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Background: Primary liver cancer, around 75%–85% are 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 re-shape 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 five-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

The ribosomal protein (RP)–MDM2 interaction is a p53 response pathway critical for preventing oncogenic c-MYC–induced tumorigenesis. To investigate whether the RP-MDM2-p53 pathway is a broad antioncogenic mechanism, we crossed mice bearing an MDM2C305F mutation, which disrupts RPL11 binding to MDM2, with mice expressing an oncogenic HrasG12V transgene. Interestingly, the MDM2C305F-mutant mice, which are hypersensitive to c-MYC–induced tumorigenesis, are not hypersensitive to oncogenic HrasG12V-induced tumorigenesis. Unlike c-MYC, which induces expression of RPL11, RAS overexpression leads to an increase in RPL23 mRNA and protein whereas RPL11 expression remains unchanged. The induction of RPL23 involves both MEK and PI3K signaling pathways and requires mTOR function. Increased expression of RPL23, which maintains binding to MDM2C305F mutant, correlates with increased p53 expression in MDM2C305F cells. Furthermore, RAS overexpression can induce p53 in the absence of p19ARF, and the induction can be abolished by downregulation of RPL23. Thus, although the RPL11–MDM2–p53 pathway coordinates with the p19ARF–MDM2–p53 pathway against oncogenic c-MYC–induced tumorigenesis, the RPL23–MDM2–p53 pathway coordinates with the p19ARF–MDM2–p53 pathway against oncogenic RAS-induced tumorigenesis. Cancer Res; 76(17); 5030–9. ©2016 AACR.

The supplemental file contains three supplemental figures (Figures S1-S3), their figure legends and additional methods not included in the manuscript. Figure S1 shows hematoxylin and eosin (H&E) staining of tumor free skin and melanomas from mice of all genotypes to demonstrate that the MDM2C305F mutation does not affect the pathophysiology of oncogenic RAS overexpression-induced tumorigenesis. Figure S2 is complementary to Figure 2 in the manuscript. It provides mRNA and protein expression of RPL23 and RPL11 in additional genotypes of mouse and MEFs. We tested RPL23 and RPL11 expression in response to RAS overexpression and MDM2C305F mutation. Additionally, Figures S2G-H show the raw data that is summarized in Figure 2J, and Figure S2I shows a summary of RPL11 half-life from the raw data in Figure S2G-H. This figure supports the notion that RPL23 mRNA and protein levels increase in response to RAS and MDM2C305F mutation and show that protein stability is unchanged in Mdm2m/m MEFs. Figure S3 is complementary to Figure 3 in the manuscript. These data show that the upregulation of RPL23 in response to RAS is conserved in a human cell line (HEK-293).

Background: The A-VENA criteria for distinguishing tumor portal vein thrombus(PVT) from bland PVT has not been validated. Methods: Clinical data from January 2018 to December 2021 of Hepatocellular Carcinoma (HCC) with PVT patients who underwent liver transplantation (LT) were retrospectively collected. The diagnostic performance of A-VENA criteria was analyzed by receiver operating characteristic (ROC) curve. Diagnostic factors for tumor PVT were evaluated by multivariable analysis. Modified criteria were proposed based on the results of multivariable analysis. Results: Of 49 HCC with PVT patients, 26 were pathologically confirmed as tumor PVT and 23 were confirmed as bland PVT. Tumor PVT group has a larger proportion of ‘AFP level >1000 ng/mL’ (61.5% vs 17.4%, P=0.002), ‘enhancement of PVT’ (92.3% vs 13.0%, P 400 ng/mL, enhancement of PVT, and adjacent to HCC were significant in multivariable analysis. The presence of ≥2 criteria of the three (AEA criteria) best characterized tumor PVT with an AUC of 0.978, 100% sensitivity, 95.7% specificity, 96.3% positive predictive value, and 100% negative predictive value. Conclusions: A-VENA criteria could accurately distinguish tumor PVT from bland PVT in LT candidates. Proposed AEA criteria (the presence of at least 2 of the following: AFP >400 ng/dL, PVT enhancement, and adjacent to HCC) is an alternative tool for the diagnosis of tumor PVT.

Fusarium oxysporum strain PkF01 is the causal agent of Polygonatum kingianum rhizome rot. Here, we report, for the first time, the genome assemblies of the F. oxysporum strain PkF01 using the PacBio Sequel system. We obtained a total base number of 51.27 Mb in 87 contigs. The number of scaffolds and scaffold N50 were 86 and 2.46 Mb, with a 47.55% GC content. The number of coding sequences was 17,265, with total length of 36.61 Mb, average length of 1.77 kb, and a gene density of 0.34 kb. A total of 11,447, 14,734, 10,759, and 4,434 genes were annotated using the Pfam, COG, GO, and KEGG databases, respectively. A total of 764, 335, 1,572, 216, 4,245, 1,591, 2,242, and 1,926 genes were annotated using the CAZy, CYP450, DFVF, CARD, PHI, SignalP, TCDB, and TMHMM databases, respectively. Collinearity analysis showed that the PkF01 genome shared more homologous genomic regions with F. oxysporum f. sp. lilii strain Fol39 than with F. oxysporum f. sp. lycopersici strain Fol4287, indicating that the PkF01 genome is more closely related to the Fol39 rather than the Fol4287 genome. The high-quality genome sequences of PkF01 will provide a valuable resource for not only investigating both the pathogenicity mechanism and host specificity in F. oxysporum but also exploring disease control measures. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Intracellular lipid accumulation is commonly seen in fibrotic livers, but its exact role in liver fibrosis remains elusive. Here, we established a multimodal nonlinear optical microscopy to quantitatively map distribution of biomolecules in fibrotic livers. Our data revealed that unsaturated triglycerides were predominantly accumulated in central vein area during liver fibrosis but not in portal vein area. Moreover, the lipid homeostasis was remarkably dysregulated in the late-stage compared to the early-stage fibrosis, including increased unsaturated triglycerides with decreased lipid unsaturation degree and decreased membrane fluidity. Such alterations were likely due to up-regulated lipogenesis, desaturation, and peroxidation, which consequently led to endoplasmic reticulum stress and cell death. Inspiringly, injured hepatocyte could be rescued by remodeling lipid homeostasis via either supply of unsaturated fatty acids or enhancement of membrane fluidity. Collectively, our study improves current understanding of the role of lipid homeostasis in fibrosis and open opportunities for treatment.

