The inhibitor of the redox activity of APE1/REF-1, APX2009, reduces the malignant phenotype of breast cancer cells

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/REF-1) is a multifunctional protein acting on cellular signaling pathways, including DNA repair and redox activities. APE1/REF-1 has emerged as a target for cancer therapy, and its role in breast cancer models would reveal new strategies for cancer therapy. APX2009 is a specific APE1/REF-1 redox inhibitor whose anticancer properties have not been described in breast cancer cells. Here, we investigated the effect of the APX2009 treatment in the breast cancer cell lines MDA-MB-231 and MCF-7. Breast cancer cell lines were cultured, and WST1 and colony formation assays were performed to evaluate cell proliferation. Annexin V-FITC/7-AAD and LDH-Glo™ assays were performed to evaluate cell death. The wound healing assay and Matrigel transwell assay were performed after APX2009 treatment to evaluate the cellular migration and invasion processes, respectively. Our findings demonstrated that APX2009 treatment decreased breast cancer cell proliferative, migratory, and invasive properties. Furthermore, it induced apoptosis in both cell lines. Our study is the first to show the effects of APX2009 treatment on apoptosis in a breast cancer cell. Therefore, this study suggested that APX2009 treatment is a promising anticancer molecule for breast cancer.

Fluoruro de estaño en el control de cavidades sin restauración en dientes temporales / Stannous fluoride in nonrestorative cavity control in primary teeth

Introducción: el control de cavidades sin restauración (NRCC, por sus siglas en inglés), es una opción de tratamiento conservador y no invasivo para dentina cariosa, sobre todo en dentición temporal. Una de las estrategias del NRCC es la remineralización. El fluoruro de estaño (FDE) puede considerarse, como una opción viable ya que existe evidencia de su eficacia cariostática. Objetivo: valorar al FDE como remineralizante alternativo en dentina de molares temporales, asociado al NRCC. Material y métodos: se efectuó un estudio clínico, epidemiológico, y descriptivo con preescolares voluntarios de 3 a 5 años de edad con consentimiento firmado de participación en el estudio, y que presentaron molares con ICDAS 5 y 6. La aplicación del FDE a 0.8%, la evaluación de la dureza de la dentina con los criterios de Nyvad, y el diagnóstico del estado pulpar, la efectuó un operador entrenado para esta finalidad. Se aplicó un análisis estadístico descriptivo y uno no paramétrico. Resultados: el efecto cariostático producido por el FDE a 0.8%, sobre dentina afectada de molares temporales de niños mexicanos fue estadísticamente significativo durante cinco meses. Conclusiones: la aplicación de fluoruro de estaño puede considerarse como una alternativa de tratamiento cariostático asociado al NRCC para niños de 3 a 5 años de edad (AU)

Introduction: nonrestorative cavity control (NRCC), is a conservative and non-invasive treatment option for carious dentin, especially in primary dentition. One of the NRCC strategies is remineralization. Stannous Fluoride (SDF) can be considered as a viable option since there is evidence of its cariostatic efficacy. Objective: to evaluate FDE as an alternative remineralizing agent in the dentin of primary molars, associated with NRCC. Material and methods: a clinical, epidemiological, and descriptive study was carried out with preschool volunteers aged 3 to 5 years with signed consent to participate in the study, and who presented molars with ICDAS 5 and 6. The application of FDE at 0.8%, the evaluation of dentin hardness with the Nyvad criteria, and the diagnosis of pulp status, was carried out by an operator trained for this purpose. A descriptive and non-parametric statistical analysis was applied. Results: the cariostatic effect produced by 0.8% FDE on affected dentin of primary molars of Mexican children was statistically significant for five months. Conclusions: the application of stannous fluoride can be considered as an alternative cariostatic treatment associated with NRCC for children 3 to 5 years of age (AU)

Golgi Transport 1A Promotes Cell Proliferation and Metastasis of Papillary Thyroid Carcinoma / 中山大学学报(医学科学版)

ObjectiveTo investigate the expression level of Golgi transport 1A （GOLT1A） in thyroid carcinoma and its effects on the proliferation， migration， invasion， and epithelial-mesenchymal transition （EMT） of thyroid carcinoma cells. MethodsThe expression of GOLT1A in thyroid carcinoma was analyzed online by tumor immune estimation resource （TIMER）， the University of Alabama at Birmingham cancer data analysis portal （UALCAN）， gene expression profiling interactive analysis 2 （GEPIA2）. The expression level of GOLT1A in thyroid carcinoma cells was detected by real-time fluorescence quantitative polymerase chain reaction （RTFQ-PCR） and western blot. Cell counting kit-8 （CCK-8） assay， colony formation assay， and transwell assay were used to detect the effects of GOLT1A expression on the proliferation， migration， and invasion of thyroid carcinoma cells. Western blot assay was used to detect the effect of GOLT1A on the expression of EMT-related genes including E-cadherin， vimentin， and N-cadherin. ResultsThe online analysis of GEPIA2， TIMER， and UALCAN showed that the expression of GOLT1A was higher in thyroid carcinoma than in normal tissues， and the expression of GOLT1A in thyroid carcinoma cells was significantly higher than in normal control cells. Knockdown of GOLT1A inhibited TPC1 cell proliferation， migration， and invasion. The expression of E-cadherin increased and the expressions of N-cadherin and vimentin decreased in GOLT1A knockdown TPC1 cells. Overexpression of GOLT1A promoted BCPAP cell proliferation， migration， and invasion. The expression of E-cadherin decreased and the expressions of N-cadherin and vimentin increased in GOLT1A overexpression BCPAP cells. ConclusionGOLT1A is highly expressed in thyroid carcinoma and can promote the proliferation， migration， and invasion of thyroid carcinoma cells.

