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Abstract Background ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is thought to play a significant role both in tumor suppression and tumor initiation, which is highly dependent upon context. Previous studies have suggested that ARID1A deficiency may contribute to cancer development. The specific mechanisms of whether ARID1A loss affects tumorigenesis by RNA editing remain unclear. Results Our findings indicate that the deficiency of ARID1A leads to an increase in RNA editing levels and alterations in RNA editing categories mediated by adenosine deaminases acting on RNA 1 (ADAR1). ADAR1 edits the CDK13 gene at two previously unidentified sites, namely Q113R and K117R. Given the crucial role of CDK13 as a cyclin-dependent kinase, we further observed that ADAR1 deficiency results in changes in the cell cycle. Importantly, the sensitivity of ARID1A-deficient tumor cells to SR-4835, a CDK12/CDK13 inhibitor, suggests a promising therapeutic approach for individuals with ARID1A-mutant tumors. Knockdown of ADAR1 restored the sensitivity of ARID1A deficient cells to SR-4835 treatment. Conclusions ARID1A deficiency promotes RNA editing of CDK13 by regulating ADAR1.

F-box only protein 38 (FBXO38) is a member of the F-box family that mediates the ubiquitination and proteasome degradation of programmed death 1 (PD-1), and thus has important effects on T cell-related immunity. While its powerful role in adaptive immunity has attracted much attention, its regulatory roles in innate immune pathways remain unknown. The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an important innate immune pathway that regulates type I interferons. STING protein is the core component of this pathway. In this study, we identified that FBXO38 deficiency enhanced tumor proliferation and reduced tumor CD8+ T cells infiltration. Loss of FBXO38 resulted in reduced STING protein levels in vitro and in vivo, further leading to preventing cGAS–STING pathway activation, and decreased downstream product IFNA1 and CCL5. The mechanism of reduced STING protein was associated with lysosome-mediated degradation rather than proteasomal function. Our results demonstrate a critical role for FBXO38 in the cGAS–STING pathway.

Abstract Alternative splicing is an important mechanism that enhances protein functional diversity. To date, our understanding of alternative splicing variants has been based on mRNA transcript data, but due to the difficulty in predicting protein structures, protein tertiary structures have been largely unexplored. However, with the release of AlphaFold, which predicts three-dimensional models of proteins, this challenge is rapidly being overcome. Here, we present a dataset of 315 predicted structures of abnormal isoforms in 18 uveal melanoma patients based on second- and third-generation transcriptome-sequencing data. This information comprises a high-quality set of structural data on recurrent aberrant isoforms that can be used in multiple types of studies, from those aimed at revealing potential therapeutic targets to those aimed at recognizing of cancer neoantigens at the atomic level.

Abstract The cytidine deaminase, Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B, herein termed A3B), is a critical mutation driver that induces genomic instability in cancer by catalyzing cytosine-to-thymine (C-to-T) conversion and promoting replication stress (RS). However, the detailed function of A3B in RS is not fully determined and it is not known whether the mechanism of A3B action can be exploited for cancer therapy. Here, we conducted an immunoprecipitation-mass spectrometry (IP-MS) study and identified A3B to be a novel binding component of R-loops, which are RNA:DNA hybrid structures. Mechanistically, overexpression of A3B exacerbated RS by promoting R-loop formation and altering the distribution of R-loops in the genome. This was rescued by the R-loop gatekeeper, Ribonuclease H1 (RNASEH1, herein termed RNH1). In addition, a high level of A3B conferred sensitivity to ATR/Chk1 inhibitors (ATRi/Chk1i) in melanoma cells, which was dependent on R-loop status. Together, our results provide novel insights into the mechanistic link between A3B and R-loops in the promotion of RS in cancer. This will inform the development of markers to predict the response of patients to ATRi/Chk1i.