Mass spectrometry imaging (MSI) of lipids in biological tissues is useful for correlating molecular distribution with pathological results, which could provide useful information for both biological research and disease diagnosis. It is well understood that the lipidome could not be clearly deciphered without tandem mass spectrometry analysis, but this is challenging to achieve in MSI due to the limitation in sample amount at each image spot. Here we develop a multiplexed MS2 imaging (MS2I) method that can provide MS2 images for 10 lipid species or more for each sampling spot, providing spatial structural lipidomic information. Coupling with on-tissue photochemical derivatization, imaging of 20 phospholipid C=C location isomers is also realized, showing enhanced molecular images with high definition in structure for mouse brain and human liver cancer tissue sections. Spatially mapped t-distributed stochastic neighbor embedding has also been adopted to visualize the tumor margin with enhancement by structural lipidomic information.

Many autonomous vehicles and advanced driver-assistance systems are equipped with front-facing cameras that detect and track objects using deep-learning-based algorithms. However, the localization capability of monocular cameras is often overlooked. In this paper, a novel method for estimating the pixel-wise error in a detected object's location versus its ground truth is proposed. As the object moves away from the camera, the pixel errors are shown to be normally distributed with unique spreads along the image's vertical axis (y-pixel). The pixel error appears to be smaller as objects get farther away, while at the same distance range, objects have similar error distribution across the camera's horizontal view. The horizontal axis (x-pixel) error appears to be smaller while the distance moves further away. However, the x-pixel location along a constant y-pixel row has no impact on the error distribution. The estimated x and y-pixel error distributions can in turn be used to form a spatial error distribution for finding the location of a detected object within a certain confidence interval. The spatial errors are then projected onto the world coordinate system using a camera transformation matrix to give a more realistic sense of what this error means. The results show that location estimation using monocular cameras generates an elliptical error distribution around the object with a larger error in the y-pixel direction compared to the x-pixel direction. This error distribution can be important to fuse information from multiple range-detecting sensors as well as multi-vehicle and multi-object tracking. The uncertainty characterization for position measurement, as demonstrated in this paper is an essential element of tracking and, is sensor and algorithm dependent.

In spite of substantial technical improvements and conceptual revolutions in advanced liver surgery, there are still straitened circumstances that pose difficulties for in-situ liver resections. Ex-vivo liver resection and autotransplantation (ELRA) is a hybrid technique combining experiences from conventional liver surgery and liver transplantation. This technique is becoming more comprehensive and popular among leading centers recently.Short-term and long-term outcomes are now the focus of the technique after more than a decade of cumulative progress and technical evolution. As the 5-year survival nowadays reaches over 80%, this technique is believed to be beneficial for advanced tumors. In recent years, ELRA has been applied by more centers on larger scales, and the learning curve was set at 53 cases. Progresses in disease selection, surgical indications, individualized outflow reconstruction, or autograft implantation, management of co-morbidities (e.g., Budd-Chiari syndrome, caval and/or neighboring organ involvements, obstructive jaundice) propelled the development of the technique.This hybrid liver surgery will benefit for carefully selected patients presented with advanced benign diseases and well-differentiated malignancies.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. More than 30% of patients with diagnosed HCC have abnormally high expression of fibroblast growth factor receptor 4 (FGFR4). Currently, clinical trials for a variety of FGFR4-specific inhibitors have started. However, the effect of these inhibitors is not ideal, and it is necessary to find a drug combination to synergistically exert anti-tumor effects. We found strong correlations between FGFR4 and HCC clinicopathological characteristics in the present study. After grouping patients according to FGFR4 expression, the key gene signatures were inputted the drug-gene related databases, which predicted several potential drug candidates. More importantly, to achieve the reliable and high throughput drug cytotoxicity assessment, we developed an efficient and reproducible agarose hydrogel microwells to generate uniform-sized multicellular tumor spheroids, which provide better mimicry of conventional solid tumors that can precisely represent anticancer drug candidates’ effects. Using high content screening, we quickly evaluated the enhanced anti-tumor effects of these combinations. Finally, we demonstrated that Parthenolide is a potential drug that can significantly enhance the clinical efficacy of FGFR4 receptor inhibitors. In general, we offered a new therapeutic way for FGFR4 positive HCC patients.