Down-regulation of METTL5 inhibits proliferation, migration and invasion of triple-negative breast cancer cells through Wnt/6-catenin signaling pathway / 中国药理学通报

Aim To investigate the role and potential mechanism of methyltransferase-like 5 (METTL5) in triple-negative breast cancer (TNBC) . Methods The expression of METTL5 in TNBC tumor tissues and cell lines was detected by immunohistochemistry and Western blot. After shRNA targeting METTL5 (shRNAMETTL5) was transfected into TNBC cells, cell proliferation, migration and invasion were detected by CCK-8, colony formation, wound healing and Transwell assays, respectively. Western blot was used to detect the expression of Wnt/p-catenin signaling-related key proteins. A xenograft tumor model was constructed to verify the effect of METTL5 knockdown on the growth of TNBC cells and Wnt/p-catenin signaling activity in vivo. Results The expression of METTL5 was up-regulated in TNBC tumor tissues and cell lines (P < 0. 01) . Knockdown of METTL5 significantly inhibited the proliferation, migration and invasion of TNBC cells and reduced the expression of Wnt/p-catenin signaling molecules (3-catenin, cyclin Dl, matrix metalloproteinase (MMP) -2 and MMP-7 (all P < 0. 01) . Knockdown of METTL5 reduced tumor growth and Wnt/pcatenin signaling activity in vivo. Conclusions Knockdown of METTL5 can inhibit the proliferation, migration and invasion of TNBC cells, which may be related to the inhibition of Wnt/p-catenin signaling pathway.

Effects of polydatin on the cell proliferation，migration，invasion and tumor growth of AML / 中国药房

OBJECTIVE To investigate the effects of polydatin （PD） on cell proliferation， migration， invasion and tumor growth of acute myeloid leukemia （AML）. METHODS Human AML cell KG-1 were divided into normal group， PD low-， medium- and high-concentration groups （10， 30， 60 μmol/L PD）， SQ22536 group [cyclic adenosine monophosphate （cAMP） inhibitor， 100 μmol/L]， high concentration of PD+SQ22536 group （60 μmol/L PD+100 μmol/L SQ22536）. The effects of PD on cell activity， apoptotic rate， invasion and migration ability， cAMP level， the expression of epithelial-mesenchymal transition （EMT） related proteins and protein kinase A （PKA） were investigated. Using BALB/c nude mice as subjects， a transplanted tumor model of AML nude mice was induced by subcutaneous inoculation of KG-1 cell suspension and then divided into control group， PD group， SQ22536 group and PD+SQ22536 group （with 6 mice in each group）. The effects of PD on tumor volume and mass were measured. RESULTS Compared with the normal group or control group， the cell viabilities， the number of migrating cells， the number of invasive cells， the relative expressions of vimentin and Snail as well as the tumor volume and mass were decreased significantly in PD groups， while the apoptotic rates， cAMP levels， the relative expressions of E-cadherin and PKA were significantly increased， with a dose-dependent manner （P＜0.05）. SQ22536 had opposite effects on cells and nude mice compared to PD， and could significantly reverse the anti-tumor activity of PD （P＜0.05）. CONCLUSIONS PD may inhibit the proliferation， migration， invasion and EMT process of KG-1 cells， induce apoptosis， and inhibit tumor growth， by activating the cAMP/PKA signaling pathway， thereby exerting anti-AML effects.

Effect of picroside Ⅱ on the malignant progression of non-small cell lung cancer / 中国药房

OBJECTIVE To investigate the effect and mechanism of picroside Ⅱ on the malignant progression of non-small cell lung cancer （NSCLC）. METHODS A549 cells were divided into the control group， picroside Ⅱ low-， medium- and high- concentration groups， K6PC-5 [sphingosine kinase 1 （SPHK1） activator] group， and picroside Ⅱ high-dose+K6PC-5 group. Cell proliferation， migration and invasion were detected. Besides， the expression of proliferating cell nuclear antigen （PCNA）， matrix metalloproteinase-2 （MMP-2）， MMP-9， SPHK1， sphingosine-1-phosphate receptor 3 （S1PR3） and extracellular signal-regulated kinase 1/2 （ERK1/2） protein in the cells were also observed. BALB/c nude mice were subcutaneously inoculated with A549 cell suspension to establish NSCLC xenograft models. Then they were assigned to the nude mouse-control group， nude mouse-picroside Ⅱ low-， medium- and high-dose groups， nude mouse-K6PC-5 group， and nude mouse-picroside Ⅱ high-dose+K6PC-5 group （with 5 mice in each group） to investigate the effect of picroside Ⅱ on their tumor mass and volume. RESULTS Compared with the control group， the OD450 values， EdU-positive cell rates， scratch healing rates， cell invasion number， and the relative expression levels of PCNA， MMP-2， MMP-9， SPHK1， S1PR3 and ERK1/2 protein in the low-， medium- and high-concentration groups of picroside Ⅱ were significantly decreased. Compared with the nude mouse-control group， the tumor mass and volume in the nude mouse-low-， medium- and high-dose groups of picroside Ⅱ were significantly decreased or shrunk. The changes of above indicators were concentration/dose-dependent （P＜0.05）. The changing trend of the corresponding indicators in the K6PC-5 ZYTS181） group and the nude mouse-K6PC-5 group was opposite （P＜0.05）. Compared with the picroside Ⅱ high-concentration group or the nude mice-picroside Ⅱ high-dose group， the above quantitative indicators in the picroside Ⅱ high- concentration+K6PC-5 group cells and the nude mouse-picroside Ⅱ high-dose+K6PC-5 group nude mice were significantly increased or enlarged （P＜0.05）. CONCLUSIONS Picroside Ⅱ may inhibit the malignant progression of NSCLC by inhibiting SPHK1/sphingosine-1-phosphate/S1PR3 signaling pathway.

