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The sintered glass-ceramic always has an uneven microstructure due to the surface crystallization, which limits the enhancement of its mechanical properties. In the present work, Cr 2 O 3 was added into CaO–MgO–Al 2 O 3 –SiO 2 –CaCl 2 glass as the nucleating agent, and the low-pressure (14 kPa) sintering technology was utilized to promote the densification process of the glass frits (0.42–2 mm). It was found that by adding 1 wt% of Cr 2 O 3 , the bulk crystallization can be achieved inside the glass particle and the microstructure of the glass-ceramic became more homogeneous. Correspondingly, the bending strength was improved from 127 to 147 MPa, and the Vickers hardness was enhanced from 6.5 to 6.7 GPa, comparing with the Cr 2 O 3 -free glass-ceramic. The current study confirmed the positive impact of nucleating agent in the performance of sintered glass-ceramic, which also provided a route for the utilizations of CaCl 2 -and Cr 2 O 3 -bearing wastes. [ABSTRACT FROM AUTHOR]

The effects of CaO/SiO 2 ratio (basicity) and CaCl 2 addition amount on the properties of CaO–MgO–Al 2 O 3 –SiO 2 –CaCl 2 glass-ceramics (GC) were investigated. When sintered at 825 °C, the increase in basicity from 0.35 to 0.75 reduced the porosity of GCs from 1.1 to 0.8 vol%, but the increase of CaCl 2 addition amount from 5 to 10 wt% increased the porosity from 0.8 to 7.0 vol%. The main crystalline phase of GC changed from augite (Ca(Mg 0 · 7 Al 0.3) (Si 1 · 7 Al 0.3)O 6) to Ca 10 Al 12 Cl 2 Si 5 O 37 by increasing the CaCl 2 addition amount to 7.5 wt%. The increase in CaCl 2 addition had adverse effects on the bending strength and Vickers hardness, while the rise in basicity deteriorated the bending strength but had little impact on the Vickers hardness. This study may have a guiding significance for preparing slag-based GCs and treating CaCl 2 -containing wastes. [ABSTRACT FROM AUTHOR]

CaCl 2 can dissolve in the silicate glasses, and thus, using the CaCl 2 -bearing glass for the preparation of glass-ceramic could be a potential method for treating CaCl 2 -bearing wastes. In this work, two kinds of glass powders, CaO-MgO-Al 2 O 3 -SiO 2 and CaO-MgO-Al 2 O 3 -SiO 2 -CaCl 2 , were sintered at 825–850 ℃ to prepare the glass-ceramic. Besides, a low-pressure (19.1kPa) hot-pressing sintering technology was applied to reduce the porosity and pore size of the glass-ceramic. The addition of CaCl 2 (5 wt%) reduced the polymerization degree, glass transition temperature, crystallization peak temperature, and crystallization activation energy of the glass. Augite was the main crystalline phase of the glass-ceramic, and the addition of CaCl 2 promoted the precipitation of anorthite. The glass-ceramic prepared from the Cl-containing glass always exhibited a higher bending strength than that obtained from the Cl-free glass. When sintered at 825 ℃ for 8 h, the glass-ceramic showed the highest bending strength of 171 MPa. [ABSTRACT FROM AUTHOR]

• CaO-MgO-Al 2 O 3 -SiO 2 glass-ceramic with high contents of Cr2O 3 was investigated. • The glass-ceramic was prepared by SPS and showed bulk crystallization behavior. • Coarse spinel crystals resulted in intergranular fracture and effectively hindered crack propagation. • The glass-ceramic showed high bending strength and vickers hardness of 214 MPa and 8.2 GPa, respectively. 2, 6, or 10 wt% of Cr 2 O 3 was added into the CaO-MgO-Al 2 O 3 -SiO 2 precursor glasses (PG), aiming to investigate the effects of high contents of Cr 2 O 3 on the crystallization behavior and mechanical properties of glass-ceramics (GCs). The PGs were milled into powder and then sintered by spark plasma sintering (SPS) technology at 750∼850 °C under the pressure of 10 MPa. It was found that Cr 2 O 3 induced the precipitation of spinel nuclei in the PGs, which served as the heterogeneous nucleation sites for the augite crystals. Augite and spinel were the main phases of the GCs, and the crystallinity increased by increasing the Cr 2 O 3 addition amount and sintering temperature. The GC prepared at 850 °C with 6 wt% Cr 2 O 3 addition showed excellent bending strength, with Vickers hardness, and fracture toughness of 214 MPa, 8.2 GPa, and 1.3 MPa·m1/2, respectively. [ABSTRACT FROM AUTHOR]

Molybdenum silicides (Mo–Si) have attracted great interest owing to their good electrical conductivity, ultra-high melting point and well oxidation resistance. In this work, the controllable syntheses of Mo 5 Si 3 and Mo 3 Si powders by silicothermic reduction of MoS 2 in the presence of lime are studied for the first time. The internal mixture composed of MoS 2 and Si is wrapped by sufficient CaO. After the reaction is finished, the synthesized molybdenum silicides can be easily separated from the desulfurization layer by peeling off the desulfurization product. The results show that Mo 3 Si and Mo 5 Si 3 can be prepared at 1500 °C for the samples with the MoS 2 :Si molar ratio of 1:1.7 and 1:2.33, respectively. In addition, the results show that both SiS 2 and SiS can be formed during the heating process. The thermodynamic analysis about the disproportionation reaction of SiS indicates that the existence of SiS 2 depends on the partial pressure of SiS (P SiS) and temperature. Moreover, it is demonstrated that SiS 2 is preferentially formed under low temperature conditions. As the temperature rises, it is much easier for SiS 2 to react with Si to form SiS. Additionally, this work experimentally proves for the first time that SiS gas can directly reduce MoS 2 to form MoSi 2 and SiS 2. Subsequently, the recovery of S in the desulfurization product was studied. S in MoS 2 was first captured by CaO in the form of CaS (accompanied by Ca 2 SiO 4 and Si). In order to solve this CaS containing desulfurization product which is detrimental to the environment, CaS in the desulfurization product is react with Fe 2 O 3 and C to form FeS. This work provides new insights into the closed-loop capture and recovery of S in the process of extracting metals or metal compounds from sulfide ores. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, the transcriptomic response of Trachinotus ovatus liver was observed against high-temperature stress. Through differential expression and short time-series expression miner (STEM) analyses, some high-temperature-related genes and biological pathways were screened, which were mainly related to protein balance, hypoxia adaptation, and energy metabolism. Our results suggest that protein dynamic balance and function, hypoxia adaptation, and energy metabolism transformation are crucial in response to acute high-temperature stress. These results contribute to understanding the molecular response mechanism of T. ovatus under acute heat stress and provide novel insights into the selection and breeding of heat-tolerant cultivars and the high-quality development of aquaculture. Trachinotus ovatus is a major economically important cultured marine fish in the South China Sea. However, extreme weather and increased culture density result in uncontrollable problems, such as increases in water temperature and a decline in dissolved oxygen (DO), hindering the high-quality development of aquaculture. In this study, liver transcriptional profiles of T. ovatus were investigated under acute high-temperature stress (31 °C and 34 °C) and normal water temperature (27 °C) using RNA sequencing (RNA-Seq) technology. Differential expression analysis and STEM analysis showed that 1347 differentially expressed genes (DEGs) and four significant profiles (profiles 0, 3, 4, and 7) were screened, respectively. Of these DEGs, some genes involved in heat shock protein (HSPs), hypoxic adaptation, and glycolysis were up-regulated, while some genes involved in the ubiquitin-proteasome system (UPS) and fatty acid metabolism were down-regulated. Our results suggest that protein dynamic balance and function, hypoxia adaptation, and energy metabolism transformation are crucial in response to acute high-temperature stress. Our findings contribute to understanding the molecular response mechanism of T. ovatus under acute heat stress, which may provide some reference for studying the molecular mechanisms of other fish in response to heat stress. [ABSTRACT FROM AUTHOR]

