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Epigenetic regulations play crucial roles in leukemogenesis and leukemia progression. SUV39H1 is the dominant H3K9 methyltransferase in the hematopoietic system, and its expression declines with aging. However, the role of SUV39H1 via its-mediated repressive modification H3K9me3 in leukemogenesis/leukemia progression remains to be explored. We found that SUV39H1 was down-regulated in a variety of leukemias, including MLL-r AML, as compared with normal individuals. Decreased levels of Suv39h1 expression and genomic H3K9me3 occupancy were observed in LSCs from MLL-r-induced AML mouse models in comparison with that of hematopoietic stem/progenitor cells. Suv39h1 overexpression increased leukemia latency and decreased the frequency of LSCs in MLL-r AML mouse models, while Suv39h1 knockdown accelerated disease progression with increased number of LSCs. Increased Suv39h1 expression led to the inactivation of Hoxb13 and Six1, as well as reversion of Hoxa9/Meis1 downstream target genes, which in turn decelerated leukemia progression. Interestingly, Hoxb13 expression is up-regulated in MLL-AF9-induced AML cells, while knockdown of Hoxb13 in MLL-AF9 leukemic cells significantly prolonged the survival of leukemic mice with reduced LSC frequencies. Our data revealed that SUV39H1 functions as a tumor suppressor in MLL-AF9-induced AML progression. These findings provide the direct link of SUV39H1 to AML development and progression.

Most cases of hepatocellular carcinoma (HCC) are already advanced at the time of diagnosis, which limits treatment options. Challenges in early‐stage diagnosis may be due to the genetic complexity of HCC. Gene fusion plays a critical function in tumorigenesis and cancer progression in multiple cancers, yet the identities of fusion genes as potential diagnostic markers in HCC have not been investigated. Here, we employed STAR‐Fusion and identified 43 recurrent fusion events in our own and four public RNA‐seq datasets. We identified 2354 different gene fusions in two hepatitis B virus (HBV)‐HCC patients. Validation analysis against the four RNA‐seq datasets revealed that only 1.8% (43/2354) were recurrent fusions. Comparison with the four fusion databases demonstrated that 19 recurrent fusions were not previously annotated to diseases and three were annotated as disease‐related fusion events. Finally, we validated six of the novel fusion events, including RP11‐476K15.1‐CTD‐2015H3.2, by RT‐PCR and Sanger sequencing of 14 pairs of HBV‐related HCC samples. In summary, our study provides new insights into gene fusions in HCC and may contribute to the development of anti‐HCC therapy. Hepatocellular carcinoma (HCC) has a complex genetic background. This article explores the fusion landscape of HCC and validates potential fusions using publicly available RNA‐seq datasets. Here, we unveil several novel and recurrent fusions in HCC, suggesting their potential as diagnostic markers or molecular therapeutic targets.

It has been proved that noncoding RNA （ncRNA） genes are much more numerous than expected. However, it remains a difficult task to identify ncRNAs with either computational algorithms or biological experiments. Recent reports have suggested that ncRNAs may also appear in the expressed sequence tags （EST＇s） database. Nevertheless, intergenic ESTs have received little attention and are poorly annotated owing to their low abundance. Here, we have developed a computational strategy for discovering ncRNA genes from human ESTs. We first collected ESTs that are located in the intergenic regions and do not have detailed annotations. The intergenic regions were divided into non-overlapping 50-nt windows and PhastCons scores obtained from the UCSC database were assigned to these windows. We kept conserved windows that had PhastCons scores of over 0.8 and that had at least three supporting ESTs to act as seeds. Each cluster of ESTs corresponding to the seeds was assembled into a long contig. We used two criteria to screen for ncRNA transcripts from these contigs： the first was that the longest predicted open reading frame was less than 300 nt and the second was that the likely Pol-II promoters exist within 2 000 nt upstream or downstream of the contigs. As a result, 118 novel ncRNA genes were identified from human low abundance ESTs. Of seven randomly selected candidates, six were transcribed in human 2BS cells as shown by RT-PCR. Our work proves that the EST is a ＇hidden treasure＇ for detecting novel ncRNA genes.

