Nerve-tumor crosstalk in tumor microenvironment: From tumor initiation and progression to clinical implications.

The autonomic nerve system (ANS) innervates organs and tissues throughout the body and maintains functional balance among various systems. Further investigations have shown that excessive activation of ANS not only causes disruption of homeostasis, but also may promote tumor formation. In addition, the dynamic interaction between nerve and tumor cells in the tumor microenvironment also regulate tumor progression. On the one hand, nerves are passively invaded by tumor cells, that is, perineural invasion (PNI). On the other hand, compared with normal tissues, tumor tissues are subject to more abundant innervation, and nerves can influence tumor progression through regulating tumor proliferation, metastasis and drug resistance. A large number of studies have shown that nerve-tumor crosstalk, including PNI and innervation, is closely related to the prognosis of patients, and contributes to the formation of cancer pain, which significantly deteriorates the quality of life for patients. These findings suggest that nerve-tumor crosstalk represents a potential target for anti-tumor therapies and the management of cancer pain in the future. In this review, we systematically describe the mechanism by which nerve-tumor crosstalk regulates tumorigenesis and progression.

Approach to a cerebral hernia caused by an intratumoral hemorrhage of a cystic oligodendroglioma: a case report.

The incidence of cerebral herniation caused by intratumoral hemorrhage (ITH) in cystic oligodendroglioma (COD) is exceedingly rare. This study presents a case of cerebral herniation subsequent to cystic oligodendroglioma (COD) and sudden intratumoral hemorrhage. Following initial emergency treatment and evaluation, we successfully circumvented the solid component of the tumor and proceeded with cystic puncture and external drainage to prevent the incidence of brain herniation and mitigate the severity of associated symptoms. Based on preoperative examination results, the cystic glioma was successfully resected, and the patient experienced an uneventful recovery. According to the pathological findings, the oligodendroglioma was classified as World Health Organization (WHO) grade III. The treatment efficacy was comparable to cases of the same pathological grade, in which neither intratumoral hemorrhage nor cerebral hernia was observed.

Identification of Transcriptomic Signatures of Pancreatic Ductal Adenocarcinoma-Derived Exosomes That Promote Macrophage M2 Polarization and Predict Prognosis: S100A9 Reveals Tumor Progression.

Background: Exosomes play a role in intercellular communication and participate in the interaction between pancreatic ductal adenocarcinoma (PDAC) cells and immune cells. Macrophages can receive tumor cell-derived exosomes to polarize into M2-type macrophages, which can enhance the invasion and metastasis of pancreatic cancer, leading to poor prognosis. However, the mechanism by which pancreatic cancer cell-derived exosomes promote M2-type macrophages is still unclear. Methods: M2 macrophage-associated exosome-derived key module genes were identified by differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) analysis using exoRbase 2.0, The Cancer Genome Atlas (TCGA), and The International Cancer Genome Consortium (ICGC) databases. Multivariate Cox regression analysis was used to identify key prognostic genes and obtain regression coefficients to establish prognostic signature. Immune infiltration, tumor mutations, and GSEA among different risk groups were compared. exoRbase 2.0, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), HPA, and TISCH2 databases were used to further analyze the expression pattern of S100A9 in pancreatic cancer. In vitro experiments, cell-derived exosome isolation, quantitative polymerase chain reaction (qPCR), western blot, flow cytometry analysis, cell transfection, transwell assay, and CCK-8 assay were applied to investigate the roles of S100A9 in macrophage M2 polarization and tumor progression. Results: The key genes of PDAC-derived exosomes promoting M2-type macrophage polarization were identified, and a risk score model was established. The risk score is related to the expression of common immune checkpoints, immune score, and stromal score, and the tumor mutational burden and biological function of high- and low-risk groups were also different. S100A9 was positively correlated with M2-type macrophage marker. In addition, scRNA-seq data from the TISCH2 database revealed that S100A9 is predominantly expressed in pancreatic cancer cells and mono/macrophage cells, suggesting that S100A9 in pancreatic cancer cells could be received by macrophages, thereby inducing macrophage polarization. In vitro, we used exosomes from BxPC-3 cell lines to coculture macrophages and found that macrophages were mainly polarized toward M2 type, which further promoted the proliferation and metastasis of PDAC. Conclusions: Our study established a reliable risk score model for PDAC-derived exosomes and M2 macrophages, identified the important role of S100A9 in macrophage M2 polarization, which provides a new strategy for the diagnosis and treatment of PDAC, and strengthened the understanding of the mechanism of tumor development and metastasis.

