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#32987254   2020/09/19 To Up

Predictive markers for pathological complete response after neo-adjuvant chemotherapy in triple-negative breast cancer.

A combination of Sox10 and GATA3 was previously identified as a marker for metastatic triple-negative breast cancer (TNBC), but it is uncertain whether their expression is associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). This study investigates the predictive value of clinicopathological characteristics, as well as protein expression of Sox10, GATA3, p53 and p63, in a consecutive series of TNBC patients treated with NAC. Archived hematoxylin & eosin stained slides of core biopsies and resection specimens from 35 TNBC patients were reviewed. The following clinicopathological characteristics were determined at the biopsy level: age at diagnosis, cancer type, Nottingham grade, lympho-vascular invasion, syncytial growth, necrosis, clear cell differentiation, myxoid peritumor stroma, stromal tumor-infiltrating lymphocytes (sTILs) and presence of an in situ component. The MD Anderson residual cancer burden (RCB) score and corresponding RCB class were determined. Immunohistochemistry for Sox10, p53, GATA3 and p63 was performed at the biopsy level. sTILs, either as a continuous or as a dichotomous variable, were the only parameter that was significantly associated with pCR in univariable and multivariable analyses. Assessment of sTILs showed moderate to good interobserver agreement. High sTILs (≥40%) were significantly associated with increased pCR rates, and this association was observer-independent. This retrospective study of a consecutive community-based cohort of TNBC patients confirms that sTILs are a robust, observer-independent predictor for therapeutic response after NAC. The combination of Sox10, GATA3 and p53 immunoreactivity is unlikely to harbor any predictive value for pCR in TNBC.
Mieke R Van Bockstal, Fanchon Noel, Yves Guiot, Francois P Duhoux, Filomena Mazzeo, Cédric Van Marcke, Latifa Fellah, Benjamin Ledoux, Martine Berlière, Christine Galant

1442 related Products with: Predictive markers for pathological complete response after neo-adjuvant chemotherapy in triple-negative breast cancer.



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#32753402   2020/08/04 To Up

Stemness in high-grade serous carcinoma of tubo-ovarian origin causes multiple immunohistochemical pitfalls: a case report.


Mieke R Van Bockstal, David Augusto

2758 related Products with: Stemness in high-grade serous carcinoma of tubo-ovarian origin causes multiple immunohistochemical pitfalls: a case report.



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#32179091   2020/03/14 To Up

Combination of PD-1 Inhibitor and OX40 Agonist Induces Tumor Rejection and Immune Memory in Mouse Models of Pancreatic Cancer.

Advanced pancreatic ductal adenocarcinoma (PDAC) is resistant to therapy, including immune checkpoint inhibitors. We evaluated the effects of a neutralizing antibody against programmed cell death 1 (PD-1) and an agonist of OX40 (provides a survival signal to activated T cells) in mice with pancreatic tumors.
Ying Ma, Jun Li, Huamin Wang, Yulun Chiu, Charles V Kingsley, David Fry, Samantha N Delaney, Spencer C Wei, Jianhua Zhang, Anirban Maitra, Cassian Yee

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#31605787   2019/10/10 To Up

Combined NK Cell Therapy and Radiation Therapy Exhibit Long-Term Therapeutic and Antimetastatic Effects in a Human Triple Negative Breast Cancer Model.

We investigated whether adoptive cell therapy with ex vivo-activated natural killer (NK) cells enhances the therapeutic efficacy of local tumor radiation therapy (RT) using a human triple-negative breast cancer xenograft model.
Kyung Won Kim, Jae-Uk Jeong, Kyung-Hwa Lee, Tung Nguyen Thanh Uong, Joon Haeng Rhee, Sung-Ja Ahn, Sang-Ki Kim, Duck Cho, Huy Phuoc Quang Nguyen, Chanh Tin Pham, Mee Sun Yoon

1175 related Products with: Combined NK Cell Therapy and Radiation Therapy Exhibit Long-Term Therapeutic and Antimetastatic Effects in a Human Triple Negative Breast Cancer Model.

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#31296660   2019/07/11 To Up

Temporal and differential regulation of KAISO-controlled transcription by phosphorylated and acetylated p53 highlights a crucial regulatory role of apoptosis.