Background The quantity of metastases lesions is an important reference when it comes to making a more informed treatment decision for patients with colorectal cancer liver metastases. However, the molecular alterations in patients with different numbers of lesions have not been systematically studied. Methods We investigated somatic alterations and microsatellite instability (MSI) of liver metastases from patients with single, multiple or diffuse metastasis lesions. A new algorithm “Pathway Damage Score” was developed to comprehensively assess the functional impact of somatic alterations at the pathway level. Pathogenic pathways of different metastasis were identified and their prognosis effects were evaluated. Furthermore, the subnetworks and affected phenotypes of the altered genes in each pathogenic pathway were analyzed. Results Somatic alterations and altered genes occurred sporadically as well as in MSI state in different metastasis types, although MSS patients had more metastatic lesions than that of the MSI patients. Every metastasis group has their own pathogenic pathways and damaged “Cargo recognition for clathrin‐mediated endocytosis” is significantly associated with poor prognosis (P < 0.001). Further pathway subnetwork analysis showed that except conventional drivers, other genes could also contribute to metastasis formation. Conclusions Progression of liver metastasis could be driven by the coefficient of all altered genes belonging to the pathways. Thus, compared to somatic alterations and genes, pathway level analysis is more reasonable for functional interpretations of molecular alterations in clinical samples. Different quantity metastasis lesions of colorectal cancer liver metastasis are driven by different pathogenic pathways. All altered genes，rather than tumor driver genes in the pathways, could play roles in the formation of different metastases.

Eukaryotic cells make many types of primary and processed RNAs that are found either in specific subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic subcellular localizations are also poorly understood. Because RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell’s regulatory capabilities are focused on its synthesis, processing, transport, modification and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three-quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations, taken together, prompt a redefinition of the concept of a gene. A description is given of the ENCODE effort to provide a complete catalogue of primary and processed RNAs found either in specific subcellular compartments or throughout the cell, revealing that three-quarters of the human genome can be transcribed, and providing a wealth of information on the range and levels of expression, localization, processing fates and modifications of known and previously unannotated RNAs. ENCODE: the transcription landscape These authors describe the ENCODE (Encyclopedia of DNA Elements) effort to provide a complete catalogue of primary and processed RNAs found either in specific sub-cellular compartments or throughout the cell. They show that three-quarters of the human genome can be transcribed, and provide a wealth of information about the range and levels of expression, localization, processing fates and modifications of both known and previously unannotated RNAs. Collectively, these observations suggest that the current concept of a gene should be revisited.

Content-based histopathological image retrieval (CBHIR) has become popular in recent years in the domain of histopathological image analysis. CBHIR systems provide auxiliary diagnosis information for pathologists by searching for and returning regions that are contently similar to the region of interest (ROI) from a pre-established database. While, it is challenging and yet significant in clinical applications to retrieve diagnostically relevant regions from a database that consists of histopathological whole slide images (WSIs) for a query ROI. In this paper, we propose a novel framework for regions retrieval from WSI-database based on hierarchical graph convolutional networks (GCNs) and Hash technique. Compared to the present CBHIR framework, the structural information of WSI is preserved through graph embedding of GCNs, which makes the retrieval framework more sensitive to regions that are similar in tissue distribution. Moreover, benefited from the hierarchical GCN structures, the proposed framework has good scalability for both the size and shape variation of ROIs. It allows the pathologist defining query regions using free curves according to the appearance of tissue. Thirdly, the retrieval is achieved based on Hash technique, which ensures the framework is efficient and thereby adequate for practical large-scale WSI-database. The proposed method was validated on two public datasets for histopathological WSI analysis and compared to the state-of-the-art methods. The proposed method achieved mean average precision above 0.857 on the ACDC-LungHP dataset and above 0.864 on the Camelyon16 dataset in the irregular region retrieval tasks, which are superior to the state-of-the-art methods. The average retrieval time from a database within 120 WSIs is 0.802 ms.

