Zeolite-supported nanoscale zero-valent iron (Z-NZVI) has great potential for metal(loid) removal, but its encapsulation mechanisms and ecological risks in real soil systems are not completely clear. ...We conducted long-term incubation experiments to gain new insights into the interactions between metal(loid)s (Cd, Pb, As) and Z-NZVI in naturally contaminated farmland soils, as well as the alteration of indigenous bacterial communities during soil remediation. With the pH-adjusting and adsorption capacities, 30 g kg−1 Z-NZVI amendment significantly decreased the available metal(loid) concentrations by 10.2–96.8% and transformed them into strongly-bound fractions in acidic and alkaline soils after 180 d. An innovative magnetic separation of Z-NZVI from soils followed by XRD and XPS characterizations revealed that B-type ternary complexation, heterogeneous coprecipitation, and/or concurrent redox reactions of metal(loid)s, especially the formation of Cd3(AsO4)2, PbFe2(AsO4)2(OH)2, and As0, occurred only under specific soil conditions. Sequencing of 16S rDNA using Illumina MiSeq platform indicated that temporary shifts in iron-resistant/sensitive, pH-sensitive, denitrifying, and metal-resistant bacteria after Z-NZVI addition were ultimately eliminated because soil characteristics drove the re-establishment of indigenous bacterial community. Meanwhile, Z-NZVI recovered the basic activities of bacterial DNA replication and denitrification functions in soils. These results confirm that Z-NZVI is promising for the long-term remediation of metal(loid)s contaminated farmland soil without significant ecotoxicity.
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•Z-NZVI combined the advantages of pH adjustment and adsorption.•Z-NZVI decreased available Cd, Pb, and As by 10.21–96.79% in acid and alkaline soils.•B-type ternary complexation, heterogeneous coprecipitation, and redox occurred.•The dynamic impacts of Z-NZVI on indigenous bacterial communities were discussed.•The secondary mineralization of Z-NZVI bonded metal(loid)s and improved soil quality.
The encapsulation mechanisms and microbial responses of Z-NZVI were investigated.
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas
. ...More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours
. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer
, there are preclinical
and clinical
rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma
( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.
Soil microbiota play a critical role in soil biogeochemical processes and have a profound effect on soil functions. Recent studies have revealed microbial co-occurrence patterns in soil microbial ...communities, yet the geographic pattern of topological features in soil microbial co-occurrence networks at the continental scale are largely unknown. Here, we investigated the shifts of topological features in co-occurrence networks inferred from soil microbiota along a continental scale in eastern China. Integrating archaeal, bacterial and fungal community datasets, we inferred a meta-community co-occurrence network and analyzed node-level and network-level topological shifts associated with five climatic regions. Both node-level and network-level topological features revealed geographic patterns wherein microorganisms in the northern regions had closer relationships but had a lower interaction influence than those in the southern regions. We further identified topological differences associated with taxonomic groups and demonstrated that co-occurrence patterns were random for archaea and non-random for bacteria and fungi. Given that microbial interactions may contribute to soil functions more than species diversity, this geographic shift of topological features provides new insight into studying microbial biogeographic patterns, their organization and impacts on soil-associated function.
Summary Background Until now, only imatinib and sunitinib have proven clinical benefit in patients with gastrointestinal stromal tumours (GIST), but almost all metastatic GIST eventually develop ...resistance to these agents, resulting in fatal disease progression. We aimed to assess efficacy and safety of regorafenib in patients with metastatic or unresectable GIST progressing after failure of at least imatinib and sunitinib. Methods We did this phase 3 trial at 57 hospitals in 17 countries. Patients with histologically confirmed, metastatic or unresectable GIST, with failure of at least previous imatinib and sunitinib were randomised in a 2:1 ratio (by computer-generated randomisation list and interactive voice response system; preallocated block design (block size 12); stratified by treatment line and geographical region) to receive either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of each 4 week cycle. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was progression-free survival (PFS). At disease progression, patients assigned placebo could crossover to open-label regorafenib. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01271712. Results From Jan 4, to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n=133) or matching placebo (n=66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4·8 months (IQR 1·4–9·2) for regorafenib and 0·9 months (0·9–1·8) for placebo (hazard ratio HR 0·27, 95% CI 0·19–0·39; p<0·0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%). Interpretation The results of this study show that oral regorafenib can provide a significant improvement in progression-free survival compared with placebo in patients with metastatic GIST after progression on standard treatments. As far as we are aware, this is the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients. Funding Bayer HealthCare Pharmaceuticals.
