1
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):692-700. eCollection 2020.
miR-21 Promotes Growth, Invasion and Migration of Lung Cancer Cells by AKT/P-AKT/cleaved-caspase 3/MMP-2/MMP-9 Signaling Pathway
Haiquan Li 1 2, Jie Zhao 2, Xiaomin Jia 2, Yanmin Zhang 2, Yongliang Du 2, Huiting Li 2, Lei Ma 2, Jian'an Huang 1
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PMID: 32355517 PMCID: PMC7191137
Free PMC article
Abstract
Objective: This study aimed to demonstrate the effects of miR-21 on the growth, migration, and invasion of lung cancer cells A549 in vitro and the possible mechanism.

Methods: In vitro cell migration and invasion potential were determined by Transwell chamber assays. FACS was used to assess the effect of miR-21 on A549 cell cycle and apoptosis. 4-6 week-old female mice were utilized to establish a lung cancer model. The pathologic biopsy was processed by H&E staining. The expression of the proteins PTEN, RECK and Caspase 3 were detected through immunohistochemy and tumor cell apoptosis was measured by TUNEL.

Results: Transwell chamber assays showed that the cells going through the membrane increased significantly compared to the negative control (P<0.05). The tumor volume resulting from miR-21 mimics was significantly greater than in normal mice. Serum ELISA showed that the protein expression levels of MMP-2 and MMP-9 in miR-21 overexpression group were increased significantly. In addition, H&E staining results showed that in miR-21 overexpression tissue, invasion is more severe and immunohistochemical results proved that the miR-21 overexpression group had high expression of Caspase 3 protein but the expression of PTEN and RECK were decreased. TUNEL experiments show that increased the expression of miR-21 can inhibit the apoptosis of tumor cells.

Conclusion: MicroRNA-21 promotes the proliferation of lung cancer cells and inhibits the apoptosis of lung cancer cells by the AKT/P-AKT/cleaved-caspase 3/MMP-2/MMP-9 signaling pathway.

Keywords: Lung cancer; apoptosis; miR-21; migration; proliferation; signaling pathway.

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2
Int J Clin Exp Pathol
. 2020 May 1;13(5):1008-1016. eCollection 2020.
Association of CD44 and CD24 Phenotype With Lymph Node Metastasis and Survival in Triple-Negative Breast Cancer
Weiyan Zou 1, Yan Yang 2, Rongsheng Zheng 2, Zishu Wang 2, Huihui Zeng 2, Zhelong Chen 3, Fen Yang 4, Junbin Wang 2
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PMID: 32509072
Abstract
Background: CD44+CD24-/low phenotypes are associated with poor outcome of triple-negative breast cancer (TNBC); however, the role of the CD44+CD24-/low phenotype in lymph node metastasis and survival has not been fully understood in TNBC.

Methods: A total of 51 TNBC patients were included. CD44 and CD24 expression was determined using immunohistochemistry by which CD44 and CD24 were double-immunostained. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method.

Results: The proportion of the CD44+CD24-/low phenotype was 33.3% in TNBC specimens without lymph node metastases and 69.0% in those with lymph node metastases. In addition, the CD44+CD24-/low phenotype correlated significantly with tumor size, histologic classification, TNM stage, and lymph node metastasis (P < 0.05). The CD44+CD24-/low phenotype was detected in 69.0% of TNBC patients with lymph node metastases, and 51.7% of TNBC patients without lymph node metastases. In TNBC patients without lymph node metastases, the median DFS and OS were 18.2 and 28 months in cases with a CD44+CD24-/low phenotype and 26.5 and 42.5 months in those without a CD44+CD24-/low phenotype (P < 0.05), and in TNBC patients with lymph node metastases, the median DFS and OS were 17.2 and 25.7 months in cases with a CD44+CD24-/low phenotype and 24.5 and 39.3 months in those without a CD44+CD24-/low phenotype, respectively (P < 0.05).

Conclusions: CD44 and CD24 are independent prognostic markers for patients with TNBC. The CD44+CD24-/low phenotype correlates with more aggressive clinicopathologic features and is strongly associated with poor prognosis in patients with TNBC.

Keywords: CD24; CD44; Triple-negative breast cancer; cancer stem cells; lymph node metastasis; survival.

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3
Int J Clin Exp Pathol
. 2020 May 1;13(5):1197-1205. eCollection 2020.
Expression and Clinical Significance of Gal-3 and NFκB Pathway-Related Factors in Epithelial Ovarian Carcinoma
Hiu-Mei Luk 1, Dong-Yan Wang 2, Ling-Ling Xie 2, Xun-Yun Liu 2, Guo-Cai Xu 2, Huai-Wu Lu 2
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PMID: 32509095
Abstract
Objective: To explore the expression and clinical significance of Gal-3 and NFκB pathway related factors in epithelial ovarian carcinoma cells.

Methods: 99 histologic specimens of epithelial ovarian cancer and 20 normal ovarian histologic specimens were collected, and the expressions of Gal-3, IκB and p65 were detected by immunohistochemistry. Their relationship with clinical characteristics was analyzed.

Results: The expression of Gal-3 and p65 was negatively correlated with the overall survival rate (P<0.05), while the expression of IκB was positively correlated with the overall survival rate (P<0.05). Expression of Gal-3, p65 and IκB were found associated with EOC platinum resistance (P<0.05), and expression of Gal-3 and p65 correlated with pathologic grading (P<0.05). IκB and Gal-3 were associated with the recurrence of EOC (P<0.05). IκB may be related to clinical stage (P<0.05). Multivariate analysis results showed that abnormal expression of Gal-3 may be an independent prognostic risk factors for the drug resistance to platinum-based chemotherapy (95% CI=5.336~34.112, P<0.05). The expression of Gal-3, p65, and IκB can be clinical immunohistochemical indicators that determine the prognosis of EOC, but the amount of Gal-3 expression was related to the epithelial ovarian cancer's pathologic type and overall survival, which suggested that Gal-3 can be used as a prognostic factor in epithelial ovarian cancer.

Conclusion: Targeted therapy of Gal-3 may become an effective potential new method against epithelial ovarian cancer.

Keywords: Galectin-3; IκB; clinical prognosis; epithelial ovarian cancer; p65.

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4
Int J Clin Exp Pathol
. 2020 May 1;13(5):1169-1175. eCollection 2020.
Correlation of MMP-9 Gene Polymorphisms With Aneurysmal Subarachnoid Hemorrhage and Its Prognosis
Keqi Hu 1, Daquan Zhou 1, Xiangsheng Ao 1, Handong Liu 1, Feng Chen 1, Hongbin Wen 2
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PMID: 32509091
Abstract
Background: Aneurysmal subarachnoid hemorrhage (aSAH)-associated gene polymorphism is of great significance for the accurate diagnosis and individualized treatment of aSAH. This study aims to investigate the expression of matrix metalloproteinase-9 (MMP-9) gene in the peripheral blood of patients with aneurysmal subarachnoid hemorrhage (aSAH) and explore the correlations of MMP-9 polymorphisms with the onset and prognosis of the disease. Methods: A total of 80 aSAH patients (aSAH group) and 24 healthy (control group) people receiving physical examination were enrolled in the study. Western blotting was applied to detect the expression of MMP-9 gene in the peripheral blood in aSAH patients and healthy people. The genotyping of single nucleotide polymorphisms (rs42512, rs56212 and rs61221) in the promoter region of MMP-9 gene was analyzed by means of conformation-difference gel electrophoresis. Chi-square test was applied to examine the applicability of the distribution frequency of MMP-9 genotypes with genetic equilibrium law. The correlations of MMP-9 alleles and gene polymorphisms with the onset and prognosis of aSAH were determined. Results: The expression of MMP-9 protein in aSAH group was significantly higher than that in control group (P<0.05). The Hardy-Weinberg equilibrium analysis showed that MMP-9 gene polymorphisms were in agreement with the genetic equilibrium law. According to the results of genetic association analysis, only the polymorphism rs42512 and its alleles were significantly correlated with the onset and prognosis of aSAH (P<0.05). However, polymorphisms rs56212 and rs61221 and their alleles had no association with the onset and prognosis of aSAH (P>0.05). Conclusion: The polymorphism rs42512 in the promoter region of MMP-9 gene is related to the onset of aSAH, which provides further evidence for the diagnosis of aSAH.

Keywords: MMP-9; aneurysmal subarachnoid hemorrhage; correlation; gene polymorphism.

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5
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):756-763. eCollection 2020.
Hematologic Derangements in HIV/AIDS Patients and Their Relationship With the CD4 Counts: A Cross-Sectional Study
Subhash Bhardwaj 1, Abdulrahman Almaeen 2, Farooq Ahmed Wani 3, Ashokkumar Thirunavukkarasu 4
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PMID: 32355524 PMCID: PMC7191136
Free PMC article
Abstract
Objective: Hematologic abnormalities are the most common complications of human immunodeficiency virus (HIV) infection being more pronounced during the late stages of the disease, thereby indicating the progressive nature of the disease. Anemia is the most frequent hematologic abnormality in HIV. However, leukopenia, lymphopenia, and thrombocytopenia have also been observed. We undertook this study to evaluate the hematologic abnormalities in HIV patients and their relationship with the CD4 cell counts.

Materials and methods: This is an analytical cross-sectional study that was carried out among patients in Jammu, India for the three years from 2015 to 2018. Data collection pro-forma has two parts. Firstly, socio-demographic details such as age, gender, marital status, and occupation were noted. Secondly, investigations such as HIV testing, complete blood counts and CD4 counts were considered. The Statistical Package for Social Sciences (SPSS) software version 20 was used for data entry and analysis. One way analysis of variance (ANOVA) was applied as appropriate to examine differences between quantitative variables.

Results: Anaemia was present in 72.5% of cases in our study. Leukopenia, lymphopenia and thrombocytopenia were observed in 18.33%, 49.17%, and 15.83% of the cases, respectively. We found statistically significant relationships of anemia, absolute lymphocyte count, and thrombocytopenia with the CD4 counts (P<0.0001, =0.018 and =0.044, respectively). However, CD4 counts at the time of presentation were not significantly related to the total leukocyte count and absolute neutrophil count.

Conclusions: Anemia was the most frequent hematologic abnormality in HIV patients followed by lymphopenia, leukopenia, and thrombocytopenia. A significant relationship was observed between the anemia, absolute lymphocyte count, and thrombocytopenia with the CD4 counts. We recommend routine hematologic investigations and timely treatment for all the hematologic derangements in HIV patients.

Keywords: AIDS; CD4 counts; HIV; Hematologic abnormality; anemia.

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6
Int J Clin Exp Pathol
. 2020 May 1;13(5):1253-1261. eCollection 2020.
Pathologic Characteristics of Spinal Tuberculosis: Analysis of 181 Cases
Yongai Li 1, Yingqi Wang 1, Huiqiang Ding 2, Ning Zhang 3, Ailing Ma 3, Jiandang Shi 2, Ningkui Niu 2
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PMID: 32509101
Abstract
Objective: This study aimed to provide a basis for the diagnosis of spinal TB by analyzing its pathologic characteristics.

Methods: The data of 181 patients with spinal TB who underwent surgery from January 2013 to January 2019 at the General Hospital of Ningxia Medical University were retrospectively analyzed. The participants comprised 80 men and 101 women with an average age of 45.1 ± 16.5 (range: 14-78) years. Based on the assessment of tissue samples, five patients had cervical TB, 49 had thoracic TB, 86 had lumbar TB, 22 had thoracolumbar TB, and 19 had lumbosacral TB. Tuberculous granulation tissue, sclerotic bone, sequestrum, and intervertebral disc tissue were collected for hematoxylin and eosin staining. The proportion of patients with atypical and typical pathologic characteristics was identified and compared for statistical analysis.

Results: The typical pathologic characteristics included tubercles, granulomas, caseous necrosis, multinuclear giant cells, infiltration of acute inflammatory cells, sequestration, and fibroblastic proliferation. A total of 119 patients had caseous necrosis, 95 had multinuclear giant cells, 68 had granulomatous inflammation, and 21 had tubercles. Moreover, 46 (25.4%) patients had at least three pathologic characteristics and only 12 (6.6%) exhibited all the pathologic characteristics. Of the 35 (19.3%) patients with atypical pathologic characteristics, 17 had lymphocyte infiltration, 10 had fibroblastic proliferation, 2 had hyaline changes, 1 had local hemorrhage, 1 chronic inflammatory change, 2 had sequestration, 1 had dilated and congested vessels, and 1 had acute suppurative inflammation.

Conclusions: The most common pathologic characteristics were caseous necrosis, multinuclear giant cells, granulomatous inflammation, and tubercles. Moreover, multiple pathologic characteristics were observed in patients with spinal TB and one type of these characteristics was dominant. However, atypical pathologic characteristics were also noted. Thus, both pathologic examination and clinical analysis must be performed to improve the diagnostic rate of spinal TB.

Keywords: Spinal tuberculosis; pathology; tissue sample.

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7
Int J Clin Exp Pathol
. 2020 May 1;13(5):1146-1158. eCollection 2020.
FOXO1 and hsa-microRNA-204-5p Affect the Biologic Behavior of MDA-MB-231 Breast Cancer Cells
Chang-Yu Liang 1, Zhi-Guang Huang 1, Zhong-Qing Tang 2, Xiao-Ling Xiao 1, Jing-Jing Zeng 1, Zhen-Bo Feng 1
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PMID: 32509089
Abstract
RNA molecules and targeting microRNA (miRNA) have been reported as novel focuses in recent research on breast cancer. This study aimed to probe the expression of FOXO1 in the MDA-MB-231 cell line and to explore the target effects of FOXO1 with hsa-microRNA-204-5p (miR-204) on the biologic behavior of MDA-MB-231 cells. The expression of FOXO1 mRNA and protein in MDA-MB-231 cells were derived and verified from the public databases, literature, and experimental assays, then the downregulation of FOXO1 was confirmed in the MDA-MB-231 cell line. The target binding of FOXO1 and miR-204 was predicted by miRWalk and confirmed by luciferase reporter assays. MiR-204 targeted the 3' untranslated region of FOXO1 and reduced FOXO1 expression in miR-204-transfected cells, resulting in cell growth amplification but inhibition of cell migration and apoptosis, which were assessed using the MTT method, wound healing assays, and flow cytometry, respectively. The protein levels of serine-threonine kinase (AKT), c-jun N-terminal kinase (JNK), extracellular regulatory protein kinase (ERK), and the phosphorylated protein kinases (P-AKT, P-JNK, and P-ERK) were measured by western blot. It was found that AKT, JNK, and ERK remained constant, but P-AKT, P-JNK, and P-ERK were upregulated after miR-204 transfection. In summary, the expression of FOXO1 was downregulated in MDA-MB-231 cells; and the target binding of miR-204 and FOXO1 affected phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signal pathways, leading to different alterations of cellular activity in MDA-MB-231 cells.

Keywords: FOXO1; MDA-MB-231; biological behavior; miR-204.

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8
Int J Clin Exp Pathol
. 2020 May 1;13(5):989-994. eCollection 2020.
The Role and Mechanism of Gastrodin in the Medial Prefrontal Cortex Autophagy of PTSD Rats
Xiuwen Lei 1 2, Yefeng Yuan 1, Qin Zou 1
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PMID: 32509070
Abstract
Background: This study provided a reliable experimental basis for exploring the pathogenesis of PTSD-induced memory impairment, fear abnormalities, and affective disorders, aiming to facilitate new thinking for the prevention, treatment, and drug development of clinical PTSD.

Material and methods: A rat model of PTSD was established by continuous single stress stimulation method. The Morris water maze was used to detect the learning and spatial memory exploration abilities of rats. The autonomic motion behavior, fear, and anxiety of rats in each group was detected by the elevated plus maze test and the open field test. The immunofluorescence method was employed to observe and detect the changes of autophagy in mPFC neurons of PTSD rats. Western blotting was used to detect the expressions of autophagy-related genes Beclin-1 and LC3, autophagy substrate p62 protein, and apoptosis-related factors Bcl-2 and Bax.

Result: Gastrodin could improve the learning and spatial memory abilities of PTSD-SPS rats, the reduction of active movement and inquiry behavior, and the autophagy of mPFC neurons, and also increase the expressions of Beclin-1, LC3-I, LC3-II, and Bax proteins, as well as decrease the expressions of Bcl-2 and p62.

Conclusions: Gastrodin is effective in the treatment of PTSD-induced memory impairment, fear abnormalities, and affective disorders. The mechanism is related to autophagy in mPFC neurons.

Keywords: Gastrodin; PTSD; autophagy; medial prefrontal cortex.

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9
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):685-691. eCollection 2020.
miR-566 Expression and Immune Changes in Patients With Intracranial Aneurysm
Hongjun Fan 1, Chun Yang 1, Chenguang Jia 1, Xingyun Xie 1, Li Du 1
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PMID: 32355516 PMCID: PMC7191142
Free PMC article
Abstract
Objective: Our study aims to investigate the correlations of micro ribonucleic acid (miR)-566 expression with the changes in immune-related indexes and differential genes in patients with intracranial aneurysm (IA).

