| 5421. |
|
|
| 5422. |
- Aboul-Enein, Mohamed N., et al.
(författare)
-
Design and synthesis of novel stiripentol analogues as potential anticonvulsants
- 2012
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 47, s. 360-369
-
Tidskriftsartikel (refereegranskat)abstract
- A series of stiripentol (SIP) analogues namely, 2-1(1E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ylidene]-N-(aryl/H)hydrazinecarboxamides 7a-h, (+/-)-(5RS)-N-(aryl/H)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazole-1-carboxamides (+/-)-8a-h, and (+/-)-[(5RS)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazol-1-yl](aryl)methanones (+/-)-13a-f was synthesized by adopting appropriate synthetic routes and was pharmacologically evaluated in the preliminary anticonvulsant screens. The selected bioactive new chemical entities were subjected to ED50 determination and neurotoxicity evaluation. The most active congeners are 7h in MES screen and (+/-)-13b in scPTZ screen which displayed ED50 values of 87 and 110 mg/kg, respectively, as compared to that of STP (ED50 = 277.7 and 115 mg/kg in MES and scPTZ, respectively). (C) 2011 Elsevier Masson SAS. All rights reserved.
|
|
| 5423. |
- Abrahamsson, Pernilla, et al.
(författare)
-
Outcome of microdialysis sampling on liver surface and parenchyma
- 2016
-
Ingår i: Journal of Surgical Research. - : Elsevier BV. - 0022-4804 .- 1095-8673. ; 200:2, s. 480-487
-
Tidskriftsartikel (refereegranskat)abstract
- Background: To investigate whether surface microdialysis (μD) sampling in probes covered by a plastic film, as compared to noncovered and to intraparenchymatous probes, would increase the technique's sensitivity for pathophysiologic events occurring in a liver ischemia-reperfusion model. Placement of μD probes in the parenchyma of an organ, as is conventionally done, may cause adverse effects, e.g., bleeding, possibly influencing outcome.Methods: A transient ischemia-reperfusion model of the liver was used in six anesthetized normoventilated pigs. μD probes were placed in the parenchyma and on the liver surface. Surface probes were either left uncovered or were covered by plastic film.Results: Lactate and glucose levels were significantly higher in plastic film covered probes than in uncovered surface probes throughout the ischemic period. Glycerol levels were significantly higher in plastic film covered probes than in uncovered surface probes at 30 and 45 min into ischemia.Conclusions: Covering the μD probe increases the sensibility of the μD–technique in monitoring an ischemic insult and reperfusion in the liver. These findings confirm that the principle of surface μD works, possibly replacing need of intraparenchymatous placement of μD probes. Surface μD seemingly allows, noninvasively from an organ's surface, via the extracellular compartment, assessment of intracellular metabolic events. The finding that covered surface μD probes allows detection of local metabolic changes earlier than do intraparenchymatous probes, merit further investigation focusing on μD probe design.
|
|
| 5424. |
- Abrahamsson, Sanna, et al.
(författare)
-
PΨFinder: a practical tool for the identification and visualization of novel pseudogenes in DNA sequencing data
- 2022
-
Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 23
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Processed pseudogenes (PΨgs) are disabled gene copies that are transcribed and may affect expression of paralogous genes. Moreover, their insertion in the genome can disrupt the structure or the regulatory region of a gene, affecting its expression level. These events have been identified as occurring mutations during cancer development, thus being able to identify PΨgs and their location will improve their impact on diagnostic testing, not only in cancer but also in inherited disorders. Results: We have implemented PΨFinder (P-psy-finder), a tool that identifies PΨgs, annotates known ones and predicts their insertion site(s) in the genome. The tool screens alignment files and provides user-friendly summary reports and visualizations. To demonstrate its applicability, we scanned 218 DNA samples from patients screened for hereditary colorectal cancer. We detected 423 PΨgs distributed in 96% of the samples, comprising 7 different parent genes. Among these, we confirmed the well-known insertion site of the SMAD4-PΨg within the last intron of the SCAI gene in one sample. While for the ubiquitous CBX3-PΨg, present in 82.6% of the samples, we found it reversed inserted in the second intron of the C15ORF57 gene. Conclusions: PΨFinder is a tool that can automatically identify novel PΨgs from DNA sequencing data and determine their location in the genome with high sensitivity (95.92%). It generates high quality figures and tables that facilitate the interpretation of the results and can guide the experimental validation. PΨFinder is a complementary analysis to any mutational screening in the identification of disease-causing mutations within cancer and other diseases.
|
|
| 5425. |
- Abtahi, Farhad, et al.