Early graft loss and poor graft function limit the use of kidneys from infant donors. Six en bloc kidney transplantations were performed from infant donors younger than 10 months into pediatric recipients between November 2012 and September 2015 at our center. We retrospectively analyzed recipient and donor demographics, surgery procedures, complications, graft function and size, and patient and graft survival with a follow-up of 6-39 months (median 15.5 months). Donor age ranged from 1 to 10 months with weight ranging from 3.5 to 10 kg. Recipient age ranged from 10 to 16 years with weight ranging from 30 to 39 kg. One kidney was removed due to arterial thrombosis during surgery, while the other kidney of this en bloc graft remained viable. Urine leak followed by bilateral ureteral obstruction occurred in one recipient. All of the recipients showed immediate graft function. The size of the en bloc kidney increased from 4.2±0.6 cm to 7.6±0.6 cm 6 months after surgery. Patient and graft survival were both 100% at the last follow-up. Our results show that en bloc kidney transplantation from infant donors younger than 10 months into pediatric recipients is effective under the condition of experienced surgical techniques and perioperative management. [ABSTRACT FROM AUTHOR]

In this study, a novel process for the recovery of Ni from Ni-bearing electroplating sludge (ES) is proposed, which involves the carbothermic reduction stage and smelting stage. In the reduction stage, the CaSO 4 , Fe 2 O 3 , and NiO in the ES were reduced by carbon at 1000 °C, and the Ni 3 S 2 and Fe 4 Ni 5 S 8 (Ni-rich phases) were generated. After that, the reduced ES was mixed with SiO 2 and smelted at 1500 °C. During the smelting stage, Ni 3 S 2 and Fe 4 Ni 5 S 8 were melted to form liquid Ni–Fe–S matte and separated from the molten slag by gravity. Finally, 58.5%Ni-13.8%Fe-27.7%S (in weight) matte and vitrified slag were obtained. The recovery ratio of Ni (97.2%) was much higher than that of Fe (14.7%). Besides, the Ni/Fe mass ratio of the ES was 0.7, while the ratio of the prepared matte was about 4.2. Therefore, the selective recovery of Ni was achieved. The obtained Ni matte can be used as the raw material for pure Ni or Ni-bearing chemicals. [Display omitted] • Ni matte was prepared from electroplating sludge (ES) by reducing-smelting method. • Ni 3 S 2 and Fe 4 Ni 5 S 8 were generated when the ES was pre-reduced by carbon at 1000 °C. • High dosage of carbon improved the Ni recovery extent but decreased the Ni grade of matte. [ABSTRACT FROM AUTHOR]

• Glass-ceramic was prepared from biomass fly ash by using a powder sintering method. • The crystallization behavior was dominated by surface crystallization. • Fine diopside grains (0.2–1 μm) were observed in the glass-ceramic. • The highest bending strength of glass-ceramic reached 212 MPa when sintered at 920 ℃ for 1 h. In this work, diopside-based CaO-MgO-Al 2 O 3 -SiO 2 glass-ceramic was prepared from biomass fly ash (BFA) by powder sintering method. The parent glass powder was prepared by melting 76%BFA-9%CaO-6%Al 2 O 3 –9%MgO (in mass) at 1450 ℃ followed by water quenching and ball milling. The glass powder was sintered at 830, 850 and 920 ℃ for 1–16 h to obtain the glass-ceramic. It was found that the crystallization behavior was controlled by surface crystallization, and diopside was the major crystalline phase. The mechanical properties of glass-ceramic were improved by prolonging the sintering time from 4 to 16 h at 830 ℃. However, the sizes of pores in glass-ceramic increased as increasing the sintering time at 850 ℃, which deteriorated the properties of the glass-ceramic. The glass-ceramic sintered at 920 ℃ for 1 h has a high crystallinity and fine grains, and showed the highest bending strength of 212 MPa. [ABSTRACT FROM AUTHOR]

A hybrid metamaterial based on a metal-solid-state plasma (SSP) structure has been demonstrated, which actively controls the transparency window by introducing the SSP. The unit cell consists of square patch with a slot and metal cut wire (CW) with SSPs embedded. The designing of a resonant frequency tuning is intrinsically more difficult than amplitude modulation, which has been extensively researched. By introducing SSP and sophisticated structural design, the frequency shifts 403 GHz when the structure switches between two states. The transmission window is switched by changing the state of SSP, allowing for a dynamical group delay of the terahertz frequency. The linearly coupled Lorentz oscillator model is utilized to explore the underlying mechanism of the actively tunable electromagnetically induced transparency behavior between the bright and bright modes. We provide fascinating possibilities for innovative optical components in certain areas, including ultrafast switching, sensing, and terahertz active filtering. [ABSTRACT FROM AUTHOR]

In this study, a Ti3C2 MXene@g-C3N4 composite powder (TM-CN) was prepared by the ultrasonic self-assembly method and then loaded onto a carbon nanofiber membrane by the self-assembly properties of MXene for the treatment of organic pollutants in wastewater. The characterization of the TM-CN and the C-TM-CN was conducted via X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectrometer (FTIR) to ascertain the successful modification. The organic dye degradation experiments demonstrated that introducing an appropriate amount of Ti3C2 MXene resulted in the complete degradation of RhB within 60 min, three times the photocatalytic efficiency of a pure g-C3N4. The C-TM-CN exhibited the stable and outstanding photocatalytic degradation of the RhB solution over a wide range of pH values, indicating the characteristics of the photodegradation of organic pollutants in a wide range of aqueous environments. Furthermore, the results of the cyclic degradation experiments demonstrated that the C-TM-CN composite film maintained a degradation efficiency of over 85% after five cycles, thereby confirming a notable improvement in its cyclic stability. Consequently, the C-TM-CN composite film exhibits excellent photocatalytic performance and is readily recyclable, making it an auspicious eco-friendly material in water environment remediation. [ABSTRACT FROM AUTHOR]

