Immune checkpoint blockade has shown remarkable efficacy, but in only a minority of patients with cancer, suggesting the need to develop additional treatment strategies. Aberrant glycosylation in ...tumors, resulting from the dysregulated expression of key enzymes in glycan biosynthesis, modulates the immune response. However, the role of glycan biosynthesis enzymes in antitumor immunity is poorly understood. We aimed to study the immunomodulatory effects of these enzymes.
We integrated transcriptional profiles of treatment-naïve human tumors and functional CRISPR screens to identify glycometabolism genes with immunomodulatory effects. We further validated our findings using
coculture and
syngeneic tumor growth assays.
We identified
, encoding an enzyme in N-glycan maturation, as a key immunomodulatory gene. Analyses of public immune checkpoint blockade trial data also suggested a synergy between MAN2A1 inhibition and anti-PD-L1 treatment. Loss of
in cancer cells increased their sensitivity to T-cell-mediated killing.
knockout enhanced response to anti-PD-L1 treatment and facilitated higher cytotoxic T-cell infiltration in tumors under anti-PD-L1 treatment. Furthermore, a pharmacologic inhibitor of MAN2A1, swainsonine, synergized with anti-PD-L1 in syngeneic melanoma and lung cancer models, whereas each treatment alone had little effect.
loss renders cancer cells more susceptible to T-cell-mediated killing. Swainsonine synergizes with anti-PD-L1 in suppressing tumor growth. In light of the limited efficacy of anti-PD-L1 and failed phase II clinical trial on swainsonine, our study reveals a potential therapy combining the two to overcome tumor immune evasion.
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Nannochloropsis oculata can accumulate large amounts of lipids under rare earth element (REE) conditions. However, the lipid accumulation mechanism responsible for REE stress has not been elucidated. ...In this study, the effects of cerium (the most abundant REE) on the growth and lipid accumulation of N. oculata were investigated. The de novo transcriptome data of N. oculata under cerium conditions were subsequently collected and analyzed. The results showed that N. oculata exhibited good cerium-resistance ability, showed slightly decrease in biomass but significantly increase in lipid content (55.8 % dry cell weight) under 6.0 mg/L cerium condition. Meanwhile, about 83.4 % cerium was biological fixated. Through transcriptome analysis, we found that the inhibited photosynthesis and carbon fixation pathways coupled with the stress-sensitive expression of ribosome biogenesis genes acclimatized the cells to REE stress. The active glycolysis pathway accelerated carbon flux to pyruvate and acetyl-CoA, and the upregulation of glycerol kinase and phosphatidate cytidylyltransferase genes further induced lipid accumulation. In addition, cerium downregulated the acyl-CoA oxidase and triacylglycerol lipase genes, which inhibited the degradation of lipids. Therefore, different responses to cerium demonstrate how N. oculata cells adapt to REE stress, and this knowledge may be used to extend our understanding of triacylglycerol (TAG) and the synthesis of other important metabolites.
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•Nannochloropsis oculata exhibited good cerium-resistance ability.•Lipid content increased by 38.5 % and reached 55.8 % dry cell weight at 6 mg/L cerium.•Ribosome genes were altered sensitively to response cerium stress.•The active glycolysis and increased glycerol kinase gene promoted lipid synthesis.•Triacylglycerol and fatty acids degradation were inhibited to prevent lipolysis.
To investigate the basic clinical characteristics of paraneoplastic neurological syndrome (PNS) in children.
To retrospectively analyze the clinical data of 12 PNS children who were hospitalized in ...neurology department in Beijing Children's Hospital from 2010 to 2011. Some patients were followed up after surgery.
In 12 patients with PNS, 11 were male and 1 was female. The mean onset age were (30.5 ± 15.3) months. The mean duration from neurological symptom onset to finding out of tumor was (112.7 ± 154.4) days. The onset of the disease in 2 patients was acute, in 3 was subacute and in the other 7 was chronic (2 of 7 had 2 to 3 relapses). Of 12 patients, 11 had symptoms of ataxia (3 patients also had opsoclonus and myoclonus, OMS), 1 had weakness of limbs at onset and then had ataxia. Nine of 12 patients had surgery, and pathologic diagnosis was neuroblastoma and ganglioneuroma. Six patients were followed-up for 8 to 21 months. One patient had a little improvement and 5 almost recovered.
