Development and validation of a model for the early prediction of progression from essential thrombocythemia to post-essential thrombocythemia myelofibrosis: a multicentre retrospective study.

Background: Essential thrombocythemia (ET), a myeloproliferative neoplasm (MPN), has a substantial risk of evolving into post-essential thrombocythemia myelofibrosis (post-ET MF). This study aims to establish a prediction nomogram for early prediction of post-ET MF in ET patients. Methods: The training cohort comprised 558 patients from 8 haematology centres between January 1, 2010, and May 1, 2023, while the external validation cohort consisted of 165 patients from 6 additional haematology centres between January 1, 2010, and May 1, 2023. Univariable and multivariable Cox regression analysis was performed to identified independent risk factors and establish a nomogram to predict the post-ET MF free survival. Both bias-corrected area under the curve (AUC), calibration curves and concordance index (C-index) were employed to assess the predictive accuracy of the nomogram. Findings: Multivariate Cox regression demonstrated that elevated red blood cell distribution width (RDW), elevated levels of lactate dehydrogenase (LDH) and the level of haemoglobin (Hb), a history of smoking and the presence of splenomegaly were independent risk factors for post-ET MF. The C-index displayed of the training and validation cohorts were 0.877 and 0.853. The 5 years, 10 years AUC values in training and external validation cohorts were 0.948, 0.769 and 0.978, 0.804 respectively. Bias-corrected curve is close to the ideal curve and revealed a strong consistency between actual observation and prediction. Interpretation: We developed a nomogram capable of predicting the post-ET MF free survival probability at 5 years and 10 years in ET patients. This tool helps doctors identify patients who need close monitoring and appropriate counselling. Funding: This research was funded by the Key R&D Program of Zhejiang (No. 2022C03137); the Public Technology Application Research Program of Zhejiang, China (No. LGF21H080003); and the Zhejiang Medical Association Clinical Medical Research special fund project (No. 2022ZYC-D09).

Prognostic significance of thromboembolism in multiple myeloma: a systematic review and meta-analysis.

Background: This study sought to investigate the clinical characteristics and prognosis of thromboembolism in multiple myeloma (MM). Methods: The PubMed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were systematically searched to retrieve relevant articles from the establishment of the databases to May 2022. This meta-analysis was performed to investigate the relationship between thromboembolism and overall survival (OS), progression-free survival (PFS), event-free survival (EFS), and mortality in MM patients. The meta-analysis of the included studies was performed using Revman5.3 software after quality evaluation. Results: A total of 9 studies from 7 articles, which included 38,047 MM patients and 6,412 cases of thromboembolism in the analysis. The levels of ß2 microglobulin affected the occurrence of thromboembolism in MM patients [standard mean difference (SMD) =-0.09, 95% confidence interval (CI): -0.18 to -0.01, P=0.02]. Venous thromboembolism (VTE) predicted poorer OS [hazard ratio (HR) = 0.79, 95% CI: 0.64-0.98, P=0.03] and higher early mortality (HR =2.27, 95% CI: 1.26-4.08, P=0.006) in MM. There was no significant difference in PFS/EFS (HR =0.81, 95% CI: 0.64-1.01, P=0.06) between thrombosis/embolism and non-thrombotic embolism. Arterial thrombosis was associated with significantly higher risk of death at 5 years (HR =1.89, 95% CI: 1.33-2.69, P<0.01). Conclusions: ß2 microglobulin levels were associated with VTE in MM. MM patients with VTE were more likely to have poorer prognosis and higher mortality rate than those without VTE. MM patients with arterial thromboembolism had higher 5-year mortality rate than those without arterial thromboembolism.

SOCS3 as a potential driver of lung metastasis in colon cancer patients.

Background: The suppressor of cytokine signaling 3 (SOCS3) is the negative feedback regulator of the JAK-STAT signaling pathway. The purpose of our study was to investigate the SOCS3 status in colon primary tumor and lung metastasis and its relationship with macrophages. Methods: The SOCS3 expression pattern and its relationship with the immune response in pan-cancer was investigated using multiple methods. Samples and corresponding clinical information of 32 colon cancer patients with lung metastasis were collected, and the CD68, CD163, and SOCS3 status were conducted using immunohistochemistry (IHC). The relationship between SOCS3 status and macrophage markers was analyzed. Besides, we explored the molecular mechanisms of SOCS3 in lung metastasis via the TCGA database. Results: High SOCS3 expression was more inclined to poor prognosis and was positively correlated with main immune cell infiltration in almost each cancer type, especially in colon cancer. Compared with the colon primary tumor, lung metastasis harbored higher CD163 and SOCS3 expression, and high SOCS3 expression was more likely to be associated with high CD163 expression in lung metastasis. Besides, the exceptional differentially expressed genes in lung metastasis significantly enriched in immune responses and regulations. Conclusions: SOCS3 possessed value as a prognostic marker and target for immunotherapeutic intervention in different tumors and might be a potential target of tumor progression and tumor immunotherapy in colon cancer.