The association of visceral pleural invasion with skip N2 metastasis on clinical stage IA NSCLC

Abstract Background Lung lymphatic drainage occurs mainly through a peribronchial path, but it is hypothesized that visceral pleural invasion could alter this path. This study aims to investigate the association between visceral pleural invasion, node upstaging, and N2 skip metastasis and the impact on survival in a population of patients with non-small cell lung cancer of 3 cm or smaller. Methods We retrospectively queried our institutional database of lung cancer resection for all patients with clinical stage IA NSCLC between June 2009 and June 2022. We collected baseline characteristics and clinical and pathological staging data. Patients were classified into two groups: The non-VPI group with negative visceral pleural invasion and the VPI group with positive. The primary results analyzed were the occurrence of nodal upstaging, skip N2 metastasis and recurrence. Results There were 320 patients analyzed. 61.3 % were women; the median age was 65.4 years. The pleural invasion occurred in 44 patients (13.7 %). VPI group had larger nodules (2.3 vs. 1.7 cm; p < 0.0001), higher 18F-FDG uptake (7.4 vs. 3.4; p < 0.0001), and lymph-vascular invasion (35.7 % vs. 13.5 %, p = 0.001). Also, the VPI group had more nodal disease (25.6 % vs. 8.7 %; p = 0.001) and skip N2 metastasis (9.3 % vs. 1.8 %; p = 0.006). VPI was a statistically independent factor for skip N2 metastasis. Recurrence occurred in 17.2 % of the population. 5-year disease-free and overall survival were worse in the VPI group. Conclusions The visceral pleural invasion was an independent factor associated with N2 skip metastasis and had worse disease-free and overall survival.

circCPA4 induces malignant behaviors of prostate cancer via miR-491-5p/ SHOC2 feedback loop

ABSTRACT Objective: circCPA4 has been defined to be an oncogenic gene. This study examined whether circCPA4 regulates Prostate Cancer (PC) development and revealed its molecular mechanism. Methods: PC tissues and PC cell lines were collected, in which circCPA4/miR-491-5p/SHOC2 levels were evaluated by RT-qPCR and immunoblot. Colony formation assay and EdU assay assessed cell proliferation, flow cytometry measured apoptosis, and Transwell assessed invasion and migration. Ki-67, cleaved caspase-3, E-cadherin, and N-cadherin were evaluated by immunoblot. Based on the luciferase reporter assay and RIP assay the authors investigated the targeting relationship between circCPA4/miR-491-5p/SHOC2. The effect of circCPA4 on tumor growth was evaluated by xenotransplantation in nude mice. Results: circCPA4 and SHOC2 levels were abundant while miR-491-5p expression was low in PC. Loss of circCPA4 decreased the proliferation and EdU-positive rate of PC cells, enhanced apoptosis, and inhibited invasion, migration, and EMT. Upregulation of circCPA4 forced the malignant behaviors of PC cells, and this promotion could be abolished when miR-491-5p was overexpressed or SHOC2 was silenced. CircCAP4 competitively decoyed miR-491-5p mediating SHOC2 expression. circCAP4 suppression inhibited PC tumor growth. Conclusion: circCAP4 acts as a novel oncogenic factor in PC, accelerating the malignant behavior of PC cells via miR-491-5p/SHOC2 interaction. This novel ceRNA axis may be a potential target for PC drug development and targeted therapy in the future.

The association of polypoid growth pattern with lymphnode involvement in endometrioid type endometrial adenocarcinoma

Background: Tumor size is an independent predictor of lymph node metastasis and survival in the endometrioid type endometrial adenocarcinoma (EC). However, some of the ECs tend to grow towards the cavity in the polypoid pattern, which can reach very large sizes. In this study, we aimed to analyze the association of growing in the polypoid pattern of the tumor with the proportion of lymph node metastasis and extrauterine tumor spread. Methods: Four hundred seven patients were analyzed retrospectively. The effect of tumor size, tumor growing pattern, myometrial invasion, grade, and lymphovascular space invasion on the lymph node metastasis and extrauterine tumor spread were investigated. Statistical analysis consisted of unpaired t?tests for parametric data and Mann Whitney?U test for non?parametric data, whereas the Chi?square test for categorical variables. Logistic Regression, Cox Regression and multivariate analysis were used to estimate the risk predictors. Results: No association was found between the growing in polypoid pattern and lymph node metastasis (P > 0.05). In the analysis of endometrioid type EC patients who had myometrial invasion less than � as a subgroup, no association was found between the growing pattern and lymph node metastasis and extrauterine disease. Tumor size was found to be a statistically significant predictor of lymph node metastasis and extrauterine disease (P < 0.05). Conclusions: Lymphovascular space invasion, grade, and myometrial invasion are associated with a higher proportion of lymph node metastasis. The polypoid growth pattern of the tumor does not correlate with any histopathological parameters

