Search

Particle erosion induced by foreign object damage (FOD) is an important factor that restricts the working life of thermal barrier coatings (TBCs). A dense α-Al2O3overlay was prepared by magnetron sputtering and vacuum treatment on the surface of 7YSZ TBCs sprayed by plasma spray-physical vapor deposition (PS-PVD) to improve the erosion resistance of the TBCs. The FOD behavior of the TBCs was systematically studied and the interface of α-Al2O3/c-ZrO2was investigated by first principles calculations. The experimental results show that the erosion rates of the PS-PVD, atmospheric plasma spraying (APS), and electron beam-physical vapor deposition (EB-PVD) TBCs were 324, 248, and 139 μg/g, respectively, while the erosion rate of the Al2O3-modified PS-PVD TBCs was reduced to 199 μg/g. In addition, the highest interface adhesive energy of 3.88 J/m2observed in the top configuration model of Al2O3/ZrO2−O is much higher than that of ZrO2/Ni (2.011 J/m 2), which results in improved interface bonding performance.

In this article, a novel design concept for bandwidth enhancement and mutual-coupling (MC) reduction of a single quad-port cross-slot antenna with simultaneously co-polarized and dual-polarized radiation patterns is proposed and designed. Initially, the first-, second-, and third-order modes (CM1–CM3) of a dual-port single-slot antenna with co-polarized pattern are theoretically studied by using a characteristic mode analysis (CMA). The results demonstrate that when one port is excited, the electric-field null of the antenna could be shifted to another unexcited port by combining these three modes, thus reducing the MC between two ports under a co- polarized pattern. Then, the short-ended bridges are loaded across the slot, resulting to move resonant frequencies of its CM1–CM3 closely to each other. After that, the microstrip lines are selected to excite the slot antenna for wide impedance matching. In addition, the linear slot is bent in order to reduce the electrical length. With these arrangements, our proposed quad-port cross-slot antenna has gained the desired co- polarized and dual-polarized radiation patterns with low MC. Finally, our designed antenna prototype is fabricated and measured. The results indicate that the isolation bandwidth ( $\vert S_{11}\vert < -10$ dB and MC $ < -17$ dB) of our designed antenna is successfully extended to about 16.18% ranging from 4.83 to 5.68 GHz, becoming obviously widened compared to the traditional counterpart. Most importantly, both co- polarized and dual-polarized radiation patterns are independently realized under four ports while holding single layer, small thickness, single element, and stable radiation pattern simultaneously.

Sorafenib was first approved as the standard treatment for advanced hepatocellular carcinoma (HCC). Despite providing an advantage in terms of patient survival, sorafenib has shown poor clinical efficacy and severe side effects after long-term treatment. Thus, combination treatment is a potential way to increase the effectiveness and reduce the dose-limiting toxicity of sorafenib. Extracts of the seeds of Annona montanahave shown synergistic antitumor activity with sorafenib, and seven annonaceous acetogenins, including three new acetogenins, muricin P (2), muricin Q (3), and muricin R (4), were isolated from the extracts by bioguided fractionation and showed synergy with sorafenib. The structures of these compounds were determined using spectroscopic and chemical methods. Annonacin (1) and muricin P (2), which reduced intracellular ATP levels and promoted apoptosis, exhibited synergistic cytotoxicity with sorafenib in vitro. In vivo, annonacin (1) displayed synergistic antitumor activity by promoting tumor cell apoptosis. Moreover, the potential mechanism of annonacin (1) was predicted by transcriptomic analysis, which suggested that SLC33A1 is a potential target in HCC. Annonacin (1) might be a novel candidate for combination therapy with sorafenib against advanced HCC.

Graphical abstract:

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.

Immunotherapy, especially immune checkpoint inhibitors, is becoming a promising treatment for hepatocellular carcinoma (HCC). However, the response rate remains limited due to the heterogeneity of HCC samples. Molecular subtypes of HCC vary in genomic background, clinical features, and prognosis. This study aims to compare the immune profiles between HCC subtypes and find subtype-specific immune characteristics that might contribute to the prognosis and potential of immunotherapy. The immune profiles consist of immune-related genes, cytolytic activity, immune pathways, and tumor-infiltrating lymphocytes. HCC-c1 samples showed an overall higher activation level of immune genes and pathways, and this pattern was consistent in validation sets. We associated the difference in immune profiles with the activation level of cancer hallmarks and genomic mutations. There was a negative correlation between most of the metabolism pathway and immune-related pathways in HCC samples. CTNNB1/WNT signaling pathway mutation, one of the common mutations in HCC, appears to be associated with the expression of immune genes as well. These results reveal the difference of immune profiles between HCC subtypes and possible reasons and influence, which may also deepen our understanding of the carcinogenesis process.

During the converter process, it is crucial to automatically identify and record ladle numbers to track steel product quality and enhance automation levels. However, the steelmaking environment presents several challenges, including intricate ladle scheduling, varying lighting conditions, severe background interference, and significant disparities between manually spray-printed ladle number characteristics and publicly available datasets. The combination of these problems makes it challenging to perform accurate and real-time ladle number identification. In response, this article suggests an automatic ladle number recognition approach based on deep learning and image processing. First, a double-region object detection model based on YOLOv5 is employed to capture keyframe images of the ladle to be identified from the video stream. Then, a method that can enable the acquisition of an accurate region of ladle numbers in sophisticated industrial settings is proposed to address the distortion of numerical features caused by lighting variations and background interference in industrial environments. Last, leveraging the proprietary dataset found and a ladle number recognition model integrating CNN and multiframe image fusion is designed, developing multithreading design and image queue management to ensure real-time and accurate ladle number recognition. In this study, the video data of a steel plant is used for testing. Through testing 176 steelmaking production cycles, all ladle numbers are accurately identified prior to finishing charging molten iron, indicating the high accuracy and real-time capability of the recognition system.