BackgroundSurgical resection is a mainstay to treat hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) in east Asia. However, the postoperative recurrence rate is high. It is necessary to explore neo-adjuvant therapy to increase the surgical resection rate and improve overall survival. Evidence has shown that lenvatinib combined with PD-1 inhibitors is safe and effective in the treatment of advanced unresectable HCC. Radiotherapy is also an effective treatment method for PVTT and has a synergistic effect in combination with PD-1 inhibitors. Surgical resection after Lenvatinib and sintilimab combined with radiotherapy as a neoadjuvant treatment regimen may be a new exploration of HCC with PVTT, but there were not any reported.MethodsThis open-label, single-arm, prospective, multi-center Phase I trial will enroll 20 HCC patients with PVTT who have a resectable primary tumor and no extra-hepatic metastasis. Eligible patients will be given radiotherapy, 3Gy*10 fraction, and will receive lenvatinib 8-12mg once daily and sintilimab 200mg once every three weeks. Surgical resection will be performed 6-8 weeks after radiotherapy. The primary endpoint is safety (number of patients ≥3G TRAE) and the number of patients who complete pre-op treatment and proceed to surgery. The secondary study endpoints include Major Pathological Response (MPR), 1-year tumor recurrence-free rate, Objective Response Rate (ORR), Imaging-Pathology Concordance Rate (IPCR), PVTT regression rate, Median Overall Survival (OS) and Recurrence Free Survival (RFS).DiscussionThis trial may confirm that surgical resection following intensive neoadjuvant therapy can provide a safe and efficient regimen for BCLC stage C patients with PVTT.Clinical trial registrationhttps://clinicaltrials.gov/, identifier (NCT05225116).

Motivation Aberrant DNA methylation is strongly associated with heterogeneity in tumors. This study investigated the prognostic value of CpG island methylator phenotype in hepatocellular carcinoma (HCC). Results A total of 319 HCC samples with 21 121 CpG sites were included in this study and 215 disease-free survival (DFS) and overall survival (OS)-related CpG sites were identified. These CpG sites were divided into seven clusters by using consensus clustering method. Cluster 4, which constructed the prognostic prediction model as the seed cluster to evaluate survival risk for DFS and OS of HCC patients, had the lowest methylation level with the worse prognosis. The low-risk group patients had a significantly prolonged DFS and OS than the patients in the high-risk group (P = 0.008 and P Availability and implementation The code of the analysis is available at https://www.bioconductor.org. Supplementary information Supplementary data are available at Bioinformatics online.

Conventional single photon emission computed tomography (SPECT) relies on mechanical collimation whose resolution and sensitivity are interdependent, the best performance a SPECT system can attain is only a compromise of these two equally desired properties. To simultaneously achieve high resolution and sensitivity, we propose to use sensitive detectors constructed in a m ulti-l a yer in t e r spaced mosa ic d e tector s (MATRICES) architecture to accomplish part of the collimation needed. We name this new approach self-collimation. We evaluate three self-collimating SPECT systems and report their imaging performance: 1) A simulated human brain SPECT achieves 3.88% sensitivity, it clearly resolves 0.5-mm and 1.0-mm hot-rod patterns at noise-free and realistic count-levels, respectively; 2) a simulated mouse SPECT achieves 1.25% sensitivity, it clearly resolves 50- $\mu \text{m}$ and 100- $\mu \text{m}$ hot-rod patterns at noise-free and realistic count-levels, respectively; 3) a SPECT prototype achieves 0.14% sensitivity and clearly separates 0.3-mm-diameter point sources of which the center-to-center neighbor distance is also 0.3 mm. Simulated contrast phantom studies show excellent resolution and signal-to-noise performance. The unprecedented system performance demonstrated by these 3 SPECT scanners is a clear manifestation of the superiority of the self-collimating approach over conventional mechanical collimation. It represents a potential paradigm shift in SPECT technology development.

Meilong Wu,1,2,* Shizhong Yang,1,2,* Xiaobin Feng,1,2 Chengquan Li,1,2 Xiangchen Liu,1,2 Zhenyu Zhang,1,2 Ying Xiao,1,3 Chuchu Liu,4 Jiahong Dong1,2 1School of Clinical Medicine, Tsinghua University, Beijing, 100084, People’s Republic of China; 2Hepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, People’s Republic of China; 3Department of pathology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, People’s Republic of China; 4Hepato-pancreato-biliary Surgery of Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, Qinghai, 810001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiahong DongHepato-pancreato-biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, People’s Republic of ChinaTel/Fax +86-10-56118888Email dongjiahong@mail.tsinghua.edu.cnPurpose: Previous studies have shown that various preoperative inflammatory indicators can predict the prognosis of hepatocellular carcinoma (HCC), but the role of postoperative inflammatory indicators remains unclear. This study aimed to explore the prognostic value of postoperative inflammatory indicators and whether combining preoperative and postoperative inflammatory indicators can improve the predictive performance of the prognostic model.Patients and Methods: Eighty-eight patients with primary HCC were included in this study. A preoperative model, postoperative model, and combined model that integrated preoperative and postoperative inflammatory indicators were established. The prognostic value of the models was evaluated by the area under the curve of time-dependent receiver operating characteristic curves (td-AUC).Results: Multivariate analysis of preoperative and postoperative inflammatory indicators and clinicopathological indicators found that tumor number, alpha-fetoprotein (AFP) level, and the preoperative platelet-lymphocyte ratio (prePLR), preoperative prognostic nutritional index (prePNI), and postoperative neutrophil-lymphocyte ratio (postNLR) were independent prognostic factors for the disease-free survival. The prognostic efficacy of the postNLR at 2 years and 3 years was better than that of tumor number, AFP level, and the prePLR, and prePNI. The combined model had higher td-AUC values than the preoperative model, postoperative model, American Joint Committee on Cancer 8th edition stage, and Barcelona Clinic Liver Cancer stage at 2 years (0.814 vs 0.754, 0.765, 0.513 and 0.527, respectively), and 3 years (0.786 vs 0.749, 0.753, 0.509 and 0.529, respectively). The predictive performance of the combined model was better than that of the preoperative model, postoperative model, and traditional clinical stage.Conclusion: Postoperative inflammatory indicators were valuable prognostic indicators. The combination of preoperative and postoperative inflammatory indicators improved the predictive performance of the prognostic model. We should pay more attention to postoperative inflammatory indicators.Keywords: hepatocellular carcinoma, inflammation, postoperative, neutrophil-lymphocyte ratio, disease-free survival

