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Zhou, Jia, Minmin Liu, Aaron M. Fleming, Cynthia J. Burrows, and Susan S. Wallace. "Neil3 and NEIL1 DNA Glycosylases Remove Oxidative Damages from Quadruplex DNA and Exhibit Preferences for Lesions in the Telomeric Sequence Context." Journal of Biological Chemistry 288, no. 38 (August 7, 2013): 27263–72. http://dx.doi.org/10.1074/jbc.m113.479055.
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The telomeric DNA of vertebrates consists of d(TTAGGG)n tandem repeats, which can form quadruplex DNA structures in vitro and likely in vivo. Despite the fact that the G-rich telomeric DNA is susceptible to oxidation, few biochemical studies of base excision repair in telomeric DNA and quadruplex structures have been done. Here, we show that telomeric DNA containing thymine glycol (Tg), 8-oxo-7,8-dihydroguanine (8-oxoG), guanidinohydantoin (Gh), or spiroiminodihydantoin (Sp) can form quadruplex DNA structures in vitro. We have tested the base excision activities of five mammalian DNA glycosylases (NEIL1, NEIL2, mNeil3, NTH1, and OGG1) on these lesion-containing quadruplex substrates and found that only mNeil3 had excision activity on Tg in quadruplex DNA and that the glycosylase exhibited a strong preference for Tg in the telomeric sequence context. Although Sp and Gh in quadruplex DNA were good substrates for mNeil3 and NEIL1, none of the glycosylases had activity on quadruplex DNA containing 8-oxoG. In addition, NEIL1 but not mNeil3 showed enhanced glycosylase activity on Gh in the telomeric sequence context. These data suggest that one role for Neil3 and NEIL1 is to repair DNA base damages in telomeres in vivo and that Neil3 and Neil1 may function in quadruplex-mediated cellular events, such as gene regulation via removal of damaged bases from quadruplex DNA.
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Ahmad, Hafiz Ishfaq, Gulnaz Afzal, Sehrish Sadia, Ghulam Haider, Shakeel Ahmed, Saba Saeed, and Jinping Chen. "Structural and Evolutionary Adaptations of Nei-Like DNA Glycosylases Proteins Involved in Base Excision Repair of Oxidative DNA Damage in Vertebrates." Oxidative Medicine and Cellular Longevity 2022 (April 4, 2022): 1–20. http://dx.doi.org/10.1155/2022/1144387.
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Oxidative stress is a type of stress that damages DNA and can occur from both endogenous and exogenous sources. Damage to DNA caused by oxidative stress can result in base modifications that promote replication errors and the formation of sites of base loss, which pose unique challenges to the preservation of genomic integrity. However, the adaptive evolution of the DNA repair mechanism is poorly understood in vertebrates. This research aimed to explore the evolutionary relationships, physicochemical characteristics, and comparative genomic analysis of the Nei-like glycosylase gene family involved in DNA base repair in the vertebrates. The genomic sequences of NEIL1, NEIL2, and NEIL3 genes were aligned to observe selection constraints in the genes, which were relatively low conserved across vertebrate species. The positive selection signals were identified in these genes across the vertebrate lineages. We identified that only about 2.7% of codons in these genes were subjected to positive selection. We also revealed that positive selection pressure was increased in the Fapy-DNA-glyco and H2TH domain, which are involved in the base excision repair of DNA that has been damaged by oxidative stress. Gene structure, motif, and conserved domain analysis indicated that the Nei-like glycosylase genes in mammals and avians are evolutionarily low conserved compared to other glycosylase genes in other “vertebrates” species. This study revealed that adaptive selection played a critical role in the evolution of Nei-like glycosylase in vertebrate species. Systematic comparative genome analyses will give key insights to elucidate the links between DNA repair and the development of lifespan in various organisms as more diverse vertebrate genome sequences become accessible.
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Cumova, Andrea, Veronika Vymetalkova, Alena Opattova, Veronika Bouskova, Barbara Pardini, Katerina Kopeckova, Renata Kozevnikovova, et al. "Genetic variations in 3′UTRs of SMUG1 and NEIL2 genes modulate breast cancer risk, survival and therapy response." Mutagenesis 36, no. 4 (June 7, 2021): 269–79. http://dx.doi.org/10.1093/mutage/geab017.
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Abstract Breast cancer (BC) is the most frequent malignancy in women accounting for approximately 2 million new cases worldwide annually. Several genetic, epigenetic and environmental factors are known to be involved in BC development and progression, including alterations in post-transcriptional gene regulation mediated by microRNAs (miRNAs). Single nucleotide polymorphisms (SNPs) located in miRNA binding sites (miRSNPs) in 3′-untranslated regions of target genes may affect miRNA-binding affinity and consequently modulate gene expression. We have previously reported a significant association of miRSNPs in the SMUG1 and NEIL2 genes with overall survival in colorectal cancer patients. SMUG1 and NEIL2 are DNA glycosylases involved in base excision DNA repair. Assuming that certain genetic traits are common for solid tumours, we have investigated wherever variations in SMUG1 and NEIL2 genes display an association with BC risk, prognosis, and therapy response in a group of 673 BC patients and 675 healthy female controls. Patients with TC genotype of NEIL2 rs6997097 and receiving only hormonal therapy displayed markedly shorter overall survival (HR = 4.15, 95% CI = 1.7–10.16, P = 0.002) and disease-free survival (HR = 2.56, 95% CI = 1.5–5.7, P = 0.02). Our results suggest that regulation of base excision repair glycosylases operated by miRNAs may modulate the prognosis of hormonally treated BC.
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Sayed, Ibrahim M., Ayse Z. Sahan, Tatiana Venkova, Anirban Chakraborty, Dibyabrata Mukhopadhyay, Diane Bimczok, Ellen J. Beswick, et al. "Helicobacter pylori infection downregulates the DNA glycosylase NEIL2, resulting in increased genome damage and inflammation in gastric epithelial cells." Journal of Biological Chemistry 295, no. 32 (June 9, 2020): 11082–98. http://dx.doi.org/10.1074/jbc.ra119.009981.
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Infection with the Gram-negative, microaerophilic bacterium Helicobacter pylori induces an inflammatory response and oxidative DNA damage in gastric epithelial cells that can lead to gastric cancer (GC). However, the underlying pathogenic mechanism is largely unclear. Here, we report that the suppression of Nei-like DNA glycosylase 2 (NEIL2), a mammalian DNA glycosylase that specifically removes oxidized bases, is one mechanism through which H. pylori infection may fuel the accumulation of DNA damage leading to GC. Using cultured cell lines, gastric biopsy specimens, primary cells, and human enteroid-derived monolayers from healthy human stomach, we show that H. pylori infection greatly reduces NEIL2 expression. The H. pylori infection-induced downregulation of NEIL2 was specific, as Campylobacter jejuni had no such effect. Using gastric organoids isolated from the murine stomach in coculture experiments with live bacteria mimicking the infected stomach lining, we found that H. pylori infection is associated with the production of various inflammatory cytokines. This response was more pronounced in Neil2 knockout (KO) mouse cells than in WT cells, suggesting that NEIL2 suppresses inflammation under physiological conditions. Notably, the H. pylori-infected Neil2-KO murine stomach exhibited more DNA damage than the WT. Furthermore, H. pylori-infected Neil2-KO mice had greater inflammation and more epithelial cell damage. Computational analysis of gene expression profiles of DNA glycosylases in gastric specimens linked the reduced Neil2 level to GC progression. Our results suggest that NEIL2 downregulation is a plausible mechanism by which H. pylori infection impairs DNA damage repair, amplifies the inflammatory response, and initiates GC.
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Huang, Hongbo, and Qingwang Hua. "NEIL3 Mediates Lung Cancer Progression and Modulates PI3K/AKT/mTOR Signaling: A Potential Therapeutic Target." International Journal of Genomics 2022 (April 30, 2022): 1–17. http://dx.doi.org/10.1155/2022/8348499.
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Background. Nei endonuclease VIII-like 3 (NEIL3) is widely involved in pathophysiological processes of the body; however, its role in lung cancer has not been conclusively determined. Objective. This study is aimed at exploring the role of NEIL3 in lung cancer. Methods. The public data used in this study were downloaded from The Cancer Genome Atlas (TCGA) database. “Limma” in R was used for the analysis of differentially expressed genes. Clinical correlations and prognostic analyses were performed using the survival package in R. The proliferative abilities of lung cancer cells were evaluated by the CCK8 and colony formation assays while their invasive and migration abilities were assessed by the transwell and wound healing assays. Quantitative real-time PCR (qRT-PCR) and western blot analyses were utilized to detect RNA and protein levels. Biological differences between groups were determined by gene set enrichment analysis (GSEA). Tumor Immune Dysfunction and Exclusion (TIDE) as well as Genomics of Drug Sensitivity in Cancer (GDSC) was used for immunotherapeutic and chemotherapeutic sensitivity analyses. Results. NEIL3 was upregulated in NSCLC tissues and cell lines, implying that it is involved in lung cancer initiation and progression. Clinical correlation and prognostic analyses showed that NEIL3 was associated with worse clinical features (stage and T and N classifications) and poor prognostic outcomes. In vitro, NEIL3 significantly enhanced NSCLC proliferation, invasion, and migration. GSEA indicated that NEIL3 might be involved in PI3K/AKT/mTOR, G2/M checkpoints, and E2F target pathways. Inhibition of NEIL3 suppressed cyclinD1 and p-AKT protein levels; however, it had no effects on AKT levels, indicating that NEIL3 can partially activate the PI3K/AKT/mTOR signaling pathway. The predicted result of TIDE indicated that immunotherapeutic nonresponders had elevated NEIL3 levels. Moreover, there was a positive correlation between NEIL3 levels and chemosensitivity to cisplatin and paclitaxel. Conclusion. In general, NEIL3 mediates NSCLC progression and affects sensitivity to immunotherapy and chemotherapy; therefore, it is a potential molecular target for treatment.
