Identifying the Crucial Biomarker of MASH-Related HCC.

OBJECTIVES: This study aimed to explore the key oncogenic factor of metabolicassociated steatohepatitis (MASH) to hepatocellular carcinoma (HCC). METHODS: We utilized four differential GEO datasets (GSE164760, GSE139602, GSE197112, and GSE49541) to identify the key oncogenic factor for MASH-related HCC. The differential genes were analyzed using the GEO2R algorithm online. The GEPIA online website was used to explore the expression of selected four genes (SPP1, GNMT, CLDN11, and THBS2). The genetic alterations in genes were estimated by the cBioPortal website. The Kaplan-Meier Plotter online database was applied to explore the prognostic value of SPP1. Univariate and multivariate Cox analyses were carried out to further confirm the prognostic value of SPP1. The GO and KEGG enrichment analysis exported associated pathways with SPP1 expression. The positively or negatively related immune cells and immune checkpoint expressions were identified through Pearson correlation analysis. The lipogenesis-associated proteins were detected using western blotting and fluorescence. The high-fat diet (HFD) mouse model was constructed, and liver samples were collected. RESULTS: SPP1, GNMT, CLDN11, and THBS2 were determined in the transformation process of MASH to liver fibrosis. SPP1 and GNMT were upregulated in the HCC tumor tissue. SPP1, in particular, had the potential to be the prognostic factor through Cox analysis. Remarkably, SPP1 was highly expressed in HCC compared to normal tissues in three independent datasets (GSE121248, GSE14520, and GSE45267). SPP1 is mainly involved in the amplification and deep deletion mutations. SPP1 was found to be strongly correlated with ANXA2 expression, and ANXA2 was also highly expressed in HCC with significant prognostic performance. Moreover, SPP1 was found to participate in the carcinogenic mechanism and correlate with immune cells and immune checkpoint expression. SPP1 knockdown suppressed the SREBP1 and FASN expressions and increased the SIRT1 expression in vitro. Moreover, the HFD model validated the upregulation of SPP1 in the fatty liver in vivo. CONCLUSION: SPP1 may be the key oncogenic factor for the transformation of MASH to HCC, and it could be a potential immunotherapeutic target in HCC.

Erratum: Linc-KILH potentiates Notch1 signaling through inhibiting KRT19 phosphorylation and promotes the malignancy of hepatocellular carcinoma: Erratum.

[This corrects the article DOI: 10.7150/ijbs.52279.].

Prediction of severe hypertriglyceridemia-associated acute pancreatitis using a nomogram based on CT findings and blood biomarkers.

Hypertriglyceridemia is a common cause of acute pancreatitis (AP). Fatty liver, a manifestation of metabolic syndrome, is related to the severity of AP. The present study aimed to construct an accurate predictive model for severe AP (SAP) by combining the fatty liver infiltration on a computerized tomography (CT) scan with a series of blood biomarkers in patients with hypertriglyceridemia-associated AP (HTG-AP). A total of 213 patients diagnosed with HTG-AP were included in the present retrospective study. Clinical information and imageological findings were retrospectively analyzed. The model was constructed from independent risk factors using univariate analysis, the least absolute shrinkage and selection operator method. Subsequently, the data from the training group of 111 patients with HTG-AP was analyzed using logistic regression analysis. The efficacy of the model was verified using an external validation group of 102 patients through the receiver operating characteristic curve (ROC). Independent predictors, including serum calcium, C-reactive protein, lactate dehydrogenase and liver-to-spleen CT attenuation ratio (L/S ratio), were incorporated into the nomogram model for SAP in HTG-AP. The model achieved a sensitivity of 91.3% and a specificity of 88.6% in the training group. Compared with the Ranson model, the established nomogram model exhibited a better discriminative ability in the training group [area under the curve (AUC): 0.957] and external validation group (AUC: 0.930), as well as better calibration and clinical benefits. The present study demonstrates that the constructed nomogram based on CT findings and blood biomarkers is useful for the accurate prediction of SAP in HTG-AP.

