A few groups have suggested that activated cytokines and nitrosative stress are closely involved in the pathogenesis of different demyelinating disorders induced by the neuroinflammatory destruction ...of neurons. The purpose of this study was to elucidate the associations of cytokines and S-nitrosothiols (RSNO) with the severity of neurodegeneration during relapse in demyelinating disorders of the central nervous system.
We measured levels of interleukin-6 (IL-6), erythropoietin, RSNO, and phosphorylated neurofilament heavy chain (pNfh) in cerebrospinal fluid (CSF) samples obtained from patients with different demyelinating disorders: multiple sclerosis (MS, n=52), acute disseminated encephalomyelitis (ADEM, n=9), and neuromyelitis optica spectrum disorders (NMOSD) with aquaporin-4 immunoglobulin G (AQP4-IgG, n=12). We compared these levels with those measured in a control group (n=24).
We found that IL-6 in CSF was elevated in NMOSD with AQP4-IgG and ADEM patients as well as in MS patients after the destruction of soluble IL-6. Erythropoietin levels were lower in MS, while RSNO levels were higher in NMOSD with AQP4-IgG and MS patients than in the control group. CSF pNfh levels were elevated in MS and ADEM patients.
These results confirm that IL-6 is activated in different demyelinating disorders, with this elevation being more prominent in the CSF of NMOSD with AQP4-IgG and ADEM patients. Moreover, S-nitrosylation is activated in demyelinating disorders with spinal-cord injury and neurodegeneration in these patients. However, we found no correlation between these biochemical markers, and so we could not confirm whether IL-6-mediated nitric oxide production is involved in spinal-cord lesions.
Non-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesophageal, and ovarian cancers may stratify patients for treatment using ...HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting probe for radionuclide imaging. In clinical studies, the DARPin Tc-99mTc-(HE)(3)-G3 labeled using a peptide-based chelator His-Glu-His-Glu-His-Glu ((HE)(3)), provided clear imaging of HER2 expressing breast cancer 2-4 h after injection. The goal of this study was to evaluate if the use of cysteine-containing peptide-based chelators Glu-Glu-Glu-Cys (E3C), Gly-Gly-Gly-Cys (G(3)C), and Gly-Gly-Gly-Ser-Cys connected via a (Gly-Gly-Gly-Ser)(3)-linker (designated as G3-(G(3)S)(3)C) would further improve the contrast of imaging using Tc-99m-labeled derivatives of G3. The labeling of the new variants of G3 provided a radiochemical yield of over 95%. Labeled G3 variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 1.9-5 nM. Biodistribution of Tc-99mTc-G3-G(3)C, Tc-99mTc-G3-(G(3)S)(3)C, and Tc-99mTc-G3-E3C in mice was compared with the biodistribution of Tc-99mTc-(HE)(3)-G3. It was found that the novel variants provide specific accumulation in HER2-expressing human xenografts and enable discrimination between tumors with high and low HER2 expression. However, Tc-99mTc-(HE)(3)-G3 provided better contrast between tumors and the most frequent metastatic sites of HER2-expressing cancers and is therefore more suitable for clinical applications.
Non-invasive radionuclide imaging of human epidermal growth factor receptor type 2 (HER2) expression in breast, gastroesophageal, and ovarian cancers may stratify patients for treatment using ...HER2-targeted therapeutics. Designed ankyrin repeat proteins (DARPins) are a promising type of targeting probe for radionuclide imaging. In clinical studies, the DARPin Tc-99mTc-(HE)(3)-G3 labeled using a peptide-based chelator His-Glu-His-Glu-His-Glu ((HE)(3)), provided clear imaging of HER2 expressing breast cancer 2-4 h after injection. The goal of this study was to evaluate if the use of cysteine-containing peptide-based chelators Glu-Glu-Glu-Cys (E3C), Gly-Gly-Gly-Cys (G(3)C), and Gly-Gly-Gly-Ser-Cys connected via a (Gly-Gly-Gly-Ser)(3)-linker (designated as G3-(G(3)S)(3)C) would further improve the contrast of imaging using Tc-99m-labeled derivatives of G3. The labeling of the new variants of G3 provided a radiochemical yield of over 95%. Labeled G3 variants bound specifically to human HER2-expressing cancer cell lines with affinities in the range of 1.9-5 nM. Biodistribution of Tc-99mTc-G3-G(3)C, Tc-99mTc-G3-(G(3)S)(3)C, and Tc-99mTc-G3-E3C in mice was compared with the biodistribution of Tc-99mTc-(HE)(3)-G3. It was found that the novel variants provide specific accumulation in HER2-expressing human xenografts and enable discrimination between tumors with high and low HER2 expression. However, Tc-99mTc-(HE)(3)-G3 provided better contrast between tumors and the most frequent metastatic sites of HER2-expressing cancers and is therefore more suitable for clinical applications.
