Integrative analysis identified two subtypes and a taurine-related signature to predict the prognosis and efficacy of immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent subtypes of primary liver cancer, with high mortality and poor prognosis. Immunotherapy has revolutionized treatment strategies for many cancers. However, only a subset of patients with HCC achieve satisfactory benefits from immunotherapy. Therefore, a reliable biomarker that could predict the prognosis and immunotherapy response in patients with HCC is urgently needed. Taurine plays an important role in many physiological processes. However, its participation in the occurrence and progression of liver cancer and regulation of the composition and function of various components of the immune microenvironment remains elusive. In this study, we identified and validated two heterogeneous subtypes of HCC with different taurine metabolic profiles, presenting distinct genomic features, clinicopathological characteristics, and immune landscapes, using multiple bulk transcriptome datasets. Subsequently, we constructed a risk model based on genes related to taurine metabolism to assess the prognosis, immune cell infiltration, immunotherapy response, and drug sensitivity of patients with HCC. The risk model was validated using several independent external cohorts and showed a robust predictive performance. In addition, we evaluated the expression patterns of taurine metabolism-related genes in the tumor microenvironment and the heterogeneity of taurine metabolism among cancer cells using a single-cell transcriptome. In conclusion, our study provides insights into the important role played by taurine metabolism in tumor progression and immune regulation. Furthermore, the risk model can serve as a biomarker to assess patient prognosis and immunotherapy response, potentially helping clinicians make more precise and personalized clinical decisions.

Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer.

Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) help tumor cells evade immune surveillance, and are regarded as important targets of anti-tumor immunotherapy. Post-translational modification of PD-L1 has potential value in immunosuppression. Here, we identified that ubiquitin-specific protease 8 (USP8) deubiquitinates PD-L1. Pancreatic cancer tissues exhibited significantly increased USP8 levels compared with those in normal tissues. Clinically, the expression of USP8 showed a significant association with the tumor-node-metastasis stage in multiple patient-derived cohorts of pancreatic cancer. Meanwhile, USP8 deficiency could reduce tumor invasion and migration and tumor size in an immunity-dependent manner, and improve anti-tumor immunogenicity. USP8 inhibitor pretreatment led to reduced tumorigenesis and immunocompetent mice with Usp8 knockdown tumors exhibited extended survival. Moreover, USP8 interacted positively with PD-L1 and upregulated its expression by inhibiting the ubiquitination-regulated proteasome degradation pathway in pancreatic cancer. Combination therapy with a USP8 inhibitor and anti-PD-L1 effectively suppressed pancreatic tumor growth by activation of cytotoxic T-cells and the anti-tumor immunity was mainly dependent on the PD-L1 pathway and CD8 + T cells. Our findings highlight the importance of targeting USP8, which can sensitize PD-L1-targeted pancreatic cancer to immunotherapy and might represent a novel therapeutic strategy to treat patients with pancreatic tumors in the future.

O-GlcNAcylation: an important post-translational modification and a potential therapeutic target for cancer therapy.

O-linked ß-D-N-acetylglucosamine (O-GlcNAc) is an important post-translational modification of serine or threonine residues on thousands of proteins in the nucleus and cytoplasm of all animals and plants. In eukaryotes, only two conserved enzymes are involved in this process. O-GlcNAc transferase is responsible for adding O-GlcNAc to proteins, while O-GlcNAcase is responsible for removing it. Aberrant O-GlcNAcylation is associated with a variety of human diseases, such as diabetes, cancer, neurodegenerative diseases, and cardiovascular diseases. Numerous studies have confirmed that O-GlcNAcylation is involved in the occurrence and progression of cancers in multiple systems throughout the body. It is also involved in regulating multiple cancer hallmarks, such as metabolic reprogramming, proliferation, invasion, metastasis, and angiogenesis. In this review, we first describe the process of O-GlcNAcylation and the structure and function of O-GlcNAc cycling enzymes. In addition, we detail the occurrence of O-GlcNAc in various cancers and the role it plays. Finally, we discuss the potential of O-GlcNAc as a promising biomarker and novel therapeutic target for cancer diagnosis, treatment, and prognosis.

