Microvesicles and Microvesicle-Associated microRNAs Reflect Glioblastoma Regression: Microvesicle-Associated miR-625-5p Has Biomarker Potential

Glioblastoma (GB) is the most aggressive and recurrent form of brain cancer in adults. We hypothesized that the identification of biomarkers such as certain microRNAs (miRNAs) and the circulating microvesicles (MVs) that transport them could be key to establishing GB progression, recurrence and therapeutic response. For this purpose, circulating MVs were isolated from the plasma of GB patients (before and after surgery) and of healthy subjects and characterized by flow cytometry. OpenArray profiling and the individual quantification of selected miRNAs in plasma and MVs was performed, followed by target genes’ prediction and in silico survival analysis. It was found that MVs’ parameters (number, EGFRvIII and EpCAM) decreased after the surgical resection of GB tumors, but the inter-patient variability was high. The expression of miR-106b-5p, miR-486-3p, miR-766-3p and miR-30d-5p in GB patients’ MVs was restored to control-like levels after surgery: miR-106b-5p, miR-486-3p and miR-766-3p were upregulated, while miR-30d-5p levels were downregulated after surgical resection. MiR-625-5p was only identified in MVs isolated from GB patients before surgery and was not detected in plasma. Target prediction and pathway analysis showed that the selected miRNAs regulate genes involved in cancer pathways, including glioma. In conclusion, miR-625-5p shows potential as a biomarker for GB regression or recurrence, but further in-depth studies are needed.     

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways’ inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways’ inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC.     

Morphine-induced conformational changes in human monocytes, granulocytes, and endothelial cells and in invertebrate immunocytes and microglia are mediated by nitric oxide

We evaluated the contribution of nitric oxide (NO) to morphine-induced rounding of spontaneously activated (mobile) ameboid human monocytes, granulocytes, or arterial endothelial cells and invertebrate immunocytes and microglia. Morphine induced significant rounding and inactivation of ameboid cells within 20 min except for arterial endothelial cells, which became rounded 24 h after morphine exposure. The effects of morphine on cell conformation were blocked in the presence of N-nitro-L-arginine, a nitric oxide synthase inhibitor. Treatment of cells with the NO donor, sodium nitroprusside, induced cell rounding similar to that observed following morphine exposure, suggesting that NO release may mediate morphine-induced changes in cell conformation. The contribution of NO release to morphine-induced cell rounding was determined by direct evaluation of NO concentration in real-time using a NO-specific amperometric probe. Significant increases in NO concentration were observed 2 min after morphine stimulation, whereas morphine-induced NO release was markedly impaired by pretreatment with N-nitro-L-arginine or the opiate alkaloid antagonist, naloxone. In contrast, opioid peptides failed to induce NO release, consistent with our previous observations that demonstrated the failure of opioid peptides to promote cell rounding. Taken together, these data suggest that morphine-induced NO release may be mediated by activation of the opiate alkaloid-selective, opioid peptide-insensitive micro3 receptor, and that functional coupling of morphine to NO production has been conserved during evolution and may modulate cellular activation.     

A high affinity, mu-opioid receptor-selective enkephalin analogue lacking an N-terminal tyrosine

We report a high affinity, mu opioid receptor selective enkephalin analogue in which the N-terminal tyrosine residue thought to be required for such high affinity is replaced by phenylalanine. The high affinity can be traced to a shift of the ligand's N-terminal residue within the mu receptor binding pocket, which diminishes the importance of the usual hydrogen bond between the tyrosine phenolic moiety and the receptor.     

On the theory of the ising model of the macromolecular solution

The partition function of a macromolecular binary solution is transposed in the partition function in Ising's model. On the basis of this model the macrocanonical function is explained by the presence of the interaction forces, in the one-dimensional as well as in the two-dimensional cases. The chemical potential of the macromolecular solution is calculated in both cases and compared with the results obtained by Flory and Huggins.     

电缆半导电屏蔽层中导电离子析出模型分析

中低压电力电缆主绝缘的水树现象是造成电缆故障的一个很重要的因素,在温度和高电场等外界条件共同作用下,电缆半导电屏蔽层中含有的游离导电离子析出后在电缆主绝缘表面形成水树现象的起始点。通过对半导电屏蔽试样水煮得到的数据进行分析,建立扩散模型,利用Fick第二扩散方程对该模型进行解析,得到t时刻试样中导电离子的浓度分布并与导电离子的析出试验数据相符。     

Endometrial thickness: individual and mean growth profiles for different hormone replacement regimens

Currently, there is a paucity of data describing endometrial growth, with most studies concentrating on endometrial thickness immediately prior to implantation or embryo transfer. This study looked at the individual and combined growth profiles of 67 volunteers receiving three different hormone replacement regimens. Each treatment regimen was in excess of that considered necessary for optimal growth, and all promoted an endometrial thickness that would be considered satisfactory for embryo transfer. Three patterns of growth were identified, but overall there was a decrease in the rate of endometrial growth with duration of treatment. As expected, analysis of variance did not show a significant difference between the mean growth profiles for the three hormone replacement regimens. The correlation (r = 0.45, P < 0.0001) between rank order on day 3 and day 10 of treatment indicates that interim analysis during early treatment cannot accurately predict later thickness, but a doubling of endometrial thickness can be expected in most cases. A relationship between endometrial thickness and either the treatment dose or serum concentrations of oestradiol was not found. These findings suggest that manipulation of endometrial growth is not possible by adjustment of either the treatment dose or serum concentration. The findings indicate that treatment beyond 12 days does not promote either a clinically significant increase in endometrial thickness of an excessive thickness, suggesting that maintenance of an oocyte recipient in a pseudo-follicular phase is unlikely to be disadvantageous to implantation.     

Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2

OBJECTIVE: To estimate the prevalence and social correlates of cardiovascular disease. DESIGN: Population-based cross-sectional survey. Survey data were obtained through a standardized home interview and a clinic visit by trained nurses. The question sequence of the London School of Hygiene (the Rose Questionnaire) was used to identify the presence of definite angina, possible infarction, definite infarction, intermittent claudication and stroke. SETTING: Eight urban communities and rural areas in Saskatchewan in 1990. PARTICIPANTS: A probability sample of 2167 noninstitutionalized men and women aged 18 to 74 years who participated in the Saskatchewan Heart Health Survey. MAIN OUTCOME MEASURES: Prevalence of cardiovascular diseases. RESULTS: Among men, the prevalence of definite angina increased gradually with age from 1.7% (95% CI 0.6% to 2.7%) in the 18 to 34 year group, 3.8% (1.3% to 6.0%) in the 35 to 54 year group to 4.8% (2.8% to 8.3%) in the 55 to 74 year group, while the prevalence among women ranged from 2.5% (1.2 to 3.7%), 4.0% (1.6% to 6.5%) to 7.1% (5.1% to 11.6%) in these same age groups. The prevalence of possible angina, definite infarction, possible infarction and intermittent claudication increased with age as well, being higher in men than in women. Generally, the conditions were more prevalent among those with less education, lower income and those who were unemployed. CONCLUSIONS: These findings indicate that there is sociodemographic inequality in the prevalence of these manifestations of cardiovascular disease, and there is a need for in-depth qualitative research into causal factors in this relationship and for targeted programs of health promotion.