Molecular profiling and prognostic analysis in Chinese cholangiocarcinoma: an observational, retrospective single-center study.

Cholangiocarcinoma (CCA) is a primary malignancy which is often diagnosed when it is advanced and inoperable due to the lack of effective biomarkers and poor sensitivity of clinical diagnosis. Molecular profiling may provide information for improved clinical management, particularly targeted therapy. The study aimed to improve the understanding of molecular characteristics and its association with prognosis in Chinese CCA. We enrolled 41 Chinese patients with CCA, including 6 intrahepatic CCA (iCCA), 14 perihilar CCA (pCCA), and 21 distal CCA (dCCA) cases, all patients underwent radical operations and tumor samples underwent next-generation sequencing (NGS) by Foundation One Dx, which analyzed 324 genes. The patients' genetic characteristics, clinical management, and prognosis were analyzed. The most mutated genes were TP53 (68%, 28/41), CDKN2A (37%, 15/41), and SMAD4 (29%, 12/41). The genetic mutations in dCCA, pCCA, and iCCA were significantly different. For example, NOTCH3 mutations were not found in dCCA. The gene mutations of AXL were specifically associated with lymph node metastasis in patients with CCA, whereas gene mutations of SMAD4 were specifically associated with lymphovascular invasion. Furthermore, mutations in APC, DAXX, FANCA, LTK, MAP2K4, and NOTCH1 were associated with a poor prognosis (P < 0.05). This study provides an overview of genetic alterations in Chinese patients with CCA, which will provide novel potential biomarkers for the diagnosis of CCA and may guide targeted therapeutic strategies for Chinese patients with CCA.

Development of flow battery technologies using the principles of sustainable chemistry.

Realizing decarbonization and sustainable energy supply by the integration of variable renewable energies has become an important direction for energy development. Flow batteries (FBs) are currently one of the most promising technologies for large-scale energy storage. This review aims to provide a comprehensive analysis of the state-of-the-art progress in FBs from the new perspectives of technological and environmental sustainability, thus guiding the future development of FB technologies. More importantly, we evaluate the current situation and future development of key materials with key aspects of green economy and decarbonization to promote sustainable development and improve the novel energy framework. Finally, we present an analysis of the current challenges and prospects on how to effectively construct low-carbon and sustainable FB materials in the future.

Benzidine Derivatives: A Class of High Redox Potential Molecules for Aqueous Organic Flow Batteries.

The development of water-soluble redox-active molecules with high potentials is one of the effective ways to enhance the energy density of aqueous organic flow batteries (AOFBs). Herein, a series of promising N-substituted benzidine analogues as water-soluble catholyte candidates with controllable redox potentials (0.78-1.01 V vs. standard hydrogen electrode (SHE)) were obtained by the molecular engineering of aqueous irreversible benzidines. Theoretical calculations reveal that the redox potentials of these benzidine derivatives in acidic solution are determined by their electronic structure and alkalinity. Among these benzidine derivatives, N,N,N',N'-tetraethylbenzidine(TEB) shows both high redox potential (0.82 V vs. SHE) and good solubility (1.1 M). Pairing with H4 [Si(W3 O10 )4 ] anolyte, the cell displayed discharge capacity retention of 99.4 % per cycle and a high coulombic efficiency (CE) of ∼100 % over 1200 cycles. The stable discharge capacity of 41.8 Ah L-1 was achieved at the 1.0 M TEB catholyte with a CE of 97.2 % and energy efficiency (EE) of 91.2 %, demonstrating that N-substituted benzidines could be promising for AOFBs.

Machine learning for flow batteries: opportunities and challenges.

With increased computational ability of modern computers, the rapid development of mathematical algorithms and the continuous establishment of material databases, artificial intelligence (AI) has shown tremendous potential in chemistry. Machine learning (ML), as one of the most important branches of AI, plays an important role in accelerating the discovery and design of key materials for flow batteries (FBs), and the optimization of FB systems. In this perspective, we first provide a fundamental understanding of the workflow of ML in FBs. Moreover, recent progress on applications of the state-of-art ML in both organic FBs and vanadium FBs are discussed. Finally, the challenges and future directions of ML research in FBs are proposed.