The load rejection transient process of bulb turbine units is critical to safety of hydropower stations, and determining appropriate closing laws of guide vanes (GVs) and runner blades (RBs) for this process is of significance. In this study, we proposed a procedure to optimize the co-closing law of GVs and RBs by using computational fluid dynamics (CFD), combined with the design of experiment (DOE) method, approximation model, and genetic optimization algorithm. The sensitivity of closing law parameters on the histories of head, speed, and thrust was analyzed, and a two-stage GVs’ closing law associating with a linear RBs’ closing law was proposed. The results show that GVs dominate the transient characteristics by controlling the change of discharge. Speeding GVs’ first-stage closing speed while shortening first-stage closing time can not only significantly reduce the maximum rotational speed but also suppress the water hammer pressure; slowing GVs’ second-stage closing speed is conducive to controlling the maximum reverse axial force. RBs directly affect the runner force. Slowing RBs’ closing speed can further reduce the rotational speed and the maximum reverse axial force. The safety margin of each control parameter, flow patterns, and pressure pulsations of a practical hydropower station were all improved after optimization, demonstrating the effectiveness of this method.

Behavioral and clinical studies have revealed a critical role of substance P (SP) in aggression; however, the neural circuit mechanisms underlying SP and aggression remain elusive. Here, we show that tachykinin-expressing neurons in the medial amygdala (MeATac1neurons) are activated during aggressive behaviors in male mice. We identified MeATac1neurons as a key mediator of aggression and found that MeATac1→ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl) projections are critical to the regulation of aggression. Moreover, SP/neurokinin-1 receptor (NK-1R) signaling in the VMHvl modulates aggressive behaviors in male mice. SP/NK-1R signaling regulates aggression by influencing glutamate transmission in neurons in the VMHvl. In summary, these findings place SP as a key node in aggression circuits.

The free vibration responses are divergent based on a complex time-domain damping model. The traditional step by step integration method cannot be used to calculate the time-domain responses. Based on the theoretic solution that eliminates the divergent term for the complex damping model, the equivalent viscous damping model is proposed and the corresponding average acceleration method is realized in this paper. The numerical cases show that the calculated results of the equivalent viscous damped system are convergent, which are equal to the ones of the deleted divergent term based on the complex damping model. The correctness of the proposed method is verified, and the computational efficiency is high.

N6-methyladenosine (m6A) RNA methylation and its associated methyltransferase like 3 (METTL3) are involved in the development and maintenance of various tumors. The present study aimed to evaluate the cross-talk of METTL3 with glucose metabolism and reveal a novel mechanism for intrahepatic cholangiocarcinoma (ICC) progression. Real-time quantitative PCR, western blotting, and immunohistochemistry analyses suggested that METTL3 was highly expressed in ICC, which was correlated with poor patient prognosis. Immunoprecipitation sequencing of m6A-RNA showed that METTL3 upregulated m6A modification of NFAT5, which recruited IGF2BP1 for NFAT5 mRNA stabilization. Elevated expression of NFAT5 increased the expression of the gluconeogenesis-related genes GLUT1 and PGK1, resulting in enhanced aerobic glycolysis, proliferation, and tumor metastasis of ICC. Moreover, higher METTL3 expression was observed in tumor tissues of ICC patients with activated ICC glucose metabolism. Importantly, STM2457, a highly potent METTL3 inhibitor, which inhibited METTL3 activity and acted synergistically with gemcitabine, suggests that reprogramming RNA epigenetic modifications may serve as a potential therapeutic strategy. Overall, our findings highlighted the role of METTL3-mediated m6A modification of NFAT5 in activating glycolytic reprogramming in ICC and proposed that the METTL3/NFAT5 axis was a clinical target for the management of ICC chemoresistance by targeting cancer glycolysis.

ABSTRACTDrug resistance has greatly limited the clinical efficacy of lenvatinib in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of lenvatinib resistance remain largely undetermined. Further in-depth exploration of mechanisms underlying lenvatinib resistance is still required for the majority of HCC patients. In this study, an integrated unbiased whole-genome CRISPR-Cas9 screen with database analysis indicated LAPTM5 (lysosomal protein transmembrane 5) as the critical contributor to lenvatinib resistance in HCC. We revealed that LAPTM5 could promote intrinsic macroautophagic/autophagic flux by facilitating autolysosome formation to drive lenvatinib resistance. The upregulation of LAPTM5 in HCC was induced by both DNA hypomethylation and driver mutations like TP53. Inhibition of autolysosome formation by either hydroxychloroquine (HCQ) or LAPTM5 abrogation worked synergistically with lenvatinib to inhibit tumor growth. In HCC cell lines, patient-derived primary cell lines and organoids, as well as human HCC xenografts and immunocompetent mouse HCC model, the close association between LAPTM5 and sensitivity to lenvatinib was consistently verified. Importantly, in clinical HCC samples, where lenvatinib was used as the first line or adjuvant therapy, LAPTM5 expression negatively correlated with lenvatinib sensitivity, implying it as a biomarker to predict patient response to lenvatinib. In conclusion, the combinational therapy targeting autophagy represented a promising strategy to overcome lenvatinib resistance in HCC, and LAPTM5 expression could provide potential guidance for clinical interference.Abbreviationscld-CASP3: cleaved caspase 3; cld-PARP: cleaved PARP; DTP: drug tolerant persister; GO: Gene Ontology; GTEx: The Genotype-Tissue Expression; HCC: hepatocellular carcinoma; HCQ: hydroxychloroquine; IC50: half maximal inhibitory concentration value; KEGG: Kyoto Encyclopedia of Genes and Genomes; LAPTM5: lysosomal protein transmembrane 5; NT: non-targeting; PDC: patient-derived primary cell lines; PDO: patient-derived primary organoid; TCGA: The Cancer Genome Atlas.

