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https://www.readbyqxmd.com/read/28819183/distribution-bias-and-biochemical-characterization-of-top1mt-single-nucleotide-variants
#1
Hongliang Zhang, Yeonee Seol, Keli Agama, Keir C Neuman, Yves Pommier
Mitochondrial topoisomerase I (TOP1MT) is a type IB topoisomerase encoded in the nucleus of vertebrate cells. In contrast to the other five human topoisomerases, TOP1MT possesses two high frequency single nucleotide variants (SNVs), rs11544484 (V256I, Minor Allele Frequency = 0.27) and rs2293925 (R525W, MAF = 0.45), which tend to be mutually exclusive across different human ethnic groups and even more clearly in a cohort of 129 US patients with breast cancer and in the NCI-60 cancer cell lines. We expressed these two TOP1MT variants and the double-variant (V256I-R525W) as recombinant proteins, as well as a less common variant E168G (rs200673353, MAF = 0...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28816939/correlations-of-icam-1-gene-polymorphisms-with-susceptibility-and-multidrug-resistance-in-colorectal-cancer-in-a-chinese-population
#2
Lu-Bing Liu, Tong Liu, Fu-Ze Xin
BACKGROUND: Colorectal cancer (CRC) is a malignant gastrointestinal tumor with a high mortality rate, including both colon and rectal cancer. In order to provide clinical guidance for the treatment of CRC, this study is conducted to investigate the correlations of intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms with susceptibility and multidrug resistance (MDR) of colorectal cancer (CRC). METHODS: A total of 195 patients with CRC were selected as the observation group and 188 healthy people enrolled as the control group...
August 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28816792/development-of-secondary-acute-myeloid-leukemia-in-a-pediatric-patient-concurrently-receiving-primary-therapy-for-ewing-sarcoma
#3
Brandon R McNew, Benjamin W Darbro, Deqin Ma, David J Gordon
Ewing sarcoma is a pediatric bone and soft tissue sarcoma that requires intensive therapy, which can cause secondary malignancies. We present a rare case of early, treatment-related AML in a pediatric patient concurrently receiving primary therapy for Ewing sarcoma. Despite AML-directed therapy, our patient died secondary to complications of hyperleukocytosis. Cytogenetic and mutation profiling of the leukemia cells revealed the DNA-topoisomerase-II-inhibitor-associated t(9;11)(p22;q23) translocation and clonal KRAS and BRAF mutations...
August 14, 2017: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/28815403/overexpression-of-topoisomerase-2-alpha-confers-a-poor-prognosis-in-pancreatic-adenocarcinoma-identified-by-co-expression-analysis
#4
Zhou Zhou, Shi Liu, Meng Zhang, Rui Zhou, Jing Liu, Ying Chang, Qiu Zhao
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of human cancer-related death in the developed countries. Its progression and prognosis are influenced by a complex network of gene interactions. AIMS: The purpose of this study is to explore key genes associated with pancreatic ductal adenocarcinoma and to predict the possible mechanisms. METHODS: A weighted gene co-expression network was constructed to identify gene modules associated with the progression of PDAC...
August 16, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28815049/multi-target-chimaeric-vlp-as-a-therapeutic-vaccine-in-a-model-of-colorectal-cancer
#5
Braeden Donaldson, Farah Al-Barwani, Simon J Pelham, Katie Young, Vernon K Ward, Sarah L Young
BACKGROUND: Colorectal cancer is responsible for almost 700,000 deaths annually worldwide. Therapeutic vaccination is a promising alternative to conventional treatment for colorectal cancer, using vaccines to induce targeted immune responses against tumour-associated antigens. In this study, we have developed chimaeric virus-like particles (VLP), a form of non-infectious non-replicative subunit vaccine consisting of rabbit haemorrhagic disease virus (RHDV) VP60 capsid proteins containing recombinantly inserted epitopes from murine topoisomerase IIα and survivin...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28814752/oncofetal-hmga2-effectively-curbs-unconstrained-and-dna-supercoiling
#6
Xiaodan Zhao, Sabrina Peter, Peter Dröge, Jie Yan
HMGA2 belongs to the family of the high mobility group (HMG) proteins. It binds DNA via three AT-hook domains to the minor groove of adenine-thymine (AT) rich DNA. Recently, a new function of HMGA2 as a replication fork chaperone that protects stem and cancer cells from replication fork collapse induced by chemotherapeutic agents was uncovered, suggesting a previously uncharacterized binding at replication forks. In this study, we examined HMGA2 binding to four DNA structures relevant to replication forks, namely ds DNA, ss DNA, forked DNA and supercoiled DNA plectonemes...
