Histological background of dedifferentiated solitary fibrous tumour

2021 ◽  
pp. jclinpath-2020-207311
Author(s):  
Yuichi Yamada ◽  
Kenichi Kohashi ◽  
Izumi Kinoshita ◽  
Hidetaka Yamamoto ◽  
Takeshi Iwasaki ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mitotic Rate ◽  
Solitary Fibrous Tumour ◽  
Cellular Component ◽  
Wild Type ◽  
Sarcomatous Component ◽  
Protein Loss ◽  
P53 Expression ◽  
Rb Protein ◽  
P16 Overexpression

AimsDedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs.MethodsClinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed.ResultsThe non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of β-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%).ConclusionsThe authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation.

scholarly journals An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Thao Thi Thanh Nguyen ◽  
Masato Shingyoji ◽  
Michiko Hanazono ◽  
Boya Zhong ◽  
Takao Morinaga ◽  
...  
Keyword(s):  
Wild Type ◽  
Inhibitory Effects ◽  
Cytotoxic Effects ◽  
P53 Expression ◽  
Nuclear Factor I ◽  
Infected Cells ◽  
Wild Type P53 ◽  
Mdm2 Inhibitor ◽  
P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

scholarly journals Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons

2020 ◽  
Vol 22 (1) ◽  
pp. 145
Author(s):  
Rohan Umesh Parekh ◽  
Srinivas Sriramula
Keyword(s):  
Protein Expression ◽  
Renin Angiotensin System ◽  
Neuronal Cultures ◽  
Wild Type ◽  
High Concentration ◽  
Neurogenic Hypertension ◽  
B1 Receptor ◽  
Gene And Protein Expression ◽  
Kinin B1 Receptor ◽  
Specific Antagonist

Angiotensin converting enzyme 2 (ACE2) is a critical component of the compensatory axis of the renin angiotensin system. Alterations in ACE2 gene and protein expression, and activity mediated by A Disintegrin And Metalloprotease 17 (ADAM17), a member of the “A Disintegrin And Metalloprotease” (ADAM) family are implicated in several cardiovascular and neurodegenerative diseases. We previously reported that activation of kinin B1 receptor (B1R) in the brain increases neuroinflammation, oxidative stress and sympathoexcitation, leading to the development of neurogenic hypertension. We also showed evidence for ADAM17-mediated ACE2 shedding in neurons. However, whether kinin B1 receptor (B1R) activation has any role in altering ADAM17 activity and its effect on ACE2 shedding in neurons is not known. In this study, we tested the hypothesis that activation of B1R upregulates ADAM17 and results in ACE2 shedding in neurons. To test this hypothesis, we stimulated wild-type and B1R gene-deleted mouse neonatal primary hypothalamic neuronal cultures with a B1R-specific agonist and measured the activities of ADAM17 and ACE2 in neurons. B1R stimulation significantly increased ADAM17 activity and decreased ACE2 activity in wild-type neurons, while pretreatment with a B1R-specific antagonist, R715, reversed these changes. Stimulation with specific B1R agonist Lys-Des-Arg9-Bradykinin (LDABK) did not show any effect on ADAM17 or ACE2 activities in neurons with B1R gene deletion. These data suggest that B1R activation results in ADAM17-mediated ACE2 shedding in primary hypothalamic neurons. In addition, stimulation with high concentration of glutamate significantly increased B1R gene and protein expression, along with increased ADAM17 and decreased ACE2 activities in wild-type neurons. Pretreatment with B1R-specific antagonist R715 reversed these glutamate-induced effects suggesting that indeed B1R is involved in glutamate-mediated upregulation of ADAM17 activity and ACE2 shedding.

scholarly journals Novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Safia Akhtar ◽  
Silas A. Culver ◽  
Helmy M. Siragy
Keyword(s):  
Protein Expression ◽  
High Fat Diet ◽  
Normal Diet ◽  
Receptor Expression ◽  
Wild Type ◽  
High Fat ◽  
Renal Gluconeogenesis ◽  
Mrna And Protein Expression ◽  
Polymerase Chain ◽  
Renal Expression