Unlocking hepatocellular carcinoma aggression: STAMBPL1-mediated TRAF2 deubiquitination activates WNT/PI3K/NF-kb signaling pathway.

STAM Binding Protein Like 1 (STAMBPL1), functions as a deubiquitinase (DUB) and plays a significant role in various types of cancers. However, its effect as a DUB participating in the HCC tumorigenesis and progression still unknown. In the study, the upregulation and strong prognosis value of STAMBPL1 were identified in HCC patients. Functionally, STAMBPL1 significantly promoted HCC cells proliferation and metastasis, and it interacts with TRAF2 and stabilize it via the deubiquitination at the K63 residue. The TRAF2 upregulation stabilized by STAMBPL1 overexpression transfers of P65 protein into the nucleus and activates the WNT/PI3K/ NF-kb signaling pathway. The 251-436 sites of STAMBPL1 particularly interact with the 294-496 sites of TRAF2, thereby exerting the function of DUB and removing the ubiquitin molecules attached to TRAF2. Our research unveiled a new function of STAMBPL1 in mediating TRAF2 deubiquitination and stabilization, thereby activating the WNT/PI3K/NF-kb signaling pathway, suggesting its potential as a novel biomarker and therapeutic target for HCC.

m6A demethylase ALKBH5 maintains stemness of intrahepatic cholangiocarcinoma by sustaining BUB1B expression and cell proliferation.

ALKBH5 plays critical roles in various cellular processes via post-transcriptional regulation of oncogenes or tumor suppressors in an N6-methyladenosine (m6A)-dependent manner. However, its function in intrahepatic cholangiocarcinoma (ICC) remains unclear. In the present study, bioinformatic analyses of The Cancer Genome Atlas (TCGA) data were performed, and the association of ALKBH5 in predicting overall survival in patients with ICC was investigated. Then, the clinical data of patients from The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University (Changzhou, China) was used to reveal the overall survival of patients with ICC with different ALKBH5 expression levels by Kaplan-Meier survival analysis. Subsequently, in vitro and in vivo studies were conducted to explore and verify the downstream genes regulated by ALKBH5. The results from TCGA data demonstrated that ALKBH5 expression is elevated in ICC and that patients with high ALKBH5 expression exhibited poor survival compared with patients with low expression. In addition, in vitro assays demonstrated that ALKBH5 promoted cell viability and maintained the stemness of ICC cells, leading to ICC progression. The present study also demonstrated that BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is the downstream gene regulated by ALKBH5 and targeting BUB1B suppressed cell growth. The in vitro and vivo experiments revealed that ALKBH5 might function through BUB1B to maintain the stemness of ICC and that altering BUB1B may suppress ICC progression.

The Biological Function of POLA2 in Hepatocellular Carcinoma.

