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1.
Birong Zhang James R. Kiefer Robert A. Blake Jae H. Chang Steven Hartman Ellen Rei Ingalla Tracy Kleinheinz Vidhi Mody Michelle Nannini Daniel F. Ortwine Yingqing Ran Amy Sambrone Deepak Sampath Maia Vinogradova Yu Zhong Jerome C. Nwachukwu Kendall W. Nettles Tommy Lai Jun Liang 《Bioorganic & medicinal chemistry letters》2019,29(7):905-911
Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays. 相似文献
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JG Hansen W Gao J Dupuis GT O’Connor W Tang M Kowgier A Sood SA Gharib LJ Palmer M Fornage SR Heckbert BM Psaty SL Booth SUNLIGHT Consortium Patricia A Cassano 《Respiratory research》2015,16(1)
Background
Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.Methods
We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.Results
We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09).Conclusions
Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.Electronic supplementary material
The online version of this article (doi:10.1186/s12931-015-0238-y) contains supplementary material, which is available to authorized users. 相似文献3.
Guido Bischoff Zoltan B?r?cz Christian Proll Johannes Kleinheinz Gert von Bally Dieter Dirksen 《Biomedizinische Technik》2007,52(4):284-289
Optical topometric 3D sensors such as laser scanners and fringe projection systems allow detailed digital acquisition of human body surfaces. For many medical applications, however, not only the current shape is important, but also its changes, e.g., in the course of surgical treatment. In such cases, time delays of several months between subsequent measurements frequently occur. A modular 3D coordinate measuring system based on the fringe projection technique is presented that allows 3D coordinate acquisition including calibrated color information, as well as the detection and visualization of deviations between subsequent measurements. In addition, parameters describing the symmetry of body structures are determined. The quantitative results of the analysis may be used as a basis for objective documentation of surgical therapy. The system is designed in a modular way, and thus, depending on the object of investigation, two or three cameras with different capabilities in terms of resolution and color reproduction can be utilized to optimize the set-up. 相似文献
4.
Screening drug effects in patient‐derived cancer cells links organoid responses to genome alterations
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Julia Jabs Franziska M Zickgraf Jeongbin Park Steve Wagner Xiaoqi Jiang Katharina Jechow Kortine Kleinheinz Umut H Toprak Marc A Schneider Michael Meister Saskia Spaich Marc Sütterlin Matthias Schlesner Andreas Trumpp Martin Sprick Roland Eils Christian Conrad 《Molecular systems biology》2017,13(11)
Cancer drug screening in patient‐derived cells holds great promise for personalized oncology and drug discovery but lacks standardization. Whether cells are cultured as conventional monolayer or advanced, matrix‐dependent organoid cultures influences drug effects and thereby drug selection and clinical success. To precisely compare drug profiles in differently cultured primary cells, we developed DeathPro, an automated microscopy‐based assay to resolve drug‐induced cell death and proliferation inhibition. Using DeathPro, we screened cells from ovarian cancer patients in monolayer or organoid culture with clinically relevant drugs. Drug‐induced growth arrest and efficacy of cytostatic drugs differed between the two culture systems. Interestingly, drug effects in organoids were more diverse and had lower therapeutic potential. Genomic analysis revealed novel links between drug sensitivity and DNA repair deficiency in organoids that were undetectable in monolayers. Thus, our results highlight the dependency of cytostatic drugs and pharmacogenomic associations on culture systems, and guide culture selection for drug tests. 相似文献
5.
Utility of the white gene in estimating phylogenetic relationships among mosquitoes (Diptera: Culicidae) 总被引:2,自引:0,他引:2
The utility of a nuclear protein-coding gene for reconstructing
phylogenetic relationships within the family Culicidae was explored.
Relationships among 13 species representing three subfamilies and nine
genera of Culicidae were analyzed using a 762-bp fragment of coding
sequence from the eye color gene, white. Outgroups for the study were two
species from the sister group Chaoboridae. Sequences were determined from
clone PCR products amplified from genomic DNA, and aligned following
conceptual intron splicing and amino acid translation. Third codon
positions were characterized by high levels of divergence and biased
nucleotide composition, the intensity and direction of which varied among
taxa. Equal weighting of all characters resulted in parsimony and
neighboring-joining trees at odds with the generally accepted phylogenetic
hypothesis based on morphology and rDNA sequences. The application of
differential weighting schemes recovered the traditional hypothesis, in
which the subfamily Anophelinae formed the basal clade. The subfamily
Toxorhynchitinae occupied an intermediate position, and was a sister group
to the subfamily Culicinae. Within Culicinae, the genera Sabethes and
Tripteroides formed an ancestral clade, while the Culex-Deinocerites and
Aedes- Haemagogus clades occupied increasingly derived positions in the
molecular phylogeny. An intron present in the Culicinae- Toxorhynchitinae
lineage and one outgroup taxon was absent in the basal Anophelinae lineage
and the second outgroup taxon, suggesting that intron insertions or
deletions may not always be reliable systematic characters.
相似文献
6.
Stefan C. Dentro Ignaty Leshchiner Kerstin Haase Maxime Tarabichi Jeff Wintersinger Amit G. Deshwar Kaixian Yu Yulia Rubanova Geoff Macintyre Jonas Demeulemeester Ignacio Vázquez-García Kortine Kleinheinz Dimitri G. Livitz Salem Malikic Nilgun Donmez Subhajit Sengupta Pavana Anur Clemency Jolly Peter Van Loo 《Cell》2021,184(8):2239-2254.e39
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Anton GT Terwisscha van Scheltinga Marjolijn N Lub-de Hooge Keelara Abiraj Carolien P Schr?der Linda Pot Birgit Bossenmaier Marlene Thomas Gabriele H?lzlwimmer Thomas Friess Jos GW Kosterink Elisabeth GE de Vries 《MABS-AUSTIN》2014,6(4):1051-1058
The humanized monoclonal antibody with high affinity for the human epidermal growth factor receptor (HER) 3, RG7116, is a glycoengineered, IgG1 class antibody. By labeling RG7116 with zirconium-89 (89Zr) we aimed to visualize in vivo HER3 expression and study the biodistribution of this antibody in human tumor-bearing mice. Biodistribution of 89Zr-RG7116 was studied in subcutaneously xenografted FaDu tumor cells (HER3-positive). Dose-dependency of 89Zr-RG7116 organ distribution and specific tumor uptake was assessed by administering doses ranging from 0.05 to 10 mg/kg RG7116 to SCID/Beige mice. Biodistribution was analyzed at 24 and 144 h after injection. MicroPET imaging was performed at 1, 3, and 6 days after injection of 1.0 mg/kg 89Zr-RG7116 in the FaDu, H441, QG-56 and Calu-1 xenografts with varying HER3 expression. The excised tumors were analyzed for HER3 expression. Biodistribution analyses showed a dose- and time-dependent 89Zr-RG7116 tumor uptake in FaDu tumors. The highest tumor uptake of 89Zr-RG7116 was observed in the 0.05 mg/kg dose group with 27.5%ID/g at 144 h after tracer injection. MicroPET imaging revealed specific tumor uptake of 89Zr-RG7116 in FaDu and H441 models with an increase in tumor uptake over time. Biodistribution data was consistent with the microPET findings in FaDu, H441, QG56 and Calu-1 xenografts, which correlated with HER3 expression levels. In conclusion, 89Zr-RG7116 specifically accumulates in HER3 expressing tumors. PET imaging with this tracer provides real-time non-invasive information about RG7116 distribution, tumor targeting and tumor HER3 expression levels. 相似文献
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