Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression.

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

The detection of circulating tumor cells indicates poor therapeutic efficacy and prognosis in patients with nonsmall cell lung cancer: A systematic review and meta-analysis.

OBJECTIVE: The efficacy and prognostic value of circulating tumor cells (CTCs) in nonsmall cell lung cancer (NSCLC) are controversial based on the existing research. This systematic review and meta-analysis evaluated the significance of CTCs in NSCLC therapy monitoring and prognosis prediction, supporting their potential as clinical biomarkers. METHODS: We conducted a comprehensive search of PubMed, Embase, Web of Science, The Cochrane Library, WanFang Data, CNKI, and VIP through September 20, 2023. Inclusion criteria were cohort studies involving NSCLC patients, focusing on peripheral blood CTCs, and assessing outcomes such as pre- and posttreatment CTC rates or levels, progression-free survival (PFS), and overall survival (OS). Two reviewers independently extracted the data and assessed risk of bias using the Newcastle-Ottawa Scale. We utilized Review Manager 5.4.1 for meta-analysis, calculating pooled odds ratios (ORs) for dichotomous outcomes, mean differences for continuous variables and hazard ratios (HRs) for survival data, applying fixed- or random-effects models based on heterogeneity assessed by the I2 statistic. This study was registered in PROSPERO (No. CRD42023450035). RESULTS: Twenty-two eligible studies with a total of 1674 NSCLC patients were included. Meta-analysis results showed that the CTCs-positive rate (OR = 0.59, 95% CI 0.45 to 0.77, p = 0.0001) and CTCs count (mean difference = -3.10, 95% CI -5.52 to -0.69, p = 0.01) were significantly decreased after antitumor treatment. Compared with the CTCs nonreduced group, the CTC-reduced group showed better PFS (HR = 1.71, 95% CI 1.35 to 2.17, p < 0.00001) and OS (HR = 1.50, 95% CI 1.21 to 1.86, p = 0.0003) after treatment. PFS and OS in CTC-positive groups were lower than those in the CTCs-negative group pretreatment (HR = 2.49, 95% CI 1.78 to 3.47, p < 0.00001; HR = 1.80, 95% CI 1.29 to 2.52, p = 0.0006) and posttreatment (HR = 3.36, 95% CI 2.12 to 5.33, p < 0.00001; HR = 3.31, 95% CI 1.75 to 6.27, p = 0.0002). CONCLUSIONS: CTCs can be used as a biomarker to monitor NSCLC efficacy, predict prognosis and guide follow-up treatment.

Immune-related adverse events associated with first-line immune checkpoint inhibitors for metastatic renal cell carcinoma: A systematic review and network meta-analysis.

BACKGROUND: In the realm of metastatic renal cell carcinoma (mRCC), the introduction of immune checkpoint inhibitors (ICIs) has revolutionized treatment paradigms. Despite their effectiveness, the comprehensive safety profile of these therapies remains inadequately explored. This network meta-analysis aims to comparing the safety profiles of ICI-based treatments in mRCC, offering vital insights that could lead to the optimization of treatment strategies and improvement of patient care. METHODS: We conducted a comprehensive search of PubMed, Cochrane Library, Embase, Web of Science, ClinicalTrials.gov, Google Schola, OpenGrey and Scopus through November 1, 2023. The risk of bias assessment was performed using the Risk of Bias version 2 tool. RESULTS: Seven randomized controlled trials (RCTs) with a total of 5976 patients were included for data analysis. The risk of bias results showed that all RCTs were considered "some concerns". The probability of hypothyroidism (surface under the cumulative ranking curve (SUCRA) = 0.981), hyperthyroidism (SUCRA = 0.983) and dermatologic immune-related adverse events (irAEs) (SUCRA = 0.955) in the Nivolumab + Cabozantinib ranked the first. The Avelumab + Axitinib had the highest incidence of adrenal insufficiency (AI) (SUCRA = 0.976), hepatitis (SUCRA = 0.937) and colitis (SUCRA = 0.864). The Nivolumab + Ipilimumab exhibited the highest incidence of pneumonitis (SUCRA = 0.755). Pembrolizumab + Lenvatinib had the highest incidence of nephritic irAEs (SUCRA = 0.788). The ICI-based group showed a higher incidence of hypothyroidism, hyperthyroidism, dermatologic irAEs, hepatitis and nephritic irAEs than sunitinib. However, the confidence in the evidence regarding the impact of ICI-based treatments on AI, pneumonia, and colitis remains limited. CONCLUSION: The analysis focused on the probability of irAEs occurrence in each system when mRCC patients were treated with different ICI-based therapies, potentially offering significant value for guiding clinical prevention, early diagnosis, and management of irAEs. The limitations of the study included the potential heterogeneity and low certainty of part of the evidence.

