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Julia Higelin, Alberto Catanese, Lena Luisa Semelink-Sedlacek, Sertap Oeztuerk, Anne-Kathrin Lutz, Julia Bausinger, Gotthold Barbi, Günter Speit, Peter M Andersen, Albert C Ludolph, Maria Demestre, Tobias M Boeckers
Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction...
June 12, 2018: Stem Cell Research
Shijia Wang, Yue Zhang, Min Chen, Yong Wang, Yifei Feng, Ziwei Xu, Dongsheng Zhang, Yueming Sun, Zan Fu
Objective: The ATR-CHEK1 and ATM-CHEK2 pathway have been confirmed to be related with the DNA damage response (DDR). Many studies have reported that genetic variants in ATR/CHEK1 and ATM/CHEK2 are associated with cancer risk. However, the association between genetic variants in ATR-CHEK1, ATM-CHEK2 pathway genes and colorectal cancer susceptibility is still unknown. In this study, we aim to explore whether these variants are correlated with the risk of colorectal cancer in a Chinese population...
June 1, 2018: Oncotarget
Minwen Zhu, Wei Liu, Linjun Shi, Xuan Xiao, Wenyan Wu, Lan Wu, Zengtong Zhou
The present study assessed the expression of the DNA doublestrand repair (DDR) proteins ATM serine/threonine kinase (ATM), checkpoint kinase 2 (CHEK2) and γH2A histone family member X (γH2AFX) in oral leukoplakia (OL) and evaluated their clinical significance and usefulness as biomarkers for predicting OL transformation. Retrospectively, ATM, CHEK2 and γH2AFX protein levels were evaluated using immunohistochemical analysis in 61 OL, 33 oral squamous cell carcinoma (OSCC) and 15 normal oral mucosa tissues...
June 2018: Oncology Letters
Mary Ellen Gee, Zahra Faraahi, Aiste McCormick, Richard J Edmondson
Treatment for advanced ovarian cancer is rarely curative; three quarters of patients with advanced disease relapse and ultimately die with resistant disease. Improving patient outcomes will require the introduction of new treatments and better patient selection. Abrogations in the DNA damage response (DDR) may allow such stratifications.A defective DNA-damage response (DDR) is a defining hallmark of high grade serous ovarian cancer (HGSOC). Indeed, current evidence indicates that all HGSOCs harbour a defect in at least one major DDR pathway...
June 20, 2018: Journal of Ovarian Research
Eva Bártová, Soňa Legartová, Jana Krejčí, Petra Řezníčková, Alena Svobodová Kovaříková, Jana Suchánková, Radek Fedr, Evgeny Smirnov, Matúš Hornáček, Ivan Raška
We studied how deficiency in lamins A/C and lamina-associated polypeptide 2α (Lap2α) affects DNA repair after irradiation. A-type lamins and Lap2α were not recruited to local DNA lesions and did not accumulate to γ-irradiation-induced foci (IRIF), as it is generally observed for well-known marker of DNA lesions, 53BP1 protein. At micro-irradiated chromatin of lmna double knockout (dn) and Lap2α dn cells, 53BP1 protein levels were reduced, compared to locally irradiated wild-type counterpart. Decreased levels of 53BP1 we also observed in whole populations of lmna dn and Lap2α dn cells, irradiated by UV light...
June 19, 2018: Journal of Cellular Biochemistry
Safder S Ganaie, Jianming Qiu
Parvovirus B19 (B19V) is pathogenic to humans and causes bone marrow failure diseases and various other inflammatory disorders. B19V infection exhibits high tropism for human erythroid progenitor cells (EPCs) in the bone marrow and fetal liver. The exclusive restriction of B19V replication to erythroid lineage cells is partly due to the expression of receptor and co-receptor(s) on the cell surface of human EPCs and partly depends on the intracellular factors essential for virus replication. We first summarize the latest developments in the viral entry process and the host cellular factors or pathways critical for B19V replication...
2018: Frontiers in Cellular and Infection Microbiology
Rawan S Olayan, Haitham Ashoor, Vladimir B Bajic
No abstract text is available yet for this article.
June 15, 2018: Bioinformatics
Dario Palmieri, Anna Tessari, Vincenzo Coppola
The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, cells activate complex and still not fully understood mechanisms, leading to a complete proliferative arrest or cell death. Several conventional and novel anti-neoplastic treatments rely on causing DNA damage or on the inhibition of the DDR in cancer cells...