Preoperative prediction of recurrence outcome in hepatocellular carcinoma (HCC) facilitates physicians’ clinical decision-making. Preoperative imaging and related clinical baseline data of patients are valuable for evaluating prognosis. With the widespread application of machine learning techniques, the present study proposed the ensemble learning method based on efficient feature representations to predict recurrence outcomes within three years after surgery. Radiomics features during arterial phase (AP) and clinical data were selected for training the ensemble models. In order to improve the efficiency of the process, the lesion area was automatically segmented by 3D U-Net. It was found that the mIoU of the segmentation model was 0.8874, and the Light Gradient Boosting Machine (LightGBM) was the most superior, with an average accuracy of 0.7600, a recall of 0.7673, a F1 score of 0.7553, and an AUC of 0.8338 when inputting radiomics features during AP and clinical baseline indicators. Studies have shown that the proposed strategy can relatively accurately predict the recurrence outcome within three years, which is helpful for physicians to evaluate individual patients before surgery.

Gastrodia elata BI. is an important cultivated medicinal plant in China. To analyze the genetic diversity and evolutionary relationship of the germplasm resources of G. elata, specific Single nucleotide polymorphism (SNP) markers were developed. SLAF analysis was used to compare 28 samples of the same G. elata cultivar. Plants from 4 different varieties or different habitats were collected to explore intraspecific variation and to lay a foundation for resource protection. This will facilitate improved variety breeding in future. In this study, Single nucleotide polymorphism (SNP) genetic variation and differentiation of G. elata f. glauca, G. elata f. viridis, and G. elata f. elata were analyzed using Specific-Locus Amplified Fragment Sequencing (SLAF-seq). A total of 75.95M reads with an average sequencing depth of 19.32 × and a mean Q30 of 91.71% were obtained. Based on the 19,675 polymorphic SLAF tags, 60,238 SNPs were identified and a subset of 22,737 SNPs with minor allele frequency > 0.05 and integrity > 0.5 were selected. A model-based analysis divided the accessions into two groups, wild type G. elata f. glauca and G. elata f. viridis groups. Phylogenetic analysis also clustered the samples into the two major groups. G. elata has high genetic diversity. Population diversity was highest in G. elata f. elata and lowest in G. elata f. viridis. Analysis of molecular variance (AMOVA) revealed significant variations within individuals (92.23%). This study provides new insights into the genetic variation and differentiation of G. elata, which can be exploited to improve existing commercial cultivars.

Tulbaghia violacea Harv. indigenous to southern African countries, is an herbaceous perennial bulbous plant belonging to the family Amaryllidaceae. It is a popular garden plant in China. This attractive plant is traditionally used as medicine and repellent (Kubec et al. 2002; Moodley et al. 2015). In June 2021, T. violacea plants showing typical tospovirus-like symptoms of chlorotic rings patterns, were found at the campus of Yunnan University of Chinese Medicine (Fig.S1). Disease incidence was about 11.0% during the field survey. Total RNA was extracted from symptomatic leaves of T. violacea plants using the TRIzol reagent (ambio, Carlsbad, CA). Reverse transcription (RT)-PCR was conducted to identify the virus using RNA extract as the template. The degenerate primers (dTospo-F2 and dTospo-R2) (Huang et al. 2018) were used to amplify the conserved regions of the orthotospoviral L RNA sequences. No amplification was obtained from extracts of two asymptomatic plants. The amplicons from four symptomatic samples were cloned into the pMD19-T vector (TaKaRa) and sequenced (three clones for each amplicon) by Tsingke (Shanghai, China). The obtained DNA fragments were determined to be 312 bp. The sequences from four symptomatic samples were identical (GenBank acc.no. OK258285) and shared the highest nucleotide identities (98.0%) with a corresponding sequence of segment L of impatiens necrotic spot virus (INSV) isolated (GQ336991) from Phalaenopsis amabilis in Yunnan province, China. To further confirm the INSV infection to T. violacea, the samples were analyzed with the specific primers for the N, NSs and NSm genes of INSV (Table S1), respectively. Amplicons of the expected size, 789 bp, 1344 bp and 912 bp, were produced, respectively. Amplicons were cloned and sequenced. The 789-bp N (ON529554) and 1344-bp NSs (ON529554) gene sequences had 99.1% and 99.3% nucleotide identities with the corresponding region of previously described INSV Phalenopsis isolate (GQ336989), respectively. The 912-bp NSm (ON529553) gene sequence shared 99.5% nucleotide identity with the corresponding region of INSV Phalenopsis isolate (GQ336990). Metavirome and Sanger sequencing were used to complete the genome of INSV from T. violacea. The leaves of the symptomatic sample were used to construct an rRNA-depleted library using Nextera XT reagents (Illumina, San Diego, CA). The library was subjected to RNA-Seq a NovaSeq 6000 platform (Illumina, San Diego, CA). A total of 33,193,233 quality-filtered reads were obtained using BBMAP (https://github.com/BioInfoTools/BBMapBBMap - Bushnell B. - sourceforge.net/projects/bbmap/). Among 161052 reads mapped to virus sequences, 151407 reads (read ratios 94.0%) were mapped to INSV. Three complete segments of INSV genome were determined to 8,778 nt (L segment, Acc. No. ON529552), 4,958 nt (M segment, Acc. No. ON529553), and 2,983 nt (S segment, Acc. No. ON529554) in length. These segments were validated by RT-PCR and Sanger sequencing. Three segments share nucleotide sequence identities of 99.6%, 99.3% and 98.9% with the L (GQ336991), M (GQ336990) and S segments (GQ336989) of INSV Phalenopsis isolate, respectively. The results of sequence comparisons showed no evidence of reassortment between INSV and another orthotospovirus. There was a report of tomato spotted wilt virus infecting T. violacea in Florida, USA (Dey et al. 2019). No other virus infecting T. violacea was reported. INSV has been reported to infect several economically important crops including Phalenopsis, pepper etc. in China (Chen et al. 2016). INSV-infected T. violacea not only losses landscaping value but also plays an important intermedia host role in the spread of INSV. Additional surveys and evaluation will be needed to understand the potential medicinal effect of this virus on this plant. To our knowledge, this is first report of INSV in T. violacea.

