排序方式: 共有15条查询结果,搜索用时 15 毫秒
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
2.
Screening drug effects in patient‐derived cancer cells links organoid responses to genome alterations 下载免费PDF全文
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
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.
The overall objective of this project was to evaluate levels of airborne fungi present after a mold remediation project and determine the effectiveness of this remediation using airborne mold levels to determine the success of these projects. Andersen N6 (viable) and Air-O-Cell (non-viable) sampling techniques were utilized. Both test methodologies demonstrated that levels of mold in the successfully remediated portions of buildings were significantly different (p<0.05) from the levels found in non-complaint and outdoor samples from the same building, respectively. Conversely, levels in unsuccessful remediation projects were not significantly different (p>0.05) to non-complaint and outdoor samples. Both techniques showed high variability in the overall mold levels found between sites; however, the ratios of specific mold groups in each area tested, within the same site, were remarkably similar. The use of either viable or non-viable mold sampling techniques after mold remediation is essential for determining the success of such projects. This project demonstrates the relationship between mold levels and the success of a mold remediation projects, and will assist in the interpretation of data collected at the conclusion of a mold remediation project. 相似文献
5.
S Dhamwichukorn G T Kleinheinz S T Bagley 《Journal of industrial microbiology & biotechnology》2001,26(3):127-133
Biofiltration systems utilizing thermophilic (55C) bacteria were constructed and tested for the removal of methanol and α-pinene
— two important volatile organic compounds (VOCs) in the forest products industry. Thermophilic bacterial mixtures that can
degrade both methanol and α-pinene were obtained via enrichment techniques. Two bench-scale thermophilic biofiltration systems (1085 and 1824 cm3) were used to examine compound removals at different residence times, with influent concentrations of 110 ppmv methanol and
15 ppmv α-pinene. At a residence time of 10.85 min, the smaller system had removal efficiencies of >98% for methanol, but
only 23% for α-pinene. The larger system was operated with the same parameters to evaluate residence time and surfactant effects
on compound removals. At a residence time of 18.24 min, both methanol and α-pinene removal rates were ≥95%. However, α-pinene
removal dropped to 26% at a residence time of 6.08 min; methanol removal was not affected. Subsequent addition of a surfactant
mixture increased α-pinene removal to 94% at the shortest residence time. No residual α-pinene was detected with the support
medium Celite R-635, indicating that the surfactant may increase mass transfer of α-pinene. Journal of Industrial Microbiology & Biotechnology (2001) 26, 127–133.
Received 06 June 2000/ Accepted in revised form 09 November 2000 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
7.
A study was performed to determine the effectiveness of using biofiltration for the removal of a complex mixture of volatile
organic compounds (VOCs) air-stripped from petroleum hydrocarbons. A biofilter was constructed which contained 264 cm3 of packing material (Celite? R-635). The unit was inoculated with a mixed culture containing a hydrocarbon-degrading Pseudomonas sp and an Alcaligenes sp. Several of the major compounds in the VOC mixture were monitored individually, along with the total VOCs, using gas chromatography.
The average influent concentration of the VOC mixture was 320 ppmv and the average total VOC removal rate was over 56%, with
the average removal rate of the monitored individual compounds ranging from 49–90%. After 30 days of operation the average
overall removal rate was 69% and the removal of the major compounds averaged 92%. The toxicity and mutagenicity of the air
stream was monitored using the Microtox and Ames assays, respectively. These data show marked decreases in toxicity and mutagenicity
of the air stream as a result of the biofiltration treatment. The biofiltration system, therefore, was not only effective
in removing VOCs from the air stream over an extended time-period, but was also effective in greatly reducing the toxicity
and mutagenicity associated with the remaining VOCs.
Received 03 July 1997/ Accepted in revised form 25 November 1997 相似文献
8.
Daniel G.M. Shore Zachary K. Sweeney Alan Beresford Bryan K. Chan Huifen Chen Jason Drummond Andrew Gill Tracy Kleinheinz Xingrong Liu Andrew D. Medhurst Edward G. McIver John G. Moffat Haitao Zhu Anthony A. Estrada 《Bioorganic & medicinal chemistry letters》2019,29(4):674-680
The discovery of disease-modifying therapies for Parkinson’s Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration. 相似文献
9.
Martin Mariano Isabelo Sabandal Edgar Schfer Simon Petsching Susanne Jung Johannes Kleinheinz Sonja Sielker 《Open biology》2022,12(6)
The circulating low-density lipoprotein concentration in blood can be reduced by the administration of statins. Frequently simvastatin (SV) is prescribed. Due to the reported pleiotropic effects of SV the aim of this study was to evaluate mineralization effects on human adipose tissue-derived stromal cells upon administration of SV. After informed consent human adipose tissue-derived stromal cells were obtained from tissue surplus of regular treatments of 14 individuals. According to established protocols after adding various SV concentrations (0.01 µM, 0.1 µM, 1.0 µM, 2.0 µM), alkaline phosphate (osteoblastic marker), mineralization capability and viability were determined at day 18, 21 and 28. The Kruskal–Wallis test was performed for statistical analysis. After adding SV a dose-dependent significant decreased viability and levels of alkaline phosphatase (p < 0.01) and a significantly increased mineralization (p < 0.01) of the primary cultures was recognized during the late mineralization stage. Mineralization of the human adipose tissue-derived stromal cells was induced by SV, possibly originated from alternative pathways than the alkaline phosphatase pathway. Further investigations should be performed regarding switching into the osteoblastic differentiation and as a possible source of cells that can be used as the basis for a potential bone graft substitute, which may allow an extension of the field of application. 相似文献
10.
A lava rock-based biofilter for the treatment of alpha-pinene 总被引:2,自引:0,他引:2
Biofiltration is an emerging technology in the United States that utilizes microorganisms to biodegrade harmful contaminants in air to carbon dioxide and water. Biofiltration is not only more cost effective, but also more environmentally friendly than traditional technologies such as thermal oxidation and chemical scrubbing. The primary objectives of the study were to operate a lava rock-based laboratory biofiltration system for the removal of alpha-pinene. A consortium of microorganisms to be used as an inoculum was recovered that was able to use alpha-pinene as a sole source of carbon and energy. The removal of alpha-pinene from the laboratory system was monitored with a total hydrocarbon analyzer (THA). Based on THA analysis, elimination capacities as high as 100+g/m(3)/h were obtained in the laboratory biofilters. Removal efficiencies averaged 99% over a two year period. The solid support maintained a neutral pH with no buffer addition throughout the two year study and microbial levels were maintained between 10(6) and 10(7) colony forming units (CFU)/g of solid support. Bacillus and Rhodococcus species were found to be the majority of the microorganisms in the biofilters over a two year period. This is the first time an organism from either of these genera has been reported to utilize alpha-pinene as a sole source of carbon and energy. Overall, a preselected consortium of microorganisms coupled with lava rock as a biofilter solid support achieved extended alpha-pinene treatment levels that far exceed previously published values. 相似文献