TET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer.

Induction of tumor vascular normalization is a crucial measure to enhance immunotherapy efficacy. cGAS-STING pathway is vital for anti-tumor immunity, but its role in tumor vasculature is unclear. Herein, using preclinical liver cancer models in Cgas/Sting-deficient male mice, we report that the interdependence between tumor cGAS and host STING mediates vascular normalization and anti-tumor immune response. Mechanistically, TET2 mediated IL-2/STAT5A signaling epigenetically upregulates tumor cGAS expression and produces cGAMP. Subsequently, cGAMP is transported via LRRC8C channels to activate STING in endothelial cells, enhancing recruitment and transendothelial migration of lymphocytes. In vivo studies in male mice also reveal that administration of vitamin C, a promising anti-cancer agent, stimulates TET2 activity, induces tumor vascular normalization and enhances the efficacy of anti-PD-L1 therapy alone or in combination with IL-2. Our findings elucidate a crosstalk between tumor and vascular endothelial cells in the tumor immune microenvironment, providing strategies to enhance the efficacy of combinational immunotherapy for liver cancer.

Inhibition of ACLY overcomes cancer immunotherapy resistance via polyunsaturated fatty acids peroxidation and cGAS-STING activation.

Adenosine 5'-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl-coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti-PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.

Case report: targeted sequencing improves the diagnosis of multiple synchronous lung cancers.

Background: The ability to distinguish satellite nodules, multiple primary lung cancers (MPLCs), and intrapulmonary metastases (IPM) is crucial for prognosis and treatment. The traditional diagnostic criteria for MPLC/IPM including the Martini and Melamed (MM) criteria and the comprehensive histologic assessment (CHA) criteria, mainly relies on histological comparison between multiple lesions. However, many challenges remain in distinguishing them in clinical practice. Case Description: We herein present a report of 3 lung adenocarcinoma cases who presented with 2 lesions, with improved diagnosis based on targeted sequencing covering driver genes. Based on histopathological features, patient 1 (P1) was classified as MPLC, whereas patients 2 and 3 (P2, P3) were classified as satellite nodules. However, targeted sequencing revealed the clonality status of these lesions and improved their diagnosis. The result of the molecular testing indicated that P1 is IPM and the other two patients (P2, P3) should be diagnosed with MPLC. Conclusions: Different lesions in the same case had different driver mutations, suggesting that the 2 lesions were driven by different molecular events. Therefore, targeted sequencing containing driver genes should be used for the diagnosis of multiple synchronous lung cancers. A limitation of this report is the short follow up period, and long-term outcomes of the patients require further follow up.

The role of fatty acid desaturase 2 in multiple tumor types revealed by bulk and single-cell transcriptomes.

BACKGROUND: Previous studies have demonstrated the important role of fatty acid desaturase 2 (FADS2) in governing tumorigenesis and tumor metastasis. Although FADS2 is an essential regulator of fatty acid metabolism, its prognostic and immunotherapeutic value remains uncertain. METHODS: The role of FADS2 was investigated across different types of tumors. Besides, the relationship between FADS2 and survival prognosis, clinicopathologic features, tumor-infiltrating immune cells, immunoregulatory genes, chemokines, chemokines receptor, tumor mutational burden (TMB), and microsatellite instability (MSI) was also explored. FADS2-related genes enrichment analysis was performed to further explore the molecular function of FADS2. Finally, the relationship between FADS2 expression and altered functional states in single-cell levels across different tumor cells was explored. RESULTS: FADS2 was increased in most tumor tissues. Elevated FADS2 expression was associated with a poor overall survival (OS) and disease-free survival (DFS). FADS2 amplification was germane to worse progress-free survival (PFS). In addition, FADS2 correlated with the majority of tumor-infiltrating immune cells, immunoregulatory genes, and chemokines. Especially, FADS2 expression positively correlated with cancer-associated fibroblast (CAFs) infiltration. Gene Ontology and KEGG analysis demonstrated that FADS2 was involved in the fatty acid metabolic process, arachidonic acid metabolism, RAS, PPAR, and VEGF pathway. FADS2 had a positive relationship with tumor biological behaviors such as inflammation, cell cycle, proliferation, DNA damage, and DNA repair response in single-cell levels. CONCLUSIONS: FADS2 can serve as a potential prognostic and immunotherapeutic biomarker for multiple tumors, revealing new insights and evidence for cancer treatment.