The complete genome sequence of a putative novel potyvirus, tentatively named "polygonatum mosaic-associated virus 1" (PMaV1), was sequenced from naturally infected Polygonatum cyrtonema Hua in China. PMaV1 has a typical genome organization of potyviruses with a single large open reading frame (nt 119-9448) that encodes a 3109-aa polyprotein that is predicted to be cleaved into 10 mature proteins by virus-encoded proteases. Pairwise comparisons revealed that PMaV1 shares 71.50% complete genome sequence identity with Polygonatum kingianum virus 4 and 80.00% amino acid sequence identity with Polygonatum kingianum virus 3 of the genus Potyvirus. Phylogenetic analysis indicated that PMaV1 clustered with other potyviruses and that it was most closely related to Polygonatum kingianum virus 3 and Polygonatum kingianum virus 4. These results suggest that PMaV1 is a new member of the genus Potyvirus of the family Potyviridae (Nucleotide sequence data reported are available in the GenBank databases under the accession number OP380926).

The complete genomic sequence of a new potyvirus was determined from Paris polyphylla var. yunnanensis. Its genomic RNA consists of 9571 nucleotides (nt) excluding the 3’ -terminal poly (A) tail, containing the typical open reading frame (ORF) of potyviruses and encoding a putative large polyprotein of 3061 amino acids. The virus shares 54.20-59.60% nt sequence identities and 51.80-57.90% amino acid sequence identities with other potyviruses. Proteolytic cleavage sites and conserved motifs of the potyviruses were identified in the polyprotein and within individual proteins. Phylogenetic analysis indicated that the virus was most closely related to lily yellow mosaic virus. The results suggest that the virus should be classified as a novel species within the genus Potyvirus, which we tentatively name “Paris yunnanensis mosaic chlorotic virus” (PyMNV).11Note: Nucleotide sequence data reported are available in the GenBank databases under the accession number no.ON871824.

A novel fijivirus, tentatively named “Sogatella furcifera reovirus” (SFRV), was detected in a Sogatella furcifera population collected from Yangon in Myanmar. The SFRV genome comprises 10 dsRNA segments encoding 11 putative proteins. The 11 ORFs and their encoded proteins has 49.1%-71.0% nucleotide and 30.5%-76.3% amino acid sequence identities with reference fijiviruses. SFRV is closest to Nilaparvata lugens reovirus in the phylogenetic tree based on the RdRP. Fijivirus-specific motifs were identified in the SFRV genome. Thus, according to the described species demarcation criteria, SFRV belongs to a new virus in the genus Fijivirus, family Reoviridae.

The complete genome sequence of a new potyvirus from Paris polyphylla var. yunnanensis was determined. Its genomic RNA consists of 9571 nucleotides (nt), excluding the 3'-terminal poly(A) tail, containing the typical open reading frame (ORF) of potyviruses and encoding a putative large polyprotein of 3061 amino acids. The virus shares 54.20%-59.60% nt sequence identity and 51.80%-57.90% amino acid sequence identity with other potyviruses. Proteolytic cleavage sites and conserved motifs of potyviruses were identified in the polyprotein and within individual proteins. Phylogenetic analysis indicated that the virus was most closely related to lily yellow mosaic virus. The results suggest that the virus should be classified as a member of a novel species within the genus Potyvirus, and we have tentatively named this virus "Paris yunnanensis mosaic chlorotic virus" (PyMCV).

Background and Aims Hepatitis B virus X (HBx) has been reported to be closely related to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). This study aimed to detect the expression pattern of HBx and explore whether HBx protein can promote HCC invasion and metastasis both in vivo and vitro. Methods HBx expression was detected in HCC tissues via immunochemistry. A recombinant adenovirus vector containing the HBx gene was constructed and transfected into the HCC cell line SMMC-7721. Wound healing, transwell migration, and invasion assays were performed to evaluate migration and invasion potentials. A splenic implant tumor nude mice model was established to confirm its invasion and metastatic abilities in vivo. Results The positive rate of HBx in HCC tissues was 67.89%. HBx overexpression significantly promoted the migration and invasion abilities of SMMC-7721 cells in vitro. The tumor model showed that splenic implant tumor volume and number of liver metastatic tumor nodes were significantly larger and higher in the HBx overexpression group than in the control group. Conclusions HBx is highly expressed in HCC tissues and promotes HCC invasion and metastasis both in vivo and vitro with oncogene activity, thereby suggesting that HBx can serve as a novel therapeutic target in HCC.