Summary: Introduction: Although the advantages of laparoscopic inguinal hernia repair in the general population have been reported, its role in octogenarians has yet to be elucidated. This retrospective study was designed to compare the outcomes of open and laparoscopic inguinal hernia repairs in octogenarians. Materials and methods: The data of octogenarians who underwent laparoscopic (n = 81) or open (n = 121) inguinal hernia repair were collected from January 2017 to December 2019. Statistical analysis variables included basic epidemiological data of patients, surgical procedures, comorbidities, postoperative pain, complications, recurrence, and other data. Results: There were no significant differences between the two groups in terms of sex, body mass index, recurrent hernias, comorbidities, postoperative complications, and recurrence. The American Society of Anesthesiologists (ASA) class and the proportion of scrotal hernias in the open group were higher than those of the laparoscopic group, whereas the proportion of bilateral hernias in the laparoscopic group was higher than that in the open group. The postoperative pain scores of the laparoscopic group were lower than those of the open group. Conclusions: In octogenarians, both laparoscopic and open inguinal hernia repairs are safe and feasible, but an appropriate surgical plan is crucial for obtaining better treatment effect.

Abstract The slightest change in the extra/intracellular concentration of metal ions results in amplified effects by signaling cascades that regulate both cell fate within the tumor microenvironment and immune status, which influences the network of antitumor immunity through various pathways. Based on the fact that metal ions influence the fate of cancer cells and participate in both innate and adaptive immunity, they are widely applied in antitumor therapy as immune modulators. Moreover, nanomedicine possesses the advantage of precise delivery and responsive release, which can perfectly remedy the drawbacks of metal ions, such as low target selectivity and systematic toxicity, thus providing an ideal platform for metal ion application in cancer treatment. Emerging evidence has shown that immunotherapy applied with nanometallic materials may significantly enhance therapeutic efficacy. Here, we focus on the physiopathology of metal ions in tumorigenesis and discuss several breakthroughs regarding the use of nanometallic materials in antitumor immunotherapeutics. These findings demonstrate the prominence of metal ion-based nanomedicine in cancer therapy and prophylaxis, providing many new ideas for basic immunity research and clinical application. Consequently, we provide innovative insights into the comprehensive understanding of the application of metal ions combined with nanomedicine in cancer immunotherapy in the past few years. Graphical Abstract

Abstract p53 is the most highly mutated tumor suppressor across multiple types of human cancers. The level and function of p53 are fine-tuned through multifaced mechanisms in which the protein–protein interaction between p53 and MDM2 is considered as a major circuit. Recent studies suggest therapeutic strategy attempts to restore p53 function by small molecule inhibitors targeting p53–MDM2 interaction can be a promising direction in treating cancers with wild-type or functional p53. Currently, clinical tests of the p53–MDM2 protein–protein interaction inhibitors (PPIs) are underway. However, it remains elusive about the biomarkers that may predict the therapeutic responses to those inhibitors. Here we report that RNA-binding protein LIN28B directly regulates p53 through binding to the 5′΄ untranslated region of p53 mRNA and blocks its translation by competing with a translation enhancer protein, ribosomal protein L26 (RPL26). This regulatory mechanism of LIN28B does not involve let-7 maturation or the canonical protein turnover pathway of p53. Furthermore, we show that inhibition of LIN28B unleashes the translational suppression of p53 through RPL26, and leads to enhanced sensitivities of cancer cells to inhibitors of p53–MDM2 interaction. Together, we demonstrate a competitive regulatory mechanism of p53 by LIN28B, which has important implications in developing biomarkers to the therapies aiming to reinstate p53 function.

E-skins currently suffer from issues to do with the predominantly non-biological materials they are made from. Here, the authors report on a gluten network which is cross-linked with EGaIn liquid metal to make a self-healing, biocompatible, biodegradable, stretchable and conductive material which is demonstrated as a movement strain sensor.

Non-noble transition metal oxides are common yet typically poor hydrogen evolution catalysts due to scarce active electronic states. This work provides a route for achieving hydrogen evolution at high current densities by stabilizing a metastable NiMoO4 phase with abundant active electronic states.

