Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer.

BACKGROUND & AIMS: Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. METHODS: An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. RESULTS: We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. CONCLUSIONS: Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.

Functional Prokaryotic-Like Deoxycytidine Triphosphate Deaminases and Thymidylate Synthase in Eukaryotic Social Amoebae: Vertical, Endosymbiotic, or Horizontal Gene Transfer?

The de novo synthesis of deoxythymidine triphosphate uses several pathways: gram-negative bacteria use deoxycytidine triphosphate deaminase to convert deoxycytidine triphosphate into deoxyuridine triphosphate, whereas eukaryotes and gram-positive bacteria instead use deoxycytidine monophosphate deaminase to transform deoxycytidine monophosphate to deoxyuridine monophosphate. It is then unusual that in addition to deoxycytidine monophosphate deaminases, the eukaryote Dictyostelium discoideum has 2 deoxycytidine triphosphate deaminases (Dcd1Dicty and Dcd2Dicty). Expression of either DcdDicty can fully rescue the slow growth of an Escherichia coli dcd knockout. Both DcdDicty mitigate the hydroxyurea sensitivity of a Schizosaccharomyces pombe deoxycytidine monophosphate deaminase knockout. Phylogenies show that Dcd1Dicty homologs may have entered the common ancestor of the eukaryotic groups of Amoebozoa, Obazoa, Metamonada, and Discoba through an ancient horizontal gene transfer from a prokaryote or an ancient endosymbiotic gene transfer from a mitochondrion, followed by horizontal gene transfer from Amoebozoa to several other unrelated groups of eukaryotes. In contrast, the Dcd2Dicty homologs were a separate horizontal gene transfer from a prokaryote or a virus into either Amoebozoa or Rhizaria, followed by a horizontal gene transfer between them. ThyXDicty, the D. discoideum thymidylate synthase, another enzyme of the deoxythymidine triphosphate biosynthesis pathway, was suggested previously to be acquired from the ancestral mitochondria or by horizontal gene transfer from alpha-proteobacteria. ThyXDicty can fully rescue the E. coli thymidylate synthase knockout, and we establish that it was obtained by the common ancestor of social amoebae not from mitochondria but from a bacterium. We propose horizontal gene transfer and endosymbiotic gene transfer contributed to the enzyme diversity of the deoxythymidine triphosphate synthesis pathway in most social amoebae, many Amoebozoa, and other eukaryotes.

RNA m6 A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy.

N6-methyladenosine (m6 A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m6 A methyltransferase, is significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy-associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m6 A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHDF1-dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6 A-dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3-mediated m6 A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m6 A modification in the resistance of HCC to sorafenib therapy.

A facile double moving redox boundary model for visual electrophoresis titration of ascorbic acid.

In this work, we proposed a double moving redox boundary (MROB) model to realize the colorless analyte electrophoresis titration (ET) by the two steps of the redox reaction. Single MROB has been proposed for the development of ET sensing (Analyst, 2013, 138, 1137. ACS Sensor, 2019, 4, 126.), and faces great challenges in detecting the analyte without color change during redox reaction. Herein, a novel model of double-MROB electrophoresis, including its mechanisms, equations, and procedures, was developed for titration by using ascorbic acid as a model analyte. The first MROB was created with ferric iron (Fe3+) and iodide ion (I-) in which Fe3+ was reduced as Fe2+ and I- was oxidized as molecular iodine (I2) used as an indicator of visible MROB due to blue starch-iodine complex. The second boundary was then formed between the molecular iodine and model analyte of ascorbic acid. Under given conditions, there was a quantitative relationship between velocity of MROB (VMROB(ii)) and ascorbic acid concentration (CVit C) in the double-MROB system (1/VMROB(ii) = 0.6502CVit C + 4.5165, and R = 0.9939). The relevant relative standard deviation values of intraday and inter-day were less than ∼5.55% and ∼6.64%, respectively. Finally, the titration of ascorbic acid in chewable vitamin C tablets was performed by the developed method, the titration results agreed with those via the classic iodometric titration. All the results briefly demonstrated the validity of the double MROB model, in which Vit C was used as a model analyte. The developed method had potential use in quantitative analysis of redox-active species in biomedical samples.