June 17, 2018: International Journal of Molecular Sciences
Zachary Kornberg, Jonathan Chou, Felix Y Feng, Charles J Ryan
Data from recent high-throughput studies analyzing local and advanced prostate cancer have revealed an incredible amount of biological diversity, which has led to the classification of distinct molecular tumor subtypes. While integrating prostate cancer genomics with clinical medicine is still at its infancy, new approaches to treat prostate cancer are well underway and being studied. With the recognition that DNA damage repair (DDR) mutations play an important role in the pathogenesis of this disease, clinicians can begin to utilize genomic information in complex treatment decisions for prostate cancer patients...
May 2018: Annals of Translational Medicine
Tingting Li, Jin'e Liu, Hao Cai, Baomei Wang, Yunfeng Feng, Jun Liu
Cell-matrix interactions play critical roles in cell adhesion, tissue remodeling and cancer metastasis. Discoidin domain receptor 2 (DDR2) is a collagen receptor belonging to receptor tyrosine kinase (RTK) family. It is a powerful regulator of collagen deposition in the extracellular matrix (ECM). Although the oligomerization of DDR extracellular domain (ECD) proteins can affect matrix remodeling by inhibiting fibrillogenesis, it is still unknown how cellular DDR2 is incorporated into collagen matrix. Using 3-dimentional (3D) imaging for migrating cells, we identified a novel mechanism that explains how DDR2 incorporating into collagen matrix, which we named as posterior remnant tethering...
2018: International Journal of Biological Sciences
Patricia Richard, Koichi Ogami, Yaqiong Chen, Shuang Feng, James J Moresco, John R Yates, James L Manley
The RNA helicase Mtr4 is a versatile protein that is a crucial component of several distinct RNA surveillance complexes. Here we describe a novel complex that contains Mtr4, but has a role distinct from any of those previously described. We found that Mtr4 association with the human homolog of fission yeast Nrl1, NRDE-2, defines a novel function for Mtr4 in the DNA damage response (DDR) pathway. We provide biochemical evidence that Mtr4 and NRDE-2 are part of the same complex and show that both proteins play a role in the DDR by maintaining low DNA double-strand break levels...
June 14, 2018: RNA Biology
Ananda Mukherjee, Amanda L Patterson, Jitu W George, Tyler J Carpenter, Zachary B Madaj, Galen Hostetter, John I Risinger, Jose M Teixeira
Endometrial adenocarcinoma (EndoCA) is the most common gynecological cancer type in the US, and its incidence is increasing. The majority of patients are disease-free after surgical resection of stage I tumors, which is often followed by radiation therapy, but most patients with advanced disease recur and have a poor prognosis, largely because the tumors become refractory to cytotoxic chemotherapies. PTEN, a commonly mutated tumor suppressor in EndoCAs, is well known for its ability to inhibit the AKT/mTOR signaling pathway...
June 13, 2018: Molecular Cancer Therapeutics
Rutuja Dhawde, Ragini Macaden, Dhananjaya Saranath, Kayzad Nilgiriwala, Appasaheb Ghadge, Tannaz Birdi
In the current study, ceftazidime- and ciprofloxacin-resistant—or dual drug-resistant (DDR)— E. coli were isolated from river Mula-Mutha, which flows through rural Pune district and Pune city. The DDR E. coli were further examined for antibiotic resistance to six additional antibiotics. The study also included detection of genes responsible for ceftazidime and ciprofloxacin resistance and vectors for horizontal gene transfer. Twenty-eight percent of the identified DDR E. coli were resistant to more than six antibiotics, with 12% being resistant to all eight antibiotics tested...
June 12, 2018: International Journal of Environmental Research and Public Health
Kersti Nilsson, Chengjun Wu, Stefan Schwartz
Human papillomaviruses (HPVs) have evolved to use the DNA repair machinery to replicate its DNA genome in differentiated cells. HPV activates the DNA damage response (DDR) in infected cells. Cellular DDR factors are recruited to the HPV DNA genome and position the cellular DNA polymerase on the HPV DNA and progeny genomes are synthesized. Following HPV DNA replication, HPV late gene expression is activated. Recent research has shown that the DDR factors also interact with RNA binding proteins and affects RNA processing...