Aphids form a tight and mutually beneficial symbiosis with their primary symbiont Buchnera aphidicola, which plays a prominent role in aphid nutrition metabolism. Here, we sequenced the genome of B. aphidicola from the wheat aphid Sitobion miscanthi and performed KEGG analysis of amino acid synthesis pathways based on our previously published S. miscanthi genome. The genome of B. aphidicola from S. miscanthi contained almost all genes of the valine (Val), leucine (Leu) and isoleucine (Ile) synthesis pathways; however, it lacked a branched-chain amino acid aminotransferase (ilvE) required in the pathways, but this gene was present in the S. miscanthi genome. Sequence analysis showed that the ilvE gene was highly conserved in aphids. ilvE was highly expressed in the 3rd and 4th instars of S. miscanthi and showed higher expression in the bacteriocyte than in other parts. After RNAi-mediated ilvE knockdown, the result showed a significant mortality and body weight losses. Meanwhile, the B. aphidicola relative abundance and the Val, Leu and Ile production decreased significantly after ilvE gene interference. These results indicate that ilvE is a “bridge” gene in the aphid genome, linking the metabolic relay between aphids and B. aphidicola and significantly affecting the vital life parameters of aphids, potentially by affecting Val, Ile and Leu production. Our study may provide a future direction for using key junctions of the metabolic relay between insects and endosymbionts as RNAi target loci to develop new strategies for agricultural pest control.

Nanozymes are nanomaterials with enzyme-mimetic activity. It is known that DNA can interact with various nanozymes in different ways, enhancing or inhibiting the activity of nanozymes, which can be used to develop various biosensors. In this work, we synthesized a photosensitive covalent–organic framework (Tph-BT) as a nanozyme, and its oxidase and peroxidase activities could be reversely regulated by surface modification of single-stranded DNA (ssDNA) for the colorimetric detection of UO22+. Tph-BT exhibits excellent oxidase activity and weak peroxidase activity, and it is surprising to find that the UO22+-specific DNA aptamer can significantly inhibit the oxidase activity while greatly enhancing the peroxidase activity. The present UO22+interacts with the DNA aptamer to form secondary structures and detaches from the surface of Tph-BT, thereby restoring the enzymatic activity of Tph-BT. Based on the reversed regulation effects of the DNA aptamer on the two types of enzymatic activities of Tph-BT, a novel “off-on” and “on-off” sensing platform can be constructed for the colorimetric analysis of UO22+. This research demonstrates that ssDNA can effectively regulate the different types of enzymatic activities of single COFs and achieve the sensitive and selective colorimetric analysis of radionuclides by the naked eye.

Background:Primary liver cancer, of which around 75–85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary:Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages:The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the “Health China 2030 Blueprint.”

The activation of nanoparticles (NPs) in the tumor microenvironment exerts synergistic therapeutic effects with chemotherapy against multiple cancers. In this study, an NP system prepared using biocompatible MIL-100 NPs was studied as an effective vehicle to deliver oxaliplatin for hepatocellular carcinoma treatment. The NPs were coated with polydopamine (PDA) and NH2-PEGTK-COOH and then loaded with oxaliplatin to create the multi-functional NP Oxa@MIL-PDA-PEGTK. Oxa@MIL-PDA-PEGTK is activated in the tumor microenvironment, causing the generation of cytotoxic reactive oxygen species (ROS) via the Fenton reaction and the release of the loaded oxaliplatin. In addition, under near-infrared (NIR) irradiation, Oxa@MIL-PDA-PEGTK can generate hyperthermia at tumor sites. Moreover, owing to the light-induced activation of the Oxa@MIL-PDA-PEGTK NPs, higher drug delivery efficiency, more precise targeted activation, and reduced off-target toxicity were observed in in vitro and in vivo experiments. Taken together, owing to its improved drug delivery efficiency and multi-functional activities, including the ability for targeted chemotherapy coupled with photothermal and chemodynamic therapy, Oxa@MIL-PDA-PEGTK may serve as a new approach for treating hepatocellular carcinoma.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as “the invasive zone”. We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs’ overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n= 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

This article proposes the necessity of reliable calibration of the high voltage impulse value and the difficulty for accurate metrology work. It outlines the problems for common linearity test methods for impulse voltage dividers and the recent research work in China for lightning impulse voltage dividers calibration.