INTRODUCTION: The role and prognostic value of POLA2 in liver cancer were comprehensively analyzed through TCGA, GEO, and ICGC databases, and the role of POLA2 in liver cancer cells and the regulatory mechanism involved were further verified through cell experiments. Hepatocellular carcinoma (HCC) is the most prevalent malignancy with high morbidity and mortality. Consequently, it is critical to identify robust and reliable predictive biomarkers and therapeutic targets for HCC patients. POLA2 is involved in the regulation of various tumors, but the specific role of POLA2 in HCC has not been reported. The regulatory role and prognostic value of POLA2 in HCC were determined by bioinformatics techniques and cell experiments. METHOD: The specific role and prognostic value of POLA2 in HCC were comprehensively analyzed by combining the expression data of POLA2 in TCGA, GEO, and ICGC databases and clinical data. In clinical samples, the expression of POLA2 in liver cancer was verified by QPCR. Further, the regulatory role of POLA2 in HCC was explored through cell experiments such as CCK-8, clonal formation experiment, EDU cell proliferation experiment, and flow cytometry. In terms of mechanism exploration, western blot was used to verify the specific regulatory mechanism that POLA2 participated in. Finally, the relationship between POLA2 and immune invasion of HCC was analyzed by using the TIMER database. RESULT: A POLA2 expression and prognosis analysis of HCC patients was conducted using the TCGA, GEO, and ICGC databases. We hypothesized that POLA2 might be one of the key factors contributing to the HCC progression. According to a combined analysis of TCGA, ICGC, and GEO databases, POLA2 was highly expressed in HCC. This was further confirmed in clinical samples using the qPCR. POLA2 knockdown was also performed in vitro on HCC cell lines to study the changes in their biological behavior. We confirmed that POLA2 was associated with HCC proliferation by CCK-8, Colony Formation, and EDU assay. We verified the POLA2's involvement in cell cycle regulation using flow techniques. The relationship between POLA2 and PI3K/AKT/mTOR pathway was explored using Western Blotting experiments regarding its mechanism. Further analysis revealed that the POLA2 expression was significantly associated with HCC immune infiltration. CONCLUSION: Our study demonstrated POLA2's importance in HCC development and progression and its potential role as a biomarker for disease progression on multiple levels. POLA2 has an important role in regulating the cell cycle and cell proliferation. By interfering with the cell cycle and proliferation, HCC cell growth is inhibited. Furthermore, POLA2 expression was significantly associated with immune infiltration. POLA2 may play a role in HCC immunotherapy based on its correlation with several immune cell types' genetic markers. The findings of this study are expected to lead to new anticancer strategies for HCC.

Pan-Cancer Analysis of Oncogenic Role of RAD54L and Experimental Validation in Hepatocellular Carcinoma.

Background: RAD54L is a prominent member of the SWI2/SNF2 protein family, primarily involved in the homologous recombination repair (HRR) process, thereby playing a pivotal role in the repair of DNA double-strand breaks (DSBs). RAD54L has been implicated in the development of numerous tumors. Consequently, we aimed to investigate the potential contribution of RAD54L in pan-cancer. Methods: Various databases and analytical tools were employed for bioinformatics analysis. Moreover, in vitro experiments were conducted to corroborate the findings from the bioinformatics analysis and delve deeper into the role of RAD54L in hepatocellular carcinoma (HCC). Results: RAD54L expression demonstrated a significant elevation in the majority of tumors, and its overexpression was strongly associated with unfavorable survival outcomes. RAD54L displayed robust correlations with the infiltration levels of various immune cells, including cancer associated fibroblasts (CAFs), endothelial cells, and myeloid-derived suppressor cells (MDSCs). Additionally, associations were observed between RAD54L and key factors such as tumor mutation burden (TMB), microsatellite instability (MSI), multiple immune checkpoints, and immune cell infiltration. Moreover, a close relationship was observed between RAD54L expression levels in HCC and clinicopathological characteristics, as well as immune cell infiltration. Experimental techniques including qRT-PCR, Western blotting, colony-forming, Cell Counting Kit-8 (CCK-8), wound-healing, and transwell assays were employed, which collectively demonstrated that RAD54L promoted the proliferation and migration of HCC cells. Conclusion: RAD54L exhibits robust expression in both pan-cancer and HCC, exerting a significant influence on the proliferation and migration of HCC cells. These findings highlight its potential as a promising biomarker for pan-cancer and a prospective target for immunotherapy.

