Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial.

BACKGROUND: First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data. METHODS: This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population. RESULTS: A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. CONCLUSIONS: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC.

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Oxidized low-density lipoprotein changes the inflammatory status and metabolomics profiles in human and mouse macrophages and microglia.

The conjunctiva of primary open angle glaucoma patients showed high level of oxidized low-density lipoprotein (ox-LDL), which is associated with the inflammatory response. Microglia and macrophages are the immune cells involved in retinal ganglion cell survival regulation; yet, their roles of the ox-LDL-induced inflammation in glaucoma remain elusive. Here we aimed to investigate the lipid uptake, inflammatory cytokine expression, and metabolomics profiles of human and murine-derived microglial and macrophage cell lines treated with ox-LDL. Under the same ox-LDL concentration, macrophages exhibited higher lipid uptake and expression of pro-inflammatory cytokines as compared to microglia. The ox-LDL increased the levels of fatty acid metabolites in macrophages and sphingomyelin metabolites in microglia. In summary, this study revealed the heterogeneity in the inflammatory capacity and metabolic profiles of macrophages and microglia under the stimulation of ox-LDL.

Pleurotus eryngii root waste and soybean meal co-fermented protein improved the growth, immunity, liver and intestinal health of largemouth bass (Micropterus salmoides).

The present study aimed to evaluate the effect of king oyster mushroom (Pleurotus eryngii) root waste and soybean meal co-fermented protein (CFP) on growth performance, feed utilization, immune status, hepatic and intestinal health of largemouth bass (Micropterus salmoides). Largemouth bass (12.33 ± 0.18 g) were divided into five groups, fed with diets containing 0 %, 5 %, 10 %, 15 % and 20 % CFP respectively for 7 weeks. The growth performance and dietary utilization were slightly improved by the supplementation of CFP. In addition, improved immunoglobulin M (IgM) content and lysozyme activity in treatments confirm the enhancement of immunity in fish by the addition of CFP, especially in fish fed 20 % CFP (P < 0.05). Furthermore, CFP significantly improved liver GSH (glutathione) content in groups D10 and D15 (P < 0.05), and slightly improved total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity while slightly reduced malondialdehyde (MDA) content. Simultaneously, the upregulation of lipolysis-related genes (PPARα, CPT1 and ACO) expression and downregulation of lipid synthesis-related genes (ACC and DGAT1) expression was recorded in the group D20 compared with the control (P < 0.05), which were consistent with the decreased liver lipid contents, suggests that lipid metabolism was improved by CFP. In terms of intestinal structural integrity, ameliorated intestinal morphology in treatments were consistent with the upregulated Occludin, Claudin-1 and ZO-1 genes expression. The intestinal pro-inflammatory cytokines (TNF-α and IL-8) expression were suppressed while the anti-inflammatory cytokines (IL-10 and TGF-ß) were activated in treatments. The expression of antimicrobial peptides (Hepcidin-1, Piscidin-2 and Piscidin-3) and intestinal immune effectors (IgM and LYZ) were slightly up-regulated in treatments. Additionally, the relative abundance of intestinal beneficial bacteria (Firmicutes) increased while the relative abundance of potential pathogenic bacteria (Fusobacterium and Proteobacteria) decreased, which indicated that the intestinal microbial community was well-reorganized by CFP. In conclusion, dietary CFP improves growth, immunity, hepatic and intestinal health of largemouth bass, these data provided a theoretical basis for the application of this novel functional protein ingredient in fish.

Fertilizer application alters cadmium and selenium bioavailability in soil-rice system with high geological background levels.

The co-occurrence of cadmium (Cd) pollution and selenium (Se) deficiency commonly exists in global soils, especially in China. As a result, there is great interest in developing practical agronomic strategies to simultaneously achieve Cd remediation and Se mobilization in paddy soils, thereby enhancing food quality/safety. To this end, we conducted a field-plot trial on soils having high geological background levels of Cd (0.67 mg kg-1) and Se (0.50 mg kg-1). We explored 12 contrasting fertilizers (urea, potassium sulfate (K2SO4), calcium-magnesium-phosphate (CMP)), amendments (manure and biochar) and their combinations on Cd/Se bioavailability. Soil pH, total organic carbon (TOC), soil available Cd/Se, Cd/Se fractions and Cd/Se accumulation in different rice components were determined. No significant differences existed in mean grain yield among treatments. Results showed that application of urea and K2SO4 decreased soil pH, whereas the CMP fertilizer and biochar treatments increased soil pH. There were no significant changes in TOC concentrations. Three treatments (CMP, manure, biochar) significantly decreased soil available Cd, whereas no treatment affected soil available Se at the maturity stage. Four treatments (CMP, manure, biochar and manure＋urea＋CMP＋K2SO4) achieved our dual goal of Cd reduction and Se enrichment in rice grain. Structural equation modeling (SEM) demonstrated that soil available Cd and root Cd were negatively affected by pH and organic matter (OM), whereas soil available Se was positively affected by pH. Moreover, redundancy analysis (RDA) showed strong positive correlations between soil available Cd, exchangeable Cd and reducible Cd with grain Cd concentration, as well as between pH and soil available Se with grain Se concentration. Further, there was a strong negative correlation between residual Cd/Se (non-available fraction) and grain Cd/Se concentrations. Overall, this study identified the primary factors affecting Cd/Se bioavailability, thereby providing new guidance for achieving safe production of Se-enriched rice through fertilizer/amendment management of Cd-enriched soils.