Introduction:Lenvatinib plus an anti-PD-1 antibody has shown promising antitumor effects in patients with advanced hepatocellular carcinoma (HCC), but with clinical benefit limited to a subset of patients. We developed and validated a radiomic-based model to predict objective response to this combination therapy in advanced HCC patients. Methods:Patients (N= 170) who received first-line combination therapy with lenvatinib plus an anti-PD-1 antibody were retrospectively enrolled from 9 Chinese centers; 124 and 46 into the training and validation cohorts, respectively. Radiomic features were extracted from pretreatment contrast-enhanced MRI. After feature selection, clinicopathologic, radiomic, and clinicopathologic-radiomic models were built using a neural network. The performance of models, incremental predictive value of radiomic features compared with clinicopathologic features and relationship between radiomic features and survivals were assessed. Results:The clinicopathologic model modestly predicted objective response with an AUC of 0.748 (95% CI: 0.656–0.840) and 0.702 (95% CI: 0.547–0.884) in the training and validation cohorts, respectively. The radiomic model predicted response with an AUC of 0.886 (95% CI: 0.815–0.957) and 0.820 (95% CI: 0.648–0.984), respectively, with good calibration and clinical utility. The incremental predictive value of radiomic features to clinicopathologic features was confirmed with a net reclassification index of 47.9% (p< 0.001) and 41.5% (p= 0.025) in the training and validation cohorts, respectively. Furthermore, radiomic features were associated with overall survival and progression-free survival both in the training and validation cohorts, but modified albumin-bilirubin grade and neutrophil-to-lymphocyte ratio were not. Conclusion:Radiomic features extracted from pretreatment MRI can predict individualized objective response to combination therapy with lenvatinib plus an anti-PD-1 antibody in patients with unresectable or advanced HCC, provide incremental predictive value over clinicopathologic features, and are associated with overall survival and progression-free survival after initiation of this combination regimen.

Background:Hepatocellular carcinoma (HCC) is one of the most common malignancies in China. Most HCC patients are first diagnosed at an advanced stage, and systemic treatments are the mainstay of treatment. Summary:In recent years, immune checkpoint inhibitors have made a breakthrough in the systemic treatment of middle-advanced HCC, breaking the single therapeutic pattern of molecular-targeted agents. To better guide the clinical treatment for effective and safe use of immunotherapeutic drugs, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association has gathered multidisciplinary experts and scholars in relevant fields to formulate the “Chinese Clinical Expert Consensus on Immunotherapy for Hepatocellular Carcinoma (2021)” based on current clinical studies and clinical medication experience for reference in China. Key Messages:The consensus contained 17 recommendations, including the preferred regimen for first- and second-line immunotherapy, evaluation and monitoring before/during/after treatment, management of complications, precautions for special patients, and potential population for immunotherapy.

A new magnetic mesoporous As(III) adsorbent of Fe3O4@SiO2@Ce-ZrO2was prepared by solvothermal and sol-gel method. The core-shell adsorbent presented a high specific surface area (168.2 m2/g) and fast magnetic separation performance (5.37 A·m2/kg). Compared with Fe3O4@SiO2@ZrO2, the Ce-doped sample exhibited 12%-23% increase in As(III) uptake over pH 3-11, which was mainly attributed to the formation of bimetal M—O—As complexes. The coexisted and weakened As(III) adsorption, Ca2+worked oppositely, but the impact of Cl-and was negligible. The As(III) maximum adsorption capacity was 24.52 mg/g at 313 K with an initial As(III) concentration of 5 mg/L at pH 7, and its kinetics was well fitted by the pseudo-second-order model. Moreover, the adsorbent exhibited remarkable recyclability. It is suggested that Fe3O4@SiO2@Ce-ZrO2is a promising adsorbent for the advanced treatment of As(III) contaminated wastewater.

Exosomes, which are small extracellular vesicles, have been unveiled to carry circular RNAs (circRNAs). CircRNA paired-related homeobox 1 (circPRRX1) can be transferred by exosomes derived from gastric cancer cells. Here, we investigated the activity and mechanism of exosomal circPRRX1 in gastric tumorigenesis and radiation sensitivity. CircPRRX1, microRNA (miR)-596, and NF-κB activating protein (NKAP) were quantified by quantitative real-time PCR and immunoblotting. Cell proliferation, motility, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and transwell assays, respectively. Cell colony formation and survival were assessed by colony formation assays. Dual-luciferase reporter assays were performed to verify the direct relationship between miR-596 and circPRRX1 or NKAP. In-vivo xenograft studies were used to evaluate the role of exosomal circPRRX1 in tumor growth. Our data showed that circPRRX1 expression was elevated in human gastric cancer, and circPRRX1 could be transferred by exosomes from gastric cancer cells. Exosomal circPRRX1 affected cell proliferation, motility, invasion, and radiation sensitivity in vitroand tumor growth in vivo. Mechanistically, circPRRX1 directly regulated miR-596 expression, and exosomal circPRRX1 affected cell biological functions at least in part through miR-596. NKAPwas identified as a direct target and functionally downstream effector of miR-596. Exosomal circPRRX1 modulated NKAPexpression by acting as a competing endogenous RNA (ceRNA) for miR-596. Our findings suggest a new mechanism, the exosomal circPRRX1/miR-596/NKAPceRNA crosstalk, in regulating gastric tumorigenesis and radiation sensitivity.

