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https://www.readbyqxmd.com/read/29158830/sustained-release-talazoparib-implants-for-localized-treatment-of-brca1-deficient-breast-cancer
#1
Jodi E Belz, Rajiv Kumar, Paige Baldwin, Noelle Castilla Ojo, Ana S Leal, Darlene B Royce, Di Zhang, Anne L van de Ven, Karen T Liby, Srinivas Sridhar
Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0...
2017: Theranostics
https://www.readbyqxmd.com/read/29158318/cisplatin-induces-the-release-of-extracellular-vesicles-from-ovarian-cancer-cells-that-can-induce-invasiveness-and-drug-resistance-in-bystander-cells
#2
Priya Samuel, Laura Ann Mulcahy, Fiona Furlong, Helen O McCarthy, Susan Ann Brooks, Muller Fabbri, Ryan Charles Pink, David Raul Francisco Carter
Ovarian cancer has a poor overall survival that is partly caused by resistance to drugs such as cisplatin. Resistance can be acquired as a result of changes to the tumour or due to altered interactions within the tumour microenvironment. Extracellular vesicles (EVs), small lipid-bound vesicles that are loaded with macromolecular cargo and released by cells, are emerging as mediators of communication in the tumour microenvironment. We previously showed that EVs mediate the bystander effect, a phenomenon in which stressed cells can communicate with neighbouring naive cells leading to various effects including DNA damage; however, the role of EVs released following cisplatin treatment has not been tested...
January 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29157102/chk1-inhibitor-sch-900776-enhances-the-antitumor-activity-of-mln4924-on-pancreatic-cancer
#3
Jian-Ang Li, Chao Song, Yefei Rong, Tiantao Kuang, Dansong Wang, Xuefeng Xu, Jian Yuan, Kuntian Luo, Bo Qin, Somaira Nowsheen, Zhenkun Lou, Wenhui Lou
MLN4924 inhibits the cullin-RING ligases mediated ubiquitin-proteasome system, and has showed antitumor activities in preclinical studies, but its effects and mechanisms on pancreatic cancer (PC) remains elusive. We found that MLN4924 inhibited the proliferation and clonogenicity of PC cells, caused DNA damage, particularly double-strand breaks, and leaded to Chk1 activation and cell-cycle arrest. Chk1 inhibitor SCH 900776 alone exhibited minimal cytotoxicity, and caused no DNA damage on PC cells. But in the combination therapy, SCH 900776 enhanced the cytotoxicity and DNA damage caused by MLN4924, likely by abrogating G2/M arrest and promoting DNA re-replication...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29157079/zeb1-inhibition-sensitizes-cells-to-the-atr-inhibitor-ve-821-by-abrogating-epithelial-mesenchymal-transition-and-enhancing-dna-damage
#4
Na Song, Wei Jing, Ce Li, Ming Bai, Yu Cheng, Heming Li, Kezuo Hou, Yanrong Li, Kai Wang, Zhi Li, Yunpeng Liu, Xiujuan Qu, Xiaofang Che
The ataxia-telangiectasia-mutated (ATM) and rad3-related (ATR) checkpoint pathway plays an essential role in modulating cellular responses to replication stress and DNA damage to maintain genomic stability. In various tumors, cancer cells have increased dependence on ATR signaling for survival, making ATR a promising target for cancer therapy. ATR inhibitors sensitize multiple tumor cell types to radiation and DNA-damaging agents, but application of an ATR inhibitor alone shows limited efficacy. In the present study, we investigated the role of epithelial-to-mesenchymal transition (EMT) and the EMT transcription factor ZEB1 in regulating cell sensitivity to the ATR inhibitor VE-821...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29156910/genetic-biomarkers-associated-with-changes-in-quality-of-life-and-pain-following-palliative-radiotherapy-in-patients-with-bone-metastases
#5
Anthony Furfari, Bo Angela Wan, Keyue Ding, Andrew Wong, Liting Zhu, Andrea Bezjak, Rebecca Wong, Carolyn F Wilson, Carlo DeAngelis, Azar Azad, Edward Chow, George S Charames
BACKGROUND: Patients with bone metastases undergoing palliative radiation therapy (RT) may experience changes in both the functional and symptomatic aspects of quality of life (QOL). The European Organization of Cancer Research and Treatment (EORTC) QOL Questionnaire Core-15 Palliative (QLQ-C15-PAL) is a validated questionnaire employed to assess QOL specifically in palliative patients. Our study aimed to identify single-nucleotide variant (SNV) genetic biomarkers associated with changes in QOL and pain...