MicroRNA-361-3p Inhibit the Progression of Lymphoma by the Wnt/ß-Catenin Signaling Pathway.

BACKGROUND: MicroRNA is involved in the development of lymphoma. It is reported that miR-361-3p has a tumor inhibitory effect, but its role in lymphoma is still unclear. The purpose of this study is to examine whether miR-361-3p can inhibit the development of lymphoma and further explore the related potential mechanism. METHODS: In this study, we first analyzed the biological function of miR-361-3p in transfected Raji that mimicked miRNA. We also analyzed the biological function of the whole population in stably expressed miR-361-3p transgenic cells. Next, we conducted a complete micro-gene network to test the genetic profile of differential expression of stable gene-modified cells. RESULTS: We found that miR-361-3p expression was often reduced in lymphoma cell lines. Cellular assays have shown a significant role in inhibiting the growth of miR-361-3p by inhibiting lymphoma proliferation and migration, and severely inhibiting the Wnt/ß-catenin series protein signal. Bioinformatics analysis shows that Wnt10A is a new target of miR-361-3p, which is confirmed by our mechanism research. It is confirmed that restoring Wnt10A can reduce the tumor inhibition of Wnt/ß-catenin during lymphoma progression and restore the normal signal of Wnt/ß-catenin series proteins. DISCUSSION: Our data indicate that miR-361-3p inhibits the Wnt/ß-catenin protein signal by locking Wnt10A, which is an important factor in inhibiting the tumor in the pathogenesis of lymphoma. The miR-361-3p/Wnt10A axis may be a promising target for the treatment of lymphoma.

Development and validation of a 10-gene prognostic signature for acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is the most common type of adult acute leukaemia and has a poor prognosis. Thus, optimal risk stratification is of greatest importance for reasonable choice of treatment and prognostic evaluation. For our study, a total of 1707 samples of AML patients from three public databases were divided into meta-training, meta-testing and validation sets. The meta-training set was used to build risk prediction model, and the other four data sets were employed for validation. By log-rank test and univariate COX regression analysis as well as LASSO-COX, AML patients were divided into high-risk and low-risk groups based on AML risk score (AMLRS) which was constituted by 10 survival-related genes. In meta-training, meta-testing and validation sets, the patient in the low-risk group all had a significantly longer OS (overall survival) than those in the high-risk group (P < .001), and the area under ROC curve (AUC) by time-dependent ROC was 0.5854-0.7905 for 1 year, 0.6652-0.8066 for 3 years and 0.6622-0.8034 for 5 years. Multivariate COX regression analysis indicated that AMLRS was an independent prognostic factor in four data sets. Nomogram combining the AMLRS and two clinical parameters performed well in predicting 1-year, 3-year and 5-year OS. Finally, we created a web-based prognostic model to predict the prognosis of AML patients (https://tcgi.shinyapps.io/amlrs_nomogram/).

Discovering master regulators in hepatocellular carcinoma: one novel MR, SEC14L2 inhibits cancer cells.

Identification of master regulator (MR) genes offers a relatively rapid and efficient way to characterize disease-specific molecular programs. Since strong consensus regarding commonly altered MRs in hepatocellular carcinoma (HCC) is lacking, we generated a compendium of HCC datasets from 21 studies and identified a comprehensive signature consisting of 483 genes commonly deregulated in HCC. We then used reverse engineering of transcriptional networks to identify the MRs that underpin the development and progression of HCC. After cross-validation in different HCC datasets, systematic assessment using patient-derived data confirmed prognostic predictive capacities for most HCC MRs and their corresponding regulons. Our HCC signature covered well-established liver cancer hallmarks, and network analyses revealed coordinated interaction between several MRs. One novel MR, SEC14L2, exerted an anti-proliferative effect in HCC cells and strongly suppressed tumor growth in a mouse model. This study advances our knowledge of transcriptional MRs potentially involved in HCC development and progression that may be targeted by specific interventions.

