Built-In Positive Valence Space Shifting the Chemical Equilibrium Forward for Nitrate Reduction to Ammonia.

The electrochemical conversion of nitrate pollutants into value-added ammonia (NH3) is an appealing alternative synthetic route for sustainable NH3 production. However, the development of the electrocatalytic nitrate-to-ammonia reduction reaction (NO3RR) has been hampered by unruly reactants and products at the interface and the accompanied sluggish kinetic rate. In this work, a built-in positive valence space is successfully constructed over FeCu nanocrystals to rationally regulate interfacial component concentrations and positively shift the chemical equilibrium. With positive valence Cu optimizing the active surface, the space between the stern and shear layers becomes positive, which is able to continuously attract the negatively charged NO3- reactant and repulse the positively charged NH4+ product even under high current density, thus significantly boosting the NO3RR kinetics. The system with a built-in positive valence space affords an ampere-level NO3RR performance with the highest NH3 yield rate of 150.27 mg h-1 mg-1 at -1.3 V versus RHE with an outstanding NH3 current density of 189.53 mA cm-2, as well as a superior Faradaic efficiency (FE) of 97.26% at -1.2 V versus RHE. The strategy proposed here underscores the importance of interfacial concentration regulation and can find wider applicability in other electrochemical syntheses suffering from sluggish kinetics.

Eliminating Concentration Polarization with Cationic Covalent Organic Polymer to Promote Effective Overpotential of Nitrogen Fixation.

Electrocatalytic nitrogen reduction reaction offers a sustainable alternative to the conventional Haber-Bosch process. However, it is currently restricted by low effective overpotential due to the concentration polarization, which arises from accumulated products, ammonium, at the reaction interface. Here, a novel covalent organic polymer with ordered periodic cationic sites is proposed to tackle this challenge. The whole network exhibits strong positive charge and effectively repels the positively charged ammonium, enabling an ultra-low interfacial product concentration, and successfully driving the reaction equilibrium to the forward direction. With the given potential unchanged, the suppressed overpotential can be much liberated, ultimately leading to a continuous high-level reaction rate. As expected, when this tailored microenvironment is coupled with a transition metal-based catalyst, a 24-fold improvement is generated in the Faradaic efficiency (73.74 %) as compared with the bare one. The proposed strategy underscores the importance of optimizing dynamic processes as a means of improving overall performance in electrochemical syntheses.

Left-side vs. right-side hepatectomy for hilar cholangiocarcinoma: a meta-analysis.

GOALS: We aim to draw a conclusion which type of hepatectomy could be the priority for hilar cholangiocarcinoma patients. BACKGROUND: Surgery is established as only potentially curative treatment for hilar cholangiocarcinoma. However, whether hepatectomy should be preferred to the left-side hepatectomy, which includes left hemihepatectomy, extended left hemihepatectomy, and left trisectionectomy, or right-side hepatectomy, which represents right hemihepatectomy, extended right hemihepatectomy, and right trisectionectomy, is debated. In this meta-analysis, we evaluated and compared the efficacy and safety of left-side hepatectomy and right-side hepatectomy in patients with hilar cholangiocarcinoma. STUDY: We systematically retrieved the MEDLINE, PubMed, and Cochrane library and related bibliography up to February 2020. The primary outcome is overall survival, and the secondary outcome includes 1-, 3-, and 5-year survival rates, morbidity, mortality, R0 resection rate, and operation time. Based on heterogeneity, fixed-effects model or random-effects models were established through meta-analysis. RESULTS: Eleven studies (11 cohort studies, totally 1031 patients) were involved in this study. The overall survival of patients who underwent left-side hepatectomy was comparable to that of patients who underwent right-side hepatectomy (hazard ratio, 1.27 [95% confidence interval, 0.98-1.63]). And there was no significant difference observed in 1-year (relative risk, 1.01 [95% CI, 0.89-1.15]), 3-year (relative risk, 0.94 [95% confidence interval, 0.80-1.11]), and 5-year survival (relative risk, 0.82 [95% confidence interval, 0.67-1.01]) rates between the left-side hepatectomy group and the right-side hepatectomy group. Comparing with the right-side hepatectomy cluster, the hilar cholangiocarcinoma patients in the left-side hepatectomy cluster presented better overall postoperative morbidity (relative risk, 0.82 [95% confidence interval, 0.71-0.96]) and major postoperative morbidity (relative risk, 0.73 [95% confidence interval, 0.56-0.95]). The post-hepatectomy liver failure rate (relative risk, 0.22 [95% confidence interval, 0.09-0.56]) and procedure-related mortality (relative risk, 0.41 [95% confidence interval, 0.23-0.70]) in the left-side hepatectomy group were better than those of the right-side hepatectomy group. Besides, the R0 resection rate was similar between the left-side hepatectomy group and the right-side hepatectomy group (relative risk, 0.95 [95% confidence interval, 0.87-1.03]). And the operation time for the left-side hepatectomy was significantly longer than that for the right-side hepatectomy (mean difference, 38.68 [95% confidence interval, 7.41-69.95]). CONCLUSION: Through meta-analysis, we explored the comparable long-term outcomes and better short-term outcomes in the left-side hepatectomy group as is compared to the right-side hepatectomy group of hilar cholangiocarcinoma patients. In this study, the evidence obtained might indicate that the choice of left-side hepatectomy or right-side hepatectomy depends on the site of hilar cholangiocarcinoma in every patient.

ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1.

BACKGROUND: N6-methyladenosine (m6A) modification is an emerging layer of epigenetic regulation which is widely implicated in the tumorigenicity of hepatocellular carcinoma (HCC), offering a novel perspective for investigating molecular pathogenesis of this disease. The role of AlkB homolog 5 (ALKBH5), one of the m6A demethylases, has not been fully explored in HCC. Here we clarify the biological profile and potential mechanisms of ALKBH5 in HCC. METHODS: Expression of ALKBH5 and its correlation with clinicopathological characteristics of HCC were evaluated using tissue microarrays and online datasets. And biological effects of ALKBH5 in HCC were determined in vitro and in vivo. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq), and following m6A dot blot, MeRIP-qPCR, RIP-qPCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of ALKBH5. RESULTS: We demonstrated that ALKBH5 was down-regulated in HCC, and decreased ALKBH5 expression was an independent prognostic factor of worse survival in HCC patients. Functionally, ALKBH5 suppressed the proliferation and invasion capabilities of HCC cells in vitro and in vivo. Mechanistically, ALKBH5-mediated m6A demethylation led to a post-transcriptional inhibition of LY6/PLAUR Domain Containing 1 (LYPD1), which could be recognized and stabilized by the m6A effector IGF2BP1. In addition, we identified that LYPD1 induced oncogenic behaviors of tumors in contrast to ALKBH5. Dysregulation of ALKBH5/LYPD1 axis impelled the progression of HCC. CONCLUSION: Our study reveals that ALKBH5, characterized as a tumor suppressor, attenuates the expression of LYPD1 via an m6A-dependent manner in HCC cells. Our findings enrich the landscape of m6A-modulated tumor malignancy, and provide new insights into potential biomarkers and therapeutic targets of HCC treatment.

Triggering Heteroatom Ensemble Effect over RuFe Alloy to Promote Nitrogen Chemisorption for Efficient Ammonia Electrosynthesis at Ambient Conditions.

Ammonia (NH3) electrosynthesis from nitrogen (N2) provides a promising strategy for carbon neutrality, circumventing the energy-intensive and carbon-emitting Haber-Bosch process. However, the current system still presents unsatisfactory performance, and the bottleneck lies in the rational synthesis of catalytic centers with efficient N2 chemisorption ability. Herein, a heteroatom ensemble effect is deliberately triggered over RuFe alloy with spatial proximity of metal sites to promote electrocatalytic nitrogen reduction. The heteronuclear RuFe ensemble with increased surface polarization and modulated electronic structure offers the feasibility to optimize the adsorption configuration of electroactive substances and facilitate chemical bond scission. The promotion of N2 chemisorption and the following hydrogenation are demonstrated by the in situ Fourier transform infrared spectroscopy characterizations. The catalyst thus permits significantly enhanced conversion of N2 to NH3 in a 0.1 M HCl environment, with a maximum ammonia yield rate of 75.45 µg h-1 mg-1 and a high Faradaic efficiency of 35.49%.

Rare-Earth Lanthanum-Evoked Amorphization and Optimization to Boost Ambient Nitrogen Fixation over Single-Atom Catalysts.