Fabrication of a sustainable superhydrophobic surface of Ag-NPs@SA on copper alloy for corrosion resistance, photocatalysis, and simulated distribution of Ag atoms.

Artificial superhydrophobic surfaces that do not absorb water, like the lotus leaf, show tremendous promise in numerous applications. However, superhydrophobic surfaces are rarely used because of their low stability and endurance. A stable organic superhydrophobic surface (SHS) composed of novel morphology Ag-nanoparticles (NPs) has been fabricated on a copper alloy via etching, immersion, spraying, and annealing treatment, along with a static water contact angle (WCA) of 158 ± 1° and sliding angle (SA) less than 2°. The surface texture, composition, and morphology of the substrate surfaces were explored by using X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, energy dispersive spectroscopy, and DFT-based Ag atom distribution. The anti-corrosion study of non-coated and Ag-NP-coated copper alloy was undertaken using electrochemical impedance spectroscopy. Ag-NPs +SA@SHS enhanced the corrosion resistance as compared with bare Cu alloy. The water droplet rolled down the coated Cu alloy, removed the chalk powder from the surface, and indicated an excellent self-cleaning function. Photodegradation of Congo red (CR) and methylene blue (MB) dye samples was assessed by measuring the absorbance through UV-Visible spectrophotometry, where the Ag-NPs coated on the copper alloy were used as a catalyst. The performance of the SHS@Ag-NPs in the aqueous solution was 99.31% and 98.12% for industrial pollutants (CR and MB), with degradation rates of 5.81 × 10-2 s-1 and 5.89 × 10-2 s-1, respectively. These findings demonstrated a simple, rapid, and low-energy fabrication technique for SHS@Ag-NPs. This research reveals a valuable approach for the fabrication of SHS@Ag-NPs on various substrates to extend the superhydrophobic surfaces with ultra-fast self-healing properties, for outdoor applications such as anti-corrosion, for an innovative approach for the remediation of polluted water treatment, and for industrial applications.

N6-methyladenosine demethylase FTO enhances chemo-resistance in colorectal cancer through SIVA1-mediated apoptosis.

N6-methyladenosine (m6A) is the most pervasive RNA modification and is recognized as a novel epigenetic regulation in RNA metabolism. Although the m6A modification involves various physiological processes, its roles in drug resistance in colorectal cancer (CRC) still remain unknown. We analyzed the RNA expression profile of m6A/A (%) with MRM mass spectrometry in human 5-fluorouracil (5-FU)-resistant CRC tissues, and used the m6A RNA immunoprecipitation assay to validate the m6A-regulated target. Our results have shown that the m6A demethylase FTO was up-regulated in human primary and 5-FU-resistant CRC. Depletion of FTO decreased cell growth, colony formation and metastasis in 5-FU-resistant CRC cells in vitro and in vivo. Mechanistically, we identified SIVA1, a critical apoptotic gene, as a key downstream target of the FTO-mediated m6A demethylation. The m6A demethylation of SIVA1 at the CDS region induced its mRNA degradation via a YTHDF2-dependent mechanism. The SIVA1 levels were negatively correlated with the FTO levels in clinical CRC tissues. Notably, inhibition of FTO significantly reduced the tolerance of 5-FU in 5-FU-resistant CRC cells via the FTO-SIVA1 axis, whereas SIVA1-depletion could restore the m6A-dependent 5-FU sensitivity in CRC cells. In summary, our findings demonstrate a critical role of FTO as an m6A demethylase enhancing chemo-resistance in CRC cells, and suggest that FTO inhibition may restore the sensitivity of chemo-resistant CRC cells to 5-FU.

A high-throughput UHPLC-MS/MS method for the determination of eight anti-tumor drugs in plasma.

