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Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy. IDO1-mediated tryptophan metabolism plays an important role in creating an immunosuppressive tumour microenvironment. Here, the authors show that deubiquitinase USP14 regulates immune suppression by inducing IDO1 stabilization and suggest USP14 as a potential therapeutic target to improve immunotherapy in colorectal cancer.

China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2–3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. This randomised, open-label, phase 2–3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab–bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab–bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8–46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5–11·7) in the sintilimab–bevacizumab biosimilar group and 10·0 months (8·4–11·7) in the sorafenib group. Patients in the sintilimab–bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1–5·7]) than did patients in the sorafenib group (2·8 months [2·7–3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46–0·70; p<0·0001). In the first interim analysis of overall survival, sintilimab–bevacizumab biosimilar showed a significantly longer overall survival than did sorafenib (median not reached [95% CI not reached–not reached] vs 10·4 months [8·5–not reached]; HR 0·57, 95% CI 0·43–0·75; p<0·0001). The most common grade 3–4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patients in the sintilimab–bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesia syndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab–bevacizumab biosimilar group and 36 (19%) patients in the sorafenib group had serious adverse events. Treatment-related adverse events that led to death occurred in six (2%) patients in the sintilimab–bevacizumab biosimilar group (one patient with abnormal liver function, one patient with both hepatic failure and gastrointestinal haemorrhage, one patient with interstitial lung disease, one patient with both hepatic faliure and hyperkalemia, one patient with upper gastrointestinal haemorrhage, and one patient with intestinal volvulus) and two (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhage and one patient with death of unknown cause). Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.

This randomized, open-label, multi-center phase 2 study (NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemotherapy in patients with esophageal squamous cell carcinoma after first-line chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with efficacy. The median OS in the sintilimab group was significantly improved compared with the chemotherapy group (median OS 7.2 vs.6.2 months; P  = 0.032; HR = 0.70; 95% CI, 0.50–0.97). Incidence of treatment-related adverse events of grade 3–5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1%). Patients with high T-cell receptor (TCR) clonality and low molecular tumor burden index (mTBI) showed the longest median OS (15.0 months). Patients with NLR < 3 at 6 weeks post-treatment had a significantly prolonged median OS (16.6 months) compared with NLR ≥ 3. The results demonstrate a significant improvement in OS of sintilimab compared to chemotherapy as second-line treatment for advanced or metastatic ESCC. Patients with advanced esophageal cancer have poor prognosis and limited treatment options. This randomized, phase II trial compares the efficacy and safety of the anti-PD-1 antibody sintilimab versus chemotherapy in Chinese patients with esophageal squamous cell carcinoma after first-line therapy

Groundwater is one of the most important natural resources for economic development and environmental sustainability. In this study, we estimated groundwater storage in 11 major river basins across Alberta, Canada, using a combination of remote sensing (Gravity Recovery and Climate Experiment, GRACE), in situ surface water data, and land surface modeling estimates (GWSAsat). We applied separate calculations for unconfined and confined aquifers, for the first time, to represent their hydrogeological differences. Storage coefficients for the individual wells were incorporated to compute the monthly in situ groundwater storage (GWSAobs). The GWSAsat values from the two satellite-based products were compared with GWSAobs estimates. The estimates of GWSAsat were in good agreement with the GWSAobs in terms of pattern and magnitude (e.g., RMSE ranged from 2 to 14 cm). While comparing GWSAsat with GWSAobs, most of the statistical analyses provide mixed responses; however the Hodrick–Prescott trend analysis clearly showed a better performance of the GRACE-mascon estimate. The results showed trends of GWSAobs depletion in 5 of the 11 basins. Our results indicate that precipitation played an important role in influencing the GWSAobs variation in 4 of the 11 basins studied. A combination of rainfall and snowmelt positively influences the GWSAobs in six basins. Water budget analysis showed an availability of comparatively lower terrestrial water in 9 of the 11 basins in the study period. Historical groundwater recharge estimates indicate a reduction of groundwater recharge in eight basins during 1960–2009. The output of this study could be used to develop sustainable water withdrawal strategies in Alberta, Canada.