Single-atom catalysts (SACs) have been widely studied in a variety of electrocatalysis. However, its application in the electrocatalytic nitrogen reduction reaction (NRR) field still suffers from unsatisfactory performance, due to the sluggish mass transfer and significant kinetic barriers. Herein, a novel rare-earth-lanthanum-evoked optimization strategy is proposed to boost ambient NRR over SACs. The incorporation of La with a large atomic radius tends to break the atomic long-range order and trigger the amorphization of SACs, endowing a greater density of dangling bonds that could modify affinity for reactants and adsorbates. Moreover, with unique 5d16s2 valence-electron configurations, its presence could further enrich the electron density and enhance the intrinsic activity of single-metal center via the valence orbital coupling. As expected, the La-modified catalyst presents excellent activity toward the electrochemical NRR, delivering a maximum ammonia yield rate of 33.91 µg h-1 mg-1 and a remarkable Faradaic efficiency of 53.82%.

Integrated Multiomics Reveals Silencing of has_circ_0006646 Promotes TRIM21-Mediated NCL Ubiquitination to Inhibit Hepatocellular Carcinoma Metastasis.

Recent studies suggest that circular RNA (circRNA)-mediated post-translational modification of RNA-binding proteins (RBP) plays a pivotal role in metastasis of hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile the regulatory networks of circRNA and RBP using a multi-omics approach. Has_circ_0006646 (circ0006646) is an unreported circRNA in HCC and is associated with a poor prognosis. Silencing of circ0006646 significantly hinders metastasis in vivo. Mechanistically, circ0006646 prevents the interaction between nucleolin (NCL) and the E3 ligase tripartite motif-containing 21 to reduce the proteasome-mediated degradation of NCL via K48-linked polyubiquitylation. Furthermore, the change of NCL expression is proven to affect the phosphorylation levels of multiple proteins and inhibit p53 translation. Moreover, patient-derived tumor xenograft and lentivirus injection, which is conducted to simulate clinical treatment confirmed the potential therapeutic value. Overall, this study describes the integrated multi-omics landscape of circRNA-mediated NCL ubiquitination degradation in HCC metastasis and provides a novel therapeutic target.

Molecular Imprinting Technology Enables Proactive Capture of Nitrogen for Boosted Ammonia Synthesis under Ambient Conditions.

Electrochemical nitrogen reduction reaction (NRR) is a burgeoning field for green and sustainable ammonia production, in which numerous potential catalysts emerge endlessly. However, satisfactory performances are still not realized under practical applications due to the limited solubility and sluggish diffusion of nitrogen at the interface. Herein, molecular imprinting technology is adopted to construct an adlayer with abundant nitrogen imprints on the electrocatalyst, which is capable of selectively recognizing and proactively aggregating high-concentrated nitrogen at the interface while hindering the access of overwhelming water simultaneously. With this favorable microenvironment, nitrogen can preferentially occupy the active surface, and the NRR equilibrium can be positively shifted to facilitate the reaction kinetics. Approximately threefold improvements in both ammonia production rate (185.7 µg h-1 mg-1 ) and Faradaic efficiency (72.9%) are achieved by a metal-free catalyst compared with the bare one. It is believed that the molecular imprinting strategy should be a general method to find further applicability in numerous catalysts or even other reactions facing similar challenges.

Turning Waste into Wealth: Sustainable Production of High-Value-Added Chemicals from Catalytic Coupling of Carbon Dioxide and Nitrogenous Small Molecules.

Carbon neutrality is one of the central topics of not only the scientific community but also the majority of human society. The development of highly efficient carbon dioxide (CO2) capture and utilization (CCU) techniques is expected to stimulate routes and concepts to go beyond fossil fuels and provide more economic benefits for a carbon-neutral economy. While various single-carbon (C1) and multi-carbon (C2+) products have been selectively produced to date, the scope of CCU can be further expanded to more valuable chemicals beyond simple carbon species by integration of nitrogenous reactants into CO2 reduction. In this Review, research progress toward sustainable production of high-value-added chemicals (urea, methylamine, ethylamine, formamide, acetamide, and glycine) from catalytic coupling of CO2 and nitrogenous small molecules (NH3, N2, NO3-, and NO2-) is highlighted. C-N bond formation is a key mechanistic step in N-integrated CO2 reduction, so we focus on the possible pathways of C-N coupling starting from the CO2 reduction and nitrogenous small molecules reduction processes as well as the catalytic attributes that enable the C-N coupling. We also propose research directions and prospects in the field, aiming to inspire future investigations and achieve comprehensive improvement of the performance and product scope of C-N coupling systems.

ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway.

