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https://www.readbyqxmd.com/read/28334334/p53-and-its-mutants-on-the-slippery-road-from-stemness-to-carcinogenesis
#1
Alina Molchadsky, Varda Rotter
Normal development, tissue homeostasis and regeneration following injury rely on the proper functions of wide repertoire of stem cells (SCs) persisting during embryonic period and throughout the adult life. Therefore, SCs employ robust mechanisms to preserve their genomic integrity and avoid heritage of mutations to their daughter cells. Importantly, propagation of SCs with faulty DNA as well as dedifferentiation of genomically altered somatic cells may result in derivation of cancer SCs, which are considered to be the driving force of the tumorigenic process...
March 15, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28325293/a-pirna-like-small-rna-induces-chemoresistance-to-cisplatin-based-therapy-by-inhibiting-apoptosis-in-lung-squamous-cell-carcinoma
#2
Yuyan Wang, Tyler Gable, Mark Z Ma, David Clark, Jun Zhao, Yi Zhang, Wei Liu, Li Mao, Yuping Mei
Lung cancer is the leading cause of cancer-related death worldwide. Although advanced drugs have benefitted patients, therapeutic success has largely been hampered because of rapid development of resistance. Here we report that PIWI-interacting RNA likes (piR-Ls), a novel type of functional sncRNAs, play key roles in chemoresistance to cisplatin (CDDP)-based chemotherapy in lung squamous cell carcinoma (LSCC). piR-L-138 was upregulated upon CDDP-based chemotherapy both in LSCC cells and in patient-derived xenograft (PDX) LSCC models...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28324749/a-phase-i-study-of-sar405838-a-novel-human-double-minute-2-hdm2-antagonist-in-patients-with-solid-tumours
#3
Maja de Jonge, Vincent A de Weger, Mark A Dickson, Marlies Langenberg, Axel Le Cesne, Andrew J Wagner, Karl Hsu, Wei Zheng, Sandrine Macé, Gilles Tuffal, Koruth Thomas, Jan H M Schellens
PURPOSE: In tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours (NCT01636479). METHODS: In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible...
March 16, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28319526/anaplastic-variant-of-diffuse-large-b-cell-lymphoma-displays-intricate-genetic-alterations-and-distinct-biological-features
#4
Mingyang Li, Yixiong Liu, Yingmei Wang, Gang Chen, Qiongrong Chen, Hualiang Xiao, Fang Liu, Chubo Qi, Zhou Yu, Xia Li, Linni Fan, Ying Guo, Qingguo Yan, Shuangping Guo, Zhe Wang
Anaplastic diffuse large B-cell lymphoma (A-DLBCL) is a rare morphologic variant characterized by the presence of polygonal, bizarre-shaped tumor cells. However, the clinicopathologic and genetic features of this variant are largely unknown. In this study, we investigated 35 cases of A-DLBCL with regard to their clinical, pathologic, and genetic characteristics. The age of the patients ranged from 23 to 89 years (median age, 62 y) with a male to female ratio of 23:12. Twenty-two of 26 (85%) patients had Ann Arbor stage III or IV disease, and 17/26 (65%) patients had a high-intermediate or high International Prognostic Index score...
March 17, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28315428/p53-modulates-the-effect-of-ribosomal-protein-s6-kinase1-s6k1-on-cisplatin-toxicity-in-chronic-myeloid-leukemia-cells
#5
Ling-Yi Xiao, Wai-Ming Kan
Chronic myeloid leukemia (CML) is characterized by the expression of the oncoprotein, BCR-ABL. BCR-ABL inhibitors revolutionized CML chemotherapy while blast crisis (BC) CML patients are less responsive. Since suppression of ribosomal protein S6 kinase1 (S6K1) phosphorylation reverses the resistance to BCR-ABL inhibitor in CML cells and S6K1 inhibitors augment cisplatin toxicity in lung cancer cells, we speculated that combination of S6K1 inhibitor and cisplatin may be beneficial for eliminating BC CML cells...
