Evaluating the impact of biochar amendment on antibiotic resistance genes and microbiome dynamics in soil, rhizosphere, and endosphere at field scale.

Biochar amendment is a promising strategy for mitigating antibiotic resistance genes (ARGs) in soil and plants, but its effects on ARGs at field scale are not fully understood. Here, field trials were executed utilizing two plant varieties, Brassica juncea and Lolium multiflorum, with four types of biochar to investigate changes in ARGs and microbiome in soil, rhizosphere, root endophytes, and leaf endophytes. Results showed that biochar altered ARG distribution in soil and plant, and restrained their transmission from soil and rhizosphere to endophytes. A reduction of 1.2-2.2 orders of magnitude in the quantity of ARGs was observed in root and leaf endophytes following biochar addition, while no significant changes were observed in soil and rhizosphere samples. Procrustes and network analyses revealed significant correlations between microbial communities and mobile genetic elements with ARGs (P < 0.05). Besides, redundancy and variation partitioning analysis indicated that bacterial communities may play a dominant role in shaping the ARGs profile, contributing to 43 % of the variation observed in ARGs. These field results suggest that biochar amendment alone may not fully alleviate ARGs in soil, but it has a significant beneficial impact on food safety and human health by effectively reducing ARGs in plant endophytes.

Combined use of arbuscular mycorrhizal fungi and alkaline lignin enhance phosphorus nutrition and alleviate cadmium stress in lettuce (Lactuca sativa L.).

The excessive application of phosphorus (P) fertiliser and its poor utilisation efficiency have led to significant amounts of P being retained in agricultural soils in unavailable forms. The application of alkaline lignin to soil and its inoculation with arbuscular mycorrhizal fungi (AMF) have both been shown to improve plant P nutrition. However, their combined effects on soil P transformation remain unclear, particularly in cadmium (Cd)-contaminated soils. A potting experiment was conducted to examine the combined effects of AMF and alkaline lignin on soil P and Cd bioavailability and on the uptake of P and Cd by lettuce (Lactuca sativa L.) that were grown for 56 d in a growth chamber. Combined AMF and alkaline lignin treatment increased soil P availability and alkaline phosphatase activity. It furthermore increased bioavailable Cd concentrations of rhizosphere and bulk soils by 48 % and 72 %, respectively, and the Cd concentration in roots by 85 %, but the Cd concentration was not affected in the edible parts (shoots) of the lettuce. Moreover, the combined treatment increased shoot biomass by 26-70 % and root biomass by 99-164 %. Our findings suggested that the combined use of AMF and alkaline lignin mobilised both P and Cd in soil but did not increase the accumulation of Cd in the shoots of plants growing in Cd-contaminated soils, these results would provide guideline for increasing Cd tolerance of plants and their yield.

Temperature-dependent trophic associations modulate soil bacterial communities along latitudinal gradients.

Understanding the environmental and biological mechanisms shaping latitudinal patterns in microbial diversity is challenging in the field of ecology. Although multiple hypotheses have been proposed to explain these patterns, a consensus has rarely been reached. Here, we conducted a large-scale field survey and microcosm experiments to investigate how environmental heterogeneity and putative trophic interactions (exerted by protist-bacteria associations and T4-like virus-bacteria associations) affect soil bacterial communities along a latitudinal gradient. We found that the microbial latitudinal diversity was kingdom dependent, showing decreasing, clumped, and increasing trends in bacteria, protists, and T4-like viruses, respectively. Climatic and edaphic drivers played predominant roles in structuring the bacterial communities; the intensity of the climatic effect increased sharply from 30°N to 32°N, whereas the intensity of the edaphic effect remained stable. Biotic associations were also essential in shaping the bacterial communities, with protist-bacteria associations showing a quadratic distribution, whereas virus-bacteria associations were significant only at high latitudes. The microcosm experiments further revealed that the temperature component, which is affiliated with climate conditions, is the primary regulator of trophic associations along the latitudinal gradient. Overall, our study highlights a previously underestimated mechanism of how the putative biotic interactions influence bacterial communities and their response to environmental gradients.

Preventive and reparative potentials of heat-inactivated and viable commensal Bacillus pumilus SE5 in ameliorating the adverse impacts of high soybean meal in grouper (Epinephelus coioides).