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•An intergraded source-exposure risk approach was developed.•Interrelationships among source, sink and human health were assessed.•Parent material and agrochemical application caused ...the highest non-cancer risk.•Industrial activities caused the highest total cancer risk.•Reducing industrial discharge and agrochemical use is key for alleviating human health risk.
Conducting integrated analysis of the source, exposure and health risk of heavy metals is critical for developing mitigation strategies of soil contamination. Taking the former electronic waste (e-waste) dismantling center in China as an example this study quantitatively apportioned source contribution of soil heavy metals in this area by statistical analysis and positive matrix factorization (PMF) model. Furthermore, the human health risk of identified sources were quantified by combining source profiles and exposure risk assessment. The seven heavy metals investigated were arsenic (As), cadmium (Cd), copper (Cu), chromium (Cr), nickel (Ni), lead (Pb) and Zinc (Zn). Results indicated that agricultural soils were mainly contaminated with Cd and Cu. Parent material and pesticide, fertilizer application, industrial discharge, and vehicle emission accounted for 46.6, 22.2, and 31.2%, respectively, of the accumulation of metals in the soil. Moreover, these sources contributed 52.9, 19.0, and 28.1%, respectively of the total non-cancer risk. For the total cancer risk, the contribution of these three sources was 39.2, 45.3, and 15.5%, respectively. Despite that industrial discharge contributed the least to the accumulation of metals (22.2%), it contributed the most to the total cancer risk (45.3%). Reducing industrial emission was crucial for minimizing the heavy metal input to agricultural soils and preventing potential health hazard. These findings could provide support for environmental protection authority to improve the management and risk prevention of contaminated farmland.
In breast cancer, epithelial-mesenchymal transition (EMT) is positively associated with programmed death ligand 1 (PD-L1) expression and immune escape, and TWIST1 silences ERα expression and induces ...EMT and cancer metastasis. However, how TWIST1 regulates PD-L1 and immune evasion is unknown. This study analyzed TWIST1 and PD-L1 expression in breast cancers, investigated the mechanism for TWIST1 to regulate PD-L1 transcription, and assessed the effects of TWIST1 and PD-L1 in cancer cells on cytotoxic CD8+ T cells. Interestingly, TWIST1 expression is correlated with high-level PD-L1 expression in ERα-negative breast cancer cells. The overexpression and knockdown of TWIST1 robustly upregulate and downregulate PD-L1 expression, respectively. TWIST1 binds to the PD-L1 promoter and recruits the TIP60 acetyltransferase complex in a BRD8-dependent manner to transcriptionally activate PD-L1 expression, which significantly accelerates the exhaustion and death of the cytotoxic CD8+ T cells. Accordingly, knockdown of TWIST1 or BRD8 or inhibition of PD-L1 significantly enhances the tumor antigen-specific CD8+ T cells to suppress the growth of breast cancer cells. These results demonstrate that TWIST1 directly induces PD-L1 expression in ERα-negative breast cancer cells to promote immune evasion. Targeting TWIST1, BRD8, and/or PD-L1 in ERα-negative breast cancer cells with TWIST1 expression may sensitize CD8+ T-cell-mediated immunotherapy.