September 28, 2017: Annals of Palliative Medicine
https://www.readbyqxmd.com/read/29156909/genetic-biomarkers-associated-with-response-to-palliative-radiotherapy-in-patients-with-painful-bone-metastases
#6
Anthony Furfari, Bo Angela Wan, Keyue Ding, Andrew Wong, Liting Zhu, Andrea Bezjak, Rebecca Wong, Carolyn F Wilson, Carlo DeAngelis, Azar Azad, Edward Chow, George S Charames
BACKGROUND: Palliative radiotherapy (RT) is effective in patients with painful bone metastases. Genetic factors may identify subgroup of patients who responded to RT. To identify DNA biomarkers associated with response to palliative RT. METHODS: Patients who received a single 8 Gy dose of RT for painful bone metastases were categorised into responders (n=36), non-responders (NR) (n=71). Saliva samples were sequenced to identify single-nucleotide variants (SNVs) in genes with known disease-causing variants from inflammation, radiation response, and DNA damage pathways...
October 10, 2017: Annals of Palliative Medicine
https://www.readbyqxmd.com/read/29156836/the-role-of-rak-in-the-regulation-of-stability-and-function-of-brca1
#7
Jung-Lye Kim, Geun-Hyoung Ha, Loredana Campo, Mitchell F Denning, Tarun B Patel, Clodia Osipo, Shiaw-Yih Lin, Eun-Kyoung Breuer
BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156796/downregulation-of-dna-repair-proteins-and-increased-dna-damage-in-hypoxic-colon-cancer-cells-is-a-therapeutically-exploitable-vulnerability
#8
Jennifer M J Jongen, Lizet M van der Waals, Kari Trumpi, Jamila Laoukili, Niek A Peters, Susanne J Schenning-van Schelven, Klaas M Govaert, Inne H M Borel Rinkes, Onno Kranenburg
Surgical removal of colorectal cancer (CRC) liver metastases generates areas of tissue hypoxia. Hypoxia imposes a stem-like phenotype on residual tumor cells and promotes tumor recurrence. Moreover, in primary CRC, gene expression signatures reflecting hypoxia and a stem-like phenotype are highly expressed in the aggressive Consensus Molecular Subtype 4 (CMS4). Therapeutic strategies eliminating hypoxic stem-like cells may limit recurrence following resection of primary tumors or metastases. Here we show that expression of DNA repair genes is strongly suppressed in CMS4 and inversely correlated with hypoxia-inducible factor-1 alpha (HIF1α) and HIF-2α co-expression signatures...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156764/the-neil1-g83d-germline-dna-glycosylase-variant-induces-genomic-instability-and-cellular-transformation
#9
Heather A Galick, Carolyn G Marsden, Scott Kathe, Julie A Dragon, Lindsay Volk, Antonia A Nemec, Susan S Wallace, Aishwarya Prakash, Sylvie Doublié, Joann B Sweasy
Base excision repair (BER) is a key genome maintenance pathway. The NEIL1 DNA glycosylase recognizes oxidized bases, and likely removes damage in advance of the replication fork. The rs5745906 SNP of the NEIL1 gene is a rare human germline variant that encodes the NEIL1 G83D protein, which is devoid of DNA glycosylase activity. Here we show that expression of G83D NEIL1 in MCF10A immortalized but non-transformed mammary epithelial cells leads to replication fork stress. Upon treatment with hydrogen peroxide, we observe increased levels of stalled replication forks in cells expressing G83D NEIL1 versus cells expressing the wild-type (WT) protein...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156754/functional-characterization-of-a-novel-transcript-of-ercc1-in-chemotherapy-resistance-of-ovarian-cancer
#10
Jia Liu, Lin Zhang, Ping Mao, Guoqiang Jiang, Likun Liu, Jing Wang, Wei Yang, Lawrence Owusu, Weiling Li
Approximately 15-20% of ovarian cancer patients receiving platinum-based chemotherapy are primary platinum-resistant. Identification of these patients and transfer to other more effective therapy could reduce the morbidity of ovarian cancer. ERCC1 is a DNA repair gene which can complex with XPF to repair cisplatin-induced DNA damage and cause chemotherapy resistance. In this study, we found a novel ERCC1 transcript initiated upstream of the normal transcription initiation site. The expression of this larger ERCC1 transcript dramatically increased following cisplatin treatment in ovarian cancer cells and was regulated by the MAPK pathway...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156686/crosstalk-between-mismatch-repair-and-base-excision-repair-in-human-gastric-cancer
#11