Profile of Lipoprotein Subclasses in Chinese Primary Open-Angle Glaucoma Patients.

To investigate the plasma lipoprotein subclasses in patients with primary open-angle glaucoma (POAG), a total of 20 Chinese POAG patients on intraocular pressure (IOP)-lowering treatment and 20 age-matched control subjects were recruited. Based on the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), the study subjects were divided into elevated- and normal-level subgroups. The plasma lipoprotein, lipoprotein subclasses, and oxidized LDL (oxLDL) levels were quantitatively measured. The discrimination potential of the lipoproteins was evaluated using the area under the receiver operating characteristic curve (AUC), and their correlation with clinical parameters was also evaluated. Compared to the control subjects with elevated TC and/or LDL-C levels, the levels of TC, LDL-C, non-high-density lipoprotein cholesterol (non-HDL), LDL subclass LDL3 and small dense LDL (sdLDL), and oxLDL were significantly higher in POAG patients with elevated TC and/or LDL-C levels. No differences in any lipoproteins or the subclasses were found between the POAG patients and control subjects with normal TC and LDL-C levels. Moderate-to-good performance of TC, LDL-C, non-HDL, LDL3, sdLDL, and oxLDL was found in discriminating between the POAG patients and control subjects with elevated TC and/or LDL-C levels (AUC: 0.710-0.950). Significant negative correlations between LDL3 and sdLDL with retinal nerve fiber layer (RNFL) thickness in the superior quadrant and between LDL3 and average RNFL thickness were observed in POAG patients with elevated TC and/or LDL-C levels. This study revealed a significant elevation of plasma lipoproteins, especially the LDL subclasses, in POAG patients with elevated TC and/or LDL-C levels, providing insights on monitoring specific lipoproteins in POAG patients with elevated TC and/or LDL-C.

Peroxydisulfate-Driven Reductive Dechlorination as Affected by Soil Constituents: Free Radical Formation and Conversion.

We report a previously unrecognized but efficient reductive degradation pathway in peroxydisulfate (PDS)-driven soil remediation. With supplements of naturally occurring low-molecular-weight organic acids (LMWOAs) in anaerobic biochar-activated PDS systems, degradation rates of 12 γ-hexachlorocyclohexanes (HCH)-spiked soils boosted from 40% without LMWOAs to a maximum of 99% with 1 mM malic acid. Structural analysis revealed that an increase in α-hydroxyl groups and a diminution in pKa1 values of LMWOAs facilitated the formation of reductive carboxyl anion radicals (COO•-) via electrophilic attack by SO4•-/•OH. Furthermore, degradation kinetics were strongly correlated with soil organic matter (SOM) contents than iron minerals. Combining a newly developed in situ fluorescence detector of reductive radicals with quenching experiments, we showed that for soils with high, medium, and low SOM contents, dominant reactive species switched from singlet oxygen/semiquinone radicals to SO4•-/•OH and then to COO•- (contribution increased from 30.8 to 66.7%), yielding superior HCH degradation. Validation experiments using SOM model compounds highlighted critical roles of redox-active moieties, such as phenolic - OH and quinones, in radical formation and conversion. Our study provides insights into environmental behaviors related to radical activation of persulfate in a broader soil horizon and inspiration for more advanced reduction technologies.

Agricultural management practices in China enhance nitrogen sustainability and benefit human health.

The potential of enhanced agricultural management practices to drive sustainability is rarely quantified at grassroots level. Here we analyse nitrogen use and loss in Chinese cropland, drawing from data collected in 2,238,550 sites in two national agricultural pollution source censuses from 2007 to 2017. We find an upswing of 10% in crop yields and an 8% reduction in nitrogen pollution during this period, owing to the promotion and adoption of various management practices (including the combination of organic and chemical fertilizers, straw recycling and deep placement of fertilizer). These practices have collectively contributed to an 18% increase in nitrogen use efficiency in the country. By fully embracing them, we project that annual cropland pollution could be further reduced by up to 1.4 Mt of nitrogen without compromising crop yields. Environmental and human health benefits are projected to consistently outweigh implementation costs in the future, with total benefits reaching US$15 billion.

