Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy.

In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

[Concentrations and pollution assessment of mercury in farmland soil of Xinqiao Mining Area of Tongling, Anhui, China.] / é“œé™µæ–°æ¡¥çŸ¿åŒºå‘¨è¾¹å†œç”°åœŸå£¤æ±žå«é‡åˆ†å¸ƒç‰¹å¾åŠå ¶æ±¡æŸ“è¯„ä»·.

To investigate the effects of mining activities on mercury (Hg) enrichment in farmland soil, soil samples were collected from four villages (Xinjian Village, Yehu Village, Xinhu Village and Hucheng Village) in the vicinity of Xinqiao Mining Area, Tongling. Hg concentration was measured by atomic fluorescence spectrophotometer. The geo-accumulation index was used to evaluate the Hg pollution level of the soils. The results showed that average concentration of total Hg in farmland soil was (0.137±0.078) mg·kg-1, which exceeded the background value of soil Hg in Tongling area. The average concentration of Hg in four villages followed the order of Xinjian Village (0.221 mg·kg-1)>Xinhu Village (0.118 mg·kg-1)>Yehu Village(0.115 mg·kg-1)>Hucheng Village (0.096 mg·kg-1). Moreover, the average Hg concentration of different forms in Xinjian Village followed the order of residue (0.036 mg·kg-1) > alkali soluble (0.031 mg·kg-1) > hydrogen peroxide soluble (0.022 mg·kg-1)> acid soluble (0.020 mg·kg-1)> water soluble (0.012 mg·kg-1). The distance from the mining area was the main factor affecting the distribution of soil Hg concentration in farmlands. The contaminated Xinqiao River, to some degree, had exa-cerbated soil Hg pollution. Soil organic matter affected the accumulation and transformation of total Hg and hydrogen peroxide Hg in the farmlands. The order of the geo-accumulation index followed as Xinjian Village(1.559) >Xinhu Village(0.654) >Yehu Village(0.616) >Hucheng Village(0.356). The pollution level of farmland soil in Xinjian Village belonged to middle level of Hg pollution,which deserved more attention.

Semi-Mechanistic Population Pharmacokinetic Modeling of L-Histidine Disposition and Brain Uptake in Wildtype and Pht1 Null Mice.

PURPOSE: To develop a semi-mechanistic population pharmacokinetic (PK) model to quantitate the disposition kinetics of L-histidine, a peptide-histidine transporter 1 (PHT1) substrate, in the plasma, cerebrospinal fluid and brain parenchyma of wildtype (WT) and Pht1 knockout (KO) mice. METHODS: L-[14C]Hisidine (L-His) was administrated to WT and KO mice via tail vein injection, after which plasma, cerebrospinal fluid (CSF) and brain parenchyma samples were collected. A PK model was developed using non-linear mixed effects modeling (NONMEM). The disposition of L-His between the plasma, brain, and CSF was described by a combination of PHT1-mediated uptake, CSF bulk flow and first-order micro-rate constants. RESULTS: The PK profile of L-His was best described by a four-compartment model. A more rapid uptake of L-His in brain parenchyma was observed in WT mice due to PHT1-mediated uptake, a process characterized by a Michaelis-Menten component (Vmax = 0.051 nmoL/min and Km = 34.94 µM). CONCLUSIONS: A semi-mechanistic population PK model was successfully developed, for the first time, to quantitatively characterize the disposition kinetics of L-His in brain under in vivo conditions. This model may prove a useful tool in predicting the uptake of L-His, and possibly other PHT1 peptide/mimetic substrates, for drug delivery to the brain.

[Spatial evolution of land use intensity and landscape pattern response of the typical basins in Guizhou Province, China]. / è´µå·žå ¸åž‹åå­åœŸåœ°åˆ©ç”¨å¼ºåº¦ç©ºé—´æ¼”å˜åŠæ™¯è§‚æ ¼å±€å“åº”.