Restoring gluconeogenesis by TEF inhibited proliferation and promoted apoptosis and immune surveillance in kidney renal clear cell carcinoma.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is the major histological subtype of kidney tumor which covers approximately 80% of the cases. Although various therapies have been developed, the clinical outcome remains unsatisfactory. Metabolic dysregulation is a key feature of KIRC, which impacts progression and prognosis of the disease. Therefore, understanding of the metabolic changes in KIRC is of great significance in improving the treatment outcomes. METHODS: The glycolysis/gluconeogenesis genes were analyzed in the KIRC transcriptome from the Cancer Genome Atlas (TCGA) by the different expression genes (DEGs) test and survival analysis. The gluconeogenesis-related miRNAs were identified by ImmuLncRNA. The expression levels of indicated genes and miRNAs were validated in KIRC tumor and adjunct tissues by QPCR. The effects of miR-4477b and PCK1 on cell proliferation and apoptosis were examined using the cell viability assay, cell apoptosis assay, and clone information. The interaction of miR-4477b with TEF was tested by the luciferase report gene assay. The different gluconeogenesis statuses of tumor cells and related signatures were investigated by single-cell RNA sequencing (scRNA-seq) analysis. RESULTS: The 11 gluconeogenesis genes were found to be suppressed in KIRC (referring as PGNGs), and the less suppression of PGNGs indicated better survival outcomes. Among the 11 PGNGs, we validated four rate-limiting enzyme genes in clinical tumor patients. Moreover, restoring gluconeogenesis by overexpressing PCK1 or TEF through miR-4477b inhibition significantly inhibited tumor cell proliferation, colony formation, and induced cell apoptosis in vitro. Independent single-cell RNA sequencing (scRNA-seq) data analysis revealed that the tumor cells had high levels of PGNG expression (PGNG + tumor cells) represented a phenotype of early stage of neoplasia and prompted immune surveillance. CONCLUSIONS: Our study suggests that the deficiency of gluconeogenesis is a key metabolic feature of KIRC, and restoring gluconeogenesis could effectively inhibit the proliferation and progression of KIRC cells.

The use of fluorescence laparoscopy in the resection of splenic tissue replantation in the right lobe of the liver: A case report and literature review.

BACKGROUND: Ectopic replantation and regeneration of splenic tissue fragments following splenic trauma or splenectomy is known as replantation of splenic tissue. It typically takes place in the abdominal cavity, however, splenic tissue replantation in the liver is extremely rare and difficult to diagnose. It is often misdiagnosed as a liver tumor and removed. CASE PRESENTATION: We present the case of a patient with a history of traumatic splenectomy 15 years prior to the replantation of splenic tissue in the liver. A 4 cm mass in the liver was found during the most recent physical examination, and a computed tomography scan indicated the possibility of a malignant tumor. The tumor was then removed using fluorescence laparoscopy. CONCLUSION: There is a possibility of intrahepatic replantation of splenic tissue in patients who have had a splenectomy in the past, have recently discovered an intrahepatic space-occupying lesion, and do not have any high-risk factors for liver cancer. Unnecessary surgery can be avoided if 99mTc-labeled red blood cells imaging using mass puncture or radionuclide examination provides a clear preoperative diagnosis. Globally, there are no reports of the use of fluorescence laparoscopy in resecting replanted splenic tissue in the liver. Specifically, in the current case, there was no indocyanine green uptake in the mass, and only a small amount was found in the normally functioning liver tissue surrounding the tumor.

MARCH9 Mediates NOX2 Ubiquitination to Alleviate NLRP3 Inflammasome-Dependent Pancreatic Cell Pyroptosis in Acute Pancreatitis.

