Explore the vast range of titles available.

Traditional chemical catalysts for polyester synthesis have enabled the generation of important commercial products. Undesirable characteristics of chemically catalyzed condensation polymerizations include the need to conduct reactions at high temperatures (150–280 °C) with metal catalysts that are toxic and lack selectivity. The latter is limiting when aspiring towards synthesis of increasingly complex and well-defined polyesters. This review describes an exciting technology that makes use of immobilized enzyme-catalysts for condensation polyester synthesis. Unlike chemical catalysts, enzymes function under mild conditions (≤100 °C), which enables structure retention when polymerizing unstable monomers, circumvents the introduction of metals, and also provides selectivity that avoids protection–deprotection steps and presents unique options for structural control. Examples are provided that describe the progress made in enzyme-catalyzed polymerizations, as well as current limitations and future prospects for developing more efficient enzyme-catalysts for industrial processes.

Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death (ICD)-inducing drugs available that can kill cancer cells, enhance tumor immunogenicity, increase the in vivo immune infiltration, and thereby boosting a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immuno-stimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still investigational. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and T cell activation assay. We identified that teniposide, a DNA topoisomerase II inhibitor, could induce high mobility group box 1 (HMGB1) release and type I interferon signaling in tumor cells, and teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling including NF-κB activation and STING-dependent type I interferon signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 on multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity, and enabled a potential chemo-immunotherapeutic approach to potentiate the therapeutic efficacy of anti-PD1 immunotherapy.

Water in Earth’s mantle plays a critical role in both geodynamic and surficial habitability. Water in the upper mantle and transition zone is widely discussed, but less is known about the water in the lower mantle despite it constituting over half of Earth’s mass. Understanding the water storage in Earth’s lower mantle relies on comprehending the water solubility of bridgmanite, which is the most abundant mineral both in the lower mantle and throughout Earth. Nevertheless, due to limited access to the lower mantle, our understanding of water in bridgmanite mainly comes from laboratory experiments and theoretical calculations, and a huge controversy still exists. In this paper, we provide a review of the commonly employed research methods and current findings concerning the solubility of water in bridgmanite. Potential factors, such as pressure, temperature, compositions, etc., that influence the water solubility of bridgmanite will be discussed, along with insights into future research directions.

The origin of major volatiles nitrogen, carbon, hydrogen, and sulfur in planets is critical for understanding planetary accretion, differentiation, and habitability. However, the detailed process for the origin of Earth’s major volatiles remains unresolved. Nitrogen shows large isotopic fractionations among geochemical and cosmochemical reservoirs, which could be used to place tight constraints on Earth’s volatile accretion process. Here we experimentally determine N-partitioning and -isotopic fractionation between planetary cores and silicate mantles. We show that the core/mantle N-isotopic fractionation factors, ranging from −4‰ to +10‰, are strongly controlled by oxygen fugacity, and the core/mantle N-partitioning is a multi-function of oxygen fugacity, temperature, pressure, and compositions of the core and mantle. After applying N-partitioning and -isotopic fractionation in a planetary accretion and core–mantle differentiation model, we find that the N-budget and -isotopic composition of Earth’s crust plus atmosphere, silicate mantle, and the mantle source of oceanic island basalts are best explained by Earth’s early accretion of enstatite chondrite-like impactors, followed by accretion of increasingly oxidized impactors and minimal CI chondrite-like materials before and during the Moon-forming giant impact. Such a heterogeneous accretion process can also explain the carbon–hydrogen–sulfur budget in the bulk silicate Earth. The Earth may thus have acquired its major volatile inventory heterogeneously during the main accretion phase. How and when Earth acquired its major volatiles N-C-H-S remains unclear. Here the authors show that Earth may have acquired its major volatiles from both reduced and oxidized impactors before and during the Moon-forming giant impact.

Objectives The increase in mental health problems among adolescents is a vital public health issue in the United States. It is crucial to understand how this concerning trend was exacerbated by the COVID-19 pandemic. Using a national representative sample, we assessed the impact of COVID-19 on mental health and access to mental health care access among adolescents. Methods Data was extracted from the 2019 and 2022 National Survey of Children’s Health (NSCH), an annually collected survey on the health and well-being of adolescents in the U.S. A total of 31,258 adolescents ages 12–17 years were included in this analysis. The two primary outcomes were reports of (1) mental health problems (yes/no) and (2) mental healthcare access (yes/no) in the past 12 months. We ran separate multiple logistic regression models to assess the changes in mental health problems and access to mental health care from 2019 to 2022. Results Overall, our results indicated a higher prevalence of adolescent mental health problems reported in 2022 (30.6% 95% CI: 29.4–31.9%) than in 2019 (26.9%, 25.2–28.6%) ( p  = 0.001). Results of a regression model showed that adolescents who identified as non-Hispanic Black, had parents with higher education levels and who experienced childhood adverse events were more likely to have parent-reported mental health problems (all p  < 0.001). Results of the regression model on access to mental health care indicated that adolescent girls were more likely to have access to mental health care than boys (AOR = 2.15, 95% CI:1.80–2.58). Adolescents from families with higher income, with insurance coverage, living in neighborhoods with more amenities, urban areas, and those who experienced adverse childhood events were all more likely to have accessed mental health care than their counterparts. (all p  < 0.05). Conclusions We found the prevalence of mental health problems in adolescents increased while the prevalence of access to mental health care decreased from 2019 to 2022, before and during the COVID-19 pandemic. This trend should be closely monitored. And special efforts are needed to help those adolescents who are affected.