Probiotic Bacillus pumilus SE5, heat-inactivated (HSE5) or active (ASE5), were supplemented to high soybean meal (HSM) (36 %) diet at whole term (0-56 days) and middle term (29-56 days) to investigate the preventing and repairing effects of B. pumilus SE5 in ameliorating the adverse effects of HSM in Epinephelus coioides. The results suggested that the HSM significantly decreased the weight gain rate (WGR), specific growth rate (SGR), and increased the feed conversion rate (FCR) at day 56 (P < 0.05), while HSE5 and ASE5 promoted the growth performance. The HSE5 and ASE5 showed preventive and reparative functions on the antioxidant capacity and serum immunity, with significantly increased the total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-PX) activities, and reduced malondialdehyde (MDA) level, and increased acid phosphatase (ACP), alkaline phosphatase (AKP), immunoglobulin M (IgM) and complement 3 (C3). The HSM impaired the intestinal health (destroyed the intestinal structure, significantly increased the contents of serum D-lactic acid and diamine oxidase, and reduced the expressions of claudin-3 and occludin), while HSE5 and ASE5 improved them at whole term and middle term. The HSM impaired the intestinal microbiota and reduced its diversity, and the HSE5 or ASE5 improved the intestinal microbiota (especially at whole term). HSE5 and ASE5 improved the intestinal mRNA expressions of anti-inflammatory genes (il-10 and tgf-ß1) and reduced the expressions of pro-inflammatory genes (il-1ß, il-8, il-12), and promoted the expressions of humoral immune factor-related genes (cd4, igm, mhcII-α) and antimicrobial peptide genes (ß-defensin, epinecidin-1 and hepcidin-1), and decreased the expressions of NF-κB/MAPK signaling pathway-related genes (ikk-α, nf-κb, erk-1), and improved the expressions of MAPK signaling pathway-related gene p38-α (P < 0.05). In conclusion, the heat-inactivated and active B. pumilus SE5 effectively prevented and repaired the suppressive effects of soybean meal in E. coioides, which underscored the potential of B. pumilus SE5 as a nutritional intervention agent in HSM diet in aquaculture.

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

Objective: The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Results: Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Changes in sediment greenhouse gases production dynamics in an estuarine wetland following invasion by Spartina alterniflora.

Invasive Spartina alterniflora (S. alterniflora) has significant impacts on sediment biogeochemical cycling in the tidal wetlands of estuaries and coasts. However, the impact of exotic Spartina alterniflora invasion on greenhouse gases (GHGs) production dynamics in sediments remain limited. Here, we investigated the dynamics of sediment physicochemical properties, GHGs production rates, and microbial gene abundances in a native Cyperus malacensis habitat and three invasive S. alterniflora habitats (6-, 10-, and 14-year) in the Minjiang River Estuary, China. The methane (CH4), carbon dioxide (CO2), and nitrous oxide (N2O) production rates varied both spatially and seasonally, while microbial gene abundances (bacterial and fungal gene abundances) and organic matter (TOC and TN) only varied spatially. GHGs production rates were also characterized by higher values in surface sediment (0-10 cm) compared to subsurface sediment (10-20 cm) and by seasonal variations with higher values in summer than in winter. S. alterniflora invasion can significantly increase CH4 and CO2 production rates, organic matter, and microbial gene abundances (p < 0.05). Temperature, organic matter and microbial gene abundances were the most dominating factor controlling the spatio-temporal variations of CH4 and CO2 production rates. Overall, our findings highlighted the significant role of S. alterniflora invasion in regulating GHGs production rates in coastal wetland sediments and provided fundamental data for estimating GHGs emissions and carbon sequestration in the complex tidal wetlands.

The critical role of organic matter for cadmium-lead interactions in soil: Mechanisms and risks.

Understanding the interaction mechanisms between complex heavy metals and soil components is a prerequisite for effectively forecasting the mobility and availability of contaminants in soils. Soil organic matter (SOM), with its diverse functional groups, has long been a focal point of research interest. In this study, four soils with manipulated levels of SOM, cadmium (Cd) and lead (Pb) were subjected to a 90-day incubation experiment. The competitive interactions between Cd and Pb in soils were investigated using Fourier transform infrared spectrometer (FTIR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and X-ray adsorption near-edge structure (XANES) analysis. Our results indicate that Pb competed with Cd for adsorption sites on the surface of SOM, particularly on carboxyl and hydroxyl functional groups. Approximately 22.6 % of Cd adsorption sites on humus were occupied by Pb. The use of sequentially extracted exchangeable heavy metals as indicators for environment risk assessments, considering variations in soil physico-chemical properties and synergistic or antagonistic effects between contaminants, provides a better estimation of metal bioavailability and its potential impacts. Integrating comprehensive contamination characterization of heavy metal interactions with the soil organic phase is an important advancement to assess the environmental risks of heavy metal dynamics in soil compared to individual contamination assessments.

