The European position of Dutch plant communities

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PPARδ Activation Acts Cooperatively with 3-Phosphoinositide-Dependent Protein Kinase-1 to Enhance Mammary Tumorigenesis

Peroxisome proliferator-activated receptorδ (PPARδ) is a transcription factor that is associated with metabolic gene regulation and inflammation. It has been implicated in tumor promotion and in the regulation of 3-phosphoinositide-dependent kinase-1 (PDK1). PDK1 is a key regulator of the AGC protein kinase family, which includes the proto-oncogene AKT/PKB implicated in several malignancies, including breast cancer. To assess the role of PDK1 in mammary tumorigenesis and its interaction with PPARδ, transgenic mice were generated in which PDK1 was expressed in mammary epithelium under the control of the MMTV enhancer/promoter region. Transgene expression increased pT308AKT and pS9GSK3β, but did not alter phosphorylation of mTOR, 4EBP1, ribosomal protein S6 and PKCα. The transgenic mammary gland also expressed higher levels of PPARδ and a gene expression profile resembling wild-type mice maintained on a diet containing the PPARδ agonist, GW501516. Both wild-type and transgenic mice treated with GW501516 exhibited accelerated rates of tumor formation that were more pronounced in transgenic animals. GW501516 treatment was accompanied by a distinct metabolic gene expression and metabolomic signature that was not present in untreated animals. GW501516-treated transgenic mice expressed higher levels of fatty acid and phospholipid metabolites than treated wild-type mice, suggesting the involvement of PDK1 in enhancing PPARδ-driven energy metabolism. These results reveal that PPARδ activation elicits a distinct metabolic and metabolomic profile in tumors that is in part related to PDK1 and AKT signaling

THE EUROPEAN POSITION OF DUTCH PLANT COMMUNITIES

In this paper it is analyzed for which plant communities (alliances) the Netherlands has an international responsibility. Data has been brought together on the range and distribution of alliances in Europe, the area of plant communities in the Netherlands and surrounding countries and the occurrence of endemic associations in the Netherlands. The analysis resulted in a list of 34 out of 93 alliances in the Netherlands which are important from an international point of view

26 Meta-analysis comparing influence of no adjuvant treatment, postoperative radiotherapy and/or chemotherapy on survival in patients after primary surgery including lymphadenectomy for early stage uterine carcinosarcoma

Introduction Uterine carcinosarcoma (UCS, malignant mixed M\ufcllerian tumor) is rare but aggressive form of endometrial cancer according to metastatic potential. Standard treatment is primary surgery. Adjuvant therapy improves survival in advance disease but its benefit remains unclear in stage I (FIGO 2009). Methods A systematic review and meta-analysis to compare influence of no adjuvant treatment (No AT) \ub1 postoperative vaginal brachytherapy (VBT), adjuvant external beam radiation therapy (EBRT) \ub1VBT, adjuvant chemotherapy (CT) \ub1VBT, and adjuvant CT + EBRT\ub1VBT on survival in patients with stage I UCS after primary surgery including at least hysterec- tomy, bilateral salpingo-oophorectomy, and lymphadenectomy. Prospectively stated selection criteria, data collection and com- prehensive search strategy was registered on PROSPERO. Investigators independently extracted data. Random-effects meta-analysis was used to estimate risk ratios (RR). Results We included 14 retrospective observational studies with 1,090 UCS patients (figure 1). No AT\ub1VBT was associated with higher mortality and recurrence compared to CT\ub1VBT and compared to CT+EBRT\ub1VBT; but no significant differ- ence from EBRT\ub1VBT. Both, CT\ub1VBT and CT+ EBRT \ub1VBT, had significantly lower mortality and recurrence com- pared to EBRT\ub1VBT. There was higher mortality associated with CT\ub1VBT compared to CT+EBRT\ub1VBT. Heterogeneity was minimal in all analyses; however, none of these compari- sons were randomized and the estimates were imprecise due to the small number of events (figure 2). Conclusion/Implications Adjuvant chemotherapy appears to be effective in controlling recurrences and reduce mortality in early stage UCS

The intriguing dose-dependent effect of selected amphiphilic compounds on insulin amyloid aggregation: Focus on a cholesterol-based detergent, Chobimalt

The amyloidogenic self-assembly of many peptides and proteins largely depends on external conditions. Among amyloid-prone proteins, insulin attracts attention because of its physiological and therapeutic importance. In the present work, the amyloid aggregation of insulin is studied in the presence of cholesterol-based detergent, Chobimalt. The strategy to elucidate the Chobimalt-induced effect on insulin fibrillogenesis is based on performing the concentration- and time-dependent analysis using a combination of different experimental techniques, such as ThT fluorescence assay, CD, AFM, SANS,andSAXS.WhileatthelowestChobimaltconcentration(0.1 µM;insulinto Chobimalt molar ratio of 1:0.004) the formation of insulin fibrils was not affected, the gradual increase of Chobimalt concentration (up to 100 µM; molar ratio of 1:4) led to a significant increase in ThT fluorescence, and the maximal ThT fluorescence was 3-4-fold higher than the control insulin fibril’s ThT fluorescence intensity. Kinetic studies confirm the dose-dependent experimental results. Depending on the concentration of Chobimalt, either (i) no effect is observed, or (ii) significantly, ~10-times prolonged lag-phases accompanied by the substantial, ~ 3-fold higher relative ThT fluorescence intensities at the steady-state phase are recorded. In addition, at certain concentrations of Chobimalt, changes in the elongation-phase are noticed. An increase in the Chobimalt concentrations also triggers the formation of insulin fibrils with sharply altered morphological appearance. The fibrils appear to be more flexible and wavy-like with a tendency to form circles. SANS and SAXS data also revealed the morphology changes of amyloid fibrils in the presence of Chobimalt. Amyloid aggregation requires the formation of unfolded intermediates, which subsequently generate amyloidogenic nuclei. Wehypothesize thatthedifferent morphology of the formed insulin fibrils is the result of the gradual binding of Chobimalt to different binding sites on unfolded insulin. A similar explanation and the existence of such binding sites with different binding energies was shown previously for the nonionic detergent. Thus, the data also emphasize the importance of a protein partially-unfolded state whichundergoestheprocessoffibrilsformation;i.e.,certain experimental conditions or the presence of additives may dramatically change not only kinetics but also the morphology of fibrillar aggregates