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JOURNAL ARTICLE
Abdul Sammad, Hanpeng Luo, Lirong Hu, Huabin Zhu, Yachun Wang
Heat stress affects granulosa cells (GCs) and the ovarian follicular microenvironment, causing poor oocyte developmental competence and fertility. This study aimed to investigate the physical responses and global transcriptomic changes in bovine GCs to acute heat stress (43 °C for 2 h) in vitro. Heat-stressed GCs exhibited transient proliferation senescence and resumed proliferation at 48 h post-stress, while post-stress immediate culture-media change had a relatively positive effect on proliferation resumption...
April 25, 2022: Cells
#22
REVIEW
Emi Hibino, Hidekazu Hiroaki
The tumor suppressor protein p53, a transcription product of the anti-oncogene TP53 , is a critical factor in preventing cellular cancerization and killing cancer cells by inducing apoptosis. As a result, p53 is often referred to as the "guardian of the genome." Almost half of cancers possess genetic mutations in the TP53 gene, and most of these mutations result in the malfunction of p53, which promotes aggregation. In some cases, the product of the TP53 mutant allele shows higher aggregation propensity; the mutant co-aggregates with the normal (functional) p53 protein, thus losing cellular activity of the p53 guardian...
February 2022: Biophysical Reviews
#23
JOURNAL ARTICLE
Junhui Li, Rati Lama, Samuel L Galster, Joseph R Inigo, Jin Wu, Dhyan Chandra, Sherry R Chemler, Xinjiang Wang
High frequency of KRAS and TP53 mutations is a unique genetic feature of pancreatic ductal adenocarcinoma (PDAC). TP53 mutation not only renders PDAC resistance to chemotherapies but also drives PDAC invasiveness. Therapies targeting activating mutant KRAS are not available and the outcomes of current PDAC treatment are extremely poor. Here we report that MMRi62, initially identified as an MDM2-MDM4-targeting small molecule with p53-independent pro-apoptotic activity, shows anti-PDAC activity in vitro and in vivo...
February 7, 2022: Molecular Cancer Therapeutics
#24
JOURNAL ARTICLE
Jiamin Cheng, Yinyin Li, Xiaohui Wang, Zheng Dong, Yan Chen, Rui Zhang, Jiagan Huang, Xueyuan Jin, Jianfei Yao, Aifang Ge, Lele Song, Yinying Lu, Zhen Zeng
Background: Immunotherapy combined with VEGF inhibitor has become the new first-line therapy for advanced or metastatic hepatocellular carcinoma (HCC). However, the biomarkers for response and prognosis stratification of HCC first-line combined immunotherapy have not been clarified. Methods: Here, we obtained the genomic alteration data from pre-therapeutic samples of 103 HCC patients using a 605-gene NGS test, and obtained the transcriptional and T cell receptor (TCR) diversity data from 18 patients who underwent the first-line combined immunotherapy using RNAseq and TCR sequencing, respectively...
2021: Journal of Hepatocellular Carcinoma
#25
JOURNAL ARTICLE
Arturo R Palomares, Adrián Alberto Castillo-Domínguez, Maximiliano Ruiz-Galdón, Kenny A Rodriguez-Wallberg, Armando Reyes-Engel
PURPOSE: Single-nucleotide polymorphisms (SNPs) in the p53 pathways have shown to play a role in endometrial receptivity and implantation in infertile women undergoing in vitro fertilization (IVF). The present study aimed to assess the influence of these gene variants over pregnancy success through a receptivity model in recipients of egg donation treatments, when factors such as age and quality of the oocytes are standardized. METHODS: A nested case-control study was performed on 234 female patients undergoing their first fresh IVF treatment as recipients of donor oocytes...
October 7, 2021: Journal of Assisted Reproduction and Genetics
#26
JOURNAL ARTICLE
Paul W Harms, Monique E Verhaegen, Kevin Hu, Steven M Hrycaj, May P Chan, Chia-Jen Liu, Marina Grachtchouk, Rajiv M Patel, Aaron M Udager, Andrzej A Dlugosz
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel...
September 30, 2021: Modern Pathology
#27
REVIEW
Fengzhi Li, Ieman A M Aljahdali, Renyuan Zhang, Kent L Nastiuk, John J Krolewski, Xiang Ling
The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e...
August 12, 2021: Journal of Experimental & Clinical Cancer Research: CR
#28
JOURNAL ARTICLE
Philippe Aftimos, Mafalda Oliveira, Alexandre Irrthum, Debora Fumagalli, Christos Sotiriou, Einav Nili Gal-Yam, Mark E Robson, Justin Ndozeng, Angelo Di Leo, Eva M Ciruelos, Evandro de Azambuja, Giuseppe Viale, Elsemieke D Scheepers, Giuseppe Curigliano, Judith M Bliss, Jorge S Reis-Filho, Marco Colleoni, Marija Balic, Fatima Cardoso, Joan Albanell, Caroline Duhem, Sandrine Marreaud, Dario Romagnoli, Beatriz Rojas, Andrea Gombos, Hans Wildiers, Angel Guerrero-Zotano, Peter Hall, Andrea Bonetti, Karolina Fs Larsson, Martina Degiorgis, Silvia Khodaverdi, Richard Greil, Ásgerdur Sverrisdóttir, Marta Paoli, Ethel Seyll, Sibylle Loibl, Barbro Linderholm, Gabriele Zoppoli, Nancy E Davidson, Oskar Th Johannsson, Philippe L Bedard, Sherene Loi, Susan Knox, David A Cameron, Nadia Harbeck, Maite Lasa Montoya, Mariana Brandão, Andrea Vingiani, Carmela Caballero, Florentine S Hilbers, Lucy R Yates, Matteo Benelli, David Venet, Martine J Piccart
AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA , and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1 ...