Introduction:Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population. Methods:In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety. Results:As of April 8, 2021, 20 and 21 patients were enrolled into groups A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval [CI], 11.9–54.3) in group A and 14.3% (95% CI, 3.0–36.3) in group B. Median duration of response was not reached (95% CI, 3.3–not evaluable [NE]) in group A and was 9.0 months (95% CI, 7.9–NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4–5.5) and 4.1 months (95% CI, 1.5–NE), and median overall survival was 11.6 months (95% CI, 6.4–NE) and 14.3 months (95% CI, 8.2–NE) in groups A and B, respectively. Conclusion:Serplulimab plus HLX04 showed a manageable safety profile and promising antitumor activity in patients with previously treated advanced HCC.

This work presents a numerical investigation of the thermal—fluid—structure coupling behavior of the liquid natural gas (LNG) transported in the flexible corrugated cryogenic hose. A three-dimensional model of the corrugated hose structure composed of multiple layers of different materials is established and coupled with turbulent LNG flow and heat transfer models in the commercial software ANSYS Workbench. The flow transport behavior, heat transfer across the hose layers, and structural response caused by the flow are analyzed. Parametric studies are performed to evaluate the impacts of inlet flow rate and thermal conductivity of insulation material on the temperature and structural stress of the corrugated hose. The study found that, compared with a regular operating condition, higher inlet flow velocities not only suppress the heat gain of the LNG but also lower the flow-induced structural stress. The insulation layer exhibits excellent performance in maintaining the temperature at the fluid-structure interface, showing little temperature change with respect to material thermal conductivity and ambient temperature. The simulation results may contribute to the research and design of the flexible corrugated cryogenic hoses and provide guidance for safer and more efficient field operations.

Numerous recent studies have shown that myeloid-derived suppressor cells (MDSCs), a strongly heterogeneous population of immunosuppressive cells, are dysregulated in the presence of many cancers. MDSCs present different phenotypes and play prominent roles in the tumor microenvironment. To date, gene therapies targeting MDSCs are the most innovative and flexible methods to specifically modify the tumor microenvironment. Here, we summarize current studies related to the phenotypes, functions, and mechanisms of MDSCs and explore the therapeutic landscape of chemokines that affect the balance between subpopulations of MDSCs.

In this research, high-strength stainless steel (HSSS) wires with ECC were used to strengthen the RC columns to take full advantage of two reinforcement materials and increase the ductility, load-carrying capacity, and durability of strengthened columns. To study strengthened columns’ properties under large eccentric compression, seven specimens were devised and examined with various strengthening schemes, initial eccentricity, and reinforcement ratios of longitudinal HSSS wires. The experimental results showed a significant improvement in the performances of RC columns strengthened with HSSS wire-ECC than those RC columns strengthened only with ECC. These improvements included higher load-carrying capacity, better flexibility, excellent cracking control, satisfactory failure patterns, etc. Specifically, the RC column SCH4–0.3 reinforced with HSSS wire-ECC showed an increase in cracking load and peak load by 129.6 % and 120.4 %, respectively, compared to the original reinforced concrete column (ORC). Additionally, compared to the ECC-reinforced RC column, SCH4–0.3 showed increases of 34.8 % and 67.2 % in cracking load and peak load, respectively. In addition, the ductility of RC columns reinforced with HSSS wire-ECC (SCH3–0.4, SCH4–0.4, and SCH5–0.4) was increased by 53 %-78 % compared with ORC columns. Moreover, the cracking and peak loads of the RC column SCH4–0.3 reinforced with HSSS wire-ECC were 129.6 % and 120.4 % higher than those of the ORC column, and 34.8 % and 67.2 % greater than those of the ECC- ECC-strengthened RC column, respectively. In addition, the ductility of RC columns reinforced with HSSS wire-ECC (SCH3–0.4, SCH4–0.4, and SCH5–0.4) was increased by 53 %-78 % than that of unreinforced specimen ORC. The surface cracking of RC columns strengthened with HSSS wire-ECC was also more uniform. As the relative initial eccentricity improved (0.3–0.5), peak and crack loads of reinforced RC columns decreased. The peak loads of specimens SCH4–0.3 and SCH4–0.4 increased by 77 % and 38.8 %, respectively, compared with those of specimen SCH4–0.5. The results showed that the load-carrying capacity and ductility of RC columns strengthened with HSSS wire-ECC were significantly improved. Based on the distribution of strain and destroy form analyses, mechanical mechanism and the calculation procedure of normal section force of RC columns strengthened with HSSS wire-ECC were proposed. The calculated results and the measurement data were consistent and could be applied to reinforcement engineering practice.

Graphical Abstract:

Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) is increasingly used for the treatment of primarily unresectable colorectal liver metastases (CRLM) because of the insufficient future liver remnant (FLR). The aim of this study was to share our experience with ALPPS for advanced CRLM and review the role of ALPPS in the management of patients with CRLM.

