An Integrated Multi-Omics Analysis Identifying Immune Subtypes of Pancreatic Cancer.

Limited studies have explored novel pancreatic cancer (PC) subtypes or prognostic biomarkers based on the altered activity of relevant signaling pathway gene sets. Here, we employed non-negative matrix factorization (NMF) to identify three immune subtypes of PC based on C7 immunologic signature gene set activity in PC and normal samples. Cluster 1, the immune-inflamed subtype, showed a higher response rate to immune checkpoint blockade (ICB) and had the lowest tumor immune dysfunction and exclusion (TIDE) scores. Cluster 2, the immune-excluded subtype, exhibited strong associations with stromal activation, characterized by elevated expression levels of transforming growth factor (TGF)-ß, cell adhesion, extracellular matrix remodeling, and epithelial-to-mesenchymal transition (EMT) related genes. Cluster 3, the immune-desert subtype, displayed limited immune activity. For prognostic prediction, we developed an immune-related prognostic risk model (IRPM) based on four immune-related prognostic genes in pancreatic cancer, RHOF, CEP250, TSC1, and KIF20B. The IRPM demonstrated excellent prognostic efficacy and successful validation in an external cohort. Notably, the key gene in the prognostic model, RHOF, exerted significant influence on the proliferation, migration, and invasion of pancreatic cancer cells through in vitro experiments. Furthermore, we conducted a comprehensive analysis of somatic mutational landscapes and immune landscapes in PC patients with different IRPM risk scores. Our findings accurately stratified patients based on their immune microenvironment and predicted immunotherapy responses, offering valuable insights for clinicians in developing more targeted clinical strategies.

Identification and biological evaluation of fused tetrahydroisoquinoline derivatives as Wnt/ß-catenin signaling inhibitors to suppress colorectal cancer.

Colorectal cancer (CRC) has been becoming one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/ß-catenin signaling is a crucial hallmark of CRC, and suppressing it is a promising strategy to treat CRC. Herein, we reported our latest efforts in the discovery of novel fused tetrahydroisoquinoline derivatives with good anti-CRC activities by screening our in-house berberine-like library and further structure-activity relationship (SAR) studies, in which we identified compound 10 is a potent lead compound with significant antiproliferation potencies. By the biotinylated probe and LC-MS/MS study, Hsp90 was identified as its molecular target, which is a fully different mechanism of action from what we reported before. Further studies showed compound 10 directly engaged the N-terminal site of Hsp90 and promoted the degradation of ß-catenin, thereby suppressing the Wnt/ß-catenin signaling. More importantly, compound 10 exhibits favorable pharmacokinetic parameters and significant anti-tumor efficacies in the HCT116 xenograft model. Taken together, this study furnished the discovery of candidate drug compound 10 possessing a novel fused tetrahydroisoquinoline scaffold with excellent in vitro and in vivo anti-CRC activities by targeting Hsp90 to disturb Wnt/ß-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.

Identification of m6A-associated LncRNAs as predict factors for the immune infiltration and prognosis of thyroid cancer.

