Tris-Functionalized Polyoxotungstovanadate-Mediated Antitumor Efficacy Involves Multiple Cell Death Pathways.

Polyoxometalates (POMs) are promising inorganic drug candidates for cancer chemotherapy. They are becoming attractive because of their easy accessibility and low cost. Herein, we report the synthesis and antitumor activity studies of four Lindqvist-type POMs with mixed-addenda atoms Na2[V4W2O16{(OCH2)3CR}] (R=-CH2OH, -CH3, -CH2CH3) and (Bu4N)2[V3W3{(OCH2)3CH2OOCCH2CH3}]. Compared with the current clinical applied antitumor drug 5-fluorouracil (5-FU) or Gemcitabine, analysis of MTT/CCK-8 assay, colony formation and wound healing assay revealed that the {V4W2} POMs had acceptable cytotoxicity in normal cells (293T) and significant inhibitory effects on cell proliferation and migration in three human tumor cell lines: human lung carcinoma cells (A549), human cervical carcinoma cells (HeLa), and human breast cancer cells (MCF-7). Interestingly, among the POMs analyzed, the therapeutic index (TI) of the {V4W2} POM with R= -CH2OH was relatively the most satisfactory. Thus, it was subsequently used for further studies. Flow cytometry analysis showed it prompted cellular apoptosis rate. qRT-PCR and Western blotting analysis indicated that multiple cell death pathways were activated including apoptosis, autophagy, necroptosis and pyroptosis during the POM-mediated antitumor process. In conclusion, our study shows that the polyoxotungstovanadate has great potential to be developed into a broad-spectrum antitumor chemotherapeutic drug.

CoS2-MoS2 Nanoflower Arrays for Efficient Hydrogen Evolution Reaction in the Universal pH Range.

To explore, highly active electrocatalysts are essential for water splitting materials. Polyoxometalates (POMs) have drawn interesting attention in recent years due to their abundant structure and unique electrocatalytic properties. In this study, by using a POM-based precursor Co2Mo10, novel bimetallic sulfide (CoS2-MoS2) nanocomposites are rationally designed and synthesized under hydrothermal conditions. The incorporation of Co2+ to the host electrocatalyst could effectively increase the exposure of active sites of MoS2. Compared to pure MoS2, the CoS2-MoS2 nanocomposite exhibited a perfect hydrogen evolution reaction (HER) ability, for it merely requires overpotentials of 120 and 153 mV for 10 mA cm-2 working current density toward the HER in 1 M KOH and 0.5 M H2SO4 electrolyte systems, respectively. Additionally, the nanocomposite exhibited outstanding chemical stability and long-term durability. This study presents a novel strategy that utilizes POMs to enrich the exposed edge sites of MoS2, resulting in the preparation of efficient electrocatalysts.

A glycosylation risk score comprehensively assists the treatment of bladder neoplasm in the real-world cohort, including the tumor microenvironment, molecular and clinical prognosis.

Background: Bladder cancer is a common urological cancer associated high significant morbidity and mortality rates. Immunotherapy has emerged as a promising treatment option, although response rates vary among patients. Glycosylation has been implicated in tumorigenesis and immune regulation. However, our current comprehensive understanding of the role of glycosylation in bladder cancer and its clinical implications is limited. Methods: We constructed a training cohort based on the downloaded TCGA-BLCA dataset, while additional datasets (Xiangya cohort, GSE32894, GSE48075, GSE31684, GSE69795 and E-MTAB-1803) from Xiangya hospital, GEO and ArrayExpress database were obtained and used as validation cohorts. To identify glycosylation-related genes associated with prognosis, univariate Cox regression and LASSO regression were performed. A Cox proportional hazards regression model was then constructed to develop a risk score model. The performance of the risk score was assessed in the training cohort using Kaplan-Meier survival curves and ROC curves, and further validated in multiple validation cohorts. Results: We classified patients in the training cohort into two groups based on glycosylation-related gene expression patterns: Cluster 1 and Cluster 2. Prognostic analysis revealed that Cluster 2 had poorer survival outcomes. Cluster 2 also showed higher levels of immune cell presence in the tumor microenvironment and increased activation in key steps of the cancer immune response cycle. We developed an independent prognostic risk score (p < 0.001) and used it to construct an accurate prognostic prediction nomogram. The high glycosylation risk score group exhibited higher tumor immune cell infiltration, enrichment scores in immune therapy-related pathways, and a tendency towards a basal subtype. Conversely, the low-risk score group had minimal immune cell infiltration and tended to have a luminal subtype. These findings were consistent in our real-world Xiangya cohort. Conclusion: This multi-omics glycosylation score based on these genes reliably confirmed the heterogeneity of bladder cancer tumors, predicted the efficacy of immunotherapy and molecular subtypes, optimizing individual treatment decisions.