Most hepatocellular carcinoma (HCC) patients are diagnosed at advanced stages and suffer limited treatment options. Challenges in early stage diagnosis may be due to the genetic complexity of HCC. Gene fusion plays a critical function in tumorigenesis and cancer progression in multiple cancers, yet the identities of fusion genes as potential diagnostic markers in HCC have not been investigated.Paired-end RNA sequencing was performed on noncancerous and cancerous lesions in two representative HBV-HCC patients. Potential fusion genes were identified by STAR-Fusion in STAR software and validated by four publicly available RNA-seq datasets. Fourteen pairs of frozen HBV-related HCC samples and adjacent non-tumor liver tissues were examined by RT-PCR analysis for gene fusion expression.We identified 2,354 different gene fusions in the two HBV-HCC patients. Validation analysis against the four RNA-seq datasets revealed only 1.8% (43/2,354) as recurrent fusions that were supported by public datasets. Comparison with four fusion databases demonstrated that three (HLA-DPB2-HLA-DRB1, CDH23-HLA-DPB1, and C15orf57-CBX3) out of 43 recurrent gene fusions were annotated as disease-related fusion events. Nineteen were novel recurrent fusions not previously annotated to diseases, including DCUN1D3-GSG1L and SERPINA5-SERPINA9. RT-PCR and Sanger sequencing of 14 pairs of HBV-related HCC samples confirmed expression of six of the new fusions, including RP11-476K15.1-CTD-2015H3.2.Our study provides new insights into gene fusions in HCC and could contribute to the development of anti-HCC therapy. RP11-476K15.1-CTD-2015H3.2 may serve as a new therapeutic biomarker in HCC.

Whether extended lymphadenectomy for right colon cancer leads to increased perioperative complications or improves survival is still controversial. This trial aimed to compare the efficacy and safety of complete mesocolic excision (CME) versus D2 dissection in laparoscopic right hemicolectomy for patients with right colon cancer. This article reports the early safety results from the trial. This randomised, controlled, phase 3, superiority, trial was done at 17 hospitals in nine provinces of China. Eligible patients were aged 18–75 years with histologically confirmed primary adenocarcinoma located between the caecum and the right third of the transverse colon, without evidence of distant metastases. Central randomisation was done by means of the Clinical Information Management-Central Randomisation System via block randomisation (block size of four). Patients were randomly assigned (1:1) to CME or D2 dissection during laparoscopic right colectomy. Central lymph nodes were dissected in the CME but not in the D2 procedure. Neither investigators nor patients were masked to their group assignment but the quality control committee were masked to group assignment. The primary endpoint was 3-year disease-free survival, but the data for this endpoint are not yet mature; thus, only the secondary outcomes—intraoperative surgical complications and postoperative complications within 30 days of surgery, graded according to the Clavien-Dindo classification, mortality (death from any cause within 30 days of surgery), and central lymph node metastasis rate in the CME group only—are reported in this Article. This early analysis of safety was preplanned. The outcomes were analysed according to a modified intention-to-treat principle (excluding patients who no longer met inclusion criteria after surgery or who did not have surgery). This study is registered with ClinicalTrials.gov, NCT02619942. Study recruitment is complete, and follow-up is ongoing. Between Jan 11, 2016, and Dec 26, 2019, 1072 patients were enrolled and randomly assigned. After exclusion of 77 patients, 995 patients were included in the modified intention-to-treat population (495 in the CME group and 500 in the D2 dissection group). The postoperative surgical complication rate was 20% (97 of 495 patients) in the CME group versus 22% (109 of 500 patients) in the D2 group (difference, −2·2% [95% CI −7·2 to 2·8]; p=0·39); the frequency of Clavien-Dindo grade I–II complications were similar between groups (91 [18%] vs 92 [18%], difference, −0·0% [95% CI −4·8 to 4·8]; p=1·0) but Clavien-Dindo grade III−IV complications were significantly less frequent in the CME group than in the D2 group (six [1%] vs 17 [3%], −2·2% [−4·1 to −0·3]; p=0·022); no deaths occurred in either group. Of the intraoperative complications, vascular injury was significantly more common in the CME group than in the D2 group (15 [3%] vs six [1%], difference, 1·8 [95% CI 0·04 to 3·6]; p=0·045). Metastases in the central lymph nodes were detected in 13 (3%) of 394 patients who underwent central lymph node biopsy in the CME group; no patient had isolated metastases to central lymph nodes. Although the CME procedure might increase the risk of intraoperative vascular injury, it generally seems to be safe and feasible for experienced surgeons. The Capital Characteristic Clinical Project of Beijing and the Chinese Academy of Medical Sciences.