Introduction: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second‐line efficacy of bortezomib in PTEN‐deficient advanced ICC patients. Methods: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single‐agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21‐day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. Results: The median follow‐up was 6.55 months (95% confidence interval [CI]: 0.7–19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress‐free survival was 2.95 months (95% CI: 2.1–5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7–21.6 months) in the intent‐to‐treat‐patients. Treatment‐related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. Conclusions: Bortezomib yielded an encouraging objective response and a favourable OS as a second‐line agent in PTEN‐deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN‐deficient ICC. Highlights: There is a limited strategy for the second‐line option of intrahepatic cholangiocarcinoma (ICC).This investigator‐initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency.The overall response rate was 18.75% and the overall survival was 7.2 months in the intent‐to‐treat cohort.These results justify further developing bortezomib in ICC patients with PTEN deficiency. [ABSTRACT FROM AUTHOR]

The study presents the use of genetic algorithm (GA) to optimize the bipolar plate channel geometry of a polymer electrolyte membrane fuel cell (PEMFC). Contrary to previous optimization techniques, laborious fuel cell design steps, including boundary setting, mesh generation, and numerical computation at every design parameter variation step, are avoided by developing an automated program via Matlab and Comsol Multiphysics software. GA with Matlab automatically checks the optimality of the present fuel cell design with a performance index obtained from Comsol Multiphysics. If a global optimal is not reached, the new geometry set of a fuel cell is generated according to GA rules toward better fuel cell performance. The new set is then fed back to Comsol Multiphysics to have the new performance index calculated through updated boundary conditions, element and mesh generations, and numerical analysis. This automated optimization technique not only saves numerous calculations, but also obtains the global optimal result of a given fuel cell geometry. Therefore, it provides a fast and efficient optimization process and renders optimal results. In this study, two channel and rib geometry arrangements are studied: one with a symmetric anode and cathode channel arrangement, wherein channels and ribs face each other; and another with an asymmetric arrangement, wherein a channel faces a rib and vice versa. First, the two-dimensional (2D) CFD model is used to obtain the optimal result in order to speed up the optimization calculation, slightly sacrificing the model accuracy. Afterwards, the three-dimensional CFD model is utilized and experimental verification is made with the same geometries to support the validation of the 2D optimization result. [ABSTRACT FROM AUTHOR]

One-way water transport is a predominant feature of comfortable textiles used in daily life. However, shortcomings related to the textiles include their poor breathability and durability. In this study, low-cost and eco-friendly PLA/low-melt (polylactic acid) LMPLA-thermoplastic polyurethane (TPU) membranes were fabricated through a needle punch/hot press and electrospinning method. The micro-/nano-channels, used for the first time, endowed the composite membranes with robust, breathable, moisture-permeable, and abrasion-resistant performance. By varying the nano- layer thickness, the resulting 16–40 μm membranes exhibited excellent one-way water transport, robust breathability and moisture permeability, and good abrasion resistance. Nano-layer thickness was found to be a critical performance factor, balancing comfort and protection. These results may be useful for developing low-cost, eco-friendly, and versatile protective products for medical application. [ABSTRACT FROM AUTHOR]

SUMMARY The construction of a reliable numerical model and the clarification of its operational conditions are necessary for maximizing fuel cell operation. Numerous operating factors, such as mole fractions of species, pressure distribution, overpotential, and inlet relative humidity, affect the performance of proton exchange membrane fuel cells (PEMFCs). Among these operational parameters, geometrical shape and relative humidity are investigated in this paper. Specifically, the land ratio of the gas channel and rib is an important parameter affecting PEMFC performance because current density distribution is influenced by this geometrical characteristic. Three main variables determine the current density distribution, namely, species concentration, pressure, and overpotential distributions. These distributions are considered simultaneously in assessing fuel cell performance with a given PEMFC cell-operating voltage. In this paper, three different land ratio models are considered to obtain better PEMFC performance. Similarly, three different inlet relative humidity variations are studied to achieve an enhanced operating condition. A three-dimensional numerical PEMFC model is developed to illustrate the current density distribution as the determining factor for PEMFC performance. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A quantum protocol for ( t, n)-threshold identity authentication based on Greenberger-Horne-Zeilinger states is presented. A trusted third party (TTP) can authenticate the users simultaneously when and only when t or more users among n apply for authentication. Compared with the previous multiparty simultaneous quantum identity authentication (MSQIA) protocols, the proposed scheme is more flexible and suitable for practical applications. [ABSTRACT FROM AUTHOR]

We assessed interactions between the astrocytic volume-regulated anion channel (VRAC) and aquaporin 4 (AQP4) in the supraoptic nucleus (SON). Acute SON slices and cultures of hypothalamic astrocytes prepared from rats received hyposmotic challenge (HOC) with/without VRAC or AQP4 blockers. In acute slices, HOC caused an early decrease with a late rebound in the neuronal firing rate of vasopressin neurons, which required activity of astrocytic AQP4 and VRAC. HOC also caused a persistent decrease in the excitatory postsynaptic current frequency, supported by VRAC and AQP4 activity in early HOC; late HOC required only VRAC activity. These events were associated with the dynamics of glial fibrillary acidic protein (GFAP) filaments, the late retraction of which was mediated by VRAC activity; this activity also mediated an HOC-evoked early increase in AQP4 expression and late subside in GFAP-AQP4 colocalization. AQP4 activity supported an early HOC-evoked increase in VRAC levels and its colocalization with GFAP. In cultured astrocytes, late HOC augmented VRAC currents, the activation of which depended on AQP4 pre-HOC/HOC activity. HOC caused an early increase in VRAC expression followed by a late rebound, requiring AQP4 and VRAC, or only AQP4 activity, respectively. Astrocytic swelling in early HOC depended on AQP4 activity, and so did the early extension of GFAP filaments. VRAC and AQP4 activity supported late regulatory volume decrease, the retraction of GFAP filaments, and subside in GFAP-VRAC colocalization. Taken together, astrocytic morphological plasticity relies on the coordinated activities of VRAC and AQP4, which are mutually regulated in the astrocytic mediation of HOC-evoked modulation of vasopressin neuronal activity. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) treatment has created the opportunity of improved outcome for patients with hepatocellular carcinoma (HCC). However, only a minority of HCC patients benefit from ICI treatment owing to poor treatment efficacy and safety concerns. There are few predictive factors that precisely stratify HCC responders to immunotherapy. In this study, we developed a tumour microenvironment risk (TMErisk) model to divide HCC patients into different immune subtypes and evaluated their prognosis. Our results indicated that virally mediated HCC patients who had more common tumour protein P53 (TP53) alterations with lower TMErisk scores were appropriate for ICI treatment. HCC patients with alcoholic hepatitis who more commonly harboured catenin beta 1 (CTNNB1) alterations with higher TMErisk scores could benefit from treatment with multi-tyrosine kinase inhibitors. The developed TMErisk model represents the first attempt to anticipate tumour tolerance of ICIs in the TME through the degree of immune infiltration in HCCs. [ABSTRACT FROM AUTHOR]

Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future. [ABSTRACT FROM AUTHOR]