ZC3H13 (zinc finger CCCH-type containing 13) is a member of the zinc finger protein family with regulatory roles in gene expression and represents a crucial m6A methyltransferase. However, the precise function of ZC3H13 in the esophageal squamous cell carcinoma tumor microenvironment (TME) remains incompletely understood. Our study primarily investigated the impact of ZC3H13 on m6A methylation modification in ESCC and explored the roles of ZC3H13 and M2 macrophages in ESCC. We employed bioinformatics analysis to assess the function of ZC3H13 in ESCC. Quantification of ZC3H13, CCL5, CXCL8, and macrophage infiltration in clinical samples and cell line-derived xenograft (CDX) tumor models was conducted using real-time quantitative PCR (qRT-PCR), western blot (WB), immunohistochemistry (IHC), Immunofluorescence (IF), and Enzyme-linked immunosorbent assay (ELISA). The colorimetric method was utilized to detect m6A methylation in cells and tissues. Tumor proliferation, migration, and invasion were evaluated using CCK8, EdU staining, colony formation tests, transwell assays, and CDX models. We found that elevated ZC3H13 expression was positively correlated with m6A methylation modification in ESCC tumor tissue. ZC3H13 mutation led to abnormal nuclear metastasis of METTL14 and METTL3. Silencing ZC3H13 inhibited ESCC tumor growth and M2 macrophage infiltration in mice. ZC3H13 silencing also suppressed the expression of CCL5 and CXCL8 mRNA. M6A modification enhanced the stability of CXCL8 mRNA. ESCC tumors promoted the polarization of M0-M2 macrophages through the CXCL8-CXCR2 axis, which CXCR2 inhibitors or anti-CXCL8 antibodies could inhibit. Migration of M0 macrophages was facilitated by CCL5. Our findings elucidate the connection between ZC3H13-mediated m6A modification and M2 macrophage infiltration in the ESCC-TME, resulting in M2 macrophage polarization and increased M2 macrophage infiltration.

Groundwater is a vital resource for human welfare. However, due to various factors, groundwater pollution is a paramount environmental concern. It is challenging to simulate groundwater quality dynamics with the Soil and Water Assessment Tool (SWAT) because it does not adequately model nutrient percolation processes in the soil. The objectives of this study were to extend the SWAT module to simulate groundwater quality for the parameters nitrate and Total Dissolved Solids (TDS). The results of the SWAT model for the Athabasca River Basin in Canada revealed a linear relationship between observed and calculated groundwater quality. This result achieved satisfactory values for coefficient of determination ( R 2 ), Nash-Sutcliffe efficiency ( NSE ), and percent bias ( PBIAS ). For nitrate, the model performance measures R 2 ranged from 0.66–0.83 during calibration and NSE from 0.61–0.83. R 2 is 0.71 during validation and NSE ranged from 0.69–0.75. Likewise, for TDS, the model performance measures R 2 ranged from 0.61–0.82 during calibration and from 0.58–0.62 during validation. When coupled with soil zone and land surface processes, nitrate and TDS concentrations in groundwater can be simulated with the SWAT model. This indicated that SWAT may be helpful in evaluating adaptive management scenarios. Hence, the extended SWAT model could be a powerful tool for regional-scale modelling of nutrient loads, and to support and effective surface and groundwater management.

BackgroundGastric cancer (GC) is one of the most common digestive system diseases and yet lacks effective therapeutic regimen.AimsThe aim of our present research was to probe the value of hsa_circ_0001017 in GC treatment.MethodsqRT-PCR and Western blot were performed to detect gene and protein expressions, respectively. CCK-8 assay and clone formation assay were used to ensure the proliferation of GC cell lines. Transwell assay was performed to measure the migration and invasion of GC cell lines. The relationship between hsa_circ_0001017 and miR-197 and that between miR-197 and RHOB 3′-UTR were ensured using the luciferase reporter assay.ResultsDecreased hsa_circ_0001017 was discovered in GC, and upregulation of hsa_circ_0001017 notably repressed proliferation, migration, and invasion of GC cell lines. We further certificated that hsa_circ_0001017 served as miR-197 sponge and suppressed the expression of miR-197. Moreover, hsa_circ_0001017 upregulation meaningfully accelerated RHOB expression in both gene and protein levels, and RHOB was a downstream target of miR-197. Overexpression of miR-197 could markedly restrain hsa_circ_0001017-induced RHOB increasing and stifle inhibition of hsa_circ_0001017 to the malignant phenotype of GC cell lines. Next, our results further confirmed that hsa_circ_0001017 increasing notably inhibited tumor growth, impeded miR-197 production, while it enhanced the expression of RHOB in vivo.ConclusionOur data demonstrated that upregulation of hsa_circ_0001017 could notably muffle the proliferation as well as the metastasis of GC cell lines and impede the formation of GC tumor via targeting to miR-197/RHOB signaling pathway. Our results evidenced that hsa_circ_0001017 may act as a rising biomarker for GC treatment.

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment. Multi-region sequencing of small cell lung cancers (SCLC) can improve our understanding of the disease. Here the authors analyse 120 multi-region samples from 40 SCLC patients with whole exome sequencing and characterise their mutational burden, evolution, heterogeneity, and potential prognostic biomarkers.