MicroRNA-150-5p inhibits the proliferation and invasion of human larynx epidermiod cancer cells though regulating peptidyl-prolyl cis/trans isomerase

Abstract Objective This study aimed to investigate the molecular mechanism of miR-150-5p regulating the malignant biological behavior of Human Epidermoid cancer cell (HEp-2) by targeting peptidyl-prolyl cis/trans isomerase NIMA-Interacting-1 (PIN1). Methods Firstly, qRT-PCR and Western blot were adopted to detect the expression levels of miR-150-5p and PIN1 in cancer tissue and paracancerous tissues of patients with LSCC, and those in human bronchial epithelial cells (16 HBE) and HEp-2. Next, the targeted relationship between miR-150-5p and PIN1 was assessed by bioinformatics website and dual-luciferase reporter assay, followed by their correlation analysis. Besides, after interfering with miR-150-5p or PIN1 expression in HEp-2 cells, CCK-8, cell colony formation assay, and transwell assay were utilized to detect the proliferation, viability, and invasion of cells, respectively. Subsequently, the protein levels of MMP-2, MMP-9, and EMT-related proteins in HEp-2 cells were checked by Western blot. Results Expression of miR-150-5p was down-regulated in LSCC tissues and HEp-2 cells. Moreover, miR-150-5p suppressed proliferation and invasion of HEp-2 cells, affected protein expression related to MMP and EMT, thereby inhibiting development of cancer. The expression of PIN1 was significantly increased in cancer tissues and HEp-2 cells, and there was a targeted relationship and negative correlation between miR-150-5p and PIN1 in cancer tissue. However, overexpression of PIN1 could reverse the effect of miR-150-5p on the proliferation and invasion of HEp-2 cells. Conclusion In a nutshell, there is a targeted relationship between PIN1 and miR-150-5p. Besides, miR-150-5p can inhibit the proliferation and invasion of HEp-2 cells by regulating the expression of PIN1. Level of evidence 3.

Hydnocarpin inhibits malignant progression of triple negative breast cancer via CNOT4-mediated ubiquitination and degradation of YAP / 中国中药杂志

This study aims to investigate the effect and mechanism of hydnocarpin(HC) in treating triple negative breast cancer(TNBC). Cell counting kit-8(CCK-8), xCELLigence real-time cellular analysis(RTCA), and colony formation assay were employed to determine the effects of HC on the proliferation of two TNBC cell lines: MDA-MB-231 and MDA-MB-436. The effects of HC on the migration and invasion of TNBC cells were detected by high-content analysis, wound-healing assay, and Transwell assay. The changes in the epithelial-mesenchymal transition(EMT) and the expression of invasion-and migration-associated proteins [E-cadherin, vimentin, Snail, matrix metalloproteinase-2(MMP-2), and MMP-9] were detected by Western blot. Western blot and RT-qPCR were employed to determine the protein and mRNA levels of Yes-associated protein(YAP) and downstream targets(CTGF and Cyr61). TNBC cells were transfected with Flag-YAP for the overexpression of YAP, and the role of YAP as a key target for HC to inhibit TNBC malignant progression was examined by CCK-8 assay, Transwell assay, and wound-healing assay. The pathway of HC-induced YAP degradation was detected by the co-treatment of proteasome inhibitor with HC and ubiquitination assay. The binding of HC to YAP and the E3 ubiquitin ligase Ccr4-not transcription complex subunit 4(CNOT4) was detected by microscale thermophoresis(MST) assay and drug affinity responsive target stability(DARTS) assay. The results showed that HC significantly inhibited the proliferation, colony formation, invasion, and EMT of TNBC cells. HC down-regulated the protein and mRNA levels of CTGF and Cyr61. HC down-regulated the total protein level of YAP, while it had no effect on the mRNA level of YAP. The overexpression of YAP antagonized the inhibitory effects of HC on the proliferation, migration, and invasion of TNBC cells. HC promoted the degradation of YAP through the proteasome pathway and up-regulated the ubiquitination level of YAP. The results of MST and DARTS demonstrated direct binding between HC, YAP, and CNOT4. The above results indicated that HC inhibited the malignant progression of TNBC via CNOT4-mediated degradation and ubiquitination of YAP.