June 12, 2018: International Journal of Molecular Sciences
Yann Wallez, Charles R Dunlop, Timothy Isaac Johnson, Siang-Boon Koh, Chiara Fornari, James Wt Yates, Sandra Bernaldo de Quirós Fernández, Alan Lau, Frances M Richards, Duncan I Jodrell
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers and overall survival rates have barely improved over the past five decades. The antimetabolite gemcitabine remains part of the standard-of-care, but shows very limited anti-tumor efficacy. Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra-S-phase DNA damage response (DDR), plays a central role in safeguarding cells from replication stress (RS) and can therefore limit the efficacy of antimetabolite drug therapies...
June 11, 2018: Molecular Cancer Therapeutics
Qi Shi, Luyan Shen, Bin Dong, Hao Fu, Xiaozheng Kang, Yongbo Yang, Liang Dai, Wanpu Yan, Hongchao Xiong, Zhen Liang, Keneng Chen
Inducing DNA damage is known to be one of the mechanisms of cytotoxic chemotherapy agents for cancer such as cisplatin. The endogenous DNA damage response confers chemoresistance to these agents by repairing DNA damage. The initiation and transduction of the DNA damage response (DDR) signaling pathway, which is dependent on the activation of ATM (ataxia-telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), is essential for DNA damage repair, the maintenance of genomic stability and cell survival...
June 8, 2018: Cancer Letters
Mengmeng Sun, Xu Feng, Zhenzhen Liu, Wenyuan Han, Yun Xiang Liang, Qunxin She
While bacteria and eukaryotes show distinct mechanisms of DNA damage response (DDR) regulation, investigation of ultraviolet (UV)-responsive expression in a few archaea did not yield any conclusive evidence for an archaeal DDR regulatory network. Nevertheless, expression of Orc1-2, an ortholog of the archaeal origin recognition complex 1/cell division control protein 6 (Orc1/Cdc6) superfamily proteins was strongly activated in Sulfolobus solfataricus and Sulfolobus acidocaldarius upon UV irradiation. Here, a series of experiments were conducted to investigate the possible functions of Orc1-2 in DNA damage repair in Sulfolobus islandicus...
June 7, 2018: Nucleic Acids Research
M Y Teo, R M Bambury, E C Zabor, E Jordan, H Al-Ahmadie, M E Boyd, N Bouvier, S A Mullane, E K Cha, N Roper, I Ostrovnaya, D M Hyman, B H Bochner, M E Arcila, D B Solit, M F Berger, D F Bajorin, J Bellmunt, G Iyer, J E Rosenberg
PURPOSE: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. EXPERIMENTAL DESIGN: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified...
May 30, 2018: Urologic Oncology
Michalina Wezyk, Magdalena Spólnicka, Ewelina Pośpiech, Beata Pepłońska, Renata Zbieć-Piekarska, Jan Ilkowski, Maria Styczyńska, Anna Barczak, Marzena Zboch, Anna Filipek-Gliszczynska, Magdalena Skrzypczak, Krzysztof Ginalski, Michał Kabza, Izabela Makałowska, Maria Barcikowska-Kotowicz, Wojciech Branicki, Cezary Żekanowski
Epigenetic mechanisms play an important role in the development and progression of various neurodegenerative diseases. Abnormal methylation of numerous genes responsible for regulation of transcription, DNA replication, and apoptosis has been linked to Alzheimer's disease (AD) pathology. We have recently performed whole transcriptome profiling of familial early-onset Alzheimer's disease (fEOAD) patient-derived fibroblasts. On this basis, we demonstrated a strong dysregulation of cell cycle checkpoints and DNA damage response (DDR) in both fibroblasts and reprogrammed neurons...
2018: Oxidative Medicine and Cellular Longevity
Fengxiang Wei, Peng Hao, Xiangzhong Zhang, Haiyan Hu, Dan Jiang, Aihua Yin, Lijuan Wen, Lihong Zheng, Jeffrey Zheru He, Wenjuan Mei, Hui Zeng, Damu Tang
DNA damage response (DDR) coordinates lesion repair and checkpoint activation. DDR is intimately connected with transcription. However, the relationship between DDR and transcription has not been clearly established. We report here RNA-sequencing analyses of MCF7 cells containing double-strand breaks induced by etoposide. While etoposide does not apparently cause global changes in mRNA abundance, it altered some gene expression. At the setting of fold alteration ≥ 2 and false discovery rate (FDR) ≤ 0.001, FDR < 0...
May 8, 2018: Oncotarget
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