Ethanol extract of Ligustrum lucidum Ait. leaves suppressed hepatocellular carcinoma in vitro and in vivo.

BACKGROUND: The present study investigated the pharmacological activity and mechanism of ethanol extract of Ligustrum lucidum Ait. leaves (EEL) on HCC. METHODS: Cell viability was determined using cell counting kit-8 (CCK-8) assay. The effects of EEL on cellular biological activities were analyzed by flow cytometry (FCM), cell wound scratch assay and transwell assay. The expression levels of related mRNA and protein were determined by performing quantitative real-time PCR (qRT-PCR), Western blotting assay and immunocytochemistry. Methylation-specific PCR (MSP) was carried out to investigate the possible mechanism underlying the DNA methylation of PTEN. RESULTS: EEL showed cytotoxicity to both Bel-7402 and Huh-7 cell lines. We also found that EEL enhanced the apoptosis of Bel-7402 and Huh-7 cells by regulating the expressions of Bcl-2 associated X (Bax), B cell lymphoma 2 (Bcl-2) and Cytochrome-C and the activity of caspase-3 and therefore promoted cell cycle arrest. Moreover, EEL also suppressed cell migration and invasion. EEL increased the expression of tissue inhibitor of metalloproteinases 2 (TIMP2) but decreased the expressions of matrix metalloproteinase2 (MMP2) and MMP9. Furthermore, EEL inhibited the phosphorylation of PI3K/Akt pathway. MSP results showed that EEL promoted the demethylation of PTEN, suggesting that the inactivation of PI3K/Akt may be related to DNA de-methylation of PTEN. In addition, EEL inhibited the tumor growth of HCC in vivo. CONCLUSIONS: EEL exerted anti-tumor effect on HCC in vitro and in vivo. EEL mediated by the inhibition of PI3K/Akt may be closely related to DNA de-methylation of PTEN. Thus, EEL could be used as a potential anti-cancer therapeutic agent of HCC.

Berberine prevents non-alcoholic steatohepatitis-derived hepatocellular carcinoma by inhibiting inflammation and angiogenesis in mice.

Hepatocellular carcinoma (HCC) is one of the most malignant and poor prognosis tumors, which was increasingly caused by nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) in western countries. In this study, we aimed to investigate the mechanism and therapeutic prospect of berberine in the treatment of NASH-HCC mice. Combination of STZ injection and high fat and high-cholesterol diet (HFHC) was used to establish NASH-HCC model. The effect of berberine intervention is studied from histology, biochemistry and molecular level. Our results showed that administration of berberine to NASH-HCC mice reduced the incidence of tumors and mitigated NASH. Berberine significantly reduced the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and total cholesterol (TC). Transcriptome sequencing and bioinformatics analysis identified numberous genes and various pathways may participate in the favorite effect of berberine. Specifically, berberine suppressed the expressions of genes related to lipogenesis, inflammation, fibrosis and angiogenesis. Moreover, our results showed that berberine suppressed phosphorylation of p38MAPK and ERK as well as COX2 expression significantly. This suggested berberine achieved its biological functions mainly by regulating inflammation and angiogenesis genes involving p38MAPK/ERK-COX2 pathways. This study demonstrated the anti-tumor effects of berberine and its possible mechanism, providing a potential drug for treating NASH-HCC.

The association between nonalcoholic fatty liver disease and risk of colorectal adenoma and cancer incident and recurrence: a meta-analysis of observational studies.

BACKGROUND & AIM: Lifestyle modification plays a key role in nonalcoholic fatty liver disease (NAFLD) and colorectal adenoma and/or cancer (CRA/CRC) development. However, the association between NAFLD and the risk of CRA/CRC has not been carefully evaluated. METHODS: In this meta-analysis, we assessed 21 eligible studies including 124,206 participants to determine the association between NAFLD and the risk of incident and recurrent CRA/CRC. RESULTS: NAFLD presence was associated with an increased risk of any incident CRA (aOR: 1.30, 95% CI: 1.19-1.43) and advanced incident CRA/CRC (aOR: 1.57, 95% CI: 1.21-2.04). The severity of NAFLD affected this correlation: compared to mild and/or moderate NAFLD, severe NAFLD was associated with an increased risk of incident CRA/CRC (aOR: 2.19, 95% CI: 1.33-3.60). Although pooled cOR revealed that NAFLD was associated with an increased risk of recurrent CRA/CRC (cOR = 1.73; 95% CI: 1.12-2.68), after adjustment for confounding factors, NAFLD had less correlation with the risk of recurrent CRA/CRC (aOR: 1.81, 95% CI: 0.70-4.65). CONCLUSIONS: The presence and severity of NAFLD are associated with an increased risk of incident CRA/CRC. However, there is insufficient evidence to indicate that NAFLD is associated with an increased risk of recurrent CRA/CRC.