The PNS children can h
Alzheimer's disease (AD) is associated with disruptions in brain activity and networks. However, there is substantial inconsistency among studies that have investigated functional brain alterations ...in AD; such contradictions have hindered efforts to elucidate the core disease mechanisms. In this study, we aim to comprehensively characterize AD‐associated functional brain alterations using one of the world's largest resting‐state functional MRI (fMRI) biobank for the disorder. The biobank includes fMRI data from six neuroimaging centers, with a total of 252 AD patients, 221 mild cognitive impairment (MCI) patients and 215 healthy comparison individuals. Meta‐analytic techniques were used to unveil reliable differences in brain function among the three groups. Relative to the healthy comparison group, AD was associated with significantly reduced functional connectivity and local activity in the default‐mode network, basal ganglia and cingulate gyrus, along with increased connectivity or local activity in the prefrontal lobe and hippocampus (p < .05, Bonferroni corrected). Moreover, these functional alterations were significantly correlated with the degree of cognitive impairment (AD and MCI groups) and amyloid‐β burden. Machine learning models were trained to recognize key fMRI features to predict individual diagnostic status and clinical score. Leave‐one‐site‐out cross‐validation established that diagnostic status (mean area under the receiver operating characteristic curve: 0.85) and clinical score (mean correlation coefficient between predicted and actual Mini‐Mental State Examination scores: 0.56, p < .0001) could be predicted with high accuracy. Collectively, our findings highlight the potential for a reproducible and generalizable functional brain imaging biomarker to aid the early diagnosis of AD and track its progression.
A series of novel conjugates of brefeldin A (11a−c, 12a−c and 13a−c) were obtained by introducing a variety of nitrogen mustards at 4-OH or 7-OH position to explore more efficacious and less toxic ...antitumor agents. The antiproliferative activities were tested against three cancer cell lines (HL-60, PC-3 and Bel-7402) and one multidrug resistant cell line Bel-7402/5-FU. Among them, compound 11a was the strongest derivative with IC50 values of 4.48, 9.37, 0.2 and 0.84 μM, respectively, and more potent than nitrogen mustards. Though the antiproliferative potency was weaker than the lead compound brefeldin A, 11a displayed lower toxicity than brefeldin A (IC50 < 0.001 μM) with an IC50 of 9.74 μM against normal human liver L-O2 cells, showing good selectivity between normal and malignant liver cells. The mechanism studies confirmed that 11a could induce apoptosis, arrest cell cycle at the G1 phase and lead to mitochondrial dysfunction in Bel-7402 cells at submicromolar concentrations. Furthermore, 11a induced the intrinsic apoptotic mitochondrial pathway in Bel-7402 cells, evidenced by the enhanced expression of the pro-apoptotic protein Bax, cyto-c and p53, and the reduced expression of the anti-apoptotic protein Bcl-2. The caspase-9 and -3 levels were also up-regulated.
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•Novel hybrids of brefeldin A and nitrogen mustards were designed and synthesized.•Some derivatives exhibited potent antiproliferative activity with low IC50 values.•Compound 11a showed good selectivity between human normal and tumor liver cells.•11a induced apoptosis and arrest cell cycle at G1 phase in Bel-7402 cells.•11a induced Bel-7402 cells apoptosis via the mitochondria-dependent pathway.