IDH Mutation Subgroup Status Associates with Intratumor Heterogeneity and the Tumor Microenvironment in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is highly heterogeneous. Here, the authors perform exome sequencing and bulk RNA sequencing on 73 tumor regions from 14 ICC patients to portray the multi-faceted intratumor heterogeneity (ITH) landscape of ICC. The authors show that ITH is highly concordant across genomic, transcriptomic, and immune levels. Comparison of these data to 8 published datasets reveals significantly higher degrees of ITH in ICC than hepatocellular carcinoma. Remarkably, the authors find that high-ITH tumors highly overlap with the IDH (isocitrate dehydrogenase)-mutant subgroup (IDH-SG), comprising of IDH-mutated tumors and IDH-like tumors, that is, those IDH-wildtype tumors that exhibit similar molecular profiles to the IDH-mutated ones. Furthermore, IDH-SG exhibits less T cell infiltration and lower T cell cytotoxicity, indicating a colder tumor microenvironment (TME). The higher ITH and colder TME of IDH-SG are successfully validated by single-cell RNA sequencing on 17 503 cells from 4 patients. Collectively, the study shows that IDH mutant subgroup status, rather than IDH mutation alone, is associated with ITH and the TME of ICC tumors. The results highlight that IDH-like patients may also benefit from IDH targeted therapies and provide important implications for the diagnosis and treatment of ICC.

Cyclooxygenase-2 expressed hepatocellular carcinoma induces cytotoxic T lymphocytes exhaustion through M2 macrophage polarization.

OBJECTIVE: Due to the tumor immune microenvironment (TIME) complexity and cancer heterogeneity, the clinical outcomes of hepatocellular carcinoma (HCC) are barely elicited from the conventional treatment options, even from the promising anti-cancer immunotherapy. As a suppressive TIME-related marker, the role played by cyclooxygenase-2 (COX-2) in HCC TIME, and its potential effects on anti-cancer T cell immune response remains unknown. In our study, to investigate the COX-2-dependent immune regulation pathway, we verified that the macrophages phenotypes were correlated to COX-2/PGE2 expressions among HCC patients. A multi-cellular co-culture platform containing HCC cells, macrophages, and T cells were established to mimic HCC TIME in vitro and in animal model. M2 macrophage polarization and activated CD8+ T cells exhaustion were observed under high COX-2 levels in HCC cells, with further evaluation using CRISPR/Cas9-based PTGS2 knocking out and COX-2 blockade (celecoxib) treatment controls. PGE2, TGF-ß, Granzyme B, and IFN-γ levels were testified by flow cytometry and ELISA to fully understand the mechanism of COX-2 suppressive effects on T cell-based anti-HCC responses. The activation of the TGF-ß pathway evaluated by auto-western blot in T cells was confirmed which increased the level of phosphorylated Smad3, phosphorylated Samd2, and FoxP1, leading to T cell de-lymphotoxin. In conclusion, high COX-2-expressing HCC cell lines can induce anti-tumor abilities exhaustion in activated CD8+ T cell through M2 TAMs polarization and TGF beta pathway. COX-2 inhibitors may reduce the inhibitory effect on CD8+ T cells through regulating TAMs in TIME, thus enhance the T cell-based cytotoxicity and improve the prognosis of HCC patients.

General Design Methodology for Organic Eutectic Electrolytes toward High-Energy-Density Redox Flow Batteries.