OBJECTIVE: The pathogenesis of acute pancreatitis mainly involves NLRP3 inflammasome-mediated pancreatic cell injury, although regulators of this inflammasome machinery are still not fully identified. Membrane-associated RING-CH 9 (MARCH9) is a member of MARCH-type finger proteins, which regulates innate immunity through catalyzing polyubiquitination of critical immune factors. The aim of present research is to examine the function of MARCH9 in acute pancreatitis. METHODS: Cerulein-induced acute pancreatitis was established on pancreatic cell line AR42J and rat model. Reactive oxygen species (ROS) accumulation and NLRP3 inflammasome-dependent cell pyroptosis in pancreas were examined by flow cytometry. RESULTS: MARCH9 was downregulated by cerulein, but overexpressing MARCH9 could inhibit NLRP3 inflammasome activation and ROS accumulation, thus suppressing pancreatic cell pyroptosis and mitigating pancreatic injury. We further uncovered that the mechanism underlying such an effect of MARCH9 is through mediating the ubiquitination of NADPH oxidase-2, whose deficiency reduces cellular ROS accumulation and inflammasome formation. CONCLUSIONS: Our results suggested that MARCH9 suppresses NLRP3 inflammasome-mediated pancreatic cell injury through mediating the ubiquitination and degradation of NADPH oxidase-2, which compromises ROS generation and NLRP3 inflammasomal activation.

Long noncoding RNA MyD88 functions as a promising diagnostic biomarker in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most frequent malignancies. Alpha-fetoprotein (AFP) has some limitations in diagnosing early HCC. Recently, long noncoding RNAs (lncRNAs) showed great potential as tumor diagnostic biomarkers, and lnc-MyD88 was previously identified as a carcinogen in HCC. Here, we explored its diagnostic value as a plasma biomarker. Materials and methods: Quantitative real-time PCR was adopted to detect lnc-MyD88 expression in plasma samples of 98 HCC patients, 52 liver cirrhosis (LC) patients, and 105 healthy people. The correlation between lnc-MyD88 and clinicopathological factors was analyzed through chi-square test. The receiver operating characteristic (ROC) curve was used to analyze the sensitivity, specificity, Youden index, and area under the curve (AUC) of lnc-MyD88 and AFP alone and in combination for the diagnosis of HCC. The relationship between MyD88 and immune infiltration was analyzed by single sample gene set enrichment analysis (ssGSEA) algorithm. Results: Lnc-MyD88 was highly expressed in plasma samples of HCC and hepatitis B virus (HBV)-associated HCC patients. Lnc-MyD88 had better diagnostic value than AFP in HCC patients using healthy people or LC patients as control (healthy people, AUC: 0.776 vs. 0.725; LC patients, AUC: 0.753 vs. 0.727). The multivariate analysis showed that lnc-MyD88 had great diagnostic value for distinguishing HCC from LC and healthy people. Lnc-MyD88 had no correlation with AFP. Lnc-MyD88 and AFP were independent diagnostic factors for HBV-associated HCC. The AUC, sensitivity, and Youden index of the combined diagnosis of lnc-MyD88 and AFP combined were higher than those of lnc-MyD88 and AFP alone. The ROC curve of lnc-MyD88 for the diagnosis of AFP-negative HCC was plotted with a sensitivity of 80.95%, a specificity of 79.59%, and an AUC value of 0.812 using healthy people as control. The ROC curve also presented its great diagnostic value using LC patients as control (sensitivity: 76.19%, specificity: 69.05%, AUC value: 0.769). Lnc-MyD88 expression was correlated with microvascular invasion in HBV-associated HCC patients. MyD88 was positively correlated with infiltrating immune cells and immune-related genes. Conclusion: The high expression of plasma lnc-MyD88 in HCC is distinct and could be utilized as a promising diagnostic biomarker. Lnc-MyD88 had great diagnostic value for HBV-associated HCC and AFP-negative HCC, and it had higher efficacy in combination with AFP.

ARHGAP21 Is Involved in the Carcinogenic Mechanism of Cholangiocarcinoma: A Study Based on Bioinformatic Analyses and Experimental Validation.