Methods: Aneurysm wall tissues from a total of 50 IA cases and the corresponding normal arterial wall tissues from 50 individuals were selected. The miR-566 expression, differential gene expression profile, and expression level of differential gene proteins were detected and analyzed by fluorescence quantitative polymerase chain reaction (qPCR), RNAseq technique and western blotting, respectively.

Results: The miR-566 level was significantly higher in intracranial aneurysm tissues than that in normal arterial wall tissues (P<0.05). The levels of cluster of differentiation (CD)3+, CD4+, CD8+, CD4+/CD8+ and CD23+ T lymphocytes in the peripheral blood of IA patients significantly declined compared with those in the control group (P<0.05). RNAseq detection showed that there were 16 immune-inflammation-related genes significantly differentially expressed in aneurysm wall tissues compared with normal arterial wall tissues in the control group. The levels of VHL and NIK in aneurysm wall tissues were significantly decreased, while those of VEGF and ALOX5 were obviously increased. Both mRNA and protein levels of these four genes also had significant changes, which had linear relations to the expression of miR-566.

Conclusion: The abnormal expression of miR-566 affects the immune function, thus promoting the occurrence and deterioration of intracranial aneurysm.

Keywords: Intracranial aneurysm; genetic screening; immune; miR-566.

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10
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):738-745. eCollection 2020.
MicroRNA-21 Depletion by CRISPR/Cas9 in CNE2 Nasopharyngeal Cells Hinders Proliferation and Induces Apoptosis by Targeting the PI3K/AKT/MOTOR Signaling Pathway
Zhenzhou Xiao 1, Yan Chen 1, Zhaolei Cui 1
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PMID: 32355522 PMCID: PMC7191151
Free PMC article
Abstract
Background: We assess the effects exerted by CRISPR/Cas9 mediated microRNA 21 (miR-21) depletion on the biologic characteristics of CNE2 nasopharyngeal carcinoma (NPC) cells and the underlying mechanisms.

Methods: The sgRNA was designed targeted at miR-21 gene, along with the construction of the CRISPR/Cas9 lentivirus system and the detection of editing efficiency through T7EN1 enzyme digestion. Effects of miR-21 depletion on the biologic characteristics of CNE2 cells were detected through CCK-8, Transwell Invasion Assay and flow cytometry. Mechanistic studies were based on bioinformatic analysis and immunoblotting.

Results: A CRISPR/Cas9 system with targeted knockdown of miR-21 gene was obtained. miR-21 depletion evidently inhibited the growth, clone formation, and invasion as well as migration abilities of CNE2 cells, thus inducing apoptosis. A total of 28 KEGG were identified through the bioinformatic analysis. Further immunoblotting showed that the expressions of proteins involved in the PI3K/AKT/mTOR signaling pathway were decreased in response to miR-21 depletion.

Conclusions: miR-21 depletion can suppress the cell growth as well as proliferation and induce apoptosis in CNE2 cells possibly by inhibiting the PI3K/AKT/mTOR signaling pathway.

Keywords: CNE2; CRISPR/Cas9; microRNA 21; nasopharyngeal carcinoma.

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11
Int J Clin Exp Pathol
. 2020 May 1;13(5):1176-1184. eCollection 2020.
Aberrant Expression of WWOX and Its Association With Cancer Stem Cell Biomarker Expression
Yunzhi Zhai 1, Yajuan Han 1, Zhengquan Han 1
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PMID: 32509092
Abstract
Background: Nanog and CD133 are biomarkers of cancer stem cells (CSCs) that regulate cancer progression. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor protein that can inhibit tumor cell proliferation. The purpose of this study was to investigate the expression and clinical significance of Nanog, CD133, and WWOX in infiltrating breast cancer (IBC).

Methods: Expressions of Nanog, CD133, and WWOX in 204 IBC specimens and their corresponding control specimens were detected by immunohistochemistry. Patients' clinicopathologic and follow-up data were also collected.

Results: The rates of positive expression of Nanog and CD133 were significantly higher in IBC specimens than in control specimens, and their expression was positively associated with tumor size, grade, and tumor stages, lymph node metastasis (LNM), and tumor-node-metastasis (TNM) stage. The rate of positive expression of WWOX was significantly lower in IBC specimens than in control specimens, and its expression was inversely associated with tumor size, grade, and tumor stages, LNM, and TNM stage. Patients whose specimens expressed Nanog, CD133, or HER2 had a reduced overall survival (OS) when compared with patients not expressing these proteins. However, patients whose specimens expressed WWOX, ER, or PR had an increased OS when compared with patients who did not show expression. Multivariate analysis demonstrated that expression of Nanog, CD133, WWOX, ER, and HER2, and the TNM stage were independent prognostic factors for IBC patients.

Conclusions: Therefore, Nanog, CD133, and WWOX should be considered as promising prognostic factors and therapeutic targets in IBC.

Keywords: CD133; Infiltrating breast cancer; Nanog; WWOX; cancer stem cells; prognosis.

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12
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):675-684. eCollection 2020.
Identification of Key lncRNAs as Prognostic Prediction Models for Colorectal Cancer Based on LASSO
Xiao Huang 1 2, Wei Cai 2 3, Wenliang Yuan 4 5, Sihua Peng 2 3
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PMID: 32355515 PMCID: PMC7191144
Free PMC article
Abstract
Colorectal cancer (CRC) is one of the most common malignancies, with varying prognoses and a high mortality. There is an urgent need to establish a new prediction model to predict the survival risk of CRC patients. The long non-coding RNAs (lncRNAs) expression profiles and corresponding clinical information of CRC patients were obtained from The Cancer Genome Atlas, TCGA. We identified a total of 1,176 lncRNAs differentially expressed between 480 CRC and 41 normal tissues. In the training test, we combined these differentially expressed lncRNAs with overall survival of CRC patients. Six lncRNAs (AL356270.1, LINC02257, AC020891.2, LINC01485, AC083967.1 and RBAKDN) were finally screened out by using LASSO regression mode to establish a novel prediction model as a prognostic indicator for CRC patients. The area under the curve (AUC) of 3- and 5-year ROC analysis in CRC were 0.6923 and 0.7328 for training set, and were 0.6803 and 0.7035 for testing set, respectively. K-M analysis revealed a significant difference between high risk and low risk in the training set (P-value = 5.0e-05) and testing set (P-value = 0.00052), respectively. Our study shows that the six lncRNAs model can improve the survival prediction mechanism of patients with CRC and provide help for patients through personalized treatment.

Keywords: CRC; LASSO regression; lncRNAs; overall survival.

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13
Int J Clin Exp Pathol
. 2020 May 1;13(5):1024-1029. eCollection 2020.
Expression of nm23-H1, p53, and Integrin β1 in Endometriosis and Their Clinical Significance
Renjie Duan 1, Yue Wang 1, Aiqin Lin 1, Likai Lian 1, Huiru Cao 1, Wenjie Gu 1, Tiechen Li 1, Qing Sun 2
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PMID: 32509074
Abstract
To investigate the expression and clinical significance of nucleoside diphosphate kinase A (nm23-H1), p53, and integrin β1 in endometriosis, normal and ectopic endometrial tissues were collected and the levels of nm23-H1, p53, and integrin β1 proteins were detected by western blotting. We also measured the mRNA expression of nm23-H1, p53, and integrin β1 in endometrial epithelial cells by droplet digital PCR, based on endometrial tissues using laser capture microdissection. Moreover, primary stromal cells from normal and ectopic endometrial tissues were also cultured and treated with different concentrations of estrogen. We assessed the mRNA levels of nm23-H1, p53, and integrin β1 by quantitative PCR. Compared with normal endometrial tissue, the levels of nm23-H1 and p53 proteins were significantly downregulated in ectopic endometrial tissues, while integrin β1 protein was upregulated. The same expression trend in the mRNA levels of nm23-H1, p53, and integrin β1 was also observed in both endometrial epithelial cells and stromal cells. In addition, with increasing estrogen concentration, nm23-H1 and p53 mRNA levels gradually decreased, while integrin β1 mRNA expression increased. Nm23-H1 and p53 may inhibit the progression of endometriosis, while integrin β1 has a promoting effect, and estrogen is involved in this process.

Keywords: Nm23-H1; endometriosis; estrogen; integrin β1; p53.

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14
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):810-817. eCollection 2020.
LIPUS Promotes Synthesis and Secretion of Extracellular Matrix and Reduces Cell Apoptosis in Human Osteoarthritis Through Upregulation of SOX9 Expression
Weizhong Ding 1, Dengli Du 1, Shirong Chen 1
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PMID: 32355531 PMCID: PMC7191152
Free PMC article
Abstract
Increasing studies have illustrated that low-intensity pulsed ultrasound (LIPUS) has a therapeutic effect in experimental animal models of osteoarthritis (OA). However, the function of the LIPUS on human chondrocytes of OA remains unclear. The aim of the current study was to observe the effect and explore the mechanism of LIPUS treatment on proliferation, apoptosis, and extracellular matrix (ECM) production of chondrocytes in vitro. Results showed that LIPUS stimulation at 30, 60, and 90 mW/cm2 intensities markedly inhibited the apoptosis of chondrocytes compared with the 0 mW/cm2 intensity; however, the effect of LIPUS stimulation at 0, 30, 60, and 90 mW/cm2 intensities on the proliferation of chondrocytes had no significant difference. Furthermore, the mRNA and protein levels of COL2A1 and ACAN were upregulated in chondrocytes treated with LIPUS stimulation at 30, 60, and 90 mW/cm2 intensities. The concentration of COL2A1 and ACAN in supernatants of chondrocytes in the 30, 60, and 90 mW/cm2 groups were obviously higher than those in the 0 mW/cm2 group. In addition, activation of SOX9 mRNA and protein expression were observed in the 30, 60, and 90 mW/cm2 groups compared with the 0 mW/cm2 group. In summary, our data demonstrated that LIPUS promotes ECM synthesis and secretion and reduces apoptosis of human OA by activation of SOX9, indicating LIPUS might bea promising therapy for the treatment of OA.

Keywords: LIPUS; apoptosis; chondrocytes; extracellular matrix; osteoarthritis.

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15
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):799-809. eCollection 2020.
Dysfunction of Regulatory T Cells Mediated by AKT-FOXO1 Signaling Pathway Occurs During the Development of Psoriasis
Zhixia Fan 1, Lingyu Li 1, Xin Wang 1, Guoying Miao 1
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PMID: 32355530 PMCID: PMC7191153
Free PMC article
Abstract
Psoriasis is an immune-mediated skin disease with abnormal T cells. Regulatory T cells (Treg) are a kind of cell group with immunosuppressive effects. This study aimed to explore the role of Treg cells in the pathogenesis of psoriasis and its possible mechanism. Imiquimod induced psoriasis mice model was conducted. The skin lesions were evaluated according to the psoriasis area and severity index (PASI). Skin biopsies were taken for HE staining and immunohistochemical staining of IL-23, IL-17, IL-33 and TNF-α. CD4+CD25+ Treg cells were isolated. The proportions of Treg cells, cell proliferation, and immunosuppressive activity were analyzed by flow cytometry. The expression of AKT, Foxo1, pAKT, pFoxo1 protein, and the localization of Foxo1 protein in Treg cells were detected by western blot and immunofluorescence. The results showed that the psoriasis mice model was established successfully. There was no significant difference in the proportion of Treg cells between the two groups (P > 0.05). The cell proliferation abilities were decreased, and the immunosuppressive functions of Treg cells were weakened in the psoriatic group (P < 0.05). Western blot showed that pAKT and pFoxo1 levels of Treg cells were significantly increased in the psoriatic group (P < 0.05). Immunofluorescence showed that Foxo1 was mainly expressed in the nucleus of Treg cells in the control group, whereas expressed in the cytoplasm in the psoriasis group. Therefore, we concluded that the cell proliferation and immunosuppressive dysfunction of Treg cells mediated by AKT-FOXO1 signaling pathway may occurs during the development of psoriasis.

Keywords: Akt-Foxo1; CD4+ T cells; CD4+CD25+Foxp3+ Treg; Psoriasis; imiquimod.

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16
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):771-777. eCollection 2020.
Clear Cell Sarcoma of the Kidney in Children: A Clinopathologic Analysis of Three Cases
Shaohua Chen 1, Ming Li 2, Ran Li 1, Jintao Cao 1, Qiong Wu 1, Ting Zhou 1, Zhaogen Cai 1, Nan Li 1
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PMID: 32355526 PMCID: PMC7191146
Free PMC article
Abstract
Background: Clear cell sarcoma of the kidney (CCSK) is a rare malignant tumor in children with uncertain histologic and immunohistologic traits. It mostly reveals atypical clinical symptoms similar to other familiar pediatric renal neoplasms, including abdominal mass, abdominal pain, hematuria, etc. Therefore, the lack of specificity in clinical symptoms may induce some challenging and controversial diagnoses.

Methods: Three cases of CCSK were acquired data from the First Affiliated Hospital of Bengbu Medical College (China) in recent years, accompanied by clinical symptoms and imaging manifestations without obvious specificity, while abdominal mass and abdominal pain were described as the main manifestations; even the initial clinical diagnosis of one case was Wilms Tumor (WT). Two of them underwent a radical nephrectomy. All 3 cases were detected by hematoxylin-eosin (H&E) staining and immunohistochemistry.

Results: Microscopic examination demonstrated the tumor component consisted of loose, locally dense tumor stroma and parenchyma composed of round or oval cells, which were separated by dendritic fibrosis. Afterwards, the unified immunophenotype were positive for Cyclin D1, Bcl-2, Vimentin, SATB-2, α-AACT, and Ki-67 (+, 30%, 40% and 80%, respectively).

Conclusion: Pathologic diagnosis of the disease should be comprehensively analyzed by multiple methods. More abundant morphologic, immunohistological, clinical and radiologic data can contribute to rigorous diagnosis and more accurate clinical treatment.

Keywords: CCSK; diagnosis; histology; immunohistochemistry.

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17
Int J Clin Exp Pathol
. 2020 May 1;13(5):1159-1168. eCollection 2020.
Diagnostic Performances of the KWAK-TIRADS Classification, Elasticity Score, and Bethesda System for Reporting Thyroid Cytopathology of TI-RADS Category 4 Thyroid Nodules
Supeng Huang 1, Ning Meng 1, Mengting Pan 2, Bo Yu 2, Juan Liu 3, Kailin Deng 3, Mingrong Hu 1, Hongwei Zhou 1, Chao Qin 1
Affiliations expand
PMID: 32509090
Abstract
Objective: To explore the value of the KWAK Thyroid Imaging Reporting and Data System (KWAK-TIRADS), elasticity score (ES), and Bethesda System for Reporting Thyroid Cytopathology (BSRTC) in the diagnosis of suspicious thyroid nodules.

Materials and methods: The study included 392 cases of TI-RADS category 4 thyroid nodules that underwent thyroidectomy between January 2017 and October 2019. All patients underwent ultrasonography, ultrasound elastography, and fine-needle aspiration cytology (FNAC) before surgery. The nodules were classified into different categories based on the KWAK-TIRADS, ES, and BSRTC. Patients were divided into two groups based on postoperative pathological characteristics. The sensitivity (Se), specificity (Sp), and area under the receiver operating characteristic (ROC) curve were calculated. Student's t-test and Pearson chi-square test were used to compare diagnostic performance.

Results: There were 159 patients in the benign group and 233 in the malignant group. The percentage of malignant nodules in KWAK-TIRADS categories 4a, 4b, and 4c were 44.3%, 64.8%, and 92.9%, respectively. The percentages of malignant nodules in ES 2, 3, 4, and 5 were 0%, 37.1%, 93.8%, and 100%, respectively. The percentage of malignant nodules in BSRTC levels I, II, III, IV, V and VI were 57.1%, 2.8%, 9.9%, 76.6%, 99.1%, and 100%, respectively. Among those methods, the BSRTC had better diagnostic efficiency than the KWAK-TIRADS and ES (Sp 81.1%, Se 93.6%, and AUC 0.918, P<0.01). Among the combined methods, KWAK-TIRADS+ES+BSRTC was more effective than KWAK-TIRADS+ES, KWAK-TIRADS+BSRTC, and ES+BSRTC (Sp 93.7%, Se 91.4%, and AUC 0.967, P<0.01).

Conclusion: The combination of KWAK-TIRADS, ES, and BSRTC can improve the accuracy of identifying category 4 thyroid nodules.

Keywords: Bethesda System for Reporting Thyroid Cytopathology; KWAK-TIRADS; diagnosis; thyroid nodule; ultrasonic elastography.