OBJECTIVE: This study aims to evaluate the prognostic value of m6A-associated long noncoding RNAs (lncRNAs) and their interaction with tumour microenvironment in thyroid cancer (THCA). METHODS: The clinical and gene expression data of tumours from 502 patients with THCA and 58 adjacent normal tissues were retrieved from The Cancer Genome Atlas (TCGA)-THCA dataset. The Pearson test was utilized to identify potential m6A-associated lncRNAs (p < 0.001 and Pearson correlation coefficient > 0.4). Quantitative real-time polymerase chain reaction was performed to verify the expression levels of lncRNAs in tissues. MTT, EdU, colony formation and wound-healing assays were performed to determine the functions of m6A-associated lncRNAs in THCA cell proliferation and metastasis. RESULTS: M6A-associated lncRNAs were identified in three cluster groups. A significant survival difference was found among them, with cluster 1 patients showing worse survival. Moreover, lower immune and estimate scores were correlated to poorer prognosis, and CD8+ T cell and memory CD4+ T cell levels were increased in cluster 1. Cluster 2, with better overall survival, had high expression of PD-L1 and CTLA-4. Eleven of the m6A-associated lncRNAs were screened to establish the risk model, including AC007365.1, AC008555.1, AC040160.1, AC064807.1, AC126773.4, AL023583.1, AL512306.2, EIF2AK3-DT, LINC00667, LYPLAL1-DT and MIR181A2HG. Based on the median risk score, THCA patients were stratified into low-risk and high-risk groups. Overall survival analysis showed a dramatic difference between the two groups. qRCR was performed to verify the expression levels of lncRNA (LYPLAL1-DT, EIF2AK3-DT and MIR181A2HG) in THCA and adjacent normal tissues. Furthermore, functional experiments showed that knockdown of MIR181A2HG obviously inhibited the proliferation and migration of papillary thyroid cancer (PTC) cells in vitro, whereas LYPLAL1-DT overexpression promoted PTC cell proliferation and migration. CONCLUSIONS: Eleven of the m6A-associated lncRNAs were identified as a risk model to predict clinical outcomes and provide a novel and efficient immunotherapeutic strategy for THCA patients.Key messagesm6A-associated lncRNAs can be used to predict the clinical outcomes of thyroid cancer patients.An m6A-associated lncRNAs risk model, which can accurately evaluate the immune status and risk stratification in individual thyroid cancer patients, was established.Knockdown/overexpression of representative lncRNAs in the risk model significantly affected the proliferation and migration of papillary thyroid cancer cells.

LIMK2 Is a Novel Prognostic Biomarker and Correlates With Tumor Immune Cell Infiltration in Lung Squamous Cell Carcinoma.

Previous research found that LIM domain kinase 2 (LIMK2) expression correlated with a poor prognosis in many cancers. However, its role in lung squamous cell carcinoma (LUSC) has not yet been clarified. Our study aimed to clarify the role of LIMK2 in LUSC prognosis prediction and explore the relationship between LIMK2 and immune infiltration in LUSC. In this study, we first analyzed the expression level and prognostic value of LIMK2 across cancers. Subsequently, we explored the association of LIMK2 expression with immune infiltrating cells and immune checkpoints. our study found that LIMK2 was highly expressed and positively associated with the overall survival of LUSC. Moreover, our study further indicated that LIMK2 expression was significantly negatively correlated with immune cell infiltration and immune checkpoints in LUSC. Finally, we confirmed upstream regulatory noncoding RNAs (ncRNAs) of LIMK2, and the PVT1 and DHRS4-AS1/miR-423-5p/LIMK2 regulatory axes were successfully constructed in LUSC. Put together, LIMK2 is a novel prognostic biomarker and correlates with tumor immune cell infiltration in LUSC, and the expression of LIMK2 is regulated by the PVT1 and DHRS4-AS1/miR-423-5p axes.

Electro-activating non-radical 1O2/H* via single atom manganese modified cathode: The indispensable role of metal active site Mn.

As an alternative to noble-metal Pt based catalysts, metal-based single atomic catalytic (SACs) exhibited excellent atom efficiency and catalytic activity via exposing abundant single atomic active centers. Here, we synthesized the monatomic Mn ligands anchored on porous N, P, S- co-doped carbon framework (Mn content over 4.5 wt%) (denoted as Mn-SAC@PZS). The single atomic Mn exhibited super mass activity (11.58 m2 g-1) and kinetic current (1.122×103 µA) with a much lower Tafel slope (4.25 mV dec-1) at 0.792 V (vs. SCE). XANES and EXAFS revealed that the mononuclear Mn were inclined to coordinate with N and S rather than P to form the R space of Mn, in which the first coordination shells backscattered with Mn-N and Mn-S. RRDE revealed that one-electron ORR pathway (72 ~ 100%) dominated at the potential of 0.5 ~ 0.7 V, oxygen molecule was absorbed/activated on site Mn* to form O* intermediate, then further activated to 1O2 via one-electron ORR pathway, while H* was electro activated by non-metallic active sites (i.e. pyri-N, sp-N, -PN and SO). In addition, the Mn-SAC@PZS was capable of highly selectively capturing and effectively degrading CIP in the presence of HA. Fast and complete removal of CIP was achieved within 30 min in the Mn-SAC@PZS-EFLP system, and the apparent rate constant (k) was up to 0.25 min-1. The energy consumption value was 0.453 kWh m-3, much lower than non-single atomic catalyst MnxOy@PZS (0.655 kWh m-3), which was comparable with the state-of-the-art advanced oxidation processes. These findings provided new insights into the maximum release of the atomic activity of the catalyst, and provides a possible way to selectively remove aromatics from multiple pollutants in complex water system.