Valeria Simonelli, Giuseppe Leuzzi, Giorgia Basile, Mariarosaria D'Errico, Paola Fortini, Annapaola Franchitto, Valentina Viti, Ashley R Brown, Eleonora Parlanti, Barbara Pascucci, Domenico Palli, Alessandro Giuliani, Fabio Palombo, Robert W Sobol, Eugenia Dogliotti
DNA repair gene expression in a set of gastric cancers suggested an inverse association between the expression of the mismatch repair (MMR) gene MLH1 and that of the base excision repair (BER) gene DNA polymerase β (Polβ). To gain insight into possible crosstalk of these two repair pathways in cancer, we analysed human gastric adenocarcinoma AGS cells over-expressing Polβ or Polβ active site mutants, alone or in combination with MLH1 silencing. Next, we investigated the cellular response to the alkylating agent methyl methanesulfonate (MMS) and the purine analogue 6-thioguanine (6-TG), agents that induce lesions that are substrates for BER and/or MMR...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156680/vemurafenib-resistance-via-de-novo-rbm-genes-mutations-and-chromosome-5-aberrations-is-overcome-by-combined-therapy-with-palbociclib-in-thyroid-carcinoma-with-braf-v600e
#12
Zeus A Antonello, Nancy Hsu, Manoj Bhasin, Giovanni Roti, Mukta Joshi, Paul Van Hummelen, Emily Ye, Agnes S Lo, S Ananth Karumanchi, Christine R Bryke, Carmelo Nucera
Purpose: Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAF(V600E) represents the PTC hallmark and is targeted with selective inhibitors (e.g. vemurafenib). Although there have been promising results in clinical trials using these inhibitors, most patients develop resistance and progress. Tumor clonal diversity is proposed as one mechanism underlying drug resistance. Here we have investigated mechanisms of primary and secondary resistance to vemurafenib in BRAF(WT/V600E)-positive PTC patient-derived cells with P16(-/-) (CDKN2A(-/-))...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156675/glioblastoma-and-glioblastoma-stem-cells-are-dependent-on-functional-mth1
#13
Linda Pudelko, Pegah Rouhi, Kumar Sanjiv, Helge Gad, Christina Kalderén, Andreas Höglund, Massimo Squatrito, Alberto J Schuhmacher, Steven Edwards, Daniel Hägerstrand, Ulrika Warpman Berglund, Thomas Helleday, Lars Bräutigam
Glioblastoma multiforme (GBM) is an aggressive form of brain cancer with poor prognosis. Cancer cells are characterized by a specific redox environment that adjusts metabolism to its specific needs and allows the tumor to grow and metastasize. As a consequence, cancer cells and especially GBM cells suffer from elevated oxidative pressure which requires antioxidant-defense and other sanitation enzymes to be upregulated. MTH1, which degrades oxidized nucleotides, is one of these defense enzymes and represents a promising cancer target...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156531/heated-naringin-mitigate-the-genotoxicity-effect-of-mitomycin-c-in-balb-c-mice-through-enhancing-the-antioxidant-status
#14
Mouna Maatouk, Nadia Mustapha, Imen Mokdad-Bzeouich, Hind Chaaban, Irina Ioannou, Kamel Ghedira, Mohamed Ghoul, Leila Chekir-Ghedira
A major problem with cancer chemotherapy is its severe toxic effects on non-target tissues. Assessment of natural products for their protective effect against anticancer drugs induced toxicity is gaining importance in cancer biology. The aim of the present study was to evaluate the effect of native and thermal treated naringin on the protective effect against mitomycin C (MMC) induced genotoxicity. The genotoxicity in liver kidney and brain cells isolated from Balb/C mice were evaluated by performing the comet assay...
November 15, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29155820/mass-spectrometry-based-quantification-of-the-cellular-response-to-ultraviolet-radiation-in-hela-cells
#15
Hong Xu, Xuanyi Chen, Nanjiao Ying, Meixia Wang, Xiaoli Xu, Rongyi Shi, Yuejin Hua
Ultraviolet (UV) irradiation is a common form of DNA damage that can cause pyrimidine dimers between DNA, which can cause gene mutations, even double-strand breaks and threaten genome stability. If DNA repair systems default their roles at this stage, the organism can be damaged and result in disease, especially cancer. To better understand the cellular response to this form of damage, we applied highly sensitive mass spectrometry to perform comparative proteomics of phosphorylation in HeLa cells. A total of 4367 phosphorylation sites in 2100 proteins were identified, many of which had not been reported previously...