(författare)
-
Electrical bioimpedance spectroscopy in time-variant systems : Is undersampling always a problem?
- 2014
-
Ingår i: Journal of Electrical Bioimpedance. - : Walter de Gruyter GmbH. - 1891-5469. ; 5:1, s. 28-33
-
Tidskriftsartikel (refereegranskat)abstract
- During the last decades, Electrical Bioimpedance Spectroscopy (EBIS) has been applied mainly by using the frequency-sweep technique, across a range of many different applications. Traditionally, the tissue under study is considered to be time-invariant and dynamic changes of tissue activity are ignored by treating the changes as a noise source. A new trend in EBIS is simultaneous electrical stimulation with several frequencies, through the application of a multi-sine, rectangular or other waveform. This method can provide measurements fast enough to sample dynamic changes of different tissues, such as cardiac muscle. This high sampling rate comes at a price of reduction in SNR and the increase in complexity of devices. Although the frequency-sweep technique is often inadequate for monitoring the dynamic changes in a variant system, it can be used successfully in applications focused on the time-invariant or slowly-variant part of a system. However, in order to successfully use frequency-sweep EBIS for monitoring time-variant systems, it is paramount to consider the effects of aliasing and especially the folding of higher frequencies, on the desired frequency e.g. DC level. This paper discusses sub-Nyquist sampling of thoracic EBIS measurements and its application in the case of monitoring pulmonary oedema. It is concluded that by considering aliasing, and with proper implementation of smoothing filters, as well as by using random sampling, frequency-sweep EBIS can be used for assessing time-invariant or slowly-variant properties of time-variant biological systems, even in the presence of aliasing. In general, undersampling is not always a problem, but does always require proper consideration.
|
|
| 5426. |
- Adamczyk, Barbara, 1985, et al.
(författare)
-
Comparison of separation techniques for the elucidation of IgG N-glycans pooled from healthy mammalian species
- 2014
-
Ingår i: Carbohydrate Research. - : Elsevier BV. - 0008-6215. ; 389, s. 174-185
-
Tidskriftsartikel (refereegranskat)abstract
- The IgG N-glycome provides sufficient complexity and information content to serve as an excellent source for biomarker discovery in mammalian health. Since oligosaccharides play a significant role in many biological processes it is very important to understand their structure. The glycosylation is cell type specific as well as highly variable depending on the species producing the IgG. We evaluated the variation of N-linked glycosylation of human, bovine, ovine, equine, canine and feline IgG using three orthogonal glycan separation techniques: hydrophilic interaction liquid chromatography (HILIC)–UPLC, reversed phase (RP)–UPLC and capillary electrophoresis with laser induced fluorescence detection (CE-LIF). The separation of the glycans by these high resolution methods yielded different profiles due to diverse chemistries. However, the % abundance of structures obtained by CE-LIF and HILIC–UPLC were similar, whereas the analysis by RP-UPLC was difficult to compare as the structures were separated by classes of glycans (highly mannosylated, fucosylated, bisected, fucosylated and bisected) resulting in the co-elution of many structures. The IgGs from various species were selected due to the complexity and variation in their N-glycan composition thereby highlighting the complementarity of these separation techniques.
|
|
| 5427. |
- Adermark, Louise, 1974, et al.
(författare)
-
Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens.