New Strategy for Specific Eradication of Implant-Related Infections Based on Special and Selective Degradability of Rhenium Trioxide Nanocubes.

The greatest bottleneck for photothermal antibacterial therapy could be the difficulty in heating the infection site directly and specifically to evade the unwanted damage for surrounding healthy tissues. In recent years, infectious microenvironments (IMEs) have been increasingly recognized as a crucial contributor to bacterial infections. Here, based on the unique IMEs and rhenium trioxide (ReO3) nanocubes (NCs), a new specific photothermal antibacterial strategy is reported. These NCs synthesized by a rapid and straightforward space-confined on-substrate approach have good biocompatibility and exhibit efficient photothermal antibacterial ability. Especially when they are utilized in antibiofilm, the expression levels of biofilm-related genes (icaA, fnbA, atlE, and sarA for Staphylococcus aureus) can be effectively inhibited to block bacterial adhesion and formation of biofilm. Importantly, the ReO3 NCs can transform into hydrogen rhenium bronze (HxReO3) in an aqueous environment, making them relatively stable within the low pH of IMEs for photothermal therapy, while rapidly degradable within the surrounding healthy tissues to decrease photothermal damage. Note that under phosphate-buffered saline (PBS) at pH 7.4 without assistant conditions, these ReO3 NCs have the highest degradation rate among all known degradable inorganic photothermal nanoagents. This special and IME-sensitive selective degradability of the ReO3 NCs not only facilitates safe, efficient, and specific elimination of implant-related infections, but also enables effective body clearance after therapy. Solely containing the element (Re) whose atomic number is higher than clinic-applied iodine in all reported degradable inorganic photothermal nanoagents under the PBS (pH 7.4) without any assistant condition, the ReO3 NCs with high X-ray attenuation ability could be further applied to X-ray computed tomography imaging-guided therapy against implant-related infections. The present work described here is the first to adopt degradable inorganic photothermal nanoagents to achieve specific antibacterial therapy and inspires other therapies on this concept.

A full-spectrum-absorption from nickel sulphide nanoparticles for efficient NIR-II window photothermal therapy.

Near-infrared (NIR) light has been widely applied in the field of photothermal therapy (PTT). Recent advances in the light wavelength for efficient cancer PTT have gradually shifted from the first NIR (NIR-I) biowindow (700-1000 nm) to the second NIR (NIR-II) biowindow (1000-1350 nm) owing to its intrinsic deeper tissue penetration ability and a higher maximum permissible exposure (MPE) value. Herein, we have prepared nickel sulphide (Ni9S8) nanoparticles (NPs) with a full-spectrum-absorption (400 nm-1100 nm) in the NIR region. By a fair comparison, it is found that the PTT using the NPs upon irradiation from an NIR-II (i.e., 1064 nm) laser is more efficient than that from an NIR-I (i.e., 808, 915, and 976 nm) laser. The large mass extinction coefficient value (22.18 L g-1 cm-1) and high photothermal conversion efficiency (46%) at 1064 nm make these NPs promising candidates for NIR-II photo-thermal therapy. This study will benefit future exploration and optimization of nickel-based photoabsorbers utilizing NIR-II light for photothermal applications.

Investigation on ultrasound-assisted extraction and separation of enduracidin from Streptomyces sp. NJWGY3665.

Ultrasound-assisted extraction of enduracidin from Streptomyces sp. NJWGY3665 was studied. The effects of various factors on the yield of target components were investigated. The results showed that the extraction by ultrasound-assisted extraction is four times faster than those by conventional solvent extraction. The results also indicated that fast extraction rate was obtained in the first 30 min, and the maximum yield was obtained at the power of 150 W. The effects of other factors such as different solvents, solvent concentration, solvent to solid ratio, and extraction batches on the field were also discussed. The optimum conditions were found at solvent of methanol, time of 30 min, power of 150 W, pH of 7.0, solvent to solid ratio of 50 ml/g, solvent concentration of 70% and extraction batches of four times.