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BackgroundAlthough cervical cancer is often characterized as preventable, its incidence continues to increase in low‐ and middle‐income countries, underscoring the need to develop novel therapeutics for this disease.This study assessed... more
BackgroundAlthough cervical cancer is often characterized as preventable, its incidence continues to increase in low‐ and middle‐income countries, underscoring the need to develop novel therapeutics for this disease.This study assessed the distribution of fusion genes across cancer types and used an RNA‐based classification to divide cervical cancer patients with a poor prognosis into subgroups.Material and MethodsRNA sequencing of 116 patients with cervical cancer was conducted. Fusion genes were extracted using StarFusion program. To identify a high‐risk group for recurrence, 65 patients who received postoperative adjuvant therapy were subjected to non‐negative matrix factorization to identify differentially expressed genes between recurrent and nonrecurrent groups.ResultsWe identified three cases with FGFR3‐TACC3 and one with GOPC‐ROS1 fusion genes as potential targets. A search of publicly available data from cBioPortal (21,789 cases) and the Center for Cancer Genomics and Advanced Therapeutics (32,608 cases) showed that the FGFR3 fusion is present in 1.5% and 0.6% of patients with cervical cancer, respectively. The frequency of the FGFR3 fusion gene was higher in cervical cancer than in other cancers, regardless of ethnicity. Non‐negative matrix factorization identified that the patients were classified into four Basis groups. Pathway enrichment analysis identified more extracellular matrix kinetics dysregulation in Basis 3 and more immune system dysregulation in Basis 4 than in the good prognosis group. CIBERSORT analysis showed that the fraction of M1 macrophages was lower in the poor prognosis group than in the good prognosis group.ConclusionsThe distribution of FGFR fusion genes in patients with cervical cancer was determined by RNA‐based analysis and used to classify patients into clinically relevant subgroups.
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Research Interests: Biochemistry, Chemistry, Library Science, Enzyme Inhibitors, Cell Biology, and 14 moreMedicine, Cell Division, Cell Differentiation, Liver, Animals, Male, Rats, Base Sequence, DNA binding proteins, Biochemistry and cell biology, Cell Growth, Hepatocyte Growth Factor, Medical biochemistry and metabolomics, and Spheroid
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We compared the spheroid formation (multi-cellular aggregation) of hepatocytes and the expression of liver specific functions such as albumin secretion when hepatocytes were cultured with various extracellular materials. We found that... more
We compared the spheroid formation (multi-cellular aggregation) of hepatocytes and the expression of liver specific functions such as albumin secretion when hepatocytes were cultured with various extracellular materials. We found that poly-D-lysine and Eudragit enhanced spheroid formation and hepatocytes in spheroids exhibited higher liver specific functions comparing to monolayer culture. The results indicated that cell-cell interaction caused by spheroid formation was a key factor to promote the expression of liver specific function. On the other hand, HGF response ability was declined when hepatocytes formed spheroids. We then examined that the relations between the expression of transcription factors and liver specific function during the spheroid formation. The expression of a CCAAT enhancer binding protein (C/EBP-α) increased and the high expression level was maintained when hepatocytes formed spheroids. The effects of cAMP and calcium ionophore on albumin secretion were also examined, and it was found that the increase of calcium ion concentration in the cells was important for the expression of the liver function.
