CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo

<p>Abstract</p> <p>Background</p> <p>To investigate whether dendritic cell (DC) precursors, recruited by injection of <b>chemokine ligand 3 (CCL3) and CCL20</b>, induce anti-tumor immunity against gastric cancer induced by a DC vaccine expressing melanoma antigen gene-1 (MAGE-1) ex vivo and in vivo.</p> <p>Methods</p> <p>B6 mice were injected with CCL3 and CCL20 via the tail vein. Freshly isolated F4/80^-B220^-CD11c⁺cells cultured with cytokines were analyzed by phenotype analysis and mixed lymphocyte reaction (MLR). For adenoviral (Ad)-mediated gene transduction, cultured F4/80^-B220^-CD11c⁺cells were incubated with Ad-MAGE-1. Vaccination of stimulated DC induced T lymphocytes. The killing effect of these T cells against gastric carcinoma cells was assayed by MTT. INF-γ production was determined with an INF-γ ELISA kit. In the solid tumor and metastases model, DC-based vaccines were used for immunization after challenge with MFC cells. <b>Tumor size, survival of mice, and number of pulmonary metastatic foci were used to assess the therapeutic effect of DC vaccines</b>.</p> <p>Results</p> <p>F4/80^-B220^-CD11c⁺cell numbers increased after <b>CCL3 and CCL20 </b>injection. Freshly isolated F4/80^-B220^-CD11c⁺cells cultured with cytokines were phenotyically identical to typical DC and gained the capacity to stimulate allogeneic T cells. These DCs were transduced with Ad-MAGE-1, which were prepared for DC vaccines expressing tumor antigen. T lymphocytes stimulated by DCs transduced with Ad-MAGE-1 exhibited specific killing effects on gastric carcinoma cells and produced high levels of INF-γ ex vivo. In vivo, tumor sizes of the experimental group were much smaller than both the positive control group and the negative control groups (<it>P </it>< 0.05). Kaplan-Meier survival curves showed that survival of the experimental group mice was significantly longer than the control groups (<it>P </it>< 0.05). In addition, MAGE-1-transduced DCs were also a therapeutic benefit on an established metastatic tumor, resulting in a tremendous decrease in the number of pulmonary metastatic foci.</p> <p>Conclusions</p> <p><b>CCL3 and CCL20</b>-recruited DCs modified by adenovirus-trasnsduced, tumor-associated antigen, MAGE-1, can stimulate anti-tumor immunity specific to gastric cancer ex vivo and in vivo. This system may prove to be an efficient strategy for anti-tumor immunotherapy.</p

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer

Background: Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral (R)-2-hydroxy FAs ((R)-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. Methods: FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo. Findings: FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with (R)-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo. Moreover, (R)-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. Interpretation: Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that (R)-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. Fund: Grants of NSF, NIH, and PAPD. Keywords: Fatty acid 2-hydroxylation, Gastric cancer, Lipid metabolism, mTOR, Chemotherapy, Hedgehog pathwa

The spatial and temporal contribution of glacier runoff to watershed discharge in the Yarkant River Basin, Northwest China

In this paper, a glacial module based on an enhanced temperature-index approach was successfully introduced into the Soil and Water Assessment Tool (SWAT) model to simulate the glacier runoff and water balance of a glacierized watershed, the mountainous region of the Yarkant River Basin (YRB) in Karakoram. Calibration and validation of the SWAT model were based on comparisons between the simulated and observed discharge with a monthly temporal resolution from 1961 to 2011 for the Kaqun hydrological station. The results reaffirmed the viability of the approach for simulating glacier runoff, as evidenced by a Nash–Sutcliff Efficiency (NSE) of 0.82–0.86 as well as a percentage bias (PBIAS) of −4.5% to 2.4%, for the calibration and validation periods, respectively. Over the last 50 years, the total discharge and glacier runoff both exhibited increasing trends with 0.031 × 109 m3·a−1 and 0.011 × 109 m3·a−1. The annual glacier runoff contribution to the streamflow was between 42.3% and 64.5%, with an average of 51.6%, although the glaciers accounted for only 12.6% of the watershed drainage area in the mountainous YRB. The monthly contribution of the glacier runoff ranged from 11.0% in April to 62.1% in August, and the glacier runoff from June to September accounted for about 86.3% of the annual glacier runoff. Runoff from the mountainous regions above 5000 m a.s.l. accounted for 70.5% of the total discharge, with glacier runoff contributions being approximately 46.4%

