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

The stress and vascular catastrophes in newborn rats: mechanisms preceding and accompanying the brain hemorrhages

In this study, we analyzed the time-depended scenario of stress response cascade preceding and accompanying brain hemorrhages in newborn rats using an interdisciplinary approach based on: a morphological analysis of brain tissues, coherent-domain optical technologies for visualization of the cerebral blood flow, monitoring of the cerebral oxygenation and the deformability of red blood cells (RBCs). Using a model of stress-induced brain hemorrhages (sound stress, 120 dB, 370 Hz), we studied changes in neonatal brain 2, 4, 6, 8 h after stress (the pre-hemorrhage, latent period) and 24 h after stress (the post-hemorrhage period). We found that latent period of brain hemorrhages is accompanied by gradual pathological changes in systemic, metabolic, and cellular levels of stress. The incidence of brain hemorrhages is characterized by a progression of these changes and the irreversible cell death in the brain areas involved in higher mental functions. These processes are realized via a time-depended reduction of cerebral venous blood flow and oxygenation that was accompanied by an increase in RBCs deformability. The significant depletion of the molecular layer of the prefrontal cortex and the pyramidal neurons, which are crucial for associative learning and attention, is developed as a consequence of homeostasis imbalance. Thus, stress-induced processes preceding and accompanying brain hemorrhages in neonatal period contribute to serious injuries of the brain blood circulation, cerebral metabolic activity and structural elements of cognitive function. These results are an informative platform for further studies of mechanisms underlying stress-induced brain hemorrhages during the first days of life that will improve the future generation's health

Recent Advances in Oncolytic Virotherapy and Immunotherapy for Glioblastoma: A Glimmer of Hope in the Search for an Effective Therapy?

To date, no targeted drugs, antibodies or combinations of chemotherapeutics have been demonstrated to be more efficient than temozolomide, or to increase efficacy of standard therapy (surgery, radiotherapy, temozolomide, steroid dexamethasone). According to recent phase III trials, standard therapy may ensure a median overall survival of up to 18–20 months for adult patients with newly diagnosed glioblastoma. These data explain a failure of positive non-controlled phase II trials to predict positive phase III trials and should result in revision of the landmark Stupp trial as a historical control for median overall survival in non-controlled trials. A high rate of failures in clinical trials and a lack of effective chemotherapy on the horizon fostered the development of conceptually distinct therapeutic approaches: dendritic cell/peptide immunotherapy, chimeric antigen receptor (CAR) T-cell therapy and oncolytic virotherapy. Recent early phase trials with the recombinant adenovirus DNX-2401 (Ad5-delta24-RGD), polio-rhinovirus chimera (PVSRIPO), parvovirus H-1 (ParvOryx), Toca 511 retroviral vector with 5-fluorocytosine, heat shock protein-peptide complex-96 (HSPPC-96) and dendritic cell vaccines, including DCVax-L vaccine, demonstrated that subsets of patients with glioblastoma/glioma may benefit from oncolytic virotherapy/immunotherapy (>3 years of survival after treatment). However, large controlled trials are required to prove efficacy of next-generation immunotherapeutics and oncolytic vectors

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