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Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce degradation by the ubiquitin-proteasome system (UPS) offer new opportunities to engage targets that remain challenging to be inhibited by conventional small molecules. One fundamental element in the degradation process is the E3 ligase. However, less than 2% amongst hundreds of E3 ligases in the human genome have been engaged in current studies in the TPD field, calling for the recruiting of additional ones to further enhance the therapeutic potential of TPD. To accelerate the development of PROTACs utilizing under-explored E3 ligases, we systematically characterize E3 ligases from seven different aspects, including chemical ligandability, expression patterns, protein-protein interactions (PPI), structure availability, functional essentiality, cellular location, and PPI interface by analyzing 30 large-scale data sets. Our analysis uncovers several E3 ligases as promising extant PROTACs. In total, combining confidence score, ligandability, expression pattern, and PPI, we identified 76 E3 ligases as PROTAC-interacting candidates. We develop a user-friendly and flexible web portal ( https://hanlaboratory.com/E3Atlas/ ) aimed at assisting researchers to rapidly identify E3 ligases with promising TPD activities against specifically desired targets, facilitating the development of these therapies in cancer and beyond. Proteolysis-targeting chimeras (PROTACs) offer new avenues for drug development. Here the authors investigate E3 ligases—key to PROTAC function—and identify candidate targets for cancer drivers such as KRAS and EGFR.

Esophageal squamous-cell carcinoma (ESCC), one of the most prevalent and lethal malignant disease, has a complex but unknown tumor ecosystem. Here, we investigate the composition of ESCC tumors based on 208,659 single-cell transcriptomes derived from 60 individuals. We identify 8 common expression programs from malignant epithelial cells and discover 42 cell types, including 26 immune cell and 16 nonimmune stromal cell subtypes in the tumor microenvironment (TME), and analyse the interactions between cancer cells and other cells and the interactions among different cell types in the TME. Moreover, we link the cancer cell transcriptomes to the somatic mutations and identify several markers significantly associated with patients’ survival, which may be relevant to precision care of ESCC patients. These results reveal the immunosuppressive status in the ESCC TME and further our understanding of ESCC. Esophageal squamous-cell carcinomas (ESCC) have poor prognosis, and detailed molecular profiles are necessary to identify prognostic markers. Here the authors analyse 60 ESCC patient samples using scRNA-seq, TCR-seq and genomics; they find mucosal immunity markers associated with survival and immunosuppressive microenvironments.

Somatic mutations that accumulate in normal tissues are associated with ageing and disease 1 , 2 . Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual. Laser-capture microdissection and mini-bulk exome sequencing are combined to analyse somatic mutations in morphologically normal tissues from nine organs from five donors, revealing variation in mutation burdens, mutational signatures and clonal expansions.

Small molecule inhibitors targeting dysregulated pathways (RAS/RAF/MEK, PI3K/AKT/mTOR, JAK/STAT) have significantly improved clinical outcomes in cancer patients. Recently Bruton’s tyrosine kinase (BTK), a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR) signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK-inhibitor, has demonstrated clinical effectiveness and tolerability in early clinical trials and has progressed into phase III trials. However, additional research is necessary to identify the optimal dosing schedule, as well as patients most likely to benefit from BTK inhibition. This review summarizes preclinical and clinical development of ibrutinib and other novel BTK inhibitors (GDC-0834, CGI-560, CGI-1746, HM-71224, CC-292, and ONO-4059, CNX-774, LFM-A13) in the treatment of B-cell malignancies and autoimmune disorders.

Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8 + response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed. The multistep processes involved in the evolution of inflammation to invasive esophageal squamous cell carcinoma (ESCC) is unclear. Here, the authors report a mouse model of ESCC and the role of interplay between carcinogen-transformed epithelial cells and their microenvironment in ESCC development.