LIPG is a novel prognostic biomarker and correlated with immune infiltrates in lung adenocarcinoma.

BACKGROUND: Although many biomarkers for lung adenocarcinoma (LUAD) have been identified, their specificity and sensitivity remain unsatisfactory. Endothelial lipase gene (LIPG) plays an important role in a variety of cancers, but its role in lung adenocarcinoma remains unclear. METHODS: TCGA, GEO, K-M plotter, CIBERSORT, GSEA, HPA, and GDSC were used to analyze LIPG in LUAD. Data analysis was mainly achieved by R 4.0.3. RESULTS: The expression of LIPG in LUAD tissues was higher than that in adjacent normal tissues, especially in women, patients aged >65 years, and those with lymph node metastasis. High expression predicted a poor prognosis. The results of enrichment analysis suggest that LIPG may exert profound effects on the development of LUAD through multiple stages of lipid metabolism and immune system regulation. In addition, LIPG expression was significantly correlated with the expression levels of multiple immune checkpoint genes and the abundance of multiple immune infiltrates, including the activated memory CD4 T cell, M1 macrophage, neutrophil, plasma cells, and T follicular helper (Tfh) cells in the LUAD microenvironment content. At the same time, patients with high LIPG expression respond well to a variety of antitumor drugs and have a low rate of drug resistance. CONCLUSIONS: LIPG is a prognostic marker and is associated with lipid metabolism and immune infiltration in LUAD.

Solid Migration to Assemble a Flower-like Nanozyme with Highly Dense Single Copper Sites for Specific Phenol Oxidation.

Nanozymes with high catalytic stability and sustainability have emerged as powerful competitors to natural enzymes for diverse biocatalytic applications. However, constructing a nanozyme with high specificity is one of their biggest challenges. Herein, we develop a facile solid migration strategy to access a flower-like single copper site nanozyme (Cu SSN) via direct transformation of copper foam activated by 2-methylimidazole. With highly clustered CuN3 sites whose local structure is similar to that of natural polyphenol oxidase, the Cu SSN exhibits excellent activity and specificity to oxidize phenols without peroxidase-like activity. Furthermore, the Cu SSN shows high sensitivity in the colorimetric detection of epinephrine with a low detection limit of 0.10 µg mL-1, exceeding that of most previously reported enzyme-mimicking catalysts. This work not only provides a simple method for the large-scale preparation of high-performance nanozymes but also offers an inspiration for the design of highly specific nanozymes by mimicking the synergy among sites in natural enzymes.

Dexmedetomidine disrupts esophagus cancer tumorigenesis by modulating circ_0003340/miR-198/HMGA2 axis.

More and more studies have focused on the regulatory role of circular RNAs (circRNAs) in various cancers. However, it is not clear how dexmedetomidine (DEX) affects esophagus cancer progression by affecting the expression of circRNAs. This study aimed to investigate the role of DEX in esophagus cancer and its underlying mechanism. Cell Counting Kit-8 assay and 5-ethynyl-2'-deoxyuridine assays were conducted to evaluate cell proliferation. Flow cytometry analysis and transwell assay were performed for cell apoptosis and invasion. The protein levels of cleaved caspase-3, matrix metallopeptidase 9, and high mobility group AT-hook 2 (HMGA2) were assessed by western blot assay. The expression levels of circ_0003340 and microRNA-198 (miR-198) were determined by quantitative real-time PCR. Dual-luciferase reporter assay was performed to verify the interaction between miR-198 and circ_0003340 or HMGA2. Murine xenograft model was established to investigate the role of circ_0003340 and DEX in vivo. DEX exerted antitumor effects in esophagus cancer cells. DEX hindered proliferation and invasion while inducing apoptosis of esophagus cancer cells, which was abolished by circ_0003340 elevation, HMGA2 overexpression, or miR-198 silencing. miR-198 directly interacted with circ_0003340 and HMGA2 in esophagus cancer cells. Moreover, knockdown of circ_0003340 could improve the anticancer role of DEX in vivo. DEX constrained cell carcinogenesis by regulating circ_0003340/miR-198/HMGA2 axis in esophagus cancer, providing an effective clinical implication for preventing the development of the esophagus cancer by the DEX.