Background and Objectives: Rho GTPase-activating protein (RhoGAP) is a negative regulatory element of Rho GTPases and participates in tumorigenesis. Rho GTPase-activating protein 21 (ARHGAP21) is one of the RhoGAPs and its role in cholangiocarcinoma (CCA) has never been disclosed in any publications. Materials and Methods: The bioinformatics public datasets were utilized to investigate the expression patterns and mutations of ARHGAP21 as well as its prognostic significance in CCA. The biological functions of ARHGAP21 in CCA cells (RBE and Hccc9810 cell) were evaluated by scratch assay, cell counting kit-8 assay (CCK8) assay, and transwell migration assay. In addition, the underlying mechanism of ARHGAP21 involved in CCA was investigated by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the most significant signaling pathway was identified through gene set enrichment analysis (GSEA) and the Western blot method. The ssGSEA algorithm was further used to explore the immune-related mechanism of ARHGAP21 in CCA. Results: The ARHGAP21 expression in CCA tissue was higher than it was in normal tissue, and missense mutation was the main alteration of ARHGAP21 in CCA. Moreover, the expression of ARHGAP21 had obvious differences in patients with different clinical characteristics and it had great prognostic significance. Based on cell experiments, we further observed that the proliferation ability and migration ability of the ARHGAP21-knockdown group was reduced in CCA cells. Several pathological signaling pathways correlated with proliferation and migration were determined by GO and KEGG analysis. Furthermore, the PI3K/Akt signaling pathway was the most significant one. GSEA analysis further verified that ARHGAP21 was highly enriched in PI3K/Akt signaling pathway, and the results of Western blot suggested that the phosphorylated PI3K and Akt were decreased in the ARHGAP21-knockdown group. The drug susceptibility of the PI3K/Akt signaling pathway targeted drugs were positively correlated with ARHGAP21 expression. Moreover, we also discovered that ARHGAP21 was correlated with neutrophil, pDC, and mast cell infiltration as well as immune-related genes in CCA. Conclusions: ARHGAP21 could promote the proliferation and migration of CCA cells by activating the PI3K/Akt signaling pathway, and ARHGAP21 may participate in the immune modulating function of the tumor microenvironment.

HMGCL-induced ß-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility.

BACKGROUND: Metabolic disorder is an essential characteristic of tumor development. Ketogenesis is a heterogeneous factor in multiple cancers, but the effect of ketogenesis on hepatocellular carcinoma (HCC) is elusive. METHODS: We aimed to explain the role of ketogenesis-related hydroxy-methyl-glutaryl-CoA lyase (HMGCL) on HCC suppression. Expression pattern of HMGCL in HCC specimens was evaluated by immunohistochemistry (IHC). HMGCL was depleted or overexpressed in HCC cells to investigate the functions of HMGCL in vitro and in vivo. The anti-tumor function of HMGCL was studied in subcutaneous xenograft and Trp53Δhep/Δhep; c-Myc-driven HCC mouse models. The mechanism of HMGCL-mediated tumor suppression was studied by IHC, western blot (WB) and Cut & Tag. RESULTS: HMGCL depletion promoted HCC proliferation and metastasis, whereas its overexpression reversed this trend. As HMGCL catalyzes ß-hydroxy-butyric acid (ß-OHB) production, we discovered that HMGCL increased acetylation at histone H3K9, which further promoted the transcription of dipeptidyl peptidase 4 (DPP4), a key protein maintains intracellular lipid peroxidation and iron accumulation, leading to HCC cells vulnerability to erastin- and sorafenib-induced ferroptosis. CONCLUSION: Our study identified a critical role of HMGCL on HCC suppression, of which HMGCL regulated H3K9 acetylation through ß-OHB and modulating the expression of DPP4 in a dose-dependent manner, which led to ferroptosis in HCC cells.

Efficacy and safety of pocket-creation method for early gastric cancers.