Through targeted next-generation sequencing of 83 non-small cell lung cancer (NSCLC) patients with first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance, we detected 11% TET2 mutations in the T790M-negative subgroup. To explore the molecular mechanism of TET2 in EGFR TKI resistance, reduced representation bisulfite sequencing (RRBS) was adopted to analyze the global genomic methylation profiles and detect the differentially methylated genes in the TET2-knockdown (KD) PC9 and control PC9 cell lines, following bioinformatics analysis of gene ontology (GO) functions and kyoto encyclopedia of genes and genomes (KEGG) signaling to screen for genes associated with drug resistance. TET2 KD attenuated gefitinib-induced apoptosis and decreased the sensitivity of EGFR-mutant lung cancer cells to gefitinib. Forty-three drug resistance genes with hypermethylated promoter regions were identified via RRBS and bioinformatic analysis in PC9 TET2 KD cells. Then, 10 candidate genes were screened for further validation. RT‒PCR demonstrated that the expression of AXIN2 and CSK was significantly lower in PC9 TET2 KD cells than in control cells. Furthermore, AXIN2 KD attenuated gefitinib-induced apoptosis and decreased the sensitivity of PC9 cells to gefitinib. Importantly, we found that the demethylation drug decitabine (DCA) could reverse gefitinib resistance in PC9 TET2 KD cells and mouse models. These results indicate that the methylation of AXIN2 induced by TET2 repression is a novel resistance mechanism of EGFR TKIs in EGFR-mutant NSCLC. Demethylation drugs have the potential to overcome EGFR TKI resistance induced by loss-of-function TET2 mutations.

Our previous study revealed that PI3K/AKT/mTOR signaling was associated with SCLC radioresistance. SBC2 cells were used as primary radioresistance models, while H446 cells were continuously exposed to ionizing radiation (IR) to develop acquired radioresistance. Cell viability and apoptosis assays were used to investigate synergistic effects of BEZ235/GSK2126458 and IR in vitro, while immunoblotting, metabolite quantitative analysis and bioinformatic analyses were utilized to explore the underlying mechanism. Both genetically engineered mouse models (GEMM) and subcutaneous tumor models were used to confirm the synergistic effect in vivo. Key molecules of PI3K/AKT/mTOR signaling were upregulated after IR, which was correlated with primary radioresistance, and they were more expressed in acquired radioresistant cells. BEZ235/GSK2126458 effectively enhanced the cytotoxic effects of IR. BEZ235/GSK2126458 plus IR elevated γ-H2AX and p-Nrf2 expression, suggesting DNA and oxidative stress damage were intensified. Mechanistically, BEZ235/GSK2126458 plus IR significantly reduced the expression of G6PD protein, the rate-limiting enzyme of the pentose phosphate pathway (PPP). In detail, PI3K/mTOR inhibitors reinforced interaction between G6PD and HSPA8/HSC70, and G6PD was degraded by chaperone-mediated autophagy processes. Their metabolites (NADPH and R-5P) were decreased, and ROS levels were indirectly elevated, both of which exacerbated cell death. PI3K/AKT/mTOR signaling activator, insulin, enhanced SCLC radioresistance, while the synergistic effect of BEZ235/GSK2126458 and IR can be attenuated by N-acetylcysteine, and enhanced by 6-amino niacinamide. GEMM and allograft transplantation assays further confirmed their synergistic effect in vivo. This study provided insights into the connection between PI3K/AKT/mTOR signaling and the PPP underlying radioresistance and provided evidence of mechanisms supporting PI3K/mTOR inhibitors as possible therapeutic strategies to abrogate SCLC radioresistance.

