Complexes of IL-2 and JES6-1 mAb (IL-2/JES6) provide strong sustained IL-2 signal selective for CD25
cells and thus they potently expand T
cells. IL-2/JES6 are effective in the treatment of ...autoimmune diseases and in protecting against rejection of pancreatic islet allografts. However, we found that IL-2/JES6 also dramatically increase sensitivity to LPS-mediated shock in C57BL/6 mice. We demonstrate here that this phenomenon is dependent on endogenous IFN-γ and T cells, as it is not manifested in IFN-γ deficient and nude mice, respectively. Administration of IL-2/JES6 leads to the emergence of CD25
Foxp3
CD4
and CD25
Foxp3
CD8
T cells producing IFN-γ in various organs, particularly in the liver. IL-2/JES6 also increase counts of CD11b
CD14
cells in the blood and the spleen with higher sensitivity to LPS in terms of TNF-α production and induce expression of CD25 in these cells. These findings indicate safety issue for potential use of IL-2/JES6 or similar IL-2-like immunotherapeutics.
Purpose
S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) is routinely used at concentrations of 0.10 μM and 0.10 mM to specifically inhibit transport of nucleosides mediated by equilibrative nucleoside ...transporters 1 (ENT1) and 2 (ENT2), respectively. We recently showed that NBMPR (0.10 mM) might also inhibit placental active efflux of
3
Hzidovudine and
3
Htenofovir disoproxil fumarate. Here we test the hypothesis that NBMPR abolishes the activity of P-glycoprotein (ABCB1) and/or breast cancer resistance protein (ABCG2).
Methods
We performed accumulation assays with Hoechst 33342 (a model dual substrate of ABCB1 and ABCG2) and bi-directional transport studies with the ABCG2 substrate
3
Hglyburide in transduced MDCKII cells, accumulation studies in choriocarcinoma-derived BeWo cells, and
in situ
dual perfusions of rat term placenta with glyburide.
Results
NBMPR inhibited Hoechst 33342 accumulation in MDCKII-ABCG2 cells (IC
50
= 53 μM) but not in MDCKII-ABCB1 and MDCKII-parental cells. NBMPR (0.10 mM) also inhibited bi-directional
3
Hglyburide transport across monolayers of MDCKII-ABCG2 cells and blocked ABCG2-mediated
3
Hglyburide efflux by rat term placenta
in situ
.
Conclusion
NBMPR at a concentration of 0.10 mM abolishes ABCG2 activity. Researchers using NBMPR to evaluate the effect of ENTs on pharmacokinetics must therefore interpret their results carefully if studying compounds that are substrates of both ENTs and ABCG2.
Magnetite and magnetite/ceria composites prepared by chemical procedures in various mutual ratios were exposed to calcination treatment in a temperature interval between 473 K and 1073 K. A ...combination of several experimental methods has provided detailed structural, phase, and magnetic properties utilisable for selection of optimal compositions and calcination conditions from the viewpoint of degradation ability tested using parathion methyl and paraoxon. It was shown that the ceria content, selected between 5 wt% and 50 wt%, influences magnetic properties. Its optimal amount was determined to be above 20 wt% and the calcination temperature of 773 K when the highest rate constant, slightly above 0.06 min−1, was obtained for parathion methyl in acetonitrile using a degradation test.
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•The study is devoted to magnetically separable sorbents based on iron and cerium oxides.•Sorbents of five compositions are calcined at different temperatures and subjected to structural and physical analysis.•Degradation sensitivity is tested in anhydrous and aqueous media.•The optimal compositions and calcination temperatures are determined with regard to degradation efficiency.
We present a familial hereditary macular dystrophy, resembling North Carolina Macular Dystrophy. In members of a family, we describe the development of diagnostic-therapeutic approaches and their ...impact on the prognosis of those whose vision was affected.
The macular dystrophy of varying degrees of severity was diagnosed in 3 consecutive generations in different family members, both men and women. Modern therapeutic tools were used for the diagnostics. In one patient of the youngest generation, the development of secondary choroidal neovascularization (CNV) was identified and treated with an anti-VEGF (vascular endothelial growth factor) agent. DNA was isolated from venous blood and genome sequencing was performed in a proband.
We analysed the data of 13 members of one family of three consecutive generations. Six of them had macular dystrophy. The first were two of three siblings, a woman (73 years old) and a man (67). The offspring of the afflicted man, a female (36) and a male (80), had maculopathy. The first daughter of the woman (12) revealed findings of maculopathy but with normal electrical activity of the retina. The second girl (18), developed secondary CNV which responded well to intravitreal anti-VEGF treatment. Genetic analysis excluded mutations previously reported to be pathogenic for NCMD.