Differential diagnosis of pulmonary nodules detected by computed tomography (CT) remains a challenge in clinical practice. Here, we characterize the global metabolomes of 480 serum samples including healthy controls, benign pulmonary nodules, and stage I lung adenocarcinoma. The adenocarcinoma demonstrates a distinct metabolomic signature, whereas benign nodules and healthy controls share major similarities in metabolomic profiles. A panel of 27 metabolites is identified in the discovery cohort ( n  = 306) to distinguish between benign and malignant nodules. The discriminant model achieves an AUC of 0.915 and 0.945 in the internal validation ( n  = 104) and external validation cohort ( n  = 111), respectively. Pathway analysis reveals elevation in glycolytic metabolites associated with decreased tryptophan in serum of lung adenocarcinoma vs benign nodules and healthy controls, and demonstrates that uptake of tryptophan promotes glycolysis in lung cancer cells. Our study highlights the value of the serum metabolite biomarkers in risk assessment of pulmonary nodules detected by CT screening. Detection of lung adenocarcinoma through serum sampling could be an alternative to CT scanning. Here, the authors use global metabolomics to create a 27 metabolite signature, which showed accuracy in detection in an external validation cohort.

BackgroundNeutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+ neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+ neutrophils in hepatocellular carcinoma.MethodsNeutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+ neutrophil infiltration. Further in vivo assays were used for verification.ResultsLenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+ neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib.ConclusionsPD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.

Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC. Isocitrate dehydrogenase (IDH) mutations are associated with cancer development and IDH-mutant inhibitors are approved to treat IDH-mutant cancer. Here, the authors show in preclinical murine models that wild-type IDH2 is a potential therapeutic target for triple-negative breast cancer.

Background Lung adenocarcinoma (LUAD), the most common and lethal subtype of lung cancer, continues to be a major health concern worldwide. Despite advances in targeted and immune therapies, only a minority of patients derive substantial benefits. As a result, the urgent need for novel therapeutic strategies to improve lung cancer treatment outcomes remains undiminished. Methods In our study, we employed the TIMER database to scrutinize TNFSF11 expression across various cancer types. We further examined the differential expression of TNFSF11 in normal and tumor tissues utilizing the TCGA-LUAD dataset and tissue microarray, and probed the associations between TNFSF11 expression and clinicopathological parameters within the TCGA-LUAD dataset. We used the GSE31210 dataset for external validation. To identify genes strongly linked to TNFSF11, we engaged LinkedOmics and conducted a KEGG pathway enrichment analysis using the WEB-based Gene SeT AnaLysis Toolkit. Moreover, we investigated the function of TNFSF11 through gene knockdown or overexpression approaches and explore its function in tumor cells. The therapeutic impact of ferroptosis inducers in tumors overexpressing TNFSF11 were also investigated through in vivo and in vitro experiments. Through these extensive analyses, we shed light on the potential role of TNFSF11 in lung adenocarcinoma, underscoring potential therapeutic targets for this malignancy. Results This research uncovers the overexpression of TNFSF11 in LUAD patients and its inverse correlation with peroxisome-related enzymes. By utilizing gene knockdown or overexpression assays, we found that TNFSF11 was negatively associated with GPX4. Furthermore, cells with TNFSF11 overexpression were relatively more sensitive to the ferroptosis inducers. Conclusions Our research has provided valuable insights into the role of TNFSF11, revealing its negative regulation of GPX4, which could be influential in crafting therapeutic strategies. These findings set the stage for further exploration into the mechanisms underpinning the relationship between TNFSF11 and GPX4, potentially opening up new avenues for precision medicine in the treatment of LUAD.

Background Isocitrate dehydrogenase-2 (IDH2) is a mitochondrial enzyme that catalyzes the metabolic conversion between isocitrate and alpha-ketoglutarate (α-KG) in the TCA cycle. IDH2 mutation is an oncogenic event in acute myeloid leukemia (AML) due to the generation of 2-hydroxyglutarate. However, the role of wild-type IDH2 in AML remains unknown, despite patients with it suffer worse clinical outcome than those harboring mutant type. Methods IDH2 expression in AML cell lines and patient samples was evaluated by RT-qPCR, western blotting and database analyses. The role of wild-type IDH2 in AML cell survival and proliferation was tested using genetic knockdown and pharmacological inhibition in AML cells and animal models. LC–MS, GC–MS, isotope metabolic tracing, and molecular analyses were performed to reveal the underlying mechanisms. Results We found that wild-type IDH2 was overexpressed in AML and played a major role in promoting leukemia cell survival and proliferation in vitro and in vivo. Metabolomic analyses revealed an active IDH2-mediated reductive TCA cycle that promoted the conversion of α-KG to isocitrate/citrate to facilitate glutamine utilization for lipid synthesis in AML cells. Suppression of wild-type IDH2 by shRNA resulted in elevated α-KG and decreased isocitrate/citrate, leading to reduced lipid synthesis, a significant decrease in c-Myc downregulated by α-KG, and an inhibition of AML viability and proliferation. Importantly, pharmacological inhibition of IDH2 showed significant therapeutic effect in mice inoculated with AML cells with wt-IDH2 and induced a downregulation of C-MYC in vivo. Conclusions Wt-IDH2 is an essential molecule for AML cell survival and proliferation by promoting conversion of α-KG to isocitrate for lipid synthesis and by upregulating c-Myc expression and could be a potential therapeutic target in AML.