Background Worldwide, the diagnosis and treatment of immune thrombocytopenia (ITP) and Henoch-Schönlein purpura (HSP) remain a major and ongoing challenge in hematology. Emerging clinical evidences suggest serum mineral elements are associated with ITP or HSP, but the causal relationship between them is still unclear. Aims Conducting a two-sample, bidirectional Mendelian randomization (MR) study to evaluate the causal association between serum mineral elements including zinc, copper, magnesium, iron and calcium with ITP and HSP. Methods In this two-sample, bidirectional MR study, summary statistics data of genome-wide association studies (GWAS) on exposures including zinc, copper, iron, magnesium and calcium were extracted from the MRC-Integrative Epidemiology Unit (MRC-IEU). The GWAS data on study outcomes, including ITP and HSP, were obtained from the FinnGen consortium. MR-Egger intercept and MR-PRESSO global test were utilized to assess the heterogeneity and horizontal pleiotropic of instrumental variables (IVs) between the exposures and outcomes, respectively. Inverse variance weighted (IVW) test was used as the primary analysis method to evaluate the causal between serum mineral elements with the risk of ITP and HSP, and weighted-median, weighted model, MR steiger, MR-PRESSO and radial MR were used as auxiliary analysis methods, moreover, the odds ratio (OR) and 95% confidence interval (CI) were calculated. Reverse MR analysis was also conducted. Leave-one-out test was further to conduct whether the association between serum mineral elements and the risk of ITP and HSP remain robust. Results No significant horizontal pleiotropy and heterogeneity between individuals IVs was found after MR-Egger and MR-PRESSO global test. Genetically predicted that high copper (OR = 0.768, 95%CI: 0.628–0.937) and magnesium (OR = 0.314, 95%CI: 0.112–0.884) concentrations may reduce the risk of ITP and HSP, respectively. High calcium concentration may increase the risk of HSP (OR = 1.823, 95%CI: 1.226–2.712). There was no significant evidence to support a causal association between iron, zinc, magnesium, and calcium with the risk of ITP, or between iron, copper, and zinc and the risk of HSP (all P  > 0.005). Moreover, no reverse causal associations between five serum mineral elements with the risk of ITP and HSP were found (all P  > 0.05), suggesting the causal associations between serum mineral elements with ITP and HSP were not bidirectional. In addition, consistent results were obtained by multiple sensitivity analyses, indicating the associations of serum mineral elements with the risk of ITP and HSP relatively robust. Conclusion In this MR study, we discovered genetically predicted that elevated serum levels of copper and magnesium decreased the risk of ITP and HSP, respectively, and elevated levels of serum calcium increased the risk of HSP. However, no reverse causal association was found between serum mineral elements with the risk of ITP and HSP.

Standard multi-task benchmarks are essential for developing pretraining models that can generalize to various downstream tasks. Existing benchmarks for natural language processing (NLP) usually focus only on understanding or generating short texts. However, long text modeling requires many distinct abilities in contrast to short texts, such as the modeling of long-range discourse and commonsense relations, and the coherence and controllability of generation. The lack of standardized benchmarks makes it difficult to assess these abilities of a model and fairly compare different models, especially Chinese models. Therefore, we propose a story-centric benchmark named LOT for evaluating Chinese long text modeling, which aggregates two understanding tasks and two generation tasks. We construct new datasets for these tasks based on human-written Chinese stories with hundreds of words. Furthermore, we release an encoder-decoder-based Chinese long text pretraining model named LongLM with up to 1 billion parameters. We pretrain LongLM on 120G Chinese novels with two generative tasks including text infilling and conditional continuation. Extensive experiments show that LongLM outperforms similar-sized pretraining models substantially on both the understanding and generation tasks in LOT.

Recent advancements in antibody-drug conjugates (ADCs) targeting trophoblast surface cell antigen 2 (Trop-2) have brought important progress in the field of targeted therapy. This progress also holds promise for the treatment of small cell lung cancer (SCLC) as anti-Trop-2 therapy appears to have a safe and effective clinical activity in metastatic SCLC patients. However, effective treatments of anti-Trop-2 ADCs rely on the comprehensive assessment of Trop-2 expression at the tumor sites, SCLC exhibits intratumoral heterogeneity, making the accurate acquisition of histological biopsies a challenge. To address this issue, we herein report the development of an anti-Trop-2 aptamer consisting of 76 bases is specifically bind to Trop-2-overexpressing SCLC cells. Further truncated anti-Trop-2 aptamer with 46 nucleotides also possesses excellent in vitro and in vivo binding affinity with Trop-2 antigens. After radiolabeling with gallium-68 radionuclide, an aptamer-based molecular imaging probe was successfully fabricated named [ 68 Ga]Ga-NOTA-TRP-c. This imaging probe demonstrated effective and precise differentiation of Trop-2-positive tumors in both murine- and human-derived animal models, exhibiting favorable metabolic profiles. Furthermore, Trop-2-positive SCLC tumors recognized by anti-Trop-2 aptamer can be treated with anti-Trop-2 ADC sacituzumab govitecan (SG), either in vitro or in vivo. Importantly, SG induces DNA damage and cell apoptosis without affecting the expression of Trop-2 on the cell surface, which makes it possible to use anti-Trop-2 aptamer to monitor the expression of Trop-2 in SCLC. This study highlights the potential of aptamer-based molecular imaging and imaging-guided SG treatment as a promising option for targeted therapy in SCLC. Graphical Abstract