Untargeted and Oxylipin-Targeted Metabolomics Study on the Plasma Samples of Primary Open-Angle Glaucoma Patients.

Purpose: to determine the metabolomics profiles in the plasma samples of primary open-angle glaucoma (POAG) patients. Methods: The plasma samples from 20 POAG patients under intraocular pressure (IOP)-lowering medication treatment and 20 control subjects were subjected to the untargeted metabolomics analysis, among which 10 POAG patients and 10 control subjects were further subjected to the oxylipin-targeted metabolomics analysis by liquid chromatography-mass spectrometry analysis. The prediction accuracy of the differentially abundant metabolites was assessed by the receiver operating characteristic curves. Pathway analysis and correlation analysis on the differentially abundant metabolites and clinical and biochemical parameters were also conducted. Results: Untargeted metabolomics profiling identified 33 differentially abundant metabolites in the POAG patients, in which the metabolism of linoleic acid, α-linolenic acid, phenylalanine, and tricarboxylic acid cycle were enriched. The correlation analysis indicated that the differentially abundant metabolites were associated with central corneal thickness, peripapillary retinal nerve fiber layer thickness, visual field defects, and lymphocytes. The oxylipin-targeted metabolomics analysis identified 15-keto-Prostaglandin F2 alpha, 13,14-Dihydro-15-keto-prostaglandin D2, 11-Dehydro-thromboxane B2, 8,9-Epoxyeicosatrienoic acid, and arachidonic acid to be significantly decreased in the POAG patients and enriched in the arachidonic acid (AA) pathway. Conclusions: This study revealed that the metabolites in the arachidonic acid metabolism pathway are differentially abundant, suggesting high IOP may not be the only detrimental factor for optic nerve cell damage in this group of POAG patients. Lipid metabolism instability-mediated alterations in oxylipins and AA pathways may be important in POAG, suggesting that oxidative stress and immune-related inflammation could be valuable directions for future therapeutic strategies.

Managing fragmented croplands for environmental and economic benefits in China.

Cropland fragmentation contributes to low productivity and high abandonment risk. Using spatial statistics on a detailed land use map, we show that 10% of Chinese croplands have no potential to be consolidated for large-scale farming (>10 ha) owing to spatial constraints. These fragmented croplands contribute only 8% of total crop production while using 15% of nitrogen fertilizers, leading to 12% of fertilizer loss in China. Optimizing the cropping structure of fragmented croplands to meet animal food demand in China can increase animal food supply by 19%, equivalent to increasing cropland proportionally. This crop-switching approach would lead to a 10% and 101% reduction in nitrogen and greenhouse gas emissions, respectively, resulting in a net benefit of US$ 7 billion yr-1. If these fragmented croplands were relocated to generate large-scale farming units, livestock, vegetable and fruit production would be increased by 8%, 3% and 14%, respectively, and reactive nitrogen and greenhouse gas emissions would be reduced by 16% and 5%, respectively, resulting in a net benefit of US$ 44 billion yr-1. Both solutions could be used to achieve synergies between food security, economic benefits and environmental protection through increased agricultural productivity, without expanding the overall cropland area.

Pembrolizumab in patients from China with microsatellite instability-high/mismatch repair deficient tumors: KEYNOTE-158.

Aim: To evaluate pembrolizumab in patients of Chinese descent with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors enrolled in KEYNOTE-158 (Cohort L). Methods: Patients with MSI-H/dMMR advanced tumors received pembrolizumab 200 mg IV Q3W. Primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: 24 patients were enrolled (20 were evaluable for efficacy). With median follow-up of 12.4 months, the ORR was 70%. DOR, PFS and OS were all not reached. A total of 19 (79%) patients had a treatment-related adverse event (AE; grade ≥3 in 4 [17%]), and 8 (33%) had an immune-mediated AE (grade ≥3 in (4 [17%]). Conclusion: Pembrolizumab provided meaningful and durable responses with manageable safety. These results are consistent with those reported for the global trial.

Hippo cooperates with p53 to maintain foregut homeostasis and suppress the malignant transformation of foregut basal progenitor cells.