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Research Interests: Oncology, Gastroenterology, Cancer, Medicine, Colorectal cancer, and 15 moreLung Cancer, Internal Medicine, Hepatocellular Carcinoma, Medical Physiology, Meta Analysis, Anticancer, C reactive protein, Clinical Significance, Chemoradiotherapy, Carcinoembryonic Antigen, Confidence Interval, Neutrophil to lymphocyte ratio, Lymphocyte, hazard ratio, and Cochrane Library
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Background: Serum p53 antibody (s-p53Ab), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were investigated to evaluate the significance of these singly and combined tumor markers in the diagnosis and prognosis of... more
Background: Serum p53 antibody (s-p53Ab), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were investigated to evaluate the significance of these singly and combined tumor markers in the diagnosis and prognosis of colorectal cancer (CRC). Patients and methods: Preoperative serum samples were obtained from 170 patients with histologically confirmed CRC, including 28 (16%) with stage I. s-p53Ab was assessed using the MESACUP Kit II, that is a new and highly specific version of a quantitative p53-Abs enzyme-linked immunosorbent assay. Results: s-p53Ab was detected in 30.6% (52 out of 170) of patients with CRC, including 31.9% (29/91) of patients with early-stage CRC. The positive rates for CEA and CA19-9 of patients with CRC were 28.8% (49/170) and 22.9% (39/170), respectively. Combining use of s-p53-Ab with CEA increased the positive rate of a diagnosis of CRC to 48.8%. Positivity for s-p53Ab in CRC did not correlate with overall survival. On the other hand, Cox regression analysis of this series revealed that high levels of CEA served as an independent prognostic factor for CRC. Kaplan-Meier analysis revealed significant differences between patients with elevated s-p53Ab and CEA and those with elevated levels of either one or neither of these factors (p<0.001). Conclusion: The diagnostic rate of s-p53Ab was better than that of CEA and CA19-9 in patients with early-stage CRC. Combined detection of s-p53Ab and CEA can improve diagnostic sensitivity and may permit more accurate stratification of patients with CRC.
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ABSTRACT
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Research Interests: Biology, Magnetic Resonance Spectroscopy, Medicine, Multidisciplinary, Macromolecular X-Ray Crystallography, and 14 moreHumans, Escherichia coli, Polymerase Chain Reaction, Histone Methylation, Tandem Mass Spectrometry, Phosphorylation, Gel Permeation Chromatography, High Performance Liquid Chromatography, Molecular cloning, Histones, Histone Code, Histone, Protein Binding, and Protein subunits
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Dozens of histone methyltransferases have been identified and biochemically characterized, but the pathological roles of their dysfunction in human diseases such as cancer remain largely unclear. Here, we demonstrate the involvement of... more
Dozens of histone methyltransferases have been identified and biochemically characterized, but the pathological roles of their dysfunction in human diseases such as cancer remain largely unclear. Here, we demonstrate the involvement of EHMT1, a histone lysine methyltransferase, in lung cancer. Immunohistochemical analysis indicated that the expression levels of EHMT1 are significantly elevated in human lung carcinomas compared with non‐neoplastic lung tissues. Through gene ontology analysis of RNA‐seq results, we showed that EHMT1 is clearly associated with apoptosis and the cell cycle process. Moreover, FACS analysis and cell growth assays showed that knockdown of EHMT1 induced apoptosis and G1 cell cycle arrest via upregulation of CDKN1A in A549 and H1299 cell lines. Finally, in 3D spheroid culture, compared to control cells, EHMT1 knockdown cells exhibited reduced aggregation of 3D spheroids and clear upregulation of CDKN1A and downregulation of E‐cadherin. Therefore, the results of the present study suggest that EHMT1 plays a critical role in the regulation of cancer cell apoptosis and the cell cycle by modulating CDKN1A expression. Further functional analyses of EHMT1 in the context of human tumorigenesis may aid in the development of novel therapeutic strategies for cancer.
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RATIONALE Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) are key molecules of the Hippo pathway. Recent studies revealed that these molecules are essential in lung development; however, the... more
RATIONALE Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) are key molecules of the Hippo pathway. Recent studies revealed that these molecules are essential in lung development; however, the precise signaling cascade involving these molecules and the differences in their role during lung development remain unknown. OBJECTIVES We aimed to investigate YAP and TAZ functions using lung epithelial-specific Taz and Yap conditional knockout mice. METHODS We generated lung epithelial-specific Taz and Yap conditional knockout mice and investigated the functions of YAP and TAZ in lung development. MEASUREMENTS AND MAIN RESULTS Selective TAZ deficiency in mouse lung epithelial cells resulted in abnormal alveolarization, which mimics lung emphysema, in adults, whereas YAP deficiency caused disruption of bronchial morphogenesis during the embryonic stage. We report that TAZ and YAP are sequentially expressed in the lung, and that this could explain their different phenotypes. Furthermore, we report that YAP stimulates Sonic hedgehog (Shh) expression and regulates the FGF-SHH feedback loop, thereby contributing to normal bronchial morphogenesis. We also found that TGF-Β stimulation induced Shh expression in the lung epithelial cells, and both TAZ and YAP are essential in this novel pathway. CONCLUSIONS Our results provide a novel insight into the molecular mechanisms underlying lung development and contributes to a better understanding of the characteristics of TAZ and YAP.