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18
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):721-729. eCollection 2020.
Astragalus Improve Aging Bone Marrow Mesenchymal Stem Cells (BMSCs) Vitality and Osteogenesis Through VD-FGF23-Klotho Axis
Xiang Pu 1, Yihui Chai 1, Liancheng Guan 1, Wen Li 1, Jie Gao 1, Zhibin Jiang 1, Qian Li 1, Yongzhen Wu 1, Yunzhi Chen 1
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PMID: 32355520 PMCID: PMC7191145
Free PMC article
Abstract
To clarify the regulation of astragalus on the aging BMSCs model and the effect of astragalus on Vitamin D (VD)-FGF23-Klotho axis. siRNA was used to interfere the expression of VDR gene in aging BMSCs. Serum containing astragalus in different concentrations was added to the cultured cells. The expression of osteocalcin and alkaline phosphatase were detected by alizarin red staining and ELISA. Cell vitality was detected by flow cytometry, CCK-8 test, and β-galactosidase staining. The expression of FGF23, Klotho, CYP27B1, and CYP24A1 was detected by qRT-PCR and western blot. The results showed that after reducing VDR gene expression, the aging BMSCs model showed decreased activity and osteogenic ability, increased expression of FGF23, Klotho and CYP24A1, and decreased expression of CYP27B1. After adding serum-containing astragalus, the activity of cells and the osteogenic ability was increased; the expression levels of FGF23, Klotho and CYP24A1 were decreased, the expression levels of CYP27B1 were increased, and the trend was more obvious with the increase of astragalus concentration. This study confirmed that astragalus could inhibit the aging of BMSCs and improve the osteogenesis ability by regulating the VD-FGF23-Klotho pathway. This study provided a certain research basis for the therapeutic of traditional Chinese medicine (TCM) on primary osteoporosis.

Keywords: Astragalus; BMSCs; VD-FGF23-Klotho axis; aging; osteogenesis differentiation.

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19
Int J Clin Exp Pathol
. 2020 May 1;13(5):827-836. eCollection 2020.
Combination of Astragaloside IV and ACEi Ameliorates Renal Injuries in Db/Db Mice
Hongyue Zhan 1 2, Pengxun Han 1, Menghua Wang 1, Yao Wang 1, Wenci Weng 1, Xuewen Yu 3, Changjian Yuan 1, Yuyan Li 1, Mumin Shao 3, Huili Sun 1
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PMID: 32509053
Abstract
Evidences demonstrated that the effect on anti-proteinuria and renal protection of Chinese herbs combination with ACEi or ARB seemed to be better than ACEi or ARB alone. Astragaloside IV could decrease the urinary albumin excretion rate and could protect against renal injuries linking to its anti-oxidation ability. We aimed to investigate the effect of astragaloside IV combined with ACEi on diabetic nephropathy and to explore whether its underlying mechanism is dependent on anti-oxidation. 8-week-old male experiment mice were randomly assigned to five groups: lean wild type (wt) group, db/db group, db/db + astragaloside IV group, db/db + enalapril group, db/db + combination therapy with astragaloside IV and enalapril group. During the experiment, 24 hours urinary albumin, fasting glucose, body weight, and metabolic parameters were monitored in regular intervals. At the end of the study, tail blood pressure, serum H2O2, lipid, and liver function were measured and kidney histological injuries were evaluated. Results of the study indicated that combination therapy with astragaloside IV and ACEi further reduced 24 hours urinary albumin excretion rate, blood pressure, and body weight. Combination therapy reduced the foot process width, glomerular base membrane thickness, glomerular tuft cell proliferation, tubular cell atrophy, tubular base membrane thickness, and improved tubular cell proliferation. It modulated the body H2O2 metabolism and up-regulated the expression of the catalase in renal cortex. Astragaloside IV combined with ACEi exerted renal protective effects in db/db mice more significantly than their individual used. The mechanism possibly involved their synergistic effects on anti-oxidation.

Keywords: Diabetic nephropathy (DN); angiotensin-II converting enzyme inhibitor (ACEi); astragaloside IV (AS-IV); combination therapy; reactive oxygen species (ROS).

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20
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):764-770. eCollection 2020.
Comparative Morphology of the Internal Elastic Lamina of Cerebral and Peripheral Arteries
Guiping Qin 1 2, Leiming Wang 1, Yulan Hua 2, Haina Hou 2, Qiuju Zou 2, Daye Wang 3, Zijing Hu 3, Dehong Lu 1
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PMID: 32355525 PMCID: PMC7191140
Free PMC article
Abstract
Background: Atherosclerosis progresses later and with fewer complicated plaques in cerebral arteries than in peripheral arteries. The internal elastic lamina has been proposed to be important for the migration of smooth muscle cells into the intima during intimal thickening and atherosclerosis.

Methods: A total of 280 segments were retrieved from 14 autopsy specimens. Five sites were selected for analysis in each case: the middle cerebral artery, basilar artery, coronary artery, iliac artery and renal artery. We investigated the differences in the internal elastic lamina of cerebral and peripheral arteries.

Results: The average thickness of the internal elastic lamina of the cerebral arteries was larger than that of the peripheral arteries in both the early and advanced atherosclerotic plaque groups. Among the cerebral arteries, the basilar arteries had a thicker internal elastic lamina than the middle cerebral arteries. Among the peripheral arteries, the renal arteries had the thickest internal elastic lamina, followed by the iliac arteries and coronary arteries. Atherosclerosis led to a reduction in the thickness of the internal elastic lamina of the basilar, middle cerebral, and renal arteries. The stratification of the internal elastic lamina of iliac arteries significantly affected its measurement. The internal elastic lamina of coronary arteries was not affected by atherosclerosis, but it appeared fragmented.

Conclusion: The results suggest that the characteristics of atherosclerotic plaques in cerebral and peripheral arteries may be related to the characteristics of the internal elastic lamina.

Keywords: Atherosclerosis; cerebral arteries; internal elastic lamina; peripheral arteries.

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21
Case Reports Int J Clin Exp Pathol
. 2020 Apr 1;13(4):778-784. eCollection 2020.
Pituitary Inflammatory Pseudotumor With Amenorrhea, Polyuria, and Impaired Vision: Case Report and Review of the Literature
Yinglei Du 1, Zhiquan Jiang 1
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PMID: 32355527 PMCID: PMC7191143
Free PMC article
Abstract
Background: Inflammatory pseudotumor (IPT) is a soft tissue lesion of unknown etiology. In 2002 the WHO classified it as a soft tissue tumor, and renamed it inflammatory myofibroblastic tumor. Inflammatory pseudotumor may involve various organs and tissues of the body, mainly the lungs and eyes. Primary intracerebral inflammatory pseudotumor is rare. If the differential diagnosis of IPT is made, surgical treatment can be avoided and the patient's trauma and risk can be reduced.

Case summary: We present a case of a 25-year-old female who presented with amenorrhea, galactorrhea, polydipsia, and polyuria. Magnetic resonance image (MRI) demonstrated a tumor (15 mm in diameter) with suprasellar extension, optic nerve compression, and pituitary stalk involvement. Preoperative examination showed a large increase in prolactin and laboratory data showed elevation of the erythrocyte sedimentation rate, but other data were within normal ranges. We applied a lateral transfrontal approach by microscopic resection of the endplate saddle area, because it was large. Postoperative pathology confirmed IPT. Small doses of hormone and thyroxine were given after surgery, and most of the tumor was resected after re-examination. Two years after the operation, no recurrence or other abnormalities were found.

Conclusion: Attention should be paid to the differential diagnosis of inflammatory pseudotumor of pituitary. Steroid hormone therapy can be used first to observe its effect. It can reduce the harm caused by invasive operation.

Keywords: IgG4; Inflammatory pseudotumor; pituitary; steroid hormone therapy.

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22
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):635-641. eCollection 2020.
Pulp Status of Teeth in Patients With Chronic Advanced Periodontitis
Baochun Tan 1, Qing Sun 2, Jianping Xiao 1, Lei Zhang 3, Fuhua Yan 1
Affiliations expand
PMID: 32355511 PMCID: PMC7191138
Free PMC article
Abstract
Objective: This study aimed to evaluate the dental-pulp status in patients with chronic advanced periodontitis.

Materials and methods: Sixty teeth were extracted from patients with advanced periodontitis. Before extraction, electric pulp tests were conducted to explore the real state of the pulp. According to the height of the residual periodontal membrane, all teeth were divided into two groups: group 1< (3 mm) and group 2 (3-6 mm). Two groups of teeth were sliced and stained with hematoxylin and eosin. The dental-pulp status of histopathologic changes was analyzed.

Results: The frequency of pulp necrosis in group 1 was significantly higher than that in group 2 (P<0.05). The frequency of a complete odontoblastic layer, vacuolar degeneration of the odontoblastic layer, pulp edema, and reticular atrophy in group 1 were significantly lower than in group 2 (P<0.05). There were no significant differences in other histopathologic changes. Histopathologic examination compared to the traditional electric pulp testing, revealed that 24.48% of dental pulps showed complete pulp necrosis and 5.75% exhibited normal pulp tissue by histopathology. However, only 9.52% of teeth exhibited no response, and 33.33% displayed responses similar to those of neighboring teeth, suggesting that the electric pulp test cannot completely detect dental-pulp status.

Conclusions: Teeth in patients with chronic advanced periodontitis, exhibited worse pulp conditions with decreased height of the residual periodontal membrane. The results of electric pulp testing were not completely representative of histopathologic results in advanced periodontitis.

Keywords: Pulp status; chronic advanced periodontitis; electric pulp testing; histopathology.

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23
Int J Clin Exp Pathol
. 2020 May 1;13(5):923-933. eCollection 2020.
Oncogenic and Prognostic Role of CKAP2L in Hepatocellular Carcinoma
Penghui Wang 1 2, Xiaodong He 1
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PMID: 32509063
Abstract
Cytoskeleton-associated protein 2-like (CKAP2L) exerts crucial function in the cell-cycle progression and mitotic spindle formation of neural stem/progenitor cells. However, in hepatocellular carcinoma (HCC), the expression pattern, clinical significance and biologic role of CKAP2L remain unexplored. We analysed The Cancer Genome Atlas (TCGA) database and found that CKAP2L was dramatically upregulated in HCC tissues at the mRNA level compared to adjacent tissues, which was validated in 48 paired HCC and para-tumor tissues using quantitative real-time PCR (qRT-PCR). Immunohistochemical analysis of tissue microarray revealed that CKAP2L was also significantly overexpressed at the protein level. Further clinical and survival analysis of the TCGA cohort revealed that increased CKAP2L expression was strongly associated with reduced overall survival. We further validated that higher CKAP2L protein expression was associated with worse prognosis in the Peking Union Medical College Hospital (PUMCH) cohort. Univariate and multivariate Cox regression analyses in the TCGA and PUMCH cohort suggested that CKAP2L overexpression was an independent risk factor for poor prognosis in HCC patients. Then, we validated that CKAP2L silencing inhibited HCC cell proliferation, migration, and invasion abilities. Knockdown of CKAP2L in Huh7 cells suppressed the growth of xenograft tumors in vivo. Furthermore, qRT-PCR and western blotting results demonstrated that the expression of Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β isoforms reduced obviously in Huh7 cells after depleting CKAP2L. This study demonstrated for the first time that high CKAP2L expression in HCC tissues is significantly correlated with poor prognosis in HCC patients and greatly facilitate the malignancy of HCC, thus providing a new prognostic biomarker and potential therapeutic target.

Keywords: CKAP2L; hepatocellular carcinoma; prognosis; therapeutic target.

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24
Int J Clin Exp Pathol
. 2020 May 1;13(5):869-879. eCollection 2020.
The Overexpression of lncRNA MEG3 Inhibits Cell Viability and Invasion and Promotes Apoptosis in Ovarian Cancer by Sponging miR-205-5p
Pingping Tao 1, Binlie Yang 1, Huiya Zhang 2, Liyan Sun 1, Yungen Wang 2, Weiping Zheng 2
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PMID: 32509057
Abstract
Purpose: Ovarian cancer is a common and fatal cancer in women. The long non-coding RNA (lncRNA) MEG3 was reported to affect the cellular processes of ovarian cancer, but the mechanisms remain unclear. Here, we aimed to explore the potential regulatory mechanism of MEG3 in ovarian cancer.

Materials and methods: A reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was conducted to analyze the expression levels of MEG3 and miR-205-5p in tissues and cell lines. An MTT assay was utilized to determine the cell viability of ovarian cancer SKOV-3 and OVCAR-8 cells. A flow cytometry analysis was employed to disclose the ovarian cancer cell apoptosis. The migration and invasion of SKOV-3 and OVCAR-8 cells were examined using a Transwell assay. A bioinformatics analysis indicated miR-205-5p as a direct target of MEG3, and a luciferase reporter assay was conducted to validate the interaction between MEG3 and miR-205-5p.

Results: MEG3 was significantly down-regulated, while miR-205-5p was up-regulated in ovarian cancer tissues and cell lines. The overexpression of MEG3 and the knockdown of miR-205-5p inhibited cell viability, migration and invasion but promoted the apoptosis rate in ovarian cancer cells. MiR-205-5p was identified as a downstream gene of MEG3 and is negatively regulated by MEG3. The introduction of miR-205-5p reversed the up-regulation of MEG3-mediated suppression effects on cell viability, migration and invasion and increased cell apoptosis in ovarian cancer cells.

Conclusion: The overexpression of lncRNA MEG3 inhibits cell proliferation and cell invasion and promotes apoptosis in ovarian cancer by sponging miR-205-5p.

Keywords: MEG3; apoptosis; cell viability; miR-205-5p; migration and invasion; ovarian cancer.

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25
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):730-737. eCollection 2020.
Linc-OIP5 Working as a ceRNA of miR-616 Promotes PON1 Expression in HUEVC Cells
Hua Chen 1, Xiaopeng Song 2, Yun Wu 1, Xin Bai 2, Xiayin Wu 1, Jiale Wang 1, Yanan Lu 1, Xi Liu 1
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PMID: 32355521 PMCID: PMC7191149
Free PMC article
Abstract
Coronary atherosclerosis affects human health all over the world. PON1 was found to be associated with coronary atherosclerosis but the specific mechanism is still unclear. Non-coding RNA plays an important role in many diseases. In recent years, studies have focused on non-coding RNA in coronary atherosclerosis. In this study, we investigated the effect of non-coding RNA Linc-OIP5 on PON1 expression. Results showed that in the serum of patients with coronary atherosclerosis, there was lower PON1 activity and PON1 level, the same trend in Linc-OIP5, and the opposite trend in miR-616 expression. Through further cell experiments, with up-regulation or down-regulation of Linc-OIP5 and miR-616, we found that Linc-OIP5 positively regulated the expression of PON1 gene and its protein level, while miR-616 negatively regulated the expression of PON1 gene and protein. Through further functional experiments, we also found that the levels of superoxide dismutase (SOD) and nitric oxide (NO) related to oxidative stress also had corresponding changes. Further dual luciferase reporter assay demonstrated that Linc-OIP5 regulated PON1 expression as a ceRNA of miR-616. Thus Linc-OIP5 working as a ceRNA of miR-616 apparently promotes PON1 expression in HUEVC cells and Linc-OIP5 and miR-616 may be an ideal target for the treatment of coronary atherosclerosis in the future.

Keywords: Coronary atherosclerosis; Linc-OIP5; PON1; miR-616; nitric oxide; superoxide dismutase.

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26
Int J Clin Exp Pathol
. 2020 May 1;13(5):995-1007. eCollection 2020.
Clinical Significance of PI3K/Akt/mTOR Signaling in Gastric Carcinoma
Eun-Jung Jung 1, Ja Hee Suh 1, Woo Ho Kim 2, Hee Sung Kim 3
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PMID: 32509071
Abstract
The mTOR signaling pathway has been linked to various cancers, but the contribution of alterations in this pathway to clinicopathological characteristics have not been established in gastric cancer. To investigate PIK3CA mutations and the expression of proteins in the PI3K/Akt/mTOR signaling pathway in sporadic gastric cancer. We analyzed PIK3CA mutation and microsatellite instability as well as immunohistochemical expressions of p-Akt, PTEN, p-mTOR, p-4EBP1, p-S6, p-p70S6, and eIF4E in 368 FFPE (formalin-fixed paraffin embedded) tissue from patients with sporadic gastric cancer. Associations between expression and clinicopathologic parameters and patient survival were evaluated. We found PIK3CA mutations in 4 of 173 cases (2.3%). In immunohistochemical analyses, we detected positive p-Akt expression in 22.0% of cases (81/368), negative PTEN expression in 21.5% of cases (79/368), positive p-mTOR expression in 68.6% of cases (243/354), positive p-4EBP1 expression in 58.2% of cases (202/347), positive p-S6 expression in 42.7% of cases (148/347), positive p-p70S6 expression in 51.1% of cases (179/350), and positive eIF4E expression in 78.3% of cases (275/351). In a clinicopathologic analysis, intestinal type was significantly associated with positive p-4EBP1 expression (P < 0.001). In a Kaplan-Meier survival analysis, PTEN loss (P = 0.002) and pS6 positivity (P = 0.043) are significantly associated with reduced overall survival (OS). PTEN loss (P = 0.001), pS6 positivity (P = 0.009), and eIF4E positivity (P = 0.003) are significantly associated with reduced disease free survival (DFS) (disease free survival). In Cox regression multivariate analysis, PTEN loss was an independent factor of reduced time. Alterations of mTOR pathway protein expression are associated with reduced survival in gastric cancer. Significance was noted in the association of pS6 positivity and eIF4E positivity e with reduced survival in univariate analysis and the association of PTEN loss and reduced DFS in univariate analysis as well as multivariate analysis for DFS.

