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101.
Ingo V. Hartung Marion Hitchcock Florian Pühler Roland Neuhaus Arne Scholz Stefanie Hammer Kirstin Petersen Gerhard Siemeister Dominic Brittain Roman C. Hillig 《Bioorganic & medicinal chemistry letters》2013,23(8):2384-2390
Using PD325901 as a starting point for identifying novel allosteric MEK inhibitors with high cell potency and long-lasting target inhibition in vivo, truncation of its hydroxamic ester headgroup was combined with incorporation of alkyl and aryl ethers at the neighboring ring position. Whereas alkoxy side chains did not yield sufficient levels of cell potency, specifically substituted aryloxy groups allowed for high enzymatic and cellular potencies. Sulfamide 28 was identified as a highly potent MEK inhibitor with nanomolar cell potency against B-RAF (V600E) as well as Ras-mutated cell lines, high metabolic stability and resulting long half-lives. It was efficacious against B-RAF as well as K-Ras driven xenograft models and showed—despite being orally bioavailable and not a P-glycoprotein substrate—much lower brain/plasma exposure ratios than PD325901. 相似文献
102.
103.
Functionalized collagen is attractive for the development of synthetic biomaterials. Herein we present the functionalization of azidoproline containing collagen model peptides with various alkynes using click chemistry. The influence on the stability of the collagen triple helix of the stereochemistry of the introduced triazolyl prolines (4R or 4S), the position of their incorporation (Xaa or Yaa) and the substituents attached to them are shown. The results provide a useful guide for the optimal functionalization of collagen using click chemistry. 相似文献
104.
Mariana Budovská Martina Pilátová Lenka Varinská Ján Mojžiš Roman Mezencev 《Bioorganic & medicinal chemistry》2013,21(21):6623-6633
An effective synthesis of analogs of the indole phytoalexin cyclobrassinin with NR1R2 group instead of SCH3 was developed starting from indole-3-carboxaldehyde. The target compounds were prepared by spirocyclization of 1-Boc-thioureas with the formation of isolable spiroindoline intermediates, followed by the trifluoroacetic acid-induced cascade reaction consisting of methanol elimination, deprotection and rearrangement of the iminium ion. The structures of novel products were elucided by the 1H and 13C NMR spectroscopy, including HMBC, HSQC, COSY, NOESY and DEPT measurements. Several newly synthesized compounds demonstrated significant antiproliferative/cytotoxic activity against human leukemia and solid tumor cell lines, as well as remarkable selectivity of these effects against cancer cells relative to the non-malignant HUVEC cells. 相似文献
105.
Lovisa Wennerström Linda Laikre Nils Ryman Fred M. Utter Nurul Izza Ab Ghani Carl André Jacquelin DeFaveri Daniel Johansson Lena Kautsky Juha Merilä Natalia Mikhailova Ricardo Pereyra Annica Sandström Amber G. F. Teacher Roman Wenne Anti Vasemägi Małgorzata Zbawicka Kerstin Johannesson Craig R. Primmer 《Biodiversity and Conservation》2013,22(13-14):3045-3065
Information on spatial and temporal patterns of genetic diversity is a prerequisite to understanding the demography of populations, and is fundamental to successful management and conservation of species. In the sea, it has been observed that oceanographic and other physical forces can constitute barriers to gene flow that may result in similar population genetic structures in different species. Such similarities among species would greatly simplify management of genetic biodiversity. Here, we tested for shared genetic patterns in a complex marine area, the Baltic Sea. We assessed spatial patterns of intraspecific genetic diversity and differentiation in seven ecologically important species of the Baltic ecosystem—Atlantic herring (Clupea harengus), northern pike (Esox lucius), European whitefish (Coregonus lavaretus), three-spined stickleback (Gasterosteus aculeatus), nine-spined stickleback (Pungitius pungitius), blue mussel (Mytilus spp.), and bladderwrack (Fucus vesiculosus). We used nuclear genetic data of putatively neutral microsatellite and SNP loci from samples collected from seven regions throughout the Baltic Sea, and reference samples from North Atlantic areas. Overall, patterns of genetic diversity and differentiation among sampling regions were unique for each species, although all six species with Atlantic samples indicated strong resistence to Atlantic-Baltic gene-flow. Major genetic barriers were not shared among species within the Baltic Sea; most species show genetic heterogeneity, but significant isolation by distance was only detected in pike and whitefish. These species-specific patterns of genetic structure preclude generalizations and emphasize the need to undertake genetic surveys for species separately, and to design management plans taking into consideration the specific structures of each species. 相似文献
106.