Background: Transketolase (TKT), a key rate‐limiting enzyme in the non‐oxidative branch of the pentose phosphate pathway (PPP), provides more than 85% of the ribose required for de novo nucleotide biosynthesis and promotes the development of hepatocellular carcinoma (HCC). Pharmacologic inhibition of TKT could impede HCC development and enhance treatment efficacy. However, no safe and effective TKT inhibitor has been approved. Methods: An online two‐dimensional TKT protein immobilised biochromatographic system was established for high‐throughput screening of TKT ligands. Oroxylin A was found to specifically bind TKT. Drug affinity responsive target stability, cellular thermal shift assay, surface plasmon resonance, molecular docking, competitive displacement assay, and site mutation were performed to identify the binding of oroxylin A with TKT. Antitumour effects of oroxylin A were evaluated in vitro, in human xenograft mice, diethylnitrosamine (DEN)‐induced HCC mice, and patient‐derived organoids (PDOs). Metabolomic analysis was applied to detect the enzyme activity. Transcriptome profiling was conducted to illustrate the anti‐HCC mechanism of oroxylin A. TKT knocking‐down HCC cell lines and PDOs were established to evaluate the role of TKT in oroxylin A‐induced HCC suppression. Results: By targeting TKT, oroxylin A stabilised the protein to proteases and temperature extremes, decreased its activity and expression, resulted in accumulation of non‐oxidative PPP substrates, and activated p53 signalling. In addition, oroxylin A suppressed cell proliferation, induced apoptosis and cell‐cycle arrest, and inhibited the growth of human xenograft tumours and DEN‐induced HCC in mice. Crucially, TKT depletion exerted identical effects to oroxylin A, and the promising inhibitor also exhibited excellent therapeutic efficacy against clinically relevant HCC PDOs. Conclusions: These results uncover a unique role for oroxylin A in TKT inhibition, which directly targets TKT and suppresses the non‐oxidative PPP. Our findings will facilitate the development of small‐molecule inhibitors of TKT and novel therapeutics for HCC. [ABSTRACT FROM AUTHOR]

Cancer cells are addicted to glutamine. However, cancer cells often suffer from glutamine starvation, which largely results from the fast growth of cancer cells and the insufficient vascularization in the interior of cancer tissues. Herein, based on clinical samples, patient‐derived cells (PDCs), and cell lines, it is found that liver cancer cells display stem‐like characteristics upon glutamine shortage due to maintaining the stemness of tumor initiating cells (TICs) and even promoting transformation of non‐TICs into stem‐like cells by glutamine starvation. Increased expression of glutamine synthetase (GS) is essential for maintaining and promoting stem‐like characteristics of liver cancer cells during glutamine starvation. Mechanistically, glutamine starvation activates Rictor/mTORC2 to induce HDAC3‐mediated deacetylation and stabilization of GS. Rictor is significantly correlated with the expression of GS and stem marker OCT4 at tumor site, and closely correlates with poor prognosis of hepatocellular carcinomas. Inhibiting components of mTORC2‐HDAC3‐GS axis decrease TICs and promote xenografts regression upon glutamine‐starvation therapy. Collectively, the data provides novel insights into the role of Rictor/mTORC2‐HDAC3 in reprogramming glutamine metabolism to sustain stemness of cancer cells. Targeting Rictor/HDAC3 may enhance the efficacy of glutamine‐starvation therapy and limit the rapid growth and malignant progression of tumors. [ABSTRACT FROM AUTHOR]

Despite the efficacy demonstrated by immunotherapy recently, liver cancer still remains one of the deadliest cancers, mainly due to heterogeneity of this disease. Continuous exploration of new therapeutics is therefore necessary. Chemical‐induced cell differentiation can serve as a promising approach, with its ability to consistently remodel gene expression profile and alter cell fate. Inspired by advances in stem cell and reprogramming field, here it is reported that a small molecule cocktail (SMC) consisted of: SB431542 (TGFβ inhibitor), CHIR99021 (GSK3β inhibitor), BIX01294 (H3K9 methyltransferase/G9a inhibitor), and all‐trans retinoic acid (ATRA), can induce differentiation of liver cancer cells including cell lines, primary cancer cells, cancer stem cells, and drug resistant cells. Treated cells lose malignant characteristics and regain hepatocyte phenotype instead. When applied in vivo, SMC induces wide range of tissue necrosis or fibrosis within the tumors, while remaining tissues begin to express hepatic nuclear factor 4α (HNF4α), the hepatic nuclear marker. SMC also leads to tumor abrogation in orthotopic xenograft models and life span extension of animals. The powerful differentiation induction of SMC is exerted through modulation of Akt/mTOR/HIF1α signaling and metabolic reprogramming, as well as suppressing Snail and enhancing HNF4α expression. Together, these results highlight that chemical‐induced differentiation has the potential to effectively treat liver cancer disregard of heterogeneity. [ABSTRACT FROM AUTHOR]

The high mutation rate of CTNNB1 (37 %) and Wnt-β-catenin signal-associated genes (54 %) has been notified in hepatocellular carcinoma (HCC). The activation of Wnt-β-catenin signal pathway was reported to be associated with an immune "desert" phenotype, but the underlying mechanism remains unclear. Here we mainly employed orthotopic HCC models to explore on it. Mass cytometry depicted the immune contexture of orthotopic HCC syngeneic grafts, unveiling that the exogenous expression of β-catenin significantly increased the percentage of myeloid-derived suppressor cells (MDSCs) and decreased the percentage of CD8+ T-cells. Flow cytometry and immunohistochemistry further confirmed the findings. The protein microarray analysis, Western blot and PCR identified PF4 as its downstream regulating cytokine. Intratumorally injection of cytokine PF4 enhanced the accumulation of MDSCs. Knockout of PF4 abolished the effect of β-catenin on recruiting MDSCs. Chromatin immunoprecipitation and luciferase reporter assay demonstrated that β-catenin increases the mRNA level of PF4 via binding to PF4's promoter region. In vitro chemotaxis assay and in vivo administration of specific inhibitors identified CXCR3 on MDSCs as receptor for recruiting PF4. Lastly, the significant correlations across β-catenin, PF4 and MDSCs and CD8+ T-cells infiltration were verified in HCC clinical samples. Our results unveiled HCC tumor cell intrinsic hyperactivation of β-catenin can recruit MDSC through PF4-CXCR3, which contributes to the formation of immune "desert" phenotype. Our study provided new insights into the development of immunotherapeutic strategy of HCC with CTNNB1 mutation. This study identifies PF4-CXCR3-MDSCs as a downstream mechanism underlying CTNNB1 mutation associated immune "desert" phenotype. • Orthotopic HCC models rather than subcutaneous tumor models find more liver-specific alteration. • The abnormal accumulation of MDSCs was found in β-catenin-activating orthotopic HCC models. • PF4 as a downstream target of β-catenin was essential for β-catenin-mediated MDSC accumulation. • PF4 receptor CXCR3 was responsible for the recruitment of MDSCs by PF4 and β-catenin. [ABSTRACT FROM AUTHOR]

