triple negative tumors (p = 0.01) and CTC in general were mostly found to be triple-negative regardless of the ER, PR, and HER-2 status of the primary tumor. Conclusions: Since the expression profile between CTC and the primary tumor differs, the consequence for the selection of adjuvant treatment targeting minimal residual disease has to be further evaluated in clinical trials. No significant financial relationships to disclose.
Detection of MSC-like cells in soft tissue sarcoma cell lines and primary tumors
2009-05-20

11000 Background: Soft tissue sarcomas (STS) are a heterogeneous group of mesodermal tumors hypothetically originating from mesenchymal stem cells (MSC). While the expression profile of bone marrow derived MSCs and their in vitro differentiation potential have been examined extensively, knowledge regarding the in vivo counterparts of MSC is still evolving. We hypothesized that MSC-like cells within STS could represent sarcoma initiating cells. Methods: To target rare human cell populations including MSCs, an exclusive antibody panel was developed. The target antigens include platelet-derived growth factor receptor-β (CD140b), HER-2/erbB2 (CD340), TNFRSF16 (CD217), frizzled-4 (CD344), the recently described W8B2 antigen, as well as several surface antigens identified by novel antibodies. To define the expression pattern of MSC-markers in STS, both cell lines and primary tumor samples in suspension and in snap frozen sections were investigated. To reveal functional differences between identified rare tumor populations single cell proliferation kinetics were investigated after FACS-sorting. Results: All cell lines und primary tumor samples revealed expression of selected markers. Antigens identifying subpopulations within all sarcoma samples investigated, were selected for functional studies. These included frizzled-4, TNFRSF16, W5C5 and W8B2. Liposarcoma (SW872), leiomyosarcoma (SK-LMS) and fibrosarcoma (HT1080) cell lines enclosed subpopulations with differential expression of above markers and by FACS based limiting dilution it was demonstrated that only fractions of viable cells contained proliferative capacity. Cells lacking expression of CD271 had lower proliferative capacity compared to mock sorted HT1080 or SK-LMS, while CD271+ SW872 had significantly higher proliferation. The antigen defined by W5C5 identified cells with high proliferative capacity compared to control in SW872 and SK-LMS and its lack in HT1080 identified a subpopulation with largely reduced proliferation. Conclusions: Subpopulations within STS cell lines and primary sarcoma tissue express novel MSC-markers and display increased proliferative capacity, potentially reflecting the existence of sarcoma initiating cells. No significant financial relationships to disclose.
Direct Injection of Protamine-protected mRNA: Results of a Phase 1/2 Vaccination Trial in Metastatic Melanoma Patients
2009-05-21

In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses and therefore offers a broadly applicable immunotherapy approach. We injected intradermally protamine-stabilized mRNAs coding for Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21 metastatic melanoma patients. In 10 patients keyhole limpet hemocyanin (KLH) was added to the vaccine. Granulocyte macrophage colony-stimulating factor was applied as an adjuvant. Endpoints were toxicity and immune responses. No adverse events more than grade II have been observed. During treatment the frequency of Foxp3+/CD4+ regulatory T cells was significantly decreased upon mRNA vaccination in peripheral blood of the patients in the KLH arm, whereas myeloid suppressor cells (CD11b+HLA-DR lo monocytes) were reduced in the patients not receiving KLH. A reproducible increase of vaccine-directed T cells was observed in 2 of 4 immunologically evaluable patients. One of 7 patients with measurable disease showed a complete response. In conclusion, we show here that direct injection of protamine-protected mRNA is feasible and safe. The significant influence of the treatment on the frequency of immunosuppressive cells, the increase of vaccine-directed T cells upon treatment in a subset of patients together with the demonstration of a complete clinical response encourage further clinical investigation of the protamine-mRNA vaccine.
Neural activity in the visual thalamus reflects perceptual suppression
2009-05-21

To examine the role of the visual thalamus in perception, we recorded neural activity in the lateral geniculate nucleus (LGN) and pulvinar of 2 macaque monkeys during a visual illusion that induced the intermittent perceptual suppression of a bright luminance patch. Neural responses were sorted on the basis of the trial-to-trial visibility of the stimulus, as reported by the animals. We found that neurons in the dorsal and ventral pulvinar, but not the LGN, showed changes in spiking rate according to stimulus visibility. Passive viewing control sessions showed such modulation to be independent of the monkeys' active report. Perceptual suppression was also accompanied by a marked drop in low-frequency power (9–30 Hz) of the local field potential (LFP) throughout the visual thalamus, but this modulation was not observed during passive viewing. Our findings demonstrate that visual responses of pulvinar neurons reflect the perceptual awareness of a stimulus, while those of LGN neurons do not.
Identification of Natural MHC Class II Presented Phosphopeptides and Tumor-Derived MHC Class I Phospholigands
2009-05-21

MHC molecules present protein-derived peptides to T lymphocytes. By developing TiO2-based microcentrifugation columns, we identified the first phosphorylated MHC class I ligands from tumor tissue (renal cell carcinoma) and, by comparison to healthy renal tissue, found one Brf1-derived ligand as potentially tumor-associated. We further discovered the first natural phosphorylated MHC class II ligands. They revealed several novel phosphorylation sites of significant transmembrane receptors, such as Frizzled 6, CXCR4 and CD20.
Altered nitric oxide calcium responsiveness of aortic smooth muscle cells in spontaneously hypertensive rats depends on low expression of cyclic guanosine monophosphate-dependent protein kinase type I
2009-05-21

The low expression of cGKI determines the lack of nitric oxide/cyclic GMP-dependent regulation on [Ca2+]i transient in SHR RASMCs. This alteration may contribute to the development of hypertension and explain suboptimal responses to nitroglycerin and other nitric oxide-releasing molecules in patients.
Response to Comment on “Effects of Native Organic Material and Water on Sorption Properties of Reference Diesel Soot”
2009-05-21

ADVERTISEMENT RETURN TO ISSUEPREVCorrespondence/Rebut...Correspondence/RebuttalResponse to Comment on "Effects of Native Organic Material and Water on Sorption Properties of Reference Diesel Soot"Satoshi Endo*, Peter Grathwohl, Stefan B. Haderlein, and Torsten C. SchmidtView Author Information Center for Applied Geoscience (ZAG), Eberhard-Karls-University of Tübingen, Sigwartstrasse 10, D-72076 Tübingen, Germany and Department of Analytical Environmental Chemistry, UFZ - Helmholtz Centre for Environmental Research, Permoserstrasse 15, D-04318 Leipzig, Germany Center for Applied Geoscience (ZAG), Eberhard-Karls-University of Tübingen, Sigwartstrasse 10, D-72076 Tübingen, Germany Instrumental Analytical Chemistry, University of Duisburg-Essen, Lotharstrasse 1, D-47048 Duisburg, GermanyCite this: Environ. Sci. Technol. 2009, 43, 13, 5160Publication Date (Web):May 21, 2009Publication History Published online21 May 2009Published inissue 1 July 2009https://pubs.acs.org/doi/10.1021/es901270rhttps://doi.org/10.1021/es901270rarticle-commentaryACS PublicationsCopyright © 2009 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views410Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (45 KB) Get e-AlertscloseSUBJECTS:Functional groups,Natural organic matter,Particulate matter,Sorption,X-ray absorption near edge spectroscopy Get e-Alerts