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Shen, Mei-jie, Ge-ge Wang, Yu-zhen Wang, Jing Xie, and Xi Ding. "Nell-1 Enhances Osteogenic Differentiation of Pre-Osteoblasts on Titanium Surfaces via the MAPK-ERK Signaling Pathway." Cellular Physiology and Biochemistry 50, no. 4 (2018): 1522–34. http://dx.doi.org/10.1159/000494651.
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Background/Aims: This study aimed to investigate the effect of Nell-1 on the osteogenic behaviors of pre-osteoblasts on titanium (Ti) surfaces and to identify the underlying signaling pathway. Methods: Nell-1 at different concentrations was added to culture medium to stimulate MC3T3-E1 subclone 14 on Ti surfaces. A CCK-8 colorimetric assay was used to detect cell proliferation. Alkaline phosphatase activity (ALP) assay and enzyme-linked immunosorbent assay (ELISA) were used to evaluate ALP activity and the osteocalcin (OCN) secretion, respectively. Indicators of osteoblastic differentiation were assessed using real-time polymerase chain reaction analysis (RT-PCR). Western blot (WB) assay was used to analyze the expression changes of the osteogenic proteins and the mitogen-activated protein kinase (MAPK) pathway. Results: Nell-1 significantly increased the osteogenic gene and protein expression levels of ALP, OCN, Runx2, osteoprotegerin (OPG), collagen type I (Col-I), and Osterix (Osx) in pre-osteoblasts on Ti surfaces. The optimal concentration of Nell-1 was 100 ng/ ml. In addition, Nell-1 activated ERK and JNK, but not P38, in MC3T3-E1 cells on the Ti surface. Except for ALP and Col-I, the promotive effects of Nell-1 on the expression of osteogenic markers were suppressed by ERK inhibitor U0126. Conclusion: Certain concentrations of Nell-1 can promote the osteogenic differentiation of pre-osteoblasts on Ti surfaces by activating the MAPK/ERK signaling pathway.
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Truong, Thien, Xinli Zhang, Dharmini Pathmanathan, Chia Soo, and Kang Ting. "Craniosynostosis-Associated Gene Nell-1 Is Regulated by Runx2." Journal of Bone and Mineral Research 22, no. 1 (October 16, 2006): 7–18. http://dx.doi.org/10.1359/jbmr.061012.
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Zhuang, Juanwei, Mingxiao Li, Xinkun Zhang, Shuyuan Xian, Jie Zhang, Huabin Yin, Yifan Liu, et al. "Construction of Bone Metastasis-Specific Regulation Network Based on Prognostic Stemness-Related Signatures in Prostate Cancer." Disease Markers 2022 (March 29, 2022): 1–27. http://dx.doi.org/10.1155/2022/8495923.
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Background. We planned to uncover the cancer stemness-related genes (SRGs) in prostate cancer (PCa) and its underlying mechanism in PCa metastasis. Methods. We acquired the RNA-seq data of 406 patients with PCa from the TCGA database. Based on the mRNA stemness index (mRNAsi) calculated by one-class logistic regression (OCLR) algorithm, SRGs in PCa were extracted by WGCNA. Univariate and multivariate regression analyses were applied to uncover OS-associated SRGs. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Pearson’s correlation analysis were performed to discover the possible mechanism of PCa metastasis. The significantly correlated transcription factors of OS-associated SRGs were also identified by Pearson’s correlation analysis. ChIP-seq was applied to validate the binding relationship of TFs and OS-associated SRGs and spatial transcriptome and single-cell sequencing were performed to uncover the location of key biomarkers expression. Lastly, we explored the specific inhibitors for SRGs using CMap algorithm. Results. We identified 538 differentially expressed genes (DEGs) between non-metastatic and metastatic PCa. Furthermore, OS-associated SRGs were identified. The Pearson correlation analysis revealed that FOXM1 was significantly correlated with NEIL3 (correlation efficient =0.89, p < 0.001 ) and identified hallmark_E2F_targets as the potential pathway mechanism of NEIL3 promoting PCa metastasis (correlation efficient =0.58, p < 0.001 ). Single-cell sequencing results indicated that FOXM1 regulating NEIL3 may get involved in the antiandrogen resistance of PCa. Rottlerin was discovered to be a potential target drug for PCa. Conclusion. We constructed a regulatory network based on SRGs associated with PCa metastasis and explored possible mechanism.
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Lloyd, R. Stephen. "Complex Roles of NEIL1 and OGG1: Insights Gained from Murine Knockouts and Human Polymorphic Variants." DNA 2, no. 4 (December 1, 2022): 279–301. http://dx.doi.org/10.3390/dna2040020.
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DNA glycosylases promote genomic stability by initiating base excision repair (BER) in both the nuclear and mitochondrial genomes. Several of these enzymes have overlapping substrate recognition, through which a degree of redundancy in lesion recognition is achieved. For example, OGG1 and NEIL1 both recognize and release the imidazole-ring-fragmented guanine, FapyGua as part of a common overall pathway to cleanse the genome of damaged bases. However, these glycosylases have many differences, including their differential breadth of substrate specificity, the contrasting chemistries through which base release occurs, the subsequent steps required to complete the BER pathway, and the identity of specific protein-binding partners. Beyond these differences, the complexities and differences of their in vivo biological roles have been primarily elucidated in studies of murine models harboring a knockout of Neil1 or Ogg1, with the diversity of phenotypic manifestations exceeding what might have been anticipated for a DNA glycosylase deficiency. Pathologies associated with deficiencies in nuclear DNA repair include differential cancer susceptibilities, where Ogg1-deficient mice are generally refractory to carcinogenesis, while deficiencies in Neil1-deficient mice confer cancer susceptibility. In contrast to NEIL1, OGG1 functions as a key transcription factor in regulating inflammation and other complex gene cascades. With regard to phenotypes attributed to mitochondrial repair, knockout of either of these genes results in age- and diet-induced metabolic syndrome. The adverse health consequences associated with metabolic syndrome can be largely overcome by expression of a mitochondrial-targeted human OGG1 in both wild-type and Ogg1-deficient mice. The goal of this review is to compare the roles that NEIL1 and OGG1 play in maintaining genomic integrity, with emphasis on insights gained from not only the diverse phenotypes that are manifested in knockout and transgenic mice, but also human disease susceptibility associated with polymorphic variants.
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Fleming, Aaron M., Judy Zhu, Shereen A. Howpay Manage, and Cynthia J. Burrows. "Human NEIL3 Gene Expression Regulated by Epigenetic-Like Oxidative DNA Modification." Journal of the American Chemical Society 141, no. 28 (June 26, 2019): 11036–49. http://dx.doi.org/10.1021/jacs.9b01847.
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Shinmura, K. "Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer." Carcinogenesis 25, no. 12 (June 24, 2004): 2311–17. http://dx.doi.org/10.1093/carcin/bgh267.
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Müller, Udo, Christina Bauer, Michael Siegl, Andrea Rottach, and Heinrich Leonhardt. "TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation." Nucleic Acids Research 42, no. 13 (June 19, 2014): 8592–604. http://dx.doi.org/10.1093/nar/gku552.
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NYE, ROBERT A. "Neil R.Davison, Jewishness and Masculinity from the Modern to the Postmodern (New York and London: Taylor & Francis Group, 2010), pp. x-xi + 262. ISBN 13: 978-0-415-87586-8 (hb)." Gender & History 25, no. 1 (March 25, 2013): 204–5. http://dx.doi.org/10.1111/gend.12008_8.
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Stanghellini, I., E. Genovese, S. Palma, C. Falcinelli, L. Presutti, and A. Percesepe. "A mild phenotype of sensorineural hearing loss and palmoplantar keratoderma caused by a novel GJB2 dominant mutation." Acta Otorhinolaryngologica Italica 37, no. 4 (August 2017): 308–11. http://dx.doi.org/10.14639/0392-100x-1382.
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Le mutazioni dominanti del gene GJB2 sono causa di forme di sordità neurosensoriale sindromiche associate a manifestazioni cutanee palmo-plantari. In questo lavoro viene descritta la correlazione genotipo / fenotipo di una nuova mutazione nel gene GJB2 identificata in tre generazioni di una famiglia italiana (probando, madre e nonno) i cui membri presentano ipoacusia neurosensoriale associata a cheratoderma palmo-plantare ad insorgenza nelletà adulta. Una nuova mutazione di GJB2 (c.66G > T, p.Lys22Asn) allo stato eterozigote è stata identificata in tutti membri affetti. La segregazione della mutazione, la sua frequenza nella popolazione generale e predizioni in silico ne attribuiscono un ruolo patogenetico. La mutazione p.Lys22Asn GJB2 determina una forma di sordità dominante associata ad unespressione variabile di cheratoderma palmo-plantare, rappresentando un modello di penetranza completa con effetto età-dipendente sul fenotipo.
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Deng, Yu, He Huang, Jiangcheng Shi, and Hongyan Jin. "Identification of Candidate Genes in Breast Cancer Induced by Estrogen Plus Progestogens Using Bioinformatic Analysis." International Journal of Molecular Sciences 23, no. 19 (October 6, 2022): 11892. http://dx.doi.org/10.3390/ijms231911892.