Astragalus polysaccharide supplementation improves production performance, egg quality, serum biochemical index and gut microbiota in Chongren hens.

This research aimed to determine whether the astragalus polysaccharide (AP) can improve the production performance and gut microbiota in Chongren hens.120 Chongren hens (240-d old) were randomly allocated into 4 treatments with 30 hens and fed with a control basal diet (CON) or CON supplemented with the different levels of AP (100, 200, and 400 mg/kg) for 56 d. The egg production and feed conversion ratio were decreased (p < .05) with the levels of AP. The yolk weight, yolk color, eggshell thickness, eggshell redness index and egg shell yellowness were increased (p < .05). AP supplementation increased CAT and T-AOC and SOD, and decreased MDA (p < .05). Supplementation of AP decreased IL-2, IL-6 and TNF-α levels (p < .05), but increased the IL-4 level in the liver (p < .05). The villus heights of duodenum, jejunum ileum, the crypt depth and V/C in the jejunum were increased (p < .05). Dietary supplementation of 200 mg/kg AP increased (P relative abundances of Firmicutes and Lactobacteriaceae in the cecum of Chongren hens. In conclusion, addition of AP improved the production performance, egg quality, antioxidant function, and intestinal morphology in hens, which might be associated with the gut microbiota.

SMYD3 confers cisplatin chemoresistance of NSCLC cells in an ANKHD1-dependent manner.

BACKGROUND: Cisplatin (DDP) remains the backbone of chemotherapy for non-small cell lung cancer (NSCLC), yet its clinical efficacy is limited by DDP resistance. We aim to investigate the role of the SET and MYND domain-containing protein 3 (SMYD3) in DDP resistance of NSCLC. METHODS: Expression pattern of SMYD3 was determined in NSCLC tissues using qRT-PCR, which also validated its correlation with NSCLC clinicopathological stages. Impacts of SMYD3 on DDP resistance were evaluated by knocking down SMYD3 in DDP-resistant cells and overexpressing it in DDP-sensitive cells, and assessed for several phenotypes: IC50 by MTT, long-term proliferation by colony formation, apoptosis and cell-cycle distribution by flow cytometry. The interaction between Ankyrin Repeat and KH Domain Containing 1 (ANKHD1) and SMYD3 was examined by co-immunoprecipitation and immunofluorescence. The transcriptional regulation of SMYD3 on cyclin-dependent kinase 2 (CDK2) promoter regions was confirmed using chromatin-immunoprecipitation. The in vivo experiments using DDP-resistant cells with altered SMYD3 and ANKHD1 expression were further performed to verify the SMYD3/ANKHD1 axis. RESULTS: Highly expressed SMYD3 was observed in NSCLC tissues or cells, acted as a sensitive indicator for NSCLC, correlated with higher TNM stages or resistant to DDP treatment, and shorter overall survival. The promotion of SMYD3 on DDP resistance requires co-regulator, ANKHD1. CDK2 was identified as a downstream effector. In vivo, SMYD3 knockdown inhibited the growth of DDP-resistant NSCLC cells, which was abolished by ANKHD1 overexpression. CONCLUSIONS: SMYD3 confers NSCLC cells chemoresistance to DDP in an ANKHD1-dependent manner, providing novel therapeutic targets to overcome DDP resistance in NSCLC .

A phase III study on neoadjuvant chemotherapy versus neoadjuvant toripalimab plus chemotherapy for locally advanced esophageal squamous cell carcinoma: Henan Cancer Hospital Thoracic Oncology Group 1909 (HCHTOG1909).

