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  • 1
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    Online Resource
    Isolation of New Colibactin Metabolites from Wild-Type Escherichia coli and In Situ Trapping of a Mature Colibactin Derivative
    American Chemical Society (ACS) ; 2021
    In:  Journal of the American Chemical Society Vol. 143, No. 14 ( 2021-04-14), p. 5526-5533
    Details
    In: Journal of the American Chemical Society, American Chemical Society (ACS), Vol. 143, No. 14 ( 2021-04-14), p. 5526-5533
    Type of Medium: Online Resource
    ISSN: 0002-7863 , 1520-5126
    URL: Article
    URL: Article
    DOI: 10.1021/jacs.1c01495
    DOI: 10.1021/jacs.1c01495.s001
    RVK:
    VA 1120 ; VA 1752
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2021
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    detail.hit.zdb_id: 3155-0
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  • 2
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    Maspin subcellular expression in wild-type and mutant TP53 gastric cancers
    Baishideng Publishing Group Inc. ; 2020
    In:  World Journal of Gastrointestinal Oncology Vol. 12, No. 7 ( 2020-7-15), p. 741-755
    Details
    In: World Journal of Gastrointestinal Oncology, Baishideng Publishing Group Inc., Vol. 12, No. 7 ( 2020-7-15), p. 741-755
    Type of Medium: Online Resource
    ISSN: 1948-5204
    URL: Article
    DOI: 10.4251/wjgo.v12.i7.741
    Language: Unknown
    Publisher: Baishideng Publishing Group Inc.
    Publication Date: 2020
    detail.hit.zdb_id: 2573696-6
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  • 3
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    Mother-to-infant transmission of the carcinogenic colibactin-producing bacteria
    Springer Science and Business Media LLC ; 2021
    In:  BMC Microbiology Vol. 21, No. 1 ( 2021-12)
    Details
    In: BMC Microbiology, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2021-12)
    Abstract: The Escherichia coli strain that is known to produce the genotoxic secondary metabolite colibactin is linked to colorectal oncogenesis. Therefore, understanding the properties of such colibactin-positive E. coli and the molecular mechanism of oncogenesis by colibactin may provide us with opportunities for early diagnosis or prevention of colorectal oncogenesis. While there have been major advances in the characterization of colibactin-positive E. coli and the toxin it produces, the infection route of the clb  + strain remains poorly characterized. Results We examined infants and their treatments during and post-birth periods to examine potential transmission of colibactin-positive E. coli to infants. Here, analysis of fecal samples of infants over the first month of birth for the presence of a colibactin biosynthetic gene revealed that the bacterium may be transmitted from mother to infant through intimate contacts, such as natural childbirth and breastfeeding, but not through food intake. Conclusions Our finding suggests that transmission of colibactin-positive E. coli appears to be occurring at the very early stage of life of the newborn and hints at the possibility of developing early preventive measures against colorectal cancer.
    Type of Medium: Online Resource
    ISSN: 1471-2180
    URL: Article
    DOI: 10.1186/s12866-021-02292-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2041505-9
    SSG: 12
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  • 4
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    Genotyping of a gene cluster for production of colibactin and in vitro genotoxicity analysis of Escherichia coli strains obtained from the Japan Collection of Microorganisms
    Springer Science and Business Media LLC ; 2020
    In:  Genes and Environment Vol. 42, No. 1 ( 2020-12)
    Details
    In: Genes and Environment, Springer Science and Business Media LLC, Vol. 42, No. 1 ( 2020-12)
    Abstract: Colibactin is a small genotoxic molecule produced by enteric bacteria, including certain Escherichia coli ( E. coli ) strains harbored in the human large intestine. This polyketide-peptide genotoxin is considered to contribute to the development of colorectal cancer. The colibactin-producing ( clb + ) microorganisms possess a 54-kilobase genomic island ( clb gene cluster). In the present study, to assess the distribution of the clb gene cluster, genotyping analysis was carried out among E. coli strains randomly chosen from the Japan Collection of Microorganisms, RIKEN BRC, Japan. Findings The analysis revealed that two of six strains possessed a clb gene cluster. These clb + strains JCM5263 and JCM5491 induced genotoxicity in in vitro micronucleus (MN) tests using rodent CHO AA8 cells. Since the induction level of MN by JCM5263 was high, a bacterial umu test was carried out with a cell extract of the strain, revealing that the extract had SOS-inducing potency in the umu tester bacterium. Conclusion These results support the observations that the clb gene cluster is widely distributed in nature and clb + E. coli having genotoxic potencies is not rare among microorganisms.