Synchronous influence of soil amendments on alkylmercury and methane emissions in mercury-contaminated paddy soil.

Mercury (Hg) alkylation and methane (CH4) emissions pose significant global concerns. Paddy soil, due to its long-term anaerobic conditions and abundant organic matter, is hotspots for soil Hg alkylation and CH4 emissions. However, the relevance between Hg alkylation and CH4 emissions, especially their simultaneous reduction strategies, remains poorly understood. Here, we investigated the effects of biochar (BC), selenium (Se) and rice straw (RS) amendments on Hg alkylation and CH4 emissions in paddy soil, and the accumulation of Hg speciation. Results found that both BC and RS amendments significantly increased the levels of soil organic carbon (SOC) and humification index (HIX). Furthermore, BC decreased the concentrations of Hg(II), methylmercury (MeHg) and ethylmercury (EtHg) by 63.1%, 53.6% and 100% in rice grains. However, RS increased Hg(II) concentration but decreased the total Hg (THg), MeHg and EtHg concentrations in rice grains. Compared to the CK, RS significantly increased CH4 emissions, while BC decreased CH4 emissions, and Se showed no significant difference. Se amendment increased the Hg(II) and EtHg concentrations by 20.3% and 17.0% respectively, and decreased the MeHg concentration in grains by 58.3%. Both BC and RS impacted the abundance of methanogens by enhancing SOC and HIX, subsequently modulating the relevance between Hg alkylation and CH4 emissions. These findings provide insights into the relevance between Hg alkylation and CH4 emissions and propose potential mitigation mechanisms in Hg-contaminated paddy soil.

Targeting Nuclear Receptor Coactivator SRC-1 Prevents Colorectal Cancer Immune Escape by Reducing Transcription and Protein Stability of PD-L1.

Programmed death-ligand 1 (PD-L1) is overexpressed in multiple cancers and critical for their immune escape. It has previously shown that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability, yet its role in CRC immune escape is unclear. Here, we demonstrate that SRC-1 is positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibits PD-L1 expression in CRC cells and retards murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration of CD8+ T cells. Genetic ablation of SRC-1 in mice also decreases PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models. Taken together, these findings highlight a crucial role of SRC-1 in regulating PD-L1 expression and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment.

Application of citric acid can enhance the accuracy for 13C-urea breath tests in the diagnosis of Helicobacter pylori infection in Chinese patients.

Previous published data have confirmed that the addition of a citric acid meal improves the accuracy of the 13C-urea breath test (13C-UBT). However, some studies have suggested that a citric acid test meal may not be necessary. Thus, the aim of this study was to evaluate the combination of a 13C-UBT with a citric acid meal for the diagnosis of Helicobacter pylori (Hp) infection in a Chinese population, particularly for patients with results in the gray zone. In this paired self-controlled study, all subjects had previously undergone 13C-UBTs without citric acid meals and were randomly divided into two groups based on different doses of citric acid (a low-dose citric acid group and a high-dose citric acid group, comprising meals with 0.68 g and 3.84 g citric acid powder, respectively). Positive rapid urease test (CLO) test and histology results were considered the 'gold standard'. The mean delta over baseline (DOB) value, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were compared between the two groups, particularly for patients with results in the gray zone. In total, 285 patients were tested. Of these patients, 189 were included in the low-dose citric acid group, and 96 were included in the high-dose citric acid group. Among patients with a positive 13C-UBT result without citric acid [delta over baseline (DOB) value ≥ 4‰, n = 174] and a negative 13C-UBT result without citric acid (DOB value < 4‰, n = 111), 8.0% (14/174) were false positive, and 0.9% (1/111) was false negative as determined by gold standard. Of 14 patients with false positive, 78.6% (11/14) false positive were in the gray zone of 4-10‰. However, there were no false positive 13C-UBT results with citric acid in the the gray zone of 4-10‰. In the comparison of the commercial 13C-UBT with the 13C-UBT in the low-dose citric acid group, the sensitivity, specificity, PPV, NPV and accuracy at 15 min were as follows: 99.1% vs. 99.1%, 97.5% vs. 88.9%, 98.2% vs. 92.2%, 98.8% vs. 98.6% and 98.4% vs. 94.7%, respectively. In the the gray zone of 4.0-10.0‰, the comparison of the commercial 13C-UBT with the 13C-UBT in the low-dose citric acid group, the sensitivity, specificity, PPV, and accuracy at 15 min were as follows: 94.4% vs. 100.0%, 100.0% vs. 0%, 100.0% vs. 75.0% and 95.8% vs. 75.0%, respectively. No significant difference was observed between the 15-min and 30-min measurement intervals in the low- and high-dose citric acid groups, including patients with results in the gray zone. The low-dose citric acid test, with an optimal measurement interval of 15 min, was highly accurate in the diagnosis of Hp infection in the Chinese population, especially for individuals with results in the gray zone.