BACKGROUND: Neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACR) are the standard treatments for esophageal squamous cell carcinoma (ESCC). However, the 5-year overall survival (OS) rate is still far from satisfactory. In recent years, immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of ESCC. More than 20 phase II clinical trials have been launched to explore combinations of ICIs in the neoadjuvant setting for ESCC. Based on our phase II clinical trial, a two-arm phase III trial was launched in Henan Cancer Hospital. ICIs combined with NAC may usher in a new era and may benefit locally advanced, resectable ESCC patients. METHODS: A two-arm phase III trial was launched in April 2020 in Henan Cancer Hospital. Patient recruitment will be completed within 18 months. The primary endpoint is event-free survival (EFS). The secondary endpoints include pathologic complete response (pCR), disease-free survival (DFS) rate, overall response rate (ORR), R0 resection rate, major pathologic response (MPR), adverse events (AEs), complication rate and quality of life (QOL). A biobank of pretreatment, resected tumor tissue and paired blood samples will be built for translational research in the future. DISCUSSION: This RCT directly compares NAC with neoadjuvant toripalimab plus chemotherapy in terms of EFS for locally advanced ESCC. The results may usher in a new era of resectable ESCC treatment. TRIAL REGISTRATION: NCT04280822 (https://www.clinicaltrials.gov/ct2/show/NCT04280822). Registered title: "A Phase III, Randomized Controlled Study of Neo-adjuvant Toripalimab (JS001) in Combination with Chemotherapy versus Neo-adjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma". Version 1.0/Nov. 21, 2019.

NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion.

NAD+ metabolism is implicated in aging and cancer. However, its role in immune checkpoint regulation and immune evasion remains unclear. Here, we find nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ biogenesis, drives interferon γ (IFNγ)-induced PD-L1 expression in multiple types of tumors and governs tumor immune evasion in a CD8+ T cell-dependent manner. Mechanistically, NAD+ metabolism maintains activity and expression of methylcytosine dioxygenase Tet1 via α-ketoglutarate (α-KG). IFNγ-activated Stat1 facilitates Tet1 binding to Irf1 to regulate Irf1 demethylation, leading to downstream PD-L1 expression on tumors. Importantly, high NAMPT-expressing tumors are more sensitive to anti-PD-L1 treatment and NAD+ augmentation enhances the efficacy of anti-PD-L1 antibody in immunotherapy-resistant tumors. Collectively, these data delineate an NAD+ metabolism-dependent epigenetic mechanism contributing to tumor immune evasion, and NAD+ replenishment combined with PD-(L)1 antibody provides a promising therapeutic strategy for immunotherapy-resistant tumors.

ATP-citrate lyase regulates stemness and metastasis in hepatocellular carcinoma via the Wnt/ß-catenin signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most highly malignant tumors. Liver tumor-initiating cells (LTICs) have been considered to contribute to HCC progression and metastasis. ATP-citrate lyase (ACLY), as a key enzyme for de novo lipogenesis, has been reported to be upregulated in various tumors. However, its expression and role in HCC and LTICs remain unknown. METHODS: The expressions of ACLY in HCC tissues were detected by quantitative real-time PCR (qRT-PCR), Western blotting and immunohistochemistry. Kaplan-Meier curves and Chi-square test were used to determine the clinical significance of ACLY expression in HCC patients. A series of assays were performed to determine the function of ACLY on stemness, migration and invasion of HCC cells. Luciferase reporter assay, Western blotting and immunoprecipitation were used to study the regulation of the Wnt/ß-catenin signaling by ACLY. Rescue experiments were performed to investigate whether ß-catenin was the mediator of ACLY-regulated stemness and migration in HCC cells. RESULTS: ACLY was highly expressed in HCC tissues and LTICs. Overexpression of ACLY was significantly correlated with poor prognosis, progression and metastasis of HCC patients. Knockdown of ACLY remarkably suppressed stemness properties, migration and invasion in HCC cells. Mechanistically, ACLY could regulate the canonical Wnt pathway by affecting the stability of ß-catenin, and Lys49 acetylation of ß-catenin might mediate ACLY-regulated ß-catenin level in HCC cells. CONCLUSIONS: ACLY is a potent regulator of Wnt/ß-catenin signaling in modulating LTICs stemness and metastasis in HCC. ACLY may serve as a new target for the diagnosis and treatment of HCC.

