Nanoparticles of biodegradable polymers for delivery of diagnostic/therapeutic agents: Their potential application in brain cancer therapy

Master'sMASTER OF SCIENC

Feasibility of flattening filter free beams for hippocampal avoidance whole-brain radiotherapy: a dosimetric and radiobiological analysis

ObjectivesThe purpose of this study is to evaluate the potential of the flattening filter free (FFF) mode of a linear accelerator for patients with hippocampal avoidance whole-brain radiotherapy (HA-WBRT) by comparison with flattened beams (FF) technique in the application of volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) using dosimetric and radiobiological indexes based on the volume of hippocampus and target.Methods2 VMAT- and 2 IMRT- plans were optimized in Eclipse planning system with 2 different delivery modes (6 MV standard vs. 6 MV FFF) for each of 25 patients. Dose distributions of the target and organs at risk (OARs), normal tissue complication probability (NTCP) of the hippocampus, monitor units, treatment time and quality assurance results were evaluated to compare the normal and FFF beam characteristics by Wilcoxon matched-pair signed-rank test with a significance level of 0.05.ResultsVMAT-FFF provided the significantly best homogeneity and conformity of the target, delivered the lowest dose to hippocampus and the other OARs, and led to the lowest NTCP of the hippocampus among all modalities, which has the potential to alleviate neurocognitive decline after WBRT. IMRT-FFF reduced the dose to the lens with similar dose distributions of the target compared with IMRT-FF, whereas the lower dose to the hippocampus was achieved using the conventional beams. The monitor units were obviously increased by 19.2% for VMAT and 33.8% for IMRT, when FFF beams w ere used. The removal of flattening filter for IMRT resulted in a 26% reduction in treatment time, but VMAT had the similar treatment time for the two modes owing to the limitation of gantry rotation speed. Gamma analysis showed an excellent agreement for all plans at 3%/2 mm, and no statistical differences were found between FF and FFF.ConclusionIn conclusion, this study suggests that FFF mode is feasible and advantageous in HA-WBRT and VMAT-FFF is the optimal solution in terms of dose distribution of the target, OARs sparing, NTCP of the hippocampus and delivery efficiency compared to the other three techniques. Additionally, the advantages of the FFF technique for VMAT are more prominent in cases with small hippocampal volumes

Convergent activation of Ca2+ permeability in two-pore channel 2 through distinct molecular routes

TPC2 is a pathophysiologically relevant lysosomal ion channel that is activated directly by the phosphoinositide PI(3,5)P2 and indirectly by the calcium ion (Ca2+)-mobilizing molecule NAADP through accessory proteins that associate with the channel. TPC2 toggles between PI(3,5)P2-induced, sodium ion (Na+)-selective and NAADP-induced, Ca2+-permeable states in response to these cues. To address the molecular basis of polymodal gating and ion-selectivity switching, we investigated the mechanism by which NAADP and its synthetic functional agonist, TPC2-A1-N, induced Ca2+ release through TPC2 in human cells. Whereas NAADP required the NAADP-binding proteins JPT2 and LSM12 to evoke endogenous calcium ion signals, TPC2-A1-N did not. Residues in TPC2 that bind to PI(3,5)P2 were required for channel activation by NAADP but not for activation by TPC2-A1-N. The cryptic voltage-sensing region of TPC2 was required for the actions of TPC2-A1-N and PI(3,5)P2 but not for those of NAADP. These data mechanistically distinguish natural and synthetic agonist action at TPC2 despite convergent effects on Ca2+ permeability and delineate a route for pharmacologically correcting impaired NAADP-evoked Ca2+ signals

Quantifying the impact of grain for green program on ecosystem service management: a case study of Exibei region, China

Evaluating the impact of an ecological restoration program on ecosystem services is crucial, given the role of such a program in boosting sustainable ecosystem management. This study examines the impact of one of the large-scale ecological restoration programs in China, the Grain for Green Program (GGP), on ecosystem service management in the Exibei region of China. This region is studied, as it is a key source water area with rich biodiversity and has been experiencing GGP for 20 years. To achieve the stated goal the changes of land use and ecosystem services value (ESV) and the ecosystem services scarcity value (ESSV) in the Exibei region were quantified and assessed based on remote sensing images from 1990, 1995, 2000, 2005, 2010, 2015 and field survey data. The results indicated that the expansion of construction land and the increase of water body were the dominant land use changes throughout the study period. Farmland, forestland and grassland decreased by 2.61%, 0.47% and 1.41% after the GGP, respectively. The ESV of the entire Exibei region increased slightly in response to land use change during 1990-2015, with an annual loss of 0.08% before the implementation of GGP and an annual growth of 0.03% after the implementation of GGP. Moreover, forestland was the dominant contributor to ESSV after the implementation of the GGP. Its annual growth rate was four times higher than before the commencement of GGP. The results of this study contribute to the protection of the Exibei region ecosystem, and more importantly, the future management of the ecosystem service in the hilly regions of southern China