Unveiling the barriers of Cd translocation from soil to rice: Insights from continuous flooding.

Understanding the spatiotemporal processes governing Cd behavior at the soil-solution-root interface is crucial for developing effective remediation strategies. This study examined the processes of chemical remediation in Cd-contaminated paddy soil using rhizotrons over the entire rice growth period. One-dimensional profile sampling with a 10 cm resolution revealed that during the initial flooding, paddy soil was strongly stimulated, followed by stabilization of porewater properties. X-ray diffraction of freeze-dried porewater confirmed the generation of submicron-precipitates such as CdS under continuous flooding, resulting in low ion levels of water-soluble Cd (<1 µg/L) and sulfate (<10 mg/L) in porewater. Two-dimensional imaging technologies indicated the maximum iron­manganese plaque (IP) within 20-110 µm of the root surface. Subsequently, monitoring O2 in the rhizosphere with a planar optode by two 100 cm2 membranes for a consecutive month revealed significant circadian O2 variations between the root base and tip. Destructive sampling results showed that acid-soluble Cd in soils, as available Cd, is crucial for Cd uptake by rice roots under continuous flooding. The IP deposited on the root surface, as the barriers of Cd translocation, increased with rice growth and blocked Cd translocation from soil to rice by about 18.11 %-25.43 % at maturity. A Si-Ca-Mg compound amendment reduced available Cd by about 10 % and improved Cd blocking efficiency by about 7.32 % through increasing IP concentration, resulting in the absorption ratio of Cd in the amendment group being half that of the control group. By unveiling the complex Cd interactions at the soil-rice interface, this study lays the groundwork for developing effective agricultural practices to mitigate Cd-contaminated paddy and ensure food safety.

Postfire Phosphorus Enrichment Mitigates Nitrogen Loss in Boreal Forests.

Net nitrogen mineralization (Nmin) and nitrification regulate soil N availability and loss after severe wildfires in boreal forests experiencing slow vegetation recovery. Yet, how microorganisms respond to postfire phosphorus (P) enrichment to alter soil N transformations remains unclear in N-limited boreal forests. Here, we investigated postfire N-P interactions using an intensive regional-scale sampling of 17 boreal forests in the Greater Khingan Mountains (Inner Mongolia-China), a laboratory P-addition incubation, and a continental-scale meta-analysis. We found that postfire soils had an increased risk of N loss by accelerated Nmin and nitrification along with low plant N demand, especially during the early vegetation recovery period. The postfire N/P imbalance created by P enrichment acts as a "N retention" strategy by inhibiting Nmin but not nitrification in boreal forests. This strategy is attributed to enhanced microbial N-use efficiency and N immobilization. Importantly, our meta-analysis found that there was a greater risk of N loss in boreal forest soils after fires than in other climatic zones, which was consistent with our results from the 17 soils in the Greater Khingan Mountains. These findings demonstrate that postfire N-P interactions play an essential role in mitigating N limitation and maintaining nutrient balance in boreal forests.

TWIST1 Drives Cytotoxic CD8+ T-Cell Exhaustion through Transcriptional Activation of CD274 (PD-L1) Expression in Breast Cancer Cells.

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.

Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans.

Declined memory is a hallmark of Alzheimer's disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HT2CR signaling regulates memory, which may inform the use of 5-HT2CR agonists in the treatment of dementia.

Value of magnetic resonance imaging for diagnosis of LR­3 and LR-4 lesions coexisting with hepatocellular carcinoma.