Molecular heterogeneity of hepatobiliary tumor including intertumoral and intratumoral disparity always leads to drug resistance. Here, seven hepatobiliary tumor organoids are generated to explore heterogeneity and evolution via single‐cell RNA sequencing. HCC272 with high status of epithelia‐mesenchymal transition proves broad‐spectrum drug resistance. By examining the expression pattern of cancer stem cells markers (e.g., PROM1, CD44, and EPCAM), it is found that CD44 positive population may render drug resistance in HCC272. UMAP and pseudo‐time analysis identify the intratumoral heterogeneity and distinct evolutionary trajectories, of which catenin beta‐1 (CTNNB1), glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), and nuclear paraspeckle assembly transcript 1 (NEAT1) advantage expression clusters are commonly shared across hepatobiliary organoids. CellphoneDB analysis further implies that metabolism advantage organoids with enrichment of hypoxia signal upregulate NEAT1 expression in CD44 subgroup and mediate drug resistance that relies on Jak‐STAT pathway. Moreover, metabolism advantage clusters shared in several organoids have similar characteristic genes (GAPDH, NDRG1 (N‐Myc downstream regulated 1), ALDOA, and CA9). The combination of GAPDH and NDRG1 is an independent risk factor and predictor for patient survival. This study delineates heterogeneity of hepatobiliary tumor organoids and proposes that the collaboration of intratumoral heterogenic subpopulations renders malignant phenotypes and drug resistance. [ABSTRACT FROM AUTHOR]

Background and aims: 4‐phenylbutyric acid (4‐PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown. Methods: 4‐PBA was administered alone or in combination with diethylnitrosamine to investigate its long‐term effect on liver tumorigenesis. The role of 4‐PBA in oncogene‐induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co‐expressed with hMet and β‐catenin point mutation (S45Y) was also observed. RNA‐seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4‐PBA on liver and validate the underlying mechanism. Results: 4‐PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b‐Fzd5 mediating β‐catenin signaling. Peroxisome proliferator‐activated receptors (PPAR)‐α induced by 4‐PBA was responsible for the activation of β‐catenin signaling. Thus, intervention of PPAR‐α reversed 4‐PBA‐induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4‐PBA could not only upregulate the expression of PPAR‐α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR‐α expression predicted poor prognosis in HCC patients. Conclusions: 4‐PBA could upregulate PPAR‐α to initiate LCSCs by activating β‐catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor‐promoting effect of 4‐PBA under HCC‐inducing environment. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is an aggressive malignancy of biliary tract with poor prognosis. Although several studies have shown the frequency of relevant genetic alterations, there are few genetic models or translational studies that really benefit for GBC treatment in the era of precision medicine. By targeted sequencing and immunohistochemistry staining, we identified that phosphate and tension homology deleted on chromosome ten (PTEN) was frequently altered in GBC specimens, and loss of PTEN expression was independently correlated with poor survival outcomes. Further drug screening assays revealed proteasome inhibitor bortezomib as a promising agent for GBC treatment, and knockdown of PTEN increased bortezomib efficacy both in vivo and in vitro. Therapeutic evaluation of patient derived xenografts (PDXs) strongly supported the utilization of bortezomib in PTEN deficient GBC. Mechanically, functional PTEN inhibited ARE-dependent transcriptional activity, the same machinery regulating the transcription of proteasome subunits, thus PTEN suppressed proteasome activity and bortezomib sensitivity. Through siRNA screening, we identified the ARE-related transcriptional suppressor BACH1 involved in PTEN-mediated proteasome inhibition and regulated by PTEN-AKT1 axis. In summary, our study indicates that proteasome activity represents a prime therapeutic target in PTEN-deficient GBC tumors, which is worthy of further clinical validation. [ABSTRACT FROM AUTHOR]

In a conventional quantum ( k, n) threshold scheme, a trusted party shares a quantum secret with n agents such that any k or more agents can cooperate to recover the original secret, while fewer than k agents obtain no information about the secret. Is the reconstructed quantum secret same with the original one? Or is the dishonest agent willing to provide a true share during the secret reconstruction? In this paper we reexamine the security of quantum ( k, n) threshold schemes and show how to construct a verifiable quantum ( k, n) threshold scheme by combining a qubit authentication process. The novelty of ours is that it can provide a mechanism for checking whether the reconstructed quantum secret is same with the original one. This mechanism can also attain the goal of checking whether the dishonest agent provides a false quantum share during the secret reconstruction such that the secret quantum state cannot be recovered correctly. [ABSTRACT FROM AUTHOR]

Anti-T-lymphocyte globulin (ATG) is frequently used in the induction regimen of renal transplantation, but its dose has not been standardized. In the present study, the efficacy of different ATG-Fresenius (ATG-F) doses was assessed in recipients of renal transplantation. A total of 131 adult recipients of renal transplantation who received ATG-F induction between August 2015 and July 2018 were included. The incidence of biopsy-confirmed acute rejection, graft function, as well as graft and patient survival within 12 months post-transplant, was assessed, and adverse events, including hematologic and infection-associated side effects, were compared between patients receiving a cumulative ATG-F dose of <7 or ≥7 mg/kg. The incidence of biopsy-confirmed acute rejection was similar between patients receiving cumulative doses of <7 and ≥7 mg/kg (7.5 vs. 4.7%, P=0.766). The incidence of infection within 12 months was lower in the ATG-F <7 mg/kg group compared with that in the ≥7 mg/kg group (26.9 vs. 50.0%, P=0.006), but the incidence of pneumonia did not differ between the ATG-F <7 and ≥7 mg/kg groups (10.4 vs. 20.3%, P=0.117). The incidence of urinary infection was higher in the ≥7 mg/kg group than in the <7 mg/kg group (20.4 vs. 7.46%, P=0.033), while the extent and duration of anemia and lymphopenia was similar between groups. There was no difference in graft function, delayed graft function, as well as overall and graft survival between the groups. In conclusion, a moderate reduction in the cumulative ATG-F dose was not associated with an increased risk of acute rejection, while the risk of infection was reduced. Optimization of the ATG-F dose for induction may facilitate the reduction of the risk of infection without compromising the induction efficacy in renal transplant recipients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Necroptosis is a form of programmed, caspase‐independent, cell death, mediated by receptor‐interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain‐like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan‐Raf inhibitor TAK‐632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK‐632 by targeting RIPK1 and RIPK3. Experimental Approach Cell viability was measured by MTT, propidium staining, or CellTiter‐Glo luminescent assays. Effects of TAK‐632 on necroptosis signalling pathways were investigated by western blotting, immunoprecipitation, and in vitro kinase assays. Downstream targets of TAK‐632 were identified by a drug affinity responsive target stability assay and a pull‐down assay with biotinylated TAK‐632. A mouse model of TNF‐α‐induced systemic inflammatory response syndrome (SIRS) was further used to explore the role of TAK‐632 in protecting against necroptosis‐associated inflammation in vivo. Key Results: TAK‐632 protected against necroptosis in human and mouse cells but did not protect cells from apoptosis. TAK‐632 directly bound with RIPK1 and RIPK3 to inhibit kinase activities of both enzymes. In vivo, TAK‐632 alleviated TNF‐induced SIRS. Furthermore, we performed a structure–activity relationship analysis of TAK‐632 analogues and generated SZM594, a highly potent inhibitor of RIPK1/3. Conclusions and Implications: TAK‐632 is an inhibitor of necroptosis and represents a new lead compound in the development of highly potent inhibitors of RIPK1 and RIPK3. [ABSTRACT FROM AUTHOR]

Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. Unlike apoptosis, necroptosis evokes inflammatory responses by releasing damage-associated molecular patterns. Recent studies suggest that tumor undergoes necroptosis in vivo and necroptosis has pro- or anti-tumoral effects in cancer development and progression. Furthermore, triggering necroptosis in tumor cells has been explored as a potential therapeutic strategy against cancer. Here, we will review the recent research progress of necroptosis in conferring anti- or pro-tumoral effects and its potential application in cancer therapy. [ABSTRACT FROM AUTHOR]

Kras mutations are among the most common genetic abnormalities in human neoplasms, including cholangiocarcinomas, pancreatic cancer and colon cancer. PTEN has previously been associated with cholangiocarcinoma development in murine models. Here, we have established novel mouse models of neoplasms by liver-specific and biliary-pancreatic Kras activation and PTEN deletion. By liver-specific disruption of PTEN and activation of Kras in mice caused rapid development of intrahepatic biliary epithelial proliferative lesions (Intrahepatic cholangiocarcinoma, ICC), which progress through dysplasia to invasive carcinoma. In contrast, Kras activation in combination with heterozygous PTEN deletion induced mixed carcinomas of liver (both ICC and hepatocellular carcinoma, HCC), whereas Kras activation alone did not induce biliary tract neoplasm. Use of Sox9-Cre-LoxP-based approach to coordinately delete PTEN and activate Kras in the adult mouse resulted in not only development of low-grade biliary lesions (ICC and extrahepatic bile duct carcinoma, ECC) but also pancreatic carcinomas. Our data provide a functional link between PTEN gene status, hepatobiliary cell fate, and HCC, biliary carcinoma, pancreatic cancer pathogenesis, and present novel genetically engineered mouse models of PTEN loss-driven malignancy. [ABSTRACT FROM AUTHOR]

Obesity is a major risk factor for hepatocellular carcinoma (HCC) and is typically accompanied by higher levels of serum dipeptidyl peptidase 4 (DPP4). However, the role of DPP4 in obesity-promoted HCC is unclear. Here, we found that consumption of a high-fat diet (HFD) promoted HCC cell proliferation and metastasis and led to poor survival in a carcinogen-induced model of HCC in rats. Notably, genetic ablation of DPP4 or treatment with a DPP4 inhibitor (vildagliptin) prevented HFD-induced HCC. Moreover, HFD-induced DPP4 activity facilitated angiogenesis and cancer cell metastasis in vitro and in vivo, and vildagliptin prevented tumor progression by mediating the pro-angiogenic role of chemokine ligand 2 (CCL2). Loss of DPP4 effectively reversed HFD-induced CCL2 production and angiogenesis, indicating that the DPP4/CCL2/angiogenesis cascade had key roles in HFD-associated HCC progression. Furthermore, concomitant changes in serum DPP4 and CCL2 were observed in 210 patients with HCC, and high serum DPP4 activity was associated with poor clinical prognosis. These results revealed a link between obesity-related high serum DPP4 activity and HCC progression. Inhibition of DPP4 may represent a novel therapeutic intervention for patients with HCC. [ABSTRACT FROM AUTHOR]

The simultaneous transformation and dissociation of minerals containing iron in reductive Bayer digestion of bauxite are important to separate iron minerals from red mud and thus reduce the waste solid disposal in alumina production. In order to better understand the reaction mechanism of iron and hematite in sodium aluminate solution, the phase composition, valence variation and micro-morphology of transformation products were studied by XRD, XPS, FT-IR and SEM respectively. The results show that the intermediate alumogoethite, α-Fe (1 − x) Al x OOH, preferentially forms by the reaction of HFeO 2 − and AlO 2 − and then converts to magnetite in Fe-Na 2 O-Al 2 O 3 -H 2 O system at digestion temperature of 533 K. Meanwhile, the transformation of hematite to magnetite in Fe-Fe 2 O 3 -Na 2 O-Al 2 O 3 -H 2 O system sequentially involves HFeO 2 − generation by dissolution of iron powder, HFeO 2 − diffusion to hematite particles, and magnetite formation on hematite particles by reaction of HFeO 2 − and hematite or dissolved FeO 2 − . Fe addition can prevent hematite particle from becoming much smaller by surface magnetization in reductive Bayer digestion compared with current industrial Bayer digestion. This work is conducive to develop a novel technology for efficiently processing high-iron diasporic bauxite. [ABSTRACT FROM AUTHOR]

Cancer cells display altered metabolic phenotypes characterized by a high level of glycolysis, even under normoxic conditions. Because of a high rate of glycolytic flux and inadequate vascularization, tumor cells often suffer from nutrient deficiency and require metabolic adaptations to address such stresses. Although tumor-initiating cells (T-ICs) have been identified in various malignancies, the cells' metabolic phenotypes remain elusive. In this study, we observed that liver T-ICs preferentially survived under restricted glucose treatment. These cell populations compete successfully for glucose uptake by preferentially expressing glucose transporters (GLUT1 and GLUT3), whereas inhibition of GLUT1 or GLUT3 abolished the survival advantage and suppressed the tumorigenic potential of liver T-ICs. Among signaling pathways related to T-ICs, IL-6/STAT3 was identified to be responsible for the elevation of glucose uptake in liver T-ICs under glucose limitation. Further investigation revealed that IL-6 stimulation upregulated GLUT1 and GLUT3 expressions in CD133+ cells, particularly during glucose deprivation. More importantly, inhibition of glucose uptake sensitized liver T-ICs to sorafenib treatment and enhanced the therapeutic efficacy in vivo. Our findings suggest that blocking IL-6/STAT3-mediated preferential glucose uptake might be exploited for novel therapeutic targets during hepatocellular carcinoma (HCC) progression. [ABSTRACT FROM AUTHOR]