    Type of Medium: Online Resource
    ISSN: 1880-7062
    URL: Article
    DOI: 10.1186/s41021-020-00149-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2269162-5
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  • 5
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    Non-CpG sites preference in G:C 〉 A:T transition of TP53 in gastric cancer of Eastern Europe (Poland, Romania and Hungary) compared to East Asian countries (China and Japan)
    Springer Science and Business Media LLC ; 2023
    In:  Genes and Environment Vol. 45, No. 1 ( 2023-01-04)
    Details
    In: Genes and Environment, Springer Science and Business Media LLC, Vol. 45, No. 1 ( 2023-01-04)
    Abstract: Mutation spectrum of TP53 in gastric cancer (GC) has been investigated world-widely, but a comparison of mutation spectrum among GCs from various regions in the world are still sparsely documented. In order to identify the difference of TP53 mutation spectrum in GCs in Eastern Europe and in East Asia, we sequenced TP53 in GCs from Eastern Europe, Lujiang (China), and Yokohama, Kanagawa (Japan) and identified the feature of TP53 mutations of GC in these regions. Subjects and method In total, 689 tissue samples of GC were analyzed: 288 samples from East European populations (25 from Hungary, 71 from Poland and 192 from Romania), 268 from Yokohama, Kanagawa, Japan and 133 from Lujiang, Anhui province, China. DNA was extracted from FFPE tissue of Chinese, East European cases; and from frozen tissue of Japanese GCs. PCR products were direct-sequenced by Sanger method, and in ambiguous cases, PCR product was cloned and up to 8 clones were sequenced. We used No. NC_000017.11(hg38) as the reference sequence of TP53 . Mutation patterns were categorized into nine groups: six base substitutions, insertion, deletion and deletion-insertion. Within G:C  〉  A:T mutations the mutations in CpG and non-CpG sites were divided. The Cancer Genome Atlas data (TCGA, ver.R20, July, 2019) having somatic mutation list of GCs from Whites, Asians, and other ethnicities were used as a reference for our data. Results The most frequent base substitutions were G:C  〉  A:T transition in all the areas investigated. The G:C  〉  A:T transition in non-CpG sites were prominent in East European GCs, compared with Asian ones. Mutation pattern from TCGA data revealed the same trend between GCs from White (TCGA category) vs Asian countries. Chinese and Japanese GCs showed higher ratio of G:C  〉  A:T transition in CpG sites and A:T  〉  G:C mutation was more prevalent in Asian countries. Conclusion The divergence in mutation spectrum of GC in different areas in the world may reflect various pathogeneses and etiologies of GC, region to region. Diversified mutation spectrum in GC in Eastern Europe may suggest GC in Europe has different carcinogenic pathway of those from Asia.