Rapidly developing UHPLC-MS/MS bioassays with high throughput and quality are challenging yet desired in routine clinics. METHODS & RESULTS: A high-throughput UHPLC-MS/MS bioassay has been built for simultaneously quantifying gefitinib, ruxolitinib, dasatinib, imatinib, ibrutinib, methotrexate, cyclophosphamide and paclitaxel. After the protein precipitation with methanol, samples were separated on an Acquity BEH C18 column following a gradient elution system with methanol and 2 mM ammonium acetate in water at 40 °C with a run time of 3 min (flow rate 0.4 mL/min). Mass quantification in the positive ion SRM mode was then performed with electrospray ionization. The method of specificity, linearity, accuracy, precision, matrix effects, recovery, stability, dilution integrity and carryover were all validated as per the guideline of the China Food and Drug Administration whose values met the admissible limits. Application of the bioassay to therapeutic drug monitoring revealed important variability in the studied anti-tumour drugs. CONCLUSION: This validated approach was shown to be reliable and effective in clinical management, being a valuable support in therapeutic drug monitoring and subsequent individualized dosing optimization.

Cold, Hot, Dry, and Wet: Locations and Dynamics of CO2 and H2O Co-Adsorbed in an Ultramicroporous MOF.

Climate change from anthropogenic carbon dioxide (CO2) emissions poses a severe threat to society. A variety of mitigation strategies currently include some form of CO2 capture. Metal-organic frameworks (MOFs) have shown great promise for carbon capture and storage, but several issues must be solved before feasible widespread adoption is possible. MOFs often exhibit reduced chemical stabilities and CO2 adsorption capacities in the presence of water, which is ubiquitous in nature and many practical settings. A comprehensive understanding of water influence on CO2 adsorption in MOFs is necessary. We have used multinuclear nuclear magnetic resonance (NMR) experiments at temperatures ranging from 173 to 373 K, along with complementary computational techniques, to investigate the co-adsorption of CO2 and water across various loading levels in the ultra-microporous ZnAtzOx MOF. This approach yields detailed information regarding the number of CO2 and water adsorption sites along with their locations, guest dynamics, and host-guest interactions. Guest adsorption and motional models proposed from NMR data are supported by computational results, including visualizations of adsorption locations and the spatial distribution of guests in different loading scenarios. The wide variety and depth of information presented demonstrates how this experimental methodology can be used to investigate humid carbon capture and storage applications in other MOFs.

Employing Visible Light To Construct Photoinitiated Polymerized Nanofiltration Membranes for High Permeation and Environmental Micropollutant Removal.

Improving the nanofiltration (NF) performance of membrane-based treatment is conducive to promoting environmental water recycling and addressing water resource depletion. Combinations of light, electricity, and heat with traditional techniques of preparing membranes should optimize membrane performance. Interfacial polymerization and photopolymerization were integrated to construct a photopolymerized thin-film composite NF membrane with a ridged surface morphology. Under visible light initiation, 2-acrylamido-2-methyl-1-propanesulfonic acid was crosslinked with the polyamide network. The control effects of light on the membrane surface and physicochemical properties were revealed via infrared thermal images and response surface methodology. To present the diffusion motion of piperazine molecules, molecular dynamics simulations were implemented. Through density functional theory simulations, the crosslinking mechanism of the photoinduced NF network was identified and verified. The surface physicochemical characteristics and perm-selectivity performance were systematically illustrated. The photopolymerized membrane outperformed the pristine in permeability and selective separation competence; without degradation of solute repulsion, the water permeation was enhanced to 33.5 L m-2 h-1 bar-1, 6.6 times that of the initial membrane. In addition, the removal of organic contaminants and antifouling capacities were improved. This work represents a novel lead for applying sustainable resources in constructing high-performance membranes for environmental challenges.

Nanofiltration Membranes with Salt-Responsive Ion Valves for Enhanced Separation Performance in Brackish Water Treatment: A Battle against the Limitation of Salt Concentration.

