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81.
Judy Strickland Qingda Zang Nicole Kleinstreuer Michael Paris David M. Lehmann Neepa Choksi Joanna Matheson Abigail Jacobs Anna Lowit David Allen Warren Casey 《Journal of applied toxicology : JAT》2016,36(9):1150-1162
One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non‐animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co‐operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using in vitro, in chemico and in silico information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h‐CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read‐across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty‐four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89–96% for the test set and 96–99% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non‐animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA. 相似文献
82.
Emilia Sokolowska Bartlomiej Kalaska Joanna Miklosz 《Expert opinion on drug metabolism & toxicology》2016,12(8):897-909
Introduction: Unfractionated heparin is a strongly anionic anticoagulant used extensively in medicine to prevent blood clotting. In the case of an emergency bleeding in response to heparin, the protamine sulfate is administered. Despite its extensive clinical use, protamine may produce life-threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. Recent studies have demonstrated new organ-specific complications of the heparin reversal with protamine.Areas covered: Past and present knowledge of the mechanisms responsible for the toxicity of protamine and the most promising potential replacements of protamine in the different phases of development.Expert opinion: Despite of the low therapeutic index, protamine is the only registered antidote of heparins. The toxicology of protamine depends on a complex interaction of the high molecular weight, a cationic peptide with the surfaces of the vasculature and blood cells. The mechanisms involve membrane receptors and ion channels targeted by different vasoactive compounds, such as nitric oxide, bradykinin or histamine. Unacceptable side effects of protamine have led to a search for new alternatives: UHRA, LMWP, and Dex40-GTMAC3 are in the preclinical stage; the two other agents (andexanet alfa and PER977) are already in the advanced clinical phases. 相似文献
83.
Joanna Krajewska Krzysztof Nowicki Krzysztof Durka Paulina H. Marek-Urban Patrycja Wiska Tomasz Stpniewski Krzysztof Wo
niak Agnieszka E. Laudy Sergiusz Luliski 《RSC advances》2022,12(36):23099
Two isomeric benzosiloxaborole derivatives 3a and 5a bearing fluorine and 4,4-dimethyl-2-oxazolin-2-yl substituents attached to the aromatic rings were obtained. Both compounds were prone to hydrolytic cleavage of the oxazoline ring after initial protonation or methylation of the nitrogen atom. The derivative 3c featuring N-methylammoniumalkyl ester functionality was successfully subjected to N-sulfonylation and N-acylation reactions to give respective derivatives which demonstrates its potential for modular synthesis of structurally extended benzosiloxaboroles. Compound 5c bearing N-ammoniumalkyl ester underwent conversion to a unique macrocyclic dimer due to siloxaborole ring opening. Furthermore, an unexpected 4-electron reduction of the oxazoline ring occurred during an attempted synthesis of 5a. The reaction gave rise to an unprecedented 7-membered heterocyclic system 4a comprising a relatively stable B–O–B–O–Si linkage and stabilized by an intramolecular N–B coordination. It could be cleaved to derivative 4c bearing BOH and SiMe2OH groups which acts as a pseudo-diol as demonstrated by formation of an adduct with Tavaborole. Apart from the multinuclear NMR spectroscopy characterization, crystal structures of the obtained products were determined in many cases by X-ray diffraction. Investigation of biological activity of the obtained compounds revealed that derivatives 3e and 3f with pendant N-methyl arylsulfonamide groups exhibit high activity against Gram-positive cocci such as methicillin-sensitive Staphylococcus aureus ATCC 6538P, methicillin-resistant S. aureus (MRSA) ATCC 43300 as well as the MRSA clinical strains, with MIC values in the range of 3.12–6.25 mg L−1. These two compounds also showed activity against Enterococcus faecalis ATCC 29212 and Enterococcus faecium ATCC 6057 (with MICs of 25–50 mg L−1). The results of the antimicrobial activity and cytotoxicity studies indicate that 3e and 3f can be considered as potential antibacterial agents, especially against S. aureus MRSA.Transformations of oxazoline–benzosiloxaborole conjugates gave rise to novel boracyclic systems as well as functionalized derivatives featuring antibacterial activity. 相似文献
84.