Effect of acetylalkannin from Arnebia euchroma on proliferation, migration, and invasion of human melanoma A375 cells / 中国中药杂志

This study aimed to explore the effect and mechanism of acetylalkannin from Arnebia euchroma on the proliferation, migration, and invasion of human melanoma A375 cells. A375 cells were divided into a blank group, and low-, medium-, and high-dose acetylalkannin groups(0.5, 1.0, and 2.0 μmol·L~(-1)). The MTT assay was used to detect cell proliferation. Cell scratch and transwell migration assays were used to detect cell migration ability, and the transwell invasion assay was used to detect cell invasion ability. Western blot was used to detect the protein expression of migration and invasion-related N-cadherin, vimentin, matrix metalloproteina-se-9(MMP-9), and Wnt/β-catenin pathway-related Wnt1, Axin2, glycogen synthase kinase-3β(GSK-3β), phosphorylated GSK-3β(p-GSK-3β), β-catenin, cell cycle protein D_1(cyclin D_1), and p21. Real-time fluorescence-based quantitative polymerase chain reaction(real-time PCR) was used to detect the mRNA expression of E-cadherin, matrix metalloproteinase-2(MMP-2), N-cadherin, vimentin, β-catenin, snail-1, and CD44. MTT results showed that the cell inhibition rates in the acetylalkannin groups significantly increased as compared with that in the blank group(P<0.01). The results of cell scratch and transwell assays showed that compared with the blank group, the acetylalkannin groups showed reduced cell migration and invasion, and migration and invasion rates(P<0.05, P<0.01) and weakened horizontal and vertical migration and invasion abilities. Western blot results showed that compared with the blank group, the high-dose acetylalkannin group showed increased expression of Axin2 protein(P<0.05), and decreased expression of N-cadherin, vimentin, MMP-9, Wnt1, p-GSK-3β, β-catenin, cyclin D_1, and p21 proteins(P<0.05, P<0.01). The expression of GSK-3β protein did not change significantly. PCR results showed that the overall trend of MMP-2, N-cadherin, vimentin, β-catenin, snail-1, and CD44 mRNA expression was down-regulated(P<0.01), and the expression of E-cadherin mRNA increased(P<0.01). Acetylalkannin can inhibit the proliferation, migration, and invasion of human melanoma A375 cells, and its mechanism of action may be related to the regulation of Wnt/β-catenin signaling pathway.

Junctional adhesion molecule-like protein as a novel target for kaempferol to ameliorate lung adenocarcinoma / 中西医结合学报

OBJECTIVE@#Although there have been improvements in targeted therapy and immunotherapy, the majority of lung adenocarcinoma (LUAD) patients still lack effective therapies. Consequently, it is urgent to screen for new diagnosis biomarkers and pharmacological targets. Junctional adhesion molecule-like protein (JAML) was considered to be an oncogenic protein and may be a novel therapeutic target in LUAD. Kaempferol is a natural flavonoid that exhibits antitumor activities in LUAD. However, the effect of kaempferol on JAML is still unknown.@*METHODS@#Small interfering RNA was used to knockdown JAML expression. The cell viability was determined using the cell counting kit-8 assay. The proliferation of LUAD cells was evaluated using the 5-ethynyl-2'-deoxyuridine incorporation assay. The migration and invasion of LUAD cells were evaluated by transwell assays. Molecular mechanisms were explored by Western blotting.@*RESULTS@#JAML knockdown suppressed proliferation, migration and invasion of LUAD cells, and JAML deficiency restrained epithelial-mesenchymal transition (EMT) via inactivating the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Using a PI3K activator (740Y-P), rescue experiments showed that phenotypes to JAML knockdown in LUAD cells were dependent on the PI3K/AKT/mTOR pathway. Kaempferol also inhibited proliferation, migration and invasion of A549 and H1299 cells and partially suppressed EMT through the PI3K/AKT/mTOR pathway. Knockdown of JAML ameliorated the inhibitory effect of kaempferol on LUAD cells. Kaempferol exerted anticancer effects by targeting JAML.@*CONCLUSION@#JAML is a novel target for kaempferol against LUAD cells. Please cite this article as: Wu Q, Wang YB, Che XW, Wang H, Wang W. Junctional adhesion molecule-like protein as a novel target for kaempferol to ameliorate lung adenocarcinoma. J Integr Med. 2023; 21(3): 268-276.

Development and validation of a nomogram model for preoperative prediction of hepatocellular carcinoma with microvascular invasion / 中华肝胆外科杂志

Objective:To develop and validate a nomogram model for predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC) based on preoperative enhanced computed tomography imaging features and clinical data.Methods:The clinical data of 210 patients with HCC undergoing surgery in the Second Affiliated Hospital of Anhui Medical University from May 2018 to May 2022 were retrospectively analyzed, including 172 males and 38 females, aged (59±10) years old. Patients were randomly divided into the training group ( n=147) and validation group ( n=63) by systematic sampling at a ratio of 7∶3. Preoperative enhanced computed tomography imaging features and clinical data of the patients were collected. Logistic regression was conducted to analyze the risk factors for HCC with MVI, and a nomogram model containing the risk factors was established and validated. The diagnostic efficacy of predicting MVI status in patients with HCC was assessed by receiver operating characteristic (ROC) curve, calibration curves, decision curve analysis (DCA), and clinical impact curve (CIC) of the subjects in the training and validation groups. Results:The results of multifactorial analysis showed that alpha fetoprotein ≥400 μg/ml, intra-tumor necrosis, tumor length diameter ≥3 cm, unclear tumor border, and subfoci around the tumor were independent risk factors predicting MVI in HCC. A nomogram model was established based on the above factors, in which the area under the curve (AUC) of ROC were 0.866 (95% CI: 0.807-0.924) and 0.834 (95% CI: 0.729-0.939) in the training and validation groups, respectively. The DCA results showed that the predictive model thresholds when the net return is >0 ranging from 7% to 93% and 12% to 87% in the training and validation groups, respectively. The CIC results showed that the group of patients with predictive MVI by the nomogram model are highly matched with the group of patients with confirmed MVI. Conclusion:The nomogram model based on the imaging features and clinical data could predict the MVI in HCC patients prior to surgery.

