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Highlights Increased use of primary tumor resection plus metastasectomy benefited patients with left-sided tumors but not those with right-sided tumors. Increased use of primary tumor resection alone did not improve survival in either left or right-sided tumor group. Overuse of palliative primary tumor resection should be avoided.

There is a lack of high-quality, large-scale, real-world evidence from patients with metastatic colorectal cancer (mCRC), especially in China. It remains unclear whether efforts to improve the quality of care for mCRC would improve patient survival outcomes in real-world practice. On the basis of an intelligent big-data platform, we established a large-scale retrospective cohort of mCRC patients. We investigated the temporal changes in the systemic and local treatment (resection, ablation, or radiation to liver, lung, or extrahepatic and/or extrapulmonary metastases) patterns of mCRC, and whether these changes were associated with improved overall survival (OS) over time. Between July 2012 and December 2018, 3403 eligible patients were included in this research. The median OS was 42.8 months (95% confidence interval (CI), 40.7–46.6) for the entire cohort, 25.6 months (95% CI, 24.7–26.9) for those treated with systemic therapy only, and not reached (95% CI, 78.6 months–not reached) for those receiving local therapy. The utility rate of local therapy increased continuously from 37.9% in 2012–2014 to 46.9% in 2017–2018. A dramatic increase in the utility rate of either cetuximab or bevacizumab was observed since 2017 (39.9%, 43.2%, and 60.3% in 2012–2014, 2015–2016, and 2017–2018, respectively). Compared with 2012–2014, the OS of the entire population significantly improved in 2015–2016 (hazard ratio (HR) = 0.87 (95% CI, 0.78–0.99); P = 0.034), but not for patients receiving systemic therapy only (HR = 0.99 (95% CI, 0.86–1.14); P = 0.889), whereas an improved OS was found in 2015–2018 for both the entire population (HR = 0.75 (95% CI, 0.70–0.81); P

Abstract Background A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking. Methods Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis. Results Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P

Background Progression-free survival (PFS) exhibits suboptimal performance as the surrogate endpoint for overall survival (OS) in trials studying immune checkpoint inhibitors (ICIs). Here we propose a novel surrogate endpoint, modified PFS (mPFS), which omits the events of disease progression (but not deaths) within 3 months after randomization.Methods PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for randomized trials studying ICIs in advanced solid tumors with available PFS and OS data up to May 2020. Individual patient-level data (IPD) for PFS and OS were reconstructed for eligible trials. A simulation-based algorithm was used to match the reconstructed, disconnected PFS and OS IPD, and 1000 independent simulated datasets of matched PFS-OS IPD were generated for each trial. mPFS durations and statuses were then measured for each of the matched PFS-OS IPD. Trial-level correlation between Cox HRs for PFS or mPFS and HRs for OS was assessed using Pearson correlation coefficient (rp) weighted by trial size; patient-level correlation between PFS or mPFS and OS was assessed using Spearman’s rank correlation coefficient (rs). Findings were further validated using the original IPD from two randomized ICI trials.Results Fifty-seven ICI trials totaling 29,429 participants were included. PFS HR showed moderate correlation with OS HR (rp=0.60), and PFS was moderately correlated with OS at the patient level (median rs=0.66; range, 0.65–0.68 among the 1000 simulations). In contrast, mPFS HR achieved stronger correlation with OS HR (median rp=0.81; range, 0.77–0.84), and mPFS was more strongly correlated with OS at the patient level (median rs=0.79; range, 0.78–0.80). The superiority of mPFS over PFS remained consistent in subgroup analyses by cancer type, therapeutic regimen, and treatment setting. In both trials with the original IPD where experimental treatment significantly improved OS, mPFS successfully captured such clinical benefits whereas PFS did not.Conclusions mPFS outperformed PFS as the surrogate endpoint for OS in ICI trials. mPFS is worthy of further investigation as a secondary endpoint in future ICI trials.