Background Coronary artery in-stent restenosis （ISR） and late stent thrombosis remain as important complications of stenting. The inflammation reactions to sirolimus and paclitaxel-eluting stents ...were investigated in a swine stenosis model induced by interleukin （IL）-1β.Methods Mini pigs （n=12; 2-3 months old and weighing 25-30 kg） were subjected to thoracotomy. Segments （10 mm）of the mid left anterior descending coronary artery and left circumflex coronary artery were exposed and aseptically wrapped with a cotton mesh soaked with IL-1β （5 μg）. After 2 weeks, the animals were anesthetized and quantitative coronary arteriography （QCA） was performed. The stenosis sites were randomized into three groups for stent insertion： a sirolimus-eluting stent （SES） group （FirebirdTM, n=7）, a paclitaxel-eluting stent （PES） group （TAXUSTM, n=9）, and a bare-metal stent （BMS） group （YINYITM, Dalian Yinyi Biomaterials Development Co., Ltd, China, n=8）. The three different stents were randomly implanted into stenosis segments. Expression of monocyte chemoattractant protein-1 （MCP-1）, tumor necrosis factor-alpha （TNF-α）, P-selectin and vascular cell adhesion molecule-1 （VCAM-1） was determined by reverse transcription-coupled polymerase chain reaction （RT-PCR）.Results QCA showed severe stenosis in IL-1β treated segments. The SES and PES groups showed lower 1-month angiographic late lumen loss （LLL） within the stent and the lesion compared with BMS （P 〈0.05） by follow-up QCA. The SES showed lower LLL than that of PES in reducing 1-month inflammation lesions in pigs by follow-up QCA （（0.15±0.06）mm vs. （0.33±0.01） mm, P 〈0.0001）. The neointimal hyperplasia areas in SES and PES showed lower than those of BMS （SES （11.6±1.7） mm2, PES （27.2±1.6） mm2 vs. BMS （76.2±1.3） mm2, P 〈0.0001）. The mRNA expression of MCP-1 by RT-PCR in SES and PES showed lower than that of BMS at 30 days after stenting （SES 0.20±0.03, PES 0.48±0.49 vs.BMS 0.58±0.07, P 〈0.05）. Levels of VCAM-1 in SES were significantly lower than those of PES and BMS （SES 0.35±0.08 vs. PES 0.65±0.13, BMS 0.70±0.06, P 〈0.05）. Histochemical immunostaining of vessel walls showed lower inflammatory chemokine MCP-1 expression in the SES and PES groups compared with BMS.Conclusion SESs were superior in reducing 1-month angiographic LLL in inflammation lesions in pigs, strongly suggesting that SESs can suppress inflammatory reactions in ISR at multiple points.
In the context of chemical recycling of mixed plastics and paper, multitemperature step pyrolysis has shown good potential for the separation of oxygenated products from hydrocarbons. Here, we report ...results of an investigation of the first pyrolysis step at low temperature, which involves the dehydrochlorination of polyvinyl chloride (PVC) and the pyrolysis of cellulose, the main component of paper. Calcium oxide (CaO), selected for its chloride adsorption ability and its catalytic activity on biooil deoxygenation, was used for upgrading the downstream products from the pyrolysis. Additionally, we studied the performance of CaO for the simultaneous adsorption of HCl and for reforming cellulose pyrolysates in the temperature range of 300–600 °C with feedstock to CaO ratios of 1:0.2, 1:0.4, and 1:1. It was found that the suitable catalytic temperature for HCl and acetic acid adsorption is lower than 400 °C. This is due to the desorption of HCl from CaCl2 and Ca(OH)Cl in the presence of water and CO2 at 400 °C and higher. A larger amount of CaO resulted in a more efficient reduction of acids and the organic liquids were found to have lower amounts of oxygen. A comparison between the cases of neat and mixed feedstock showed that pyrolysis of mixed feedstock produced more water, H2, CO, and polycyclic aromatic hydrocarbons (PAHs) when compared to the case of neat materials over CaO.
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•YRh0.5Fe0.5O3 with perovskite structure was loaded on ZrO2 by using citrate complexing method.•The formation of YRh0.5Fe0.5O3 is much favorable for generating Rh-Fe alloy ...NPs..•YRh0.5Fe0.5O3/ZrO2 exhibited good activity and high selectivity to alcohols.•Among the alcohols, the mass fraction of ethanol was 74%.•The formation of Rh-Fe alloys favors the improvement of the selectivity to ethanol.
Traditional Rh-Fe catalysts usually exhibit high alkane or methanol selectivity due to the existence of mono iron and rhodium in the catalysts, and thus the selectivity to higher alcohols is low. To overcome this problem, in this work, YRh0.5Fe0.5O3 with perovskite structure was loaded on ZrO2 by using the citrate complexing method and used for higher alcohols synthesis. Compared with RhOx/ZrO2, YRhO3/ZrO2 and Rh-FeOx/ZrO2, the prepared YRh0.5Fe0.5O3/ZrO2 exhibited better activity and higher selectivity to higher alcohols, the mass fraction of higher alcohols in the total alcohols is more than 80%, especially ethanol occupied 74%. The high selectivity and activity of YRh0.5Fe0.5O3/ZrO2 are attributed to the formation of the homogeneous and highly dispersed Rh-Fe alloys. YRh0.5Fe0.5O3/ZrO2 also showed very good stability. More importantly, this preparation scheme can be extended for the preparation of other multi-component nano alloy catalysts.
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