Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage gastric ...cancer, but their efficacy in the neoadjuvant/conversion setting is unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate the efficacy of a combination of ICI (camrelizumab), antiangiogenesis (apatinib), and chemotherapy (S-1 ± oxaliplatin) for neoadjuvant/conversion treatment of cT4a/bN+ gastric cancer. The primary endpoints are pathological responses and their potential biomarkers. Secondary endpoints include safety, objective response, progression-free survival, and overall survival. Complete and major pathological response rates are 15.8% and 26.3%. Pathological responses correlate significantly with microsatellite instability status, PD-L1 expression, and tumor mutational burden. In addition, multi-omics examination reveals several putative biomarkers for pathological responses, including RREB1 and SSPO mutation, immune-related signatures, and a peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes in dominant tumor subclones, immune microenvironments, and T cell receptor repertoires during neoadjuvant immunotherapy. The toxicity and post-surgery complications are limited. These data support further validation of ICI- and antiangiogenesis-based neoadjuvant/conversion therapy in large randomized trials and provide candidate biomarkers.
Cadmium (Cd) is harmful to plant growth and can be easily transferred from soil to plants. Plant cell wall plays important role in preventing Cd from entering cells. Salicylic acid (SA) mediated ...defense response increases plant resistance to heavy metals. In this study, all tomato seedlings were pre-treated with 100 μM SA for 3 d, then seedlings were used to analyze the role of SA in regulating plant cell wall resistance to Cd stress. The results showed that exogenous SA significantly reduced Cd accumulation in tomato plants and changed Cd distribution. By analyzing the cell wall composition, it was found cellulose, hemicellulose, pectin, and lignin were induced by SA. Interestingly, the content of Cd in pectin decreased by SA pretreatment, however it was increased in cellulose. Gene expression analysis showed SA up-regulated the expression level of lignin and cellulose synthase genes, but down-regulated the expression of pectin methylesterase related genes. In addition, SA down-regulated the activity of pectin methylesterase. These results indicated that SA pretreatment up-regulated cell wall polysaccharide synthesis and related gene expression to thicken the cell wall and block Cd from passing through. Furthermore, SA decreased pectin methylesterase activity and content to reduce cell wall Cd accumulation and change the Cd partition ratio.
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•Exogenous SA can reduce Cd accumulation in tomato plants and subcellular cells.•SA reduces Cd content in the cell wall and increases the cell wall polysaccharide.•SA changed the activity of pectin methylesterase and lignin synthase.•SA decreased the distribution ratio of Cd in pectin.•SA increased the distribution ratio of Cd in lignin and cellulose.
To evaluate the microbial loading in aerosols produced after air-puff by non-contact tonometer (NCT) as well as the effect of alcohol disinfection on the inhibition of microbes and thus to provide ...suggestions for the prevention and control of COVID-19 in ophthalmic departments of hospitals or clinics during the great pandemics.
A cross-sectional study was carried out in this study. A NIDEK NCT was used for intraocular pressure (IOP) measurement for patients who visited Department of Ophthalmology in Qilu Hospital of Shandong University during March 18-25 2020. After ultra-violate (UV) light disinfection, the room air was sampled for 5 minutes. Before and after alcohol disinfection, the air samples and nozzle surface samples were respectively collected by plate exposure method and sterile moist cotton swab technique after predetermined times of NCT air-puff. Microbial colony counts were calculated after incubation for 48 hours. Finally, mass spectrometry was performed for the accurate identification of microbial species.
Increased microbial colonies were detected from air samples close to NCT nozzle after air-puff compared with air samples at a distance of 1 meter from the nozzle (p = 0.001). Interestingly, none microbes were detected on the surface of NCT nozzle. Importantly, after 75% alcohol disinfection less microbes were detected in the air beside the nozzle (p = 0.003). Microbial species identification showed more than ten strains of microbes, all of which were non-pathogenic.