Controlling Product Distribution of Polyethylene Hydrogenolysis Using Bimetallic RuM3 (M = Fe, Co, Ni) Catalysts.

Plastic hydrogenolysis is an attractive approach for producing value-added chemicals due to its mild reaction conditions, but controlling product distribution is challenging due to the formation of undesired CH4. This work reports several bimetallic RuM3/CeO2 (M = Fe, Co, Ni) catalysts that shift the product of low-density polyethylene hydrogenolysis toward longer-chain hydrocarbons. These catalysts were characterized by using X-ray absorption fine structure spectroscopy, electron microscopy imaging, and H2 temperature-programmed reduction. The combined catalytic evaluation and characterization results revealed that the product distribution was regulated by the formation of bimetallic alloys. A model compound, n-hexadecane, was selected to further understand the differences in hydrogenolysis over the Ru-based catalysts. Although a longer reaction time shifted the product toward smaller molecules, the bimetallic (RuCo3/CeO2) catalyst limited the further conversion of C2-C5 into CH4. This work highlights the role of bimetallic alloys in tailoring the interaction with hydrocarbons, thereby controlling the product distribution of polymer hydrogenolysis.

Transcriptome data-based status of PI3K/AKT/mTOR pathway indicates heterogeneity and immune modulation in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options. The PI3K/AKT/mTOR pathway is commonly activated in PDAC and plays a critical role in its progression. METHODS AND RESULTS: In this study, the effect of taselisib (a selective PI3K inhibitor) on PDAC cell proliferation was investigated, and a significant decrease in viability was observed with increasing concentrations of taselisib. Differential analysis on samples from the Genotype-Tissue Expression and The Cancer Genome Atlas databases revealed 24 dysregulated PI3K/AKT/mTOR pathway-related genes (PRGs). Unsupervised clustering-based analysis of transcriptome cohorts revealed two clusters with high consistency between RNA-seq and microarray cohorts. Cluster B had higher enrichment of immune cells, particularly CD8+ T cells, and lower levels of immunosuppressive Treg cells. Moreover, we investigated the relationship between drug sensitivity and different clusters and found that cluster A had a better response to PI3K/AKT/mTOR pathway-related inhibitors and chemotherapy. Finally, cluster A exhibited significant activation of PI3K/AKT/mTOR and related oncogenic pathways, contributing to poor prognosis. The study also developed a risk score based on the expression profiles of PRGs and machine learning, which showed a significant increase in overall survival time among patients in the low-risk group. Importantly, the PI3K/AKT/mTOR pathway could be used to better predict individual risk scores, as evidenced by stratified survival analysis. CONCLUSIONS: These findings suggest that targeting the PI3K/AKT/mTOR pathway may have therapeutic potential in PDAC, and distinct pathway states, immune modulation and tumor microenvironments have prognostic value.

Transcriptomic landscape of endothelial cells: Key tumor microenvironment components indicating variable clinical outcomes in pancreatic ductal adenocarcinoma.

