Fatty acid acylated Fab-fragments of antibodies to neurospecific proteins as carriers for neuroleptic targeted delivery in brain

AbstractA method for targeted delivery of neuroleptics from blood in brain based on using Fab-fragments of antibodies to antigens of brain glia cells (acid gliofibrillar antigen and α2-glycoprotein) is suggested. The essence of the technique is that the molecule of neuroleptic (trifluoperazine) is conjugated with Fab-fragments of these antibodies. The conjugate thus obtained is modified by stearoylchloride in the system of Aerosol OT reversed micelles in octane. The study of the distribution of 125I-labelled conjugates in the rat organism after intracordial introduction is performed. On the contrary to the nonmodified conjugates and conjugate, containing fatty acylated Fab-fragments of antibodies, nonspecific to the rat brain, the conjugate of trifluoperazine with stearoylated Fab-fragments of antibodies to neurospecific antigens accumulate in brain tissues. The drastic increase of the neuroleptic activity of trifluoperazine resulting from its coupling with stearoylated Fab-fragments of antiglial antibodies is observed

Association between malnutrition and leucopenia in patients with osteosarcoma

Background and aimLeucopenia (LP) greatly limits the efficacy of chemotherapy in osteosarcoma patients. This study aimed to evaluate the nutritional status of osteosarcoma patients before chemotherapy, assess the risk of LP during the perichemotherapy period, and explore the association between malnutrition and LP.Materials and methodsThis study retrospectively analyzed osteosarcoma patients treated in the Tianjin Medical University Cancer Institute and Hospital, China, between January 2009 and December 2020 according to the inclusion and exclusion criteria. Malnutrition in adolescents (5 to 19 years old) and adults (≥20 years old) was diagnosed using WHO AnthroPlus software (version 1.0.4) and Global Leadership initiative on Malnutrition (GLIM), respectively. According to the diagnostic criteria of LP in CTCAE 5.0, patients were divided into the LP group and the non-LP group.ResultsA total of 245 osteosarcoma patients were included. The incidence of malnutrition was 49.0%, and the incidence of LP was 51.8%. The incidence of malnutrition in adolescent patients was 53.1%, and their incidence of LP was 55.2%; the incidence of malnutrition in adult patients was 43.1%, and their incidence of LP was 47.1%. Logistic regression analysis showed that malnutrition before chemotherapy was an independent risk factor for the occurrence of LP after chemotherapy (OR = 6.85, 95% CI = 2.16-25.43; and OR = 35.03, 95% CI = 6.98-238.46 in mildly and severely malnourished young patients; OR = 6.06; 95% CI = 1.43-30.16; and OR = 38.09, 95% CI = 7.23-285.78 in mildly and severely malnourished adult patients, respectively). The results showed that age and nutritional status had a joint effect on the occurrence of LP.ConclusionThe nutrition status of osteosarcoma patients before chemotherapy is significantly correlated with the occurrence and severity of LP during peri-chemotherapy period. During osteosarcoma chemotherapy, necessary nutritional support should be given to patients of different ages to correct their malnutrition status in a timely manner, ultimately improving the efficacy of chemotherapy and the prognosis of patients

New Experimental Model of Brain Tumors in Brains of Adult Immunocompetent Rats

Aims: Xenograft models, namely heterotransplantation of human cancer cells or tumor biopsies into immunodeficient rodents are the major preclinical approach for the development of novel cancer therapeutics. However, in these models the animals must be used only after the severe systemic immune suppression in order to ensure graft survival. Thus, additional new human brain tumor models without immune suppression of the recipient rodent may be required. Place and Duration of Study: Laboratory of Immunochemistry, V.P. Serbsky National Research Centre for Social and Forensic Psychiatry and Department of Nanobiotechnology, N.I. Pirogov Russian State Medical University and Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics between June 2009 and July 2010. Methodology: Brain tumor modeling was performed by intracerebral stereotactic implantation of cells to the healthy adult rats without any artificial immunodepression. Cells were implanted to the striatum region of ketamine-anesthetized rats at specific coordinates according to Swanson's rat brain atlas. Tumor growth was monitored weekly via registration of neurological signs and in vivo Bruker MRI system. Results: On the 21st day after implantation of C6 glioma, U251 or 293_CHI3L1 cells severe neurological deficit appeared in rats. Huge intracerebral tumors were found in each animal under investigation while no tumor growth was observed for at least 8 weeks in rats injected with empty vector-transfected 293 cells. Tumors contained the dense superficial cell layer and prominent lobules with central newly ingrowing blood vessels. Histological assay revealed displacement of median cerebral structures and hydrocephalus in contralateral hemisphere. All tumors were surrounded by numerous GFAP-positive reactive astrocytes. Conclusion: Positive results with transplantation of 293_CHI3L1 cells into adult rat brains without any immunosupression show the validity of this animal model. In all experiments such implantations provoked malignant tumor formation while there were no visible tumors in control rats. We believe this to be the first animal model of human brain tumor that displays the possibility to study various biologic features of and host therapeutic response to brain tumor in an immunocompetent host