    Type of Medium: Online Resource
    ISSN: 1880-7062
    URL: Article
    DOI: 10.1186/s41021-022-00257-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2269162-5
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  • 6
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    Online Resource
    Mass spectrometric profiling of DNA adducts in the human stomach associated with damage from environmental factors
    Springer Science and Business Media LLC ; 2021
    In:  Genes and Environment Vol. 43, No. 1 ( 2021-12)
    Details
    In: Genes and Environment, Springer Science and Business Media LLC, Vol. 43, No. 1 ( 2021-12)
    Abstract: A comprehensive understanding of DNA adducts, one of the most plausible origins of cancer mutations, is still elusive, especially in human tissues in clinical settings. Recent technological developments have facilitated the identification of multiple DNA adducts in a single experiment. Only a few attempts toward this “DNA adductome approach” in human tissues have been reported. Geospatial information on DNA adducts in human organs has been scarce. Aim Mass spectrometry of human gastric mucosal DNA was performed to identify DNA adducts associated with environmental factors. Materials and methods From 59 subjects who had received gastrectomy for gastric cancer, 306 samples of nontumor tissues and 15 samples of tumors (14 cases) were taken for DNA adductome analysis. Gastric nontumor tissue from autopsies of 7 subjects without gastric cancer (urothelial cancer, hepatocellular carcinoma, lung cancer each; the other four cases were without any cancers) was also investigated. Briefly, DNA was extracted from each sample with antioxidants, digested into nucleosides, separated by liquid chromatography, and then electrospray-ionized. Specific DNA adducts were identified by mass/charge number and column retention time compared to standards. Information on lifestyle factors such as tobacco smoking and alcohol drinking was taken from the clinical records of each subject. Results Seven DNA adducts, including modified bases, C5-methyl-2′-deoxycytidine, 2′-deoxyinosine, C5-hydroxymethyl-2′-deoxycytidine, N6-methyl-2′-deoxyadenosine, 1,N6-etheno-2′-deoxyadenosine, N6-hydroxymethyl-2′-deoxyadenosine, and C8-oxo-2′-deoxyguanosine, were identified in the human stomach and characterized. Intraindividual differences according to the multiple sites of these adducts were noted but were less substantial than interindividual differences. N6-hydroxymethyl-2′-deoxyadenosine was identified in the human stomach for the first time. The amount of C5-hydroxymethyl-2′-deoxycytidine was higher in the stomachs of subjects without gastric cancer than in the nontumor and tumor portions of the stomach in gastric cancer patients. Higher levels of 1,N6-etheno-2′-deoxyadenosine were detected in the subjects who reported both smoking and drinking than in those without these habits. These DNA adducts showed considerable correlations with each other. Conclusions We characterized 7 DNA adducts in the nontumor portion of the human stomach in both gastric cancer subjects and nongastric cancer subjects. A reduction in C5-hydroxymethyl-dC even in the nontumor mucosa of patients with gastric cancer was observed. Smoking and drinking habits significantly influenced the quantity of one of the lipid peroxidation-derived adducts, etheno-dA. A more expansive DNA adductome profile would provide a comprehensive understanding of the origin of human cancer in the future.
    Type of Medium: Online Resource
    ISSN: 1880-7062
    URL: Article
    DOI: 10.1186/s41021-021-00186-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2269162-5
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  • 7
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    TP53 mutations in Romanian patients with colorectal cancer
    Springer Science and Business Media LLC ; 2023
    In:  Genes and Environment Vol. 45, No. 1 ( 2023-07-01)
    Details
    In: Genes and Environment, Springer Science and Business Media LLC, Vol. 45, No. 1 ( 2023-07-01)
    Abstract: Colorectal cancer (CRC) has been ranked as the second most deadly cancer and the third most diagnosed cancer cases for the year 2020. Specifically for Romania, the number of CRC-related deaths in 2019 was estimated at 6307 people, with a standardized mortality rate of 33.8 per 100,000 inhabitants. Although the tumor protein 53 ( TP53 ) gene is intensively studied, there are few data on TP53 mutations in Romanian CRC. Furthermore, since genetic alterations may show geographical differences, our study aimed to analyze the clinical status and TP53 somatic variation in Romanian CRC patients. Subjects and methods DNA from 40 randomly selected cases of CRC was extracted from formalin-fixed paraffin-embedded tissues and sequenced using direct Sanger sequencing techniques, and variants were annotated according to the recommendations of the Human Genome Variation Society. Novel variants were analyzed using MutationTaster2021 to predict their effects. Results The mean age was 63.6 years (range 33–85 years) with a male to female ratio of 2.3. More than 45% (18/40) had an advanced cancer stage (≥ stage III). Mutations were found in 21/40 cases (52.5%), with one case having two mutations, giving a total of twenty-two mutations in the TP53 coding DNA. These mutations include 3 (13.6%) insertion-deletion mutations, two of which are novel frameshift mutations: c.165delT (in exon 4) and c.928_935dup (in exon 9), both of which are predicted to lead to nonsense-mediated mRNA decay and are classified as deleterious. The remaining 19 (86.36%) were substitution mutations: 1 nonsense and 18 (81.8%) missense mutations, with G  〉  A (n = 7/19; 36.8%) and C  〉  T (n = 6/19; 31.5%) transitions being the most common. The G  〉  T transversion was found in 21.05% (4/19) of the substitution mutations. Conclusion We have described two novel frameshift mutations in TP53 . The discovery of novel mutations following the efforts of The Cancer Genome Atlas and other large-scale cancer genome sequencing projects may be further evidence of the heterogeneous nature of mutations in cancer and may indicate that the identification of carcinogenic mutations is not yet saturated. Further sequencing is therefore needed, especially in less studied populations. Importantly, consideration of their geographical environment will shed light on population-specific carcinogenesis.