November 2021: Cancer Discovery
#29
JOURNAL ARTICLE
Xiaoxuan Wang, Yoshiyuki Yamamoto, Mamiko Imanishi, Xiaochen Zhang, Masashi Sato, Akinori Sugaya, Mitsuaki Hirose, Shinji Endo, Yukikazu Natori, Toshikazu Moriwaki, Kenji Yamato, Ichinosuke Hyodo
Murine double minute homolog 2 (MDM2) is an oncoprotein that induces p53 degradation via ubiquitin-ligase activity. MDM4 cooperates with MDM2-mediated p53 degradation, directly inhibiting p53 transcription by binding to its transactivation domain. Our previous study reported that the simultaneous inhibition of MDM2 and MDM4 using nutlin-3 (an inhibitor of the MDM2-p53 interaction) and chimeric small interfering RNA with DNA-substituted seed arms (named chiMDM2 and chiMDM4) more potently activated p53 than the MDM2 or MDM4 inhibitor alone and synergistically augmented antitumor effects in various types of cancer cells with the wild-type (wt) TP53 ...
July 2021: Oncology Letters
#30
JOURNAL ARTICLE
Liv B Gansmo, Benedicte A Lie, Marthe T Mæhlen, Lars Vatten, Pål Romundstad, Kristian Hveem, Per E Lønning, Stian Knappskog
BACKGROUND: In addition to being a tumour suppressor, TP53 is a suppressor of inflammation, and dysfunction of this gene has been related to autoimmune diseases. Patients with autoimmunity, such as rheumatoid arthritis (RA) have an increased risk of certain cancers, like lymphomas, indicating that some underlaying mechanisms may modulate risk of both cancers and autoimmunity. METHODS: We genotyped 5 common genetic variants in TP53 and its main regulators MDM2 and MDM4 in a sample of 942 RA patients and 3,747 healthy controls, and mined previously published GWAS-data, to assess the potential impact of these variants on risk of RA...
May 30, 2021: Gene
#31
REVIEW
Dennis M Timmerman, Tessa L Remmers, Sanne Hillenius, Leendert H J Looijenga
The P53 pathway is the most important cellular pathway to maintain genomic and cellular integrity, both in embryonic and non-embryonic cells. Stress signals induce its activation, initiating autophagy or cell cycle arrest to enable DNA repair. The persistence of these signals causes either senescence or apoptosis. Over 50% of all solid tumors harbor mutations in TP53 that inactivate the pathway. The remaining cancers are suggested to harbor mutations in genes that regulate the P53 pathway such as its inhibitors Mouse Double Minute 2 and 4 (MDM2 and MDM4, respectively)...
May 20, 2021: International Journal of Molecular Sciences
#32
JOURNAL ARTICLE
Natasha T Hill, David Kim, Klaus J Busam, Emily Y Chu, Clayton Green, Isaac Brownell
Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Most MCC tumors contain integrated Merkel cell polyomavirus DNA (virus-positive MCC, VP-MCC) and carry a low somatic mutation burden whereas virus-negative MCC (VN-MCC) possess numerous ultraviolet-signature mutations. In contrast to viral oncogenes and sequence mutations, little is known about genomic structural variants in MCC. To identify copy number variants in commonly altered genes, we analyzed genomic DNA from 31 tumor samples using the Nanostring nCounter copy number cancer panel...
March 6, 2021: Cancers
#33
JOURNAL ARTICLE
TP53/miR-129/MDM2/4/TP53 feedback loop modulates cell proliferation and apoptosis in retinoblastoma.
Xiaolei Yao, Hui Shen, Qinghua Peng, Jingsheng Yu
Retinoblastoma (RB) is commonly-seen cancer in children. The p53 pathway dysfunction, which can lead to elevated MDM2 or MDM4 (p53 antagonists) protein expression, is frequently observed in almost all human cancers, including RB. The present study attempted to investigate the underlying mechanism from the perspective of non-coding RNA regulation. Here, we demonstrated that p53 and miR-129 were positively correlated with each other in RB. miR-129 directly targeted MDM2/4 to inhibit expression, therefore counteracting MDM2/4-mediated p53 signaling suppression and modulating RB cell proliferation and apoptosis...