Distribution and Clinical Significance of Th17 Cells in the Tumor Microenvironment and Peripheral Blood of Pancreatic Cancer Patients

This study was designed to investigate the distribution of Th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients, its clinical significance, and the expression profile of Th17 cell-associated cytokines. The percentage of Th17 cells detected by flow cytometry analysis (FACS) was significantly higher in 46 pancreatic tumor tissues (5.28 ± 1.65%) compared with corresponding adjacent normal tissues (2.57 ± 0.83%) (P = 0.031). In addition, the percentage of Th17 cells was significantly higher in stage III-IV tumors than stage I-II tumors (P = 0.039). The percentage of Th17 cells in peripheral blood of 20 pancreatic cancer patients (3.99 ± 1.15%) was significantly higher than 15 healthy volunteers (1.98 ± 0.57%) (P = 0.027). Immunohistochemistry (IHC) was performed to detect IL-17+ cells in 46 pancreatic tumor tissues, as well as expression of CD34 in 24 tumor tissues. IL-17 was shown to mainly locate in cytoplasm, and the frequency of IL-17+ cells in tumor tissues (39/46) was higher than control (29/46). The presence of IL-17+ cells in tumor tissues was associated with tumor, node, and metastasis (TNM) stage, and lymph node metastasis (P = 0.012 and P = 0.009) but not with patient sex, age, tumor size, and histological grade (P > 0.05). Interestingly, distribution of Th17 cells in tumor tissues was positively correlated with microvessel density (MVD) (r = 0.86, P = 0.018). Furthermore, the median survival time of patients with high and low level of IL-17+ cells frequency was 14.5 and 18.5 months respectively (P = 0.023). The serum levels of Th17 cell-associated cytokines, IL-17 and IL-23 in 20 pancreatic patients detected by enzyme-linked immunosorbent assay (ELISA) were 69.2 ± 28.5 pg/mL and 266.5 ± 98.1 pg/mL, respectively, which were significantly higher than 15 healthy volunteers (P = 0.015 and P = 0.02). Moreover, levels of IL-17 and IL-23 were significantly higher in stage III-IV tumors than stage I-II tumors (P = 0.04 and P = 0.036). This study suggests that increase in Th17 cells frequency and its related cytokines levels in pancreatic tumor tissues may indicate involvement in the invasion and metastasis of pancreatic cancer, which may thereby affect patient prognosis. Therefore, Th17 cells and related cytokines may be served as important immune indicators for predicting the prognosis of pancreatic cancer patients

Land Surface Snow Phenology Based on an Improved Downscaling Method in the Southern Gansu Plateau, China