March 14, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28303455/duodenal-cancer-in-a-young-patient-with-peuts-jeghers-syndrome-harboring-an-entire-deletion-of-the-stk11-gene
#6
Satoshi Teramae, Koichi Okamoto, Kumiko Tanaka, Reika Matsumoto, Shinji Kitamura, Tetsuo Kimura, Masahiro Sogabe, Hiroshi Miyamoto, Naoki Muguruma, Yoshimi Bando, Mitsuo Shimada, Tetsuji Takayama
A 21-year-old woman with Peuts-Jeghers syndrome (PJS) was referred to our hospital for gastrointestinal surveillance. She had been diagnosed as having PJS from a young age based on her family history and the presence of mucocutaneous pigmentation on her lips and oral mucosa. Her mother and brother had PJS harboring an entire deletion of the STK11 gene. She had tetralogy of Fallot, atrial tachycardia, sick sinus syndrome, and mental retardation in her past history. Esophagogastroduodenoscopy identified a protruded lesion with a depressed area that occupied the lumen half-circumferentially in the duodenal second portion and also showed a 10-mm protruded lesion on the anterior wall of the lower gastric body...
March 16, 2017: Clinical Journal of Gastroenterology
https://www.readbyqxmd.com/read/28302063/epigenetic-and-genetic-alterations-and-their-influence-on-gene-regulation-in-chronic-lymphocytic-leukemia
#7
Di Huang, Ivan Ovcharenko
BACKGROUND: To understand the changes of gene regulation in carcinogenesis, we explored signals of DNA methylation - a stable epigenetic mark of gene regulatory elements - and designed a computational model to profile loss and gain of regulatory elements (REs) during carcinogenesis. We also utilized sequencing data to analyze the allele frequency of single nucleotide polymorphisms (SNPs) and detected the cancer-associated SNPs, i.e., the SNPs displaying the significant allele frequency difference between cancer and normal samples...
March 16, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28299675/a-regulatory-role-for-runx1-runx3-in-the-maintenance-of-genomic-integrity
#8
Vaidehi Krishnan, Yoshiaki Ito
All human cells are constantly attacked by endogenous and exogenous agents that damage the integrity of their genomes. Yet, the ensuing damage is mostly fixed and very rarely gives rise to genomic defects that promote cancer formation. This is due to the co-ordinated functioning of DNA repair proteins and checkpoint mechanisms that accurately detect and repair DNA damage to ensure genomic fitness. According to accumulating evidence, the RUNX family of transcription factors participate in the maintenance of genomic stability through transcriptional and non-transcriptional mechanisms...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28297660/progesterone-prevents-high-grade-serous-ovarian-cancer-by-inducing-necroptosis-of-p53-defective-fallopian-tube-epithelial-cells
#9
Na-Yiyuan Wu, Hsuan-Shun Huang, Tung Hui Chao, Hsien Ming Chou, Chao Fang, Chong-Zhen Qin, Chueh-Yu Lin, Tang-Yuan Chu, Hong Hao Zhou
High-grade serous ovarian carcinoma (HGSOC) originates mainly from the fallopian tube (FT) epithelium and always carries early TP53 mutations. We previously reported that tumors initiate in the FT fimbria epithelium because of apoptotic failure and the expansion of cells with DNA double-strand breaks (DSB) caused by bathing of the FT epithelial cells in reactive oxygen species (ROSs) and hemoglobin-rich follicular fluid (FF) after ovulation. Because ovulation is frequent and HGSOC is rare, we hypothesized that luteal-phase progesterone (P4) could eliminate p53-defective FT cells...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28296564/azd1775-induces-toxicity-through-double-stranded-dna-breaks-independently-of-chemotherapeutic-agents-in-p53-mutated-colorectal-cancer-cells
#10
Peter John Webster, Anna Tiffany Littlejohns, Hannah Jane Gaunt, K Raj Prasad, David John Beech, Dermot Anthony Burke
AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 μM to 3.5 μM...