Utilizing brackish water resources has imposed a high requirement on the design and construction of nanofiltration membranes. To overcome the limitation of high salt concentration on the nanofiltration separation performance resulting from the weakened Donnan effect, a nanofiltration membrane with the effect of salt-responsive ion valves was developed by incorporating zwitterionic nanospheres into the polyamide layer (PA-ZNs). The interaction between the nanospheres and membranes at high salinity was revealed through a combination analysis from the perspectives of water transport model, positron annihilation spectroscopy, and solute rejection, contributing to the formation of the valve effect. The PA-ZNs membrane presented a breakthrough in overcoming the limitation of increased salt concentrations on nanofiltration separation performance, achieving a high selectivity of 105 for mono/multivalent anions. To reveal the role of the ion valve effect in ion transport through the membrane, the membrane conductance was determined at different salt concentrations, confirming channel-controlled transport at low salinity and ion valve-controlled transport at high salinity. Moreover, the main membrane separation mechanisms were systematically studied. The concept of salt-responsive ion valves may contribute to expanding the application of nanofiltration in brackish water treatment.

Effect of a Permanganate-Bearing Reactive Oxidant on Flocs in Electrocoagulation: Transformations and Interfacial Interactions.

The electrocoagulation/ultrafiltration (ECUF) process is expected to address the issues of current wastewater increments and complex water reuse. However, the underlying mechanism associated with flocs remains unclear in the ECUF system, especially in the upgraded permanganate-bearing ECUF (PECUF) system. Herein, flocs and their formation, response to organic matter (OM), and interfacial features in the PECUF process were systematically explored. Results demonstrated that permanganate contributed to the rapid start-up of the coagulation process by forming MnO2 and blocking the ligand-metal charge transfer process between adsorbed Fe(II) and solid-phase Fe(III). The response of flocs to natural OM (NOM) exhibited obvious time- and particle size-dependent characteristics. Based on this, the optimal NOM adsorption window was found to be in the interval of 5-20 min, whereas the optimal NOM removal window was located at the 20-30 min interval. Furthermore, the extended Derjaguin-Landau-Verwey-Overbeek theory revealed the underlying principle of the PECUF module for optimizing UF performance. On the one hand, it reduced the inherent resistance of the cake layer by modifying the colloidal solution, which guaranteed a small drop (15%) in initial flux. On the other hand, it enhanced the repulsive force among suspended particles to achieve a long-term antifouling effect. This study may provide insights into the selection and performance control of on-demand assembly modules in decentralized water treatment systems.

Evaluation of Front-Face Fluorescence for Assessing Cyanobacteria Fouling in Ultrafiltration.

Cyanobacteria fouling in ultrafiltration (UF) drinking water treatment poses a significant threat to the stability and sustainability of the process. Both phycocyanin found in cyanobacteria and the polymer membrane exhibit strong fluorescence, which could be readily detected using front-face excitation-emission matrix (FF-EEM) spectroscopy. In this study, FF-EEM was employed for the nondestructive and in situ characterization of algae fouling evolution in UF, while also analyzing fouling mechanisms and reversibility. The results indicated that phycocyanin fluorescence on the membrane surface showed a linear correlation with the specific algal cell count on the membrane surface before reaching saturation. As fouling progressed, membrane fluorescence decreased, which was associated with the extent of the surface coverage on the membrane. The plateau in membrane fluorescence indicated full coverage, coinciding with the cake filtration mechanism, cake compression, and deterioration of fouling reversibility. These findings highlight the promise of FF-EEM as a valuable tool for monitoring and evaluating fouling of cyanobacteria in UF systems.

Fe(II)-Modulated Microporous Electrocatalytic Membranes for Organic Microcontaminant Oxidation and Fouling Control: Mechanisms of Regulating Electron Transport toward Enhanced Reactive Oxygen Species Activation.