By virtue of strong molecular interactions, eutectic electrolytes provide highly concentrated redox-active materials without other auxiliary solvents, hence achieving high volumetric capacities and energy density for redox flow batteries (RFBs). However, it is critical to unveil the underlying mechanism in this system, which will be undoubtedly beneficial for their future research on high-energy storage systems. Herein, a general formation mechanism of organic eutectic electrolytes (OEEs) is developed, and it is found that molecules with specific functional groups such as carbonyl (CO), nitroxyl radical (NO•), and methoxy (OCH3 ) groups can coordinate with alkali metal fluorinated sulfonylimide salts (especially for bis(trifluoromethanesulfonyl)imide, TFSI), thereby forming OEEs. Molecular designs further demonstrate that the redox-inactive methoxy group functionalized ferrocene derivative maintains the liquid OEE at both reduced and oxidized states. Over threefold increase in solubility is obtained (2.8 m for ferrocene derivative OEE) and high actual discharge energy density of 188 Wh L-1 (75% of the theoretical value) is achieved in the Li hybrid cell. The established mechanism presents new ways of designing desirable electrolytes through molecular interactions for the development of high-energy-density organic RFBs.

Insights into the Redox Chemistry of Organosulfides Towards Stable Molecule Design in Nonaqueous Energy Storage Systems.

Nonaqueous redox flow batteries (RFBs) have great potential to achieve high-energy storage systems. However, they have been limited by low solubility and poor stability of active materials. Here we demonstrate organosulfides as a new-type model material system to explore the rational design of redox-active molecules in nonaqueous systems. The tetraethylthiuram disulfide (TETD) molecule shows high solubility in various common organic solvents and achieves a high reversible capacity of ca. 50 Ah L-1 at a high concentration of 1 M. The resonance structures in the reduced product endow the molecule with high electrochemical stability in different organic electrolytes. The underlying mechanism in redox chemistry of organodisulfides involving the cleavage and reformation of disulfide bonds is revealed by material/structural characterizations. This study provides a new perspective of molecule designs for the development of redox-active materials for high-performance nonaqueous RFBs.

TIGIT Can Exert Immunosuppressive Effects on CD8+ T Cells by the CD155/TIGIT Signaling Pathway for Hepatocellular Carcinoma In Vitro.

The efficacy of adoptive cellular immunotherapy against cancer cells is limited due to the presence of immunosuppressive cells within the solid tumor microenvironment. The upregulation of certain coinhibitory receptors may lead to exhaustion of the immune effector cells. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune inhibitory receptor expressed by regulatory T cells and activated T cells and natural killer cells. The aim of this study was to determine the immunosuppressive effects of CD155/TIGIT signaling on CD8 T cells of adoptive cellular immunotherapy in hepatocellular carcinoma (HCC). Our studies found that CD155 was overexpressed in HCC, and CD155 HCC cells upregulated TIGIT on CD8 T cells, which decreased the secretion of interferon-γ, tumor necrosis factor-α, and interleukin-17A and increased that of interleukin-10 from the effector cells. However, TIGIT blockade or CD155-knockdown reversed the inhibitory effect of HCC cells on CD8 T-cell effector function. These results indicate that TIGIT can exert an immunosuppressive effect on CD8 T cells by modulating cytokine production through CD155, and is a promising target to optimize adoptive cellular immunotherapy against HCC.

Molecular Engineering of Azobenzene-Based Anolytes Towards High-Capacity Aqueous Redox Flow Batteries.

Aqueous redox flow batteries (RFBs) are promising alternatives for large-scale energy storage. However, new organic redox-active molecules with good chemical stability and high solubility are still desired for high-performance aqueous RFBs due to their low crossover capability and high abundance. We report azobenzene-based molecules with hydrophilic groups as new active materials for aqueous RFBs by utilizing the reversible redox activity of azo groups. By rationally tailoring the molecular structure of azobenzene, the solubility is favorably improved from near zero to 2 M due to the highly charged asymmetric structure formed in alkaline environment. DFT simulations suggest that the concentrated solution stability can be enhanced by adding hydrotropic agent to form intermolecular hydrogen bonds. The demonstrated RFB exhibits long cycling stability with a capacity retention of 99.95 % per cycle over 500 cycles. It presents a viable chemical design route towards advanced aqueous RFBs.

Reversible redox chemistry in azobenzene-based organic molecules for high-capacity and long-life nonaqueous redox flow batteries.