Effects of methyl methanesulfonate and UV sensitive gene clone 81 on hepatocellular carcinoma cells / 中华肝胆外科杂志

Objective:To detect the expression of methyl methanesulfonate and UV sensitive gene clone 81 (Mus81) in hepatocellular carcinoma(HCC) and to observe the effects of Mus81 on the migration, invasion and metastatic ability of human HCC cells.Methods:Thirty-two tissue specimens were selected from HCC tissues and corresponding paraneoplastic tissues of patients with HCC who underwent surgical resection in Guangzhou Red Cross Hospital Affiliated to Jinan University from January 2020 to June 2021. The expression levels of Mus81 in 32 HCC specimens, 374 HCC samples from the cancer genome atlas database, human normal liver cell line HL-7702 and human HCC cell lines JHH-7, Huh-7 and Hep3B were analyzed. Mus81 knockdown in JHH-7, Huh-7 and overexpressed in Hep3B HCC cell lines were constructed, and the effects of Mus81 on HCC cells were observed by scratch assay, Transwell migration and invasion assay and tail vein injection transfer assay in nude mice.Results:The expression of Mus81 was higher in HCC tissues or cell lines than which in paraneoplastic tissues or normal hepatocyte lines (all P<0.05). The migration rate, metastatic and invasive cell numbers of Mus81-knockdown Huh-7 HCC cells were 22.24%±2.16%, 49.04±5.62, 3.81±1.08, the negative control group were 26.89%±1.15%, 86.81±4.79, 19.78±3.30, and the differences between the two groups were statistically significant ( t=4.24, 26.59, 23.92, all P<0.01). The migration rate, metastatic and invasive cell numbers of Mus81-overexpressed Hep3B HCC cells were 80.57%±5.12%, 18.74±8.07, 33.81±8.44, which were significantly higher than those of the empty vector group 64.17%±7.20%, 10.96±5.32, 3.04±1.13, and the differences were statistically significant ( t=4.15, 4.18, 18.78, all P<0.01). Tail vein transfer experiments in nude mice showed that the total fluorescence expression, weight of metastatic tumors, and the metastatic rates in kidney, vertebral column, neck, axilla and subcutis in nude mice injected with Mus81-knockdown JHH-7 cells were significantly lower than those in the control group (all P<0.05). Conclusion:Mus81 gene expression is upregulated in HCC and promotes the migration, invasion and metastatic ability of HCC cells, suggesting that Mus81 may be a potential therapeutic target for HCC.

Performance of laminin γ2 in diagnosing hepatocellular carcinoma and in microvascular invasion / 中华肝胆外科杂志

Objective:To analyze the value of laminin γ2 (LAMC2) in the diagnosis of hepatocellular carcinoma (HCC) and the difference in patients with different types of microvascular invasion (MVI).Methods:A cohort of 100 patients with HCC who underwent surgical treatment at the Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital from January 2021 to March 2022 were prospectively enrolled. There were 80 males and 20 females, aged (55.7±11.1) years. The data of 17 patients with hepatic hemangioma without cirrhosis who underwent operation at the same hospital during the study period were collected to serve as the control group (6 males, 11 females), aged (42.8±9.8) years. LAMC2 in serum was determined by enzyme linked immunosorbent assay. The levels of alpha-fetoprotein (AFP) and LAMC2 were compared between the two groups, and receiver operating characteristic (ROC) curves were drawn to compare these two markers in the diagnosis of HCC. The LAMC2 of different MVI patients were compared.Results:The levels of LAMC2 and AFP were 1 334.2(838.9, 2 656.0) pg/ml and 19.0(4.6, 778.6) μg/L in the HCC group, which were significantly higher than 375.2(221.2, 691.7)pg/ml and 3.3(2.5, 3.5) μg/L in the control group ( Z=-4.32, -4.63, both P<0.001). The areas under the ROC curve were 0.829(95% CI: 0.748-0.892) for LAMC2 and 0.852(95% CI: 0.769-0.910) for AFP, and was 0.949(95% CI: 0.911-0.988) for using both in the diagnoses. The diagnostic efficacy of combining LAMC2 and AFP was significantly better than that of LAMC2 alone and AFP alone (area under ROC: Z=3.15, 3.07, P=0.002, 0.002). When the patients were divided into the M0 group (61 patients), the M1 Group (25 patients) and the M2 Group (14 patients) based on MVIs, the concentrations of LAMC2 were 1 168.6(834.3, 2 521.4) pg/ml, 942.2(614.0, 2 056.6) pg/ml and 3 128.4(1 852.7, 7 191.3) pg/ml, respectively. The level of LAMC2 in the M2 group was significantly higher than that in the M0 and M1 groups ( Z=-3.46, -3.32, P=0.001, 0.004). Conclusion:The diagnostic efficacy of LAMC2 combined with AFP for HCC was significantly higher than that of either LAMC2 alone or AFP alone. Serum LAMC2 levels were significant different among the groups of HCC patients with different types of MVI.