Regulation of the fast electron transport process for the generation and utilization of reactive oxygen species (ROS) by achieving fortified electron "nanofluidics" is effective for electrocatalytic oxidation of organic microcontaminants. However, limited available active sites and sluggish mass transfer impede oxidation efficiency. Herein, we fabricated a conductive electrocatalytic membrane decorated with hierarchical porous vertically aligned Fe(II)-modulated FeCo layered double hydroxide nanosheets (Fe(II)-FeCo LDHs) in an electro-Fenton system to maximize exposure of active sites and expedite mass transfer. The nanospaced interlayers of Fe(II)-FeCo LDHs within the microconfined porous structure formed by its vertical nanosheets highly boost the micro/nanofluidic distribution of target pollutants to active centers/species, achieving accelerated mass transferability. Aliovalent substitution by Fe(II) activates in-plane metallics to maximize the available active sites and makes each Fe(II)-FeCo LDH nanosheet a geometrical nanocarrier for constructing a fast electron "nanofluidic" to accelerate Fe(II) regeneration in Fe(III)/Fe(II) cycles. As a result, the Fe(II)-FeCo LDHs exhibited improved reactivity in catalyzing H2O2 to •OH and 1O2. Accordingly, the membrane exhibited a higher atrazine degradation kinetic (0.0441 min-1) and degradation rate (93.2%), which were 4.7 and 2.1 times more than those of the bare carbon nanotube membrane, respectively. Additionally, the enhanced hydrophilic and strongly oxidized reactivity synergistically mitigated the organic fouling occurring in the pores and surface of the membrane. These findings clarify the activation mechanism of ROS over an innovative electrocatalytic membrane reactor design for organic microcontaminant treatment.

Accelerated screening and assembly of promising MOFs with open Cu sites for isobutene/isobutane separation using a data-driven approach.

As the by-products of catalytic cracking or alkane dehydrogenation, isobutene (2-methyl-propylene) and isobutane (2-methyl-propane) are important chemical feedstocks, but the separation of their mixture is a challenging issue in the petrochemical industry. Herein, we report the first example of large-scale computational screening of metal-organic frameworks (MOFs) with copper open metal sites (Cu-OMS) on the adsorptive separation of isobutene/isobutane using configuration-bias Monte Carlo (CBMC) simulations and machine learning among >330 000 MOFs data. We discovered that the optimal structural features governing the MOFs-based separation of isobutene/isobutane were density (ρ) and porosity (φ), with ranges of 0.2-0.5 g cm-3 and 0.8-0.9, respectively. Furthermore, the key genes (metal nodes or linkers of frameworks) contributing to such adsorptive separation were data-mined by feature engineering of ML. These genes were cross-assembled into novel frameworks using a material-genomics strategy. The screened AVAKEP, XAHPON, HUNCIE, Cu2O8-mof177-TDPAT_No730 and assembled Cu2O8-BTC_B-core-4_No1 possessed high isobutene uptake and isobutene/isobutane selectivity of >19.5 mmol g-1 and 4.7, with high thermal stability (as validated by molecular-dynamics simulations) overcoming the critical "trade-off" problem to some extent. The macroporous structures (pore-limiting diameter >12 Å) of these five promising frameworks with multi-layer adsorption on isobutene resulted in high isobutene loading, as validated by adsorption isotherms and CBMC simulations. The higher adsorption energy and heat of adsorption of isobutene than those of isobutane indicated that the thermodynamic equilibrium drove their selective adsorption. Generalized charge decomposition analysis and localized orbit locator calculations based on density functional theory wavefunctions suggested that high selectivity was due to complexation of feedback π bonds between isobutene and Cu-OMS, but also the strong π-π stacking interaction induced by the CC bond of isobutene with the multiple aromatic rings and unsaturated bonds of frameworks. Our theoretical results and data-driven approach may provide insights into the development of efficient MOF materials for the separation of isobutene/isobutane and other mixtures.

A systemic evaluation of aerobic granular sludge among granulation, operation, storage, and reactivation processes in an SBR.