March 15, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28295252/meta-analysis-of-biomarkers-predicting-risk-of-malignant-progression-in-barrett-s-oesophagus
#11
REVIEW
K Altaf, J-J Xiong, D De la Iglesia, L Hickey, A Kaul
BACKGROUND: Barrett's oesophagus is a precursor to the development of oesophageal adenocarcinoma. This study sought to clarify the role of genetic, chromosomal and proliferation biomarkers that have been the subjects of multiple studies through meta-analysis. METHODS: MEDLINE, Embase, PubMed and the Cochrane Library were searched for clinical studies assessing the value of p53, p16, Ki-67 and DNA content abnormalities in Barrett's oesophagus. The main outcome measure was the risk of development of high-grade dysplasia (HGD) or oesophageal adenocarcinoma...
April 2017: British Journal of Surgery
https://www.readbyqxmd.com/read/28293986/clear-cell-change-in-thyroid-carcinoma-a-clinicopathologic-and-molecular-study-with-identification-of-variable-genetic-anomalies
#12
Nicole A Cipriani, Shweta Agarwal, Dora Dias-Santagata, William C Faquin, Peter M Sadow
Clear cell carcinoma of the thyroid has been regarded as a variant of follicular (FTC) or papillary (PTC) thyroid carcinoma. 21 primary thyroid carcinomas with clear cell features, diagnosed in 20 patients (12 female, 8 male) were identified between 1992 and 2012 (0.5% of in-house thyroid carcinomas). H&E slides were reviewed. SNaPshot multi-gene mutational analysis and a translocation panel were successfully performed on 15 of these cases. 12 (57%) were FTC, 5 were conventional PTC, 2 were follicular variant (FV) of PTC, and 2 were poorly differentiated thyroid carcinoma (PDTC)...
March 15, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28293485/a-long-term-survivor-of-metastatic-pancreatic-adenocarcinoma-free-of-recurrence-12-years-after-treatment-of-oligometastatic-disease
#13
John M Stahl, Zenta Walther, Bryan W Chang, Howard S Hochster, Kimberly L Johung
Aggressive local therapy for patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC) has traditionally not been pursued due to high rates of distant progression. We describe a 62-year-old male initially presenting with resectable PDAC who underwent the Whipple procedure but developed multiple liver metastases within two months of starting adjuvant gemcitabine. Oxaliplatin was added to the regimen and complete resolution of the liver lesions resulted. He remained disease-free for five years until re-staging revealed a small lung nodule...
February 2, 2017: Curēus
https://www.readbyqxmd.com/read/28292898/multisite-aggregation-of-p53-and-implications-for-drug-rescue
#14
GuoZhen Wang, Alan R Fersht
Protein aggregation is involved in many diseases. Often, a unique aggregation-prone sequence polymerizes to form regular fibrils. Many oncogenic mutants of the tumor suppressor p53 rapidly aggregate but form amorphous fibrils. A peptide surrounding Ile254 is proposed to be the aggregation-driving sequence in cells. We identified several different aggregating sites from limited proteolysis of harvested aggregates and effects of mutations on kinetics and products of aggregation. We present a model whereby the amorphous nature of the aggregates results from multisite branching of polymerization after slow unfolding of the protein, which may be a common feature of aggregation of large proteins...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28292017/-curine-induces-cell-cycle-arrest-and-cell-death-in-hepatocellular-carcinoma-cells-in-a-p53-independent-way
#15
Shu Gong, Dongsheng Xu, Fangdong Zou, Rui Peng
Hepatocellular carcinoma(HCC) is one of the most common malignancies worldwide, however, drug resistance is still a tough problem of it. As in many other cancers, p53 mutations are commonly observed in HCCs (Hussain et al., 2007; Levine et al., 1994) [1,2]. Tumor tissues with mutant p53 seems to be more aggressive and resist to chemotherapy than that harboring wide-type p53 (Harris and Hollstein, 1994; Parrales and Iwakuma, 2015) [3,4]. (-)-Curine, a novel bisbenzylisoquinoline alkaloid, is one of the main components isolated from the roots of Cyclea wattii...