Molecular vasculogenic mimicry-Related signatures predict clinical outcomes and therapeutic responses in bladder cancer: Results from real-world cohorts.

Bladder cancer (BLCA) is a heterogeneous disease, and there are many classical molecular subtypes that reflect tumor immune microenvironment (TME) heterogeneity but their clinical utility is limited and correct individual treatment and prognosis cannot be predicted based on them. To find reliable and effective biomarkers and tools for predicting patients' clinical responses to several therapies, we developed a new systemic indicator of molecular vasculogenic mimicry (VM)-related genes mediated by molecular subtypes based on the Xiangya cohort and additional external BLCA cohorts using a random forest algorithm. A correlation was then done between the VM_Score and classical molecular subtypes, clinical outcomes, immunophenotypes, and treatment options for BLCA. With the VM_Score, it is possible to predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic potential of BLCA with high accuracy. The VM_Scores of high levels indicate a more anticancer immune response but a worse prognosis due to a more basal and inflammatory phenotype. The VM_Score was also found associated with low sensitivity to antiangiogenic and targeted therapies targeting the FGFR3, ß-catenin, and PPAR-γ pathways but with high sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy. A number of aspects of BLCA biology were reflected in the VM_Score, providing new insights into precision medicine. Additionally, the VM_Score may be used as an indicator of pan-cancer immunotherapy response and prognosis.

Gut Microbiota and Tumor Immune Escape: A New Perspective for Improving Tumor Immunotherapy.

The gut microbiota is a large symbiotic community of anaerobic and facultative aerobic bacteria inhabiting the human intestinal tract, and its activities significantly affect human health. Increasing evidence has suggested that the gut microbiome plays an important role in tumor-related immune regulation. In the tumor microenvironment (TME), the gut microbiome and its metabolites affect the differentiation and function of immune cells regulating the immune evasion of tumors. The gut microbiome can indirectly influence individual responses to various classical tumor immunotherapies, including immune checkpoint inhibitor therapy and adoptive immunotherapy. Microbial regulation through antibiotics, prebiotics, and fecal microbiota transplantation (FMT) optimize the composition of the gut microbiome, improving the efficacy of immunotherapy and bringing a new perspective and hope for tumor treatment.

Cuproptosis depicts tumor microenvironment phenotypes and predicts precision immunotherapy and prognosis in bladder carcinoma.

Background: Though immune checkpoint inhibitors (ICIs) exhibit durable efficacy in bladder carcinomas (BLCAs), there are still a large portion of patients insensitive to ICIs treatment. Methods: We systematically evaluated the cuproptosis patterns in BLCA patients based on 46 cuproptosis related genes and correlated these cuproptosis patterns with tumor microenvironment (TME) phenotypes and immunotherapy efficacies. Then, for individual patient's evaluation, we constructed a cuproptosis risk score (CRS) for prognosis and a cuproptosis signature for precise TME phenotypes and immunotherapy efficacies predicting. Results: Two distinct cuproptosis patterns were generated. These two patterns were consistent with inflamed and noninflamed TME phenotypes and had potential role for predicting immunotherapy efficacies. We constructed a CRS for predicting individual patient's prognosis with high accuracy in TCGA-BLCA. Importantly, this CRS could be well validated in external cohorts including GSE32894 and GSE13507. Then, we developed a cuproptosis signature and found it was significantly negative correlated with tumor-infiltrating lymphocytes (TILs) both in TCGA-BLCA and Xiangya cohorts. Moreover, we revealed that patients in the high cuproptosis signature group represented a noninflamed TME phenotype on the single cell level. As expected, patients in the high cuproptosis signature group showed less sensitive to immunotherapy. Finally, we found that the high and low cuproptosis signature groups were consistent with luminal and basal subtypes of BLCA respectively, which validated the role of signature in TME in terms of molecular subtypes. Conclusions: Cuproptosis patterns depict different TME phenotypes in BLCA. Our CRS and cuproptosis signature have potential role for predicting prognosis and immunotherapy efficacy, which might guide precise medicine.