MiR-429 regulates the metastasis and EMT of HCC cells through targeting RAB23.

Accumulating documents have revealed that microRNAs (miRNAs) play critical roles in the development and progression of tumors. MiR-429 has been reported to be involved in regulating various cellular processes. However, its biological role and underlying mechanism in hepatocellular carcinoma (HCC) still need to be further studied. The present study aimed to investigate the function of miR-429 in the progression of HCC. In terms of this paper, it was found that miR-429 was down-regulated in HCC tissues and cells. After being transfected with miR-429 mimics, miR-429 decreased the migratory capacity and reversed the EMT to MET in HCC cells. RAB23 was confirmed as a target of miR-429. Rescue assays further verified that the function of miR-429 in HCC cells was exerted through targeting RAB23. In general, it was concluded that the signal pathway miR-429/RAB23 might be a potential target for HCC treatment.

Characterization of transcriptional modules related to fibrosing-NAFLD progression.

Based on the severity of liver fibrosis, low or high-risk profile of developing end-stage liver disease was present in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms inducing transition from mild to advanced NAFLD are still elusive. We performed a system-level study on fibrosing-NAFLD by weighted gene co-expression network analysis (WGCNA) to identify significant modules in the network, and followed by functional and pathway enrichment analyses. Moreover, hub genes in the module were analyzed by network feature selection. As a result, fourteen distinct gene modules were identified, and seven modules showed significant associations with the status of NAFLD. Module preservation analysis confirmed that these modules can also be found in diverse independent datasets. After network feature analysis, the magenta module demonstrated a remarkably correlation with NAFLD fibrosis. The top hub genes with high connectivity or gene significance in the module were ultimately determined, including LUM, THBS2, FBN1 and EFEMP1. These genes were further verified in clinical samples. Finally, the potential regulators of magenta module were characterized. These findings highlighted a module and affiliated genes as playing important roles in the regulation of fibrosis in NAFLD, which may point to potential targets for therapeutic interventions.

Isocitrate Dehydrogenase 2 Suppresses the Invasion of Hepatocellular Carcinoma Cells via Matrix Metalloproteinase 9.

BACKGROUND/AIMS: Isocitrate dehydrogenase 2 (IDH2) is a mitochondrial NADP-dependent isocitrate dehydrogenase, and has been found to be a tumor suppressor in several types of tumors. However, the roles of IDH2 in hepatocellular carcinoma (HCC) as well as underlying mechanisms remain unknown. METHODS: The IDH2 and matrix metalloproteinase 9 (MMP9) levels in the specimens from 24 HCC patients were investigated by Western blot and ELISA, respectively. Their relationship was examined by correlation analyses. Patient survival with high IDH2 levels and low IDH2 levels was compared. IDH2 levels and MMP9 levels were modified in a human HCC cell line. The effects of IDH2 or MMP9 modulation on the expression of the other were analyzed. The effects of IDH2 on cell invasion were analyzed in a transwell cell invasion assay. The dependence of nuclear factor x03BA;B (NF-x03BA;B) signaling was examined using a specific inhibitor. RESULTS: The IDH2 levels significantly decreased in HCC, and were lower in HCC with metastases, compared to those without metastases. IDH2 levels inversely correlated with MMP9 levels in HCC. HCC patients with Low IDH2 had lower 5-year survival. MMP9 levels did not regulate IDH2 levels, while IDH2 inhibited MMP9 levels in HCC cells, in a NF-x03BA;B signaling dependent manner, possibly through ix03BA;B, to suppress HCC cell invasion. CONCLUSIONS: Down regulation of IDH2 may promote HCC cell invasion via NF-x03BA;B-dependent increases in MMP9 activity. IDH2 may be a potential therapeutic target for HCC.