Transcriptional regulator KAISO plays a critical role in cell cycle arrest and apoptosis through modulation of p53 acetylation by histone acetyltransferase p300. KAISO potently stimulates apoptosis in cells expressing WT p53, but not in p53-mutant or p53-null cells. Here, we investigated how KAISO transcription is regulated by p53, finding four potential p53-binding sites (p53-responsive DNA elements; p53REs) located in a distal 5'-upstream regulatory element, intron 1, exon 2 coding sequence, and a 3'-UTR region. Transient transcription assays of pG5-p53RE-Luc constructs with various p53REs revealed that p53 activates transcription by acting on p53RE1 (-4326 to -4227) of the 5'-upstream region and on p53RE3 (+2929 to +2959) of the exon 2 coding region during early DNA damage responses (DDRs). ChIP and oligonucleotide pulldown assays further disclosed that p53 binds to the p53RE1 and p53RE3 sites. Moreover, ataxia telangiectasia mutated (ATM) or ATM-Rad3-related (ATR) kinase-mediated p53 phosphorylation at Ser-15 or Ser-37 residues activated transcription by binding its p53RE1 or p53RE3 sites during early DDR. p53RE1 uniquely contained three p53-binding half-sites, a structural feature important for transcriptional activation by phosphorylated p53 Ser-15·Ser-37. During the later DDR phase, a KAISO-mediated acetylated p53 form (represented by a p53QRQ acetyl-mimic) robustly activated transcription by acting on p53RE1 in which this structural feature is not significant, but it provided sufficient KAISO levels to confer a p53 "apoptotic code." These results suggest that the critical apoptosis regulator is a p53 target gene that is differently regulated by phosphorylated p53 or acetylated p53, depending on DDR stage.
Seo-Hyun Choi, Dong-In Koh, Su-Yeon Cho, Min-Kyeong Kim, Kyung-Sup Kim, Man-Wook Hur

1857 related Products with: Temporal and differential regulation of KAISO-controlled transcription by phosphorylated and acetylated p53 highlights a crucial regulatory role of apoptosis.

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#31172579   2019/06/06 To Up

Stimulating DDX3 expression by serotonin 5-HT receptor 7 through phosphorylation of p53 via the AC-PKA-ERK signaling pathway.

DDX3 is a host viral factor that can inhibit the hepatitis B virus-induced innate immune responses. In this study, the 20 bioactive compounds have screened the effects on DDX3 and we found that 5-HT upregulated DDX3 promoter activity via the 5-HT receptor on liver hepatocellular cells (HepG2 cells) by using a luciferase assay, reverse transcription-polymerase chain reaction analysis, and Western blot analysis. Furthermore, we are trying to elucidate the pathways involved in the stimulating effect of 5-HT on DDX3 expression to induce innate immune responses against hepatitis B virus infection. A knockdown of the 5-HT receptor by transfection si-5-HT receptors or si-control into HepG2 cells treated by 5-HT (or 5-HT plus agonist) confirmed the role of the 5-HT receptor in DDX3 expression. The IFN-β-Luc expression and level of hepatitis B virus surface Antigen (HBsAg) showed that DDX3 mediated by the 5-HT agonist (AS-19) increased IFN-β expression and inhibited HBV replication. Luciferase assays showed the involvement of 5-HT receptors in DDX3 expression via cAMP/AC/PKA pathways by using protein kinase A (PKA) and adenylyl cyclase inhibitor (MDL 12330A). AS-19 mediated DDX3 promoter activated PKA extracellular signal-regulated kinase ERK signaling the p53 phosphorylation (-1080/-1070) resulted in upregulation of DDX3 promoter transactivation via the 5-HT receptors agonist. Overall, 5-HT was found to be a new potential target to inhibit hepatitis B infection by activating AC/PKA/ERK pathways by phosphorylating p53 via the 5-HT agonist response by mediating DDX3 expression.
Li-Jung Kang, Khoa V A Nguyen, Sanung Eom, Yeo-Jin Choi, Cam Ngoc Nguyen, Jaeeun Lee, Chaelin Kim, Shinhui Lee, Seong-Gene Lee, Jun-Ho Lee

1296 related Products with: Stimulating DDX3 expression by serotonin 5-HT receptor 7 through phosphorylation of p53 via the AC-PKA-ERK signaling pathway.

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#31145683   2019/05/15 To Up

A balancing act: PHLPP2 fine tunes AKT activity and MYC stability in prostate cancer.

PTEN loss stimulates prostate tumor progression by sustaining AKT activation. Nowak et al. (2019. https://doi.org/10.1083/jcb.201902048) surprisingly show that the AKT-suppressing phosphatase PHLPP2 promotes disease progression in the context of dual PTEN and p53 loss by increasing MYC stability.
Roxanne Toivanen, Luc Furic

1492 related Products with: A balancing act: PHLPP2 fine tunes AKT activity and MYC stability in prostate cancer.



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#31111215   2019/05/20 To Up

Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia.

Valproic acid (VPA) is suggested to be therapeutically beneficial in combination with interferon-alpha (IFNα) in various cancers. Therefore, we examined IFNα and VPA alone and in combinations in selected AML models, examining immune regulators and intracellular signaling mechanisms involved in phospho-proteomics.
Rakel Brendsdal Forthun, Monica Hellesøy, André Sulen, Reidun Kristin Kopperud, Gry Sjøholt, Øystein Bruserud, Emmet McCormack, Bjørn Tore Gjertsen

2766 related Products with: Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia.