An EMT-based risk score thoroughly predicts the clinical prognosis, tumor immune microenvironment and molecular subtypes of bladder cancer.

Background: Epithelial mesenchymal transition (EMT) is closely related to the occurrence, development, metastasis and antitumor immunity of tumors. However, comprehensive studies correlating EMT and prognosis, tumor microenvironment (TME) and molecular subtypes of bladder cancer (BLCA) are lacking. Methods: TCGA-BLCA was chosen as our training cohort, while Xiangya cohort, GSE13507, GSE48075 were selected as our validation cohorts. Prognostic genes were screened out using univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) algorithm. Then we developed an EMT risk score based on these prognostic genes and systematically correlated the risk score with prognosis, TME and molecular subtypes of BLCA. Results: Based on EMT related genes, we developed two different EMT patterns, named EMT cluster 1 and cluster 2, and found that cluster 2 showed a worse prognosis and an inflammatory TME phenotype. For personalized prognosis and TME phenotypes predicting, we developed and validated an EMT-based risk score by 7 candidate genes (ANXA10, CNTN1, FAM180A, FN1, IGFL2, KANK4 and TOX3). Patients with high EMT risk scores had lower overall survival (OS) with high predictive accuracy both in the training cohort and validation cohort. In addition, we comprehensively correlated the EMT risk score with TME and molecular subtype, and found that high EMT risk score suggested higher levels of immune cell infiltration and more inclined to present the basal molecular subtype. It was noteworthy that the same results also appeared in the validation of Xiangya cohort. Conclusions: EMT related genes play an important role in tumor progression and immunity in BLCA. Our EMT risk score could accurately predict prognosis and immunophenotype of a single patient, which could guide more effective precision medical strategies.

Cuproptosis-related modification patterns depict the tumor microenvironment, precision immunotherapy, and prognosis of kidney renal clear cell carcinoma.

Background: Due to the different infiltration abundance of immune cells in tumor, the efficacy of immunotherapy varies widely among individuals. Recently, growing evidence suggested that cuproptosis has impact on cancer immunity profoundly. However, the comprehensive roles of cuproptosis-related genes in tumor microenvironment (TME) and in response to immunotherapy are still unclear. Methods: Based on 43 cuproptosis-related genes, we employed unsupervised clustering to identify cuproptosis-related patterns and single-sample gene set enrichment analysis algorithm to build a cuproptosis signature for individual patient's immune cell infiltration and efficacy of immune checkpoint blockade (ICB) evaluation. Then, the cuproptosis-related genes were narrowed down using univariate Cox regression model and least absolute shrinkage and selection operator algorithm. Finally, a cuproptosis risk score was built by random survival forest based on these narrowed-down genes. Results: Two distinct cuproptosis-related patterns were developed, with cuproptosis cluster 1 showing better prognosis and higher enrichment of immune-related pathways and infiltration of immune cells. For individual evaluation, the cuproptosis signature that we built could be used not only for predicting immune cell infiltration in TME but also for evaluating an individual's sensitivity to ICBs. Patients with higher cuproptosis signature scores exhibited more activated cancer immune processes, higher immune cell infiltration, and better curative efficacy of ICBs. Furthermore, a robust cuproptosis risk score indicated that patients with higher risk scores showed worse survival outcomes, which could be validated in internal and external validation cohorts. Ultimately, a nomogram which combined the risk score with the prognostic clinical factors was developed, and it showed excellent prediction accuracy for survival outcomes. Conclusion: Distinct cuproptosis-related patterns have significant differences on prognosis and immune cell infiltration in kidney renal clear cell carcinoma (KIRC). Cuproptosis signature and risk score are able to provide guidance for precision therapy and accurate prognosis prediction for patients with KIRC.