Redox-active organic molecules have drawn extensive interests in redox flow batteries (RFBs) as promising active materials, but employing them in nonaqueous systems is far limited in terms of useable capacity and cycling stability. Here we introduce azobenzene-based organic compounds as new active materials to realize high-performance nonaqueous RFBs with long cycling life and high capacity. It is capable to achieve a stable long cycling with a low capacity decay of 0.014% per cycle and 0.16% per day over 1000 cycles. The stable cycling under a high concentration of 1 M is also realized, delivering a high reversible capacity of ~46 Ah L-1. The unique lithium-coupled redox chemistry accompanied with a voltage increase is observed and revealed by experimental characterization and theoretical simulation. With the reversible redox activity of azo group in π-conjugated structures, azobenzene-based molecules represent a class of promising redox-active organics for potential grid-scale energy storage systems.

Eutectic Electrolytes as a Promising Platform for Next-Generation Electrochemical Energy Storage.

ConspectusThe rising global energy demand and environmental challenges have spurred intensive interest in renewable energy and advanced electrochemical energy storage (EES), including redox flow batteries (RFBs), metal-based rechargeable batteries, and supercapacitors. While many researchers focus on the design of new chemistry and structures for high-capacity and stable electrode materials, the electrolyte also plays a significant role in enabling the successful function of these new electrode materials and chemistries. Discovery of new electrolytes is urgently needed to keep up with the rapid growth of EES. Benefiting from the strong intermolecular interaction between different components, eutectic electrolytes possess various specific functionalities that conventional electrolytes do not have, such as highly concentrated systems, non-flammability, high degrees of structural flexibility, and good thermal and chemical stability, thereby leading researchers to consider them as a new class of ionic fluids for EES applications.In this Account, we aim to provide a mechanistic understanding of this energy chemistry and an overview of recent progress in the development of eutectic electrolytes for next-generation EES. First, we describe different mechanisms that guide the formation of eutectic electrolytes and discuss the structure-property relations, electron transfer and ion transport mechanisms, and interfacial chemistry in eutectic electrolytes. Generally, three main intermolecular interactions, namely hydrogen-bond interactions, Lewis acid-base interactions, and van der Waals interactions, control the formation of eutectic electrolytes and determine their unique characters in terms of electrochemical, thermal, ion transport, and interfacial properties. These versatile intermolecular interactions can be further modified by tailoring the functional moieties of organic molecules and/or selecting suitable compositions of mixtures. The solvent-free eutectic electrolyte can maximize the molar ratio of redox-active materials, thus increasing the energy density of RFBs. We discuss the relationships between eutectic parameters (viscosity, polarity, ionic conductivity, surface tension, and coordination environment) and the molar ratio, stability, utilization, and electrochemical reversibility of redox-active materials, RFB power, and energy density. We then introduce the application of both metal- and organic-based eutectic electrolytes in the RFB field, along with the relevant perspective for future study in this field. The highly concentrated eutectic electrolytes show attractive features at electrolyte/electrode interfaces to expand the electrochemical window and meanwhile inhibit metal dendrite formation in metal-based rechargeable batteries, supercapacitors, and hybrids of these. The remaining challenges and potential research directions in these areas are also discussed. Eutectic electrolytes offer enormous opportunities and open appealing prospects as redox reaction and charge transport media for EES. We hope this Account provide guidance for the future design of advanced eutectic electrolytes toward next-generation EES systems.

Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids.