Background & Aims Considerable evidence suggests that adrenergic signaling played an essential role in tumor progression. However, its role in hepatocellular carcinoma (HCC) and the underlying mechanisms remain unknown. Methods The effect of adrenaline in hepatocarcinogenesis was observed in a classical diethylnitrosamine-induced HCC mouse model. Effects of ADRB2 signaling inhibition in HCC cell lines were analyzed in proliferation, apoptosis, colony formation assays. Autophagy regulation by ADRB2 was assessed in immunoblotting, immunofluorescence and immunoprecipitation assays. In vivo tumorigenic properties and anticancer effects of sorafenib were examined in nude mice. Expression levels of ADRB2 and hypoxia-inducible factor-1α (HIF1α) in 150 human HCC samples were evaluated by immunohistochemistry. Results We uncovered that adrenaline promoted DEN-induced hepatocarcinogenesis, which was reversed by the ADRB2 antagonist ICI118,551. ADRB2 signaling also played an essential role in sustaining HCC cell proliferation and survival. Notably, ADRB2 signaling negatively regulated autophagy by disrupting Beclin1/VPS34/Atg14 complex in an Akt-dependent manner, leading to HIF1α stabilization, reprogramming of HCC cells glucose metabolism, and the acquisition of resistance to sorafenib. Conversely, inhibition of ADRB2 signaling by ICI118,551, or knockdown ADRB2 expression, led to enhanced autophagy, HIF1α destabilization, tumor growth suppression, and improved anti-tumor activity of sorafenib. Consistently, ADRB2 expression correlated positively with HIF1α in HCC specimens and was associated with HCC outcomes. Conclusions Our results uncover an important role of ADRB2 signaling in regulating HCC progression. Given the efficacy of ADRB2 modulation on HCC inhibition and sorafenib resistance, adrenoceptor antagonist appears to be a putative novel treatment for HCC and chemoresistance. Lay summary ADRB2 signaling played an essential role in sustaining hepatocellular carcinoma cell proliferation and survival. ADRB2 signaling negatively regulated autophagy, leading to hypoxia-inducible factor-1α stabilization, reprogramming of hepatocellular carcinoma cells glucose metabolism, and the acquisition of resistance to sorafenib. Adrenoceptor antagonist appears to be a putative novel treatment for hepatocellular carcinoma and chemoresistance. [ABSTRACT FROM AUTHOR]

Background & Aims We have previously reported that Shp2, a tyrosine phosphatase previously known as a pro-leukemogenic molecule, suppresses the initiation of hepatocellular carcinoma (HCC). However, the role of Shp2 in HCC progression remains obscure. Methods Shp2 expression was determined in human HCC using real-time PCR, immunoblotting and immunohistochemistry. Clinical significance of Shp2 expression was analyzed in 301 HCC tissues with clinico-pathological characteristics and follow-up information. Short hairpin RNA was utilized to investigate the function of Shp2 in hepatoma cell behavior. Role of Shp2 in HCC progression was monitored through nude mice xenograft assay. Kinase activity assay and co-immunoprecipitation were used for mechanism analysis. Results Elevated expression of Shp2 was detected in 65.9% (394/598) of human HCCs, and its levels were even higher in metastasized foci. Overexpression of Shp2 correlated well with the malignant clinico-pathological characteristics of HCC and predicted the poor prognosis of patients. Interference of Shp2 expression suppressed the proliferation of hepatoma cells in vitro and inhibited the growth of HCC xenografts in vivo . Down-regulation of Shp2 attenuated the adhesion and migration of hepatoma cells and diminished metastasized HCC formation in mice. Our data demonstrated that Shp2 promotes HCC growth and metastasis by coordinately activating Ras/Raf/Erk pathway and PI3-K/Akt/mTOR cascade. Moreover, down-regulation of Shp2 enhanced the sensitivity of hepatoma cells upon sorafenib treatment, and patients with low Shp2 expression exhibited superior prognosis to sorafenib. Conclusions Shp2 promotes the progression of HCC and may serve as a prognostic biomarker for patients. [ABSTRACT FROM AUTHOR]

BACKGROUND The functions of cytoskeleton-associated membrane protein 4 (CKAP4), one kind of type II transmembrane protein, are associated with the palmitoyl acyltransferase DHHC2. The objective of the current study was to investigate CKAP4/DHHC2 expression and its prognostic significance in patients with hepatocellular carcinoma (HCC). METHODS Two independent cohorts of 416 patients with HCC were enrolled. All the patients included had defined clinicopathologic and follow-up data. Using real-time polymerase chain reaction and immunohistochemical assay, CKAP4 and DHHC2 expression were evaluated. The association between CKAP4/DHHC2 expression and HCC-specific disease-free survival and overall survival was analyzed by Kaplan-Meier curves, the log-rank test, and Multivariate Cox regression analyses. RESULTS The data documented that CKAP4 expression was much higher in HCC tumor tissues compared with adjacent normal tissues and its expression was significantly correlated with tumor size, intrahepatic metastases, portal venous invasion, and Barcelona Clinic Liver Cancer stage of disease in 2 cohorts of patients. On survival analysis, patients with high CKAP4 expression appeared to have a favorable overall survival and a longer disease-free survival compared with those with low expression. DHHC2 expression was also examined in tissue microarray analysis by immunohistochemistry and the results demonstrated that 87.6% of the cases had low expression of DHHC2. Kaplan-Meier analysis indicated that a high level of DHHC2 expression predicted favorable overall survival and disease-free survival rates in both the training cohort and validation set. Furthermore, the combination of CKAP4 and DHHC2 was found to have a more powerful efficiency in prognosis prediction than either one alone. CONCLUSIONS To the best of our knowledge, the current study is the first to demonstrate that the expression of CKAP4 and its palmitoyl acyltransferase DHHC2 correlates with disease progression and metastasis in patients with HCC and may provide prognostic and therapeutic value. Cancer 2014;120:1520-1531. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background & Aims: Systemic chemotherapy serves as an adjuvant treatment for post-operation patients with hepatocellular carcinoma (HCC), and provides curative option for the patients with unresectable HCC. However, its efficiency is largely limited because of the high incidence of chemo-resistance. Increasing evidence has shown that tumor initiating cells (TICs) not only have the ability to self-renew and drive the initiation and progression of cancer, but also exhibit greater resistance to conventional chemo- and radio-therapies than non-TICs. It was the aim of this study to investigate the effects of ATRA with and without cisplatin on TIC differentiation and apoptosis in human HCC. Methods: In the present study, we evaluated the TICs of HCC cell differentiation induced by all-trans retinoic acid (ATRA), and developed a novel chemotherapeutic approach to HCC, by characterizing the function of combinatorial treatment with cis-diammineplatinum(II) (cisplatin) and ATRA in vitro and in vivo. Results: ATRA effectively induced differentiation of TICs, which potentiated the cytotoxic effects of cisplatin. The combinatorial treatment of ATRA acid and cisplatin reduced protein kinase B (AKT) (Thr308) phosphorylation, and promoted apoptosis of HCC cells more significantly than treatment with cisplatin alone. In addition, the combined treatment with the two drugs exerted stronger inhibition on either HCC cell migration in vitro or metastasis in vivo, when compared to the treatment with either drug alone. Conclusions: These results indicated that ATRA could significantly improve the effect of cisplatin, which is at least partially attributed to ATRA-induced differentiation of HCC TICs, and the subsequent decrease in this chemo-resistant subpopulation. [Copyright &y& Elsevier]