Silvio Schueler Stefan Kapeller Heino Konrad Thomas Geburek Michael Mengl Michele Bozzano Jarkko Koskela François Lefèvre Jason Hubert Hojka Kraigher Roman Longauer Ditte C. Olrik 《Biodiversity and Conservation》2013,22(5):1151-1166
Genetic resources of forest trees are considered as a key factor for the persistence of forest ecosystems because the ability of tree species to survive under changing climate depends strongly on their intraspecific variation in climate response. Therefore, utilizing available genetic variation in climate response and planting alternative provenances suitable for future climatic conditions is considered as an important adaptation measure for forestry. On the other hand, the distribution of adaptive genetic diversity of many tree species is still unknown and the predicted shift of ecological zones and species’ distribution may threaten forest genetic resources that are important for adaptation. Here, we use Norway spruce in Austria as a case study to demonstrate the genetic variation in climate response and to analyse the existing network of genetic conservation units for its effectiveness to safeguard the hotspots of adaptive and neutral genetic diversity of this species. An analysis of the climate response of 480 provenances, clustered into 9 groups of climatically similar provenances, revealed high variation among provenance groups. The most productive and promising provenance clusters for future climates originate from three regions that today depict the warmest and driest areas of the natural spruce distribution in Austria. Gap analysis of the Austrian genetic conservation units in the EUFGIS Portal suggests adequate coverage of the genetic hotspots in southern parts of Austria, but not in eastern and northern Austria. Therefore conservation measures and sustainable utilization of the valuable genetic resources in these regions need to be expanded to cover their high adaptive genetic variation and local adaptation to a warmer climate. The study shows that current conservation efforts need to be evaluated for their effectiveness to protect genetic resources that are important for the survival of trees in a future climate. 相似文献
107.
Roman J. Lichtenecker Katharina Weinhäupl Walther Schmid Robert Konrat 《Journal of biomolecular NMR》2013,57(4):327-331
13C-α-ketoacid metabolic precursors of phenylalanine and tyrosine effectively enter the metabolism of a protein overexpressing E. coli strain to label Phe- and Tyr-residues devoid of any cross-labelling. The methodology gives access to highly selective labelling patterns as valuable tools in protein NMR spectroscopy without the need of 15N-chiral amino acid synthesis using organic chemistry. 相似文献
108.
Sebastian Ullrich Phillip Bremer Christine Neumann-Grutzeck Helge Otto Christoph Rüther Cay Uwe von Seydewitz Gerd Peter Meyer Keihan Ahmadi-Simab Joachim R?ther Barbara Hogan Wolfgang Schwenk Roman Fischbach J?rg Caselitz Jochen Puttfarcken Susanne Huggett Petra Tiedeken Jordan Pober Nancy C. Kirkiles-Smith Friedrich Hagenmüller 《PloS one》2013,8(2)
Objectives
Shiga-toxin producing O157:H7 Entero Haemorrhagic E. coli (STEC/EHEC) is one of the most common causes of Haemolytic Uraemic Syndrome (HUS) related to infectious haemorrhagic colitis. Nearly all recommendations on clinical management of EHEC infections refer to this strain. The 2011 outbreak in Northern Europe was the first to be caused by the serotype O104:H4. This EHEC strain was found to carry genetic features of Entero Aggregative E. coli (EAEC) and extended spectrum β lactamase (ESBL). We report symptoms and complications in patients at one of the most affected centres of the 2011 EHEC O104 outbreak in Northern Germany.Methods
The courses of patients admitted to our hospital due to bloody diarrhoea with suspected EHEC O104 infection were recorded prospectively. These data include the patients’ histories, clinical findings, and complications.Results
EHEC O104 infection was confirmed in 61 patients (female = 37; mean age: 44±2 years). The frequency of HUS was 59% (36/61) in our cohort. An enteric colonisation with co-pathogens was found in 57%. Thirty-one (51%) patients were treated with plasma-separation/plasmapheresis, 16 (26%) with haemodialysis, and 7 (11%) with Eculizumab. Patients receiving antibiotic treatment (n = 37; 61%) experienced no apparent change in their clinical course. Twenty-six (43%) patients suffered from neurological symptoms. One 83-year-old patient died due to comorbidities after HUS was successfully treated.Conclusions
EHEC O104:H4 infections differ markedly from earlier reports on O157:H7 induced enterocolitis in regard to epidemiology, symptomatology, and frequency of complications. We recommend a standard of practice for clinical monitoring and support the renaming of EHEC O104:H4 syndrome as “EAHEC disease”. 相似文献109.