As a biological promising wastewater treatment technology, aerobic granular sludge (AGS) technology had been widely studied in sequencing batch reactors (SBRs) for the decades. Presently, the whole processes of its granulation, long-term operation, storage, and reactivation have not been thoroughly evaluated, and also the relationships among microbial diversity, granular size, and characteristics were still not that clear. Hence, they were systematically evaluated in an AGS-SBR in this work. The results demonstrated that Proteobacteria and Bacteroidetes were the dominant phyla, Flavobacterium, Acinetobacter, Azoarcus, and Chryseobacterium were the core genera with discrepant abundances in diverse stages or granular size. Microbial immigration was significant in various stages due to microbial diversity had a line relationship with COD/MLVSS ratio (R2 = 0.367). However, microbial diversity had no line relationship with granular size (R2 = 0.001), indicating the microbial diversity in different-sized AGS was similar, although granular size had a line relationship with settleability (R2 = 0.978). Overall, compared to sludge traits (e.g., sludge size, settleability), COD/MLVSS played a key role on microbial evolution. This study revealed the relationships between granule characteristics and microbial community, and contributed to the future AGS-related studies.

Insights into the Diffusion Behaviors of Water over Hydrophilic/Hydrophobic Catalysts During the Conversion of Syngas to High-Quality Gasoline.

Although considerable efforts towards directly converting syngas to liquid fuels through Fischer-Tropsch synthesis have been made, developing catalysts with low CO2 selectivity for the synthesis of high-quality gasoline remains a big challenge. Herein, we designed a bifunctional catalyst composed of hydrophobic FeNa@Si-c and HZSM-5 zeolite, which exhibited a low CO2 selectivity of 14.3 % at 49.8 % CO conversion, with a high selectivity of 62.5 % for gasoline in total products. Molecular dynamic simulations and model experiments revealed that the diffusion of water molecules through hydrophilic catalyst was bidirectional, while the diffusion through hydrophobic catalyst was unidirectional, which were crucial to tune the water-gas shift reaction and control CO2 formation. This work provides a new fundamental understanding about the function of hydrophobic modification of catalysts in syngas conversion.

Loss-of-Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia.

BACKGROUND AND AIMS: Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical development of this approach is lacking in the study of HCC. APPROACH AND RESULTS: From a genome-wide CRISPR/CRISPR-associated 9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia. Knockdown of ALDOA in HCC cells leads to lactate depletion and consequently inhibits tumor growth. Supplementation with lactate partly rescues the inhibitory effects mediated by ALDOA knockdown. Upon hypoxia, ALDOA is induced by hypoxia-inducible factor-1α and fat mass and obesity-associated protein-mediated N6 -methyladenosine modification through transcriptional and posttranscriptional regulation, respectively. Analysis of The Cancer Genome Atlas shows that elevated levels of ALDOA are significantly correlated with poor prognosis of patients with HCC. In a screen of Food and Drug Administration-approved drugs based on structured hierarchical virtual platforms, we identified the sulfamonomethoxine derivative compound 5 (cpd-5) as a potential inhibitor to target ALDOA, evidenced by the antitumor activity of cpd-5 in preclinical patient-derived xenograft models of HCC. CONCLUSIONS: Our work identifies ALDOA as an essential driver for HCC cell growth under hypoxia, and we demonstrate that inhibition of ALDOA in the hypoxic TME is a promising therapeutic strategy for treating HCC.