BACKGROUND: The mechanism underlying sorafenib resistance in hepatocellular carcinoma (HCC) remains unclear. Accumulating evidence suggests that tumor-initiating cells (TICs) are a pivotal driving force. Both CD44 and Hedgehog signaling play crucial roles in TIC properties in HCC. In this study, we explored the roles of CD44 and Hedgehog signaling in sorafenib resistance and evaluated the therapeutic effect of cotreatment with sorafenib and Hedgehog signaling inhibitors in HCC patient-derived organoid (PDO) models to improve treatment efficacy. METHODS: We collected HCC specimens to establish PDO models. Cell viability and malignant transformation properties were investigated after treatment with different TIC-related inhibitors alone or in combination with sorafenib to evaluate the therapeutic effect in PDOs and cell lines by in vitro and in vivo experiments. Expression levels of Hedgehog signaling proteins and CD44 were monitored to reveal potential relationships. RESULTS: We demonstrated that our HCC PDO models strongly maintained the histological features of the corresponding tumors and responded to drug treatment. Furthermore, CD44-positive HCC PDOs were obviously resistant to sorafenib, and sorafenib increased CD44 levels. A drug screen showed that compared with Notch, Hippo and Wnt signaling inhibitors, a Hedgehog signaling inhibitor (GANT61) potently suppressed HCC PDO cell viability. In addition, there was a highly synergistic effect in vitro and in vivo on the suppression of cell viability and malignant properties when sorafenib and GANT61 were added to CD44-positive HCC PDOs and cell lines, respectively. Furthermore, the upregulation of CD44 and Hedgehog signaling induced by sorafenib was reversed by GANT61. CONCLUSIONS: GANT61 significantly suppressed Hedgehog signaling to reverse sorafenib resistance in CD44-positive HCC. The combination of sorafenib and Hedgehog signaling inhibitors might be effective in HCC patients with high CD44 levels as a personalized-medicine approach.

A Dual-Ion Organic Symmetric Battery Constructed from Phenazine-Based Artificial Bipolar Molecules.

Symmetric batteries received an increasing research interest in the past few years because of their simplified fabrication process and reduced manufacturing cost. In this study, we propose the first dual-ion organic symmetric cell based on a molecular anion of 4,4'-(phenazine-5,10-diyl)dibenzoate. The alkali salt of 4,4'-(phenazine-5,10-diyl)dibenzoate allows a facile transport of cations and large anions, and remains stable in both oxidized and reduced states. The large potential difference between phenazine and benzoate results in a high cell voltage of 2.5 V and an energy density of 127 Wh kg-1 at a current rate of 1 C. The introduction of bipolar organic materials may further consolidate the development of symmetric batteries that are fabricated from abundant elements and environmentally friendly materials.

Biredox Eutectic Electrolytes Derived from Organic Redox-Active Molecules: High-Energy Storage Systems.

One promising candidate for high-energy storage systems is the nonaqueous redox flow battery (NARFB). However, their application is limited by low solubility of redox-active materials and poor performance at high current density. Reported here is a new strategy, a biredox eutectic, as the sole electrolyte for NARFB to achieve a significantly higher concentration of redox-active materials and enhance the cell performance. Without other auxiliary solvents, the biredox eutectic electrolyte is formed directly by the molecular interactions between two different redox-active molecules. Such a unique electrolyte possesses high concentration with low viscosity (3.5 m, for N-butylphthalimide and 1,1-dimethylferrocene system) and a relatively high working voltage of 1.8 V, enabling high capacity and energy density of NARFB. The resulting high-performance NARFB demonstrates that the biredox eutectic based strategy is potentially promising for low-cost and high-energy storage systems.

Phenothiazine-Based Organic Catholyte for High-Capacity and Long-Life Aqueous Redox Flow Batteries.

Redox-active organic materials have been considered as one of the most promising "green" candidates for aqueous redox flow batteries (RFBs) due to the natural abundance, structural diversity, and high tailorability. However, many reported organic molecules are employed in the anode, and molecules with highly reversible capacity for the cathode are limited. Here, a class of heteroaromatic phenothiazine derivatives is reported as promising positive materials for aqueous RFBs. Among these derivatives, methylene blue (MB) possesses high reversibility with extremely fast redox kinetics (electron-transfer rate constant of 0.32 cm s-1 ), excellent stability in both neutral and reduced states, and high solubility in an acetic-acid-water solvent, leading to a high reversible capacity of ≈71 Ah L-1 . Symmetric RFBs based on MB electrolyte demonstrate remarkable stability with no capacity decay over 1200 cycles. Even concentrated MB catholyte (1.5 m) is still able to deliver stable capacity over hundreds of cycles in a full cell system. The impressive cell performance validates the practicability of MB for large-scale electrical energy storage.

Efficient Solar Energy Harvesting and Storage through a Robust Photocatalyst Driving Reversible Redox Reactions.