Lipid metabolic reprogramming plays a pivotal role in hepatocellular carcinoma (HCC) development, but the underlying mechanisms are incompletely characterized. Long chain acyl CoA synthetase 4 (ACSL4), a member of acyl-CoA synthetases (ACS) family, has been identified as a novel marker of alpha-fetoprotein-high subtype HCC and as an oncogene. Here, we identified a new function of ACSL4 in HCC lipid metabolism. ACSL4 can modulate de novo lipogenesis by accumulating intracellular triglycerides, cholesterols, and lipid droplets in HCC. Mechanistically, ACSL4 upregulates the master lipogenesis regulator sterol regulatory element binding protein 1 (SREBP1) and its downstream lipogenic enzymes in HCC cells via c-Myc. Moreover, SREBP1 is crucial for ACSL4-mediated regulation of lipogenesis as well as HCC cell proliferation and metastasis, as SREBP1 overexpression rescues lipogenic deficiency and decreased oncogenic capabilities associated with ACSL4 suppression in vitro and in vivo. Clinically, our data showed that the expression of ACSL4 was positively correlated with that of SREBP1 in HCC patients, and the combinational biomarkers showed strong predictive value for HCC. Together, our findings uncover a new mechanism by which ACSL4 modulates aberrant lipid metabolism and promotes the progression of HCC.

A Mini Review of the Preparation and Photocatalytic Properties of Two-Dimensional Materials.

The successful preparation and application of graphene shows that it is feasible for the materials with a thickness of a single atom or few atomic layers to exist stably in nature. These materials can exhibit unusual physical and chemical properties due to their special dimension effects. At present, researchers have made great achievements in the preparation, characterization, modification, and theoretical research of 2D materials. Because the structure of 2D materials is often similar, it has a certain degree of qualitative versatility. Besides, 2D materials often carry good catalytic performance on account of their more active sites and adjustable harmonic electronic structure. In this review, taking 2D materials as examples [graphene, boron nitride (h-BN), transition metal sulfide and so on], we review the crystal structure and preparation methods of these materials in recent years, focus on their photocatalyst properties (carbon dioxide reduction and hydrogen production), and discuss their applications and development prospects in the future.

NKILA, a prognostic indicator, inhibits tumor metastasis by suppressing NF-κB/Slug mediated epithelial-mesenchymal transition in hepatocellular carcinoma.

The metastasis of hepatocellular carcinoma (HCC) is one of the major obstacles hindering its therapeutic efficacy, leading to low surgical resection rate, high mortality and poor prognosis. Accumulating evidence has shown that both long noncoding RNA (lncRNA) and NF-κB play vital roles in the regulation of cancer metastasis. However, the clinical significance and biological function of NKILA (NF-κB interacting lncRNA) and its interaction with NF-κB in HCC remain unknown. In this study, we demonstrated that NKILA was down-regulated in HCC tissues and cell lines, and decreased NKILA expression was significantly associated with larger tumor size and positive vascular invasion in HCC patients. NKILA reduction was an independent risk factor of HCC patients' poor prognosis, and the 5-year overall survival (OS) rates of patients with low and high NKILA expression were 15.6% and 60.0%, respectively. Moreover, NKILA inhibits migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NKILA prevents Slug/epithelial to mesenchymal transition (EMT) pathway via suppressing phosphorylation of IκBα, p65 nuclear translocation and NF-κB activation. In conclusion, these results indicate that NKILA might serve as an effective prognostic biomarker and a promising therapeutic target against HCC metastasis.

High-metastatic cancer cells derived exosomal miR92a-3p promotes epithelial-mesenchymal transition and metastasis of low-metastatic cancer cells by regulating PTEN/Akt pathway in hepatocellular carcinoma.

Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene, miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC.

LY2228820 induces synergistic anti-cancer effects with anti-microtubule chemotherapeutic agents independent of P-glycoprotein in multidrug resistant cancer cells.