Acquired resistance to chemotherapy and radiation therapy is one of the major obstacles decreasing efficiency of treatment of the oncologic diseases. In this study, on the two cell lines (ovarian ...carcinoma SKOV-3 and neuroblastoma NGP-127), we modeled acquired resistance to five target anticancer drugs. The cells were grown on gradually increasing concentrations of the clinically relevant tyrosine kinase inhibitors (TKIs) Sorafenib, Pazopanib and Sunitinib, and rapalogs Everolimus and Temsirolimus, for 20 weeks. After 20 weeks of culturing, the half-inhibitory concentrations (IC
) increased by 25 - 186% for the particular combinations of the drugs and cell types. We next subjected cells to 10 Gy irradiation, a dose frequently used in clinical radiation therapy. For the SKOV-3, but not NGP-127 cells, for the TKIs Sorafenib, Pazopanib and Sunitinib, we noticed statistically significant increase in capacity to repair radiation-induced DNA double strand breaks compared to naïve control cells not previously treated with TKIs. These peculiarities were linked with the increased activation of ATM DNA repair pathway in the TKI-treated SKOV-3, but not NGP-127 cells. Our results provide a new cell culture model for studying anti-cancer therapy efficiency and evidence that there may be a tissue-specific radioresistance emerging as a side effect of treatment with TKIs.
Purpose of Review
The efficacy of direct oral anticoagulants (DOACs) in antiphospholipid syndrome (APS) is discussed. Results from randomized controlled trials are available. It has been stated that ...a history of arterial thrombosis and triple positivity was associated with a higher risk of thrombosis in APS patients treated with DOACs. However, their efficacy in non-high-risk APS patients with isolated venous manifestations is unsolved. Therefore, we performed a sub-group analysis of a previously published meta-analysis after the exclusion of patients with triple positivity and those with history of arterial or small vessel thrombosis.
Recent Findings
We identified 290 APS patients with previous isolated venous event treated with DOACs; among them, 25 (8.6%) patients experienced a recurrent thrombosis in comparison to 16% in the original cohort.
Summary
We found that the rate of recurrent thrombosis is lower in APS patients with isolated venous manifestations than in overall APS patients including high-risk patients. Research about DOAC use in non-high-risk APS patients needs to be continued.
Whether voluntary or enforced, increasing patterns of migration have significantly impacted schools by making them linguistically, culturally, religiously and ethnically more diverse than ever ...before. This increasing diversity requires school leaders to put in place mechanisms to ensure equity of participation for migration background students. Dimmock and Walker (2005) believe that school leaders need to play a vital role in promoting and sustaining an environment that embraces diversity and, by association, contributes to solving the macro problems of society. To accomplish this emerging role, there is a need for ‘new approaches to educational leadership in which leaders exhibit culturally responsive organisational practices, behaviours and competencies’ (Madhlangobe and Gordon, 2012: p. 177). This is all well and good in theory, but the current and historical context in which school leaders operate, together with the training and supports that are provided, influences, to a significant extent, how culturally responsive leadership can operate in practice. This study, which is part of a European Commission Erasmus+ funded project entitled Supporting Culturally Responsive Leadership and Evaluation in Schools (CReLES), examines these assumptions by mapping out the factors and actors that can hinder and facilitate the flourishing of such practices in four European countries, Austria, Ireland, Russia and Spain.
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