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Menopausal hormone therapy (MHT) was widely used to treat menopause-related symptoms in menopausal women. However, MHT therapies were controversial with the increased risk of breast cancer because of different estrogen and progestogen combinations, and the molecular basis behind this phenomenon is currently not understood. To address this issue, we identified differentially expressed genes (DEGs) between the estrogen plus progestogens treatment (EPT) and estrogen treatment (ET) using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data. As a result, a total of 96 upregulated DEGs were first identified. Seven DEGs related to the cell cycle (CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3) were validated by RT-qPCR. Specifically, these seven DEGs were increased in EPT compared to ET (p < 0.05) and had higher expression levels in breast cancer than adjacent normal tissues (p < 0.05). Next, we found that estrogen receptor (ER)-positive breast cancer patients with a higher CNNE2 expression have a shorter overall survival time (p < 0.05), while this effect was not observed in the other six DEGs (p > 0.05). Interestingly, the molecular docking results showed that CCNE2 might bind to 17β-estradiol (−6.791 kcal/mol), progesterone (−6.847 kcal/mol), and medroxyprogesterone acetate (−6.314 kcal/mol) with a relatively strong binding affinity, respectively. Importantly, CNNE2 protein level could be upregulated with EPT and attenuated by estrogen receptor antagonist, acolbifene and had interactions with cancer driver genes (AKT1 and KRAS) and high mutation frequency gene (TP53 and PTEN) in breast cancer patients. In conclusion, the current study showed that CCNE2, CDCA5, RAD51, TCF19, KNTC1, MCM10, and NEIL3 might contribute to EPT-related tumorigenesis in breast cancer, with CCNE2 might be a sensitive risk indicator of breast cancer risk in women using MHT.
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Chen, Weiwei, Xinli Zhang, Ronald K. Siu, Feng Chen, Jia Shen, Janette N. Zara, Cymbeline T. Culiat, Sotirios Tetradis, Kang Ting, and Chia Soo. "Nfatc2 is a primary response gene of nell-1 regulating chondrogenesis in ATDC5 cells." Journal of Bone and Mineral Research 26, no. 6 (May 24, 2011): 1230–41. http://dx.doi.org/10.1002/jbmr.314.
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Wang, Chenyu, Yingnan Wang, Cunyi Wang, Chao Liu, Wen Li, Shiyu Hu, Na Wu, Shijie Jiang, and Jiejun Shi. "Therapeutic application of 3B-PEG injectable hydrogel/Nell-1 composite system to temporomandibular joint osteoarthritis." Biomedical Materials 17, no. 1 (November 19, 2021): 015004. http://dx.doi.org/10.1088/1748-605x/ac367f.
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Abstract This study aims to construct a composite system of the tri-block polyethylene glycol injectable hydrogel (3B-PEG IH) and neural epithelial growth factor-like protein 1 (Nell-1), and to analyze its therapeutic effect on temporomandibular joint osteoarthritis (TMJOA). Sol-gel transition temperature was measured via inverting test. The viscoelastic modulus curves was measured by rheometer. Degradation and controlled release profiles of 3B-PEG IH were drawn in vitro. In vivo gel retention and biocompatibility were completed subcutaneously on the back of rats. After primary chondrocytes were extracted and identified, the cell viability in 3B-PEG IH was measured. Evaluation of gene expression in hydrogel was performed by real-time polymerase chain reaction. TMJOA rabbits were established by intra-articular injection of type II collagenase. Six weeks after composite systems being injected, gross morphological score, micro-CT, histological staining and grading were evaluated. The rusults showed that different types of 3B-PEG IH all reached a stable gel state at 37 °C and could support the three-dimensional growth of chondrocytes, but poly(lactide-co-caprolactone)-block-poly(ethyleneglycol)-block-poly(lactide-co-caprolactone) (PLCL-PEG-PLCL) hydrogel had a wider gelation temperature range and better hydrolytic stability for about 4 weeks. Its controlled release curve is closest to the zero-order release kinetics. In vitro, PLCL-PEG-PLCL/Nell-1 could promote the chondrogenic expression and reduce the inflammatory expression. In vivo, TMJOA rabbits were mainly characterized by the disorder of cartilage structure and the destruction of subchondral bone. However, PLCL-PEG-PLCL/Nell-1 could reverse the destruction of the subchondral trabecula, restore the fibrous and proliferative layers of the surface, and reduce the irregular hyperplasia of fibrocartilage layer. In conclusion, by comparing the properties of different 3B-PEG IH, 20 wt% PLCL-PEG-PLCL hydrogel was selected as the most appropriate material. PLCL-PEG-PLCL/Nell-1 composite could reverse osteochondral damage caused by TMJOA, Nfatc1-Runx3 signaling pathway may play a role in it. This study may provide a novel, minimally-invasive therapeutic strategy for the clinical treatment of TMJOA.
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Kakhkharova, Zarina I., Dmitry O. Zharkov, and Inga R. Grin. "A Low-Activity Polymorphic Variant of Human NEIL2 DNA Glycosylase." International Journal of Molecular Sciences 23, no. 4 (February 17, 2022): 2212. http://dx.doi.org/10.3390/ijms23042212.
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Human NEIL2 DNA glycosylase (hNEIL2) is a base excision repair protein that removes oxidative lesions from DNA. A distinctive feature of hNEIL2 is its preference for the lesions in bubbles and other non-canonical DNA structures. Although a number of associations of polymorphisms in the hNEIL2 gene were reported, there is little data on the functionality of the encoded protein variants, as follows: only hNEIL2 R103Q was described as unaffected, and R257L, as less proficient in supporting the repair in a reconstituted system. Here, we report the biochemical characterization of two hNEIL2 variants found as polymorphisms in the general population, R103W and P304T. Arg103 is located in a long disordered segment within the N-terminal domain of hNEIL2, while Pro304 occupies a position in the β-turn of the DNA-binding zinc finger motif. Similar to the wild-type protein, both of the variants could catalyze base excision and nick DNA by β-elimination but demonstrated a lower affinity for DNA. Steady-state kinetics indicates that the P304T variant has its catalytic efficiency (in terms of kcat/KM) reduced ~5-fold compared with the wild-type hNEIL2, whereas the R103W enzyme is much less affected. The P304T variant was also less proficient than the wild-type, or R103W hNEIL2, in the removal of damaged bases from single-stranded and bubble-containing DNA. Overall, hNEIL2 P304T could be worthy of a detailed epidemiological analysis as a possible cancer risk modifier.
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Kinslow, C. J., R. A. El-Zein, C. M. Rondelli, C. E. Hill, J. K. Wickliffe, and S. Z. Abdel-Rahman. "Regulatory regions responsive to oxidative stress in the promoter of the human DNA glycosylase gene NEIL2." Mutagenesis 25, no. 2 (November 27, 2009): 171–77. http://dx.doi.org/10.1093/mutage/gep058.
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Teng, Pai-Chi, Shu-Pin Huang, Chia-Hsin Liu, Ting-Yi Lin, Yi-Chun Cho, Yo-Liang Lai, Shu-Chi Wang, et al. "Identification of DNA Damage Repair-Associated Prognostic Biomarkers for Prostate Cancer Using Transcriptomic Data Analysis." International Journal of Molecular Sciences 22, no. 21 (October 29, 2021): 11771. http://dx.doi.org/10.3390/ijms222111771.
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In the recent decade, the importance of DNA damage repair (DDR) and its clinical application have been firmly recognized in prostate cancer (PC). For example, olaparib was just approved in May 2020 to treat metastatic castration-resistant PC with homologous recombination repair-mutated genes; however, not all patients can benefit from olaparib, and the treatment response depends on patient-specific mutations. This highlights the need to understand the detailed DDR biology further and develop DDR-based biomarkers. In this study, we establish a four-gene panel of which the expression is significantly associated with overall survival (OS) and progression-free survival (PFS) in PC patients from the TCGA-PRAD database. This panel includes DNTT, EXO1, NEIL3, and EME2 genes. Patients with higher expression of the four identified genes have significantly worse OS and PFS. This significance also exists in a multivariate Cox regression model adjusting for age, PSA, TNM stages, and Gleason scores. Moreover, the expression of the four-gene panel is highly correlated with aggressiveness based on well-known PAM50 and PCS subtyping classifiers. Using publicly available databases, we successfully validate the four-gene panel as having the potential to serve as a prognostic and predictive biomarker for PC specifically based on DDR biology.
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Zhang, Xinli, Dale Carpenter, Nobuyuki Bokui, Chia Soo, Steve Miao, Thien Truong, Benjamin WU, et al. "Overexpression of Nell-1 , a Craniosynostosis-Associated Gene, Induces Apoptosis in Osteoblasts During Craniofacial Development." Journal of Bone and Mineral Research 18, no. 12 (December 2003): 2126–34. http://dx.doi.org/10.1359/jbmr.2003.18.12.2126.
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Post, Annemarie E. M., Johan Bussink, Fred C. G. J. Sweep, and Paul N. Span. "Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 28, no. 1 (February 7, 2020): 33–40. http://dx.doi.org/10.3727/096504019x15555794826018.
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Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.
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Benítez-Buelga, Carlos, Juan Miguel Baquero, Tereza Vaclova, Victoria Fernández, Paloma Martín, Lucia Inglada-Perez, Miguel Urioste, Ana Osorio, and Javier Benítez. "Genetic variation in the NEIL2 DNA glycosylase gene is associated with oxidative DNA damage in BRCA2 mutation carriers." Oncotarget 8, no. 70 (November 23, 2017): 114626–36. http://dx.doi.org/10.18632/oncotarget.22638.
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Romano, Rosa, Apostolos Zaravinos, Kyriaki Liadaki, Rozina Caridha, Johanna Lundin, Göran Carlsson, Jacek Winiarski, Qiang Pan-Hammarström, and Lennart Hammarström. "NEIL1 is a candidate gene associated with common variable immunodeficiency in a patient with a chromosome 15q24 deletion." Clinical Immunology 176 (March 2017): 71–76. http://dx.doi.org/10.1016/j.clim.2017.01.006.
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Sobczak, Maciej, Julita Pietrzak, Tomasz Płoszaj, and Agnieszka Robaszkiewicz. "BRG1 Activates Proliferation and Transcription of Cell Cycle-Dependent Genes in Breast Cancer Cells." Cancers 12, no. 2 (February 4, 2020): 349. http://dx.doi.org/10.3390/cancers12020349.