The restoration and protection of wetlands are crucial in reducing greenhouse gas emissions. In this research, the SWAT model was modified to investigate and estimate the groundwater table, net ecosystem exchange (NEE), and soil respiration impact on carbon dioxide (CO2) emission in the cold regions in Alberta. There is a lack of a process-based model that accounts explicitly for the CO2 emission and ecosystem exchange resulting from interactions between hydrological and biogeochemical processes. The SWAT model is modified to make unique contributions to wetlands by estimating CO2 emissions, soil temperature, and soil respiration that account for the dynamics of water tables and the relationship between subsurface and surface water storage. The modified model results predicted daily NEE with a very good model fit resulting in an R2 (Coefficient of determination), NSE (Nash-Sutcliffe Efficiency), PBIAS (percent bias), and RMSE (root mean square error) of 0.88, 0.72, 2.5, and 0.45 in the calibration period and 0.82, 0.67, −1.8, and 0.56 for the validation period, respectively. The prediction result indicated that the modified model performed well in predicting soil temperature, the groundwater table, and ecosystem respiration in the calibration and validation periods. In general, this study concluded that the modified model has the capability of representing the effects of water table dynamics on CO2 emissions and NEE in cold wetlands.

There is an unmet need for additional and more efficacious therapies for patients with unresectable metastatic oesophageal cancer. We aimed to evaluate the efficacy and safety of adding tiragolumab and atezolizumab to chemotherapy as first-line treatment for unresectable or metastatic oesophageal squamous cell carcinoma. The SKYSCRAPER-08 randomised, double-blind, placebo-controlled, phase 3 trial was done at 67 centres in mainland China, South Korea, Thailand, Taiwan, and Hong Kong and enrolled adult patients (aged ≥18 years) with treatment-naive, unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma, with an Eastern Cooperative Oncology Group performance status of 0–1. Patients were randomly assigned (1:1) to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) and chemotherapy (paclitaxel [175 mg/m2] and cisplatin [60–80 mg/m2]) or placebo and chemotherapy through intravenous infusion for six 21-day cycles. The primary outcomes were independent review facility-assessed progression-free survival and overall survival in the intention-to-treat population (defined as all randomly assigned patients, regardless of whether they received any study treatment). This study was registered with ClinicalTrials.gov, NCT04540211, and is ongoing. Between Oct 30, 2020, and Nov 30, 2021, 461 patients were assigned to receive tiragolumab plus atezolizumab and chemotherapy (n=229) or placebo and chemotherapy (n=232); 406 (88%) were male and 55 (12%) female, and all patients were Asian. Median survival follow-up was 12·6 months (IQR 6·8–18·0). Median independent review facility-assessed progression-free survival (cutoff June 15, 2022) in the tiragolumab plus atezolizumab and chemotherapy group was 6·2 months (95% CI 5·7–7·2) versus 5·4 months (95% CI 4·4–5·5) in the placebo and chemotherapy group (HR 0·56, 95% CI 0·45–0·70; p<0·0001). Median overall survival (cutoff Feb 13, 2023) was 15·7 months (95% CI 13·3–20·4) and 11·1 months (95% CI 9·6–13·6; HR 0·70, 95% CI 0·55–0·88; p=0·0024). The most common grade 3–4 adverse events in the tiragolumab plus atezolizumab and chemotherapy group versus the placebo and chemotherapy group were white blood cell count decrease (46 [20%] of 228 vs 35 [15%] of 227), neutrophil count decrease (78 [34%] vs 78 [34%]), and anaemia (19 [8%] vs 24 [11%]). Serious adverse events occurred in 94 (41%) of 228 patients in the tiragolumab plus atezolizumab and chemotherapy group and 89 (39%) of 227 in the placebo and chemotherapy group; the most common serious adverse event was pneumonia (17 [7%] of 228 and 13 [6%] of 227). Treatment-related deaths occurred in six patients (3%) in the tiragolumab plus atezolizumab and chemotherapy group (immune-mediated lung disease, pneumonitis, cardiac arrest, gastrointestinal haemorrhage, hepatic failure, and bacterial pneumonia) and two (1%) in the placebo and chemotherapy group (gastrointestinal infection and death of unknown cause). No new safety signals were identified. Independent review facility-assessed progression-free survival and overall survival were significantly better in the tiragolumab plus atezolizumab and chemotherapy group compared with chemotherapy alone for unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma. These data support the rationale for exploring dual checkpoint inhibition added to chemotherapy for this group of patients with a high unmet need. F Hoffmann-La Roche–Genentech.