IDO1 can impair NK cells function against non-small cell lung cancer by downregulation of NKG2D Ligand via ADAM10.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the rate-limiting step in tryptophan catabolism along the kynurenine (Kyn) pathway and exerts immunosuppressive properties mainly via activation of transcription factor aryl hydrocarbon receptor (AhR) pathway. IDO1 induces NK cells dysfunction via downregulation of the activating receptor NKG2D on NK cells, but whether and how it affects the expression of NKG2D Ligand (NKG2DL) on tumor cells remains unclear. Since a disintegrin and metalloprotease 10 (ADAM10) plays a potential role in the shedding of NKG2DL and the releasing of soluble NKG2DL (sNKG2DL), we investigated how IDO1 modulates the expression of NKG2DL via ADAM10 in non-small cell lung cancer (NSCLC). We found that IDO1 expression was negatively correlated with NKG2DL expression while positively correlated with ADAM10 expression with human lung cancer brain metastasis tissue, NSCLC cells and LLC tumor-bearing mice. IDO1 could regulate ADAM10 expression via IDO1-Kyn-AhR signaling pathway and subsequently regulate NKG2DL expression. IDO1 deficiency led to retarded tumor growth and improved NK cells function in NSCLC mice. IDO1 inhibitors improved NK cells function in vitro and in vivo. The combo of IDO1 inhibitor and NK cells exhibited more therapeutic efficacy than either of the single IDO1 inhibitor or NK cells treatment.

Exposure to Polybrominated Diphenyl Ether Flame Retardants Causes Deoxyribonucleic Acid Damage in Human Thyroid Cells In Vitro.

INTRODUCTION: The incidence of papillary thyroid cancer (PTC) in the United States has tripled in the past 30 y. Polybrominated diphenyl ethers (PBDEs) are flame retardants that were ubiquitously used over that time period, and exposure to PBDEs has been associated with PTC prevalence. They are potential carcinogens via their induction of reactive oxygen species (ROS) formation and resultant deoxyribonucleic acid (DNA) damage. We sought to determine the effects of PBDE and tris(2-chloroethyl) phosphate (TCEP), another flame retardant implicated in PTC incidence, on thyrocytes in vitro and measure PBDE levels in human thyroid tissue to determine their carcinogenic potential. METHODS: Nthy-Ori, an immortalized benign human thyroid follicular cell line was used as a model of normal human thyroid. MTT assays were used to measure cell viability after exposure to PBDEs and TCEP. ROS levels and double-stranded and single-stranded DNA breaks were measured to determine genotoxicity. DNA damage response protein levels were measured with immunoblotting. RESULTS: Exposure to 20µM PBDE or TCEP for 48 h had minimal effects on thyrocyte viability. There was no significant increase in intracellular ROS up to 6 h following PBDE or TCEP exposure in thyrocytes; however, cells exposed to PBDE 47 showed evidence of DNA single-stranded and double-stranded breaks. There was a dose-dependent increase in γH2AX levels following exposure to PBDEs 47 and 209 in Nthy-Ori cells but not with TCEP treatment. CONCLUSIONS: PBDE 47 and 209 demonstrated genotoxicity but not cytotoxicity in follicular thyrocytes in vitro. Therefore, PBDE 47 and 209 may be carcinogenic in human thyroid cells.

Mechanistic Insights of a Thermoresponsive Interface for Fouling Control of Thin-Film Composite Nanofiltration Membranes.

In spite of extensive research, fouling is still the main challenge for nanofiltration membranes, generating an extra transport resistance and requiring a larger operational pressure in practical applications. We fabricated a highly antifouling nanofiltration membrane by grafting poly(N-isopropylacrylamide) (PNIPAM) chains on a bromine-containing polyamide layer. The resulting membrane was found to have a double permeance compared to the pristine membrane, while the rejection of multivalent ions remained the same. In addition, PNIPAM chains yielded a better deposition resistance and adhesion resistance, thereby mitigating the increase of fouling and promoting the recovery of flux during the filtration and traditional cleaning stages, respectively. Moreover, PNIPAM chains shrank when the water temperature was above the lower critical solution temperature (LCST), indicating the formation of a buffer layer between the membrane and pollutants. The buffer layer would eliminate the membrane-foulant interaction energy, thus further enhancing the detachment of pollutants. This simple and efficient cleaning method could act as an enhanced cleaning procedure to remove irreversible fouling. This provides new insights into the fabrication of enhanced antifouling membranes using smart responsive polymer chains.