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Cancer malignancy is usually characterized by unlimited self-renewal. In some types of advanced tumors that are rapidly dividing, gene expression profiles depict elevations in pro-proliferative genes accompanied by coordinately elevated transcription of factors responsible for removal of DNA lesions. In our studies, fast proliferating breast cancer cell lines (MDA-MB-231 and MCF7), BRG1, a component of the SWI/SNF complex, emerges as an activator of functionally-linked genes responsible for activities such as mitotic cell divisions and DNA repair. Products of at least some of them are considerably overrepresented in breast cancer cells and BRG1 facilitates growth of MCF7 and MDA-MB-231 cell lines. BRG1 occurs at the promoters of genes such as CDK4, LIG1, and NEIL3, which are transcriptionally controlled by cell cycle progression and highly acetylated by EP300 in proliferating cells. As previously documented, in dividing cells BRG1 directly activates gene transcription by evicting EP300 modified nucleosomes from the promoters and, thereby, relaxing chromatin. However, the deficiency of BRG1 or EP300 activity for 48 h leads to cell growth arrest and to chromatin compaction, but also to the assembly of RB1/HDAC1/EZH2 complexes at the studied cell cycle-dependent gene promoters. Epigenetic changes include histone deacetylation and accumulation of H3K27me trimethylation, both known to repress transcription. Cell cycle arrest in G1 by inhibition of CDK4/6 phenocopies the effect of the long-term BRG1 inhibition on the chromatin structure. These results suggest that BRG1 may control gene transcription also by promoting expression of genes responsible for cell cycle progression in the studied breast cancer cells. In the current study, we show that BRG1 binding occurs at the promoters of functionally linked genes in proliferating breast cancer cells, revealing a new mechanism by which BRG1 defines gene transcription.
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Hayes, D. Neil Neil, Greg Mayhew, Josh Uronis, and Jose Zevallos. "Abstract 2142: Prognostic and predictive applications from mesenchymal gene expression subtype analysis for early-stage, HPV(-) head and neck squamous cell carcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2142. http://dx.doi.org/10.1158/1538-7445.am2022-2142.
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Abstract Introduction: Although often presented as one disease for genomic studies, head and neck squamous cell carcinoma (HNSCC) is treated according to clinical factors such as anatomic subsite, and tumor stage. Oral cavity squamous cell carcinoma (OCSCC) comprises 1/3 of all HNSCC and is predominantly HPV(-). Depending upon clinical stage, OCSCC treatment involves surgical resection +/- neck dissection, followed by radiation +/- chemotherapy. Our group and others previously described four mRNA expression patterns (classical, atypical, basal, and mesenchymal), each with unique genomic features and prognosis. Here, we further examine the clinical utility of gene expression subtyping in HNSCC and introduce the potential for predictive applications in HPV(-) HNSCC according to clinically relevant subgroups including oral cavity cancer. Experimental Procedures: Multiple independent HNSCC datasets were obtained from public repositories, totaling 562 patients, including from MD Andersen (MDA) (GSE41117) and the Cancer Genome Atlas (TCGA) sourced from the Genome Data Commons. Cases were included for further analysis if they had N stage and overall survival values. Samples were assigned molecular subtypes (basal, mesenchymal, atypical or classical) using a reduced gene set version of the classifier reported earlier. HPV status was determined by HPV gene expression. The clinical endpoint was overall survival at censured at 36 months. Kaplan-Meier (KM) plots and logrank tests were used to investigate associations between clinical variables and survival. Cox models were used to adjust for potential confounders. All statistics were performed using the survival package in R. Results: Of the 418 training patients from the TCGA dataset that met analysis criteria, nearly 20% presented with stage I and II tumors. In the clinically relevant subgroup of node(-) OCSCC patients, mesenchymal subtype was associated with worse survival (HR 2.4, p=0.021), offering a novel and potentially actionable biomarker in otherwise early-stage and low risk disease. Associations in the MDA validation cohort confirmed the association. Node(-) non-mesenchymal OCSCC patients had far better survival (no deaths observed) compared to node(-) mesenchymal and all node(+) patients which had similarly poor survival. Differential responses as a function of radiation will be presented. Summary and Conclusions: This study confirms that the mesenchymal subtype is associated with worse outcomes across all cases of HNSCC. However, we demonstrate that mesenchymal subtype is associated with poor survival, even in the clinically relevant setting of early-stage, node(-) OCSCC treated with surgical resection. These findings highlight the potential value of gene expression subtyping as an adjunct to pathology for deciding which treatment option is best suited for patients with HNSCC. Citation Format: D. Neil Neil Hayes, MD, MS, MPH, Greg Mayhew, Josh Uronis, Jose Zevallos. Prognostic and predictive applications from mesenchymal gene expression subtype analysis for early-stage, HPV(-) head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2142.
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Jelinek, Jaroslav, Marcos R. H. Estecio, Kimie Kondo, Rong He, Jiri Zavadil, and Jean-Pierre J. Issa. "Classifying Leukemias Based on Epigenetic Alterations." Blood 110, no. 11 (November 16, 2007): 2123. http://dx.doi.org/10.1182/blood.v110.11.2123.2123.
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Abstract Acute leukemia is caused by alterations of blood-forming stem cells leading to uncontrolled growth and diminished capacity to differentiate into mature functional blood elements. Beside genetic changes, epigenetic alterations are increasingly recognized as important events in the pathogenesis of leukemia. Cytosine methylation in CpG islands at gene transcription start regions can cause heritable gene silencing and have the same functional effects as inactivating mutations. Hundreds of genes may become epigenetically silenced in leukemia. While many of the methylated genes are not expressed in blood cells, silencing of genes critically important for control of stem cell self-renewal, proliferation, differentiation, and/or survival can contribute to the malignant phenotype. We used a genome-wide method to identify methylated genes by hybridizing a CpG island microarray with amplicons obtained by the methylated CpG island amplification technique (MCAM). We analyzed 10 leukemia cell lines with different cellular origin (myeloid cell lines KG1, KG1a, HEL, K562, and TF1; T lymphoid cell lines CEM and JTAg; and B lymphoid cell lines ALL1, BJAB, and Raji). On average, 266 genomic loci were found to be hypermethylated in these cell lines, ranging from 56 (KG1) to 483 loci (Raji), reinforcing the idea of extensive epigenome alteration in leukemia. Unsupervised hierarchical clustering showed distinct methylation pattern in the cell lines of lymphoid origin versus myeloid leukemia cell lines and a GM-CSF-dependent erythroleukemia cell line TF-1, justifying the use of methylation markers for uncovering of tumor-specific pathways of gene inactivation. There was a striking difference in the number of hypermethylated genes between two closely related myeloid leukemia cell lines: KG1 (56 methylated loci) and its undifferentiated variant KG1a (225 methylated loci). cDNA microarray analysis showed that deoxy-azacitidine treatment induced expression of genes differentially methylated in KG1a (DKKL1, GBX, HIVEP3, KCNAB1, KIAA1102, NAV2, NEIL1, and RAX) but not in KG1 cells where these genes were unmethylated. Finally, we used bisulfite PCR followed by pyrosequencing analysis to quantitatively measure DNA methylation of several genes detected by MCAM. Ongoing analyses of bone marrow samples from leukemia patients showed hypermethylation of the following genes: GDNF (in 4/22 [18%] AML and 7/20 [35%] ALL patients), HAND2 (in 5/22 [23%] AML and 7/20 [35%] ALL patients), HIVEP3 (in 9/22 [41%] AML and 6/20 [30%] ALL patients), MPDZ (in 2/6 [33%] AML and 15/20 [75%] ALL patients), and NEIL1 (in 2/20 [10%] AML and 1/12 [8%] ALL patients). Mapping of DNA methylation abnormalities may detect epigenetic markers important for leukemia classification and prognosis. Identification of pathways frequently silenced by DNA methylation may also suggest new targets for specific therapy.
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He, Yuyun, Xiaoyao Yin, Jingjing Dong, Qing Yang, Yongning Wu, and Zhiyong Gong. "Transcriptome Analysis of Caco-2 Cells upon the Exposure of Mycotoxin Deoxynivalenol and Its Acetylated Derivatives." Toxins 13, no. 2 (February 22, 2021): 167. http://dx.doi.org/10.3390/toxins13020167.
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Deoxynivalenol (DON), 3-acetyldeoxynivalenol (3-ADON) and 15-acetyldeoxynivalenol (15-ADON) are type B trichothecenes; one of the major pollutants in food and feed products. Although the toxicity of DON has been well documented, information on the toxicity of its acetylated derivative remains incomplete. To acquire more detailed insight into 3-ADON and 15-ADON, Caco-2 cells under 0.5 µM DON, 3-ADON and 15-ADON treatment for 24 h were subjected to RNA-seq analysis. In the present study, 2656, 3132 and 2425 differentially expressed genes (DEGs) were selected, respectively, and were enriched utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Gene Ontology (GO) database. The upregulation of ataxia-telangiectasia mutated kinase (ATM), WEE1 homolog 2 (WEE2) and downregulation of proliferating cell nuclear antigen (PCNA), minichromosome maintenance (MCMs), cyclin dependent kinase (CDKs), and E2Fs indicate that the three toxins induced DNA damage, inhibition of DNA replication and cell cycle arrest in Caco-2 cells. Additionally, the upregulation of sestrin (SENEs) and NEIL1 implied that the reason for DNA damage may be attributable to oxidative stress. Our study provides insight into the toxic mechanism of 3-ADON and 15-ADON.
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Blenk, S., J. Engelmann, M. Weniger, J. Schultz, M. Dittrich, A. Rosenwald, H. K. Müller-Hermelink, T. Müller, and T. Dandekar. "Germinal Center B Cell-Like (GCB) and Activated B Cell-Like (ABC) Type of Diffuse Large B Cell Lymphoma (DLBCL): Analysis of Molecular Predictors, Signatures, Cell Cycle State and Patient Survival." Cancer Informatics 3 (January 2007): 117693510700300. http://dx.doi.org/10.1177/117693510700300004.