- 2011
-
Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 16:1, s. 43-54
-
Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT Elevated dopamine levels are believed to contribute to the rewarding sensation of ethanol (EtOH), and previous research has shown that strychnine-sensitive glycine receptors in the nucleus accumbens (nAc) are involved in regulating dopamine release and in mediating the reinforcing effects of EtOH. Furthermore, the osmoregulator taurine, which is released from astrocytes treated with EtOH, can act as an endogenous ligand for the glycine receptor, and increase extracellular dopamine levels. The aim of this study was to address if EtOH-induced swelling of astrocytes could contribute to elevated dopamine levels by increasing the extracellular concentration of taurine. Cell swelling was estimated by optical sectioning of fluorescently labeled astrocytes in primary cultures from rat, and showed that EtOH (25-150 mM) increased astrocyte cell volumes in a concentration- and ion-dependent manner. The EtOH-induced cell swelling was inhibited in cultures treated with the Na(+)/K(+)/2Cl(-) cotransporter blocker furosemide (1 mM), Na(+)/K(+)-ATPase inhibitor ouabain (0.1 mM), potassium channel inhibitor BaCl(2) (50 microM) and in cultures containing low extracellular sodium concentration (3 mM). In vivo microdialysis performed in the nAc of awake and freely moving rats showed that local treatment with EtOH enhanced the concentrations of dopamine and taurine in the microdialysate, while glycine and beta-alanine levels were not significantly modulated. EtOH-induced dopamine release was antagonized by local treatment with the glycine receptor antagonist strychnine (20 microM) or furosemide (100 microM or 1 mM). Furosemide also prevented EtOH-induced taurine release in the nAc. In conclusion, our data suggest that extracellular concentrations of dopamine and taurine are interconnected and that swelling of astrocytes contributes to the acute rewarding sensation of EtOH.
|
|
| 5428. |
- Adrian, Gabriel, et al.
(författare)
-
The FLASH effect depends on oxygen concentration
- 2019
-
Ingår i: British Journal of Radiology. - : British Institute of Radiology. - 1748-880X .- 0007-1285. ; 93:1106
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Recent in vivo results have shown prominent tissue sparing effect of radiotherapy with ultra-high dose rates (FLASH) compared to conventional dose rates (CONV). Oxygen depletion has been proposed as the underlying mechanism, but in vitro data to support this have been lacking. The aim of the current study was to compare FLASH to CONV irradiation under different oxygen concentrations in vitro. METHODS: Prostate cancer cells were irradiated at different oxygen concentrations (relative partial pressure ranging between 1.6 and 20%) with a 10 MeV electron beam at a dose rate of either 600 Gy/s (FLASH) or 14 Gy/min (CONV), using a modified clinical linear accelerator. We evaluated the surviving fraction of cells using clonogenic assays after irradiation with doses ranging from 0 to 25 Gy. RESULTS: Under normoxic conditions, no differences between FLASH and CONV irradiation were found. For hypoxic cells (1.6%), the radiation response was similar up to a dose of about 5-10 Gy, above which increased survival was shown for FLASH compared to CONV irradiation. The increased survival was shown to be significant at 18 Gy, and the effect was shown to depend on oxygen concentration. CONCLUSION: The in vitro FLASH effect depends on oxygen concentration. Further studies to characterize and optimize the use of FLASH in order to widen the therapeutic window are indicated. ADVANCES IN KNOWLEDGE: This paper shows in vitro evidence for the role of oxygen concentration underlying the difference between FLASH and CONV irradiation.
|
|
| 5429. |
- Afshari, Ali, et al.
(författare)
-
Evaluation of the robustness of cerebral oximetry to variations in skin pigmentation using a tissue-simulating phantom
- 2022
-
Ingår i: Biomedical Optics Express. - Washington, DC, United States : Optica Publishing Group. - 2156-7085. ; 13:5, s. 2909-2928
-
Tidskriftsartikel (refereegranskat)abstract
- Clinical studies have demonstrated that epidermal pigmentation level can affect cerebral oximetry measurements. To evaluate the robustness of these devices, we have developed a phantom-based test method that includes an epidermis-simulating layer with several melanin concentrations and a 3D-printed cerebrovascular module. Measurements were performed with neonatal, pediatric and adult sensors from two commercial oximeters, where neonatal probes had shorter source-detector separation distances. Referenced blood oxygenation levels ranged from 30 to 90%. Cerebral oximeter outputs exhibited a consistent decrease in saturation level with simulated melanin content; this effect was greatest at low saturation levels, producing a change of up to 15%. Dependence on pigmentation was strongest in a neonatal sensor, possibly due to its high reflectivity. Overall, our findings indicate that a modular channel-array phantom approach can provide a practical tool for assessing the impact of skin pigmentation on cerebral oximeter performance and that modifications to algorithms and/or instrumentation may be needed to mitigate pigmentation bias.