The immunosuppressive effects and mechanisms of loureirin B on collagen-induced arthritis in rats

IntroductionRheumatoid arthritis (RA) is a common disease mainly affecting joints of the hands and wrists. The discovery of autoantibodies in the serum of patients revealed that RA belonged to the autoimmune diseases and laid a theoretical basis for its immunosuppressive therapy. The pathogenesis of autoimmune diseases mainly involves abnormal activation and proliferation of effector memory T cells, which is closely related to the elevated expression of Kv1.3, a voltage-gated potassium (Kv) channel on the effector memory T cell membrane. Drugs blocking the Kv1.3 channel showed a strong protective effect in RA model animals, suggesting that Kv1.3 is a target for the discovery of specific RA immunosuppressive drugs.MethodsIn the present study, we synthesized LrB and studied the effects of LrB on collagen- induced arthritis (CIA) in rats. The clinical score, paw volume and joint morphology of CIA model rats were compared. The percentage of CD3+, CD4+ and CD8+ T cells in rat peripheral blood mononuclear and spleen were analyzed with flow cytometry. The concentrations of inflammatory cytokines interleukin (IL)-1b, IL-2, IL-4, IL-6, IL-10 and IL-17 in the serum of CIA rats were analyzed with enzyme-linked immunosorbent assay. The IL-1b and IL-6 expression in joints and the Kv1.3 expression in peripheral blood mononuclear cells (PBMCs) were quantified by qPCR. To further study the mechanisms of immunosuppressive effects of LrB, western blot and immunofluorescence were utilized to study the expression of Kv1.3 and Nuclear Factor of Activated T Cells 1 (NFAT1) in two cell models - Jurkat T cell line and extracted PBMCs.ResultsLrB effectively reduced the clinical score and relieved joint swelling. LrB could also decrease the percentage of CD4+ T cells, while increase the percentage of CD8+ T cells in peripheral blood mononuclear and spleen of rats with CIA. The concentrations of inflammatory cytokines interleukin (IL)-1b, IL-2, IL-6, IL-10 and IL-17 in the serum of CIA rats were significantly reduced by LrB. The results of qPCR showed that Kv1.3 mRNA in the PBMCs of CIA rats was significantly higher than that of the control and significantly decreased in the LrB treatment groups. In addition, we confirmed in cell models that LrB significantly decreased Kv1.3 protein on the cell membrane and inhibited the activation of Nuclear Factor of Activated T Cells 1 (NFAT1) with immune stimulus.ConclusionIn summary, this study revealed that LrB could block NFAT1 activation and reduce Kv1.3 expression in activated T cells, thus inhibiting the proliferation of lymphocytes and the release of inflammatory cytokines, thereby effectively weakening the autoimmune responses in CIA rats. The effects of immunosuppression due to LrB revealed its potential medicinal value in the treatment of RA

Integrating supply and demand factors for estimating ecosystem services scarcity value and its response to urbanization in typical mountainous and hilly regions of south China

10.1016/j.scitotenv.2021.149032Science of The Total Environment796149032-149032United State

Ecosystem Service Response to Human Disturbance in the Yangtze River Economic Belt: A Case of Western Hunan, China

Ecosystem conservation is one of the core elements of sustainable development. Studying the relationship between human disturbance and the ecosystem service value (ESV) change is an urgent need for the future. The Yangtze River Economic Belt is one of the key economic strategies implemented by the Chinese government and is also a demonstration zone for ecological conservation. Western Hunan is an important ecological barrier in the Yangtze basin where different ethnic groups live together and various cultures coexist. In this study, using land-use data and spatial analysis modeling, the changes in the ecosystem service value at five topographic gradients were evaluated. Human disturbance and its spatial correlation with the ecosystem service value from 1990 to 2015 were also investigated. The results demonstrated the following: (1) the proportional area of forestland and grassland increased as the topographic gradient index increased and other types of land-use gradually decreased; (2) The ecosystem service value at middle gradients increased over the study period; but ESV of the lowest topographic gradient showed a significant decline and a substantial decrease, as well as a terrain index under 0.7970; (3) The spatial analysis of human disturbance showed that more than 90% of intense human disturbance was distributed in the area of the lowest topographic gradient where topographic features were low-altitude and low-slope, and little human disturbance was scattered at other gradients; (4) There was a significant spatial aggregation distribution between the ecosystem service value and human disturbance in western Hunan, the high disturbance and low ESV aggregation was mainly distributed in Loudi City, the area east of Shaoyang City and Zhangjiajie City all belonged to the lowest topographic gradient, and the low–high and high–high aggregations were mainly distributed in Huaihua City and Xiangxi Tujia and Miao Autonomous Prefecture. Population density and gross domestic product were the main driving factors, while topography was the main ecological factor. This study could provide additional spatial information and theoretical guidance for ecosystem service management for sustainable development in western Hunan, China