Snow is involved in and influences water–energy processes at multiple scales. Studies on land surface snow phenology are an important part of cryosphere science and are a hot spot in the hydrological community. In this study, we improved a statistical downscaling method by introducing a spatial probability distribution function to obtain regional snow depth data with higher spatial resolution. Based on this, the southern Gansu Plateau (SGP), an important water source region in the upper reaches of the Yellow River, was taken as a study area to quantify regional land surface snow phenology variation, together with a discussion of their responses to land surface terrain and local climate, during the period from 2003 to 2018. The results revealed that the improved downscaling method was satisfactory for snow depth data reprocessing according to comparisons with gauge-based data. The downscaled snow depth data were used to conduct spatial analysis and it was found that snow depth was on average larger and maintained longer in areas with higher altitudes, varying and decreasing with a shortened persistence time. Snow was also found more on steeper terrain, although it was indistinguishable among various aspects. The former is mostly located at high altitudes in the SGP, where lower temperatures and higher precipitation provide favorable conditions for snow accumulation. Climatically, factors such as precipitation, solar radiation, and air temperature had significantly singular effectiveness on land surface snow phenology. Precipitation was positively correlated with snow accumulation and maintenance, while solar radiation and air temperature functioned negatively. Comparatively, the quantity of snow was more sensitive to solar radiation, while its persistence was more sensitive to air temperature, especially extremely low temperatures. This study presents an example of data and methods to analyze regional land surface snow phenology dynamics, and the results may provide references for better understanding water formation, distribution, and evolution in alpine water source areas

Regional vegetation dynamics and its response to climate change—a case study in the Tao River Basin in Northwestern China

The 30-year normalized-difference vegetation index (NDVI) time series from AVHRR/MODIS satellite sensors was used in this study to assess the regional vegetation dynamic changes in the Tao River Basin, which cuts across the Eastern Tibetan Plateau (ETP) and the Southwestern Loess Plateau (SLP). First, principal component and correlation analyses were carried out to determine the key climatic variables driving ecological change in the region. Then, regression models were tested to correlate NDVI with the selected climatic variables to determine their predictive power. Finally, Sen’s slope method was used to determine how terrestrial vegetation has responded to regional climate change in the region. The results indicated an average winter season NDVI value of 0.14 in the ETP but only 0.04 in the SLP. Primarily driven by increasing temperature, vegetation growth has generally been enhanced since 1981; spring NDVI increased by 0.03 every 10 years in the ETP and 0.02 in the SLP. Further, results from trend analyses suggest vegetation growth in the ETP shifted to earlier-start and earlier-end dates, however in the SLP, the growing season has been extended with an earlier-start and later-end date. The precipitation threshold for vegetation germination, measured by the cumulative spring rainfall, was found to be 44 mm for both the ETP and SLP

Runoff Simulation by SWAT Model Using High-Resolution Gridded Precipitation in the Upper Heihe River Basin, Northeastern Tibetan Plateau

The scarcity and uneven distribution of precipitation stations in the inland river basins of the Northeastern Tibetan Plateau restrict the application of the distributed hydrological model and spatial analysis of water balance component characteristics. This study used the upper Heihe River Basin as a case study, and daily gridded precipitation data with 3 km resolution based on the spatial interpolation of gauged stations and a regional climate model were used to construct a soil and water assessment tool (SWAT) model. The aim was to validate the precision of high-resolution gridded precipitation for hydrological simulation in data-scarce regions; a scale transformation method was proposed by building virtual stations and calculating the lapse rate to overcome the defects of the SWAT model using traditional precipitation station data. The gridded precipitation was upscaled from the grid to the sub-basin scale to accurately represent sub-basin precipitation input data. A satisfactory runoff simulation was achieved, and the spatial variability of water balance components was analysed. Results show that the precipitation lapse rate ranges from 40 mm/km to 235 mm/km and decreases from the southeastern to the northwestern areas. The SWAT model achieves monthly runoff simulation compared with gauged runoff from 2000 to 2014; the determination coefficients are higher than 0.71, the Nash–Sutcliffe efficiencies are higher than 0.76, and the percentage bias is controlled within ±15%. Meadow and sparse vegetation are the major water yield landscapes, and the elevation band from 3500 m to 4500 m is the major water yield area. Precipitation and evapotranspiration present a slightly increasing trend, whereas water yield and soil water content present a slightly decreasing trend. This finding indicates that the high-resolution gridded precipitation data fully depict its spatial heterogeneity, and scale transformation significantly promotes the application of the distributed hydrological model in inland river basins. The spatial variability of water balance components can be quantified to provide references for the integrated assessment and management of basin water resources in data-scarce regions