Ferroptosis is regulated by genes and participates in the physiological and pathological processes of ischemia-reperfusion injury, stroke, tumor and other diseases. The pathogenic mechanism is not yet clear. It is known that regulating p53 gene can induce ferroptosis of endothelial cells and tumor cells. Inhibiting ferroptosis enables GPX4 to function normally, blocking lipid oxidation on cell membranes, reducing the accumulation of reactive oxygen species (ROS), and protecting normal cells. In view of the polyreactivity of ferroptosis, it may help kill cancer cells and may damage normal cells. Therefore, genes related to regulatory ferroptosis sensitivity and the trigger mechanism need to be elucidated urgently. This article mainly reviews the known functional mechanisms of regulatory ferroptosis sensitive genes such as GPX4, FSP1, SLC7A11, P53, et al, in order to provide a reference for the in-depth analysis of ferroptosis research and the selection of drugs for major diseases. [ABSTRACT FROM AUTHOR]

To achieve sustainable production of hydrogen (H2) through water splitting, establishing efficient and earth-abundant electrocatalysts is of great necessity. Morphology engineering of graphene is now shown to modulate the electronic structure of carbon skeleton and in turn endow it with excellent ability of proton reduction. Three-dimensional (3D) graphene networks with a high density of sharp edge sites are synthesized. Electrocatalytic measurements indicate that the obtained 3D graphene networks can electrocatalyze H2 evolution with an extremely low onset potential of about 18 mV in 0.5 m H2SO4 solution, together with good stability. A combination of control experiments and density functional theory (DFT) investigations indicates that the exceptional H2 evolution performance is attributed to the abundant sharp edge sites of the advanced frameworks, which are responsible for promoting the adsorption and reduction of protons. [ABSTRACT FROM AUTHOR]

Abstract: Photoelectrochemical (PEC) water splitting involving a sensitized photocathode has emerged as an extremely promising pathway for achieving solar‐to‐fuel conversion. Here it is reported that merely by modulating the morphology of hole‐transfer layer of NiO film to give a regular porous structure, the PEC performance of quantum dots (QDs) sensitized photocathodes can be dramatically enhanced. Mechanistic insights reveal that the porous structure not only increases the loading amount of QDs for enhanced light capture, but also facilitates the process of interfacial hole transfer and migration, which enable a 2.6‐fold enhancement of PEC performance to a photocurrent of ≈136 μA cm−2. The strategy introduced here provides an effective and facile pathway for further improving the efficiency of artificial photosynthesis. [ABSTRACT FROM AUTHOR]

Due to their enhanced light harvesting, favored interfacial charge transfer and excellent proton reduction activity, hybrid photocatalysts of metallic 1T-MoS2 nanosheets and inorganic-ligand stabilized CdSe/ZnS QDs obtained via a self-assembly approach can produce H2 gas with a rate of ∼155 ± 3.5 μmol h−1 mg−1 under visible-light irradiation (λ = 410 nm), the most exceptional performance of solar H2 evolution using MoS2 as a cocatalyst known to date. [ABSTRACT FROM AUTHOR]

Experience replay can reuse past experience to update target policy and improve the utilization of samples,which has become an important component of deep reinforcement learning.Prioritized experience replay performs selective sampling based on experience replay to use samples more efficiently.Nevertheless,the current prioritized experience replay methods will reduce the diversity of samples sampled from the experience buffer,causing the neural network to converge to the local optimum.To tackle the above issue,a novel method named exploration and exploitation balanced experience replay (E3R) is proposed to ba-lances exploration and utilization.This method can comprehensively consider the exploration utility and utilization utility of the samples,and sample according to the weighted sum of two similarities.One of them is the similarity between the behavior strategy and the target strategy in the same state of action,and the other is the similarity between the current state and the past state.Besides,the E3R is combined with the policy gradient algorithm soft actor-critic and the value function algorithm deep Q lear-ning,and experiments are carried out on the suite of OpenAI gym tasks.Experimental results show that,compared to traditional random sampling and sequential differential priority sampling,E3R can achieve faster convergence speed and higher cumulative return.