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Aiming to find key genes and events, we analyze a large data set on diffuse large B-cell lymphoma (DLBCL) gene-expression (248 patients, 12196 spots). Applying the loess normalization method on these raw data yields improved survival predictions, in particular for the clinical important group of patients with medium survival time. Furthermore, we identify a simplified prognosis predictor, which stratifies different risk groups similarly well as complex signatures. We identify specific, activated B cell-like (ABC) and germinal center B cell-like (GCB) distinguishing genes. These include early (e.g. CDKN3) and late (e.g. CDKN2C) cell cycle genes. Independently from previous classification by marker genes we confirm a clear binary class distinction between the ABC and GCB subgroups. An earlier suggested third entity is not supported. A key regulatory network, distinguishing marked over-expression in ABC from that in GCB, is built by: ASB13, BCL2, BCL6, BCL7A, CCND2, COL3A1, CTGF, FN1, FOXP1, IGHM, IRF4, LMO2, LRMP, MAPK10, MME, MYBL1, NEIL1 and SH3BP5. It predicts and supports the aggressive behaviour of the ABC subgroup. These results help to understand target interactions, improve subgroup diagnosis, risk prognosis as well as therapy in the ABC and GCB DLBCL subgroups.
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Liu, Menghe, Katja Hummitzsch, Monica D. Hartanti, Roseanne Rosario, Nicole A. Bastian, Nicholas Hatzirodos, Wendy M. Bonner, et al. "Analysis of expression of candidate genes for polycystic ovary syndrome in adult and fetal human and fetal bovine ovaries†." Biology of Reproduction 103, no. 4 (July 17, 2020): 840–53. http://dx.doi.org/10.1093/biolre/ioaa119.
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Abstract Polycystic ovary syndrome (PCOS) appears to have a genetic predisposition and a fetal origin. We compared the expression levels of 25 PCOS candidate genes from adult control and PCOS human ovaries (n = 16) using microarrays. Only one gene was potentially statistically different. Using qRT-PCR, expression of PCOS candidate genes was examined in bovine fetal ovaries from early stages when they first developed stroma through to completion of development (n = 27; 60–270 days of gestation). The levels of ERBB3 mRNA negatively correlated with gestational age but positively with HMGA2, FBN3, TOX3, GATA4, and DENND1A.X1,2,3,4, previously identified as correlated with each other and expressed early. PLGRKT and ZBTB16, and less so IRF1, were also correlated with AMH, FSHR, AR, INSR, and TGFB1I1, previously identified as correlated with each other and expressed late. ARL14EP, FDFT1, NEIL2, and MAPRE1 were expressed across gestation and not correlated with gestational age as shown previously for THADA, ERBB4, RAD50, C8H9orf3, YAP1, RAB5B, SUOX, and KRR1. LHCGR, because of its unusual bimodal expression pattern, had some unusual correlations with other genes. In human ovaries (n = 15; <150 days of gestation), ERBB3.V1 and ERBB3.VS were expressed and correlated negatively with gestational age and positively with FBN3, HMGA2, DENND1A.V1,3,4, DENND1A.V1-7, GATA4, and FSHR, previously identified as correlated with each other and expressed early. Thus, the general lack of differential expression of candidate genes in adult ovaries contrasting with dynamic patterns of gene expression in fetal ovaries is consistent with a vulnerability to disturbance in the fetal ovary that may underpin development of PCOS.
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Aghaloo, Tara, Xinquan Jiang, Chia Soo, Zhiyuan Zhang, Xiuli Zhang, Jingzhou Hu, Hongya Pan, et al. "A Study of the Role of Nell-1 Gene Modified Goat Bone Marrow Stromal Cells in Promoting New Bone Formation." Molecular Therapy 15, no. 10 (October 2007): 1872–80. http://dx.doi.org/10.1038/sj.mt.6300270.
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Xia, Lunguo, Yuanjin Xu, Qing Chang, Xiaojuan Sun, Deliang Zeng, Wenjie Zhang, Xiuli Zhang, Zhiyuan Zhang, and Xinquan Jiang. "Maxillary Sinus Floor Elevation Using BMP-2 and Nell-1 Gene-Modified Bone Marrow Stromal Cells and TCP in Rabbits." Calcified Tissue International 89, no. 1 (May 17, 2011): 53–64. http://dx.doi.org/10.1007/s00223-011-9493-1.
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Wang, Xiaoyu, Fang Ju, Ang Li, Shuo Geng, Jiabing Sun, Renhao Liu, Chenglin Yang, and Zhenggang Bi. "Nell-1 Gene Modified Mesenchymal Stem Cells on Biomimetic Porous Nano-Hydroxyapatite/Polyamide 66 Scaffolds Effectively Prevent Nonunion in Rats." Journal of Biomaterials and Tissue Engineering 6, no. 5 (May 1, 2016): 408–16. http://dx.doi.org/10.1166/jbt.2016.1456.
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He, Wenfang, Jinshi Zhang, Shizhu Yuan, Mingzhu Liang, Weidong Chen, and Juan Jin. "Integrative analysis of miRNA–mRNA network in idiopathic membranous nephropathy by bioinformatics analysis." PeerJ 9 (September 29, 2021): e12271. http://dx.doi.org/10.7717/peerj.12271.
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Background Currently, several specific antigens, M-type receptor for secretory phospholipase A2(PLA2R1), thrombospondin type-1 domain-containing 7A(THSD7A), and neural epidermal growth factor-like 1 protein (NELL-1), are discovered associated with the onset of idiopathic membranous nephropathy (IMN). But the pathomechanisms of IMN still need to be further claried. Understanding the mechanisms of IMN is required to improve its diagnosis and treatment. Methods In this study, we constructed miRNA regulatory networks to investigate IMN development. Moreover, miRNAs and mRNAs that were differentially expressed between Idiopathic Membranous Nephropathy (IMN) patients and normal controls were examined using the GSE115857 dataset and our previous sequence study. DE miRNA target genes were determined based on the FUNRICH software, starBase, miRDB, and miRWalk, and an miRNA-mRNA network was designed using DE-mRNAs that were negatively correlated with DE-miRNAs. The miRNA-mRNA network contained 228 miRNA-mRNA pairs. Thereafter, we conducted KEGG pathway, GO functional annotation, immune-related gene screening, protein interaction networks, and potential hub gene analyses. Furthermore, 10 miRNAs and 10 genes were determined and preliminarily validated using the validation dataset from GEO. Finally, we identified which pair may offer more accurate diagnosis and therapeutic targets for IMN. Results Two miRNA-mRNA pairs, miR-155-5p-FOS and miR-146a-5p-BTG2, were differentially expressed in IMN, indicating that these genes may affect IMN through immune processes. These findings may offer more accurate diagnoses and therapeutic targets for IMN.
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Wang, Li, Wenjun Zhang, Tao Yang, Le He, Yunmei Liao, and Jiaxi Lu. "Construction and Comprehensive Analysis of a Stratification System Based on AGTRAP in Patients with Hepatocellular Carcinoma." Disease Markers 2021 (November 17, 2021): 1–18. http://dx.doi.org/10.1155/2021/6144476.
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Background. With the development of sequencing technology, several signatures have been reported for the prediction of prognosis in patients with hepatocellular carcinoma (HCC). However, the above signatures are characterized by cumbersome application. Therefore, the study is aimed at screening out a robust stratification system based on only one gene to guide treatment. Methods. Firstly, we used the limma package for performing differential expression analysis on 374 HCC samples, followed by Cox regression analysis on overall survival (OS) and disease-free interval (PFI). Subsequently, hub prognostic genes were found at the intersection of the above three groups. In addition, the topological degree inside the PPI network was used to screen for a unique hub gene. The rms package was used to construct two visual stratification systems for OS and PFI, and Kaplan-Meier analysis was utilized to investigate survival differences in clinical subgroups. The ssGSEA algorithm was then used to reveal the relationship between the hub gene and immune cells, immunological function, and checkpoints. In addition, we also used function annotation to explore into putative biological functions. Finally, for preliminary validation, the hub gene was knocked down in the HCC cell line. Results. We discovered 6 prognostic genes (SKA1, CDC20, AGTRAP, BIRC5, NEIL3, and CDC25C) for constructing a PPI network after investigating survival and differential expression genes. According to the topological degree, AGTRAP was chosen as the basis for the stratification system, and it was revealed to be a risk factor with an independent prognostic value in Kaplan-Meier analysis and Cox regression analysis ( P < 0.05 ). In addition, we constructed two visualized nomograms based on AGTRAP. The novel stratification system had a robust predictive value for PFI and OS in ROC analysis and calibration curve ( P < 0.05 ). Meanwhile, AGTRAP upregulation was associated with T staging, N staging, M staging, pathological stage, grade, and vascular invasion ( P < 0.05 ). Notably, AGTRAP was overexpressed in tumor tissues in all pancancers with paired samples ( P < 0.05 ). Furthermore, AGTRAP was associated with immune response and may change immune microenvironment in HCC ( P < 0.05 ). Next, gene enrichment analysis suggested that AGTRAP may be involved in the biological process, such as cotranslational protein targeting to the membrane. Finally, we identified the oncogenic effect of AGTRAP by qRT-PCR, colony formation, western blot, and CCK-8 assay ( P < 0.05 ). Conclusion. We provided robust evidences that a stratification system based on AGTRAP can guide survival prediction for HCC patients.
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Jiraskova, Katerina, David Hughes, Stefanie Brezina, Tanja Gumpenberger, Veronika Veskrnova, Tomas Buchler, Michaela Schneiderova, et al. "Functional Polymorphisms in DNA Repair Genes Are Associated with Sporadic Colorectal Cancer Susceptibility and Clinical Outcome." International Journal of Molecular Sciences 20, no. 1 (December 27, 2018): 97. http://dx.doi.org/10.3390/ijms20010097.