Background & Aims: Hepatocellular carcinoma (HCC) develops in response to chronic hepatic injury. Although induced cell death is regarded as the major component of p53 tumor-suppressive activity, we recently found that sustained p53 activation subsequent to DNA damage promotes inflammation-associated hepatocarcinogenesis. Here we aim at exploring the mechanism linking p53 activation and hepatic inflammation during hepatocarcinogenesis. Methods: p53−/− hepatocytes expressing inducible p53 and primary wild type hepatocytes were treated to induce p53 expression. The supernatants were collected and analyzed for the presence of released inflammatory cytokines. Ethyl pyruvate was used in a rat model of carcinogen-induced hepatocarcinogenesis to examine its effect on p53-dependent chronic hepatic injury, inflammation, and tumorigenesis. Results: Here we show that cytoplasmic translocation and circulating levels of potent inflammatory molecule high-mobility group protein 1 (HMGB1) were greater in wild type rats than in p53+/− rats following carcinogen administration. Restoration of p53 expression in p53-null hepatocytes or induction of endogenous p53 in wild type hepatocytes gives rise to the release of HMGB1. Administration of the HMGB1 release inhibitor ethyl pyruvate, which does not affect p53-mediated hepatic apoptosis, substantially prevented carcinogen-induced cirrhosis and tumorigenesis in rat livers. Conclusions: These results suggest that although p53 is usually regarded as a tumor suppressor, its constant activation can promote pro-tumorigenic inflammation, at least in part, via inducing HMGB1 release. Application of HMGB1 inhibitors when restoring p53 in cancer therapy might protect against pro-tumorigenic effects while leaving p53-mediated clearance of malignant cells intact. [Copyright &y& Elsevier]

Highlights: [•] CKAP4 was overexpressed in the majority of ICC cases. [•] CKAP4 was significantly associated with lymph node metastasis features. [•] CKAP4 was an independent predictor for overall survival for ICC. [Copyright &y& Elsevier]

Abstract: β-Catenin plays many critical roles during various liver physiological and pathological processes. However, the role of β-Catenin in acute liver failure remains unclear. Using hepatocyte specific β-Catenin knockout mice, we found that loss of β-Catenin in hepatocyte significantly reduced GalN/LPS-induced liver damage and hepatocyte apoptosis, but exacerbated Jo2-mediated liver injury. Mechanistically, the dual effects of β-Catenin attributes on its function of inhibiting NF-κB signaling, which aggravates oxidative stress but decreases Fas expression under injury conditions. In conclusion, β-Catenin plays an important role in regulating the balance between TNF-α and Fas-induced liver injury via its effect on NF-κB. [Copyright &y& Elsevier]

With the increase of pipelines, corrosion leakage accidents happen frequently. Therefore, nondestructive testing technology is important for ensuring the safe operation of the pipelines and energy mining. In this paper, the structure and principle of magnetic flux leakage (MFL) in-line inspection system is introduced first. Besides, a mathematic model of the system according to the ampere circuit rule, flux continuity theorem, and column coordinate transform is built, and the magnetic flux density in every point of space is calculated based on the theory of finite element analysis. Then we analyze and design the disposition of measurement section probes and sensors combining both three-axis MFL in-line inspection and multi-sensor fusion technology. Its advantage is that the three-axis changes of magnetic flux leakage field are measured by the multi-probes at the same time, so we can determine various defects accurately. Finally, the theory of finite element analysis is used to build a finite element simulation model, and the relationship between defects and MFL inspection signals is studied. Simulation and experiment results verify that the method not only enhances the detection ability to different types of defects but also improves the precision and reliability of the inspection system. [ABSTRACT FROM AUTHOR]

Summary: Portal vein tumor thrombus (PVTT) is strongly correlated to a poor prognosis for patients with hepatocellular carcinoma (HCC). In this study, we uncovered a causative link between hepatitis B virus (HBV) infection and development of PVTT. Mechanistically, elevated TGF-β activity, associated with the persistent presence of HBV in the liver tissue, suppresses the expression of microRNA-34a, leading to enhanced production of chemokine CCL22, which recruits regulatory T (Treg) cells to facilitate immune escape. These findings strongly suggest that HBV infection and activity of the TGF-β-miR-34a-CCL22 axis serve as potent etiological factors to predispose HCC patients for the development of PVTT, possibly through the creation of an immune-subversive microenvironment to favor colonization of disseminated HCC cells in the portal venous system. [Copyright &y& Elsevier]

Background & Aims: Accumulating evidence suggests the involvement of tumor-initiating cells (T-ICs) in cancer genesis, but whether liver T-ICs contribute to HCC invasion and metastasis remains unclear. Methods: OV6+ T-ICs were isolated from SMMC7721 and HuH7 cell lines by magnetic sorting. Characteristics of T-ICs were assessed by in vitro and mouse xenograft assays. Expression of OV6 was determined by immunostaining in specimens from 218 HCC patients, and Kaplan–Meier survival analysis was used to determine the correlation of OV6 expression with prognosis. Results: OV6+ T-ICs isolated from HCC cell lines not only possess a higher capacity to form tumor spheroids in vitro, but also had a greater potential to form tumors when implanted in non-obese diabetic/severe combined immunodeficient mice, suggesting their elevated self-renewal capacity and tumorigenicity. Moreover, OV6+ T-ICs exhibited more invasive and metastatic potentials both in vitro and in vivo. Patients with more OV6+ tumor cells were associated with aggressive clinicopathologic features and poor prognosis. CXCR4 is expressed at higher levels in OV6+ cells. Recombinant stromal cell-derived factor-1 (SDF-1) treatment expanded the OV6+ HCC T-ICs population, by sustaining the stem cell property of OV6+ cells. The SDF-1 effect was blocked by a specific CXCR4 inhibitor, AMD3100, or transfection of siRNA targeting CXCR4. Conclusions: OV6+ HCC cells may represent a subpopulation of T-ICs with augmented invasion and metastasis potential, which contribute to progression and metastasis of HCC. The SDF-1/CXCR4 axis also provides therapeutic targets for elimination of liver T-ICs. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: To investigate the molecular mechanisms whereby the Chinese medicinal compound Tongxinluo improves vascular endothelial function through studying the induction of endothelial nitric oxide synthase (eNOS) and its upstream signaling pathway. Materials and methods: Hyperhomocysteinemia was induced in Wistar rats by a methionine-rich diet followed by Tongxinluo treatment. The aorta ring was isolated for measuring vascular dilation of aorta and eNOS expression. Human umbilical vein endothelial cells (HUVECs) were transfected with AP-1, NF-κB, HRE or eNOS reporter plasmid followed by Tongxinluo exposure. Expression of the reporter genes was measured by luciferase assay. The level of eNOS was studied by western blot and the nitric oxide content was measured using the nitrate reductase method. HUVECs were also transiently transfected with the dominant negative mutant of HIF-1, PI-3K or Akt to explore the role of HIF and PI-3K/Akt pathway in eNOS induction by Tongxinluo. Results: Tongxinluo could significantly up-regulate the expression of eNOS in the aortic tissue and improve the endothelium-dependent vasodilation of the aorta ring. Additionally, Tongxinluo at various doses could significantly enhance the expression of HRE and eNOS reporter gene as well as up-regulate the protein level of eNOS. Meanwhile, Tongxinluo caused a dose-dependent increase in the NO content in the supernatant of HUVECs. Suppression of HIF-1 activation by DN-HIF or inhibition of PI-3K/Akt pathway by ΔP85 or DN-Akt both attenuated HRE reporter gene activation and eNOS induction by Tongxinluo. Conclusion: Tongxinluo, a compound Chinese traditional medicine, up-regulates the expression of eNOS via the PI-3K/Akt/HIF-dependent signaling pathway, thus improving the endothelium-dependent vasodilation. [Copyright &y& Elsevier]