August 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28813519/expression-and-inhibition-of-brd4-ezh2-and-top2a-in-neurofibromas-and-malignant-peripheral-nerve-sheath-tumors
#7
Azadeh Amirnasr, Rob M Verdijk, Patricia F van Kuijk, Walter Taal, Stefan Sleijfer, Erik A C Wiemer
Malignant peripheral nerve sheath tumors (MPNST) are rare, highly aggressive sarcomas that can occur spontaneously or from pre-existing plexiform neurofibromas in neurofibromatosis type1 (NF1) patients. MPNSTs have high local recurrence rates, metastasize easily, are generally resistant to therapeutic intervention and frequently fatal for the patient. Novel targeted therapeutic strategies are urgently needed. Standard treatment for patients presenting with advanced disease is doxorubicin based chemotherapy which inhibits the actions of the enzyme topoisomerase IIα (TOP2A)...
2017: PloS One
https://www.readbyqxmd.com/read/28806910/multi-target-chimaeric-vlp-as-a-therapeutic-vaccine-in-a-model-of-colorectal-cancer
#8
Braeden Donaldson, Farah Al-Barwani, Simon J Pelham, Katie Young, Vernon K Ward, Sarah L Young
BACKGROUND: Colorectal cancer is responsible for almost 700,000 deaths annually worldwide. Therapeutic vaccination is a promising alternative to conventional treatment for colorectal cancer, using vaccines to induce targeted immune responses against tumour-associated antigens. In this study, we have developed chimaeric virus-like particles (VLP), a form of non-infectious non-replicative subunit vaccine consisting of rabbit haemorrhagic disease virus (RHDV) VP60 capsid proteins containing recombinantly inserted epitopes from murine topoisomerase IIα and survivin...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28802254/tdp1-is-critical-for-the-repair-of-dna-breaks-induced-by-sapacitabine-a-nucleoside-also-targeting-atm-and-brca-deficient-tumors
#9
Muthana Al Abo, Hiroyuki Sasanuma, Xiaojun Liu, Vinodh N Rajapakse, Shar-Yin N Huang, Evgeny Kiselev, Shunichi Takeda, William Plunkett, Yves Pommier
2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes beta-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes non-phosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1-/- DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC...
August 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28797568/the-combination-of-a-966492-and-topotecan-for-effective-radiosensitization-on-glioblastoma-spheroids
#10
Fereshteh Koosha, Ali Neshasteh-Riz, Abbas Takavar, Nazila Eyvazzadeh, Zohreh Mazaheri, Samira Eynali, Mehdi Mousavi
Radiotherapy is one of the modalities in the treatment of glioblastoma patients, but glioma tumors are resistant to radiation and also chemotherapy drugs. Thus, researchers are investigating drugs which have radiosensitization capabilities in order to improve radiotherapy. PARP enzymes and topoisomerase I enzymes have a critical role in repairing DNA damage in tumor cells. Thus, inhibiting activity of these enzymes helps stop DNA damage repair and increase DSB lethal damages. In the current study, we investigated the combination of TPT as a topoisomerase I inhibitor, and A-966492 as a novel PARP inhibitor for further radiosensitization...