Ir-based electrocatalysts promoted by TME-substituted polyoxovanadate-derived vanadium carbide for efficient hydrogen evolution and oxygen evolution.

A novel trimethylolethane (TME)-substituted polyoxovanadate (POV) was designed as a precursor to prepare ultrasmall vanadium carbide nanoparticles, which markedly promoted the hydrogen evolution reaction and oxygen evolution reaction of iridium (Ir)-based electrocatalysts. This work is the first example employing organic ligand-substituted POV as the precursor for metal carbide, and is also the first combination of Ir and vanadium carbide, providing new insights into the design of excellent electrocatalysts.

Anderson-type polyoxometalates: from structures to functions.

Anderson-type polyoxometalates (POMs) are one of the most important groups of the POM family. In the past decade, the functionalization of Anderson-type POMs has achieved significant progress and these materials have already shown unique charm in catalysis, molecular devices, energy materials, and inorganic biochemical drugs. In particular, their highly flexible topological structure and diverse functionalization methods make them the most convenient and universal platforms for rational design and controllable synthesis. This review provides a deep discussion on the recent progress in the synthetic methodology, structural exploration, and promising applications of Anderson-type POMs. It also summarizes the latest research directions and provides future prospects.

Structural and Magnetical Studies of Mixed-Valence Hexavanadate Hybrids: How Organic Ligands Affect the Magnetism of Polyoxometalates?

In this Communication, we illustrate the influence of organic ligands on magnetic structure and behavior by employing a mixed-valence Lindqvist-type hexavanadate as a research platform. Through covalently attaching to different halogen-containing organic ligands, the derived hybrid materials have different magnetism compared to their parent structure. Single-crystal X-ray analyses show that the introduction of organic ligands can modify the crystal packing manners of the derivatives, leading to further changes of the interaction between magnetic units. This work demonstrates that organic functionalization can remarkably affect the magnetism of polyoxometalates by adjusting the distance and location of the magnetic fractions.

A New Family of Polyoxometalates: Tris-functionalized Lindqvist-Type Hexatungstovanadates.

We successfully designed and obtained a new family of polyoxometalates (POMs) containing mixed-metal elements and a trialkoxyl (TRIS) ligand via a very simple one-pot process under mild condition. Single-crystal X-ray diffraction revealed that this family belongs to compact Lindqvist-type hexatungstovanadates. In particular, the hydroxyl-containing product can be further functionalized through esterification. Not only does this work open a broad door for unusual POM clusters involving vanadium and tungsten atoms in the future, but also the design concept of this work also provides new insight for the synthesis and further exploration of POMs.

TNF Family-Based Signature Predicts Prognosis, Tumor Microenvironment, and Molecular Subtypes in Bladder Carcinoma.

Background: Tumor necrosis factor (TNF) family members play vital roles in cancer development and antitumor immune responses. However, the expression patterns, prognostic values, and immunological characteristics of TNF members in bladder carcinoma (BLCA) remain unclear. Methods: The training cohort, TCGA-BLCA, was downloaded from The Cancer Genome Atlas; another two Gene Expression Omnibus datasets (GSE13507 and GSE32894) and the Xiangya cohort (RNA-sequencing cohort collected from our hospital) were used as the external validation cohort. The least absolute shrinkage and selection operator (LASSO) algorithm and cross-validation were used to screen variables. Cox regression model and random survival forest (RSF) were used to develop the risk score, respectively. Then, we systematically correlated the TNF risk score with the tumor microenvironment (TME) cell infiltration, molecular subtypes of BLCA, and the potential value for predicting the efficacy of immunotherapy. Results: We developed two TNF-based patterns, named TNF cluster 1 and TNF cluster 2. TNF cluster 1 exhibited poorer survival outcome and an inflamed TME characteristic compared with TNF cluster 2. We then filtered out 196 differentially expressed genes between the two TNF clusters and applied the LASSO algorithm and cross-validation to screen out 22 genes to build the risk score. For risk score, we found that RSF exhibited higher efficacy than the Cox regression model, and we chose the risk score developed by RSF for the following analysis. BLCA patients in the higher risk score group showed significantly poorer survival outcomes. Moreover, these results could be validated in the external validation cohorts, including the GSE13507, GSE32894, and Xiangya cohorts. Then, we systematically correlated the risk score with TME cell infiltration and found that it was positively correlated with the infiltration of a majority of immune cells. Also, a higher risk score indicated a basal subtype of BLCA. Notably, the relationship between risk score, TME cell infiltration, and molecular subtypes could be validated in the Xiangya cohort. Conclusion: We developed and validated a robust TNF-based risk score, which could predict prognostic outcomes, TME, and molecular subtypes of BLCA. However, the value of risk score predicting the efficacy of immunotherapy needs further research.