Preoperative prediction of vessel invasion in locally advanced gastric cancer based on venous phase enhanced CT radiomics and machine learning / 中华放射学杂志

Objective:To evaluate the value of preoperative prediction of vessel invasion (VI) of locally advanced gastric cancer by machine learning model based on the venous phase enhanced CT radiomics features.Methods:A retrospective analysis of 296 patients with locally advanced gastric cancer confirmed by pathology in the First Affiliated Hospital of Zhengzhou University from July 2011 to December 2020 was performed. The patients were divided into VI positive group ( n=213) and VI negative group ( n=83) based on pathological results. The data were divided into training set ( n=207) and test set ( n=89) according to the ratio of 7∶3 with stratification sampling. The clinical characteristics of patients were recorded, and the independent risk factors of gastric cancer VI were screened by multivariate logistic regression. Pyradiomics software was used to extract radiomic features from the venous phase enhanced CT images, and the minimum absolute shrinkage and selection algorithm (LASSO) was used to screen the features, obtain the optimal feature subset, and establish the radiomics signature. Four machine learning algorithms, including extreme gradient boosting (XGBoost), logistic, naive Bayes (GNB), and support vector machine (SVM) models, were used to build prediction models for the radiomics signature and the screened clinical independent risk factors. The efficacy of the model in predicting gastric cancer VI was evaluated by the receiver operating characteristic curve. Results:The degree of differentiation (OR=13.651, 95%CI 7.265-25.650, P=0.003), Lauren′s classification (OR=1.349, 95%CI 1.011-1.799, P=0.042) and CA199 (OR=1.796, 95%CI 1.406-2.186, P=0.044) were independent risk factors for predicting the VI of locally advanced gastric cancer. Based on the venous phase enhanced CT images, 864 quantitative features were extracted, and 18 best constructed radiomics signature were selected by LASSO. In the training set, the area under the curve (AUC) of XGBoost, logistic, GNB and SVM models for predicting gastric cancer VI were 0.914 (95%CI 0.875-0.953), 0.897 (95%CI 0.853-0.940), 0.880 (95%CI 0.832-0.928) and 0.814 (95%CI 0.755-0.873), respectively, and in the test set were 0.870 (95%CI 0.769-0.971), 0.877 (95%CI 0.788-0.964), 0.859 (95%CI 0.755-0.961) and 0.773 (95%CI 0.647-0.898). The logistic model had the largest AUC in the test set. Conclusions:The machine learning model based on the venous phase enhanced CT radiomics features has high efficacy in predicting the VI of locally advanced gastric cancer before the operation, and the logistic model demonstrates the best diagnostic efficacy.

Value of spectral CT based iodine concentration for the preoperative prediction of vascular invasion in gastric cancer / 中华放射学杂志

Objective:To investigate the value of spectral CT based iodine concentration (IC) parameters for preoperative prediction of lymphovascular invasion (LVI) in gastric cancer.Methods:Between January 2021 and November 2021, 266 patients diagnosed as gastric adenocarcinomas by endoscopy and undergoing gastrectomy at the Affiliated Cancer Hospital of Zhengzhou University were recruited prospectively. They were divided into LVI and non-LVI groups according to pathological reports. Triple phase contrasted enhanced CT scans, including arterial phase (AP), venous phase (VP) and delayed phase (DP) were performed on a spectral CT platform within one week before surgery. The IC of gastric cancer lesions at three enhanced phases were measured based on iodine maps, and the normalized IC (nIC) was calculated. The thickness of the tumor was measured. Clinicopathological features were collected, including ulceration, pathological tumor staging (pT), pathological node staging (pN), histodifferentiation, Lauren subtype, perineural invasion (PNI), positive node numbers and positive node ratio. Student′s t tes t or Mann-Whitney U test were used to compare the differences of continuous variables between the two groups, while Chi-square test or Fisher′s exact test was used for categorical data. Multivariable logistic regression analysis was used to screen independent risk factors of LVI, and to build a combined parameter based on risk factors. The receiver operating characteristic curve analysis was performed to determine the predictive efficacy of IC parameters and the combined parameter for LVI. DeLong′s test was used to compare the differences among different area under the curve (AUC). Results:There were statistical differences in tumor thickness, ulceration, pT, pN, histodifferentiation, positive node numbers, positive node ratio, Lauren subtype and PNI between LVI and non-LVI groups ( P<0.05). The values of IC VP, IC DP, nIC VP, nIC DP in LVI group were statistically higher than those in non-LVI group ( t=3.77, 4.23, 4.25, 6.12, all P<0.001), with the AUC (95%CI) of 0.674 (0.610-0.738), 0.677 (0.614-0.741), 0.731 (0.671-0.792), 0.700 (0.636-0.764) for predicting LVI, respectively. Multivariable logistic regression analysis revealed that tumor thickness (OR=1.148, 95%CI 1.085-1.237, P<0.001) and nIC VP (OR=209.904, 95%CI 14.874-644.362, P<0.001) were independent predictors for LVI, the combined parameter incorporating these two factors yielded an AUC (95%CI) of 0.790 (0.736-0.937), which was statistically higher than any single parameter of IC VP, IC DP, nIC VP and nIC DP ( Z=3.07, 3.29, 2.10, 2.60, P=0.002, 0.001, 0.036, 0.009). Conclusion:The IC and nIC values of gastric cancer lesions derived from the VP and DP on spectral CT can effectively predict LVI status in gastric adenocarcinomas, and the combination of nIC VP and tumor thickness can further improve the predictive efficacy.