Madhura S. Mehta Sonia C. Dolfi Roman Bronfenbrener Erhan Bilal Chunxia Chen Dirk Moore Yong Lin Hussein Rahim Seena Aisner Romona D. Kersellius Jessica Teh Suzie Chen Deborah L. Toppmeyer Dan J. Medina Shridar Ganesan Alexei Vazquez Kim M. Hirshfield 《PloS one》2013,8(7)
Several epidemiological studies have suggested a link between melanoma and breast cancer. Metabotropic glutamate receptor 1 (GRM1), which is involved in many cellular processes including proliferation and differentiation, has been implicated in melanomagenesis, with ectopic expression of GRM1 causing malignant transformation of melanocytes. This study was undertaken to evaluate GRM1 expression and polymorphic variants in GRM1 for associations with breast cancer phenotypes. Three single nucleotide polymorphisms (SNPs) in GRM1 were evaluated for associations with breast cancer clinicopathologic variables. GRM1 expression was evaluated in human normal and cancerous breast tissue and for in vitro response to hormonal manipulation. Genotyping was performed on genomic DNA from over 1,000 breast cancer patients. Rs6923492 and rs362962 genotypes associated with age at diagnosis that was highly dependent upon the breast cancer molecular phenotype. The rs362962 TT genotype also associated with risk of estrogen receptor or progesterone receptor positive breast cancer. In vitro analysis showed increased GRM1 expression in breast cancer cells treated with estrogen or the combination of estrogen and progesterone, but reduced GRM1 expression with tamoxifen treatment. Evaluation of GRM1 expression in human breast tumor specimens demonstrated significant correlations between GRM1 staining with tissue type and molecular features. Furthermore, analysis of gene expression data from primary breast tumors showed that high GRM1 expression correlated with a shorter distant metastasis-free survival as compared to low GRM1 expression in tamoxifen-treated patients. Additionally, induced knockdown of GRM1 in an estrogen receptor positive breast cancer cell line correlated with reduced cell proliferation. Taken together, these findings suggest a functional role for GRM1 in breast cancer. 相似文献
110.
Ana Gvozdenovic Matthias J. E. Arlt Carmen Campanile Patrick Brennecke Knut Husmann Walter Born Roman Muff Bruno Fuchs 《PloS one》2013,8(4)
Osteosarcoma (OS) is the most frequent primary malignant bone cancer in children and adolescents with a high propensity for lung metastasis. Therefore, it is of great importance to identify molecular markers leading to increased metastatic potential in order to devise more effective therapeutic strategies that suppress metastasis, the major cause of death in OS. CD44, the principal receptor for the extracellular matrix component hyaluronan (HA), is frequently found overexpressed in tumor cells and has been implicated in metastatic spread in various cancer types. Here, we investigated the effects of stable shRNA-mediated silencing of CD44 gene products on in vitro and in vivo metastatic properties of the highly metastatic human 143-B OS cell line. In vitro, CD44 knockdown resulted in a 73% decrease in the adhesion to HA, a 57% decrease in the migration rate in a trans-filter migration assay, and a 28% decrease in the cells'' capacity for anchorage-independent growth in soft agar compared to the control cells, implicating that CD44 expression contributes to the metastatic activity of 143-B cells. However, making use of an orthotopic xenograft OS mouse model, we demonstrated that reduced CD44 expression facilitated primary tumor growth and formation of pulmonary metastases. The enhanced malignant phenotype was associated with decreased adhesion to HA and reduced expression of the tumor suppressor merlin in vivo. In conclusion, our study identified CD44 as a metastasis suppressor in this particular experimental OS model. 相似文献