Endothelial cells (ECs) present in the tumor microenvironment (TME) exhibit significant diversity that may impact the efficacy of anti-tumor treatments. Thus, our study sought to elucidate the various clusters of ECs present in pancreatic ductal adenocarcinoma (PDAC) and explore their possible interactions and influence on clinical outcomes. We obtained single-cell transcriptome data from 24 PDAC tumors and 11 normal pancreases, minimizing any batch effects between samples. Next, we compared the relative abundance of various ECs clusters across distinct sample types. Pseudo-time analysis was employed to investigate the differentiation origin of ECs. A variety of bioinformatics methods were used to investigate potential communication between ECs and malignant cells, as well as assess metabolic changes, pathway alterations, and immune-related markers expression within distinct EC clusters. Lastly, we investigated the impact of particular ECs clusters on patient prognosis in bulk transcriptome data. Our study identified seven distinct clusters of ECs, denoted as CA4+ ECs, MMP2+ ECs, SPP1+ ECs, MT1F+ ECs, CCL5+ ECs, RGS5+ ECs, and TYROBP+ ECs. Pseudo-time analysis suggested that the loss of CA4+ ECs and MT1F+ ECs may promote malignant progression. Cell communication elucidated that MT1F+ ECs exhibited the strongest outgoing interaction strength, whereas RGS5+ ECs displayed the strongest incoming interaction strength. Furthermore, TYROBP+ ECs exhibited greater metabolic activity, and notably, CCL5+ ECs displayed increased expression of immune-related molecules. Lastly, across cohorts of bulk transcriptome levels, CA4+ ECs, MT1F+ ECs, and RGS5+ ECs consistently demonstrated prognostic indicative effects. PDAC patients exhibit the presence of seven distinct EC clusters, each demonstrating significant metabolic and immunological heterogeneity. Targeted therapeutic approaches directed toward CA4+ ECs and MT1F+ ECs may prove advantageous in addressing challenges associated with PDAC treatment. Additionally, variations in the relative abundance of CA4+ ECs, MT1F+ ECs, and RGS5+ ECs were indicated as predictive of patient prognosis.

Regulating Electrostatic Interactions toward Thermoresponsive Hydrogels with Low Critical Solution Temperature.

Low critical solution temperature (LCST) of commonly used thermoresponsive polymers in water is basically dominated by hydrophobic interactions. Herein, a novel thermoresponsive system based on electrostatic interactions is reported. By simply loading aluminum chloride (AlCl3 ) into non-responsive poly(2-hydroxyethyl acrylate) (PHEA) hydrogels, PHEA-Al gels turn to have reversible thermoresponsive behavior between transparent and opaque without any volume change. Further investigations by changing metal ion-polymer compositions unravel the necessity of specific electrostatic interactions, namely, cation-dipole bonding interactions between hydroxy groups and trivalent metal ions. The thermoresponsive hydrogel demonstrates high transparency (≈95%), excellent luminous modulation capability (>98%), and cyclic reliability, suggesting great potential as an energy-saving material. Although LCST control by salt addition is widely known, salt-induced expression of thermoresponsiveness has barely been discussed before. This design provides a new approach of easy fabrication, low cost, and scalability to develop stimuli-responsive materials.

Research on Flesh Texture and Quality Traits of Kiwifruit (cv. Xuxiang) with Fluctuating Temperatures during Cold Storage.

Kiwifruits are often exposed to various temperature fluctuations (TFs) during postharvest transportation and storage. To evaluate the effect of TFs on the qualities of kiwifruits during storage, kiwifruits were stored at 2 °C, 2 °C or 5 °C (TF2 °C-5 °C, alternating every 12 h), 2 °C or 7 °C (TF2 °C-7 °C, alternating every 12 h) for 3 d before long time storage at 2 °C. Observations revealed that kiwifruits stored at a constant 2 °C showed the lowest loss of weight and vitamin C because of minimized ethylene production and respiratory rate compared with that of TF2 °C-5 °C and TF2 °C-7 °C. Moreover, the results of RT-qPCR verified that the expression levels of genes encoding polygalacturonase, ß-galacturonidase, and pectin methylesterase were significantly increased by the treatment of TF. Hence, TF accelerated the degradation of cell walls, softening, translucency, and relative conductivity of the flesh of kiwifruits. In addition, the impact of TF2 °C-7 °C on kiwifruits was more significant relative to TF2 °C-5 °C. The present study provides a theoretical basis for kiwifruit during cold storage.