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DNA repair processes are involved in both the onset and treatment efficacy of colorectal cancer (CRC). A change of a single nucleotide causing an amino acid substitution in the corresponding protein may alter the efficiency of DNA repair, thus modifying the CRC susceptibility and clinical outcome. We performed a candidate gene approach in order to analyze the association of non-synonymous single nucleotide polymorphisms (nsSNPs) in the genes covering the main DNA repair pathways with CRC risk and clinical outcome modifications. Our candidate polymorphisms were selected according to the foremost genomic and functional prediction databases. Sixteen nsSNPs in 12 DNA repair genes were evaluated in cohorts from the Czech Republic and Austria. Apart from the tumor-node-metastasis (TNM) stage, which occurred as the main prognostic factor in all of the performed analyses, we observed several significant associations of different nsSNPs with survival and clinical outcomes in both cohorts. However, only some of the genes (REV3L, POLQ, and NEIL3) were prominently defined as prediction factors in the classification and regression tree analysis; therefore, the study suggests their association for patient survival. In summary, we provide observational and bioinformatics evidence that even subtle alterations in specific proteins of the DNA repair pathways may contribute to CRC susceptibility and clinical outcome.
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Kip, Markus. "Krisendiagnostik einer kritischen Stadtforschung." sub\urban. zeitschrift für kritische stadtforschung 9, no. 1/2 (April 23, 2021): 171–77. http://dx.doi.org/10.36900/suburban.v9i1/2.680.
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Höhne und Michel (2021) beschreiben Symptome einer „Krise der Städte“, die im Zuge der Coronapandemie deutlicher zum Vorschein kommen. Mit ihren Thesen legen sie nahe, dass es auf ein Ende des Städtischen – as we know it – hinauslaufen könnte. Im Grunde genommen bezeichnen viele der Thesen Entwicklungen, die schon vor der Pandemie zu beobachten waren. Gerne gehe ich auf die Einladung ein, über die Krisendiagnostik einer sich als kritisch verstehenden Stadtforschung zu reflektieren. Anstoß nehme ich daran, dass die Perspektive der Krisendiagnostik im Debattenaufschlag ungeklärt bleibt. Aus wessen Sicht wird hier eine Krise diagnostiziert und mit welchem Zweck? „Kritisch“ im von mir vorgeschlagenen Sinne ist eine Stadtforschung, die sich in der Krise zu verorten und (Ent-)Scheidungen herbeizuführen weiß. Dieser Beitrag argumentiert für eine kritische Stadtforschung als konsequente Fortsetzung des Erbes der Frankfurter Schule. Er baut auf Kernideen aus „What is Critical about Critical Urban Theory?“ von Neil Brenner (2009) auf.
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Skarpengland, Tonje, Lars Erik Laugsand, Imre Janszky, Luisa Luna, Bente Halvorsen, Carl G. P. Platou, Wei Wang, et al. "Genetic variants in the DNA repair gene NEIL3 and the risk of myocardial infarction in a nested case–control study. The HUNT Study." DNA Repair 28 (April 2015): 21–27. http://dx.doi.org/10.1016/j.dnarep.2015.01.013.
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Sobczak, Pitt, Spickett, and Robaszkiewicz. "PARP1 Co-Regulates EP300–BRG1-Dependent Transcription of Genes Involved in Breast Cancer Cell Proliferation and DNA Repair." Cancers 11, no. 10 (October 11, 2019): 1539. http://dx.doi.org/10.3390/cancers11101539.
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BRG1, an active subunit of the SWI/SNF chromatin-remodeling complex, enables the EP300-dependent transcription of proliferation and DNA repair genes from their E2F/CpG-driven promoters in breast cancer cells. In the current study, we show that BRG1–EP300 complexes are accompanied by poly-ADP-ribose polymerase 1 (PARP1), which emerges as the functional component of the promoter-bound multiprotein units that are capable of controlling gene expression. This enzyme is co-distributed with BRG1 at highly acetylated promoters of genes such as CDK4, LIG1, or NEIL3, which are responsible for cancer cell growth and the removal of DNA damage. ADP-ribosylation is necessary to maintain active transcription, since it ensures an open chromatin structure that allows high acetylation and low histone density. PARP1-mediated modification of BRG1 and EP300 does not affect the association of enzymes with gene promoters; however, it does activate EP300, which acetylates nucleosomes, leading to their eviction by BRG1, thus allowing mRNA synthesis. Although PARP1 was found at BRG1 positive/H3K27ac negative promoters of highly expressed genes in a transformed breast cancer cell line, its transcriptional activity was limited to genes simultaneously controlled by BRG1 and EP300, indicating that the ADP-ribosylation of EP300 plays a dominant role in the regulation of BRG1–EP300-driven transcription. In conclusion, PARP1 directs the transcription of some proliferation and DNA repair genes in breast cancer cells by the ADP-ribosylation of EP300, thereby causing its activation and marking nucleosomes for displacement by BRG1. PARP1 in rapidly dividing cells facilitates the expression of genes that confer a cancer cell phenotype. Our study shows a new mechanism that links PARP1 with the removal of DNA damage in breast cancer cells via the regulation of BRG1–EP300-dependent transcription of genes involved in DNA repair pathways.
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Smatlikova, Petra, Georgina Askeland, Michaela Vaskovicova, Jiri Klima, Jan Motlik, Lars Eide, and Zdenka Ellederová. "Age-Related Oxidative Changes in Primary Porcine Fibroblasts Expressing Mutated Huntingtin." Neurodegenerative Diseases 19, no. 1 (2019): 22–34. http://dx.doi.org/10.1159/000500091.
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Background: Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by CAG triplet expansions in the huntingtin gene. Oxidative stress is linked to HD pathology, although it is not clear whether this is an effect or a mediator of disease. The transgenic (TgHD) minipig expresses the N-terminal part of human-mutated huntingtin and represents a unique model to investigate therapeutic strategies towards HD. A more detailed characterization of this model is needed to fully utilize its potential. Methods: In this study, we focused on the molecular and cellular features of fibroblasts isolated from TgHD minipigs and the wild-type (WT) siblings at different ages, pre-symptomatic at the age of 24–36 months and with the onset of behavioural symptoms at the age of 48 months. We measured oxidative stress, the expression of oxidative stress-related genes, proliferation capacity along with the expression of cyclin B1 and D1 proteins, cellular permeability, and the integrity of the nuclear DNA (nDNA) and mitochondrial DNA in these cells. Results: TgHD fibroblasts isolated from 48-month-old animals showed increased oxidative stress, which correlated with the overexpression of SOD2 encoding mitochondrial superoxide dismutase 2, and the NEIL3 gene encoding DNA glycosylase involved in replication-associated repair of oxidized DNA. TgHD cells displayed an abnormal proliferation capacity and permeability. We further demonstrated increased nDNA damage in pre-symptomatic TgHD fibroblasts (isolated from animals aged 24–36 months). Conclusions: Our results unravel phenotypic alterations in primary fibroblasts isolated from the TgHD minipig model at the age of 48 months. Importantly, nDNA damage appears to precede these phenotypic alterations. Our results highlight the impact of fibroblasts from TgHD minipigs in studying the molecular mechanisms of HD pathophysiology that gradually occur with age.
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Chakladar, Jaideep, Neil Shende, Wei Tse Li, and Weg M. Ongkeko. "Abstract 1337: Pan-cancer analysis of immune-associated genes and pathways dysregulated by tobacco reveals osteopontin as a key mediator of smoking-associated carcinogenesis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1337. http://dx.doi.org/10.1158/1538-7445.am2022-1337.
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Abstract Background: Smoking remains a primary etiological agent of 12 different cancers. However, current understanding of the pathogenesis and progression of these smoking-induced cancers remains unclear. Though vaping has been proposed as a safer alternative to cigarette smoking, more research is needed to fully understand its potential to cause cancer. In particular, the chemicals in e-cigarette (e-cig) vapor have previously been demonstrated to cause immune dysregulation, similar to conventional cigarette smoke. In this study, we aimed to investigate the immune-associated (IA) genomic and transcriptomic landscapes of a panel of smoking-induced cancers in order to identify common and unique elements among these cancers and to determine whether certain immune dysregulations may be shared between smoking and vaping. Methods: Whole genome sequencing data from tumors and adjacent normal samples was obtained from The Cancer Genome Atlas (TCGA) to compare the IA landscapes of 5 different smoking-induced cancers: head and neck squamous cell carcinoma (HNSCC), esophageal carcinoma (ESCA), bladder urothelial carcinoma (BLCA), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). Differentially expressed genes were identified and correlated to tumor stage and patient survival. Gene Set Enrichment Analysis and ReactomeFi were used to correlate IA gene expression to cancer pathway enrichment. The REVEALER algorithm was used to correlate gene expression to copy number variations and mutations. Results: We found that the genomic landscapes of smoking-induced cancers were largely unique. However, Osteopontin (OPN), an IA gene capable of regulating the EGFR and CD44 signaling cascades, was found to be upregulated along with its downstream targets in HNSCC, LUAD, LUSC, and ESCA smoking patients. Such upregulation was correlated to poorer prognosis for all 4 cancers. In vitro study indicated an upregulation of OPN and its downstream targets in cell lines exposed to both e-cig vapor and cigarette smoke. Conclusions: Despite few similarities among the IA landscapes of these smoking-induced cancers, we suggest the importance of OPN upregulation in HNSCC, LUSC, LUAD, and ESCA pathogenesis caused by smoking and, potentially, vaping. Citation Format: Jaideep Chakladar, Neil Shende, Wei Tse Li, Weg M. Ongkeko. Pan-cancer analysis of immune-associated genes and pathways dysregulated by tobacco reveals osteopontin as a key mediator of smoking-associated carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1337.
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Morton, Lindsay M., Danielle M. Karyadi, Steven Hartley, Megan Frone, Joshua N. Sampson, Rebecca M. Howell, Joseph Philip Neglia, et al. "Subsequent neoplasm risk associated with rare variants in DNA repair and clinical radiation sensitivity syndrome genes: A report from the Childhood Cancer Survivor Study." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 10028. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.10028.