BACKGROUND: Endoscopic submucosal dissection (ESD) is the standard endoscopic treatment for early gastric cancers (EGCs). However, obscured view and difficulty in submucosal lifting during ESD have been demonstrated. Additionally, ESD is time-consuming and poses a high risk of perforation and bleeding when performed in challenging locations. The pocket-creation method (PCM) is a newly developed strategy for colorectal tumors, while the outcomes of application in the treatment of EGCs are rarely reported. In the present study, we aimed to compare the technical efficacy and safety of PCM-ESD and the conventional ESD (c-ESD) technique for the treatment of EGCs. METHODS: This was a single-center retrospective study consisting of 162 patients with EGCs who underwent ESD between February 2019 and February 2021. One-to-one propensity score matching (PSM) was performed. In addition, clinicopathological characteristics and treatment outcomes were also compared. RESULTS: PCM-ESD was more likely to be used in patients with larger lesions than c-ESD with/without traction. In addition, the resection speed for lesions of the PCM-ESD was faster compared with c-ESD without traction (median dissection speed: 19.6 mm2/min vs. 15 mm2/min; p < 0.001) and c-ESD with traction (median dissection speed after PSM: 19.9 mm2/min vs. 15 mm2/min; p = 0.001). In multiple linear regression analysis, significant factors related to a higher dissection speed were the treatment method of PCM-ESD (p = 0.034), the long diameter of the resected lesion (p = 0.001), and lesion location (p = 0.046). CONCLUSIONS: Collectively, PCM-ESD appeared to be a safer and more effective treatment for EGCs than c-ESD. In addition, PCM-ESD could significantly improve the speed of tumor resection.

A Nomogram-based Model to Predict Neoplastic Risk for Patients with Gallbladder Polyps.

Background and Aims: Gallbladder polyp (GBP) assessment aims to identify the early stages of gallbladder carcinoma. Many studies have analyzed the risk factors for malignant GBPs. In this retrospective study, we aimed to establish a more accurate predictive model for potential neoplastic polyps in patients with GBPs. Methods: We developed a nomogram-based model in a training cohort of 233 GBP patients. Clinical information, ultrasonographic findings, and blood test findings were analyzed. Mann-Whitney U test and multivariate logistic regression analyses were used to identify independent predictors and establish the nomogram model. An internal validation was conducted in 225 consecutive patients. Performance and clinical benefit of the model were evaluated using receiver operating characteristic curves and decision curve analysis (DCA), respectively. Results: Age, cholelithiasis, carcinoembryonic antigen, polyp size, and sessile shape were confirmed as independent predictors of GBP neoplastic potential in the training group. Compared with five other proposed prediction methods, the established nomogram model presented better discrimination of neoplastic GBPs in the training cohort (area under the curve [AUC]: 0.846) and the validation cohort (AUC: 0.835). DCA demonstrated that the greatest clinical benefit was provided by the nomogram compared with the other five methods. Conclusions: Our developed preoperative nomogram model can successfully be used to evaluate the neoplastic potential of GBPs based on simple clinical variables that maybe useful for clinical decision-making.

PI3K/AKT/mTOR Pathway-Associated Genes Reveal a Putative Prognostic Signature Correlated with Immune Infiltration in Hepatocellular Carcinoma.

Background: The dysregulated PI3K/AKT/mTOR pathway acts as the main regulator of tumorigenesis in hepatocellular carcinoma (HCC). Aim: Here, we identify the prognostic significance of PI3K/AKT/mTOR pathway-associated genes (PAGs) as well as their putative signature based on PAGs in an HCC patient's cohort. Methods: The transcriptomic data and clinical feature sets were queried to extract the putative prognostic signature. Results: We identified nine PAGs with different expressions. GO and KEGG indicated that these differentially expressed genes were associated with various carcinogenic pathways. Based on the signature-computed median risk score, we categorized the patients into groups of low risk and high risk. The survival time for the low-risk group is longer than that of the high-risk group in Kaplan-Meier (KM) curves. The prognostic value of risk score (ROC = 0.736) of receiver operating characteristic (ROC) curves performed better in comparison to that of other clinicopathological features. In both the GEO database and ICGC database, these outcomes were verified. The predictions of the overall survival rates in HCC patients of 1 year, 3 years, and 5 years can be obtained separately from the nomogram. The risk score was associated with the immune infiltrations of CD8 T cells, activated CD4 memory T cells, and follicular helper T cells, and the expression of immune checkpoints (PD-1, TIGIT, TIM-3, BTLA, LAG-3, and CTLA4) was positively relevant to the risk score. The sensitivity to several chemotherapeutic drugs can also be revealed by the signature. CDK1, PITX2, PRKAA2, and SFN were all upregulated in the tumor tissue of clinical samples. Conclusion: A putative and differential dataset-validated prognostic signature on the basis of integrated bioinformatic analysis was established in our study, providing the immunotherapeutic targets as well as the personalized treatment in HCC with neoteric insight.