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#30536898   2019/01/09 To Up

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma.

High-risk neuroblastoma, a predominantly TP53 wild-type (wt) tumour, is incurable in >50% patients supporting the use of MDM2 antagonists as novel therapeutics. Idasanutlin (RG7388) shows in vitro synergy with chemotherapies used to treat neuroblastoma. This is the first study to evaluate the in vivo efficacy of the intravenous idasanutlin prodrug, RO6839921 (RG7775), both alone and in combination with temozolomide in TP53 wt orthotopic neuroblastoma models. Detection of active idasanutlin using liquid chromatography-mass spectrometry and p53 pathway activation by ELISA assays and Western analysis showed peak plasma levels 1 h post-treatment with maximal p53 pathway activation 3-6 h post-treatment. RO6839921 and temozolomide, alone or in combination in mice implanted with TP53 wt SHSY5Y-Luc and NB1691-Luc cells showed that combined RO6839921 and temozolomide led to greater tumour growth inhibition and increase in survival compared to vehicle control. Overall, RO6839921 had a favourable pharmacokinetic profile consistent with intermittent dosing and was well tolerated alone and in combination. These preclinical studies support the further development of idasanutlin in combination with temozolomide in neuroblastoma in early phase clinical trials.
Lindi Chen, Fabio Pastorino, Philip Berry, Jennifer Bonner, Calum Kirk, Katrina M Wood, Huw D Thomas, Yan Zhao, Antonio Daga, Gareth J Veal, John Lunec, David R Newell, Mirco Ponzoni, Deborah A Tweddle

1360 related Products with: Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma.

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#30469529   2018/11/22 To Up

Recruitment of 53BP1 Proteins for DNA Repair and Persistence of Repair Clusters Differ for Cell Types as Detected by Single Molecule Localization Microscopy.

DNA double stranded breaks (DSBs) are the most serious type of lesions introduced into chromatin by ionizing radiation. During DSB repair, cells recruit different proteins to the damaged sites in a manner dependent on local chromatin structure, DSB location in the nucleus, and the repair pathway entered. 53BP1 is one of the important players participating in repair pathway decision of the cell. Although many molecular biology details have been investigated, the architecture of 53BP1 repair foci and its development during the post-irradiation time, especially the period of protein recruitment, remains to be elucidated. Super-resolution light microscopy is a powerful new tool to approach such studies in 3D-conserved cell nuclei. Recently, we demonstrated the applicability of single molecule localization microscopy (SMLM) as one of these highly resolving methods for analyses of dynamic repair protein distribution and repair focus internal nano-architecture in intact cell nuclei. In the present study, we focused our investigation on 53BP1 foci in differently radio-resistant cell types, moderately radio-resistant neonatal human dermal fibroblasts (NHDF) and highly radio-resistant U87 glioblastoma cells, exposed to high-LET N-ion radiation. At given time points up to 24 h post irradiation with doses of 1.3 Gy and 4.0 Gy, the coordinates and spatial distribution of fluorescently tagged 53BP1 molecules was quantitatively evaluated at the resolution of 10⁻20 nm. Clusters of these tags were determined as sub-units of repair foci according to SMLM parameters. The formation and relaxation of such clusters was studied. The higher dose generated sufficient numbers of DNA breaks to compare the post-irradiation dynamics of 53BP1 during DSB processing for the cell types studied. A perpendicular (90°) irradiation scheme was used with the 4.0 Gy dose to achieve better separation of a relatively high number of particle tracks typically crossing each nucleus. For analyses along ion-tracks, the dose was reduced to 1.3 Gy and applied in combination with a sharp angle irradiation (10° relative to the cell plane). The results reveal a higher ratio of 53BP1 proteins recruited into SMLM defined clusters in fibroblasts as compared to U87 cells. Moreover, the speed of foci and thus cluster formation and relaxation also differed for the cell types. In both NHDF and U87 cells, a certain number of the detected and functionally relevant clusters remained persistent even 24 h post irradiation; however, the number of these clusters again varied for the cell types. Altogether, our findings indicate that repair cluster formation as determined by SMLM and the relaxation (i.e., the remaining 53BP1 tags no longer fulfill the cluster definition) is cell type dependent and may be functionally explained and correlated to cell specific radio-sensitivity. The present study demonstrates that SMLM is a highly appropriate method for investigations of spatiotemporal protein organization in cell nuclei and how it influences the cell decision for a particular repair pathway at a given DSB site.
Elizaveta Bobkova, Daniel Depes, Jin-Ho Lee, Lucie Jezkova, Iva Falkova, Eva Pagacova, Olga Kopecna, Mariia Zadneprianetc, Alena Bacikova, Elena Kulikova, Elena Smirnova, Tatiana Bulanova, Alla Boreyko, Evgeny Krasavin, Frederik Wenz, Felix Bestvater, Georg Hildenbrand, Michael Hausmann, Martin Falk

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