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10028 Background: Radiotherapy for childhood cancer is associated with strikingly elevated risk for developing subsequent neoplasms (SNs). Whether mutations in DNA repair and radiation sensitivity genes modulate SN risks is largely unknown. Methods: We conducted whole-exome sequencing in 5105 long-term childhood cancer survivors of European descent (mean follow-up = 32.7 years). SnpEff and ClinVar identified potentially damaging rare variants in 476 DNA repair or radiation sensitivity genes. Conditional logistic regression assessed SN risk associated with these variants aggregated by gene or pathway (N = 155 with ≥5 carriers). Controls were matched on sex, childhood cancer type and diagnosis age, radiation dose to the SN site, and survival. Exact p-values were calculated by permutation. Analyses used all survivors or subsets stratified on radiation dose. Results: A total of 1108 (21.7%) survivors developed at least one SN type known to be related to ionizing radiation exposure (e.g., breast cancer, basal cell carcinoma, meningioma, thyroid cancer, sarcoma). Radiation-related SN risk was associated with homologous recombination (HR) gene variants for SN sites that received > 0- < 10 Gy (20.9% cases, 11.0% controls; odds ratio [OR] = 2.20, 95% confidence interval [CI] 1.52-3.18; P = 1.41x10-4), most notably for FANCM (3.1% cases, 0.5% controls; OR = 9.91, 95%CI 3.73-26.4; P = 2.85x10-4). For radiation-related SNs at sites with higher doses (≥10 Gy), associations were not observed for the HR pathway (14.4% cases, 12.4% controls, P = 0.17) but were observed for two individual genes implicated in double-strand DNA break repair, EXO1 (1.8% cases, 0.4% controls; OR = 6.50, 95%CI 3.49-12.1; P = 7.43x10-4) and NEIL3 (0% cases, 1.0% controls; P = 3.23x10-4). Conclusions: In this discovery study, we identified dose-specific novel associations between SN risk after radiotherapy for childhood cancer and potentially damaging rare variants in genes involved in double-strand DNA break repair, particularly HR. If replicated, these results could impact long-term screening of childhood cancer survivors and risk-benefit assessments of treatment approaches.
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Pan, Yi, Lisa E. Kelly, and Heithem M. El-Hodiri. "Identification of retinal homeobox (rax ) gene -dependent genes by a microarray approach: The DNA endoglycosylase neil3 is a major downstream component of the rax genetic pathway." Developmental Dynamics 247, no. 11 (November 2018): 1199–210. http://dx.doi.org/10.1002/dvdy.24679.
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Clarke, Raymond A., Zhiming Fang, Dedee Murrell, Tabrez Sheriff, and Valsamma Eapen. "GDF6 Knockdown in a Family with Multiple Synostosis Syndrome and Speech Impairment." Genes 12, no. 9 (August 29, 2021): 1354. http://dx.doi.org/10.3390/genes12091354.
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Multiple synostoses syndrome type 4 (SYNS4; MIM 617898) is an autosomal dominant disorder characterized by carpal-tarsal coalition and otosclerosis-associated hearing loss. SYSN4 has been associated with GDF6 gain-of-function mutations. Here we report a five-generation SYNS4 family with a reduction in GDF6 expression resulting from a chromosomal breakpoint 3′ of GDF6. A 30-year medical history of the family indicated bilateral carpal-tarsal coalition in ~50% of affected family members and acquired otosclerosis-associated hearing loss in females only, whereas vertebral fusion was present in all affected family members, most of whom were speech impaired. All vertebral fusions were acquired postnatally in progressive fashion from a very early age. Thinning across the 2nd cervical vertebral interspace (C2-3) in the proband during infancy progressed to block fusion across C2-7 and T3-7 later in life. Carpal-tarsal coalition and pisiform expansion were bilaterally symmetrical within, but varied greatly between, affected family members. This is the first report of SYNS4 in a family with reduced GDF6 expression indicating a prenatal role for GDF6 in regulating development of the joints of the carpals and tarsals, the pisiform, ears, larynx, mouth and face and an overlapping postnatal role in suppression of aberrant ossification and synostosis of the joints of the inner ear (otosclerosis), larynx and vertebrae. RNAseq gene expression analysis indicated >10 fold knockdown of NOMO3, RBMXL1 and NEIL2 in both primary fibroblast cultures and fresh white blood cells. Together these results provide greater insight into the role of GDF6 in skeletal joint development.
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Uytingco, Cedric, Jennifer Chew, Naishitha Anaparthy, Jun D. Chiang, Christina Galonska, Karthik Ganapathy, Ryo Hatori, et al. "Abstract 3814: Multiomic characterization of the tumor microenvironment in FFPE tissue by simultaneous protein and gene expression profiling." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3814. http://dx.doi.org/10.1158/1538-7445.am2022-3814.
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Abstract The tumor microenvironment (TME) is composed of highly heterogeneous structures and cell types that dynamically influence and communicate with each other. The constant interaction between a tumor and its microenvironment plays a critical role in how the cancer develops, progresses, and responds to therapies. Traditionally, Hematoxylin and Eosin (H&E) staining has been used to annotate and characterize tissues and associated pathologies. Recent single analyte approaches spatially interrogate targeted or transcriptome-wide expression of RNA in tissue sections, while others capture phenotypes using a limited number of protein markers. However, for a more comprehensive understanding of the unique characteristics of cell types, cell states, and cell-cell interactions within the TME, multiple layers of information are needed and must be studied together. Here we demonstrate a novel, streamlined multiomic spatial assay that integrates histological staining and imaging with simultaneous transcriptome-wide gene expression and highly multiplexed protein expression profiling from the same formalin-fixed paraffin embedded (FFPE) tissue section. In short, tissue sections from archived FFPE samples were placed on slides containing arrayed capture oligos with unique positional barcodes. The H&E or immunofluorescence stained tissues were then imaged, followed by incubation with transcriptome-wide probes and a high-plex DNA-barcoded antibody panel containing intra- and extracellular markers. Transcriptome probes and antibody-barcodes were then spatially captured on the slide and converted into sequencing-ready libraries. Our data analysis and interactive visualization software enable interrogation of all data layers (H&E/immunofluorescence, RNA, protein) from the same tissue section. We apply this method to simultaneously measure gene and protein expression within the TME of human breast cancer and melanoma FFPE samples using whole transcriptome probes and an immune-oncology antibody panel. The data enables comparison and correlation of multiple analytes and their patterns within the same sample section. In addition, this simultaneous detection enables marker-guided regional selection and differential gene expression analysis on the defined regions. Taken together, our data demonstrates that a spatially resolved, multiomic approach provides a more comprehensive understanding of cellular behavior in and around tumors, yielding new insights into disease progression, predictive biomarkers, drug response and resistance, and therapeutic development. Citation Format: Cedric Uytingco, Jennifer Chew, Naishitha Anaparthy, Jun D. Chiang, Christina Galonska, Karthik Ganapathy, Ryo Hatori, Alexander Hermes, Layla Katiraee, Anna-Maria Katsori, William Nitsch, Patrick Roelli, Joe Shuga, Rapolas Spalinskas, Mesruh Turkekul, Benton Veire, Dan Walker, Neil Weisenfeld, Stephen R. Williams, Zachary Bent, Marlon Stoeckius. Multiomic characterization of the tumor microenvironment in FFPE tissue by simultaneous protein and gene expression profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3814.
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Williams, Stephen Richardson, Valeria Giangarra, Naishitha Anaparthy, Mesruh Turkekul, Paulius Mielinis, Caroline Gallant, Neil I. Weisenfeld, Sarah E. Taylor, and James Chell. "Abstract 3812: Spatial whole transcriptome profiling of the tumor microenvironment in FFPE prostate carcinoma using the Visium platform." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3812. http://dx.doi.org/10.1158/1538-7445.am2022-3812.
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Abstract Despite years of prostate cancer-related research, balancing the risk of treatment-derived complications with tumor progression risk remains a challenge. The inability to dissect heterogeneous tumor microenvironments (TME) and immune compartments partly contribute to this knowledge gap. Spatially resolved molecular tumor profiling can enhance our understanding of these complexities and bring us closer to personalized treatment; however, deploying such methods in oncology workflows is challenging as the prevalent tissue preservation technique of formalin fixation and paraffin embedding (FFPE) leads to RNA degradation.We used tissue-wide whole transcriptome analysis with 10x Genomics Visium Spatial Gene Expression Solution for FFPE tissue to resolve the tumor microenvironment of two prostate cancer samples. This assay incorporates ~5,000 molecularly barcoded, spatially encoded capture probes in spots over which the tissue is placed, imaged, and permeabilized. Imaging and sequencing data are processed together for spatially resolved transcriptional readout. We analyzed, and resolved whole transcriptome tumorigenic profiles in sections of normal, stage III invasive adenocarcinoma, and stage IV acinar cell carcinoma FFPE human prostate tissues. Computational clustering of the whole-transcriptome data automatically identified spatial gene expression patterns that aligned well with pathologist annotations. Well known prostate gland and prostate cancer markers were over-expressed in the corresponding healthy and cancerous tumor tissue, validating this method. The data showed that basal cells and luminal cells are spatially organized in healthy tissue while this pattern is lost in tumor samples as the luminal cells encroach the invasive carcinoma region and do not colocalize with basal cells. Moreover, T lymphocytes are dispersed throughout the whole tissue in the adenocarcinoma, while plasma B cells are in the peritumoral region which could impact prognosis. Using computational methods to infer CNV profiles, we identified aneuploidy regions and specific loci that may be driving the underlying genomic profile of the cancerous regions. We demonstrated that spatial whole transcriptome analysis can successfully resolve FFPE prostate samples. Whole-transcriptome data can rapidly confirm known patterns of cell type and tumor region-specific gene expression while giving a better understanding of the TME for drug target identification or biomarker discovery that may lead to patient-tailored therapies and improved patient stratification. Citation Format: Stephen Richardson Williams, Valeria Giangarra, Naishitha Anaparthy, Mesruh Turkekul, Paulius Mielinis, Caroline Gallant, Neil I. Weisenfeld, Sarah E. Taylor, James Chell. Spatial whole transcriptome profiling of the tumor microenvironment in FFPE prostate carcinoma using the Visium platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3812.