Systemic and local immunosuppression in glioblastoma and its prognostic significance

The effectiveness of tumor therapy, especially immunotherapy and oncolytic virotherapy, critically depends on the activity of the host immune cells. However, various local and systemic mechanisms of immunosuppression operate in cancer patients. Tumor-associated immunosuppression involves deregulation of many components of immunity, including a decrease in the number of T lymphocytes (lymphopenia), an increase in the levels or ratios of circulating and tumor-infiltrating immunosuppressive subsets [e.g., macrophages, microglia, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)], as well as defective functions of subsets of antigen-presenting, helper and effector immune cell due to altered expression of various soluble and membrane proteins (receptors, costimulatory molecules, and cytokines). In this review, we specifically focus on data from patients with glioblastoma/glioma before standard chemoradiotherapy. We discuss glioblastoma-related immunosuppression at baseline and the prognostic significance of different subsets of circulating and tumor-infiltrating immune cells (lymphocytes, CD4+ and CD8+ T cells, Tregs, natural killer (NK) cells, neutrophils, macrophages, MDSCs, and dendritic cells), including neutrophil-to-lymphocyte ratio (NLR), focus on the immune landscape and prognostic significance of isocitrate dehydrogenase (IDH)-mutant gliomas, proneural, classical and mesenchymal molecular subtypes, and highlight the features of immune surveillance in the brain. All attempts to identify a reliable prognostic immune marker in glioblastoma tissue have led to contradictory results, which can be explained, among other things, by the unprecedented level of spatial heterogeneity of the immune infiltrate and the significant phenotypic diversity and (dys)functional states of immune subpopulations. High NLR is one of the most repeatedly confirmed independent prognostic factors for shorter overall survival in patients with glioblastoma and carcinoma, and its combination with other markers of the immune response or systemic inflammation significantly improves the accuracy of prediction; however, more prospective studies are needed to confirm the prognostic/predictive power of NLR. We call for the inclusion of dynamic assessment of NLR and other blood inflammatory markers (e.g., absolute/total lymphocyte count, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, and systemic immune response index) in all neuro-oncology studies for rigorous evaluation and comparison of their individual and combinatorial prognostic/predictive significance and relative superiority

SCIENCEDOMAIN international Phosphate Transfer Enzymes as the Nuclear Spin Selective Nanoreactors

ABSTRACT Magnesium isotope effect manifests itself in the enzymatic ATP synthesis at relatively high concentrations of Mg 2+ ions. At low concentrations, there is no isotope effect at all so the nucleophylic mechanism of the ATP synthesis dominates. Concentration of Mg 2+ ions exceeds intracellular one by 50-100 times, a huge isotope effect appears which means that the new ionradical mechanism of ATP synthesis is switched on. This provides an additional and considerable source of ATP. This mechanism implies the electron transfer from Mg P nuclei and by Zeeman interaction. Due to these two interactions, the yield of ATP is a function of nuclear magnetic moment and magnetic field. Electron transfer reaction does not depend on m but strongly depends on n. It is exoergic and energy allowed at (0 ≤ n << ∞) for the deprotonated pyrophosphate anions and at (0 ≤ n < 4) for the protonated ones; for other values of n, the reaction is energy deficient and forbidden. The boundary between exoergic and endoergic regimes corresponds to the trigger magnitude n* (n* = 4 for protonated anions and 6 < n* << ∞ for deprotonated ones). These results explain why the ATP synthesis occurs only in some special nanodevices, i.e. within a very few molecular enzymatic machines, but not in water (n = ∞). Research Article International Research Journal of Pure & Applied Chemistry, 1(1): 1-15, 2011 2 Biomedical and biotechnological consequences of the ion-radical enzymatic ATP synthesis as well as its protein (catalytic site) nanotopology background are under discussion

Low-Frequency Dynamic Magnetic Fields Decrease Cellular Uptake of Magnetic Nanoparticles

Magnetic nanoparticles have gained attention as a potential structure for therapy and diagnosing oncological diseases. The key property of the magnetic nanoparticles is the ability to respond to an external magnetic field. It is known that magnetofection causes an increase in the cellular uptake of RNA and DNA in complexes with magnetic nanoparticles in the presence of a permanent magnetic field. However, the influence of a dynamic magnetic field on the internalization of MNPs is not clear. In this work, we propose the idea that applying external low-frequency dynamic magnetic fields may decrease the cellular uptake, such as macrophages and malignant neuroblastoma. Using fluorescence microscopy and atomic emission spectroscopy, we found that oscillating magnetic fields decreased the cellular uptake of magnetic nanoparticles compared to untreated cells by up to 46%. In SH-SY5Y tumor cells and macrophage RAW264.7 cells, the absolute values of Fe per cell differed by 0.10 pg/cell and 0.33 pg/cell between treated and untreated cells, respectively. These results can be applied in the control of the cellular uptake in different areas of biomedicine