85.
Depa-Martynów M Walczyk-Matyja K Szyfter J Przewoźna J Pawelczyk L Jedrzejczak P Bogacka O 《Ginekologia polska》2008,79(2):115-119
INTRODUCTION: Psychological factors are believed to play an important role in infertility and its treatment Psychological problems may be considered to be risk factors and the cause of reduced infertility, as well as contribute to an unsuccessful outcome of infertility treatment. OBJECTIVES: The aim of the study was to investigate the correlation between semen parameters and quality of life in male patients with fertility problems. MATERIAL AND METHODS: 70 patients with infertility treated in Andrology Clinic were divided into two groups according to semen parameters: bad and good quality of semen. The quality of life has been with the help of Campbell questionnaires. RESULTS: Significantly lower questionnaire score in bad quality of semen group has been observed, in comparison with normozoospermic men. High correlation between concentration, motility and morphology in comparison with the quality of life has been observed in the studied group of patients. CONCLUSION: The quality of life is directly associated with semen parameters such as concentration, motility and morphology of sperm. 相似文献
86.
Value of the intraoperative assessment of the depth of myometrial invasion in endometrial carcinoma 总被引:1,自引:0,他引:1
Obrzut B Obrzut M Skret-Magierło J Skret A Ulman D Król P Zmuda M 《Ginekologia polska》2008,79(6):404-409
OBJECTIVES: The aim of the study was to evaluate the value of intraoperative assessment of depth of myometrial invasion in patients with FIGO stage I of the endometrial carcinoma. MATERIAL AND METHODS: A total number of 112 patients with FIGO stage I of the endometrial carcinoma undergoing surgery were enrolled in the study. All patients had undergone intraoperative assessment of the depth of myometrial invasion performed by a surgeon. The depth was determined as more or less than 50% of myometrial thickness according to FIGO classification. Gross visual estimation of the depth of myometrial invasion at the time of the operation was compared with the final histopathological report. Sensitivity, specificity and positive and negative predictive values of the method were determined by means of statistical analyses. RESULTS: The depth of the myometrial invasion was accurately determined by the surgeon in 82.1% of cases. Sensitivity and specificity were 68% and 82.1%, respectively. The accurate prediction rate of the myometrial invasion in the group of patients with well differentiated (G1) endometrial carcinoma was higher (88.4%) than in group with moderately and low differentiated tumour (78.3%). CONCLUSIONS: The accuracy of macroscopic evaluation of myometrial invasion is high and reaches up to 82.1%. The accurate determination rate increases if the differentiation of tumour is higher. 相似文献
87.
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89.
Pipingas A Silberstein RB Vitetta L Rooy CV Harris EV Young JM Frampton CM Sali A Nastasi J 《Phytotherapy research : PTR》2008,22(9):1168-1174
Dietary interventions may have the potential to counter age-related cognitive decline. Studies have demonstrated an improvement in age-related cognitive impairment in animals after supplementation with plant extracts containing flavonoids but there are few human studies. This double-blind, controlled study examined the effects on cognitive performance of a 5 week supplementation with Enzogenol Pinus radiata bark extract containing flavonoids, in 42 males aged 50-65 years, with a body mass index >25. Participants were supplemented for 5 weeks either with Enzogenol plus vitamin C, or with vitamin C only. A battery of computerized cognitive tests was administered, and cardiovascular and haematological parameters were assessed prior to and following supplementation. The speed of response for the spatial working memory and immediate recognition tasks improved after supplementation with Enzogenol plus vitamin C, whereas vitamin C alone showed no improvements. A trend in a reduction of systolic blood pressure was observed with Enzogenol plus vitamin C, but not with vitamin C alone. The blood safety parameters were unchanged. The findings suggest a beneficial effect of supplementation with Enzogenol on cognition in older individuals. Larger studies are needed to ascertain its potential as a preventive treatment for age-related cognitive decline. 相似文献
90.