Negative Pressure Pyrolysis Induced Highly Accessible Single Sites Dispersed on 3D Graphene Frameworks for Enhanced Oxygen Reduction.

Herein, we report a negative pressure pyrolysis to access dense single metal sites (Co, Fe, Ni etc.) with high accessibility dispersed on three-dimensional (3D) graphene frameworks (GFs), during which the differential pressure between inside and outside of metal-organic frameworks (MOFs) promotes the cleavage of the derived carbon layers and gradual expansion of mesopores. In situ transmission electron microscopy and Brunauer-Emmett-Teller tests reveal that the formed 3D GFs possess an enhanced mesoporosity and external surface area, which greatly favor the mass transport and utilization of metal sites. This contributes to an excellent oxygen reduction reaction (ORR) activity (half-wave potential of 0.901 V vs. RHE). Theoretical calculations verify that selective carbon cleavage near Co centers can efficiently lower the overall ORR theoretical overpotential in comparison with intact atomic configuration.

Cation-Exchange Induced Precise Regulation of Single Copper Site Triggers Room-Temperature Oxidation of Benzene.

The controllable synthesis of stable single-metal site catalysts with an expected coordination environment for high catalytic activity and selectivity is still challenging. Here, we propose a cation-exchange strategy for precise production of an edge-rich sulfur (S) and nitrogen (N) dual-decorated single-metal (M) site catalysts (M = Cu, Pt, Pd, etc.) library. Our strategy relies on the anionic frameworks of sulfides and N-rich polymer shell to generate abundant S and N defects during high-temperature annealing, further facilitating the stabilization of exchanged metal species with atomic dispersion and excellent accessibility. This process was traced by in situ transmission electron microscopy, during which no metal aggregates were observed. Both experiments and theoretical results reveal the precisely obtained S, N dual-decorated Cu sites exhibit a high activity and low reaction energy barrier in catalytic hydroxylation of benzene at room temperature. These findings provide a route to controllably produce stable single-metal site catalysts and an engineering approach for regulating the central metal to improve catalytic performance.

A Supported Nickel Catalyst Stabilized by a Surface Digging Effect for Efficient Methane Oxidation.

A surface digging effect of supported Ni NPs on an amorphous N-doped carbon is described, during which the surface-loaded Ni NPs would etch and sink into the underneath carbon support to prevent sintering. This process is driven by the strong coordination interaction between the surface Ni atoms and N-rich defects. In the aim of activation of C-H bonds for methane oxidation, those sinking Ni NPs could be further transformed into thermodynamically stable and active metal-defect sites within the as-generated surface holes by simply elevating the temperature. In situ transmission electron microscopy images reveal the sunk Ni NPs dig themselves adaptive surface holes, which would largely prevent the migration of Ni NPs without weakening their accessibility. The reported two-step strategy opens up a new route to manufacture sintering-resistant supported metal catalysts without degrading their catalytic efficiency.

The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62.

Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5'-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62's aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.

Induction therapy for clinical stage T2N0M0 esophageal cancer: A systematic review and meta-analysis.

OBJECTIVE: It is still controversial whether patients with clinical T2N0M0 (cT2N0M0) esophageal cancer are treated with induction therapy. The aim of this study was to determine the effect of induction therapy on cT2N0M0 esophageal cancer. METHODS AND MATERIALS: We searched PubMed, Embase, the Cochrane Library, and Medline databases from inception up to May 1, 2017. This meta-analysis was performed to compare odds ratios (OR) for 5-year overall survival (OS), pathologically understaged and overstaged after esophagectomy. RESULTS: Eight retrospective studies of 2646 patients were included in the meta-analysis. Data showed that no statistically significant difference in 5-year over survival was observed between induction therapy group and direct operation group. The pooled OR and 95% confidence interval (CI) for 5-year OS were 0.92 (95% CI = 0.72-1.18; P = .52). Whereas, compared with induction therapy group, direct operation group had more pathologically understaged and less overstaged after esophagectomy. CONCLUSIONS: Currentclinical staging for T2N0M0 esophageal carcinoma remains inaccurate. In this study, we found that direct operation group had more pathologically understaged and less overstaged after esophagectomy compared with induction therapy group. Induction therapy could degrade the tumor staging but not improve the patient's survival.