Preoperative breast MRI combined with axillary ultrasound for the prediction of lymphovascular invasion in invasive ductal carcinoma of the breast / 中华放射学杂志

Objective:To investigate the value of preoperative breast MRI combined with axillary ultrasound in predicting lymphovascular invasion (LVI) of breast invasive ductal carcinoma.Methods:The clinical, pathological and imaging features of 160 female patients [age 25-74(49±10)years] with breast invasive ductal carcinoma from March 2014 to December 2017 in Shanxi Cancer Hospital were retrospectively analyzed. According to the LVI status determined by postoperative pathology, 160 patients were divided into LVI positive group (56 cases) and LVI negative group (104 cases). The clinical characteristics, pathological characteristics and imaging features of LVI positive group and LVI negative group were compared by the independent t test, Mann-Whitney U test or χ 2 test. Multivariate logistic regression analysis was performed to identify independent predictors for predicting LVI and construct a predictive model. The receiver operating characteristic (ROC) curve and area under the curve (AUC) was used to evaluate the discrimination of the prediction model, and the Hosmer-Lemeshow test was used to evaluate its calibration. Results:There was no significant difference in age, menopausal status, estrogen receptor, progesterone receptor, human epidermal growth factor 2, Ki67 index and molecular subtype between LVI positive group and negative group ( P>0.05). Tumor size, peritumoral edema, adjacent vessel sign, multifocality or multicentricity, peritumoral maximum-apparent diffusion coefficient (ADC), peritumour-tumour ADC ratio, MRI axillary lymph node status and ultrasound axillary lymph node status between LVI positive group and LVI negative group showed significantly statistical difference ( P<0.05). Variables with significant difference in the univariate analysis were entered into multivariate logistic regression analysis to explore predictors for LVI. Peritumoral edema (OR=3.367, 95%CI 1.382-8.201, P=0.008), multifocality or multicentricity (OR=4.026, 95%CI 1.268-12.776, P=0.018), high peritumoral-tumor ADC ratio (OR=7.321, 95%CI 2.226-24.079, P=0.001) and positive ultrasound axillary lymph node (OR=6.779, 95%CI 2.819-16.303, P<0.001) were independent predictors for predicting LVI. A logistic regression model was constructed using the above four indicators, and ROC showed AUC of this model for predicting LVI was 0.882, superior to any of the single indicator ( P<0.05); its sensitivity was 80.36% and specificity was 84.62%. Hosmer-lemeshow test showed that the prediction model had good calibration ( P=0.503). Conclusion:The combined prediction model constructed by preoperative breast MRI and axillary ultrasound could help to predict the LVI status of breast invasive ductal carcinoma.

The predictive model of microvascular invasion in hepatocellular carcinoma established based on multimodality imaging / 中华超声影像学杂志

Objective:To explore the risk factors of microvascular invasion (MVI) in hepatocellular carcinoma (HCC), and to predict MVI preoperatively, non-invasively and accurately.Methods:A total of 150 HCC patients (183 HCC lesions) were retrospectively collected in the First Affiliated Hospital of Xi′an Jiaotong University from January 2016 to June 2022.The clinical data and hematological data, gray-scale ultrasonography (US), contrast-enhanced ultrasonography (CEUS), enhanced magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (EOB-MRI) and pathological data of these patients were recorded. According to the pathological diagnosis of MVI, the lesions were divided into MVI (+ ) group and MVI (-) group. The indicators between the two groups were compared. All 183 lesions were put into the training set, and the prediction model with nomogram was constructed according to the risk factors of MVI selected by multivariate Logistic regression. The internal verification was carried out by ten-fold cross-validation method.Results:There were significant statistical differences in the following parameters between MVI (+ ) group ( n=109) and MVI (-) group ( n=74) (all P<0.05). These were cirrhosis, serological parameters (alpha-fetoprotein, albumin, total bilirubin), qualitative indexes of US (size, boundary, internal echo), qualitative indexes of CEUS (hyper/iso/hypovascularity of lesions in arterial phase, portal phase, and delayed phase compared with hepatic parenchyma), and quantitative indexes of EOB-MRI [post enhancement rate (post ratio) and gadolinium disodium rate (EOB ratio)] calculated mainly in terms of lesions and surrounding liver parenchyma in hepatobiliary phase and unenhanced T1 images). Finally, cirrhosis of patients, the size, boundary, internal echo of lesions in US; arterial phase (AP), portal phase (PP), post-vascular phase (PVP) features in CEUS; the EOB rate and post rate of EOB-MRI entered the prediction model of MVI. The training set exhibited good calibration and net gain rate. The areas under the ROC curve for the training set and the validation set were 0.981 and 0.961, respectively, while the diagnostic accuracy were 92.9% and 85.8%, respectively. Conclusions:The model constructed mainly by multimodality imaging methods can achieve favorable predictive performance for MVI, which provides valuable ideas for noninvasively predicting the incidence of MVI and optimizing the MVI-related treatment of MVI in HCC patients.