Simultaneous solar energy conversion and storage is receiving increasing interest for better utilization of the abundant yet intermittently available sunlight. Photoelectrodes driving nonspontaneous reversible redox reactions in solar-powered redox cells (SPRCs), which can deliver energy via the corresponding reverse reactions, present a cost-effective and promising approach for direct solar energy harvesting and storage. However, the lack of photoelectrodes having both high conversion efficiency and high durability becomes a bottleneck that hampers practical applications of SPRCs. Here, it is shown that a WO3 -decorated BiVO4 photoanode, without the need of extra electrocatalysts, can enable a single-photocatalyst-driven SPRC with a solar-to-output energy conversion efficiency as high as 1.25%. This SPRC presents stable performance over 20 solar energy storage/delivery cycles. The high efficiency and stability are attributed to the rapid redox reactions, the well-matched energy level, and the efficient light harvesting and charge separation of the prepared BiVO4 . This demonstrated device system represents a potential alternative toward the development of low-cost, durable, and easy-to-implement solar energy technologies.

Zn-based eutectic mixture as anolyte for hybrid redox flow batteries.

Developing greener batteries with new chemistries is a formidable challenge, and a major focus for years to come. Redox flow batteries are receiving increasing research interest for grid-scale electrochemical energy storage owing to their unique architecture. However, challenges still remain by their low energy density as well as corrosive and/or toxic electrolytes. An anolyte based on aprotic Zn deep-eutectic-solvent, which uses low cost, abundant and environmentally benign materials, exhibits a utilizable concentration of Zn2+ ca. 1.7 M, resulting in a reversible volumetric capacity of ca. 90 A h·L-1. Combined with high efficiencies and relatively low redox potential of -1.12 V vs. Ag/AgCl, such an anolyte provides an alternative way to explore a family of anolytes using new chemistries for rechargeable Zn batteries that meet the criteria for grid-scale electrical energy storage.

Molecular engineering of organic electroactive materials for redox flow batteries.

With high scalability and independent control over energy and power, redox flow batteries (RFBs) stand out as an important large-scale energy storage system. However, the widespread application of conventional RFBs is limited by the uncompetitive performance, as well as the high cost and environmental concerns associated with the use of metal-based redox species. In consideration of advantageous features such as potentially low cost, vast molecular diversity, and highly tailorable properties, organic and organometallic molecules emerge as promising alternative electroactive species for building sustainable RFBs. This review presents a systematic molecular engineering scheme for designing these novel redox species. We provide detailed synthetic strategies for modifying the organic and organometallic redox species in terms of solubility, redox potential, and molecular size. Recent advances are then introduced covering the reaction mechanisms, specific functionalization methods, and electrochemical performances of redox species classified by their molecular structures. Finally, we conclude with an analysis of the current challenges and perspectives on future directions in this emerging research field.

A Sustainable Redox-Flow Battery with an Aluminum-Based, Deep-Eutectic-Solvent Anolyte.

Nonaqueous redox-flow batteries are an emerging energy storage technology for grid storage systems, but the development of anolytes has lagged far behind that of catholytes due to the major limitations of the redox species, which exhibit relatively low solubility and inadequate redox potentials. Herein, an aluminum-based deep-eutectic-solvent is investigated as an anolyte for redox-flow batteries. The aluminum-based deep-eutectic solvent demonstrated a significantly enhanced concentration of circa 3.2 m in the anolyte and a relatively low redox potential of 2.2 V vs. Li+ /Li. The electrochemical measurements highlight that a reversible volumetric capacity of 145 Ah L-1 and an energy density of 189 Wh L-1 or 165 Wh kg-1 have been achieved when coupled with a I3- /I- catholyte. The prototype cell has also been extended to the use of a Br2 -based catholyte, exhibiting a higher cell voltage with a theoretical energy density of over 200 Wh L-1 . The synergy of highly abundant, dendrite-free, multi-electron-reaction aluminum anodes and environmentally benign deep-eutectic-solvent anolytes reveals great potential towards cost-effective, sustainable redox-flow batteries.