ABSTRACTAlcoholic liver disease (ALD) denotes a series of liver diseases caused by ethanol. Recently, immune-related genes (IRGs) play increasingly crucial role in diseases. However, it’s unclear the role of IRGs in ALD. Bioinformatic analysis was used to discern the core immune-related differential genes (IRDGs) in the present study. Subsequently, Cell Counting Kit-8 say, oil red O staining, and triglyceride detection were employed to explore optimal experimental conditions of establishing hepatocellular models of early ALD. Ultimately, real-time reverse transcription-PCR and immunohistochemistry/immunocytochemistry methods were adopted to verify the expressions of mRNA and proteins of core IRDGs, respectively. C-X-C Motif Chemokine Ligand 1 (Cxcl1) and Cxcl6were regarded as core IRDGs via integrated bioinformatics analysis. Besides, Lieber Decarli Ethanol feeding and 200 mM and 300 mM ethanol stimulating L02 cells for 36 h can both successfully hepatocellular model. In ethanol groups, the levels of CXCL1 and CXCL6 mRNA were significantly upregulated than pair-fed groups (P < 0.0001). Also, immunohistochemistry revealed that positive particles of CXCL1 and CXCL6 in mice model of early ALD were obviously more than control groups (P < 0.0001). Besides, in L02 hepatocytes stimulated by ethanol, CXCL1 and CXCL6 mRNA were over-expressed, compared with normal L02 cells (P < 0.0001). Meanwhile, immunocytochemistry indicated that CXCL1 and CXCL6 proteins in hepatocellular model of early ALD were higher than normal L02 hepatocytes stimulus (P < 0.0001). Ethanol promoted the upregulation of Cxcl1and Cxcl6mRNA and proteins in models of early ALD, denoting their potentiality of acting as biomarkers of ALD.

Cancer stem cells (CSCs) drive tumor initiation, progression, metastasis, and drug resistance. We report here that programmed cell death ligand 1 (PD-L1) is constitutively expressed in cancer cells to maintain and expand CSC through a novel mechanism in addition to promoting cancer cell immune evasion. We discovered that PD-L1 interacts with receptor Frizzled 6 to activate β-catenin signaling and increase β-catenin-targeted gene expression, such as a putative stem cell marker leucine-rich-repeat-containing G-protein-coupled receptor 5. Blockage of PD-L1 function, using a specific small hairpin RNA or a specific antibody, inhibits disease progression by reducing the CSC population in both colorectal and breast tumors. Moreover, β-catenin conversely regulates PD-L1 expression through a β-catenin complex binding site in the PD-L1 promoter. Our discoveries reveal that besides assistant tumor cell immune escaping, PD-L1 and β-catenin signaling form a positive feedback loop to promote cancer progression through CSC maintenance and expansion.

Portal vein tumor thrombus (PVTT) is very common and it plays a major role in the prognosis and clinical staging of hepatocellular carcinoma (HCC). We have published the first version of the guideline in 2016 and revised in 2018. Over the past several years, many new evidences for the treatment of PVTT become available, especially for the advent of new targeted drugs and immune checkpoint inhibitors which have further improved the prognosis of PVTT. So, the Chinese Association of Liver Cancer and Chinese Medical Doctor Association revised the 2018 version of the guideline to adapt to the development of PVTT treatment. Future treatment strategies for HCC with PVTT in China would depend on new evidences from more future clinical trials.

A charge density wave (CDW) is a collective quantum phenomenon in metals and features a wavelike modulation of the conduction electron density. A microscopic understanding and experimental control of this many-body electronic state in atomically thin materials remain hot topics in materials physics. By means of material engineering, we realized a dimensionality and Zr intercalation induced semiconductor–metal phase transition in 1T-ZrX2(X = Se, Te) ultrathin films, accompanied by a commensurate 2 × 2 CDW order. Furthermore, we observed a CDW energy gap of up to 22 meV around the Fermi level. Fourier-transformed scanning tunneling microscopy and angle-resolved photoemission spectroscopy reveal that 1T-ZrX2films exhibit the simplest Fermi surface among the known CDW materials in TMDCs, consisting only of a Zr 4d derived elliptical electron conduction band at the corners of the Brillouin zone.

IMPORTANCE: KRAS variants are associated with tumor progression; however, the prevalence of KRAS variant subtypes and their association with survival and recurrence in patients with intrahepatic cholangiocarcinoma (ICC) after curative resection are largely unknown. OBJECTIVE: To explore the prognostic association of KRAS variant subtypes with survival and recurrence in patients with ICC. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, patients who underwent curative resection for ICC from January 2009 through December 2016 at a single hospital in China were recruited, and whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify KRAS variants. Kaplan-Meier and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Data were analyzed from April 2020 to January 2021. INTERVENTIONS: Hepatectomy in patients with ICC. MAIN OUTCOMES AND MEASURES: The association of KRAS variant subtypes with OS and DFS. RESULTS: Of 1024 included patients with ICC, 621 (60.6%) were male, and the mean (SD) age was 59.2 (10.2) years. A total of 14 different subtypes of KRAS somatic variants affecting 127 patients (12.4%) were identified. G12D was the most frequent allele in this cohort, accounting for 55 of 127 identified KRAS variants (43.3%), followed by G12V (25 [19.7%]), G12C (9 [7.1%]), and G13D (8 [6.3%]). Compared with patients with wild-type KRAS, patients with variant KRAS were more likely to have high levels of carbohydrate antigen 19-9 (92 of 127 [72.4%] vs 546 of 897 [60.9%]; P = .01) and γ-glutamyltransferase (72 of 127 [56.7%] vs 420 of 897 [46.8%]; P = .04). Multivariable analysis revealed that G12 KRAS variants but not non-G12 KRAS variants were independently associated with worse OS (hazard ratio [HR], 1.69; 95% CI, 1.31-2.18; P &lt; .001) and DFS (HR, 1.47; 95% CI, 1.16-1.88; P = .002). Among the patients with G12 KRAS variants, the G12V KRAS variant was the strongest prognostic determinant for the worst OS (HR, 3.05; 95% CI, 1.94-4.79; P &lt; .001) and DFS (HR, 1.79; 95% CI, 1.13-2.85; P = .01). CONCLUSIONS AND RELEVANCE: In this cohort study, the distribution of KRAS variant subtypes was characterized in a large cohort of patients with ICC from China. The presence of G12 KRAS variants but not non-G12 KRAS variants was associated with worse survival and increased risk of recurrence. Patients with the G12V variant exhibited the worst outcomes in the whole cohort.