BACKGROUND: Hyperbilirubinemia is a major barrier to anti-tumor treatment in patients with end-stage primary liver cancer. However, no research has demonstrated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) in primary liver cancer patients with hyperbilirubinemia. This study investigated HAIC with a modified oxaliplatin, fluorouracil, and leucovorin (mFOLFOX) regimen. The efficacy and safety of the treatment regimen was evaluated and the optimal conditions for further anti-tumor treatments were identified. METHODS: A total of 34 patients with hyperbilirubinemia (with an elevation of more than three times the upper limit of normal range in total bilirubin) who were not candidates for surgery, transplantation, tyrosine kinase inhibitor therapy, nor immune checkpoint inhibitor (ICI) therapy, and who received HAIC with the mFOLFOX regimen were enrolled in this study. The laboratory indexes (total bilirubin, tumor markers, and blood count), quality of life [World Health Organization Quality of Life (WHOQOL)-100 score], adverse reactions [Common Terminology Criteria for Adverse Events (CTCAE)-5.0], and overall survival were analyzed. RESULTS: Between June 2017 and January 2021, 34 patients received a total of 81 cycles of HAIC after percutaneous transhepatic biliary drainage (PTBD). The total bilirubin (TBIL) decreased significantly at 1 month after the last cycle of HAIC (127.8 vs. 68.3 µmol/L; P

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To investigate the clinical feasibility of preoperative routine clinical dynamic Gd-EOB-DTPA-enhanced MRI alone to predict post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). 116 patients with HCC who underwent liver resection in Southwest Hospital from 2014 through 2017 were selected in this retrospective cohort study. The remnant function (RF) of the liver RFUR and RFRE15 were calculated by the sum of the uptake rate (UR) or relative enhancement at 15 min (RE15) from dynamic Gd-EOB-DTPA-enhanced MR images in the remnant liver regions, and standardized by standard liver volume (SLV) to generate sRFUR (standardized RFUR) and sRFRE15 (standardized RFRE15). Student’s t test or Mann–Whitney U test, logistic regression, and ROC analyses were used to test the associations of preoperative RFUR, sRFUR, RFRE15, sRFRE15, the remnant liver volume (RLV)/SLV, ICG retention rate at 15 min (ICG R15) and sRFICG-K [ICG clearance rate (ICG-K) × RLV/SLV] with PHLF. 28 patients were found to have PHLF, who showed lower RFUR, sRFUR, RFRE15, sRFRE15, RLV/SLV, sRFICG-K, and higher ICG R15 than patients without PHLF (p

BACKGROUND The aim was to evaluate the value of Tc-labeled galactosyl human serum albumin (Tc-GSA) with single-photon emission computerized tomography (SPECT) in the preoperative assessment of regional liver function and prediction of posthepatectomy liver failure (PHLF) in patients with hilar cholangiocarcinoma (hCCA). METHODS Patients with hCCA who underwent Tc-GSA SPECT/computed tomography (CT) before hepatectomy were included. The liver functional parameters of functional liver density (FLD) and predictive residual index (PRI) were calculated based on Tc-GSA SPECT/CT. PHLF was defined according to the International Study Group of Liver Surgery criteria. Univariate and multivariate analyses were used to analyze the risk factors for PHLF. The prediction of PHLF was calculated using receiver operating characteristic curve. RESULTS A total of 34 patients were included, 23 of whom underwent preoperative biliary drainage. FLD was significantly higher in patients with drained lobes than that in patients with undrained lobes (0.615 ± 0.190 versus 0.500 ± 0.211, P

Highlights • Liver injury is not very severe in pregnant COVID-19 patients. • Pregnant COVID-19 patients with liver injury had higher inflammation. • Newborns of COVID-19 patients with liver injury were negative for SARS-CoV-2., Liver injury is not very severe in pregnant COVID-19 patients. Pregnant COVID-19 patients with liver injury had higher inflammation than those without liver injury. All newborns delivered by pregnant COVID-19 patients with liver injury were negative for SARS-CoV-2.

Cholangiography is important for evaluating the resectability of hilar cholangiocarcinoma. This study evaluated Dyna-CT combined with direct cholangiography in the assessment of tumor extent and resectability of hilar cholangiocarcinoma. Sixteen patients with pathologically proven hilar cholangiocarcinoma who underwent preoperative biliary drainage and the Dyna-CT with direct cholangiography (percutaneous transhepatic cholangiography [PTC]) were included in this retrospective study. The image quality was compared with MRI cholangiography. An experienced radiologist and surgeon reviewed the image to evaluate the tumor extent for the involvement of extra- and intrahepatic ducts. The reader performance was evaluated by calculating sensitivity, specificity, and overall accuracy. Correlations were made with the resected specimens or surgical findings. All of the patients required biliary drainage, and the PTC procedure was performed successfully. No major complications were encountered. The Dyna-CT image processing can produce a precise three-dimensional overview of the biliary tree. The image quality score of the Dyna-CT was similar to the MRI cholangiography. The Dyna-CT had some advantage for more small branches. In addition, the shape-fitting of intrahepatic bile ducts was excellent. For image analysis, the overall accuracy for predicting the involvement of the bilateral secondary biliary confluences was 96.9%. Surgery showed good consistency with the Dyna-CT cholangiography. The Dyna-CT-based three-dimensional cholangiography is a new imaging method that can provide surgeons with three-dimensional and intuitive images of the biliary tree and provide useful information for evaluating the anatomical structure of the bile duct prior to surgery.