Aerosols containing microbes were produced by NCT air-puff in the ophthalmic consultation room, which may be a possible virus transmission route in the department of ophthalmology during the COVID-19 pandemic. Alcohol disinfection for the nozzle and the surrounding air was efficient at decreasing the microbes contained in the aerosols and theoretically this prevention measure could also inhibit the virus. This will give guidance for the prevention of virus transmission and protection of hospital staff and patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A number of recent studies identified hydrogen sulfide (H
S) as an important signal in plant development and adaptation to environmental stress. H
S has been proven to participate in ethylene-induced ...stomatal closure, but how the signaling pathways of H
S and ethylene interact is still unclear. Here, we reveal how H
S controls the feedback-regulation of ethylene biosynthesis in tomato (
) under osmotic stress. We found that ethylene induced the production of H
S in guard cells. The supply of hypotaurine (HT; a H
S scavenger) or DL-pro-pargylglycine (PAG; a synthetic inhibitor of H
S) removed the effect of ethylene or osmotic stress on stomatal closure. This suggests that ethylene-induced H
S is a downstream component of osmotic stress signaling, which is required for ethylene-induced stomatal closure under osmotic stress. We further found that H
S inhibited ethylene synthesis through inhibiting the activity of 1-aminocyclopropane-1-carboxylic acid (ACC) oxidases (ACOs) by persulfidation. A modified biotin-switch method (MBST) showed that H
S can induce persulfidation of LeACO1 and LeACO2 in a dose-dependent manner, and that persulfidation inhibits the activity of LeACO1 and LeACO2. We also found that LeACO1 is persulfidated at cysteine 60. These data suggested that ethylene-induced H
S negatively regulates ethylene biosynthesis by persulfidation of LeACOs. In addition, H
S was also found to inhibit the expression of
genes. The results provide insight on the general mode of action of H
S and contribute to a better understanding of a plant's response to osmotic stress.
SMARCA4, the essential ATPase subunit of SWI/SNF chromatin remodeling complex, regulates transcription through the control of chromatin structure and is increasingly thought to play significant roles ...in human cancers. This study aims to explore the potential role of SMARCA4 with a view to providing insights on pathologic mechanisms implicated here.
The potential roles of SMARCA4 in different tumors were explored based on The Cancer Genome Atlas (TCGA), Genotype-tissue expression (GTEx), Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA) datasets. The expression difference, mutation and phosphorylation status, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), and immune cell infiltration related to SMARCA4 were analyzed.
High expression levels of SMARCA4 were observed in most cancer types. SMARCA4 expression in tumor samples correlates with poor overall survival in several cancers. Lung adenocarcinoma cases with altered SMARCA4 showed a poorer prognosis. Enhanced phosphorylation levels of S613, S695, S699, and S1417 were observed in several tumors, including breast cancer. SMARCA4 correlated with tumor immunity and associated with different immune cells and genes in different cancer types. TMB, MSI, MMR, and DNA methylation correlated with SMARCA4 dysregulation in cancers. SMARCA4 expression was negatively associated with CD8+ T-cell infiltration in several tumors. Furthermore, the SWI/SNF superfamily-type complex and ATPase complex may be involved in the functional mechanisms of SMARCA4, albeit these data require further confirmation.
Our study offers a comprehensive understanding of the oncogenic roles of SMARCA4 across different tumors. SMARCA4 may correlate with tumor immunity.
Electrical impedance flow cytometry (EIFC) based on microfluidic chips has be en applied to particle and bacterial cell analysis, but detection of submicron particles is limited by the sensitivity of ...the existing microfluidic systems. Our objective was to increase the sensitivity of a coplanar electrode EIFC system and fulfill the increasing demand of analyzing submicron-organisms such as bacteria, apoptotic bodies, extracellular vesicles, exosomes and viruses. To this end, we optimized a series of parameters, including the width of the electrodes (We) of the microfluidic chip, the width (Wc) and height (Hc) of the channel’s sensing zone, and the buffer conductivity. The results indicated that 10 µm and 5 µm are the optimal We and Wc values, respectively, for microparticle detection. Based on these results, we developed an EIFC chip to test the detection of ⌀ 3.0 µm microspheres and yeast cells suspended in buffers of different conductivity. The optimal conductivities for microsphere and yeast cell detection were approximately 1.6 S/m and 6.4 S/m, respectively. Moreover, submicrospheres of ⌀ 0.2–0.6 µm and bacterial cells of species such as Serratia marcescens (with a cell size of 0.5 × (0.5–1.0) µm) were detected using the optimized EIFC system with a wide channel (Wc = 5 µm). In conclusion, our results demonstrate that the optimized EIFC system can be used to detect almost all types of bacteria in a high-throughput approach, allowing an effective and accurate enumeration of bacteria or other submicron-organisms in liquid samples in the future.