The wheat aphid, Sitobion miscanthi, is one of the most destructive pests of wheat plants in the temperate regions of China. Little is known about the genetic structure evolution of the different geographic populations of S. miscanthiwith its migration. In this study, we investigated the population genetic structure and demographic history of S. miscanthiby analysing 18 geographical populations across China using one mitochondrial gene, COI; one nuclear gene, EF-1α; and two endosymbiont Buchneragenes, gndand trpA. Analysis of data from the various groups showed high haplotype diversity and low nucleotide variation. SAMOVA analysis did not find a correlation between genetic distance and geographic distance. However, areas with high population diversity exhibited high haplotype diversity. Therefore, we speculate that there are two main natural migration pathways of S. miscanthiin China. One is from Yunnan to the Sichuan Basin, and the other is from Wuhan, Xinyang and Jiaodong Peninsula areas to the northwest. Based on this hypothesis, we inferred that these aphid populations appear first in the southwestern and southern regions and spread to the north with the help of the southeastern and southwestern monsoons, which occur in spring and summer. In autumn, the aphids spread southward with the northeastern and northwestern monsoons.

Background: Laparoscopic liver resection (LLR) has now been established as a safe and minimally invasive technique that is deemed feasible for treating hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). However, the role of LLR in treating combined hepatocellular-cholangiocarcinoma (cHCC-CC) patients has been rarely reported. This study aimed to assess the efficacy of LLR when compared with open liver resection (OLR) procedure for patients with cHCC-CC. Methods: A total of 229 cHCC-CC patients who underwent hepatic resection (34 LLR and 195 OLR patients) from January 2014 to December 2018 in Zhongshan Hospital, Fudan University were enrolled and underwent a 1:2 propensity score matching (PSM) analysis between the LLR and OLR groups to compare perioperative and oncologic outcomes. Overall survival (OS) and recurrence-free survival (RFS) parameters were assessed by the log-rank test and the sensitivity analysis. Results: A total of 34 LLR and 68 OLR patients were included after PSM analysis. The LLR group displayed a shorter postoperative hospital stay (6.61 vs.8.26 days; p value&lt; 0.001) when compared with the OLR group. No significant differences were observed in the postoperative complications’ incidence or a negative surgical margin rate between the two groups (p value= 0.409 and p value= 1.000, respectively). The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory indicators in the LLR group were significantly lower than those in the OLR group on the first and third postoperative days. Additionally, OS and RFS were comparable in both the LLR and OLR groups (p value= 0.700 and p value= 0.780, respectively), and similar results were obtained by conducting a sensitivity analysis. Conclusion: LLR can impart less liver function damage, better inflammatory response attenuation contributing to a faster recovery, and parallel oncologic outcomes when compared with OLR. Therefore, LLR can be recommended as a safe and effective therapeutic modality for treating selected cHCC-CC patients, especially for those with small tumors in favorable location.

The aim of this study was to identify novel prognostic mRNA and microRNA (miRNA) biomarkers for hepatocellular carcinoma(HCC) using methods in systems biology. Differentially expressed mRNAs, miRNAs, and long non-coding RNAs (lncRNAs) were compared between HCC tumor tissues and normal liver tissues in The Cancer Genome Atlas (TCGA) database. Subsequently, a prognosis-associated mRNA co-expression network, an mRNA–miRNA regulatory network, and an mRNA–miRNA–lncRNA regulatory networkwere constructed to identify prognostic biomarkers for HCC through Cox survival analysis. Seven prognosis-associated mRNA co-expression modules were obtained by analyzing these differentially expressed mRNAs. An expression module including 120 mRNAs was significantly correlated with HCC patient survival. Combined with patient survival data, several mRNAs and miRNAs, including CHST4, SLC22A8, STC2, hsa-miR-326, and hsa-miR-21 were identified from the network to predict HCC patient prognosis. Clinical significance was investigated using tissue microarray analysis of samples from 258 patients with HCC. Functional annotation of hsa-miR-326 and hsa-miR-21-5p indicated specific associations with several cancer-related pathways. The present study provides a bioinformatics method for biomarker screening, leading to the identification of an integrated mRNA–miRNA–lncRNA regulatory network and their co-expression patterns in relation to predicting HCC patient survival.

