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Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP + fibroblasts and SPP1 + macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP + fibroblasts and SPP1 + macrophages interaction to improve immunotherapy. Tumour microenvironment profiling during colorectal cancer progression may enable the discovery of therapeutic targets. Here, single cell and spatial RNA sequencing of tumour and adjacent normal tissues reveals an interaction between FAP + fibroblasts and SPP1 + macrophages that could be disrupted as an immunotherapy strategy.

Gallbladder cancer (GBC) is the most common malignant tumor of biliary tract. Isoliquiritigenin (ISL) is a natural compound with chalcone structure extracted from the roots of licorice and other plants. Relevant studies have shown that ISL has a strong anti-tumor ability in various types of tumors. However, the research of ISL against GBC has not been reported, which needs to be further investigated. The effects of ISL against GBC cells in vitro and in vivo were characterized by cytotoxicity test, RNA-sequencing, quantitative real-time polymerase chain reaction, reactive oxygen species (ROS) detection, lipid peroxidation detection, ferrous ion detection, glutathione disulphide/glutathione (GSSG/GSH) detection, lentivirus transfection, nude mice tumorigenesis experiment and immunohistochemistry. ISL significantly inhibited the proliferation of GBC cells in vitro. The results of transcriptome sequencing and bioinformatics analysis showed that ferroptosis was the main pathway of ISL inhibiting the proliferation of GBC, and HMOX1 and GPX4 were the key molecules of ISL-induced ferroptosis. Knockdown of HMOX1 or overexpression of GPX4 can reduce the sensitivity of GBC cells to ISL-induced ferroptosis and significantly restore the viability of GBC cells. Moreover, ISL significantly reversed the iron content, ROS level, lipid peroxidation level and GSSG/GSH ratio of GBC cells. Finally, ISL significantly inhibited the growth of GBC in vivo and regulated the ferroptosis of GBC by mediating HMOX1 and GPX4. ISL induced ferroptosis in GBC mainly by activating p62-Keap1-Nrf2-HMOX1 signaling pathway and down-regulating GPX4 in vitro and in vivo. This evidence may provide a new direction for the treatment of GBC.

Piwi proteins are normally restricted in germ cells to suppress transposons through associations with Piwi-interacting RNAs (piRNAs), but they are also frequently activated in many types of human cancers. A great puzzle is the lack of significant induction of corresponding piRNAs in cancer cells, as we document here in human pancreatic ductal adenocarcinomas (PDACs), which implies that such germline-specific proteins are somehow hijacked to promote tumorigenesis through a different mode of action. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. This is in contrast to piRNA-dependent PIWIL1 ubiquitination and removal by APC/C during late spermiogenesis. These findings unveil a piRNA-dependent mechanism to switch PIWIL1 from a substrate in spermatids to a co-activator of APC/C in human cancer cells.Li et al. report that PIWIL1 executes a piRNA-independent function in promoting pancreatic cancer metastasis. Mechanistically, PIWIL1 acts as a co-activator for the ubiquitin E3 ligase APC/C.

Abstract Biliary tract cancers (BTC), a heterogeneous disease with poor prognosis, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC). Although surgery is currently the primary regimen to treat BTC, most BTC patients are diagnosed at an advanced stage and miss the opportunity of surgical eradication. As a result, non-surgical therapy serves as the main intervention for advanced BTC. In recent years, immunotherapy has emerged as one of the most promising therapies in a number of solid cancers, and it includes immune checkpoint inhibitors (ICIs) monotherapy or combined therapy, tumor vaccines, oncolytic virus immunotherapy, adoptive cell therapy (ACT), and cytokine therapy. However, these therapies have been practiced in limited clinical settings in patients with BTC. In this review, we focus on the discussion of latest advances of immunotherapy in BTC and update the progress of multiple current clinical trials with different immunotherapies.

Background Liver cancer remains the leading cause of cancer death globally, and the treatment strategies are distinct for each type of malignant hepatic tumors. However, the differential diagnosis before surgery is challenging and subjective. This study aims to build an automatic diagnostic model for differentiating malignant hepatic tumors based on patients’ multimodal medical data including multi-phase contrast-enhanced computed tomography and clinical features. Methods Our study consisted of 723 patients from two centers, who were pathologically diagnosed with HCC, ICC or metastatic liver cancer. The training set and the test set consisted of 499 and 113 patients from center 1, respectively. The external test set consisted of 111 patients from center 2. We proposed a deep learning model with the modular design of SpatialExtractor-TemporalEncoder-Integration-Classifier (STIC), which take the advantage of deep CNN and gated RNN to effectively extract and integrate the diagnosis-related radiological and clinical features of patients. The code is publicly available at https://github.com/ruitian-olivia/STIC-model . Results The STIC model achieved an accuracy of 86.2% and AUC of 0.893 for classifying HCC and ICC on the test set. When extended to differential diagnosis of malignant hepatic tumors, the STIC model achieved an accuracy of 72.6% on the test set, comparable with the diagnostic level of doctors’ consensus (70.8%). With the assistance of the STIC model, doctors achieved better performance than doctors’ consensus diagnosis, with an increase of 8.3% in accuracy and 26.9% in sensitivity for ICC diagnosis on average. On the external test set from center 2, the STIC model achieved an accuracy of 82.9%, which verify the model’s generalization ability. Conclusions We incorporated deep CNN and gated RNN in the STIC model design for differentiating malignant hepatic tumors based on multi-phase CECT and clinical features. Our model can assist doctors to achieve better diagnostic performance, which is expected to serve as an AI assistance system and promote the precise treatment of liver cancer.