Keywords: PI3K; immunohistochemistry; mTOR; mutation; survival; therapeutic target.

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27
Int J Clin Exp Pathol
. 2020 May 1;13(5):1094-1107. eCollection 2020.
Clinical and Biologic Roles of PDGFRA in Papillary Thyroid Cancer: A Study Based on Immunohistochemical and in Vitro Analyses
Lin Shi 1, Hao Chen 1, Yong-Ying Qin 1, Ting-Qing Gan 2, Kang-Lai Wei 1
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PMID: 32509085
Abstract
Background: Platelet-derived growth factor receptor alpha (PDGFRA) plays essential roles in several malignant tumors. Nevertheless, its clinical function in papillary thyroid cancer (PTC) is still unclear. This study aimed to examine the clinicopathologic implication and potential molecular underpinning of PDGFRA in PTC.

Material and methods: Relative PDGFRA expression levels in eight cases of normal thyroid tissue, 15 cases of benign thyroid disease, and 90 cases of PTC were examined by immunohistochemistry (IHC). The prognostic value of PDGFRA was assessed by data mining of The Cancer Genome Atlas dataset. LV-PDGFRA overexpression and negative control CON220 lentivirus vectors were constructed and transfected into a PTC cell line. The capacity for cell proliferation, status of the cell cycle, efficiency of colony-forming, and migration ability of the PTC cells after PDGFRA were detected by multiple assays including methyl thiazolyl tetrazolium, flow cytometry, colony formation, transwell assay, and wound healing. Furthermore, bioinformatics analyses were conducted to determine the potential biologic mechanisms of PDGFRA.

Results: Results of IHC showed that PDGFRA expression was significantly upregulated in PTC samples and was associated with an advanced pathologic stage. Furthermore, patients with PDGFRA overexpression showed poor survival. Ectopically overexpressed PDGFRA accelerated the migration and invasion of PTC cells. Results of the bioinformatics analyses suggested that PDGFRA was involved in several cell proliferation-related pathways.

Conclusion: Collectively, our results indicate that PDGFRA overexpression is associated with the poor survival of patients with PTC and that PDGFRA is a potent oncogene in PTC because it significantly increases PTC cell migration and invasion. Thus, PDGFRA may be a promising novel biomarker and therapeutic target for treating PTC.

Keywords: Platelet-derived growth factor receptor alpha; migration; papillary thyroid cancer.

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28
Int J Clin Exp Pathol
. 2020 May 1;13(5):1066-1072. eCollection 2020.
Differences in Pathologic Characteristics Between Ductal Carcinoma in Situ (DCIS), DCIS With Microinvasion and DCIS With Invasive Ductal Carcinoma
Bing-Tian Liu 1, Jia-Ning Ding 2, Jian-Li Wang 3, Zhi-Shuang Li 4, Yin-Lu Ding 1, Rong Ma 5
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PMID: 32509080
Abstract
In order to further our understanding of pathologic features in various ductal carcinoma in situ (DCIS) related breast ductal cancers, including DCIS, DCIS with microinvasion (DCIS-Mi) and DCIS with invasive ductal carcinoma (DCIS-IDC), a retrospective study including 453 cases of DCIS, 88 cases of DCIS-Mi, and 269 cases of DCIS-IDC was conducted. Statistical analysis showed significant pathological differences were found in DCIS, DCIS-Mi, and DCIS-IDC. Compared with DCIS, DCIS-IDC was significantly more associated with high nuclear grade, large tumor size, high Ki67 index, and lymph node metastasis (all P<0.05). Higher expression of steroid receptors was shown in DCIS-IDC than in DCIS (all P<0.05), but the status of HER2 between the two groups was similar (P=0.269). Compared with DCIS, DCIS-Mi was significantly more associated with high nuclear grade, large tumor size, comedonecrosis, absence of steroid receptors, HER2 overexpression, and high Ki67 index (all P<0.05). These features remain consistently even when compared with DCIS-IDC. According to the immunohistochemistry surrogate classification, the dominant types of DCIS and DCIS-IDC were luminal types (luminal A and luminal B, respectively), while the dominant type of DCIS-Mi was HER2 overexpression. These findings suggest that DCIS-Mi represents a distinct entity, and DCIS with features including high nuclear grade, large tumor size, comedonecrosis, steroid receptors negativity, HER2 positivity, and high Ki67 expression was more likely to have microinvasion than DCIS without these features.

Keywords: DCIS; ER; HER2; IDC; PR; microinvasion.

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29
Int J Clin Exp Pathol
. 2020 May 1;13(5):972-978. eCollection 2020.
Nicotinamide Nucleotide Transhydrogenase Acts as a New Prognosis Biomarker in Hepatocellular Carcinoma
Zhijiao Duan 1, Yang Song 1, Xuejing Zou 1, Shanshan Liu 1, Wanli Zhang 1, Li Liu 1
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PMID: 32509068
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Lipid metabolism is essential for cancer development. Nicotinamide nucleotide transhydrogenase (NNT) is abnormally expressed in multiple cancers; however, its role in HCC is unclear. We assessed the NNT expression level in The Cancer Genome Atlas (TCGA) cohort and Gene Expression Omnibus (GEO) datasets and found that the expression level of NNT was lower in HCC patients than non-cancer control subjects in the public databases. Survival analysis was conducted according to high and low NNT expression. Low NNT expression was significantly associated with a poor prognosis. For confirmation, the gene and protein expression of NNT in cancer and adjacent non-cancer tissues from HCC patients at our institute cohort indicated the lower expression level of NNT in cancer compared to adjacent non-cancer tissues using quantitative polymerase chain reaction and western blot, respectively. Bioinformatics was used to analyze the underlying mechanisms and establish the protein-protein interaction network of NNT. It showed that NNT is associated with functions of bile acid and fatty acid metabolism and their related genes. To conclude, our results supported that NNT expression is downregulated in HCC, and can serve as a novel prognostic biomarker.

Keywords: Hepatocellular carcinoma; lipid metabolism; nicotinamide nucleotide transhydrogenase; prognosis.

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30
Int J Clin Exp Pathol
. 2020 May 1;13(5):854-868. eCollection 2020.
INHBA Knockdown Inhibits Proliferation and Invasion of Nasopharyngeal Carcinoma SUNE1 Cells in Vitro
Sida Peng 1 2, Jiani Wang 3, Pan Hu 3, Wenhui Zhang 4, Huan Li 3, Lihua Xu 1 5 2
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PMID: 32509056
Abstract
Up-regulated expression of INHBA has been reported in multiple malignant tumors. However, in nasopharyngeal carcinoma (NPC), the expression pattern and clinical significance of INHBA are still unclear. This study aimed to detect the expression of INHBA and its prognostic significance in NPC, then explore the tumor-associated functions of INHBA gene and the potential mechanism. The INHBA expression of mRNA levels in tumor tissues and noncancerous nasopharyngeal tissues was investigated by RT-qPCR. The protein expression in cells were detected by western blot. Cell proliferation was detected by CCK assay and cell invasion ability was evaluated by Transwell assay. The expression of INHBA in paraffin-embedded NPC tissues was detected by immunohistochemistry (IHC). Statistical analyses were further applied to assess the clinical significance of INHBA expression. The result reveals INHBA mRNA level is elevated in NPC tissues compared to those in noncancerous nasopharyngeal epithelial tissues. In paraffin-embedded NPC tissues, immunoreactivity of INHBA was primarily detected in 53.70% (58/108) of these patients. The overexpression was notably associated with the clinical stage (UICC) (P=0.048), N classification (P=0.042), carotid sheath involvement (P=0.016), and decreased disease-free survival (DFS) (P=0.004) and overall survival (OS) (P=0.010). Multivariate analysis revealed that INHBA expression was an independent prognostic factor for DFS (P=0.028). CCK assay showed SUNE1 cells' proliferation was decreased in INHBA knockdown group than control. Transwell assay showed the invasion of SUNE1 cells was decreased in INHBA knockdown group by comparison with control. Further study showed knockdown of INHBA expression in SUNE1 cells could block the TGF-β signaling pathway. In conclusion, INHBA is up-regulated in NPC, and is significantly correlated with clinical stage (UICC), N stage, carotid sheath involvement, and survival. Knockdown INHBA in SUNE1 cells could inhibit the cells' proliferation and invasion. The underlying mechanism may be blockade of the TGF-β signaling pathway.

Keywords: INHBA; NPC; invasion; prognosis; proliferation.

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31
Int J Clin Exp Pathol
. 2020 May 1;13(5):889-895. eCollection 2020.
miR-149 Regulates the Proliferation and Apoptosis of Human Colonic Carcinoma Cells by Targeting FZD5
Xiaozhu Liu 1, Yinfeng Li 1, Cuicui Chen 2, Laiqing Li 2
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PMID: 32509059
Abstract
Objective: To explore the effects of miR-149 on the cell proliferation and apoptosis of colorectal cancer (CRC) and its potential molecular mechanism.

Methods: miR-149 expression patterns were detected in human CRC cell lines by quantitative real-time RT-PCR (Q-PCR). Online prediction software and luciferase reporter assay were performed to screen the functional targets of miR-149. CRC cells were transfected with miR-149 mimics or siRNAs of FZD5 and then divided into NC group (negative control), miR-149 mimics group (cells transfected with miR-149 mimics) and miR-149 mimics + SiFZD5 group (cells transfected by miR-149 mimics and SiFZD5). Moreover, the effects of miR-149 on the proliferation and apoptosis of CRC cells were also analyzed by MTT and flow cytometry assay. In addition, the expression of Wnt/β-catenin signal pathways related factors were shown by western blot analysis.

Results: Q-PCR results demonstrated that the expression of miR-149 was significantly lower in SW480 than that in the FHC cell line. Frizzled class receptor 5 (FZD5) was identified as a functional target of miR-149 through a series of experiments including Q-PCR, western blot analysis, and luciferase assay. Cellular functional experiments demonstrated that the cell viability and proliferation were greatly inhibited after miR-149 overexpression in SW480 cells. Furthermore, the proportion of apoptotic cells increased significantly after introducing miR-149 into SW480 cells. Furthermore, Wnt/β-catenin signal pathway was activated because of the lower expression of β-catenin and cyclinD1 in miR-149 mimics group. However, reducing FZD5 expression restored the expression of β-catenin and cyclin D.

Conclusions: Our data suggested that miR-149 may function as a tumor suppressor in CRC cells lines by targeting FZD5. miR-149/FZD5 may become a new therapeutic target for CRC.

Keywords: Frizzled class receptor 5 (FZD5); Wnt/β-catenin signal pathway; colorectal cancer (CRC); miR-149.

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32
Int J Clin Exp Pathol
. 2020 May 1;13(5):901-911. eCollection 2020.
miR-16-5p and miR-145-5p Trigger Apoptosis in Human Gingival Epithelial Cells by Down-Regulating BACH2
Xiaoming Liu 1, Kai Su 2, Shijun Kuang 2, Min Fu 1, Zhiguang Zhang 2
Affiliations expand
PMID: 32509061
Abstract
Background: Periodontitis is the second most common dental disease worldwide. TNF-α is up-regulated in periodontal disease and induces inflammation and cell apoptosis in gingival epithelial cells (GECs). miRNAs/mRNA axis play an important role in cell progression and inflammation. However, studies on the pathogenesis of periodontitisare still scarce, especially in the regulation mechanism of miRNAs.

Methods: The expression and protein level of miR-16-5p, miR-145-5p, BACH2, and caspase 3 were determined by quantitative real time PCR and western blot, respectively. Cell viability was measured by MTT assay. Cell apoptosis was detected by flow cytometry. Dual-luciferase assay was applied to verify miR-16-5p and miR-145-5p target to the 3'UTR of BACH2.

Results: TNF-α induced miR-16-5p, miR-145-5p and caspase 3 expression, inhibited cell viability, promoted cell apoptosis in GECs. However, down-regulated miR-16-5p and miR-145-5p can restore the effects of TNF-α on GECs. In addition, dual-luciferase assay determined that BACH2 was a common target of miR-16-5p and miR-145-5p. Knockdown of BACH2 induced GECs apoptosis. Of note, cell apoptosis induced by miR-16-5p mimic, miR-145-5p mimic, and TNF-α was significantly reversed by up-regulating BACH2.

Conclusion: miR-16-5p and miR-145-5p mediate apoptosis induced by TNF-α in human gingival epithelial cells by targeting BACH2.

Keywords: BACH2; GECs; apoptosis; miR-145-5p; miR-16-5p.

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33
Int J Clin Exp Pathol
. 2020 May 1;13(5):1017-1023. eCollection 2020.
Expression of circRNA circ_0026344 in Gastric Cancer and Its Clinical Significance
Xinrong Zhang 1, Lei Zhang 2, Lihong Cui 1, Ming Chen 1, Dongying Liu 3, Jingjing Tian 1
Affiliations expand
PMID: 32509073
Abstract
Emerging evidence indicates that circular RNAs (circRNAs) are a novel class of biomarkers and therapeutic targets in malignancies. Circ_0026344 has been reported to be downregulated in colorectal cancer, and associated with prognosis. However, little is currently known regarding its expression and clinical significance in gastric cancer. In this study, we evaluated the expression level of circ_0026344 in two previous circRNAs chips (GSE78092 and GSE89143) for gastric cancer. 93 pairs of gastric cancer and adjacent non-tumour tissues were collected, and qRT-PCR was applied to determine circ_0026344 expression. The level of circ_0026344 in gastric cancer cells (MKN45 and AGS) and a normal gastric epithelial cell line (GES-1) was also analyzed. Chi-square test was used to identify the association between circ_0026344 level and clinicopathologic factors. Kaplan-Meier method with log-rank test was applied to compare survival curves. Cox regression analyses were used to assess the prognostic value of circ_0026344. In GSE24549 and GSE24550 datasets, downregulation of circ_0026344 was observed. In 93 cases of gastric cancer, circ_0026344 in cancer tissues was significantly decreased compared to adjacent non-cancerous tissues, and its level was markedly associated with tumour size, lymph node metastasis, TNM stage, and invasive depth. Furthermore, patients with lower expression of circ_0026344 showed significantly worse overall survival than those with higher expression. Additional, circ_0026344 expression was an independent predictor for overall survival. Summarily, our study highlights that downregulation of circ_0026344 is associated with tumour malignant behavior and it is a potential biomarker for gastric cancer prognosis.

Keywords: biomarker; circRNAs; circ_0026344; gastric cancer; prognosis.

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34
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):642-654. eCollection 2020.
miR-19 Promotes Development of Renal Fibrosis by Targeting PTEN-mediated Epithelial-Mesenchymal Transition
Yun Zhang 1, Guo-Xin Zhang 2, Li-Shuang Che 1, Shu-Han Shi 1, Wei-Yuan Lin 1
Affiliations expand
PMID: 32355512 PMCID: PMC7191147
Free PMC article
Abstract
In recent years, it has been found that miRNA may play an important role in the field of gene regulation; miRNAs can participate in the regulation of various physiologic processes such as cell differentiation, proliferation, apoptosis, metabolism, and insulin secretion by regulation of target genes. The purpose of this study is to observe the relationship between the expression of miR-19 and renal fibrosis, to analyze the regulatory effect of miR-19 on renal tubular EMT, and to reveal its role and working mechanism in renal fibrosis. We found that the expression of miR-19 was significantly increased in peripheral blood of patients with renal fibrosis, in renal tissue of unilateral ureteral occlusion (UUO) mice, and in NRK-52E cells treated with TGF-β1. Overexpression of miR-19 could decrease the expression of E-cadherin and increase the expression of α-SMA and fibronectin, while inhibition of miR-19 reverses TGF-β1-induced EMT. Further studies revealed that miR-19 could inhibit its expression by binding to the 3'-UTR of PTEN. MiR-19 inhibitor or Akt inhibitor blocks phospho-Akt by TGF-β1, and Akt inhibitors block miR-19 mimic-induced EMT. In UUO mice, overexpression of miR-19 promoted the development of renal fibrosis, while inhibition of miR-19 expression produced the opposite result. These results indicate that abnormal expression of miR-19 is associated with renal fibrosis. Moreover, miR-19 activates the Akt signaling pathway by targeting PTEN, and induces EMT in renal tubular epithelial cells, thereby promoting renal fibrosis.