AbstractRecent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. However, the mechanisms responsible for such stimulation are not well understood. Recently, our laboratory demonstrated that mice fed high fat diet (HFD) exhibited increase in renal Atp6ap2 [also known as (Pro)renin receptor] expression. We hypothesized that HFD upregulates renal gluconeogenesis via Atp6ap2-PGC-1α and AKT pathway. Using real-time polymerase chain reaction, western blot analysis and immunostaining, we evaluated renal expression of the Atp6ap2 and renal gluconeogenic enzymes, PEPCK and G6Pase, in wild type and inducible nephron specific Atp6ap2 knockout mice fed normal diet (ND, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 8 weeks. Compared with ND, HFD mice had significantly higher body weight (23%) (P < 0.05), renal mRNA and protein expression of Atp6ap2 (39 and 35%), PEPCK (44 and 125%) and G6Pase (39 and 44%) respectively. In addition, compared to ND, HFD mice had increased renal protein expression of PGC-1α by 32% (P < 0.05) and downregulated AKT by 33% (P < 0.05) respectively in renal cortex. Atp6ap2-KO abrogated these changes in the mice fed HFD. In conclusion, we identified novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway.

Adenovirus-mediated wild-type P53 expression suppresses growth of lung adeno-carcinoma cells

1998 ◽  
Vol 10 (3) ◽  
pp. 178-181
Author(s):  
Jian Li ◽  
Yongjing Xia ◽  
Lei Jiang ◽  
Hongxia Li ◽  
Yajun Hu ◽  
...  
Keyword(s):  
Carcinoma Cells ◽  
Wild Type ◽  
P53 Expression ◽  
Wild Type P53 ◽  
Adeno Carcinoma

Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells

1994 ◽  
Vol 8 (2) ◽  
pp. 171-176 ◽  
Author(s):  
Erwin G. Van Meir ◽  
Peter J. Polverini ◽  
Victoria R. Chazin ◽  
H.-J. Su Huang ◽  
Nicolas de Tribolet ◽  
...  
Keyword(s):  
Wild Type ◽  
Glioblastoma Cells ◽  
P53 Expression ◽  
Wild Type P53

scholarly journals HOXA11 Regulates Chemoresistance By Modulating p53 Gene Expression in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5182-5182
Author(s):  
Xutao Guo ◽  
Bowen Yan ◽  
Yi Qiu
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
P53 Gene ◽  
Resistant Cell ◽  
Wild Type ◽  
P53 Expression ◽  
Acute Myeloid ◽  
Resistant Cells

Acute myeloid leukemia (AML) exhibits large intrinsic variation in drug responsiveness due to its inherent heterogeneity. Therefore, it is important to understand the resistant mechanism in order to improve the treatment. In our previously study, the OCI-AML2-resistant cell lines were established to resist cytarabine (Ara-C) in the concentration of 50 µM (OCI-AML2 R50). The RNA-seq results showed that many genes changed in the resistant cells compared to wild type OCI-AML2 cells. One of the most remarkably decreased gene in resistant cells was HOXA11 (Homeobox A11). It is the part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which regulates gene expression, morphogenesis, and differentiation. In this study, we have evaluated the importance of HOXA11 in AML chemoresistance. We found that knockdown of HOXA11 repressed the WT OCI-AML2 cell proliferation and increased the population of cells expressing CD123 and CD47 LSC (Leukemia stem cell) markers and enhanced the resistance to Ara-C in vitro, while overexpression of HOXA11 showed the reverse effect. These results support the idea that HOXA11 promotes drug sensitivity and apoptosis in AML. However, the result also showed that overexpression of HOXA11 repressed the OCI-AML2 R50 cell proliferation and enhanced the resistance. Therefore, HOXA11 plays opposite role in sensitive cells and resistant cells. We further investigated the mechanism for these effects. We found that knockdown of HOXA11 decreased the p53 gene expression and overexpression of HOXA11 increased the expression of p53 in OCI-AML2 and R50 cells. Further, in OCI-AML2 R50 cells p53 has a hotspot mutation in DNA binding site and studies have shown that p53 mutation enhance cancer cell survival and chemoresistance. Therefore, our study shows dual roles for HOXA11 in cell survival. In p53 wild type parental AML2 cells, HOXA11 induces wild type p53 expression to enhance drug sensitivity while in resistant cell, HOXA11 promotes mutant p53 expression and enhances the resistance of chemotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Mutational Landscape of PTK7 in Congenital Scoliosis and Adolescent Idiopathic Scoliosis