March 8, 2021: Cell Cycle
#34
JOURNAL ARTICLE
Seyed Pairawan, Ming Zhao, Erkan Yuca, Allen Annis, Kurt Evans, David Sutton, Luis Carvajal, Jian-Guo Ren, Solimar Santiago, Vincent Guerlavais, Argun Akcakanat, Coya Tapia, Fei Yang, Priya Subash Chandra Bose, Xiaofeng Zheng, Ecaterina Ileana Dumbrava, Manuel Aivado, Funda Meric-Bernstam
BACKGROUND: MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. METHODS: Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination...
March 4, 2021: Breast Cancer Research: BCR
#35
JOURNAL ARTICLE
Vaios Sinatkas, Konstantina Stathopoulou, Ioanna Xagoraris, Jingjing Ye, Dimitra Vyrla, Vasilios Atsaves, Vasiliki Leventaki, L Jeffrey Medeiros, George Z Rassidakis, Elias Drakos
We hypothesized that murine double minute X (MDMX), a negative p53-regulator, may be involved in dysfunctional p53-signaling in anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive and ALK-negative, characterized frequently by non-mutated TP53 (wt-p53) . By western blot analysis, MDMX was highly expressed in ALK + ALCL and expressed at variable levels in ALK- ALCL cell lines. By immunohistochemistry, high MDMX levels were observed more frequently in ALK + ALCL (36/46; 78%), compared with ALK- ALCL tumors (12/29; 41%) ( p < ...
February 11, 2021: Leukemia & Lymphoma
#36
JOURNAL ARTICLE
Sarah E Woodfield, Yan Shi, Roma H Patel, Zhenghu Chen, Aayushi P Shah, Rohit K Srivastava, Richard S Whitlock, Aryana M Ibarra, Samuel R Larson, Stephen F Sarabia, Andrew Badachhape, Zbigniew Starosolski, Ketan B Ghaghada, Pavel Sumazin, D Allen Annis, Dolores López-Terrada, Sanjeev A Vasudevan
Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes...
February 3, 2021: Scientific Reports
#37
JOURNAL ARTICLE
Zerrin Karaaslan, Özlem Timirci Kahraman, Elif Şanlı, Hayriye Arzu Ergen, Canan Ulusoy, Başar Bilgiç, Vuslat Yılmaz, Erdem Tüzün, Haşmet Ayhan Hanağası, Cem İsmail Küçükali
Our aim was to identify the differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMC) of Parkinson's disease (PD) patients and healthy controls by microarray technology and analysis of related molecular pathways by functional annotation. Thirty PD patients and 30 controls were enrolled. Agilent Human 8X60 K Oligo Microarray was used for gene level expression identification. Gene ontology and pathway enrichment analyses were used for functional annotation of DEGs. Protein-protein interaction analyses were performed with STRING...
January 27, 2021: Scientific Reports
#38
JOURNAL ARTICLE
Changjing He, Huatao Qin, Haizhou Tang, Di Yang, Yufeng Li, Zhenwen Huang, Donghu Zhang, Changheng Lv
Background: Differential expression of tumor protein 53 (TP53, or p53) has been observed in multiple cancers. However, the expression levels and prognostic role of TP53 signaling pathway genes in Wilms' tumor (WT) have yet to be fully explored. Methods: The expression levels of TP53 signaling pathway genes including TP53, mouse double minute 2 (MDM2), mouse double minute 4 (MDM4), cyclin-dependent kinase 2A (CDKN2A), cyclin-dependent kinase 2B (CDKN2B), and tumor suppressor p53-binding protein 1 (TP53BP1) in WT were analyzed using the Oncomine database...
October 2020: Annals of Translational Medicine
#39
JOURNAL ARTICLE
Argyri Mathioudaki, Viktor Ljungström, Malin Melin, Maja Louise Arendt, Jessika Nordin, Åsa Karlsson, Eva Murén, Pushpa Saksena, Jennifer R S Meadows, Voichita D Marinescu, Tobias Sjöblom, Kerstin Lindblad-Toh
Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC (n = 765). The selected genes were either from human BC studies (n = 294) or from within canine mammary tumor associated regions (n = 471)...
November 9, 2020: Scientific Reports
#40
JOURNAL ARTICLE
Kathryn T Bieging-Rolett, Alyssa M Kaiser, David W Morgens, Anthony M Boutelle, Jose A Seoane, Eric L Van Nostrand, Changyu Zhu, Shauna L Houlihan, Stephano S Mello, Brian A Yee, Jacob McClendon, Sarah E Pierce, Ian P Winters, Mengxiong Wang, Andrew J Connolly, Scott W Lowe, Christina Curtis, Gene W Yeo, Monte M Winslow, Michael C Bassik, Laura D Attardi
Although TP53 is the most commonly mutated gene in human cancers, the p53-dependent transcriptional programs mediating tumor suppression remain incompletely understood. Here, to uncover critical components downstream of p53 in tumor suppression, we perform unbiased RNAi and CRISPR-Cas9-based genetic screens in vivo. These screens converge upon the p53-inducible gene Zmat3, encoding an RNA-binding protein, and we demonstrate that ZMAT3 is an important tumor suppressor downstream of p53 in mouse KrasG12D -driven lung and liver cancers and human carcinomas...
November 5, 2020: Molecular Cell
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