The deep cryogenic temperatures present significant challenges for the performance of elastic materials. Here, the authors present a low density covalently crosslinked polyimide (PI) aerogels with super-elastic properties at deep cryogenic temperatures.

BackgroundRecently, the combination of immunotherapy with chemotherapy has been recommended as first-line treatment of metastatic gastric/gastroesophageal junction (G/GEJ) in the clinical guidelines of many countries; the therapeutic potential of this application needs to be further investigated for neoadjuvant therapy of advanced G/GEJ cancer patients.MethodsWe performed a prospective, single-arm, open-label, phase 2 trial of the PD-1 inhibitor tislelizumab combined with S-1 plus oxaliplatin (SOX) in patients with advanced LAG/GEJ cancer. All patients underwent the three-cycle (21 days/cycle) treatment except for one patient who underwent two cycles. The primary endpoints were tumor major pathology response (MPR) and other events of tumor response assessed by the RECIST 1.1 and Becker criteria. Moreover, we constructed a few-shot learning model to predict the probability of MPR, which could screen those patients who might benefit from the neoadjuvant immunotherapy–chemotherapy scheme. This study was registered at https://clinicaltrials.gov/ct2/show/NCT0-4890392.ResultsThirty-two patients were enrolled; 17 patients (53.1%) achieved MPR (≤10% viable tumor cells) after treatment, and among them, 8 (25.0%) had a pathological complete response (pCR). The 1-year overall survival (OS) rate was 91.4% and the 1-year recurrence-free survival (RFS) rate was 90.0%. Adverse events occurred in 24 patients (65.6%) and grade III–IV adverse events were observed in 4 patients (12.5%) during the neoadjuvant period. Furthermore, we found commonly used preoperative assessment tools such as CT and EUS, which presented limited accuracy of tumor therapeutic response in this study; thus, we developed a therapeutic response predictive model that consisted of TNFα, IFNγ, IL-10, CD4, and age of patient, and the AUC of this FSL model was 0.856 (95% CI: 0.823–0.884).DiscussionOur study showed that the neoadjuvant PD-1 inhibitor tislelizumab combined with SOX had promising application potential and presented no increasing treatment-related adverse events in patients with advanced G/GEJ cancer. Moreover, the predictive model could help therapists to evaluate the therapeutic response of this scheme accurately.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT0-4890392, identifier [NCT04890392].

Abstract Recent technical advances have led to the discovery of novel functions of extrachromosomal DNA (ecDNA) in multiple cancer types. Studies have revealed that cancer-associated ecDNA shows a unique circular shape and contains oncogenes that are more frequently amplified than that in linear chromatin DNA. Importantly, the ecDNA-mediated amplification of oncogenes was frequently found in most cancers but rare in normal tissues. Multiple reports have shown that ecDNA has a profound impact on oncogene activation, genomic instability, drug sensitivity, tumor heterogeneity and tumor immunology, therefore may offer the potential for cancer diagnosis and therapeutics. Nevertheless, the underlying mechanisms and future applications of ecDNA remain to be determined. In this review, we summarize the basic concepts, biological functions and molecular mechanisms of ecDNA. We also provide novel insights into the fundamental role of ecDNA in cancer.

Abstract Mammalian SWI/SNF complex is a key chromatin remodeler that reshapes nucleosomes and regulates DNA accessibility. Mutations in SWI/SNF subunits are found in a broad spectrum of human cancers; however, the mechanisms of how these aberrations of SWI/SNF complex would impact tumorigenesis and cancer therapeutics remain to be elucidated. Studies have demonstrated that immune checkpoint blockade (ICB) therapy is promising in cancer treatment. Nevertheless, suitable biomarkers that reliably predict the clinical response to ICB are still lacking. Emerging evidence has suggested that SWI/SNF components play novel roles in the regulation of anti-tumor immunity, and SWI/SNF deficiency can be therapeutically targeted by ICB. These findings manifest the prominence of the SWI/SNF complex as a stratification biomarker that predicts treatment (therapeutic) response to ICB. In this review, we summarize the recent advances in ICB therapy by harnessing the cancer-specific vulnerability elicited by SWI/SNF deficiency. We provide novel insights into a comprehensive understanding of the underlying mechanisms by which SWI/SNF functions as a modulator of anti-tumor immunity.