Background:Hepatocellular carcinoma (HCC) is the most common type of liver cancer and causes many cancer-related deaths worldwide; in China, it is the second most prevalent cause of cancer deaths. Most patients are diagnosed clinically with advanced stage disease. Summary:For more than a decade, sorafenib, a small-molecular-weight tyrosine kinase inhibitor (SMW-TKI) was the only molecular targeted drug available with a survival benefit for the treatment of advanced HCC. With the development of novel TKIs and immune checkpoint inhibitors for advanced HCC, the management of patients has been greatly improved. However, though angiogenic-based targeted therapy remains the backbone for the systemic treatment of HCC, to date, no Chinese guidelines for novel molecular targeted therapies to treat advanced HCC have been established. Our interdisciplinary panel on the treatment of advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists, radiologists, pathologists, orthopedic surgeons, traditional Chinese medicine physicians, and interventional radiologists has reviewed the literature in order to develop updated treatment regimens. Key Messages:Panel consensus statements for the appropriate use of new molecular -targeted drugs including doses, combination therapies, adverse reaction management as well as efficacy evaluation, and predictions for treatment of advanced HCC with evidence levels based on published data are presented, thereby providing an overview of molecular targeted therapies for healthcare professionals.

Plasma SARS-CoV-2 RNA may represent a viable diagnostic alternative to respiratory RNA levels, which rapidly decline after infection. Quantitative PCR with reverse transcription (RT–qPCR) reference assays exhibit poor performance with plasma, probably reflecting the dilution and degradation of viral RNA released into the circulation, but these issues could be addressed by analysing viral RNA packaged into extracellular vesicles. Here we describe an assay approach in which extracellular vesicles directly captured from plasma are fused with reagent-loaded liposomes to sensitively amplify and detect a SARS-CoV-2 gene target. This approach accurately identified patients with COVID-19, including challenging cases missed by RT–qPCR. SARS-CoV-2-positive extracellular vesicles were detected at day 1 post-infection, and plateaued from day 6 to the day 28 endpoint in a non-human primate model, while signal durations for 20–60 days were observed in young children. This nanotechnology approach uses a non-infectious sample and extends virus detection windows, offering a tool to support COVID-19 diagnosis in patients without SARS-CoV-2 RNA detectable in the respiratory tract.

To investigate the status quo and influencing factors of general postpartum well-being in primiparas, analyze its correlation with postpartum depression, and provide a theoretical foundation for enhancing the postpartum well-being of primiparas. From the start of November 2021 to the end of December 2021, the General Information Questionnaire, General Well-Being Scale, and the Edinburgh Postpartum Depression Scale were used to survey primiparas in a tertiary hospital, and the correlation between general well-being and postpartum depression was analyzed. We surveyed a total of 225 primiparas. The average score for general well-being in primiparas was 77.84 ± 6.83, and the total score for postpartum depression was 9.11 ± 2.51. Confinement location, planned pregnancy, pregnancy complications, neonatal sex, medical expenses, etc, had statistically significant effects on the general well-being scores (P < .05), whereas per capita monthly income, pregnancy complications, maternal and infant care skills, and medical expenses had statistically significant effects on postpartum depression scores (P < .05). Postpartum depression scores were negatively correlated with general well-being, health anxiety, energy, sad or happy mood, relaxation, and tension. There is a negative correlation between the general well-being of primiparas and postpartum depression, suggesting that in clinical care, the focus should be on primiparas with pregnancy complications, and psychological counseling should be provided in advance to prevent postpartum depression and the resulting decrease in well-being.

DnaJ homolog subfamily A member 3 (DNAJA3), also known as the tumorous imaginal disc (Tid1), is shown to be crucial in T cell development. DNAJA3 functions as a tumor suppressor implicated in lymphocyte development and survival. However, the role of DNAJA3 in B cell development and immune function remains unknown. In this study, we utilized a mouse model of B cell-specific DNAJA3 knockout (CD19-Cre/+; DNAJA3flx/flx) to investigate the physiological function of DNAJA3 in B cell development and immune function.

Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.

Background: The concurrent presence of liver cirrhosis and hepatocellular carcinoma (HCC) poses a challenge for laparoscopic surgeons to establish a routine practice. The aim of this study was to gather evidence and produce recommendations on the safe and effective practice of laparoscopic hepatectomy for patients with solitary HCC (=?5 cm) and liver cirrhosis. Methods: Between October 2013 and October 2014, 356 curative hepatectomies were performed for patients pathologically diagnosed with solitary HCC (=?5 cm) accompanied by cirrhosis (stage 4 fibrosis). To overcome selection bias, a 1:2 match using propensity score matching analysis was conducted between laparoscopic and open hepatectomy. Perioperative outcomes were compared between the groups, including hospitalization, operation time, blood loss, and surgical complications. Perioperative inflammation-based markers, including systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were collected from medical records and analyzed. Results: There were 43 and 77 patients in the laparoscopic and open groups, respectively. The laparoscopic group had less hepatic inflow occlusion (16.3% vs. 61%; P?&lt;?0.001), shorter operation time (155 vs. 170 min; P?=?0.004), and shorter postoperative hospital stay (4 vs. 7 days; P?&lt;?0.001). Although the difference was not significant (P?=?0.154), the rate of postoperative complications tended to be lower in the laparoscopic group (2.3%) compared with the open group (9.1%). The increase in postoperative SII, NLR, and LMR for laparoscopic hepatectomy were significantly lower than for open hepatectomy. NLR?&lt;?5.8 on postoperative day 3 was significantly correlated with shorter hospital stay (P?&lt;?0.001). Conclusions: Compared with open hepatectomy, laparoscopic hepatectomy for selected HCC patients, even in the presence of cirrhosis, might result in better perioperative outcomes and postoperative inflammatory response attenuation, and ultimately promote faster recovery. This provides evidence for considering routine laparoscopic hepatectomy through careful selection of patients with HCC.