Application of polyoxometalates in photocatalytic degradation of organic pollutants.

Organic pollutants are highly toxic, accumulative, and difficult to degrade or eliminate. As a low-cost, high-efficiency and energy-saving environmental purification technology, photocatalytic technology has shown great advantages in solving increasingly serious environmental pollution problems. The development of efficient and durable photocatalysts for the degradation of organic pollutants is the key to the extensive application of photocatalysis technology. Polyoxometalates (POMs) are a kind of discrete metal-oxide clusters with unique photo/electric properties which have shown promising applications in photocatalytic degradation. This review summarizes the recent advances in the design and synthesis of POM-based photocatalysts, as well as their application in the degradation of organic dyes, pesticides and other pollutants. In-depth perspective views are also proposed in this review.

Direct Syntheses of Nanocages and Frameworks Based on Anderson-Type Polyoxometalates via One-Pot Reactions.

A new one-step synthetic protocol of tris-functionalized Anderson polyoxomolybdates directly from heptamolybdate salts was presented in this Communication. Through this new method, we obtained the first example of Anderson-type polyoxomolybdates with vanadium as the heteroatom. Moreover, the crystals of the products exhibited interesting nanocage or framework extended structures, which were greatly affected by the trialkoxyl ligands as well as the counterions.

A new scheme for rational design and synthesis of polyoxovanadate hybrids with high antitumor activities.

A new strategy to construct polyoxovanadate hybrids incorporating amino acid esters in mild conditions was presented in this paper. These new hybrids were not only structurally determined by Single Crystal X-Ray diffraction, but also exhibited higher antitumor activities against laryngeal carcinoma, rhabdomyoma, and breast adenocarcinoma tumor cells compared with the traditional commercial medicine 5-fluorouracil. These results would provide a promising lead scaffold for further design and synthesis of potential anticancer agents.

Syntheses and post-functionalization of tri-substituted polyalkoxohexavanadates containing tris(alkoxo) ligands.

A new synthetic approach to tri-substituted trisalkoxy-hexavanadate clusters containing different organic groups was developed in this work. Four mixed-valence or fully reduced POV hybrids were synthesized and structurally characterized, including an amino-containing derivative of hexavanadate, Na2[VVO10{NH2C(CH2O)3}3] (1). Furthermore, a novel mixed-valence POV hybrid was prepared via the amidation of 1, indicating that 1 can be used as an excellent building block for the design and synthesis of mixed-valence POV functional materials.

Bottom-up construction of POM-based macrostructures: coordination assembled paddle-wheel macroclusters and their vesicle-like supramolecular aggregation in solution.

A bottom-up approach to obtain nanoclusters and large, uniform vesicle-like structures containing organic functionalized hexamolybdates in solution state were developed. Hexamolybdate functionalized carboxylic acid coordinated with two copper ions to form paddle-wheel tetrapolyoxometalate clusters with the features of macro-ions, which can spontaneously assemble into large, stable blackberry-type structures in suitable solvents, completing a hierarchical organization from small POM molecules to nanoscale complexes and then to supramolecular structures.

Polyoxometalate-organic hybrid molecules as amphiphilic emulsion catalysts for deep desulfurization.

So emulsional: Two hexavanadate-organic hybrids were synthesized and their amphiphilic properties were confirmed by forming emulsions in mixtures of water and nonpolar organic solvents, and were utilized as "emulsion catalysts" in deep desulfurization reactions (see figure). Their catalytic activities show a pH-dependent behavior, which can be explained by the size-change of emulsions and the appearance of reverse emulsions.