PURPOSE: To explore which preoperative clinical data and conventional magnetic resonance imaging (MRI) features may indicate the presence of hepatocellular carcinoma (HCC) in HCC patients coexisting with LR-3 and LR-4 lesions. METHODS: HCC Patients coexisting with LR-3 and LR-4 lesions who participated in a prospective clinical trial (XX) were included in this study. Two radiologists independently assessed the preoperative MRI features and each lesion was assigned according to the liver imaging reporting and data system (LI-RADS). The preoperative clinical data were also evaluated. The relative values of these parameters were assessed as potential predictors of HCC for coexisting LR-3 and LR-4 lesions. RESULTS: We enrolled 102 HCC patients (58.1 ± 11.5 years; 84.3% males) coexisting with 110 LR-3 and LR-4 lesions (HCCs group [n = 66]; non-HCCs group [n = 44]). The presence of restricted diffusion (OR: 18.590, p < 0.001), delayed enhancement (OR: 0.113, p < 0.001), and mild-moderate T2 hyperintensity (OR: 3.084, p = 0.048) were found to be independent predictors of HCC diagnosis. The sensitivity and specificity of the above independent variables for the diagnosis of HCC ranged from 66.7 to 80.3% and 56.8 to 88.6%, respectively. ROC analysis showed that, in discriminating HCC, the AUCs of the above factors were 0.777, 0.686, and 0.670, respectively. Combining these three findings for the prediction of HCC resulted in a specificity greater than 97%, and the AUC further increased to 0.874. CONCLUSION: The presence of restricted diffusion, delayed enhancement, and mild-moderate T2 hyperintensity can be useful features for risk stratification of coexisting LR-3 and LR-4 lesions in HCC patients. Trial registration a prospective clinical trial (ChiCTR2000036201).

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.

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.

Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool.

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.

Discussion: Embracing microfluidics to advance environmental science and technology.

Microfluidics, also called lab-on-a-chip, represents an emerging research platform that permits more precise and manipulation of samples at the microscale or even down to the nanoscale (nanofluidic) including picoliter droplets, microparticles, and microbes within miniaturized and highly integrated devices. This groundbreaking technology has made significant strides across multiple disciplines by providing an unprecedented view of physical, chemical, and biological events, fostering a holistic and an in-depth understanding of complex systems. The application of microfluidics to address the challenges in environmental science is likely to contribute to our better understanding, however, it's not yet fully developed. To raise researchers' interest, this discussion first delineates the valuable and underutilized environmental applications of microfluidic technology, ranging from environmental surveillance to acting as microreactors for investigating interfacial dynamic processes, and facilitating high-throughput bioassays. We highlight, with examples, how rationally designed microfluidic devices lead to new insights into the advancement of environmental science and technology. We then critically review the key challenges that hinder the practical adoption of microfluidic technologies. Specifically, we discuss the extent to which microfluidics accurately reflect realistic environmental scenarios, outline the areas to be improved, and propose strategies to overcome bottlenecks that impede the broad application of microfluidics. We also envision new opportunities and future research directions, aiming to provide guidelines for the broader utilization of microfluidics in environmental studies.

Distinct biophysical and chemical mechanisms governing sucrose mineralization and soil organic carbon priming in biochar amended soils: evidence from 10 years of field studies.

While many studies have examined the role of biochar in carbon (C) accrual in short-term scale, few have explored the decadal scale influences of biochar on non-biochar C, e.g., native soil organic C (SOC) and added substrate. To address this knowledge gap, soils were collected from decade-old biochar field trials located in the United Kingdom (Cambisol) and China (Fluvisol), with each site having had three application rates (25-30, 50-60 and 75-100 Mg ha-1) of biochar plus an unamended Control, applied once in 2009. We assessed physicochemical and microbial properties associated with sucrose (representing the rhizodeposits) mineralization and the priming effect (PE) on native SOC. Here, we showed both soils amended with biochar at the middle application rate (50 Mg ha-1 biochar in Cambisol and 60 Mg ha-1 biochar in Fluvisol) resulted in greater substrate mineralization. The enhanced accessibility and availability of sucrose to microorganisms, particularly fast-growing bacterial genera like Arenimonas, Spingomonas, and Paenibacillus (r-strategists belonging to the Proteobacteria and Firmicutes phyla, respectively), can be attributed to the improved physicochemical properties of the soil, including pH, porosity, and pore connectivity, as revealed by synchrotron-based micro-CT. Random forest analysis also confirmed the contribution of the microbial diversity and physical properties such as porosity on sucrose mineralization. Biochar at the middle application rate, however, resulted in the lowest PE (0.3 and 0.4 mg of CO2-C g soil-1 in Cambisol and Fluvisol, respectively) after 53 days of incubation. This result might be associated with the fact that the biochar promoted large aggregates formation, which enclosed native SOC in soil macro-aggregates (2-0.25 mm). Our study revealed a diverging pattern between substrate mineralization and SOC priming linked to the biochar application rate. This suggests distinct mechanisms, biophysical and physicochemical, driving the mineralization of non-biochar carbon in a field where biochar was applied a decade before. Supplementary Information: The online version contains supplementary material available at 10.1007/s42773-024-00327-0.