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1791
Author(s):  
Zhe Su ◽  
Yang Yang ◽  
Shengru Wang ◽  
Sen Zhao ◽  
Hengqiang Zhao ◽  
...  
Keyword(s):  
Adolescent Idiopathic Scoliosis ◽  
Idiopathic Scoliosis ◽  
Protein Expression ◽  
Rare Variants ◽  
Congenital Scoliosis ◽  
Loss Of Function ◽  
Wild Type ◽  
Cellular Location ◽  
Mutational Landscape

Depletion of ptk7 is associated with both congenital scoliosis (CS) and adolescent idiopathic scoliosis (AIS) in zebrafish models. However, only one human variant of PTK7 has been reported previously in a patient with AIS. In this study, we systemically investigated the variant landscape of PTK7 in 583 patients with CS and 302 patients with AIS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study. We identified a total of four rare variants in CS and four variants in AIS, including one protein truncating variant (c.464_465delAC) in a patient with CS. We then explored the effects of these variants on protein expression and sub-cellular location. We confirmed that the c.464_465delAC variant causes loss-of-function (LoF) of PTK7. In addition, the c.353C>T and c.2290G>A variants identified in two patients with AIS led to reduced protein expression of PTK7 as compared to that of the wild type. In conclusion, LoF and hypomorphic variants are associated with CS and AIS, respectively.

scholarly journals Comparison of protein expression during wild-type, and E1B-55k-deletion, adenovirus infection using quantitative time-course proteomics

2017 ◽  
Vol 98 (6) ◽  
pp. 1377-1388 ◽  
Author(s):  
Yen Rong Fu ◽  
Andrew S. Turnell ◽  
Simon Davis ◽  
Kate J. Heesom ◽  
Vanessa C. Evans ◽  
...  
Keyword(s):  
Protein Expression ◽  
Time Course ◽  
Adenovirus Infection ◽  
Wild Type

scholarly journals Identification of prognostic values defined by copy number variation, mRNA and protein expression of LANCL2 and EGFR in IDH1/2-wild-type glioblastoma

2021 ◽  
Author(s):  
Hua-fu Zhao ◽  
Xiu-ming Zhou ◽  
Jing Wang ◽  
Fan-fan Chen ◽  
Chang-peng Wu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Copy Number ◽  
Intracellular Localization ◽  
Methylation Status ◽  
Growth Factor Receptor ◽  
Copy Number Variations ◽  
Wild Type ◽  
Number Variation ◽  
Newly Diagnosed Glioblastoma ◽  
Mrna And Protein Expression

Abstract Background Epidermal growth factor receptor (EGFR) and lanthionine synthetase C-like 2 (LanCL2) genes locate in the same amplicon, and co-amplification of EGFR and LANCL2 is frequent in glioblastoma. However, the prognostic value of LANCL2 and EGFR co-amplification, and their mRNA and protein expression in glioblastoma remain unclear yet. Methods This study analyzed the prognostic values of the copy number variations (CNVs), mRNA and protein expression of LANCL2 and EGFR in glioblastoma specimens from TCGA database or our tumor banks. Results The amplification of LANCL2 or EGFR, and their co-amplification were frequent in glioblastoma of TCGA database and our tumor banks. CNVs of LANCL2 or EGFR were significantly correlated with IDH1/2 mutation but not MGMT promoter methylation status. LANCL2 or EGFR amplification, and their co-amplification were significantly associated with reduced overall survival (OS) of glioblastoma patients, rather than IDH1/2-wild-type glioblastoma patients. mRNA and protein overexpression of LANCL2 and EGFR was also frequently found in glioblastoma. LANCL2, rather than EGFR, was overexpressed in relapsing glioblastoma, compared with newly diagnosed glioblastoma. However, mRNA or protein expression of EGFR and LANCL2 was not significantly correlated with OS of glioblastoma patients. In addition, the intracellular localization of LanCL2, not EGFR, was associated with the grade of gliomas. Conclusions Taken together, amplification and mRNA overexpression of LANCL2 and EGFR, and their co-amplification and co-expression were frequent in glioblastoma patients. Our findings suggest that CNVs of LANCL2 and EGFR were the independent diagnostic and prognostic biomarkers for histological glioblastoma patients, but not for IDH1/2-wild-type glioblastoma patients.

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