Keywords: EMT; PTEN; Renal fibrosis; miR-19.

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35
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):701-710. eCollection 2020.
YAP Promotes Epithelial Mesenchymal Transition by Upregulating Slug Expression in Human Colorectal Cancer Cells
Dan Cheng 1, Lan Jin 1, Yunhe Chen 1, Xueyan Xi 1 2, Yang Guo 1 2
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PMID: 32355518 PMCID: PMC7191148
Free PMC article
Abstract
Yes-associated protein (YAP) contributes to the development of multiple tumors, including colorectal cancer (CRC). However, the underlying mechanisms involved in YAP-induced CRC migration and invasion are not fully elucidated. By performing immunohistochemistry (IHC), we found that YAP is highly expressed in CRC tissues and significantly correlated with invasive depth. The expression of YAP was elevated in CRC cell lines. Therefore, we sought to illustrate whether the up-regulation of YAP contributes to CRC the epithelial-mesenchymal transition (EMT). Here migration and transwell assays showed that YAP overexpression promoted migration and invasion inCRC cells. YAP knockdown inhibited migration and invasion in CRC cells. Furthermore, western blotting showed that CRC YAP overexpression causes the down-regulation of the epithelial marker E-cadherin and the up-regulation of the EMT-related transcription factor Slug, which in turn promotes the EMT in CRC. YAP knockdown inhibited EMT by up-regulating E-cadherin and down-regulating Slug. Furthermore, in YAP-overexpressing CRC cells, Slug knockdown promoted E-cadherin expression and inhibited EMT. In CRC cells with low expression of YAP, high expression of Slug can inhibit E-cadherin expression and promote EMT. Importantly, luciferase assays confirmed that YAP directly transcriptionally activated Slug expression. Based on the above results, our study shows that YAP is a driver of EMT in CRC, which inhibits E-cadherin expression by activating transcriptional Slug expression.

Keywords: CRC; E-cadherin; Slug; YAP; epithelial-mesenchymal transition.

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None.

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36
Int J Clin Exp Pathol
. 2020 May 1;13(5):964-971. eCollection 2020.
Sepsis Causes Heart Injury Through Endoplasmic Reticulum Stress-Mediated Apoptosis Signaling Pathway
Lei Li 1, Xin Peng 1, Lichun Guo 1, Yuhan Zhao 1, Qinghong Cheng 1 2
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PMID: 32509067
Abstract
Endoplasmic reticulum stress (ERS), arising from the loss of dynamic balance in endoplasmic reticulum function under stress and inflammation, has been implicated in the progression of sepsis. Multiple organ failure caused by sepsis still has a high mortality rate, of which the heart is one of the more damaged organs. In this research, a rat model of sepsis was set up by cecal ligation and puncture (CLP); serum myocardial enzyme levels were measured using an automated biochemical analyzer, inflammatory cytokine levels were measured by ELISA kit, and cardiac histology and cardiomyocyte apoptosis were measured by hematoxylin and eosin (H&E) staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to assess the extent of myocardial damage. Western blot was used to detect expression of related proteins. The results showed that serum myocardial enzymes and pro-inflammatory factors were elevated in septic rats, and the increase was most significant in the CLP 24 h group. At the same time, the myocardium of septic rats had a histopathologic abnormality. After CLP, levels of endoplasmic reticulum stress related protein were upregulated. After 12 and 24 hours, the density of apoptotic cells in the myocardium of CLP-treated rats increased significantly, and the expression of apoptosis-related proteins changed significantly. This suggests that the unfolded protein response occurs during sepsis and causes damage to the heart muscle. Endoplasmic reticulum stress-mediated apoptotic signaling pathway is one of the causes of cardiac injury caused by sepsis, and may be a key to clinical prevention of cardiac dysfunction caused by sepsis.

Keywords: Sepsis; endoplasmic reticulum stress; myocardial injury.

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Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1073-1080. eCollection 2020.
A Case of Small Hepatocellular Carcinoma With Malignant Ductular Reaction
Tomohiro Iwasaki 1, Aki Kubota 1, Makoto Suzuki 1, Tadashi Terada 1
Affiliations expand
PMID: 32509081
Abstract
Herein reported is the unique case of a small hepatocellular carcinoma (HCC) with several foci of a minor (10% in area) component of "malignant ductular reactions". The patient was 51-year-old man who was a drinker. HBV/HCV were negative. The tumor was small (12×10×11 mm), solid, expansile and reddish-brown, and contained fibrous septa. The background was cirrhotic without alcoholic features. Histologically, the tumor was well differentiated HCC, and, besides the HCC, it contained several small foci consisting of the following four biliary epithelial elements: clusters of small cells (CSC), ductules (D), ductular hepatocytes (DH), and bile ducts (BD). The proportion of area was as follows: HCC 90%, CSC 3%, D 3%, DH 2%, and BD 2%. These non-HCC elements were intimately admixed and formed several foci that were characteristically located in the fibrous septa (FS), except for CSC which were situated among HCC cells close to FS. There were gradual merges between HCC and CSC, CSC and D, D and DH, and D and BD, respectively. Cells of CSC and D resembled rat oval cells. Cells of these four elements had atypical features regarded as malignant. Immunohistochemically (IHC), HCC were positive for arginase, HepPar1, and less frequently CK7. CSC were positive for CK7. D were positive for arginase, HepPar1, CK7, CK19, EMA, and EpCAM. DH were positive for arginase, HepPar1, and CK7. BD were positive for CK7, CK19, EMA, EpCAM and mucin. Although such tumors as this have been termed stem cell-related cancers, our case lacked definite evidence for stem cell origin in histology as well as in the IHC that showed negativity for KIT, CD34, and OCT3/4. The above findings suggest that CSC, D, DH and BD are analogous to the ductular reaction seen in hepatic inflammation. Therefore, we termed the phenomenon "malignant ductular reaction". It is suggested in the present tumor that at first only HCC developed, and then HCC cells in the interface with FS transformed to CSC, like a fetal ductal plate. Then, the CSC gave rise to D, which in turn led to DH and BD in FS, all findings of which are most likely sequential considering embryonic biliary development. The idea that the present tumor was at first D carcinoma and then D developed on one hand into CSC and HCC, and on the other into DH and BD seems possible, but its probability appears low because the vast majority of the present tumor had the phenotype of HCC.

Keywords: HCC; case report; ductular reaction; liver stem cells.

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38
Int J Clin Exp Pathol
. 2020 May 1;13(5):837-845. eCollection 2020.
Reliability of Acellular Decalcified and Decalcified Teeth as Bone Graft Material: An Experimental and Pathological Study in Rats
Ke Guo 1, Wenchao Wang 1, Zonglin Liu 1, Weifeng Xu 1, Shanyong Zhang 1, Chi Yang 1
Affiliations expand
PMID: 32509054
Abstract
Objective: The present study aimed to investigate the reliability of acellular decalcified teeth in the development of bone scaffolds and in bone regeneration in rats.

Methods: (1) Forty-eight human teeth were divided into two groups in vitro: twenty-four were decalcified, while the remaining twenty-four were decalcified and decellularized, following which a conventional scanning-electron microscope analysis was performed. (2) In another experiment, six male SD rats aged 10-12 weeks were selected, then decalcified and acellular decalcified teeth were embedded subcutaneously in the abdomen of the rats. After 4 weeks, the rats were sacrificed for H-E staining and immunohistochemical staining to observe the inflammatory reaction around the two materials. (3) In the ectopic osteogenesis experiment, bone defects were simulated in bilateral craniotectal areas of 12 male SD rats (age 10-12 weeks), following which acellular decalcified teeth were implanted in the right bone defect. The non-implanted left side was used as blank control. At week 4 and week 8, 6 rats were randomly selected for execution, complete specimens were obtained, and micro-CT scan was performed to compare the bone mass from gross morphology. H-E staining was performed at 4 and 8 weeks to observe the surrounding inflammatory response and immunohistochemistry was performed at 8 weeks to observe the degree of new bone formation. SPSS 23.0 software package was used for statistical processing.

Results: (1) Under scanning electron microscope, cells in the teeth subjected to acellular decalcification completely disappeared, leaving only inorganic scaffolds. (2) After 4 weeks, the amount of inflammatory reaction in the tissues surrounding acellular decalcified teeth was significantly lower than that in the tissues surrounding decalcified teeth. (3) After four and eight weeks, the amount of bone formation in the bone defects was significantly higher in rats implanted with acellular decalcified teeth than in those in the blank control group (P<0.05). After four and eight weeks, hematoxylin-eosin staining revealed that the degree of inflammatory response was similar around acellular decalcified teeth and blank controls. Immunohistochemistry indicated that the osteocalcin levels were significantly higher around acellular decalcified teeth than that around blank controls.

Conclusion: Acellular decalcified teeth show significantly decreased inflammatory reaction, better biocompatibility, better osteogenic potential, and better plasticity than decalcified teeth alone.

Keywords: Cranial defects; acellular bone matrix; decalcified bone matrix; extracted human teeth; rat.

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39
Int J Clin Exp Pathol
. 2020 May 1;13(5):1053-1059. eCollection 2020.
Borderline Ovarian Tumor in the Pediatric and Adolescent Population: A Clinopathologic Analysis of Fourteen Cases
Mengwei Xu 1, Bowei Wang 2, Yonghua Shi 1
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PMID: 32509078
Abstract
Borderline ovarian tumors (BOTs) are rare among children and adolescents. This study was to probe into the clinicopathologic characteristics and prognosis in children and adolescents with BOT. A retrospective investigation was performed on 14 adolescents younger than age 21 years diagnosed with BOT. Clinical presentation, preoperative characteristics, surgery, tumor stage, histology, and recurrence were collected. The results showed that median age at diagnosis was 17.5 years, mostly after menarche. Abdominal mass/pain were the most common presenting symptoms. Median tumor size was 14 cm. Cancer antigen-125 (CA-125) in the blood serum was elevated by 41.67% (5/12), and CA-199 was elevated by 16.67% (2/12). All patients had fertility-preserving surgery: 66.67% (8/12) via laparoscopy (LSC) and cystectomy, 33.33% (4/12) via laparotomy and unilateral salpingo-oophorectomy (USO), and 1 case recurred, and underwent panhysterectomy and bilateral salpingo-oophorectomy. 4 out of 14 tumors (28.57%) had serous and 10 of 14 (71.43%) had mucinous histology. Five tumors showed histological microinvasion. Median follow-up time was 52 months. 10 of 14 cases were alive at last follow-up without disease, and 4 of 14 cases were at lost visit. Thus BOTs in children and adolescents are very rare tumors which have excellent prognosis even in advanced stages, when managed with fertility-preserving procedures. Close follow-up is important because of the high recurrence rates many years after diagnosis.

Keywords: Borderline ovarian tumor; adolescent; pediatric.

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40
Int J Clin Exp Pathol
. 2020 May 1;13(5):1108-1120. eCollection 2020.
Stable Silencing of ROR1 Regulates Cell Cycle, Apoptosis, and Autophagy in a Lung Adenocarcinoma Cell Line
Qi Zhou 1, Shiyi Zhou 1, Huili Wang 1, Yanping Li 1, Xiaoqian Xiao 1, Jiahui Yang 1
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PMID: 32509086
Abstract
Lung cancer has the highest mortality and recurrence rate among cancers in the world. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been widely recognized for its role in promoting the growth and metastasis of lung cancer, but its comprehensive role and molecular mechanisms in regulating cell cycle, apoptosis, and autophagy remain unclear. In this study, a series of ROR1-stably silenced monoclonal clones from lung adenocarcinoma cell lines PC9, PC9erlo, and NCI-H1975 were successfully selected and confirmed by qRT-PCR, western blot, and flow cytometry, and used as cell models in the following assays. Our study clearly shows that blocking ROR1 significantly downregulates cell cycle-inducing molecules such as CDK4 and Cyclin E1, and anti-apoptotic molecules such as Bcl-XL and Bcl-2, while it markedly upregulates pro-apoptotic molecules such as Bak, Caspase-3, and Caspase-7, which extends our previous observation on the molecular mechanism of ROR1-mediated tumor growth in lung adenocarcinoma. Our data also show that silencing ROR1 promotes autophagy since the key molecules involved in autophagy including ATG7, ATG12, BNIP3L, LC3A, LC3B, and NBS1 were up-regulated. We further screened key phosphokinase signaling pathways downstream of ROR1 in lung adenocarcinoma by a human phospho-kinase array. Our data indicate that blocking ROR1 could deactivate Akt, then activate GSK-3α/β by de-phosphorylation, and finally deactivate mTOR. In this way blocking ROR1 could effectively regulate the cell cycle, apoptosis, and autophagy in lung cancer.

Keywords: ROR1; apoptosis; autophagy; cell cycle; lung adenocarcinoma.

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41
Int J Clin Exp Pathol
. 2020 May 1;13(5):934-943. eCollection 2020.
Myocyte-specific Enhancer Factor 2D Promotes Tumorigenesis and Progression in Tongue Squamous Cell Carcinoma
Yang Liu 1, Wenjun Yu 1, Yan Zhu 1, Zhenni Sun 1, Xingang Huang 2, Jianhua Zhou 3, Ruyong Yao 4, Qian Zhang 4, Jianzhong Qiu 3, Lu Yue 1
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PMID: 32509064
Abstract
Tongue squamous cell carcinoma (TSCC) ranks as one of the most common cancers worldwide and has a poor prognosis. Myocyte-specific enhancer factor 2 (MEF2D) has recently been considered as a novel factor involved in cancer development. In the present study, the function and underlying mechanism of MEF2D in TSCC were investigated. The levels of MEF2D mRNA and protein were determined in human TSCC samples by RT-qPCR and western blot, respectively. The interaction between MEF2D expression and clinicopathologic features was evaluated by IHC and analysis of clinical information. MEF2D-mediated effects on proliferation, migration, and invasion were explored in TSCC cells after transfection with MEF2D-siRNA. The results showed higher expression of MEF2D at both the mRNA and protein levels in TSCC carcinoma tissues than in paracarcinoma tissues. Furthermore, high expression of MEF2D was positively correlated with tumor differentiation and lymphatic metastasis. MEF2D knocked down TSCCA cells also had reduced proliferative, migratory, and invasive abilities compared to those of control cells. Together, these data confirmed that knockdown of MEF2D might suppress the growth and metastasis of TSCC, which further indicated that MEF2D might serve as a therapeutic target for TSCC treatment.

Keywords: Tongue squamous cell carcinoma (TSCC); myocyte-specific enhancer factor 2 (MEF2D); proliferation; tumorigenesis.

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42
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):655-663. eCollection 2020.
Effect of oxLDL on Transcriptional Expression of Human Lens Epithelial Cells
Ru Zhang 1, Yang Fang 2, Suwen Bai 2, Huiwen Gao 2, Hongbo Chen 3, Zhiguo Zhang 4, Juan Du 2, Bing Shen 2, Yong Wang 1
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PMID: 32355513 PMCID: PMC7191155
Free PMC article
Abstract
Age-related cataract patients regularly have hypertension, hyperglycemia, and hyperlipidemia. In oxidative conditions, increased reactive oxygen species can oxidize natural low-density lipoprotein into oxidative low-density lipoprotein (oxLDL). However, the relationship between oxLDL and the occurrence of cataracts is still unclear. In this study, 1515 differentially expressed transcripts were identified by analyzing the results of RNA sequencing in a human lens epithelial cell line (HLEpiC). Compared with control groups, oxLDL-treated HLEpiC had 806 up-regulated transcripts and 709 down-regulated transcripts. Our genome-wide transcriptome results showed that differentially expressed genes, such as Rho signaling (Rho A and Cdc42) and Na+/K+-ATPase family (ATP1B1), are involved in lens epithelial cell differentiation and cell homeostasis. In conclusion, oxLDL greatly influences transcriptional expression and these differentially expressed genes may play an important role in the development of cataracts. Our findings may provide new targets in the treatment for cataracts.

Keywords: HLEpiC; OxLDL; RNA sequence; cataract; cell differentiation.

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43
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):664-674. eCollection 2020.
Comparison of Two Commonly Used Methods in Measurement of Cancer Volume in Prostate Biopsy
Viharkumar Patel 1, Samuel Hubbard 1, Wei Huang 1
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PMID: 32355514 PMCID: PMC7191135
Free PMC article
Abstract
Currently, cancer volume in prostate biopsy samples is commonly calculated as linear length of carcinoma divided by total core length and reported as percentage involvement. The measurement of the linear length of carcinoma can be problematic particularly when there are two or more separate foci of carcinoma in a single core. There are two most methods commonly used by practicing pathologists. One method is to measure the exact linear extent of each discrete carcinoma foci in millimeters and then add up the linear length (the exact method, E method). The other method is to measure the core length encompassing all carcinoma foci including the intervening benign prostate tissue (glands and/or stroma) (the scattered method, S method). In this study, we used digital pathology to compare the site-specific and overall cancer volumes measured with the E and S methods and analyzed their correlation with the cancer volume in the corresponding prostatectomy specimens. Our results showed that prostate-cancer volumes estimated with both E and S methods on biopsy samples positively correlate with cancer volume at radical prostatectomy. However, the cancer volumes measured with both E and S methods in the majority of biopsy samples were significantly larger than that in prostatectomy (P<0.001). The E method more closely predicts the cancer volume compared to the S method. The overall cancer volume is better than site-specific cancer volume at biopsy in predicting cancer volume at prostatectomy.