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Martin, Sara Barberan, Satyamaanasa Polubothu, Alicia Bruzos, Neil Bulstrode, Gavin Kelly, and Veronica Kinsler. "Abstract 2014: Mosaic BRAF fusions are a recurrent cause of multiple congenital melanocytic naevi." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2014. http://dx.doi.org/10.1158/1538-7445.am2022-2014.
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Abstract Congenital melanocytic naevi (CMN) are moles present at birth, and when multiple or very extensive can involve other organ systems as well as predisposing to melanoma. Some CMN patients develop a highly proliferative multinodular phenotype leading to chronic intense pruritus, and the causes for that specific phenotype progression are poorly understood. Genotypically CMN are mosaic single gene disorders. Thus far only two recurrent variants have been described as clearly causative: NRAS missense variants affecting codon 61 accounting for 68% of cases, and BRAF missense variants affecting codon 600 accounting for 7% of cases. Small numbers of cases of CMN have been reported to carry gene-fusions, and in 2 cases in the world literature (one BRAF-fusion and one RAF1-fusion) these have been shown to be clonal and therefore likely causal. We sought to address the issue of causation of the remaining 25%. From an initial large cohort study, skin biopsies from 19 patients were shown to be double wildtype for NRAS/BRAF and had sufficient tissue for further study after deep whole exome sequencing. These 19 samples then underwent transcriptome-wide paired-end RNA sequencing with bioinformatics analysis (STAR-Fusion v1.6 and Fusion Inspector v2.3) for gene fusion transcripts. 11/19 patients were found to have BRAFgene fusions, of which 7 had the multinodular proliferative phenotype. Fusions were confirmed on Sanger sequencing of the cDNA across the fusion junction, specifically demonstrated in 8 children from more than one separate skin lesion, confirming clonality. In the fusions identified, BRAF was fused to 11 different partner genes (GOLGA4, QKI, STRN3, AGAP3, MKRN2, PHIP, LCA5, EEA1, AKAP9, SEC31A, MIER3). This resulted in loss of the 5’ regulatory domain of BRAF but preservation of the kinase domain, such that expression was driven by the 5’ fusion partner. This structure follows the pattern of somatic BRAF-fusions reported previously in solid tumors including melanoma. Potential dimerization domains in the partner genes were identified in 9 cases. We identify here mosaic BRAF fusions as a recurrent cause of multiple CMN allowing genetic diagnosis in a further 15% of cases and linking this genotype to a highly proliferative pruritic phenotype. In vitro data from melanoma cell lines have suggested that higher expression levels of the fusion protein as well as dimerization domains in the partner gene correlate with resistance and/or paradoxical MAP-kinase activation after treatment with RAF and MEK inhibitors. This may have implications for the use of targeted therapies for attempted reduction of the nodular phenotype, or where melanoma arises in CMN patients caused by mosaic BRAF-fusions. Citation Format: Sara Barberan Martin, Satyamaanasa Polubothu, Alicia Bruzos, Neil Bulstrode, Gavin Kelly, Veronica Kinsler. Mosaic BRAF fusions are a recurrent cause of multiple congenital melanocytic naevi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2014.
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Costa, Rosalina Pisco. "Book Review: Gene H Bell-Villada and Nina Sichel (eds), (with Faith Eidse and Elaine Neil Orr), Writing Out of Limbo: International Childhoods, Global Nomads and Third Culture Kids." International Sociology 30, no. 2 (March 2015): 191–93. http://dx.doi.org/10.1177/0268580915571816.
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Kay, Neil E., Terry J. Hamblin, Diane F. Jelinek, Gordon W. Dewald, John C. Byrd, Sherif Farag, Margaret Lucas, and Thomas Lin. "Chronic Lymphocytic Leukemia." Hematology 2002, no. 1 (January 1, 2002): 193–213. http://dx.doi.org/10.1182/asheducation-2002.1.193.
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Abstract This update of early stage B-cell chronic lymphocytic leukemia (B-CLL) embraces current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. Emphasis on early stage is based on the rapid advancement in our understanding of the disease parameters and our increasing ability to predict for a given early stage patient whether there is a need for more aggressive management. In Section I, Dr. Terry Hamblin addresses the nature of the disease, accurate diagnostic procedures, evidence for an early “preclinical” phase, the use of newer prognostic features to distinguish who will be likely to progress or not, and whether it is best to watch or treat early stage disease. In Section II, Dr. Neil Kay and colleagues address the biologic aspects of the disease and how they may relate to disease progression. Review of the newer insights into gene expression, recurring genetic defects, role of cytokines/autocrine pathways, and the interaction of the CLL B cell with the microenvironment are emphasized. The relationship of these events to both trigger disease progression and as opportunities for future therapeutic intervention even in early stage disease is also considered. In Section III, Dr. John Byrd and colleagues review the historical and now current approaches to management of the previously untreated progressive B-CLL patient. They discuss what decision tree could be used in the initial decision to treat a given patient. The use of single agents versus newer combination approaches such as chemoimmunotherapy are discussed here. In addition, the place of marrow transplant and some of the newer antibodies available for treatment of B-CLL are considered. Finally, a challenge to utilize our growing knowledge of the biology of B-CLL in the early stage B-CLL is proffered.
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Zhang, Xu, Jihyun Song, Binal N. Shah, Galina Miasnikova, Adelina Sergueeva, Josef T. Prchal, and Victor R. Gordeuk. "Hypoxic Response-Dependent Genetic Regulation Revealed By Allele-Specific Expression in Reticulocytes of Chuvash Polycythemia." Blood 130, Suppl_1 (December 7, 2017): 926. http://dx.doi.org/10.1182/blood.v130.suppl_1.926.926.
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Abstract Homozygosity for the VHLR200W mutation in Chuvash polycythemia (CP) leads to decreased degradation of the α subunits of hypoxia inducible factor (HIF)-1 and HIF-2 by the hypomorphic variant of VHL, the principal negative regulator of HIFs. The constitutively activated HIFs directly regulate the transcription of a suite of hypoxic responsible genes, including the principal regulators of erythropoiesis, vessel development, and glycolytic metabolism, which further trigger a downstream cascade of gene expression. Besides these transcriptional factors, cis acting elements play an important role in the hypoxic gene regulatory network. To assess the extent of cis regulatory variation in hypoxic gene expression, we compared allele-specific expression (ASE) in purified reticulocytes between VHLR200W homozygote individuals and age- and gender-matched wild type control individuals living at the same altitude of ~200 meters from the Chuvash population. Cell fractions of reticulocytes were purified from 17 VHLR200W homozygotes and 13 wild type individuals. Total RNA was extracted, depleted of ribosomal RNA and hemoglobin transcripts, and reverse transcribed. Strand-specific libraries were constructed for 125 bp paired-end sequencing to 30-45 million read pairs per sample using Illumina HiSeq 2500 platform. The samples were collected and processed in three batches across two years, with VHL genotype randomized in each batch. The sequencing data were mapped to human reference genome and analyzed for differential expression and differential ASE between VHLR200W homozygotes and wild type individuals. At 5% false discovery rate (FDR, i.e., <5 false positives in 100 detected genes), 1,267 genes were differentially expressed with more than 1.2-fold change in CP patients, 703 elevated and 564 decreased. Genes up-regulated in CP were enriched (fold enrichment >5, FDR <0.05) in REACTOME pathways of epigenetic remodeling (Packaging of telomere ends, DNA methylation, HDACs deacetylate histones, PRC2 methylates histones and DNA, Deposition of new CENPA-containing nucleosomes at the centromere, HATs acetylate histones) and oxidative stress induced senescence (DNA damage/telomere stress induced senescence, Senescence-associated secretory phenotype, Oxidative stress induced senescence). Genes decreased in CP were enriched in REACTOME pathways of cell cycle (E2F-enabled inhibition of pre-replication complex formation, Nuclear pore complex disassembly, SUMOylation of DNA replication proteins) and DNA damage repair (Activation of ATR in response to replication stress, SUMOylation of DNA damage response and repair proteins). ASE was analyzed between CP and wild type individuals to assess hypoxic response-dependent genetic effects on gene expression. For the 1,267 genes differentially expressed in the CP, we selected genes containing exonic SNPs with heterozygous alleles for ASE analysis. With a null hypothesis of no cis acting regulation on the gene expression, both alleles are expected to be expressed at the same level, whereas allelic imbalance indicates linked cis regulation. At a given bi-allelic SNP, individuals with ≥2 read counts covering each of the reference and alternative alleles and with ≥20 total counts were included in the analysis. Exonic SNPs with at least one individual in each of the CP and wild type group were further selected to test for differential ASE between the CP and wild type groups, using a generalized linear model. A total of 147 genes passed the filtering and were analyzed, among which 32 were detected to have significant CP-dependent ASE at 5% FDR. Some of these genes may have important roles in hypoxic responses in CP reticulocytes, for example NEIL3, encoding a DNA glycosylase that initiates the first step in base excision repair by cleaving bases damaged by reactive oxygen species, and STOM, encoding an integral membrane protein that localizes to the cell membrane of red blood cells, loss of which is associated with hereditary stomatocytosis. Our study reveals plethora of gene expression changes in CP reticulocytes compared to wild type controls, among which 22% could be regulated by hypoxic response-specific cis genetic variations. These observations indicate the prominence of cis elements in hypoxic response, for which substantial inter-individual differences exist even among a relatively isolated population. Disclosures Gordeuk: Emmaus Life Sciences: Consultancy.