Chilli pepper (Capsicum annuum L.) is one of the most important crops in Yunnan Province, China. An orthotospovirus isolate 14YV855 was isolated from a diseased chilli pepper plant exhibiting yellow ringspots and necrosis on leaves in Shiping County, Honghe Hani and Yi Autonomous Prefecture, Yunnan Province in 2014. The complete genome sequence of 14YV855 was determined. The small, medium, and large RNAs are 3,428, 4,781, and 8,917 nucleotides long, respectively. The complete nucleocapsid (N) protein of 14YV855 shares a high amino acid identity of 84.8 to 89.9% to that of Capsicum chlorosis virus (CaCV), Groundnut bud necrosis virus (GBNV), Watermelon bud necrosis virus (WBNV), and Watermelon silver mottle virus (WSMoV), which is slightly less than the 90% identity threshold for the demarcation of new Orthotospovirus sp. Phylogenetic analyses revealed that the N protein and RNA-dependent RNA polymerase of 14YV855 are the most related to WSMoV, while the NSs, NSm, and Gn/Gc proteins are similar to those of GBNV. As expected, 14YV855 is serologically related to CaCV, GBNV, WBNV, and WSMoV when the monoclonal antibody against the N protein of WSMoV was used; however, 14YV855 can be distinguished from other orthotospoviruses by reverse-transcription PCR using the specific primers. Our results indicate that 14YV855 is a new Orthotospovirus sp. belonging to the WSMoV serogroup and is provisionally named Chilli yellow ringspot virus.

Background: Although minimally invasive pancreatic necrosectomy (MIPN) is a new invasive technique for necrotizing pancreatitis, it has some disadvantages. This study aimed to improve the debrideme...

Duloxetine (DLX) has been approved for the successful treatment of psychiatric diseases, including major depressive disorder, diabetic neuropathy, fibromyalgia and generalized anxiety disorder. However, since the usage of DLX carries a manufacturer warning of hepatotoxicity given its implication in numerous cases of drug-induced liver injuries (DILI), it is not recommended for patients with chronic liver diseases. In our previous study, we developed an enhanced human-simulated hepatic spheroid (EHS) imaging model system for performing drug hepatotoxicity evaluation using the human hepatoma cell line HepaRG and the support of a pulverized liver biomatrix scaffold, which demonstrated much improved hepatic-specific functions. In the current study, we were able to use this robust model to demonstrate that the DLX-DILI is a human CYP450 specific, metabolism-dependent, oxidative stress triggered complex hepatic injury. High-content imaging analysis (HCA) of organoids exposed to DLX showed that the potential toxicophore, naphthyl ring in DLX initiated oxidative stress which ultimately led to mitochondrial dysfunction in the hepatic organoids, and vice versa. Furthermore, DLX-induced hepatic steatosis and cholestasis was also detected in the exposed EHSs. We also discovered that a novel compound S-071031B, which replaced DLX’s naphthyl ring with benzodioxole, showed dramatically lower hepatotoxicities through reducing oxidative stress. Thus, we conclusively present the human-relevant EHS model as an ideal, highly competent system for evaluating DLX induced hepatotoxicity and exploring related mechanisms in vitro. Moreover, HCA use on functional hepatic organoids has promising application prospects for guiding compound structural modifications and optimization in order to improve drug development by reducing hepatotoxicity.

BackgroundRecent breakthroughs in cholangiocarcinoma (CCA) genomics have led to the discovery of many unique identifying mutations, of which HER2 has been found to be overexpressed specifically in cases of extrahepatic CCA. However, whether or not lapatinib (an oral tyrosine kinase inhibitor selective for inhibition of HER2), or a combination of lapatinib and gemcitabine, exerts inhibitory effects on HER2-overexpressed CCA is still unclear.MethodsThe effect of lapatinib and a lapatinib-gemcitabine combination treatment on CCA was determined using organoid and cell line models. Cell cycle arrest, apoptosis and proteins involving HER2-dependent downstream signaling pathways were analyzed to assess the effect of lapatinib on HER2+ CCA. The synergistic effect of lapatinib and gemcitabine was interpreted by docking analysis, ABCB1-associated ATPase assay, rhodamine transport assay and LC-MS/MS analyses.ResultsdFdCTP, the active metabolite of gemcitabine, is proved to be the substrate of ABCB1 by docking analysis and ATPase assay. The upregulation of ABCB1 after gemcitabine treatment accounts for the resistance of gemcitabine. Lapatinib exerts a dual effect on HER2-overexpressed CCA, suppressing the growth of CCA cells by inhibiting HER2 and HER2-dependent downstream signaling pathways while inhibiting ABCB1 transporter function, allowing for the accumulation of active gemcitabine metabolites within cells.ConclusionsOur data demonstrates that lapatinib can not only inhibit growth of CCA overexpressing HER2, but can also circumvent ABCB1-mediated chemoresistance after gemcitabine treatment. As such, this provides a preclinical rationale basis for further clinical investigation into the effectiveness of a combination treatment of lapatinib with gemcitabine in HER2-overexpressed CCA.

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.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.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.

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.

Intrahepatic cholangiocarcinoma (iCCA) is a complex malignancy carrying poor prognosis. Liver transplantation (LT) was historically contraindicated for iCCA, due to poor outcomes after LT. However, an increasing number of studies have challenged this premise, because LT alone or combined with neoadjuvant chemotherapy has achieved relatively satisfactory transplant outcomes in well selected iCCA cases. This current review based on existing clinical researches, evinced that LT might serve as a viable option in iCCA cases as follows: ① unresectable tumor restricted to 2 cm, along with context of chronic liver diseases; and ② unresectable tumor locally advanced within the liver (without extrahepatic metastasis or vascular invasion) but responses to tumor down-staging treatments (namely, systemic neoadjuvant therapy and/or locoregional therapy). On the contrary, it is recommended as contraindications in iCCA cases as follows: ① patients with tumor progression while waiting for a transplant (increase of diameter, macrovascular invasion, new nodules, escalation of carbohydrate antigen 19-9, or extrahepatic spread); ② patients with iCCA recurrence. Conclusively, tumor burden, tumor biology, and response to down-staging strategies should be taken into consideration before LT. Whereas, the concept of “locally advanced stage” remains to be defined in the future, especially the optimized combination of “maximum size of largest lesion”, “number of lesions”, with/without “tumor differentiation”, just like the Milan criteria which is widely used for hepatocellular carcinoma. Given the scarcity of donor organ, and also the debate about LT in iCCA, accurate consensus about LT for iCCA patients is still urgently warranted.