Keywords: Exact method; cancer volume; prostate biopsy; scattered method.

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Conflict of interest statement
This study was partially supported by Dhristi, Inc, in which Dr. Huang holds stock shares.

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44
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):711-720. eCollection 2020.
Downregulation of microRNA-519 Enhances Development of Lung Cancer by Mediating the E2F2/PI3K/AKT Axis
Hua Zhang 1, Aisikeer Tulahong 1, Wenran Wang 1, Yiliyaer Nuerrula 1, Yuefen Zhang 1, Ge Wu 1, Shaya Mahati 1, Hui Zhu 2
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PMID: 32355519 PMCID: PMC7191141
Free PMC article
Abstract
MicroRNA-519 (miR-519) acts as an inhibitor in different kinds of tumors. The current study was set to probe the function of miR-519 in lung cancer and to explore the potential molecular mechanism. The expression difference of miRNAs between lung cancer and paracancerous tissues was analyzed by microarray. miR-519 expression was significantly diminished in lung cancer tissues and cells. After that, EdU staining, CCK-8 assay, Transwell assay, Hoechst 33258 staining and PI/Annexin-V staining revealed that overexpression of miR-519 in lung cancer cells inhibited their viability and promoted apoptosis. TragetScan and miRSearch were employed to predict the target mRNAs of miR-519, which were verified by a luciferase activity assay. miR-519 bound to the 3'untranslated region of E2F transcription factor 2 (E2F2) mRNA. Finally, the extent of PI3K/AKT signaling pathway phosphorylation was examined, which illustrated that upregulation of miR-519 repressed the phosphorylation of the PI3K/AKT pathway in SPC-A-1 and 95C cells. miR-519 reduces PI3K/AKT pathway activities by suppressing the transcription activity of E2F2, thereby potentially inhibiting the occurrence of lung cancer.

Keywords: E2F2; Lung cancer; PI3K/AKT signaling pathway; microRNA-519; migration; proliferation.

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45
Int J Clin Exp Pathol
. 2020 May 1;13(5):880-888. eCollection 2020.
Infiltration of CD8 + FOXP3 + T Cells, CD8 + T Cells, and FOXP3 + T Cells in Non-Small Cell Lung Cancer Microenvironment
Jianqing Hao 1, Helin Wang 1 2, Lai Song 3, Shuping Li 4, Nanying Che 5, Shucai Zhang 1, Hongtao Zhang 4, Jinghui Wang 1
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PMID: 32509058
Abstract
Background: Studies about CD8+ FOXP3+ T cells as a subtype of regulatory T cells (Treg cells) in non-small cell lung cancer (NSCLC) are few. Associations among the clinicopathologic factors of NSCLC and tumor-infiltrating lymphocytes (TILs) such as CD8+ FOXP3+ T cells, CD8+ T cells, FOXP3+ T cells and tumor PD-L1 expression are unclear.

Methods: We retrospectively enrolled 192 patients who underwent resections for NSCLC. We used tissue microarrays (TMA) with multiplex immunofluorescence and immunohistochemistry staining to evaluate the expression of CD8, FOXP3, cytokeratin, DAPI and PD-L1. We then used Wilcoxon test, Kaplan-Meier method, and Cox hazard proportion model to analyze their relationships with clinicopathologic factors and prognosis.

Results: Density of tumor CD8+ FOXP3+ T cells was significant by univariate analysis, and positively associated with tumor CD8+ T cells and FOXP3+ T cells. Density of tumor CD8+ T cells was higher in lung adenocarcinoma (LUAD) than squamous cell carcinoma (LUSC), and was an independent prognostic factor for NSCLC. The density of tumor FOXP3+ T cells decreased with tumor size. Tumor PD-L1 expression was higher in LUSC than LUAD. Cox hazard proportion model analysis correlated being younger than 65 years, early TNM stage, early T stage, high tumor CD8+ T cell density, and adjuvant chemotherapy with longer overall survival.

Conclusion: Infiltration of CD8+ FOXP3+ T cells, CD8+ T cells, and FOXP3+ T cells is important in non-small cell lung cancer microenvironment, and needs to be investigated more.

Keywords: CD8+ FOXP3+ T cells; Lung cancer; PD-L1; multiplex immunofluorescence staining.

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46
Int J Clin Exp Pathol
. 2020 May 1;13(5):846-853. eCollection 2020.
Effects of Jinlongshe Granules on Gastric Precancerous Lesions in Rats and Its Mechanism
Xiaowei Wang 1, Jingyu Xu 1, Xuan Zhang 1, Chenxi Zhang 2, Wenyi Zheng 2, Jianpeng Jiao 1, Xuan Liu 1, Xiaoqiang Yue 1
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PMID: 32509055
Abstract
Objective: To investigate the anti-gastric precancerous lesions effect and mechanism of Traditional Chinese Medicine Jinlongshe (JLS) granules in ethanol extractive of A. manshuriensis (EEA)-induced gastric precancerous lesions rats.

Methods: A rat model with the part typical proliferation of the gastric epithelium mucosa was established by EEA. These rats received different doses of JLS granules treatment for four weeks. Bodyweight, histological and ultrastructural changes of gastric precancerous lesions were evaluated. The expression of Apelin and CD34 mRNA and proteins of the gastric tissue were analyzed by quantitative Realtime PCR, western blot and immunohistochemical staining.

Results: We found that the treatment of JLS granules prevented the bodyweight loss and improved behavioral abnormalities of rats that received EEA. The histological and ultrastructural analysis also showed that JLS granules ameliorated EEA induced gastric precancerous lesions in a dose-dependent manner. The expression levels of two critical proteins involved in the angiogenesis of gastric carcinoma, Apelin, and CD34, were significantly reduced by the treatment of JLS granules.

Conclusion: Our results indicated that JLS could inhibit the expression of the Apelin and CD34 genes in rat gastric mucosa, which reversed gastric precancerous lesions.

Keywords: Apelin; CD34; Gastric precancerous lesions; Jinlongshe; Traditional Chinese Medicine.

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47
Int J Clin Exp Pathol
. 2020 May 1;13(5):954-963. eCollection 2020.
Murine Embryonic Mesenchymal Stem Cells Attenuated Xerostomia in Sjögren-like Mice via Improving Salivary Gland Epithelial Cell Structure and Secretory Function
Bangdong Gong 1, Ling Zheng 2, Wanxue Huang 1, Jincheng Pu 1, Shengnan Pan 1, Yuanyuan Liang 1, Zhenzhen Wu 1, Jianping Tang 1
Affiliations expand
PMID: 32509066
Abstract
Background: Xerostomia is the main manifestation from patients with Sjögren syndrome (SS). However, traditional immunosuppressive agents are nearly invalid due to complicated etiopathogenesis in salivary glands, including aberrant immune dysregulation, epithelial structure destruction, and diminished secretory function.

Objective: To investigate the therapeutic effect of murine embryonic mesenchymal stem cells (ME-MSCs) on salivary glandular epithelium structure and secretory function in Sjögren-like mice.

Methods: Salivary flow rate (SFR), blood glucose, and body weight was weekly monitored among treatment group, disease group, and health control group. ME-MSCs were used to treat NOD mice via tail vein injection. HE staining and transmission electron microscope was used to evaluate the structure of salivary gland epithelial cells (SGEC). TUNEL fluorescence staining and PCNA immumohistochemical staining was used to evaluate the SGEC apoptosis and proliferation. The SGEC secretory function was tested by PAS staining and amylase immumohistochemical staining.

Results: ME-MSC treatment could elevate SFR, restore the acini and micromorphologies, promote the SGEC proliferation, and suppress the SGEC apoptosis in NOD mice, but not restore to that in health control group. The SGEC structure was more intact in treatment group. Mucopolysaccharide and amylase of salivary acinar cells in treatment group was better than that in disease group, although transmission electron microscopy showed secretory granules were lower than those in healthy control.

Conclusion: ME-MSCs demonstrated its potential as a candidate treatment for xerostomia due to some effects on salivary flow rate in NOD mice by restoring the SGEC impairment and secretory function.

Keywords: Mesenchymal stem cells; Sjögren syndrome; salivary gland epithelium cells; xerostomia.

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48
Int J Clin Exp Pathol
. 2020 May 1;13(5):979-988. eCollection 2020.
Overexpression of EP300-interacting Inhibitor of Differentiation 3 Predicts Poor Prognosis in Patients With Glioblastoma Multiforme
Peng-Yu Diao 1, Shao-Xun Li 2, Jin Peng 1, Ji-Hu Yang 1, Yu-Chen Pan 1, Xiang-Ping Xu 1, Han Tang 1, Jin-Xian Hu 1, Hua-Fu Zhao 1, Guo-Dong Huang 1
Affiliations expand
PMID: 32509069
Abstract
EP300-interacting inhibitor of differentiation 3 (EID3) is a member of the IED family and has been associated with tumorigenesis and tumor development in different cancer types. However, the role of EID3 in glioblastoma multiforme (GBM) prognosis is not clear. Whole transcriptome sequencing data of 249 and 149 GBM patients were collected from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) database respectively. The correlation between EID3 expression and overall survival (OS)/clinical pathologic features of GBM patients was investigated. Based on the Wilcoxon rank-sum test, EID3 expression in GBM tissues was significantly lower than in normal brain tissues (P < 0.001), and significantly higher than in LGG (low-grade glioma) (P < 0.001).There was a significant correlation between high EID3 expression with poor OS in CGGA (P = 0.049) and TCGA data (P = 0.024). Gene set enrichment analysis (GSEA) data analysis revealed a significant difference (FDR < 0.25, NOM p-value < 0.05) in the enrichment of MSigDB Collection (h.all.v6.2.symbols.gmt). A total of eight enriched pathways were identified in the high EID3 expression group, including Myc Targets V1, Kras signaling DN, and DNA repair pathways. Multivariate Cox regression analysis indicated that high expression of EID3 correlated with poor OS (P = 0.032, HR = 1.41, CI: 1.03-1.90). We conclude that EID3 could serve as an independent factor for predicting the prognosis of patients with GBM. Moreover, it is associated with GBM development through the regulation of the Myc Targets, Kras signaling DN, and DNA repair pathways.

Keywords: EID3; glioblastoma; overall survival; prognosis.

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49
Int J Clin Exp Pathol
. 2020 May 1;13(5):1185-1189. eCollection 2020.
Preliminary Investigation of Demographic Signatures of Intestinal Parasitic Infection in Rural Residents of Guangxi Zhuang Autonomous Region in China
Chen Huang 1 2, Rong Li 3, Jian Chen 3, Tippawan Liabsuetrakul 1, Wuxiang Shi 2
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PMID: 32509093
Abstract
Background: Our present study was designed to initially unveil the epidemiological characteristics and underlying etiology of intestinal parasitic infection (IPI) in rural residents of Guangxi province in China through conducting a community-based cross-sectional survey.

Material and methods: By use of an epidemiological questionnaire survey and morphologic examination, a total 700 residents from dissimilar regions around rural areas in Guangxi province were recruited for fecal samples to explore ethnic differences in IPI. The fecal specimen was collected and used for microscopic inspection of visible signs of parasitic eggs. In addition, parasitic egg samples were screened and identified to characterize the parasite-bearing IPI cases.

Results: The statistical epidemiologic data exhibited that the early pathologic signs of ethnicity-sorted IPI-based rural residents occurred in a two-week period, such as headache and itchy skin. Following further one-year tracing, some potential pathological symptoms of rural locales with IPI were screened and identified, including diarrhea and anemia. Insufficient education seemed to be an underlying cause of IPI in rural residents. In addition, further morphologic signs of parasitic eggs and protozoa in IPI-based residents with pathologic symptoms were validated.

Conclusions: Overall, these preliminary epidemiologic findings demonstrate that detectable pathologic signs of IPI-based rural residents in Guangxi province were associated with poor education, thus local government needs a strategy for reducing IPI and improving quality of life in locals.

Keywords: Epidemiology; etiology; intestinal parasitic infection; symptom.

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50
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):818-826. eCollection 2020.
Smooth Muscle Tumor of Uncertain Malignant Potential (STUMP): A Clinicopathologic Analysis of 26 Cases
Yuan-Yin Zheng 1, Xiao-Bin Liu 1, Ying-Yu Mao 1, Mao-Hua Lin 1
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PMID: 32355532 PMCID: PMC7191150
Free PMC article
Abstract
Background: To investigate the clinicopathologic features, differential diagnosis, and factors associated with recurrence in patients with smooth muscle tumors of uncertain malignant potential (STUMP).

Methods: The clinical and pathologic data of STUMP patients diagnosed in Mindong Hospital of Ningde City from 2017 to 2018 were collected and slides reviewed, the high-frequency color Doppler ultrasound and pathological characteristics were observed, and the literature was reviewed.

Results: All the STUMP diagnoses were confirmed by slide review. The age of onset was 23-61 years (mean 42.96 years). The main clinical symptoms were leiomyoma of uterus, prolonged menstruation, and increased menstruation. Color Doppler ultrasonography showed hypoechoic uterine wall nodules. The mean follow-up time was 62.9 months (range: 13-96 months).

Conclusions: Smooth muscle tumors of undetermined malignant potential (STUMP) in the uterus are one of the rare gynecologic neoplasms. Although not malignant, they should be considered as low malignant potential tumors because they occasionally recur. Six of 13 recurrent tumors recurred in the years following hysterectomy with preservation. These six recurrent tumors are the only ones that had a strong immune response to p16 and p53. In support of early observation, these markers may help predict STUMP behavior. Patients diagnosed with STUMP should be monitored over time.

Keywords: Uterine neoplasm; clinicopathologic characteristic; immunohistochemistry; smooth muscle tumor of uncertain malignant potential (STUMP).

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51
Case Reports Int J Clin Exp Pathol
. 2020 Apr 1;13(4):792-798. eCollection 2020.
Pulmonary Papillary Adenoma With Malignant Transformation: Report of One Case and Review of the Literature
Hongfei Ma 1, Yanli Wang 2, Peng Chen 1, Zhixue Zhang 1, Jing Xu 3
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PMID: 32355529 PMCID: PMC7191156
Free PMC article
Abstract
Pulmonary papillary adenoma is a rare tumor. A total of 32 cases was studied, include 31 cases in the literature. Most of the patients were asymptomatic, and tumor was usually discovered during a routine chest roentgenogram or with other disease. Most cases demonstrated benign behavior and there have been no recurrent cases after the operation or biopsy with the follow up of 6 to 120 months. However, there was some evidence indicating it can be locally aggressive or potentially malignant. We present the first case report of cancer development in a pulmonary papillary adenoma. In our case, the imaging findings progressed from initial well-defined border, without 18F-FDG accumulation, to one side rough edge after two years of follow up. Postoperative pathology revealed a partly well-defined tumor, without a fibrous capsule, but focally infiltrated the alveoli. Our case had definite areas of papillary adenoma, with focal acinar and micropapillary adenocarcinoma area near the central fibrosis. The papillary adenoma cells were with polarity and low expression of Ki67 and C-myc, without atypia or mitosis. But the adenocarcinoma cells were obviously different from them, with high expression of Ki67 and C-myc, indicating cancer development. MYC activation may play a role in tumorigenesis, and further investigation was needed. There was no EGFR mutation in both of the components.

Keywords: C-myc; FDG; Pulmonary; cancer development; papillary adenoma.

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52
Int J Clin Exp Pathol
. 2020 Apr 1;13(4):746-755. eCollection 2020.
Decreased Vitamin D Receptor Protein Expression Is Associated With Progression and Poor Prognosis of Colorectal Cancer Patients
Qi Shi 1, Xue-Ping Han 1, Jie Yu 2, Hao Peng 1, Yun-Zhao Chen 2, Feng Li 1 3, Xiao-Bin Cui 1
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PMID: 32355523 PMCID: PMC7191154
Free PMC article
Abstract
This study aimed to investigate vitamin D receptor (VDR) expression levels and evaluate their clinical significance in patients with colorectal cancer (CRC). VDR protein expression was validated by immunohistochemistry in 188 CRC tissues and 134 normal colorectal tissues. The associations between VDR expression and clinicopathologic characteristics, including prognostic outcomes, were analyzed. VDR expression in normal colorectal tissue was higher than that in CRC (83.6% versus 34.6%, P = 4.489 × 10-20) and generated moderate diagnostic performance for CRC detection (AUC = 0.88, sensitivity = 0.87, specificity = 0.84). Low VDR expression was associated with invasion depth (P = 0.001) and poor survival in CRC (P = 0.031). Univariate Cox analysis demonstrated VDR expression (P = 0.036) was a significant prognostic predictor for survival in patients with CRC. Low VDR expression could be a valuable diagnostic and prognostic biomarker for CRC patients. Targeting VDR may offer a potential therapeutic strategy for blocking CRC.