August 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28794467/tdp2-suppresses-chromosomal-translocations-induced-by-dna-topoisomerase-ii-during-gene-transcription
#11
Fernando Gómez-Herreros, Guido Zagnoli-Vieira, Ioanna Ntai, María Isabel Martínez-Macías, Rhona M Anderson, Andrés Herrero-Ruíz, Keith W Caldecott
DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation 'hotspot', MLL...
August 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28782777/an-efficient-one-pot-approach-for-the-regio-and-diastereoselective-synthesis-of-trans-dihydrofuran-derivatives-cytotoxicity-and-dna-binding-studies
#12
Yellaiah Tangella, Kesari Lakshmi Manasa, V Laxma Nayak, Manda Sathish, B Sridhar, Abdullah Alarifi, Narayana Nagesh, Ahmed Kamal
An operationally facile and high yielding one-pot, three-component protocol has been developed for the preparation of selectively trans-2,3-dihydrofuro[3,2-c]coumarins and trans-1,2-dihydrobenzo[h]furo[3,2-c]quinolinones. This protocol proceeds through a domino Knoevenagel condensation, a Michael addition followed by intramolecular SN2 cyclisation. All the synthesized compounds have been evaluated for their in vitro cytotoxic activity against selected human cancer cell lines. Interestingly, most of the compounds have exhibited considerable cytotoxicity with IC50 values <10 μM in all the tested cell lines...
August 16, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28774614/investigation-of-nuclear-enzyme-topoisomerase-as-a-putative-molecular-target-of-monohaloacetonitrile-disinfection-by-products
#13
Yukako Komaki, Michael J Plewa
Disinfection by-products occur widely as the unintended effect of water disinfection and are associated with toxicity and adverse human health effects. Yet the molecular mechanisms of their toxicity are not well understood. To investigate the molecular basis of hyperploidy induction by monohaloacetonitriles, the interaction of monohaloacetonitriles with topoisomerase II in Chinese hamster ovary cells was examined. We showed a concentration-dependent inhibition of DNA decatenation activity of topoisomerase under acellular conditions while in vitro monohaloacetonitrile treatment expressed mixed results...
August 2017: Journal of Environmental Sciences (China)
https://www.readbyqxmd.com/read/28771333/highly-cytotoxic-palladium-ii-pincer-complexes-based-on-picolinylamides-functionalized-with-amino-acids-bearing-ancillary-s-donor-groups
#14
Svetlana G Churusova, Diana V Aleksanyan, Ekaterina Yu Rybalkina, Olga Yu Susova, Valentina V Brunova, Rinat R Aysin, Yulia V Nelyubina, Alexander S Peregudov, Evgenii I Gutsul, Zinaida S Klemenkova, Vladimir A Kozlov
The reactions of picolinyl and 4-chloropicolinyl chlorides with methyl esters of S-methyl-l-cysteine, l- and d-methionine, and l-histidine afforded a series of functionalized carboxamides, which readily formed pincer-type complexes upon interaction with PdCl2(NCPh)2 in solution under mild conditions. The direct cyclopalladation of the ligands derived was also accomplished in the solid phase, in particular, mechanochemically, although it was complicated by the partial deactivation of the starting amides. The resulting complexes with 5,5- and 5,6-membered fused metallocycles were fully characterized by IR and NMR spectroscopy, including variable-temperature and 2D-NMR studies...
August 3, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28765160/genome-integrity-and-disease-prevention-in-the-nervous-system
#15
REVIEW
Peter J McKinnon
Multiple DNA repair pathways maintain genome stability and ensure that DNA remains essentially unchanged over the life of a cell. Various human diseases occur if DNA repair is compromised, and most of these impact the nervous system, in some cases exclusively. However, it is often unclear what specific endogenous damage underpins disease pathology. Generally, the types of causative DNA damage are associated with replication, transcription, or oxidative metabolism; other direct sources of endogenous lesions may arise from aberrant topoisomerase activity or ribonucleotide incorporation into DNA...