    Type of Medium: Online Resource
    ISSN: 1880-7062
    URL: Article
    DOI: 10.1186/s41021-023-00277-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2269162-5
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  • 8
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    Abstract 2131: m6A demethylase ALKBH5 promote tumor growth through IGF2BPs' recognition of m6A modified CDKN1A in non-small lung cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2131-2131
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2131-2131
    Abstract: Background: N6-methyladenosine (m6A), the most prevalent and abundant RNA modification on eukaryote mRNA, is regulated by the methylation complex (writer) and demethylase (eraser), subsequently being recognized by RNA-binding protein (reader). As an m6A eraser, ALKBH5 has been shown to promote the development of breast cancer and glioblastoma. In lung cancer, two experiments described contradictory findings that one is a cancer-promoting effect and the other is a cancer-suppressing effect. Accordingly, the carcinogenic mechanisms of ALKBH5 are not completely elucidated in lung cancer. The purpose of this study is to investigate the role of m6A demethylase ALKBH5 in lung cancer. Method: We investigated the relationship between eraser protein expression level by immunostaining (IHC) and prognosis in 629 patients with non-small cell lung cancer (NSCLC). Small interfering RNA transfection was used to down-regulate ALKBH5 in PC9 and A549 cells. Then, cell function assays (cell proliferation, migration ability, cell cycle, apoptosis) were conducted in cells. In addition, mRNA and m6A expression under the ALKBH5 knockdown were comprehensively analyzed by microarray. The m6A target genes were identified by Methylated RNA immunoprecipitation (MeRIP) assay using m6A antibody. Furthermore, the mRNA stability and protein expression of the m6A target gene was examined. Result: High expression of ALKBH5 showed a poor prognosis (p & lt;0.001). ALKBH5 knockdown suppressed cell proliferation ability in PC9 and A549. G1 arrest and increased apoptotic cells were observed by ALKBH5 knockdown in cells. In addition, overexpression of ALKBH5 increased the cell proliferation ability in HEK293 and BEAS2B. Comprehensive analysis of microarray revealed up-regulation of CDKN1A, E2F1, GADD45A, TIMP3, and DNMT3B, and down-regulation of CASP14 and CCNG2 by ALKBH5 knockdown. m6A microarray showed up-regulation of m6A modification in 22 genes by ALKBH5 knockdown. MeRIP qPCR with fragmented mRNA showed m6A level in 3'UTR regions of CDKN1A, TIMP3, E2F1, DNMT3B, and CCNG2 were increased by ALKBH5 knockdown. The CDKN1A mRNA was stabilized by ALKBH5 knockdown, and the increased expression of CDKN1A was down-regulated by IGF2BPs knockdown. The protein expression of p21, MFAP5, and TIMP3 was up-regulated by ALKBH5 knockdown. The up-regulated expression of p21 was p53-independent. Conclusion: High expression of ALKBH5 has an unfavorable prognostic value in NSCLC. ALKBH5 knockdown increases m6A of 3'UTR of CDKN1A, which is recognized by IGF2BPs and enhances mRNA stability. The increased expression of p21 leads to the regulation of the cell cycle, regulating cell proliferation ability. Taken together, ALKBH5 plays a cancer-promoting role in non-small cell lung cancer. Citation Format: Kazuo Tsuchiya, Katsuhiro Yoshimura, Yusuke Inoue, Yuji Iwashita, Tsutomu Ohta, Hidetaka Yamada, Hirofumi Watanabe, Hong Tao, Akikazu Kawase, Masayuki Tanahashi, Hiroshi Ogawa, Kazuhito Funai, Kazuya Shinmura, Takafumi Suda, Haruhiko Sugimura. m6A demethylase ALKBH5 promote tumor growth through IGF2BPs' recognition of m6A modified CDKN1A in non-small lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2131.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2131