Side-effects and resistance substantially limit the efficacy of chemotherapy. One possible solution to this persistent problem would be co-administration of targeted therapy and chemotherapy to achieve synergistic anti-cancer effects without extra toxicity. Here, we reported that LY2228820, a selective inhibitor of p38-MAPK signaling pathway, could induce synergistic anti-cancer effects with anti-microtubule (AMT) chemotherapy both in vitro and in vivo. In drug-resistant cancer cells, treatment with either LY2228820 or AMT drug alone was compatible with viability, while co-administration of both led to dramatic cytotoxicity, G2/M arrest and apoptosis. Moreover, co-treatment with LY2228820 notably improved the effectiveness of paclitaxel without exhibiting adverse effects in vivo. Mechanistic studies showed that LY2228820 sensitized cancer cells to AMT agents independent of P-gp. LY2228820 did not influence either the expression or the function of P-gp. Instead, it could inhibit p38-HSP27 signaling axis by down-regulating p-HSP27. Furthermore, LY2228820 blocked the p-HSP27 mediated protective response against AMT drugs in tumor cells, resulting in mitochondrial instability and the activation of mitochondrial death pathways. This P-gp-independent regime containing LY2228820 and AMT agents could produce synergistic anti-cancer effects without extra systematic toxicity. Our study offers a novel strategy for improving the therapeutic efficacy of AMT drugs by achieving a better balance between efficacy and toxicity. This new combination regime could be advantageous in patients who show little response to the maximal dosage of AMT chemotherapy, as well as those unable to tolerate the systematic toxicity of these agents in clinic.

Cabazitaxel, a novel chemotherapeutic alternative for drug-resistant hepatocellular carcinoma.

The prognosis of advanced hepatocellular carcinoma (HCC) patients remains extremely poor, partially due to the development of acquired resistance to sorafenib and chemotherapy. Cabazitaxel, a semisynthetic taxane, has been approved for the therapy of docetaxel-resistant prostate cancer. However, no studies have been performed on the effect of cabazitaxel on HCC, and whether cabazitaxel remains sensitive in chemotherapy-resistant and sorafenib-resistant HCC cells is not clear. Our results demonstrate that cabazitaxel is highly toxic to HCC cell lines in a time- and dose-dependent manner by inducing G2/M phase arrest and apoptosis in vitro. Cabazitaxel also significantly suppresses HCC tumor growth in vivo. In chemotherapy-resistant HCC cell Huh-TS-48 with P-gp-overexpression, cabazitaxel shows less cross-resistant to other chemotherapeutic agents. The resistance fold of cabazitaxel, doxorubicin, paclitaxel, docetaxel and vinorelbine is 1.53, 8.60, 38.58, 15.53 and 18.06 respectively. Furthermore, sorafenib-resistant HCC cell SK-sora-5 is still sensitive to cabazitaxel. The IC50 values of cabazitaxel after 72 h exposure for parental cell SK-hep-1 and resistant cell SK-sora-5 are 0.84 and 0.73 nM. The results indicate that cabazitaxel is a potential agent to treat HCC after developing chemotherapy resistance caused by overexpression of P-gp and acquired resistance to sorafenib, and might improve prognosis in advanced HCC patients.

Atypical hemangioma mimicking mixed hepatocellular cholangiocarcinoma: Case report.

RATIONALE: Hemangioma of the liver is a benign hepatic tumor, more common in women than in men, which is typically asymptomatic, solitary, and incidentally discovered. Atypical hemangioma is a variant of hepatic hemangioma with atypical imaging finding features on CT and MRI that can be confused with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and mixed hepatocellular cholangiocarcinoma (HCC-CC). PATIENT CONCERNS: We report a case of atypical hepatic hemangioma mimicking HCC-CC: A 59-year-old man was referred to our hospital for a hepatic lesion that was 4.7×3.6 cm in size and located in segments 2 and 3 of the liver. Serum alpha-fetoprotein (AFP) level increased from 17.03 ng/mL to 374.9 ng/mL. The patient was positive for hepatitis B. DIAGNOSES: Atypical hepatic hemangioma. INTERVENTIONS: US, CT, MRI and Tc-99m RBC liver scans were performed. Dynamic contrast-enhanced MRI showed no uptake in the corresponding area during the arterial phase, peripheral nodular enhancement during the portal phase and delayed phase, and hypo-intensity in the central area. An initial diagnosis of HCC-CC was offered based on the history and imaging findings. Finally, percutaneous liver biopsy (PLB) was offered to the patient. Histopathologic examination of the liver lesions revealed nodular cirrhosis and atypical hyperplasia of liver cells with cavernous hemangioma, where numerous old Schistosoma japonicum eggs were found. OUTCOMES: Accurate diagnosis of the patient obviated the need for surgery. The patient's recovery after liver puncture was uneventful, and he was discharged on the seventh post-operative day. LESSONS: In some cases, accurate preoperative imaging of focal hepatic lesions is essential but insufficient for diagnosis. PLB and histopathological examination are important, especially in patients with suspected malignancy.