Controlled Atmosphere Brazing of 3003 Aluminum Alloy Using Low-Melting-Point Filler Metal Fabricated by Melt-Spinning Technology.

3003 aluminum alloy was widely used for the manufacturing of heat exchangers in the automotive industry by employing controlled atmosphere brazing (CAB) with NOCOLOK flux brazing technology. However, commercially available filler metals for NOCOLOK flux brazing technology are usually required to be carried out at a relatively high temperature, causing the assembled heat exchanger to be partially molten or easily deformed. A new low-melting-point brazing filler metal Al-5.0Si-20.5Cu-2.0Ni was prepared by using melt-spinning technology and then applied to CAB of 3003 aluminum alloy in this research. The solidus and liquidus of brazing filler metal was 513.21 °C and 532.48 °C. All elements were evenly distributed and free from elemental segregation. The microstructure of brazing filler metal was uniform, and the grain size was less than 500 nm. As the brazing temperature reached 575 °C, the void in the joint disappeared completely. The morphology of CuAl2 was sensitive to the brazing temperature and dwell time. The appearance of net-like CuAl2 brazed at 575 °C for 20 min was more beneficial to improve joint mechanical properties. The leakage rate of the joint was qualified to be 10-10 Pa·m3/s when the brazing temperature was 570 °C or higher. The maximum shear strength of 76.1 MPa can be obtained when the joint was brazed at 575 °C for 20 min. More dwell time induced growth of the interfacial layer and reduced joint shear strength. The open circuit potential and corrosion current density test indicated that the brazing filler metal Al-5.0Si-20.5Cu-2.0Ni had better corrosion resistance than that of 3003 aluminum alloy.

A Comparative Genomic Approach to Determine the Virulence Factors and Horizontal Gene Transfer Events of Clinical Acanthamoeba Isolates.

Acanthamoeba species are among the most ubiquitous protists that are widespread in soil and water and act as both a replicative niche and vectors for dispersal. They are the most important human intracellular pathogens, causing Acanthamoeba keratitis (AK) and severely damaging the human cornea. The sympatric lifestyle within the host and amoeba-resisting microorganisms (ARMs) promotes horizontal gene transfer (HGT). However, the genomic diversity of only A. castellanii and A. polyphaga has been widely studied, and the pathogenic mechanisms remain unknown. Thus, we examined 7 clinically pathogenic strains by comparative genomic, phylogenetic, and rhizome gene mosaicism analyses to explore amoeba-symbiont interactions that possibly contribute to pathogenesis. Genetic characterization and phylogenetic analysis showed differences in functional characteristics between the "open" state of T3 and T4 isolates, which may contribute to the differences in virulence and pathogenicity. Through comparative genomic analysis, we identified potential genes related to virulence, such as metalloprotease, laminin-binding protein, and HSP, that were specific to the genus Acanthamoeba. Then, analysis of putative sequence trafficking between Acanthamoeba and Pandoraviruses or Acanthamoeba castellanii medusaviruses provided the best hits with viral genes; among bacteria, Pseudomonas had the most significant numbers. The most parsimonious evolutionary scenarios were between Acanthamoeba and endosymbionts; nevertheless, in most cases, the scenarios are more complex. In addition, the differences in exchanged genes were limited to the same family. In brief, this study provided extensive data to suggest the existence of HGT between Acanthamoeba and ARMs, explaining the occurrence of diseases and challenging Darwin's concept of eukaryotic evolution. IMPORTANCEAcanthamoeba has the ability to cause serious blinding keratitis. Although the prevalence of this phenomenon has increased in recent years, our knowledge of the underlying opportunistic pathogenic mechanism maybe remains incomplete. In this study, we highlighted the importance of Pseudomonas in the pathogenesis pathway using comprehensive a whole genomics approach of clinical isolates. The horizontal gene transfer events help to explain how endosymbionts contribute Acanthamoeba to act as an opportunistic pathogen. Our study opens up several potential avenues for future research on the differences in pathogenicity and interactions among clinical strains.