March 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28291966/molecular-characteristics-of-pancreatic-ductal-adenocarcinomas-with-high-grade-pancreatic-intraepithelial-neoplasia-panin-are-different-from-those-without-high-grade-panin
#16
Tetsuyuki Miyazaki, Yoshihiro Ohishi, Yoshihiro Miyasaka, Yasunori Oda, Shinichi Aishima, Keigo Ozono, Atsushi Abe, Eishi Nagai, Masafumi Nakamura, Yoshinao Oda
AIMS: We reported that pancreatic ductal adenocarcinomas (PDACs) without high-grade pancreatic intraepithelial neoplasia (PanIN) in the vicinity had worse prognoses than PDACs with high-grade PanIN. However, the molecular characteristics of PDACs with and without high-grade PanIN have not been compared. The aim of this study is to clarify the molecular characteristics of PDACs with and without high-grade PanIN. METHOD AND RESULTS: We reviewed all of a consecutive series of 100 patients with PDACs and divided them into 2 groups: the PDACs with PanIN-2 or PanIN-3 in the background (the PanIN-high group, n = 60) and the PDACs without PanIN-2 or PanIN-3 in the background (the PanIN-low group, n = 40)...
March 15, 2017: Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28291250/site-to-site-interdomain-communication-may-mediate-different-loss-of-function-mechanisms-in-a-cancer-associated-nqo1-polymorphism
#17
Encarnación Medina-Carmona, Jose L Neira, Eduardo Salido, Julian E Fuchs, Rogelio Palomino-Morales, David J Timson, Angel L Pey
Disease associated genetic variations often cause intracellular enzyme inactivation, dysregulation and instability. However, allosteric communication of mutational effects to distant functional sites leading to loss-of-function remains poorly understood. We characterize here interdomain site-to-site communication by which a common cancer-associated single nucleotide polymorphism (c.C609T/p.P187S) reduces the activity and stability in vivo of NAD(P)H:quinone oxidoreductase 1 (NQO1). NQO1 is a FAD-dependent, two-domain multifunctional stress protein acting as a Phase II enzyme, activating cancer pro-drugs and stabilizing p53 and p73α oncosuppressors...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28290700/metabolic-response-to-everolimus-in-patient-derived-triple-negative-breast-cancer-xenografts
#18
Leslie R Euceda, Deborah K Hill, Endre Stokke, Rana Hatem, Rania El Botty, Ivan Bièche, Elisabetta Marangoni, Tone F Bathen, Siver A Moestue
Patients with triple negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n=103 animals)...
March 14, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28289249/control-of-cellular-aging-tissue-function-and-cancer-by-p53-downstream-of-telomeres
#19
Caitlin M Roake, Steven E Artandi
Telomeres, the nucleoprotein complex at the ends of eukaryotic chromosomes, perform an essential cellular role in part by preventing the chromosomal end from initiating a DNA-damage response. This function of telomeres can be compromised as telomeres erode either as a consequence of cell division in culture or as a normal part of cellular ageing in proliferative tissues. Telomere dysfunction in this context leads to DNA-damage signaling and activation of the tumor-suppressor protein p53, which then can prompt either cellular senescence or apoptosis...
March 13, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28289221/gentamicin-b1-is-a-minor-gentamicin-component-with-major-nonsense-mutation-suppression-activity
#20
Alireza Baradaran-Heravi, Jürgen Niesser, Aruna D Balgi, Kunho Choi, Carla Zimmerman, Andrew P South, Hilary J Anderson, Natalie C Strynadka, Marcel B Bally, Michel Roberge
Nonsense mutations underlie about 10% of rare genetic disease cases. They introduce a premature termination codon (PTC) and prevent the formation of full-length protein. Pharmaceutical gentamicin, a mixture of several related aminoglycosides, is a frequently used antibiotic in humans that can induce PTC readthrough and suppress nonsense mutations at high concentrations. However, testing of gentamicin in clinical trials has shown that safe doses of this drug produce weak and variable readthrough activity that is insufficient for use as therapy...
March 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
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