Keywords: Colorectal cancer; prognosis; progression; vitamin D receptor.

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53
Int J Clin Exp Pathol
. 2020 May 1;13(5):1190-1196. eCollection 2020.
Chance to Rein in a cancer--Spontaneous Regression of Lung Carcinoma (1988-2018): A 30-year Perspective
Jingyao Zhang 1, Haijuan Wang 1, Chunxiao Li 1, Haili Qian 1
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PMID: 32509094
Abstract
Background: Spontaneous regression of tumor is an extremely rare phenomenon in the oncology field and even rarer for lung cancer. However, the underlying mechanism is poorly understood. Summarizing the available clinical information and the supposed mechanism shed new light on lung cancer therapy strategies in the new era of immunotherapy.

Summary: We conducted a PubMed search using the retrieval tactics ("Lung Neoplasms" [Mesh]) AND "Neoplasm Regression, Spontaneous" [Mesh] for reports from 1988 to January 2018, and all references in the relevant literature were subsequently investigated for relevance. Using the criteria of Everson and Cole, 14 cases were finally defined as spontaneous regression and were reviewed in the research. Key messages: The information regarding patient characteristics, treatments, and follow-up has been summarized. In this review, we found that spontaneous lung cancer regression cases fall into two categories including: (1) neurologic disorders in 6 cases, half of whom suffered with paraneoplastic neurological syndromes (PNS) and (2) immunological reactions in 7 cases. Getting data on more spontaneous regression cases and more detailed information will definitely help us understand the mechanism for the body's surveillance system-cancer balance, creating a big chance to increase cancer immunotherapy.

Keywords: Spontaneous regression; immunological reaction; lung carcinoma; paraneoplastic neurological syndrome.

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54
Int J Clin Exp Pathol
. 2020 May 1;13(5):1220-1242. eCollection 2020.
Overexpressed Gene Signature of EPH Receptor A/B Family in Cancer Patients-Comprehensive Analyses From the Public High-Throughput Database
Nam Nhut Phan 1, Shirui Liu 2 3, Chih-Yang Wang 4 5 6, Hui-Ping Hsu 7, Ming-Derg Lai 4, Chung-Yen Li 4, Chien-Fu Chen 8, Chung-Chieh Chiao 8, Meng-Chi Yen 9, Zhengda Sun 10, Jia-Zhen Jiang 11
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PMID: 32509099
Abstract
Although a previous study suggested that erythropoietin-producing hepatoma (EPH) receptors play important roles in tumor progression and the overexpression of EPHs in cancer patients is related to poor prognoses, high-throughput gene expression profiling of EPH family members in different types and subtypes of cancers has so far not been conducted. We herein carried out a series of bioinformatic analyses on expressive profiles of every EPH member across 21 different types of clinical cancers versus matched normal tissues gathered from the Oncomine platform. We validated these results by protein expression study of all EPHs family members by The Human Protein Atlas repository. Our results uncovered the overexpression of most EPH subunits in numerous cancer types, especially the dramatic overexpression of six EPHs members, namely EPHA1, EPHA2, EPHA3, EPHA4 and EPHB1, EPHB2, EPHB3, EPHB4 in bladder, colorectal, esophageal, gastric, and prostate cancers. Furthermore, EPHB2 was specifically highly expressed in cervical cancer, EPHA3 in liver cancer, and EPHB1 in uterine cancer. Collectively, expressive profiles of these EPHs were confirmed and correlated with different cancer subtypes as potential biomarkers. This study provides useful information for further studies on cancer development and clinical treatments.

Keywords: Erythropoietin-producing hepatoma (EPH) receptors; bioinformatics; ephrins; erythropoietin-producing hepatocellular type-A (EPHA) receptor; erythropoietin-producing hepatocellular type-B (EPHB) receptor; medical oncology.

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55
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1212-1215. eCollection 2020.
Simultaneous Multiple Primary Cancers With Concomitant Inflammatory Myofibroblastic Tumor: A Case Report
Xingyu Lv 1 2, Jianming Ye 3, Guangyi Jiang 1 2, Yifan Wang 1 2, Jisheng Lv 4, Yong Wang 1
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PMID: 32509097
Abstract
Multiple primary cancers are of rare occurrence. Most multiple primary cancers are metachronous multiple primary cancers, while simultaneous multiple primary cancers are rare. Inflammatory myofibroblastic tumors are rare. Inflammatory myofibroblastic tumor occurs most frequently in children and young adults. Herein, we report a rare case of simultaneous multiple primary cancers and inflammatory myofibroblastic tumor. A 44-year-old woman was admitted for a breast mass evaluation. The patient was positive for antinuclear, anti-mitochondrial, and anti-RO52 antibodies. Breast magnetic resonance imaging revealed a right breast mass. After neoadjuvant chemotherapy, modified radical mastectomy was performed. Postoperative histopathology revealed an invasive ductal carcinoma. Two months later, computed tomography revealed a nodule in the right upper lobe and ground-glass opacity in the lower lobe of the lungs. Lobectomy and lobe biopsy were performed. Postoperative histopathology revealed that the mass in the right upper lobe was an inflammatory myofibroblastic tumor and the right lower lobe lesion was an invasive adenocarcinoma. Immunohistochemistry of the inflammatory myofibroblastic tumor revealed negativity for anaplastic lymphoma kinase. At the 4-month follow-up, the patient showed good recovery. The etiology of multiple primary cancers and inflammatory myofibroblastic tumors is still unknown; in this case, we believe that autoimmune factors are the main cause of multiple primary cancers with concomitant inflammatory myofibroblastic tumor. Tissue biopsy is needed to ensure correct diagnosis of multiple primary cancers and inflammatory myofibroblastic tumor. Surgery-based comprehensive therapy is recommended. The prognosis is favorable and regular follow-up is necessary.

Keywords: Inflammatory myofibroblastic tumor; multiple primary cancers; primary breast cancer; primary lung cancer.

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56
Int J Clin Exp Pathol
. 2020 May 1;13(5):1262-1269. eCollection 2020.
Risk Factors and Prognosis in Patients With Adenocarcinoma of Esophagogastric Junction With Lymph Node Metastasis of Siewert II/III
Zhi Zheng 1 2, Yuxi Shang 3, Rui Xu 4, Haiqiao Zhang 1 2, Jie Yin 1 2, Jun Zhang 1 2, Zhongtao Zhang 1 2
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PMID: 32509102
Abstract
Adenocarcinoma of the esophagogastric junction (AEG) has a high incidence, while the extent of lymph node dissection and prognosis are still controversial. This study aimed to explore the risk factors of lymph node metastasis and prognosis in Siewert II/III AEG patients. Between July 2013 and May 2017, a total of 65 patients who underwent surgical operation in Beijing Friendship Hospital were retrospectively reviewed. The patients were followed up until September 2017. Data were analyzed using logistic regression. Survival analyses were performed using Kaplan-Meier. Multivariate analysis revealed that histologic classification (OR=3.437, 95% CI: 1.046~11.294, P=0.042) and intravascular cancer embolus (OR=6.614, 95% CI: 1.942~22.524, P=0.003) were correlated with lymph node metastasis. The lymph nodes No. 1, 2, 3, 7, 11 and 110 indicated higher metastatic rate. The 3-year overall survival analysis revealed that lymph node metastasis (P=0.167) and tumor stage (P=0.429) exhibited no significant differences. Findings suggest that histologic type and vascular neoplasia are independent risk factors for lymph node metastasis. For Siewert II/III AEG patients, it is reasonable to perform radical gastrectomy combined with D2 lymph node dissection. For No. 110 lymph nodes should be dissected routinely. However, the long-term prognosis remains to be further studied.

Keywords: Adenocarcinoma of esophagogastric junction; Siewert II/III; logistic regression analysis; lymphatic metastasis; survival analysis.

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57
Int J Clin Exp Pathol
. 2020 May 1;13(5):1045-1052. eCollection 2020.
Differential Expression Profiles of circRNAs in Human Prostate Cancer Based on Chip and Bioinformatic Analysis
Shengyang Ge 1, Chuanyu Sun 1, Qingfeng Hu 1, Yijun Guo 2, Guowei Xia 1, Yuanyuan Mi 3, Lijie Zhu 3
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PMID: 32509077
Abstract
Background: Increasing evidence suggests that circRNAs are involved in the pathogenesis of multiple kinds of cancer. Nevertheless, the differential expression of circRNAs in prostate cancer (PCA) is rarely reported.

Material/method: In our present analyses, circRNAs expression profiles were identified in PCA, based on 5 pairs of PCA and matched non-PCA tissues using circRNA chips.

Results: A number of 749 differential circRNAs were expressed between PCA tumor and paracancerous tissues (Fold Change, FC ≥ 2.0 and P < 0.05): 261 were upregulated, whereas 487 were downregulated in PCA tissues. Gene ontology and KEGG pathway analyses indicated that many of the circRNAs are related to carcinogenesis. Circ_0033074 and circ_0016064 both showed changes of maximum magnitude among differentially expressed circRNAs.

Conclusions: Our study detected a relative comprehensive differential map of circRNAs in PCA, which may become novel biomarkers for diagnosis, treatment and follow-up in the future.

Keywords: Prostate cancer; circRNA; expression; microarray.

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58
Int J Clin Exp Pathol
. 2020 May 1;13(5):1243-1252. eCollection 2020.
Long Noncoding RNA MALAT1 Promotes High Glucose-Induced Inflammation and Apoptosis of Vascular Endothelial Cells by Regulating miR-361-3p/SOCS3 Axis
Kai Huang 1, Xuxia Yu 1, Yushan Yu 1, Lu Zhang 1, Yin Cen 1, Jinguo Chu 1
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PMID: 32509100
Abstract
Vascular complications are the important pathophysiologic manifestations of patients with diabetes mellitus (DM) and many long non-coding RNAs (LncRNAs) are involved in this process. In this study, we aimed to investigate the relationships among LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), microRNA-361-3p (miR-361-3p), and suppressor of cytokine signaling 3 (SOCS3) in high glucose (HG)-induced human umbilical vein endothelial cell (HUVEC) injury and its underlying mechanism. We found that HG treatment significantly promotes MALAT1 and SOCS3 expressions, but inhibits miR-361-3p expression in HUVECs. Furthermore, through bioinformatics analysis and dual luciferase assay, we found that MALAT1 directly sponges miR-361-3p to counteract its suppression on SOCS3 expression. Moreover, knockdown of MALAT1 evidently inhibits HG-induced inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 expressions in HUVECs (and HUVEC apoptosis) by regulating the miR-361-3p/SOCS3 axis. In conclusion, our results indicate that knockdown of MALAT1 inhibits HG-induced vascular endothelial injury through regulating miR-361-3p/SOCS3 axis, suggesting that inhibition of MALAT1 as a potential target for endothelial injury therapy for DM.

Keywords: Diabetes mellitus; high glucose; metastasis-associated lung adenocarcinoma transcript 1; microRNA-361-3p; suppressor of cytokine signaling 3.

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59
Int J Clin Exp Pathol
. 2020 May 1;13(5):1060-1065. eCollection 2020.
β-Coronavirus Infectious Diseases: Recommended Strategies for the Prevention and Control of Transmission
Guozhong He 1, Zhong Sun 2, Yao Zhao 1, Shuwei Zhang 1, Hongyu Chen 1, Zizhao Zhao 1, Guang Yang 1, Quan Zhou 1
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PMID: 32509079
Abstract
In recent years, the incidence and mortality of infectious diseases in China are increasing. Infectious diseases, especially new infectious diseases, seriously threaten people's lives. Recent works found that most of the emerging infectious diseases come from wild life. At the same time, the impact of human activities on the environment has further deteriorated the living environment of wildlife. However, with the conducted in-depth research on virus, human beings increase the risk of getting infected. Taking Beta Coronavirus as the example, we analyzed the transmission risks of coronavirus in the prevention and control of the outbreaks of emerging infectious diseases, and recommend the prevention and control strategies before, during and after the viral outbreak. Additional works are urgently needed to better define the biological and epidemiological characteristics of these viruses.

Keywords: environment; infectious diseases; preventive measures; wildlife; β-Coronavirus.

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60
Int J Clin Exp Pathol
. 2020 May 1;13(5):1035-1044. eCollection 2020.
Semi-comprehensive Analysis of Gene Amplification in Thymic Malignant Tumors Using Multiplex Ligation-Dependent Probe Amplification and Fluorescence in Situ Hybridization
Seiichi Kakegawa 1, Isao Matsumoto 1, Masaya Tamura 1, Munehisa Takata 1, Shuhei Yoshida 1, Daisuke Saito 1, Yusuke Tanaka 1, Hirofumi Takemura 1, Akishi Ooi 2
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PMID: 32509076
Abstract
Research on the amplification of oncogenes in thymic malignant tumor is limited. In this study, we aimed to determine the gene amplification status of receptor tyrosine kinases and other cell regulator genes in thymic malignant tumors, with a view toward the future introduction of molecular targeted therapy. In addition, we examined the usefulness of multiplex, ligation-dependent probe amplification (MLPA) in the semi-comprehensive detection of these gene amplifications. The participants of this study were nine patients with thymic carcinoma and one patient with atypical carcinoid who underwent resection at our department from 1999 to 2016. Twenty-four oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, BRAF, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR) were analyzed for amplification by MLPA. In cases where amplification by MLPA was suspected, confirmation was performed by fluorescence in situ hybridization (FISH). Immunostaining for detected oncoproteins and p53 were performed in cases with confirmed oncogene amplification. MYC (2/10, 20%) and MDM2 (1/10, 10%) amplifications were detected using MLPA and FISH. Immunostaining in both cases was positive. The MDM2-amplified tumor relapsed and spread rapidly after operation despite the use of post-operative chemo-radiotherapy. MYC amplification may be involved in the carcinogenesis of thymic malignant tumors. In addition, MDM2 amplification may be a concern in the increased malignancy.

Keywords: MDM2; MYC; Thymic carcinoma; fluorescence in situ hybridization; gene amplification; multiplex ligation-dependent probe amplification.

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61
Case Reports Int J Clin Exp Pathol
. 2020 Apr 1;13(4):785-791. eCollection 2020.
Gastric Duplication Cyst Lined by Pseudostratified Columnar Ciliated Epithelium Masquerading as a Pancreatic Mucinous Cystic Neoplasm: A Case Report and Literature Review
Canyang Zhan 1, Bo Zhou 2
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PMID: 32355528 PMCID: PMC7191139
Free PMC article
Abstract
Gastric duplication cyst (GDC) with a pseudostratified columnar ciliated epithelial (PCCE) is a congenital rare cystic neoplasm, which is often difficult to distinguish from other entities by imaging techniques, and as a consequence it may be wrongly overtreated. We herein report a case of a 52-year-old female incidentally found to have an abdominal mass by ultrasonography and computed tomography. Additionally, endoscopic ultrasonography and fluid analysis were consistent with a pancreatic mucinous cystic neoplasm with a markedly elevated fluid amylase, carcinoembryonic antigen, and carbohydrate antigen 19-9. Then, laparoscopic resection of the cyst originating from the stomach and wedge gastrectomy were performed. Final pathology revealed a GDC with PCCE. In addition, we also performed a literature review of 31 reports of GDC with PCCE. Although rare, GDC lined by PCCE should be included in the differential diagnosis of pancreatic cystic neoplasms or a gastric wall mass.

Keywords: Gastric duplication cyst; laparoscopic resection; pancreatic mucinous cyst; pseudostratified columnar ciliated epithelium.

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62
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1086-1089. eCollection 2020.
Pseudovascular Adenoid Squamous Cell Carcinoma of the Tongue: A Case Report and Literature Review
Xiaodong Han 1, Xiaozhen Lin 1, Xiaojun Shao 1
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PMID: 32509083
Abstract
Pseudovascular adenoid squamous cell carcinoma (PASCC) is an uncommon histologic variant of squamous cell carcinoma, characterized by acantholysis in the cancer nests resulting in a pseudovascular appearance, and a subtype of acantholytic squamous cell carcinoma. It is relatively common in sun-exposed skin, but is extremely rare in oral cavity. A 56-year-old woman was referred to our department presented with a fast-growing mass in the front of the tongue for more than two months. Physical examination revealed a exophytic lesion with a pedicle in the anterior tongue. An incisional biopsy was performed. On microscopic examination, the tumor was composed of vessel-like anastomosing channels and dilated vessel-like spaces, similar to hemangioma, and the anastomosing channels contained free tumor cells. The nests of tumor cells with significant acantholysis were observed in some regions. Immunohistochemical examination revealed cells positive for pan-CK, CK5/6, p63, and negative for CD31 and CD34. The pathological diagnosis was confirmed as pseudovascular adenoid squamous cell carcinoma. The extended resection of the tumor and neck dissection was performed. There was no tumor recurrence or distant metastasis after 15 months of follow-up.

