Разработка алгоритмического и программного обеспечения для дозиметрического планирования курсов лучевой нейтронной терапии онкологических заболеваний

Выпускная квалификационная работа направлена на разработку и программную реализацию алгоритма, предназначенного для дозиметрического планирования лучевой нейтронной терапии онкологических заболеваний. В результате исследования были изучены алгоритмы расчета поглощенных доз нейтронов. Была разработана программа на основе изученных алгоритмов. Для визуализации распределения доз нейтронов была построена топографическая карта.The final qualification work is aimed at the development and software implementation of an algorithm designed for dosimetric planning of radiation neutron cancer therapy. As a result of the study, the algorithms for calculating the absorbed doses of neutrons were studied. The program was developed based on the studied algorithms. A topographic map was built to visualize the distribution of neutron doses

Therapeutic and Adverse Effects of a Non-Steroidal Glucocorticoid Receptor Ligand in a Mouse Model of Multiple Sclerosis

-methyl-ethylammonium chloride (CpdA), a dissociating non-steroidal GR ligand, in the context of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).. Administration of high-dose CpdA to mice was lethal while treatment of EAE with low to intermediate amounts of CpdA dissolved in water significantly ameliorated the disease. The beneficial effect of CpdA required expression of the GR in T cells and was achieved by down regulating LFA-1 and CD44 on peripheral Th cells and by repressing IL-17 production.. Hence, non-steroidal GR ligands require careful analysis prior to their translation into new therapeutic concepts

Vitamin D deficiency decreases survival of bacterial meningoencephalitis in mice

Background Meningoencephalitis caused by Escherichia coli is associated with high rates of mortality and risk of neurological sequelae in newborns and infants and in older or immunocompromised adults. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D. Methods In vivo, we studied the effects of vitamin D3 on survival and the host’s immune response in experimental bacterial meningoencephalitis in mice after intracerebral E. coli infection. To produce different systemic vitamin D3 concentrations, mice received a low, standard, or high dietary vitamin D3 supplementation. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration was assessed by histological scores, and tissue cytokine or chemokine concentrations were measured. Results Mice fed a diet with low vitamin D3 concentration died earlier than control animals after intracerebral infection. Vitamin D deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in blood, spleen, or brain homogenates. The release of proinflammatory interleukin (IL)-6 was decreased and the release of anti-inflammatory IL-10 was increased in mice fed a diet with high vitamin D3 supplementation. Conclusion Our observations suggest a detrimental role of vitamin D deficiency in bacterial central nervous system infections. Vitamin D may exert immune regulatory functions

Carcinoma cells misuse the host tissue damage response to invade the brain

The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis

T Cell-Dependence of Lassa Fever Pathogenesis

Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development

History of Microglia

The term 'microglia' was first introduced into the scientific literature a century ago. The various eras of microglial research have been defined not only by the number of reports subsequently generated but, more critically, also by the concepts that have shaped our present-day views and understanding of microglia. Key methods, technologies, and models, as well as seminal discoveries made possible through their deployment have enabled breakthroughs, and now pave the way for lines of investigation that could not have been anticipated even a decade ago. Advances in our understanding of the microglial origin, forms, and functions have relied fundamentally on parallel developments in immunology. As the 'neuro-immune' cells of the brain, microglia are now under the spotlight in various disciplines. This chapter surveys the gradual processes and precipitous events that helped form ideas concerning the developmental origin of microglia and their roles in health and disease. It first covers the dawning phase during which the early pioneers of microglial research discovered cellular entities and already assigned functions to them. Following a recess period, the 1960s brought about a renaissance of active interest, with the development of tools and models-and fundamental notions on microglial contributions to central nervous system (CNS) pathologies. These seminal efforts laid the foundation for the awakening of a sweeping research era beginning in the 1980s and spurred on by a blast of immunological discoveries. Finally, this chapter stresses the advancements in molecular, genetic, and imaging approaches to the study of microglia with the turn of the millennium, enabling insights into virtually all facets of microglial physiology. Moving forward, it is clear that the future holds substantial promise for further discoveries. The next epoch in the history of microglial research has just begun