•A series of parameters were optimized to increase the sensitivity of an EIFC system.•Submicrospheres of ⌀ 200 nm and different species of bacterial cells were detected.•Almost all known bacterial cells at the submicron level can be detected.•Optimal buffer conductivities in EIFC test for beads and bacteria cells are different.•The height of the channel can affect the EIFC sensing, especially in event counting.
Various stress conditions, such as drought, salt, heavy metals, and extreme temperatures, have severe deleterious effects on plant growth and directly lead to a decline in yield and quality ...
Microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. However, a recent Japanese trial showed that ...regorafenib plus nivolumab had encouraging anti-cancer activity in MSS or pMMR mCRCs.
We retrospectively reviewed the efficacy and safety data of combination therapy with regorafenib plus anti-PD-1 antibody in patients with refractory MSS or pMMR mCRC in the medical centers of Shandong Province in China.
Twenty-three patients with MSS or pMMR mCRC received regorafenib plus anti-PD-1 antibody. Eighteen (78.3%) patients experienced stable disease as best response, five (21.7%) patients had progressive disease, and no partial response was observed. The disease control rate (DCR) was 78.3% (18/23), and the median progression-free survival (PFS) was 3.1 months (95% CI, 2.32-3.89). Four of five (80.0%) patients with progressive disease had baseline liver metastasis, while nine of 18 (50.0%) patients with stable disease displayed no liver metastasis. One patient receiving radiofrequency ablation treatment for liver and abdominal wall metastases prior to combination treatment experienced a remarkably prolonged PFS of 9.2 months with SD. Neither liver metastasis status nor previous exposure to regorafenib was associated with treatment outcome. Treatment-related grade 3 toxicities were observed in 5/23 (21.7%) patients.
No objective response was observed with the combination of regorafenib plus anti-PD-1 antibody, suggesting its little clinical activity in unselected Chinese patients with pMMR/MSS mCRC. Meanwhile, it exhibited some potential benefit in this cohort in terms of DCR and PFS. Adverse events were generally tolerable and manageable. Prospective studies with large sample sizes are needed to verify the findings. This combination strategy plus local ablative therapy might be worthy of further exploration.
•The extraction process of mulberry leaf protein was optimized with the protein dissolution amount as the index;•The Fourier transform infrared spectroscopy and scanning electron microscopy of ...extracted mulberry leaf protein were measured;•The functional characteristics of protein extracted by the ultrasound-assisted cellulase degradation method were evaluated.
The mulberry leaf protein extracted by ultrasound-assisted cellulase degradation (UACD) method was optimized with the protein dissolution amount (PDA) as the index. The Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy of extracted mulberry leaf protein were measured. The functional characteristics of protein extracted by the UACD method were evaluated. Results showed that the extraction condition was optimized and adjusted to the following parameters: pH value of 7.20, ultrasound temperature of 35.00 °C, enzyme dosage of 4.20% and ultrasound time of 10.00 min. Under these optimized conditions, the experimental verification value of PDA was 13.87 mg/mL, which was approaching to the predicted value of 13.54 mg/mL. The analysis results of FTIR showed that after extraction by the UACD method, the mulberry leaf protein with the vibrational peak of ester carbonyl (C = O) absorption peak (1734.66 cm−1) disappeared. The α-helix content of protein extracted by the UACD decreased by 8.13%, and the β-turn and random coil content of protein increased by 20.22% and 18.79%, respectively, compared to that of the blank. The microstructure of mulberry leaf protein showed that the UACD method could break the dense structure of protein raw materials, reduce the average size of proteins and increase the specific surface area and roughness of proteins. According to the results of functional characteristics, the mulberry leaf protein extracted by the UACD method presented the highest enzymolysis properties and solubility, which was beneficial for the application in the food industry. In conclusion, the UACD method was a very effective way to extract protein from mulberry leaf.
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