June 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28760966/neuronal-cytoskeletal-gene-dysregulation-and-mechanical-hypersensitivity-in-a-rat-model-of-rett-syndrome
#16
Aritra Bhattacherjee, Ying Mu, Michelle K Winter, Jennifer R Knapp, Linda S Eggimann, Sumedha S Gunewardena, Kazuto Kobayashi, Shigeki Kato, Dora Krizsan-Agbas, Peter G Smith
Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced...
August 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28760107/exploring-the-binding-interaction-of-potent-anticancer-drug-topotecan-with-human-serum-albumin-spectroscopic-calorimetric-and-fibrillation-study
#17
Asma Yasmeen Khan, Gopinatha Suresh Kumar
This manuscript describes the interaction of the topoisomerase I inhibitor anticancer drug topotecan with human serum albumin using microcalorimetry, circular dichroism, and atomic force microscopy imaging techniques. Conformational change in albumin was ascertained from circular dichroism and synchronous fluorescence study that revealed a small but definitive partial unfolding of the protein structure upon drug binding. Isothermal titration calorimetry study indicated a favorable exothermic interaction with a binding affinity of the order of ~10(5) M(-1) at 293...
August 7, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28757138/early-life-antibiotic-exposure-causes-intestinal-dysbiosis-and-exacerbates-skin-and-lung-pathology-in-experimental-systemic-sclerosis
#18
Heena Mehta, Philippe-Olivier Goulet, Shunya Mashiko, Jade Desjardins, Gemma Pérez, Martial Koenig, Jean-Luc Senécal, Marco Constante, Manuela M Santos, Marika Sarfati
Patients with systemic sclerosis (SSc) display altered intestinal microbiota. However, the influence of intestinal dysbiosis on development of experimental SSc remains unknown. Topoisomerase I peptide-loaded dendritic cells (TOPOIA DCs) immunization induces SSc-like disease, with progressive skin and lung fibrosis. Breeders were given streptomycin and pups continued to receive antibiotic (ATB) until endpoint (lifelongATB). Alternately, ATB was withdrawn (earlyATB) or initiated (adultATB) during adulthood. TOPOIA DCs (no ATB) immunization induced pronounced skin fibrosis, with increased matrix (Col1a1), pro-fibrotic (Il13, Tweakr) and vascular function (Serpine1) gene expression...
July 27, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28755093/her2-and-top2a-gene-amplification-and-protein-expression-in-upper-tract-urothelial-carcinomas
#19
Klaus Aumayr, Tobias Klatte, Barbara Neudert, Peter Birner, Shahrokh Shariat, Manuela Schmidinger, Martin Susani, Andrea Haitel
HER2, a potential target for therapy, has been described to be amplified in urothelial carcinomas. As the topoisomerase II alpha (TOP2A) gene is located close to the HER2 gene on chromosome 17q12-q21, it is frequently either co-amplified or deleted with HER2 amplification. The purpose of this study was to assess the impact HER2 and TOP2A gene amplification as well as protein expression on outcomes of upper tract urothelial carcinoma (UTUC). HER2 and TOP2A gene amplification and protein expression were assessed in 81 patients with radical nephroureterectomy for UTUC...
July 28, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28753517/design-synthesis-and-antiproliferative-activity-of-decarbonyl-luotonin-analogues
#20
Abdulrahman I Almansour, Natarajan Arumugam, Raju Suresh Kumar, S M Mahalingam, Samaresh Sau, Giulia Bianchini, J Carlos Menéndez, Mohammad Altaf, Hazem A Ghabbour
A small library of benzimidazole-fused pyrrolo[3,4-b]quinoline has been synthesized from readily available benzimidazole 2-carbaldehyde and various substituted arylamines in good to excellent yields utilizing an intramolecular Povarov reaction catalyzed by boron trifluoride diethyl etharate as the key final step. The compounds thus synthesized can be considered as decarbonyl analogues of the anticancer alkaloid luotonin A and were evaluated in a DNA relaxation assay for their ability to inhibit human topoisomerase I...
July 18, 2017: European Journal of Medicinal Chemistry
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