Based on the small scale characteristics of the basin, which is a kind of special landform influenced by the human activities obviously in Karst mountain area, the system grid method and the semivariogram model were used to analyze the 15 basins which belonged to three types in the territory of Guizhou Province to reveal the general pattern of spatial evolution of land use intensity and the mutual relationship with the landscape pattern change of the typical basins in the Karst mountainous area of Guizhou Province in 2005, 2010 and 2015. The results showed that the dynamic spatial evolution of land use intensity and response mode of landscape pattern showed obvious difference under the different basin types. In general, with the decrease of economic level of the basins from high to low, the land use intensity decreased in the form of a gradient. At the level of microcosmic evolution, the land use intensity of basins in the center of the cities and counties descended first and then ascended in the form of concentric band around the periphery of the center in the basin, and the spatial evolution trend of this kind of basin exhibited a stable and expanded form. The land use intensity of basins surrounding cities and towns, with a high intensity center, that could either increase or decrease, exhibited a fluctuating spatial evolution trend. The land use intensity of remote basins was basically stable, even slightly weakened and its space evolution was stable and debilitating. Because of the divergence of dominant function of the basins, there were five different modes of response between the change of land use intensity and landscape pattern of basins. During the study period, the spatial evolution of land use intensity of these 3 basin types was driven by natural and human factors. The interaction among various factors formed the typical characteristics of the land use intensity spatial evolution type of different basins.

[Ecological suitability assessment and optimization of urban land expansion space in Guiyang City].

Based on the case study of Guiyang City, the minimum cumulative resistance model integrating construction land source, ecological rigid constraints and ecological function type resistance factor, was built by use of cost-distance analysis of urban spatial expansion resistance value through ArcGIS 9.3 software in this paper. Then, the ecological resistance of city spatial expansion of Guiyang from 2010 was simulated dynamically and the ecological suitability classification of city spatial expansion was assessed. According to the conflict between the newly increased city construction land in 2014 and its ecological suitability, the unreasonable city land spatial allocation was discussed also. The results showed that the ecological suitability zonation and the city expansion in the study area were basically consistent during 2010-2014, but the conflict between the new city construction and its land ecological suitability was more serious. The ecological conflict area accounted for 58.2% of the new city construction sites, 35.4% of which happened in the ecological control area, 13.9% in the limited development area and 8.9% in the prohibition development area. The intensification of ecological land use conflict would impair the ecological service function and ecological safety, so this paper put forward the city spatial expansion optimal path to preserve the ecological land and improve the construction land space pattern of Guiyang City so as to ensure its ecological safety.

Efficient in vitro siRNA delivery and intramuscular gene silencing using PEG-modified PAMAM dendrimers.

Although siRNA techniques have been broadly applied as a tool for gene knockdown, substantial challenges remain in achieving efficient delivery and in vivo efficacy. In particular, the low efficiency of target gene silencing in vivo is a critical limiting step to the clinical application of siRNA therapies. Poly(amidoamine) (PAMAM) dendrimers are widely used as carriers for drug and gene delivery; however, in vivo siRNA delivery by PAMAM dendrimers remains to be carefully investigated. In this study, the effectiveness of G5 and G6 PAMAM dendrimers with 8% of their surface amines conjugated to MPEG-5000 was studied for siRNA delivery in vitro and for intramuscular in vivo delivery in mice. The results from the PEG-modified dendrimers were compared to the results from the parent dendrimers as well as Lipofectamine 2000 and INTERFERin. Both PEG-modifed dendrimers protect the siRNA from being digested by RNase and gave high transfection efficiency for FITC-labeled siRNA in the primary vascular smooth muscle cells (VSMC) and mouse peritoneal macrophages. The PEG-modified dendrimers achieved knockdown of both plasmid (293A cells) and adenovirus-mediated green fluorescence protein (GFP) expression (Cos7 cells) in vitro with efficiency similar to that shown for Lipofectamine 2000. We further demonstrated in vivo that intramuscular delivery of GFP-siRNA using PEG-modified dendrimer significantly suppressed GFP expression in both transiently adenovirus infected C57BL/6 mice and GFP transgenic mice.

[Effects of extreme drought on plant species in Karst area of Guizhou Province, Southwest China].

Based on the investigation data of damaged vegetations in Karst areas of Guizhou Province during the extreme drought in 2010, an investigation was made on the species composition, floristic composition, life form, leaf characteristics, and environmental conditions of drought-damaged plants at six sampling plots. At these plots, there were 31 plant species drought-damaged, among which, Cunninghamia lanceolata, Celastrus orbiculatus, Rapanea neriifolia, Myrsine semiserrata, Cyclobalanopsis glauca, and Cinnamomum glanduliferum damaged most, and the tropical evergreen arbors with mesophyllous, leathery, and simple leaf suffered more seriously. The damaged plants mainly located on the middle or upper part of steep slopes, and on the thin limestone soils originated from horizontal attitude carbonate rocks. The plants in the microhabitats with soil layer < 30 cm and rock-soil were damaged most, accounting for 87.4% and 40.0% of the total, respectively. It was suggested that the temperate deciduous trees with microphyll could be more planted in Karst areas, and that the microhabitat for the afforestation could be in gully and with thicker soil layer and good site condition.