Virus diseases are the major limiting factors of chilli production in China. A virus isolate of chilli ringspot virus-Yunnan (ChiRSV-YN) from chilli (Capsicum annuum L.) showing mild mosaic, leaf crinkling, ringspot, and vein banding symptoms was recently identified in Yunnan, China. The electron microscopy confirmed the virus as a typical potyvirus having flexuous filamentous particles ca. 780 nm in length. Several chilli and tobacco varieties were tested through mechanical inoculation and found to be susceptible to the virus isolate ChiRSV-YN. The viral genome was sequenced through RNA sequencing. The complete genomic RNA of the isolate (GenBank Acc. No. KX258620) consisted of 9,652 nucleotides (nt) excluding the poly (A) tail at the 3′ end. The isolate contains a large ORF which encodes a polyprotein of 3,086 amino acids (aa) with Mr. of 349.21 kDa. It had a typical genomic organization of potyviruses. The complete nucleotide and polyprotein sequences of ChiRSV-YN had 87.6 and 93.2% identities with the ChiRSV-HN/14, respectively. The result showed ChiRSV-YN is a new isolate of ChiRSV and it is the first full-length genome characterization of ChiRSV in Yunnan, China. Understanding of the characteristics of this virus isolate might provide the basis for disease diagnosis and control in the future.

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.

ObjectiveTransarterial chemoembolization (TACE) stands for an ideal therapy for patients with intermediate stage HCC. This study was carried out to observe the effect of microparticles-transarterial chemoembolization (microparticles-TACE, m-TACE) on the immune function of hepatocellular carcinoma (HCC) patients by detecting the proportion of regulatory (Treg) cells in the peripheral blood of HCC patients before and after m-TACE, and to determine whether m-TACE has a positive regulatory effect on the immune function of HCC patients.Methods33 HCC patients treated with Gelatn Sponge Microparticles (GSMs-TACE) were enrolled. Flow cytometry was used to determine the proportion of Treg cells and CD4+/CD8+ T cells in peripheral blood of HCC patients 1 day before GSMs-TACE, 1 to 2 weeks and 3 to 5 weeks after GSMs-TACE, respectively.ResultsThe Tregs cell proportion of HCC patients was significantly higher than that of the healthy and cirrhosis controls and was associated with various clinical indicators of HCC patients. The Treg cell proportion in HCC patients with BCLC stage C was higher than that of stage B patients; The Treg cell proportion at 1 to 2 weeks postoperatively was 8.54 ± 1.27%, which was significantly lower than that before the GSMs-TACE. The Treg cell proportion at 3 to 5 weeks postoperatively was 7.59 ± 1.27%, which continued to decline. The ratio of CD4+/CD8+ T cells was 1.31 ± 0.56, 1.86 ± 0.73, 1.76 ± 0.58% (PConclusionThese results indicated that m-TACE could exert a positive regulatory effect on the anticancer immune function of HCC patients, which may be used in combination with immune adjuvant therapies to enhance the efficacy of HCC.

Rationale: Intraductal papillary neoplasm of the bile ducts (IPNB) is a relatively rare tumor that is clinically characterized by digestive symptoms. The concurrent occurrence of chronic disseminated intravascular coagulation (DIC) with thrombosis is an extremely rare combination, reported in patients with IPNB. The clinical features of chronic DIC include microangiopathic hemolytic anemia, thrombocytopenia, and hypofibrinogenemia. Here, we report the case of a mucin-producing IPNB patient with hematological abnormalities. Patient concerns: A 58-year-old male patient suffered from abdominal distension for more than 2 months with obstructive jaundice appearance. Abdominal contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography showed a neoplasm in the right hepatic lobe. Multiple intravascular fillings were found in the inferior vena cava, pulmonary artery, and right atrium. Anemia and hypofibrinogenemia were discovered through routine laboratory tests. The count of platelets began to decline 25 days after admission, while 1 month after hospitalization, the patient developed abdominal pain, fever, and shock. Diagnosis: Pathological examination demonstrated IPNB with a part of high-grade intraepithelial neoplasia. Cardiac and inferior vena cava emboli were diagnosed as thrombi without neoplastic cells. Immunohistochemically, tumor cells were positive for Vimentin (mesenchyme), CK7, CK19, MUC-1, MUC-5AC, MUC-6, S-100p (focal), Ki-67 (12%), and negative for Inhibin-α, ER, CK20, CEA, and MUC-2. Additionally, immunohistochemistry indicated that IPNB was a mucus-secretion gastric type. The laboratory tests confirmed the presence of chronic DIC. Interventions: The patient was given anticoagulant therapy before hepatectomy and right atrium thrombectomy was performed under cardiopulmonary bypass. Outcomes: After anticoagulant therapy, the levels of hemoglobin, platelet, and fibrinogen of the patient returned to normal. Hepatectomy and thrombus removal was successfully performed. Then, the patient was discharged 12 days after the operation. After 12 months of follow-up, the patient recovered well without any hematologic abnormalities and no signs of tumor recurrence were observed. Lessons: IPNB may cause hematological complications, which can be easily misdiagnosed. It is essential to pay particular attention to the hematological abnormalities of patients with IPNB. Early detection and differential diagnosis of chronic DIC and thrombosis are necessary. We note that anticoagulant therapy coupled with surgery is an effective strategy to treat these complications.