Keywords: Pseudovascular adenoid squamous cell carcinoma; acantholytic squamous cell carcinoma; immunohistochemistry; oral cavity.

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63
Int J Clin Exp Pathol
. 2020 May 1;13(5):944-953. eCollection 2020.
High Expression of ZNF93 Promotes Proliferation and Migration of Ovarian Cancer Cells and Relates to Poor Prognosis
Xiao-Xiao Cui 1 2, Chen Zhou 3, Huan Lu 2, Yan-Li Han 1, Feng-Mian Wang 2, Wei-Rong Fan 2, Yuan Ren 1 2, Rong Zhang 1 2
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PMID: 32509065
Abstract
Ovarian cancer (OC) is most common type of gynecologic cancer and is frequently lethal. It is important to determine the pathologic mechanisms underlying OC. ZNF93 is a member of the zinc finger protein family. Abnormal expression of ZNF93 has been observed in various tumor cells. However, its clinical significance and biologic function in ovarian cancer remain unclear. In the present study, we established that ZNF93 expression was highly up-regulated in OC samples and was closely correlated with clinical stage, indicating poor prognosis. We then established that ZNF93 promoted OC cell proliferation and migration. The results of our study may provide insight into the use of ZNF93 as a marker of clinical outcome and as a potential therapeutic target in OC.

Keywords: Ovarian cancer; cell migration; cell proliferation; small interfering siRNA; transcription factor ZNF93.

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64
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1090-1093. eCollection 2020.
Pseudoglandular Myxoid Adrenocortical Adenoma With Positive Epithelial Markers: A Case Report and Review of the Literature
Ming-He Bai 1, Li-Yun Liu 1, Meng Zhao 1, Qian Wu 1, Xiao-Juan Zheng 1, Ji-Xian Wang 1, Zhi-Yong Zhang 1
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PMID: 32509084
Abstract
Myxoid adrenal cortical adenoma with a pseudoglandular structure is a special histological variant and is extremely rare. We report about a 32-year-old Chinese woman with a right adrenal mass during a routine physical examination. The cut surface of the mass had a vague nodular, which gross appearance was pale, yellowish, and semitransparent. Histologically, the region is mostly characterised by pseudoglandular pattern with myxoid stroma. They are filled with clear cells or eosinophilic cells, as well as semitransparent regions, in which anastomosing small eosinophilic cells arranged in pseudoglandular, cord-like, or wreath-shaped structure float in the mucous pool. Immunohistochemical staining shows Melan-A, vimentin, and CD56 were positive and CK (AE1/AE3) were nucleus-side staining. A small number of tumor cells were positive for alpha-inhibin and synaptophysin, ki-67 labeling index was 3%. EMA, chromogranin A, WT-1, and P63 were negative. This report aimed to emphasize pseudoglandular patterns with mucus secretion which could occur in adenomas of the adrenal cortex, nucleus-side positive for CK is remarkable. However, this type may have malignant potential, so regular follow-up is needed.

Keywords: CK; Myxoid adrenal cortical adenoma; nucleus-side; pseudoglandular pattern.

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65
Int J Clin Exp Pathol
. 2020 May 1;13(5):1136-1145. eCollection 2020.
Lin28 Is Associated With Astrocytic Proliferation During Intracerebral Hemorrhage
Wensen Ding 1, Yuqin Wang 2, Yaqin Cheng 2, Xin Chen 2, Weiguan Chen 3, Peng Zuo 2, Weihai Chen 4, Zhenguo Qiao 5, Xingjuan Fan 2
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PMID: 32509088
Abstract
As an evolutionarily conserved RNA-binding protein, LIN28 is known to be involved in the regulation of the translation and stability of a large number of mRNAs and the biogenesis of certain miRNAs. Increasing evidence indicates that LIN28 regulates many cellular processes, such as embryonic stem cell proliferation, cell fate succession, developmental timing, and oncogenesis. However, the expression and function of LIN28 after intracerebral hemorrhage (ICH) are still unclear. In this study, we performed an intracranial hemorrhage model in adult rats and western blot, immunohistochemistry, as well as immunofluorescence showed that LIN28 was obviously up-regulation in neurons adjacent to the hematoma after ICH. Besides, the transitory increase of LIN28 expression was paralleled with the up-regulation of proliferating cell nuclear antigen (PCNA) as well as GFAP. Hence, LIN28 might play an important role in astrocyte proliferation after ICH.

Keywords: LIN28; astrocytes; intracerebral hemorrhage; proliferation.

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66
Int J Clin Exp Pathol
. 2020 May 1;13(5):912-922. eCollection 2020.
Pathogenesis and Anti-Proliferation Mechanisms of Crocin in Human Gastric Carcinoma Cells
Yushuang Luo 1, Pengjie Yu 1, Junhui Zhao 1, Qijing Guo 1, Baohua Fan 1, Yinzhuo Diao 1, Yulong Jin 1, Chengwu Zhang 1
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PMID: 32509062
Abstract
Gastric cancer is the fourth most common cause of cancer death globally and the second most common in Asia. Many studies suggest that Crocin has the potential for gastric cancer antineoplastic combined chemotherapy protocols. Here we investigated genomic changes related to the inhibitory effect of Crocin, and elucidated the molecular mechanism of this inhibition in gastric carcinoma cells. We found that, compared with the control group, 216 significantly upregulated and 301 significantly downregulated genes were identified in Crocin-treated AGS cells. Many of these differentially expressed genes in AGS cells are involved in Nrf2-mediated oxidative stress response, p53 signaling, and integrin signaling, which suggested the mechanism of Crocin functions in therapy of gastric cancer. In summary, our study indicates that Crocin has the potential for gastric cancer adjuvant treatment through reducing cell oxidative stress levels.

Keywords: Crocin; IPA; Nrf2; gastric cancer; oxidative stress.

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67
Int J Clin Exp Pathol
. 2020 May 1;13(5):896-900. eCollection 2020.
Placental Mesenchymal Dysplasia in a Normal Female Infant: A Rare Case Report With Follow-Up
Yajing Sun 1, Jie Zheng 1, Zhongmin Jiang 1, Lidong Zhang 1, Shanshan Ding 2, Xiaozhi Liu 3
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PMID: 32509060
Abstract
Placental mesenchymal dysplasia (PMD) is a rare disorder of unknown etiology, which is often misdiagnosed as partial hydatidiform mole because of their similarity in ultrasonographic, gross, and histologic presentations. However, the treatment and prognosis of these two conditions are different. Patients with PMD often have intrauterine growth restriction, intrauterine fetal death, and Beckwith-Wiedemann syndrome, but there may also be a normal fetus. PMD with a normal female infant is extremely rare, and only a few cases have been reported. We report a case of PMD in a normal female infant and its follow-up results.

Keywords: P57; Placenta; hydatidiform mole; placental mesenchymal dysplasia (PMD).

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68
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1081-1085. eCollection 2020.
Aggressive Natural killer/T-cell Lymphoma Masquerading as Acute Orbital Hemorrhage: A Case Report
Jing Zhang 1, Hui Chen 2, Wei Lin 2, Zhengzheng Wu 2
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PMID: 32509082
Abstract
Natural killer T-cell lymphoma (NKTCL) is a highly aggressive tumor that usually affects the nasal cavity and/or paranasal sinuses. Primary orbital NKTCL is extremely rare, with only a few cases reported in the literature. The clinical presentation of orbital involvement by NKTCL is atypical and usually misdiagnosed as orbital cellulitis or orbital pseudotumor. A 23-year-old male patient was admitted to our hospital complaining of severe eye pain and manifested as acute orbital hemorrhage. Isolated orbital natural killer T-cell lymphoma (NKTCL) was confirmed by biopsy. This patient's orbital NKTCL did not respond to CHOP (cyclophosphamide, epirubicin, vincristine, prednisone) chemotherapy, but shrank significantly after receiving 1 cycle of C-SMILE (chidamide, steroid, methotrexate, isophosphamide, L-pegaspargase, etoposide). However, he still died after 3 cycles of C-SMILE chemotherapy at a follow-up time of 4 months. Primary orbital NKTCL can present clinically as a rare acute orbital hemorrhage, and the disease is aggressive and has a poor prognosis.

Keywords: Nasal natural killer/T-cell lymphoma; SMILE regimen; orbital hemorrhage; orbital lymphoma.

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69
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1206-1211. eCollection 2020.
Long-term Surveillance of Intrahepatic Cholangiocarcinoma Diagnosed After 20 Years Follow-Up for Hepatic Hemangioma: A Case Report and Literature Review
Yuzhe Wu 1, Weimin Wang 1, Bin Shu 2, Min Li 1, Jianjun Xu 1, Qichang Zheng 1
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PMID: 32509096
Abstract
Intrahepatic cholangiocarcinoma is the second most common primary malignancy of liver with poor prognosis. Four patients of intrahepatic cholangiocarcinoma were diagnosed after several years' observation with hepatic hemangioma in recent reports. Herein, we present a rare case of much longer surveillance of intrahepatic cholangiocarcinoma diagnosed after 20 years follow up for hepatic hemangioma. An asymptomatic 74-year old Chinese man was admitted to our hospital for a recent enlarged liver mass lesion, after 20 years follow-up for hepatic hemangioma. He was first diagnosed with a hemangioma in segment 8 of liver by abdominal ultrasound in February 1994, on basis of slightly hyperechoic feature with 1.6 × 1.1 cm in size. The mass lesion has enlarged markedly since 2013, which was confirmed by ultrasonography, computed tomography, magnetic resonance imaging, and positron emission tomography. Thus, hepatectomy was performed and histological characteristic revealed that the mass lesion was intrahepatic cholangiocarcinoma. This is the longest disease course of intrahepatic cholangiocarcinoma ever reported, which may change the former understanding of the biological behavior of intrahepatic cholangiocarcinoma and is worthy of further study.

Keywords: Intrahepatic cholangiocarcinoma; hepatectomy; hepatic hemangioma; long-term surveillance.

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70
Int J Clin Exp Pathol
. 2020 May 1;13(5):1030-1034. eCollection 2020.
Hypoxia Promotes Proliferation of Pituitary Adenomas by HIF-1α/ALKBH5 Signaling in vitro
Yuan Qian 1 2, Chao Zhang 3, Wei Wang 3 4, Di Lu 5, Junjun Li 3, Liyan Li 6, Yao Li 3, Yisheng Qiao 3, Hao Song 3, Xingli Deng 3
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PMID: 32509075
Abstract
Hypoxia is a common phenomenon in pituitary adenomas (PAs). The role and mechanism of hypoxia in the PAs remains elusive. This work aimed to explore the effect of hypoxia on PAs in vitro. PA cells GT1-1 were cultured and treated under hypoxic condition. Cell proliferation assay showed the proliferation of PA cells was increased significantly by hypoxia treatment, with a peak at 12 hours. qPCR and western blot indicated that the expression of HIF-1α, ALKBH5, and Nanog were elevated by hypoxia stimuli. In conclusion, our funding demonstrated that hypoxia could increase Nanog expression through HIF-1α/ALKBH5 signaling, thereby promoting the proliferation of PA cells.

Keywords: ALKBH5; HIF-1α; Nanog; Pituitary adenoma; hypoxia.

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71
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1275-1282. eCollection 2020.
Alveolar Soft Part Sarcoma of the Tongue: A Case Report and Review of the Literature
Youjie Gong 1, Mengmeng Liu 1, Qiong Wu 1, Yuanyuan Liu 1, Jinlian Zhang 2, Lili Yao 2, Yurong Ou 1
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PMID: 32509104
Abstract
Alveolar soft part sarcoma (ASPS) is a soft tissue malignant tumor of unknown origin in which tissues or cells are arranged like acini or organs. It usually presents in the deep muscles or fascia of the extremities, and rarely occurs in the head and neck, let alone the tongue. To our knowledge, only 49 cases of ASPS have been previously published in the tongue. Therefore, the course, age of onset, tumor size, and prognosis of ASPS in the tongue are not well understood. We present a case of ASPS in the dorsum of left tongue of a 24-year-old female. Histology of the resected tumor showed features of ASPS. She is currently disease-free at 12-month follow-up.

Keywords: Alveolar soft part sarcoma; immunohistochemistry; tongue.

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72
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1270-1274. eCollection 2020.
Breast Metastases in Advanced Rectal Cancer: A Case Report
Yunyao Ye 1 2, Zhaoxia Wang 2, Wei Xiao 3, Gaohua Han 1
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PMID: 32509103
Abstract
Breast metastasis from solid tumors rarely occurs, although primary breast cancer is one of the most common malignancies in women worldwide. Rectal cancer metastasis is rarely reported. We report a case of a 49-year-old Chinese woman with advanced rectal cancer, who presented with mass in her left breast and several irregular dusky-red nodular knurls in the skin around the left nipple. Based on percutaneous echo-guided biopsy of the breast lesion, a poorly differentiated adenocarcinoma was consistent with rectal cancer metastasis histologically and immunohistochemically. This should be considered in any patient with history of cancer and confirmed histologically and immunohistochemically.

Keywords: Breast metastasis (BM); cutaneous metastasis; rectal cancer.

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73
Int J Clin Exp Pathol
. 2020 May 1;13(5):1121-1135. eCollection 2020.
Discovery and Characterization of a Novel Splice Variant of the p53 Tumor Suppressor Gene in a Human T Cell Leukemia Cellline
Xiaomei Li 1 2, Yingshou Lei 1 2, Yang Yu 1 2, Yaqian Zhang 1 2, Wenfeng Zhang 1 2, Han Shen 1 2, Changli Tao 1 2, Fenglin Wu 1 2, Shulin Huang 1 2 3, Hongwei Shao 1 2
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PMID: 32509087
Abstract
Alternative splicing produces multiple mRNA variants of TP53 which have diverse biologic functions. In this study, we identified a novel splice variant of TP53 lacking a 200 nt portion of exon 4 (p53ΔE4p) from a human leukemia T cell line. No protein product of p53ΔE4p was identifiable by western blot; however, forced expression of the variant in HEK-293T cells expressing wild-type p53 could inhibit cell proliferation and promote cell death. Interestingly, this novel variant also significantly enhances the expression of reporter genes. Moreover, transcriptome analysis showed that genes related to DNA binding and regulation of transcription by RNA polymerase II function were significantly upregulated following p53ΔE4p transfection, suggesting a role for this variant in the regulation of gene expression.

Keywords: Jurkat; TP53; expression regulation; splice variant; transcriptome.

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74
Case Reports Int J Clin Exp Pathol
. 2020 May 1;13(5):1216-1219. eCollection 2020.
Diagnosis of Intracranial Embryonal Carcinoma by Cerebrospinal Fluid Cytology: A Case Report
Xizhuang Bi 1, Dachun Zhao 2, Qiaowei He 3, Fengjie Liu 4, Li Gong 1, Hua Li 5
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PMID: 32509098
Abstract
Background: The incidence of primary intracranial germ cell tumors (GCTs) is relatively low comparing to other ones. Embryonal carcinoma (EC) is an especially rare subtype and the diagnosis presents to be a challenge. Few cases have been reported.

Case presentation: We report a case of intracranial EC located in the temporal lobe with malignant tumor cells occasionally detected by the cytology of cerebrospinal fluid (CSF). The pathology confirmed the diagnosis after the patient underwent tumor resection.

Conclusion: This is the first report about one case of intracranial primary EC located in the temporal lobe. It is also the first report of tumor cells of EC detected in the CSF.

Keywords: Embryonal carcinoma; cerebrospinal fluid cytology; temporal lobe.

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75
Published Erratum Int J Clin Exp Pathol
. 2020 May 1;13(5):1283-1284. eCollection 2020.
Erratum: MiR-30a-5p Suppresses Cell Growth and Enhances Apoptosis of Hepatocellular Carcinoma Cells via Targeting AEG-1
Rongquan He 1, Lihua Yang 1, Xiaomiao Lin 2, Xin Chen 3, Xinggu Lin 4, Fanglin Wei 3, Xiaona Liang 3, Yihuan Luo 3, Yuzhuang Wu 3, Tingqing Gan 1, Yiwu Dang 3, Gang Chen 3
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PMID: 32509105
Abstract
[This corrects the article on p. 15632 in vol. 8, PMID: 26884832.].

IJCEP Copyright © 2020.

Erratum for
MiR-30a-5p suppresses cell growth and enhances apoptosis of hepatocellular carcinoma cells via targeting AEG-1.
He R, Yang L, Lin X, Chen X, Lin X, Wei F, Liang X, Luo Y, Wu Y, Gan T, Dang Y, Chen G.
Int J Clin Exp Pathol. 2015 Dec 1;8(12):15632-41. eCollection 2015.
PMID: 26884832 Free PMC article.
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