A nomogram-based model and ultrasonic radiomic features for gallbladder polyp classification.

BACKGROUND AND AIM: Gallbladder polyps (GBPs) are relatively common. Many studies have attempted to distinguish between benign and neoplastic GBPs to identify early-stage gallbladder carcinoma. We have established an accurate neoplastic predictive model and evaluated the effectiveness of radiomics in predicting malignancy in patients with GBPs. METHODS: A total of 503 patients confirmed through postoperative pathology were included in this retrospective study. Clinical information and ultrasonographic findings were retrospectively analyzed. The model was constructed from independent risk factors using Spearman correlation and logistic regression analysis of a training cohort of 250 GBP patients, and its efficacy was verified using an internal validation group of 253 consecutive patients through the receiver operating characteristic curve (ROC). The area of GBPs was delimited manually, and the texture features of ultrasound images were analyzed using correlation and ROC analysis. RESULTS: Independent predictors, including age, gallstones, carcinoembryonic antigen, polyp size, and sessile shape, were incorporated into the nomogram model for the neoplastic potential of GBPs. Compared with other proposed prediction methods, the established nomogram model showed good discrimination ability in the training group (area under the curve [AUC]: 0.865) and validation group (AUC: 0.845). Regarding ultrasonic radiomics, the minimum caliper diameter was identified as the only independent predictor (AUC: 0.841). CONCLUSIONS: Our preoperative nomogram model can successfully evaluate the neoplastic potential of GBPs using simple clinical data, and our study verified the use of radiomics in GBP identification, which may be valuable for avoiding unnecessary surgery in patients.

Long-term iTBS promotes neural structural and functional recovery by enhancing neurogenesis and migration via miR-551b-5p/BDNF/TrkB pathway in a rat model of cerebral ischemia-reperfusion injury.

As a novel form of repetitive transcranial stimulation, intermittent theta burst stimulation (iTBS) has potentials to be widely used in patients with stroke. Yet little is known about the idiographic actions of iTBS with different stimulation parameters on rehabilitative aspects of stroke patients, nor is the molecular mechanism underlying. In the present study, effects of iTBS with different stimulation parameters were evaluate to identify the optimal protocol of iTBS against damage induced by ischemia/reperfusion (I/R). Herein we found the short-term iTBS application seemed to have no significant effects on outcomes of rats during acute phase after I/R, including the neurological deficits, cerebral infarction and edema. However, behavioral functional tests demonstrated that long-term iTBS treatment provided effective therapy during subacute stage after two weeks post-stroke onset, which possibly by increasing proliferation and migration of adult neural stem cells. To explore the possible mechanisms of, microRNAs (miRs) expressional profiles were analyzed by microarray technology. Further bioinformatic analysis of binding sites revealed miR-551b-5p directly targeted the brain-derived neurotrophic factor (BDNF), which was confirmed by luciferase reporter and qRT-PCR. Moreover, the level phosphorylated-TrkB, the downstream of BDNF, was elevated accompanied by above-mentioned changes of long-term iTBS. Taken together, experimental data reveals a direct link between miR-551b-5p and BDNF-mediated signaling cascade in early convalescence of stroke. Our findings provide new insights into the molecular mechanisms underlying curative effects of iTBS on stroke, thus aiding in the prognosis and personalized therapies.