The use of mitochondrial targeting resveratrol liposomes modified with a dequalinium polyethylene glycol-distearoylphosphatidyl ethanolamine conjugate to induce apoptosis in resistant lung cancer cells.

Intrinsic multidrug resistance (MDR) of cancers remains a major obstacle to successful chemotherapy. A dequalinium polyethylene glycol-distearoylphosphatidylethanolamine (DQA-PEG(2000)-DSPE) conjugate was synthesized as a mitochondriotropic molecule, and mitochondrial targeting resveratrol liposomes were developed by modifying DQA-PEG(2000)-DSPE on the surface of liposomes for overcoming the resistance. Evaluations were performed on the human lung adenocarcinoma A549 cells and resistant A549/cDDP cells, A549 and A549/cDDP tumor spheroids as well as the xenografted resistant A549/cDDP cancers in nude mice. The yield of DQA-PEG(2000)-DSPE conjugate synthesized was about 87% and the particle size of mitochondrial targeting resveratrol liposomes was approximately 70 nm. The mitochondrial targeting liposomes significantly enhanced the cellular uptake, and selectively accumulated into mitochondria when encapsulating coumarin as the fluorescent probe. Furthermore, mitochondrial targeting resveratrol liposomes induced apoptosis of both non-resistant and resistant cancer cells by dissipating mitochondria membrane potential, releasing cytochrome c and increasing the activities of caspase 9 and 3. They also exhibited significant antitumor efficacy in two kinds of cancer cells, in tumor spheroids by penetrating deeply into the core, and in xenografted resistant A549/cDDP cancers in nude mice. Mitochondrial targeting resveratrol liposomes co-treating with vinorelbine liposomes significantly enhanced the anticancer efficacy against the resistant A549/cDDP cells. In conclusion, mitochondrial targeting resveratrol liposomes would provide a potential strategy to treat the intrinsic resistant lung cancers by inducing apoptosis via mitochondria signaling pathway.

Highly efficient and mild method for regioselective de-O-benzylation of saccharides by Co2(CO)8-Et3SiH-CO reagent system.

A highly efficient and mild method for the de-O-benzylation of protected saccharides was developed by transforming terminal benzyl ethers into silyl ethers using Co(2)(CO)(8)-Et(3)SiH under 1 atm of CO. The method was successfully used for the de-O-benzylation of perbenzylated monosaccharides with various anomeric protecting groups, as well as natural disaccharides and trisaccharides such as sucrose, raffinose, and melezitose in good yields (>80%).

PEG-conjugated PAMAM dendrimers mediate efficient intramuscular gene expression.

Generations 5 and 6 (G5 and G6) poly(amidoamine) (PAMAM) dendrimers have been shown to be highly efficient nonviral carriers in in vitro gene delivery. However, their high toxicity and unsatisfied in vivo efficacy limit their applications. In this study, to improve their characteristics as gene delivery carriers, polyethylene glycol (PEG, molecular weight 5,000) was conjugated to G5 and G6 PAMAM dendrimers (PEG-PAMAM) at three different molar ratios of 4%, 8%, and 15% (PEG to surface amine per PAMAM dendrimer molecular). Compared with unconjugated PAMAM dendrimers, PEG conjugation significantly decreased the in vitro and in vivo cytotoxicities and hemolysis of G5 and G6 dendrimers, especially at higher PEG molar ratios. Among all of the PEG-PAMAM dendrimers, 8% PEG-conjugated G5 and G6 dendrimers (G5-8% PEG, G6-8% PEG) resulted in the most efficient muscular gene expression when polyplexes were injected intramuscularly to the quadriceps of neonatal mice. Consistent with the in vivo results, these two 8% PEG-conjugated PAMAM dendrimers could also mediate the highest in vitro transfection in 293A cells. Therefore, G5-8% PEG and G6-8% PEG possess a great potential for gene delivery both in vivo and in vitro.