|
|
| 5430. |
- Afshari, Maryam K.
(författare)
-
Transcriptomic and functional studies of fusion oncogene-driven salivary gland tumors
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fusion genes are potent oncogenic drivers resulting from exchange of regulatory/coding sequences between two genes. They were originally identified in leukemias but are now recognized as key oncogenic events also in many solid tumors, including salivary gland tumors (SGTs). Adenoid cystic carcinoma (ACC) is a highly malignant SGT with no effective treatment for patients with recurrent and/or metastatic disease. The MYB-NFIB fusion is the main genomic hallmark of ACC and a po- tential therapeutic target. Here, oncogenic signaling pathways as well as the molecular consequences and regulation of MYB-NFIB were assessed in cultured ACC cells and in ACC surgical samples. A combination of molecular and functional assays was used including RNAi, qPCR, western blot, phospho-receptor tyrosine kinase (RTK) arrays, proliferation/apoptosis/sphere assays, and gene expression microarrays. ACC patient- derived xenografts (PDX) were used to study the effects of RTK-inhibition on tumor growth. MYB-NFIB was shown to promote proliferation and spherogenesis of ACC cells. The fusion regulated expression of genes involved in DNA replication/repair, cell cycle, and RNA processing, and induced an MYC-like transcriptional program. MYB-NFIB was shown to be regulated by IGF1R through IGF2-activated AKT-signaling and phar- macological inhibition of IGF1R partially reversed the transcriptional program induced by MYB-NFIB. Moreover, IGF1R, EGFR, and MET were co-activated in ACC cells. Combined inhibition of these receptors in ACC cells and PDX-models induced differentiation and synergistic growth inhibition. The results provide new insights about the function and regulation of MYB-NFIB and are the first to show that a druggable cell surface receptor can regulate a fusion oncogene encoding a transcription factor. Importantly, the results also highlight novel potential treatment strategies for ACC patients. Pleomorphic adenoma (PA) is the most common SGT. Although it is a benign tumor, treatment may be complicated by recurrence and/or malignant transformation. Previous studies of PA have revealed recurrent chromosomal rearrangements that activate the key oncogenes PLAG1 and HMGA2 by gene fusion events. Here, detailed studies of previously uncharacterized subsets of PAs with 8;9- or 9;12-rearrangements revealed breakpoints within or in the proximity of either PLAG1 or HMGA2, and NFIB. Further analyses using RNA- seq, RT-PCR, qPCR, and arrayCGH revealed a novel NFIB-PLAG1 fusion in a PA with an ins(9;8) and HMGA2-NFIB fusions in cases with t(9;12). These findings highlight the role of NFIB as a fusion partner gene in both benign and malignant SGTs and indicate that NFIB can activate both PLAG1 and HMGA2 by gene fusion/enhancer hijacking events in PA. Furthermore, RNA-seq based transcriptomic analysis of PAs revealed a high frequency of PLAG1 and HMGA2 fusions (≈80% of the cases) and multiple novel fusion partner genes. The findings indicate that gene fusions are more common in PA than previously documented. Global gene expression and pathway analyses revealed several activated oncogenic signaling pathways and showed that the expression profile reflects certain morphological features typical of PA. Finally, the results showed that PLAG1 and HMGA2 drive tumorigenesis via shared signaling pathways. The results provide further insights into the pathogenesis of PA and reveal new potential therapeutic targets.
|
|