2017: PloS One
https://www.readbyqxmd.com/read/29155239/mechanisms-controlling-the-anti-neoplastic-functions-of-foxo-proteins
#16
REVIEW
Tianyun Hou, Zhiming Li, Ying Zhao, Wei-Guo Zhu
The Forkhead box O (FoxO) proteins comprise a family of evolutionarily conserved transcription factors that predominantly function as tumor suppressors. These proteins assume diverse roles in the cellular anti-neoplastic response, including regulation of apoptosis and autophagy, cancer metabolism, cell-cycle arrest, oxidative stress and the DNA damage response. More recently, FoxO proteins have been implicated in cancer immunity and cancer stem-cell (CSC) homeostasis. Interestingly, in some sporadic sub-populations, FoxO protein function may also be manipulated by factors such as β-catenin whereby they instead can facilitate cancer progression via maintenance of CSC properties or promoting drug resistance or metastasis and invasion...
November 18, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29152614/ataxia-telangiectasia-mutated-kinase-role-in-myocardial-remodeling
#17
Patsy Thrasher, Mahipal Singh, Krishna Singh
Ataxia-telangiectasia mutated kinase (ATM) is a serine/threonine kinase. Mutations in the ATM gene cause a rare autosomal multisystemic disease known as Ataxia-telangiectasia (AT). Individuals with mutations in both copies of the ATM gene suffer from increased susceptibility to ionizing radiation, predisposition to cancer, insulin resistance, immune deficiency, and premature aging. Patients with one mutated allele make-up ~1.4 to 2% of the general population. These individuals are spared from most of the symptoms of the disease...
2017: Journal of Rare Diseases Research & Treatment
https://www.readbyqxmd.com/read/29152229/ticking-time-bombs-connections-between-circadian-clocks-and-cancer
#18
REVIEW
Katja A Lamia
Connections between mammalian circadian and cell division cycles have been postulated since the early 20th century, and epidemiological and genetic studies have linked disruption of circadian clock function to increased risk of several types of cancer. In the past decade, it has become clear that circadian clock components influence cell growth and transformation in a cell-autonomous manner. Furthermore, several molecular mechanistic connections have been described in which clock proteins participate in sensing DNA damage, modulating DNA repair, and influencing the ubiquitination and degradation of key players in oncogenesis (c-MYC) and tumor suppression (p53)...
2017: F1000Research
https://www.readbyqxmd.com/read/29150967/drug-delivery-strategies-for-chemoprevention-of-uvb%C3%A2-induced-skin-cancer-a-review
#19
REVIEW
Arvind Bagde, Arindam Mondal, Mandip Singh
Annually, more skin cancer cases are diagnosed than the collective incidence of the colon, lung, breast and prostate cancer. Persistent contact with sunlight is a primary cause for all the skin malignancies. UVB radiation induces reactive oxygen species (ROS) production in the skin which eventually leads to DNA damage and mutation. Various delivery approaches for the skin cancer treatment/prevention have been evolving and are directed towards improvements in terms of delivery modes, therapeutic agents and site-specificity of therapeutics delivery...
November 18, 2017: Photodermatology, Photoimmunology & Photomedicine
https://www.readbyqxmd.com/read/29150876/toxicological-characterization-of-zno-nanoparticles-in-malignant-and-non-malignant-cells
#20
Helena Moratin, Agmal Scherzad, Thomas Gehrke, Pascal Ickrath, Katrin Radeloff, Norbert Kleinsasser, Stephan Hackenberg
The increasing usage of zinc oxide nanoparticles (ZnO-NPs) in industrial applications as well as in consumer products raises concern regarding their potential adverse effects to a greater extend. Numerous studies have demonstrated toxic properties of NPs, however there is still a lack of knowledge concerning the underlying mechanisms. This study was designed to systematically investigate cytotoxicity, apoptosis, cell cycle alterations, and genotoxicity induced by ZnO-NP. Moreover, it was an aim of the investigations to specify the diverse effects of nanoparticle exposure in malignant in comparison with non-malignant cells...
November 18, 2017: Environmental and Molecular Mutagenesis
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