Background and aim: Fuzheng Huayu Recipe (FZHY) is a Chinese patent medicine (approval No. Z20020074) included in the national medical insurance catalogue, which is mainly used for anti-hepatic fibrosis treatment of hepatitis B virus (HBV) induced liver fibrosis and liver cirrhosis. In clinical practice, we discovered that FZHY might also have a direct anti-HBV effect on inhibiting HBeAg production, but the mechanism underlying was unclear. This study aimed to clarify the molecular mechanism of the inhibition effect of FZHY on HBeAg production. Methods: The decrease degree of serum HBeAg titer in FZHY + entecavir (ETV) group patients were analyzed through clinical data. C57BL/6N-Tg (1.28HBV)/Vst HBV transgenic mice were used for in vivo experiments. HepG2. 2.15 cells (wild-type HBV replication cells) were used for in vitro experiments. Results: The clinical study results showed that the decrease degree of serum HBeAg titer in FZHY+ETV group was significantly higher than that in ETV group after 48 weeks treatment. In vivo experiments results showed that FZHY could significantly reduce the serum HBeAg titer in HBV transgenic mice, and promote HBeAg seroconversion. In vitro experiments results showed that FZHY could reduce HBeAg titer dependently, but it did not significantly inhibit the expression of HBsAg and HBV-DNA. Further cell experiments in vitro discovered that TOMM34 might be the key target for FZHY to inhibit HBeAg production. The subsequent pharmacological screening experiment of 20 active compounds in FZHY showed that quercetin, baicalin and cordycepin could promote the expression of TOMM34 gene and reduce the production of HBeAg. Conclusion: In conclusion, FZHY and its active compounds quercetin, baicalin and cordycepin could inhibit HBeAg production by promoting the expression of TOMM34 gene in HBV-infected hepatocytes.

Background and aim: Pro-inflammatory macrophages aggravated progress of pulmonary fibrosis (PF) both in patients and animal models. Fuzheng Huayu (FZHY) formula, a Chinese herbal product, is effective in treating pulmonary fibrosis in our previous study. But its action mechanism against PF relating to macrophage activation was unclear. This study was designed to evaluate the anti-fibrotic and anti-inflammatory roles of FZHY in pulmonary fibrosis and to elucidate the potential mechanisms. Methods: Network pharmacology was employed to identify the interrelationships among compounds of FZHY, potential targets and putative pathways on anti-pulmonary fibrosis. According to the data of bioinformatics analysis, the key pharmacological target for FZHY against PF was screened. The network pharmacological prediction was validated by a series of experimental assays, including CCK8, western blot and immunofluorescence staining. Then molecular mechanism of FZHY on relating to the predictive target were studied in bleomycin induced pulmonary fibrosis in mice with methylprednisolone as a positive control, and in lipopolysaccharide (LPS) stimulated cultured macrophages in culture, respectively. Results: The network pharmacology analysis reveal that a total of 12 FZHY–PF crossover proteins were filtered into a protein-protein interaction network complex and designated as the potential targets of FZHY against pulmonary fibrosis, while TNF-α signal pathway ranked at the top. FZHY and methylprednisolone could attenuate the lung fibrosis and decrease pulmonary TNF-α expression in bleomycin induced fibrotic mice, without difference between two treatments. While TNF-α was mainly originated from macrophages identified by double fluorescent staining of TNF-α and F4/80. LPS stimulated cultured macrophage polarization and activation demonstrated by the enhance contents of TNF-α and iNOS but decreased level of Arg-1. FZHY could alleviate the LPS stimulated macrophage polarization and activation demonstrated by decreasing TNF-α and iNOS and increasing Arg-1. In particular, FZHY could significantly reduce the production of p65 and the nuclear translocation of phosphorylated p65. Conclusion: Fuzheng Huayu formula has a good effect against pulmonary fibrosis induced by bleomycin in mice, whose action mechanism was associated with down-regulation of NF-κB/TNF-α signaling pathway in pro-inflammatory macrophages. These findings provided an important strategy for developing new agents against lung fibrosis and accelerated FZHY product application on patients with lung fibrosis.