Homoporous polydimethylsiloxane membrane microfilter for ultrafast label-free isolation and recognition of circulating tumor cells in peripheral blood.

The detection of circulating tumor cells (CTCs) in peripheral blood is a novel and accurate technique for the early diagnosis of cancers. However, this method is challenging because of the need for high collection efficiency due to the ultralow content and similar size of CTCs compared with other blood cells. To address the aforementioned issue, we proposed a homoporous polydimethylsiloxane (PDMS) membrane and its microfilter device to perform the ultrafast isolation and identification of CTCs directly from peripheral blood without any labeling treatment. The membrane pores can be homogenously controlled at a size of 6.3 µm through the cross-linking time of PDMS during a filtration-coating strategy. Within only 10 s, the designed device achieved a retention rate greater than 70% for pancreatic cancer cells, and it exhibited excellent cell compatibility to support cell proliferation. The isolated CTCs on this membrane can be easily observed and identified using a fluorescence microscope.

Tumor cell-derived exosomes regulate macrophage polarization: Emerging directions in the study of tumor genesis and development.

As an extracellular vesicle, exosomes play an important role in intercellular information transmission, delivering cargos of the parent cell, such as RNA, DNA, proteins, and lipids, activating different signaling pathways in the target cell and regulating inflammation, angiogenesis, and tumor progression. In particular, exosomes secreted by tumor cells can change the function of surrounding cells, creating a microenvironment conducive to tumor growth and metastasis. For example, after macrophages phagocytose exosomes and accept their cargos, they activate macrophage polarization-related signaling pathways and polarize macrophages into M1 or M2 types to exert antitumor or protumor functions. Currently, the study of exosomes affecting the polarization of macrophages has attracted increasing attention. Therefore, this paper reviews relevant studies in this field to better understand the mechanism of exosome-induced macrophage polarization and provide evidence for exploring novel targets for tumor therapy and new diagnostic markers in the future.

mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance.

Pancreatic cancer is one of the most aggressive cancers with a median survival time of less than 5 months, and conventional chemotherapeutics are the main treatment strategy. Poly(ADP-ribose) polymerase (PARP) inhibitors have been recently approved for BRCA1/2-mutant pancreatic cancer, opening a new era for targeted therapy for this disease. However, most pancreatic cancer patients carry wild-type BRCA1/2 with resistance to PARP inhibitors. Here, we reported that mammalian target of rapamycin complex 2 (mTORC2) kinase is overexpressed in pancreatic cancer tissues and promotes pancreatic cancer cell growth and invasion. Moreover, we found that knockdown of the mTORC2 obligate subunit Rictor sensitized pancreatic cancer cells to the PARP inhibitor olaparib. Mechanistically, we showed that mTORC2 positively regulates homologous recombination (HR) repair by modulating BRCA1 recruitment to DNA double-strand breaks (DSBs). In addition, we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the PARP inhibitor olaparib synergistically inhibited pancreatic cancer growth in vivo. Thus, this study provides a novel target and strategy for optimizing PARP inhibitor efficiency in pancreatic cancers.

Effect of different PD-1 inhibitor combination therapies for unresectable intrahepatic cholangiocarcinoma.

BACKGROUND: Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC). AIM: To compare the effect of different anti-PD-1 combination therapies as the first-line treatments for uICC. METHODS: This study included 318 patients who received chemotherapy alone (Chemo), anti-PD-1 plus chemotherapy (ICI-chemo), anti-PD-1 plus targeted therapy (ICI-target) or anti-PD-1 plus targeted therapy and chemotherapy (ICI-target-chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. RESULTS: Patients with ICI-chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42-0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39-0.94; p = 0.026), ICI-target (7.2 months; HR: 0.54, 95% CI: 0.36-0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35-0.84; p = 0.006) or ICI-target-chemo (6.9 months; HR: 0.65, 95% CI: 0.47-0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31-0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI-target was not inferior to ICI-chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55-1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51-1.55; p = 0.680). ICI-target-chemo yielded similar prognoses as ICI-chemo (HR for PFS: 1.07, 95% CI: 0.70-1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45-1.31; p = 0.328) and ICI-target (HR for PFS: 1.20, 95% CI: 0.77-1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51-1.47; p = 0.583) but resulted in more adverse events (p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings. CONCLUSIONS: Among patients with uICC, ICI-chemo or ICI-target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI-target-chemo.