IMPORTANCE: Patients with metastatic colorectal cancer (CRC) have limited effective and tolerable treatment options. OBJECTIVE: To evaluate the efficacy and safety of oral fruquintinib, a vascular ...endothelial growth factor receptor (VEGFR) inhibitor, as third-line or later therapy in patients with metastatic CRC. DESIGN, SETTING, AND PARTICIPANTS: FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) was a randomized, double-blind, placebo-controlled, multicenter (28 hospitals in China), phase 3 clinical trial. From December 2014 to May 2016, screening took place among 519 patients aged 18 to 75 years who had metastatic CRC that progressed after at least 2 lines of chemotherapy but had not received VEGFR inhibitor therapy; 416 met the eligibility criteria and were stratified by prior anti-VEGF therapy and K-ras status. The final date of follow-up was January 17, 2017. INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Key secondary efficacy endpoints were progression-free survival (time from randomization to disease progression or death), objectiveresponse rate (confirmed complete or partial response), and disease control rate (complete or partial response, or stabledisease recorded ≥8 weeks postrandomization). Duration of response was also assessed. Safety outcomes included treatment-emergent adverse events. RESULTS: Of the 416 randomized patients (mean age, 54.6 years; 161 38.7% women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months 95% CI, 8.2-10.5 vs 6.6 months 95% CI, 5.9-8.1); hazard ratio (HR) for death, 0.65 (95% CI, 0.51-0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months 95% CI, 3.7-4.6 vs 1.8 months 95% CI, 1.8-1.8 months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization. CONCLUSIONS AND RELEVANCE: Among Chinese patients with metastatic CRC who had tumor progression following at least 2 prior chemotherapy regimens, oral fruquintinib compared with placebo resulted in a statistically significant increase in overall survival. Further research is needed to assess efficacy outside of China. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02314819
Heavy-metal contamination in soil has long been a persistent challenge and the utilization of agricultural waste for in-situ stabilization remediation presents a promising approach to tackle this ...problem. Agricultural wastes exhibit promising potential in the remediation of contaminated land and modification could improve the adsorption performance markedly. Citric acid and Fe3O4 treated sugarcane bagasse adsorbed more heavy metals than raw materials in the aqueous system, employing these materials for heavy metal remediation in soil holds significant implications for broadening the raw material source of passivators and enhancing waste utilization efficiency. In this paper, a 120-day soil incubation study was conducted to compare the effects of pristine sugarcane bagasse (SB), citric-acid modified (SSB1, SSB2 and SSB3 with increasing proportion of citric acid) and citric-acid/Fe3O4 modified (MSB1, MSB4 and MSB7 with increasing proportion of Fe3O4) sugarcane bagasse at 1 % addition rate on cadmium (Cd) and copper (Cu) passivation. The SB, SSB1 and MSB1 did not always decrease the content of CaCl2-extractable Cd while all the seven amendments decreased the CaCl2-extractable Cu during the experiment period. Among all materials, SSB3 and MSB7 exhibited the highest efficiency in reducing the concentrations of CaCl2-extractable Cd and Cu. At Day 120, SB, SSB3 and MSB7 reduced the content of CaCl2-extractable Cd by 8 %, 18 % and 24 %, and of CaCl2-extractable Cu by 25 %, 50 % and 61 %, respectively. The efficiency of Cd and Cu immobilization was associated positively with the pH, functional groups and H-bonds of the amendments. The results suggest that the efficiency of sugarcane bagasse in heavy-metal passivation can be largely enhanced through chemical modifications using high proportions of citric acid and Fe3O4.
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•Novel sugarcane bagasse (SB)-based amendments immobilize Cd and Cu in soil.•The amendments are more effective to immobilize Cu than Cd.•SSB3 and MSB7 exhibit the best performance in passivating both Cd and Cu.•CaCl2-extractable Cd is the main component of acid-soluble Cd.•Cd and Cu immobilization results from high pH, functional groups and H-bonding.
Active damping is a popular approach to suppress the resonance in LCL-filtered grid-connected inverter owing to lossless damping and efficient system design. In capacitor voltage (CV) damping ...methods, a differential compensator is essentially needed in feedback path, where the damping effectiveness depends on emulated derivative characteristics of the compensator. Such CV feedback compensation methods face design limitation at the critical resonance frequency and may require additional delay reduction to ensure stability. In this article, an alternative parallel feedforward compensation method is proposed to synthesize an almost strictly positive real plant and achieved damping with modified stability characteristics. A second-order bandpass section is employed as a compensator in damping loop based on the proposed control scheme. The main features of the proposed method are effective damping without critical resonance frequency damping limit, extended stable damping region, improved control performance, and good robustness under filter parameters and grid inductance variation conditions. The simulation and experimental results are presented to verify the effectiveness of the proposed method.
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