Paclitaxel (PTX), a tubulin-binding agent, is widely used and has shown good efficacy in the initial period of treatment for non-small cell lung cancer (NSCLC). However, the relatively rapid acquisition of resistance to PTX treatments that is observed in virtually all cases significantly limits its utility and remains a substantial challenge to the clinical management of NSCLC. The aim of this study was to identify candidate genes and mechanisms that might mediate acquired paclitaxel resistance. In this work, we established paclitaxel-resistant cells (A549-T) from parental cell lines by step-dose selection in vitro. Using methylation chip analysis and transcriptome sequencing, 43,426 differentially methylated genes and 2,870 differentially expressed genes are identified. Six genes (KANK1, ALDH3A1, GALNT14, PIK3R3, LRG1, WEE2), which may be related to paclitaxel resistance in lung adenocarcinoma, were identified. Among these genes, KANK1 exhibited significant differences in methylation and expression between cell lines. Since KANK1 plays an important role in the development of renal cancer and gastric cancer, we hypothesised that it may also play a role in acquired resistance in lung adenocarcinoma. Transient transfection of SiKANK1 significantly reduced the expression of KANK1, reducing apoptosis, increasing cell migration, and enhancing the tolerance of A549 cells to paclitaxel. KANK1 acts as a tumour suppressor gene, mediating the resistance of lung adenocarcinoma A549 to paclitaxel. The reduction of KANK1 expression can increase the paclitaxel resistance of non-small cell lung cancer and increase the difficulty of clinical treatment.

Summary: Lithium-sulfur (Li-S) batteries are regarded as one of the most promising alternatives for next-generation energy storage and conversion due to the low cost of raw materials and high theoretical energy density. However, their practical applications have been plagued by rapid capacity decay, which is mainly ascribed to issues with the design and balance of components inside the batteries. In recent years, many advanced components have been reported, but few have been applied in practical Li-S batteries. Inspired by the wooden-barrel effect, in this perspective, we propose an optimized combination that integrates all advanced components into one system. For a better understanding of this topic, the typically advanced designs applied in Li-S pouch cells are summarized. Subsequently, the safety performance of Li-S pouch cells under extreme testing conditions are provided. Finally, our personal insights for the future development direction of Li-S pouch cells are proposed.

DNA damage induces checkpoints to ensure that damage is not transferred to the next generation, but the molecular pathways responsible for checkpoint recovery are not clear. Here the authors show that the nutrient sensor mTORC1 is a determinant for G2/M checkpoint recovery through regulation of cyclin B1 and PLK1 expression.

Considering the complexity of lane changing using automated vehicles and the frequency of turning lanes in city settings, this paper aims to generate an accelerated lane-changing trajectory using vehicle-to-vehicle collaboration (V2VC). Based on the characteristics of accelerated lane changing, we used a polynomial method and cooperative strategies for trajectory planning to establish a lane-changing model under different degrees of collaboration with the following vehicle in the target lane by considering vehicle kinematics and comfort requirements. Furthermore, considering the shortcomings of the traditional elliptical vehicle and round vehicle models, we established a rectangular vehicle model with collision boundary conditions by analysing the relationships between the possible collision points and the outline of the vehicle. Then, we established a simulation model for the accelerated lane-changing process in different environments under different degrees of collaboration. The results show that, by using V2VC, we can achieve safe accelerated lane-changing trajectories and simultaneously satisfy the requirements of vehicle kinematics and comfort control.