If there is a maculopathy of unclear etiology in younger patients or in patients with unclear development or appearance, it is advisable to focus carefully on the family history and trace the occurrence of impaired vision in other family members.
The scanning electron microscopy, X-ray diffraction, positron annihilation spectroscopy, Mössbauer spectrometry, and measurements of magnetic characteristics by vibrating sample magnetometer ...complemented by theoretical simulations are applied in the present investigations of the Fe-Al-Co alloys with 25 at% Al and Co substituting Fe in amount of 15 at% or 25 at%. The alloys prepared by slightly different technologies resulting in different structural morphologies are subjected to thermal treatment followed by slow cooling and water cooling. It is shown that the alloy with lower Co content and the initial A2 structure is more sensitive to the thermal treatments from the viewpoints of changes in morphology, defects concentration and magnetic properties in comparison to the other one with the initial B2 structure. This is reflected almost in all experimentally obtained results.
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•Fe-25 at.% Al and Co substituting Fe alloys are prepared and thermally treated.•Morphology, phase, defect, and magnetic studies are concentrated to region of phase separation.•Hysteresis loops are simulated by the Jiles-Atherton model extended for anisotropic materials.•Theoretical calculations of lifetimes determine type of defects.•Vacancies, vacancy clusters and/or triple defects are discussed from the structural and compositional viewpoint.
The objective of this study was to evaluate the efficacy of diabetic macular edema (DME) therapy using subthreshold micropulse laser (SMPL) with a wavelength of 577 nm during a long-term monitoring ...period of 5 years.
The cohort included the total number of 52 eyes of 34 patients with DME. All underwent the standard laser treatment for the diabetic retinopathy outside the macula and DME treatment with SMPL. Subsequent check-ups were followed every 3 months in the first year of treatment, and every 4 to 6 months in the following years. The treatment was combined neither with focal macular laser nor with anti-VEGF therapy.
The mean central retinal thickness (CRT) was 345.9 µm SD 122.6 µm at the beginning of the monitoring. At the end of the follow-up period five years after treatment it was 256.4 µm SD 98.4 µm. The mean CRT decreased by 89.5 µm SD 153.6 µm during 5 years. At the beginning of the monitoring, before treatment with SMPL, the best corrected visual acuity (BCVA) was 70.0, SD 10.1 ETDRS letters. One year after therapy, BCVA was 72, SD 10.0 letters, two years later it was 71.4, SD 10.4 letters and decreased to 66.9, SD 12.1 letters after 5 years. The mean BCVA decreased by merely 3.1, SD 10.9 letters during 5 years.
Based on our long-term observations, the DME treatment with SMPL appears to be an effective method for reducing DME and protecting BCVA against rapid worsening.
We investigate the state complexity of some operations on binary regular languages. In particular, we consider the concatenation of languages represented by deterministic finite automata, and the ...reversal and complementation of languages represented by nondeterministic finite automata. We prove that the upper bounds on the state complexity of these operations, which were known to be tight for larger alphabets, are tight also for binary alphabets.
Psoriasis is a chronic, immune-mediated, inflammatory disease primarily affecting the skin. It is currently coming to light that patients with psoriasis have disrupted intestinal barrier and often ...suffer from comorbidities associated with the gastrointestinal tract. Moreover, there is growing evidence of both cutaneous and intestinal paradoxical reactions during biologic treatment in patients with psoriasis. This review focuses on barrier defects and changes in immune responses in patients with psoriasis, which play an important role in the development of the disease but are also influenced by modern biological treatments targeting IL-17 and TNFα cytokines. Here, we highlight the relationship between the gut–skin axis, microbiota, psoriasis treatment, and the incidence of paradoxical reactions, such as inflammatory bowel disease in patients with psoriasis. A better understanding of the interconnection of these mechanisms could lead to a more personalized therapy and lower the incidence of treatment side effects, thereby improving the quality of life of the affected patients.
Background. Tumor necrosis factor-alpha (TNF-α) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not ...respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. Methods. We analyzed the power of serum biomarkers to predict the failure of anti-TNF-α. We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF-α, CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor-β1 (TGF-β1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). Results. We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF-β1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF-β1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. Conclusions. The TGF-β1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF-β) are not markedly influenced by the treatment and that anti-TNF-α therapy decreases MMP-9 without influencing the treatment outcome.
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