The patient‐derived xenograft (PDX) model is a crucial in vivo model extensively employed in cancer research that has been shown to maintain the genomic characteristics and pathological structure of patients across various subtypes, metastatic, and diverse treatment histories. Various treatment strategies utilized in PDX models can offer valuable insights into the mechanisms of tumor progression, drug resistance, and the development of novel therapies. This review provides a comprehensive overview of the establishment and applications of PDX models. We present an overview of the history and current status of PDX models, elucidate the diverse construction methodologies employed for different tumors, and conduct a comparative analysis to highlight the distinct advantages and limitations of this model in relation to other in vivo models. The applications are elucidated in the domain of comprehending the mechanisms underlying tumor development and cancer therapy, which highlights broad applications in the fields of chemotherapy, targeted therapy, delivery systems, combination therapy, antibody–drug conjugates and radiotherapy. Furthermore, the combination of the PDX model with multiomics and single‐cell analyses for cancer research has also been emphasized. The application of the PDX model in clinical treatment and personalized medicine is additionally emphasized. This review presents the establishment and application of patient‐derived xenograft (PDX) models, underscoring their extensive application in various therapeutic strategies including chemotherapy, targeted therapy, delivery systems, combination therapy, antibody–drug conjugates, and radiotherapy. Additionally, the integration of PDX models with multiomics and single‐cell analysis in cancer research is highlighted. Pertinent clinical studies are further examined and discussed, thereby advancing the development of cancer treatment strategies.

The uniformity of nitrogen (N) doping concentration in 4H-SiC epitaxial wafers is a critical determinant of electrical consistency and device reliability. In this study, key chemical vapor deposition (CVD) growth parameters, including the C/Si ratio, H2 carrier gas flow rate, flow split ratio, and growth temperature, were systematically adjusted to investigate their effects on the N doping concentration and uniformity of 6-inch 4H-SiC homoepitaxial layers. The relationships between these parameters and characteristic phenomena such as site-competition epitaxy, along-track depletion of carbon source, and the distinct “W-shaped” doping profile were comprehensively analyzed. Furthermore, simulations of the flow and temperature fields within the reaction chamber and across the SiC epitaxial wafer revealed that under optimized conditions a stable parallel flow field forms above the wafer, accompanied by a uniform temperature distribution, thereby creating an ideal environment for homogeneous N doping. This work provides both theoretical insight and practical guidance for enhancing doping uniformity in large-size SiC epitaxial wafers.

The chemical vapor deposition (CVD) method is a key technology for producing silicon carbide (SiC) epitaxial wafers used in high-performance power devices. Defects in the epitaxial wafers, such as triangular, threading dislocations (TDs); basal plane dislocations (BPDs); and stacking faults (SFs), are considered the critical bottleneck determining device performance and long-term reliability. This review aims to systematically elucidate the fundamental physical and chemical principles underlying defect generation during epitaxial growth of SiC by CVD and provide a comprehensive assessment of corresponding defect reduction strategies. Starting from the essential condition of thermodynamic growth, we analyze the main mechanisms of defect formation, including nonequilibrium kinetics, surface reaction kinetics, and the inheritance of substrate defects. Emphasis is placed on discussing the mechanisms and methods for suppressing defect formation through substrate engineering (off-angle design and surface pretreatment), precise control of the growth parameters (C/Si ratio, temperature, gas composition, and so on), as well as advanced post-treatment techniques. This leads to the proposal of practical strategies focusing on substrate engineering and growth parameter optimization toward practical application. Finally, we summarize the inspection techniques and outline future research directions toward intrinsic low-defect-density SiC epitaxial materials for high-voltage applications.

Yingbin Liu, Yun Liu, Hui Wang and colleagues perform whole-exome and targeted gene sequencing of gallbladder carcinoma. They identify recurrent somatic alterations in components of the ErbB signaling pathway and show that these alterations are associated with poor clinical outcomes. Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR) < 0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR , ERBB2 , ERBB3 , ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome ( P = 0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis.

Abstract Background: Biliary tract carcinomas (BTCs) are relatively rare but lethal primary malignant tumors derived from the biliary tract system. The burden of BTCs varies according to sex, age, region, and country, but limited attention has been paid to the burden of BTCs. We sought to explore the up-to-date data from the Global Burden of Disease Study (GBD) and expand findings by accessing the demographic features of BTC disease burden. Methods: Using the latest data from the GBD 2021, we evaluated and analyzed the distributions and patterns of BTC disease burden in various age groups, sexes, regions, and countries. Results: The number of incident cases, deaths, and disability-adjusted life-years (DALYs) tended to increase and peaked at 216,770 (95% uncertainty interval [UI]: 181,890–245,240), 171,960 (95% UI: 142,350–194,240), and 3,732,100 (95% UI: 3,102,900–4,317,000) person-years, respectively, in 2021. However, the average global age-standardized rates (ASRs) of incident cases, deaths, and DALYs shrunk by −11.46% (95% UI: −21.91 to 3.35%), −24.09% (95% UI: −33.19 to 16.88%), and −26.25% (95% UI: −35.53 to 18.36%), respectively, from 1990 to 2021. Meanwhile, the male/female ratio (male per 100 female) of incidence, deaths, and DALYs changed from 76.40, 75.41, and 74.72 to 86.89, 79.11, and 82.29, respectively. In 2021, the highest number of incident cases, deaths, and DALYs occurred in East Asia. The top three highest incidences, deaths, and DALYs were observed in China, India, and Japan, and the highest ASRs were observed in Chile in 2021. Analysis of the Human Development Index along with disease burden estimates of BTCs also suggests that the burden of the disease is related to the level of comprehensive development of the society. Conclusion: This study provided a comprehensive comparison of differences in the burden of disease across populations and over time, and further presented evidence concerning the formulation of prevention and control policies and etiologic studies for BTCs and proposed logical hypotheses to investigate.