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8563 Background: Predicting the risk of postoperative recurrence is becoming increasingly important in EGFR mutation positive ( EGFR-m) non-small cell lung cancer (NSCLC). Only a few reports conducted whole exome sequencing (WES) for... more
8563 Background: Predicting the risk of postoperative recurrence is becoming increasingly important in EGFR mutation positive ( EGFR-m) non-small cell lung cancer (NSCLC). Only a few reports conducted whole exome sequencing (WES) for genomic profiling in large scale EGFR-m NSCLC cases. Methods: We conducted WES and analyzed the clinical course of patients (pts) with NSCLC who underwent surgery between 1985 and 2019 in the PRISM project of our institute. We evaluated the EGFR-m patients’ characteristics, recurrence-free survival (RFS), and developed a prediction model using machine learning, Overlapping Group LASSO to predict whether the EGFR-m patients will recur within 5 years or not as "high-risk" and "low-risk". To develop and validate the prediction model, we divided the data from 2006 as the training cohort data set and the data before 2006 as the validation cohort data set. After the development of the prediction model, we performed a stratified Cox proportional hazards model to compare the RFS between the predicted groups. Results: A total of 585/1351(43.3%) pts were EGFR-m included in the PRISM project. Of all pts, stage I, EGFR-m were 205 pts. The median RFS of the stage I, EGFR-m 123.1 months (m). In the training cohort, the model detected 43 pts for high-risk and 88 pts for low-risk. In the validation cohort, the model predicted 29 pts for high-risk and 45 pts for low-risk. Median RFS of high-risk vs. low-risk were 52.2 m vs. 105 m (HR 2.43, p=0.01). The 1-year RFS rate, 2-year RFS rate, and 5-year RFS rates for high-risk and low-risk pts were 100% vs. 98.5%, 66.7% vs. 89.2%, and 41.7% vs. 66.1%, respectively. Twenty-eight gene set coefficients were non-zero in the prediction model. The gene sets with large positive coefficients that were considered important for prediction as "high risk" were the gene sets affected by KRAS gene overexpression and p53 gene knockdown. In contrast, gene sets repressed by mTOR inhibition and genes repressed by TBK1 gene knockdown and KRAS gene overexpression had large negative coefficients. Conclusions: We developed and validated the prediction model whether the EGFR-m patients will recur within 5 years or not. EGFR-m NSCLC recurrence appears to be high risk with pathways associated with KRAS and p53 genes, and low risk with mutations in the gene sets suppressed by the mTOR pathway and TBK1 gene. [Table: see text]
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Clinical studies on cefmenoxime (CMX) concentration in prostatic tissue and bladder wall were made and the following results were obtained. In 40 patients undergoing operation, 1 g of CMX was administered intravenously by bolus technique... more
Clinical studies on cefmenoxime (CMX) concentration in prostatic tissue and bladder wall were made and the following results were obtained. In 40 patients undergoing operation, 1 g of CMX was administered intravenously by bolus technique and CMX levels in peripheral blood, prostatic tissue and bladder wall were examined. The maximum level of prostatic tissue was 35 micrograms/g after 0.41 hour and bladder wall was 62 micrograms/g after 0.37 hour, and T1/2 was 1.41 hours both. CMX, a new broad spectrum cephalosporin, can be considered as one of the highly useful antibiotics for the treatment of postoperative infection.