Basal progenitor cells serve as a stem cell pool to maintain the homeostasis of the epithelium of the foregut, including the esophagus and the forestomach. Aberrant genetic regulation in these cells can lead to carcinogenesis, such as squamous cell carcinoma (SCC). However, the underlying molecular mechanisms regulating the function of basal progenitor cells remain largely unknown. Here, we use mouse models to reveal that Hippo signaling is required for maintaining the homeostasis of the foregut epithelium and cooperates with p53 to repress the initiation of foregut SCC. Deletion of Mst1/2 in mice leads to epithelial overgrowth in both the esophagus and forestomach. Further molecular studies find that Mst1/2-deficiency promotes epithelial growth by enhancing basal cell proliferation in a Yes-associated protein (Yap)-dependent manner. Moreover, Mst1/2 deficiency accelerates the onset of foregut SCC in a carcinogen-induced foregut SCC mouse model, depending on Yap. Significantly, a combined deletion of Mst1/2 and p53 in basal progenitor cells sufficiently drives the initiation of foregut SCC. Therefore, our studies shed light on the collaborative role of Hippo signaling and p53 in maintaining squamous epithelial homeostasis while suppressing malignant transformation of basal stem cells within the foregut.

Biogeographic patterns and drivers of soil viromes.

Viruses are crucial in shaping soil microbial functions and ecosystems. However, studies on soil viromes have been limited in both spatial scale and biome coverage. Here we present a comprehensive synthesis of soil virome biogeographic patterns using the Global Soil Virome dataset (GSV) wherein we analysed 1,824 soil metagenomes worldwide, uncovering 80,750 partial genomes of DNA viruses, 96.7% of which are taxonomically unassigned. The biogeography of soil viral diversity and community structure varies across different biomes. Interestingly, the diversity of viruses does not align with microbial diversity and contrasts with it by showing low diversity in forest and shrubland soils. Soil texture and moisture conditions are further corroborated as key factors affecting diversity by our predicted soil viral diversity atlas, revealing higher diversity in humid and subhumid regions. In addition, the binomial degree distribution pattern suggests a random co-occurrence pattern of soil viruses. These findings are essential for elucidating soil viral ecology and for the comprehensive incorporation of viruses into soil ecosystem models.

Exploring additives beyond phthalates: Release from plastic mulching films, biodegradation and occurrence in agricultural soils.

It is widely recognized that applications of plastic films result in plastic pollution in agroecosystems. However, there is limited knowledge on the release and occurrence of additives beyond phthalates in agricultural soil. In this study, the rates of release and biodegradation of various additives, including phthalates, bisphenols, organophosphate esters, phenolic antioxidants, and ultraviolet absorbents from mulching films in soil were quantified by laboratory incubation. The rates of release and biodegradation ranged from 0.069 d-1 to 5.893 d-1 and from 1.43 × 10-3 d-1 to 0.600 d-1, respectively. Both of these rates were affected by temperature, flooding, and the properties of additives, films, and soils. An estimated 4000 metric tons of these additives were released into soil annually in China exclusively. The total concentrations of these additives in 80 agricultural soils varied between 228 and 3455 µg kg-1, with phenolic antioxidants, phthalates, and bisphenols accounting for 54.1%, 25.2%, and 17.9% of the total concentrations, respectively. A preliminary risk assessment suggested that the current levels of these additives could potentially present moderate hazards to the soil ecosystem.

Residual effects of chlorinated organic pollutants on microbial community and natural redox processes in coastal wetlands.

Chlorinated organic pollutants (COPs) are common in flooded environments. To examine the residual status and effects of COPs on flooded environments, a survey of 7 coastal wetlands in Zhejiang, East China was conducted. Total COP concentrations detected from 95.69 to 412.76 ng g-1 dw. Gamma-HCH and o,p'-DDT posed the greatest risk with exceedance rates of 100% according to sediment quality guidelines. Samples with higher COP pollution had higher microbial diversity, more complex microbial networks, more deterministic community assembly processes and lower microbiome stability, indicating an improved soil function for balance cycle of substances, especially for COP degradation. Further analysis using quantitative real-time PCR suggested COP-dechlorination interacted with natural redox processes, especially sulfate reduction and methanogenesis. The positive correlation between CH4 and pentachlorobenzene indicated a potential increase in greenhouse gas emissions caused by COP pollution. Correlation between dsr gene and COPs demonstrated the ability of sulfate-reducing bacteria to degrade COPs. Particularly, facultative OHRB such as sulfate-reducing bacteria hold significant importance in the process of COP-dechlorination. This finding provides a reference for COP pollution remediation. Collectively, our study offers new insight into the residual effect of COPs in coastal wetlands and contributes to an improved understanding of bioremediation strategies for COP pollution.

Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation.