LncRNA HClnc1 facilitates hepatocellular carcinoma progression by regulating PKM2 signaling and indicates poor survival outcome after hepatectomy.

AIM: Long noncoding RNAs (lncRNAs) are key mediators with a wide range of pathophysiological functions, but their role in human hepatocellular carcinoma (HCC) is still unclear. METHODS: An unbiased microarray study evaluated a novel lncRNA, HClnc1, that is linked to the development of HCC. In vitro cell proliferation assays and an in vivo xenotransplanted HCC tumor model were performed to determine its functions, followed by antisense oligo-coupled mass spectrometry to identify HClnc1-interacting proteins. To study relevant signaling pathways, in vitro experiments were performed, including chromatin isolation by RNA purification, RNA immunoprecipitation, luciferase, and RNA pull-down assay. RESULTS: HClnc1 levels were considerably greater in patients with advanced tumor-node-metastatic stages, and it was found to be inversely connected to survival rates. Moreover, the proliferative and invasive potential of the HCC cells was attenuated by HClnc1 RNA knockdown in vitro, while HCC tumor growth and metastasis were found to be reduced in vivo. HClnc1 interacted with pyruvate kinase M2 (PKM2) to prevent its degradation and thus facilitated aerobic glycolysis and PKM2-STAT3 signaling. CONCLUSIONS: HClnc1 is involved in a novel epigenetic mechanism of HCC tumorigenesis and PKM2 regulation. HClnc1 is not only a more accurate prognostic indicator of HCC but also a potential therapeutic target for HCC treatment.

Correction: One-step mild preparation of tough and thermo-reversible poly(vinyl alcohol) hydrogels induced by small molecules.

Correction for 'One-step mild preparation of tough and thermo-reversible poly(vinyl alcohol) hydrogels induced by small molecules' by Chuang Dong et al., Chem. Commun., 2021, 57, 3789-3792, https://doi.org/10.1039/D1CC00578B.

Tuning the reactivity of carbon surfaces with oxygen-containing functional groups.

Oxygen-containing carbons are promising supports and metal-free catalysts for many reactions. However, distinguishing the role of various oxygen functional groups and quantifying and tuning each functionality is still difficult. Here we investigate the role of Brønsted acidic oxygen-containing functional groups by synthesizing a diverse library of materials. By combining acid-catalyzed elimination probe chemistry, comprehensive surface characterizations, 15N isotopically labeled acetonitrile adsorption coupled with magic-angle spinning nuclear magnetic resonance, machine learning, and density-functional theory calculations, we demonstrate that phenolic is the main acid site in gas-phase chemistries and unexpectedly carboxylic groups are much less acidic than phenolic groups in the graphitized mesoporous carbon due to electron density delocalization induced by the aromatic rings of graphitic carbon. The methodology can identify acidic sites in oxygenated carbon materials in solid acid catalyst-driven chemistry.

ACR-Based Probe for the Quantitative Profiling of Histidine Reactivity in the Human Proteome.

The quantitative profiling of residue reactivity in proteins promotes the discovery of covalent druggable targets for precise therapy. Histidine (His) residues, accounting for more than 20% of the active sites in enzymes, have not been systematically characterized for their reactivity, due to lack of labeling probes. Herein, we report a chemical proteomics platform for the site-specific quantitative analysis of His reactivity by combination of acrolein (ACR) labeling and reversible hydrazine chemistry enrichment. Based on this platform, in-depth characterization of His residues was conducted for the human proteome, in which the rich content of His residues (>8200) was quantified, including 317 His hyper-reactive residues. Intriguingly, it was observed that the hyper-reactive residues were less likely to be the sites for phosphorylation, and the possible mechanism of this antagonistic effect still needs to be evaluated in further research. Based on the first comprehensive map of His residue reactivity, many more residues could be adopted as the bindable sites to disrupt the activities of a diverse number of proteins; meanwhile, ACR derivatives could also be used as a novel reactive warhead in the development of covalent inhibitors.

Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer.

Integrin subunit alpha 3 (ITGA3) expression correlates with the development and prognosis of human cancers. This study aimed to investigate the association of ITGA3 expression with pancreatic cancer (PCa) prognosis. The ITGA3 gene expression data were extracted from The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma (PAAD) cohort and 14 Gene Expression Omnibus microarray datasets. The differences in ITGA3 expression levels between tumor and non-tumor tissues were compared using the Mann-Whitney U test. Cox regression analysis and meta-analysis were performed to detect the association of ITGA3 expression with PCa prognosis. ITGA3 expression was higher in tumors than in controls. Tumors with advanced grades (3/4) had higher ITGA3 levels compared with early-grade tumors (1/2). The meta-analysis of the TCGA PAAD cohort and seven microarray datasets (GSE28735, GSE62452, GSE79668, GSE71729, GSE57495, GSE78229, and GSE21501) showed that ITGA3 was a prognostic biomarker in PCa (hazard ratio (HR) = 1.38, 95% confidence interval (CI) 1.26-1.51, p < 0.00001). Five ITGA3-related genes, including ITGB1 (HR = 1.6), ITGB5 (HR = 1.6), ITGB6 (HR = 1.6), LAMA3 (HR = 2.1), and CD9 (HR = 2.3), correlated with PCa prognosis significantly (p < 0.05). Functional enrichment analysis showed that ITGA3 was related to "hsa04151: PI3K-Akt signaling pathway" and "hsa04510: Focal adhesion." We concluded that high ITGA3 expression was a potential prognostic biomarker in PCa.

The Crosstalk Between Immune Infiltration, Circulating Tumor Cells, and Metastasis in Pancreatic Cancer: Identification of HMGB3 From a Multiple Omics Analysis.

Metastasis is the major cause of death in patients with pancreatic ductal adenocarcinoma (PDAC), and circulating tumor cells (CTCs) play an important role in the development of metastasis. However, few studies have uncovered the metastasis mechanism of PDAC based on CTCs. In this study, the existing bulk RNA-sequencing (bulk RNA-seq) and single-cell sequencing (scRNA-seq) data for CTCs in pancreatic cancer were obtained from the Gene Expression Omnibus (GEO) database. Analysis of tumor-infiltrating immune cells (TIICs) by CIBERSORT showed that the CTCs enriched from the peripheral blood of metastatic PDAC were found to contain a high proportion of T cell regulators (Tregs) and macrophages, while the proportion of dendritic cells (DCs) was lower than that enriched from localized PDAC. Through weighted gene co-expression network analysis (WGCNA) and the result of scRNA-seq, we identified the hub module (265 genes) and 87 marker genes, respectively, which were highly associated with metastasis. The results of functional enrichment analysis indicated that the two gene sets mentioned above are mainly involved in cell adhesion and cytoskeleton and epithelial-mesenchymal transition (EMT). Finally, we found that HMGB3 was the hub gene according to the Venn diagram. The expression of HMGB3 in PDAC was significantly higher than that in normal tissues (protein and mRNA levels). HMGB3 expression was significantly positively correlated with both EMT-related molecules and CTC cluster-related markers. Furthermore, it was also found that HMGB3 mutations were favorably related to tumor-associated immune cells through the TIMER2.0 online tool. We further demonstrated that PDAC patients with higher HMGB3 expression had significantly worse overall survival (OS) in multiple datasets. In summary, our study suggests that HMGB3 is a hub gene associated with EMT in CTCs, the formation of CTC clusters, and infiltration patterns of immune cells favorable for tumor progression and metastasis to distant organs.