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1.
Deniz Caylioglu Rieke Johanna Meyer Dana Hellmold Carolin Kubelt Michael Synowitz Janka Held-Feindt 《International journal of molecular sciences》2021,22(7)
Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences. 相似文献
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Nicholas Caffes David B. Kurland Volodymyr Gerzanich J. Marc Simard 《International journal of molecular sciences》2015,16(3):4973-4984
Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1–transient receptor potential melastatin 4 (Sur1–Trpm4) channels and, in some cases, microglial KATP (Sur1–Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke. 相似文献
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Previous experimental results indicate that the humidification conditions at the anode have an impact on the liquid water distribution in the cathode gas diffusion layer. Numerical simulations are developed to reproduce and analyze this effect. Results consistent with the experimental results are first obtained by playing with the partition coefficients of an advanced pore network model computing the liquid water formation and transfer in the cathode gas diffusion layer (GDL) for a large range of operating conditions. Then, a model for the full anode – cathode assembly is developed by combining the pore network model of the cathode GDL and a 1D model describing the heat and water transfer in the various components of the anode-cathode assembly. This enables one to generalize the dry – wet regime diagram introduced in a previous work by incorporating the effect of the humidity condition at the anode. 相似文献
6.
Lingfeng Zhou Zhipeng Zeng Michael P. Brady Donovan N. Leonard Harry M. Meyer Yukinori Yamamoto Wenyuan Li Greg Collins Xingbo Liu 《International Journal of Hydrogen Energy》2021,46(41):21619-21633
The chromium (Cr) evaporation behavior of several different types of iron (Fe)-based AFA alloys and benchmark Cr2O3-forming Fe-based 310 and Ni-based 625 alloys was investigated for 500 h exposures at 800 °C to 900 °C in air with 10% H2O. The Cr evaporation rates from alumina-forming austenitic (AFA) alloys were ~5 to 35 times lower than that of the Cr2O3-forming alloys depending on alloy and temperature. The Cr evaporation behavior was correlated with extensive characterization of the chemistry and microstructure of the oxide scales, which also revealed a degree of quartz tube Si contamination during the test. Long-term oxidation kinetics were also assessed at 800 to 1000 °C for up to 10,000 h in air with 10% H2O to provide further guidance for SOFC BOP component alloy selection. 相似文献
7.
Shamila Vibhushan Manuela Bratti Juan Eduardo Montero-Hernndez Alaa El Ghoneimi Marc Benhamou Nicolas Charles Eric Daugas Ulrich Blank 《International journal of molecular sciences》2021,22(1)
A sizable part (~2%) of the human genome encodes for proteases. They are involved in many physiological processes, such as development, reproduction and inflammation, but also play a role in pathology. Mast cells (MC) contain a variety of MC specific proteases, the expression of which may differ between various MC subtypes. Amongst these proteases, chymase represents up to 25% of the total proteins in the MC and is released from cytoplasmic granules upon activation. Once secreted, it cleaves the targets in the local tissue environment, but may also act in lymph nodes infiltrated by MC, or systemically, when reaching the circulation during an inflammatory response. MC have been recognized as important components in the development of kidney disease. Based on this observation, MC chymase has gained interest following the discovery that it contributes to the angiotensin-converting enzyme’s independent generation of angiotensin II, an important inflammatory mediator in the development of kidney disease. Hence, progress regarding its role has been made based on studies using inhibitors but also on mice deficient in MC protease 4 (mMCP-4), the functional murine counterpart of human chymase. In this review, we discuss the role and actions of chymase in kidney disease. While initially believed to contribute to pathogenesis, the accumulated data favor a more subtle view, indicating that chymase may also have beneficial actions. 相似文献
8.
Valence M. K. Ndesendo Yahya E. Choonara Leith C. R. Meyer Pradeep Kumar Lomas K. Tomar Charu Tyagi 《Drug development and industrial pharmacy》2015,41(8):1274-1287
Context and objective: The aim of this study was to develop, characterize and evaluate a mucoadhesive caplet resulting from a polymeric blend (polymeric caplet) for intravaginal anti-HIV-1 delivery.Materials and methods: Poly(lactic-co-glycolic) acid, ethylcellulose, poly(vinylalcohol), polyacrylic acid and modified polyamide 6, 10 polymers were blended and compressed to a caplet-shaped device, with and without two model drugs 3′-azido-3′-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Thermal analysis, infrared spectroscopy and microscopic analysis were carried out on the caplets employing temperature-modulated DSC (TMDSC), Fourier transform infra-red (FTIR) spectrometer and scanning electron microscope, respectively. In vitro and in vivo drug release analyses as well as the histopathological toxicity studies were carried out on the drug-loaded caplets. Furthermore, molecular mechanics (MM) simulations were carried out on the drug-loaded caplets to corroborate the experimental findings.Results and discussion: There was a big deviation between the Tg of the polymeric caplet from the Tg's of the constituent polymers indicating a strong interaction between constituent polymers. FTIR spectroscopy confirmed the presence of specific ionic and non-ionic interactions within the caplet. A controlled near zero-order drug release was obtained for AZT (20 d) and PSS (28 d). In vivo results, i.e. the drug concentration in plasma ranged between 0.012–0.332?mg/mL and 0.009–0.256?mg/mL for AZT and PSS over 1–28 d.Conclusion: The obtained results, which were corroborated by MM simulations, attested that the developed system has the potential for effective delivery of anti-HIV-agents. 相似文献
9.
Thioux Marc; Stark David E.; Klaiman Cheryl; Schultz Robert T. 《Canadian Metallurgical Quarterly》2006,32(5):1155
Some individuals are able to determine the weekday of a given date in a few seconds (finding for instance that June 12, 1900, was a Tuesday). This ability has fascinated scientists for many years because it is predominantly observed in people with limited intelligence and may appear very early in life. Exceptional visual memory, exceptional concentration abilities, or privileged access to lower levels of information not normally available through introspection have been advanced to explain such phenomena. In the present article, the authors show that a simple cognitive model can explain all aspects of the performance of Donny, a young autistic savant who is possibly the fastest and most accurate calendar prodigy ever described. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
10.
Reports an error in "Tradeoffs and Theory: The Double-Mediation Model" by Marc Scholten and Steven J. Sherman (Journal of Experimental Psychology: General, 2006 May, Vol 135[2], 237-261). This article was inadvertently printed with the incorrect title. The original title was "Tradeoffs and Conflict: The Double-Mediation Model." This title highlights the relation between tradeoffs and conflict as investigated by the authors and accounted for by their model. However, readers are asked to refer to the article by the title with which it was printed to facilitate its retrieval.. (The following abstract of the original article appeared in record 2006-06642-006.) Most theories of decision making suggest that, when options imply tradeoffs between their attributes, conflict increases as tradeoff size increases, because greater sacrifices are to be incurred in choosing one option instead of another. An alternative view is that conflict decreases as tradeoff size increases, because stronger arguments can be made for any decision. The authors propose a unified model, the double-mediation model, which combines the mediating effects of sacrifice and argumentation. Our model generally predicts an inverse U-shaped relation between tradeoff size and conflict. Results support this prediction. Also, when the decision situation increases the mediating effect of sacrifice relative to that of argumentation, the relation between tradeoff size and conflict changes in an upward direction; conversely, when the decision situation increases the mediating effect of argumentation relative to that of sacrifice, the relation changes in a downward direction. Results support these predictions as well. Commonalities and differences between our model and other formulations are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献