The intracellular ATP-ribosyltransferases PARP1 and PARP2, contribute to DNA base excision repair (BER) and DNA demethylation and have been implicated in epigenetic programming in early mammalian development. Recently, proteomic analyses identified BER proteins to be covalently poly-ADP-ribosylated by PARPs. The role of this posttranslational modification in the BER process is unknown. Here, we show that PARP1 senses AP-sites and SSBs generated during TET-TDG mediated active DNA demethylation and covalently attaches PAR to each BER protein engaged. Covalent PARylation dissociates BER proteins from DNA, which accelerates the completion of the repair process. Consistently, inhibition of PARylation in mESC resulted both in reduced locus-specific TET-TDG-targeted DNA demethylation, and in reduced general repair of random DNA damage. Our findings establish a critical function of covalent protein PARylation in coordinating molecular processes associated with dynamic DNA methylation.

Surufatinib plus toripalimab in patients with advanced neuroendocrine tumours and neuroendocrine carcinomas: An open-label, single-arm, multi-cohort phase II trial.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib revealed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumours in a phase I study. PATIENTS AND METHODS: This was an open-label, single-arm, multi-cohort phase II study in China. Patients with advanced neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) or mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) who had failed or were intolerable of standard treatment were given surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary end-point was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end-points included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled into two cohorts by tumour types (NET, n = 19; NEC-MiNEN, n = 21). ORRs (95% CIs) were 21.1% (6.1-45.6) and 23.8% (8.2-47.2) in the NET and NEC-MiNEN cohorts, respectively. Median DoR was 7.1 months (6.9-not evaluable [NE]) and 4.1 months (3.0-NE), respectively. Median PFS was 9.6 months (4.1-NE) and 4.1 months (1.5-5.5); median OS was 27.3 (15.3-NE) and 10.9 months (9.1-14.6), respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 18 (45.0%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed antitumour activity and a tolerable safety profile in patients with previously treated NETs/NECs/MiNENs. Further study of this combination regimen is ongoing for advanced NECs, for which current therapeutic options remain limited. CLINICALTRIALS: gov: NCT04169672.

Microbial resistance and resilience to drought and rewetting modulate soil N2O emissions with different fertilizers.

Future climate models indicate an enhanced severity of regional drought and frequent rewetting events, which may cause cascading impacts on soil nitrogen cycle and nitrous oxide (N2O) emissions, but the underlying microbial mechanism remains largely unknown. Here we report an incubation study that examined the impacts of soil moisture status and nitrification inhibitor (DCD) on the N2O-producers and N2O-reducers following the application of urea and composted swine manure in an acid soil. The soil moisture treatments included 100 % water-holding capacity (WHC) (wetting, 35.3 % gravimetric soil water content), 40 % WHC (drought, 7 % gravimetric soil water content), and 40 % to 100 % WHC (rewetting). The results showed that N2O emissions were significantly decreased under drought conditions and were significantly increased after rewetting. The resistance of ammonia-oxidizing bacteria and nosZII, which was inhibited by urea or manure application, modulated N2O emissions under drought conditions. The resilience of the functional guilds modulated their dominant role in N2O emissions with rewetting. Ammonia-oxidizing bacteria, nirS-type denitrifying bacteria and nosZI showed significant resilience in response to rewetting. Significant negative relationships were observed between N2O emissions and nosZII clade under wetting condition and between N2O emissions and nosZI clade after rewetting. Our results highlighted the importance of microbial resistance and resilience in modulating N2O emissions, which help to better understand the dominant way of N2O emissions, and consequently make efficient mitigation strategies under the global climate change.

Managing urban development could halve nitrogen pollution in China.

Halving nitrogen pollution is crucial for achieving Sustainable Development Goals (SDGs). However, how to reduce nitrogen pollution from multiple sources remains challenging. Here we show that reactive nitrogen (Nr) pollution could be roughly halved by managed urban development in China by 2050, with NH3, NOx and N2O atmospheric emissions declining by 44%, 30% and 33%, respectively, and Nr to water bodies by 53%. While rural-urban migration increases point-source nitrogen emissions in metropolitan areas, it promotes large-scale farming, reducing rural sewage and agricultural non-point-source pollution, potentially improving national air and water quality. An investment of approximately US$ 61 billion in waste treatment, land consolidation, and livestock relocation yields an overall benefit of US$ 245 billion. This underscores the feasibility and cost-effectiveness of halving Nr pollution through urbanization, contributing significantly to SDG1 (No poverty), SDG2 (Zero hunger), SDG6 (Clean water), SDG12 (Responsible consumption and production), SDG14 (Climate Action), and so on.