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Geospatial Assessments of DNA Adducts in the Human Stomach: A Model of Field Cancerization
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 15 ( 2021-07-24), p. 3728-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 15 ( 2021-07-24), p. 3728-
    Abstract: Background: Field cancerization is a popular concept regarding where cancer cells arise in a plane, such as the opened-up gastrointestinal mucosa. The geospatial distribution of DNA adducts, some of which are believed to initiate mutation, may be a clue to understanding the landscape of the preferred occurrence of gastric cancer in the human stomach, such that the occurrence is much more frequent in the lesser curvature than in the greater curvature. Methods: Seven DNA adducts, C5-methyl-2′-deoxycytidine, 2′-deoxyinosine, C5-hydroxymethyl-2′-deoxycytidine, N6-methyl-2′-deoxyadenosine, 1,N6-etheno-2′-deoxyadenosine, N6-hydroxymethyl-2′-deoxyadenosine, and C8-oxo-2′-deoxyguanosine, from different points and zones of the human stomach were semi quantitatively measured by liquid chromatography/tandem mass spectrometry. The differences in the quantity of these DNA adducts from the lesser and greater curvature, the upper, middle and lower third zones, the anterior and posterior wall of the stomach, and the mucosae distant from and near the tumor were compared to determine whether the location preference of cancer in the stomach could be explained by the distribution of these DNA adducts. Comparisons were conducted considering the tumor locations and operation methods. Conclusions: Regarding the DNA adducts investigated, significant differences in quantities and locations in the whole stomach were not noted; thus, these DNA adducts do not explain the preferential occurrence of cancer in particular locations of the human stomach.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13153728
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 10
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    Clinicopathological Characteristics and Mutational Landscape of APC, HOXB13, and KRAS among Rwandan Patients with Colorectal Cancer
    MDPI AG ; 2023
    In:  Current Issues in Molecular Biology Vol. 45, No. 5 ( 2023-05-16), p. 4359-4374
    Details
    In: Current Issues in Molecular Biology, MDPI AG, Vol. 45, No. 5 ( 2023-05-16), p. 4359-4374
    Abstract: Cancer research in Rwanda is estimated to be less than 1% of the total African cancer research output with limited research on colorectal cancer (CRC). Rwandan patients with CRC are young, with more females being affected than males, and most patients present with advanced disease. Considering the paucity of oncological genetic studies in this population, we investigated the mutational status of CRC tissues, focusing on the Adenomatous polyposis coli (APC), Kirsten rat sarcoma (KRAS), and Homeobox B13 (HOXB13) genes. Our aim was to determine whether there were any differences between Rwandan patients and other populations. To do so, we performed Sanger sequencing of the DNA extracted from formalin-fixed paraffin-embedded adenocarcinoma samples from 54 patients (mean age: 60 years). Most tumors were located in the rectum (83.3%), and 92.6% of the tumors were low-grade. Most patients (70.4%) reported never smoking, and 61.1% of patients had consumed alcohol. We identified 27 variants of APC, including 3 novel mutations (c.4310_4319delAAACACCTCC, c.4463_4470delinsA, and c.4506_4507delT). All three novel mutations are classified as deleterious by MutationTaster2021. We found four synonymous variants (c.330C 〉 A, c.366C 〉 T, c.513T 〉 C, and c.735G 〉 A) of HOXB13. For KRAS, we found six variants (Asp173, Gly13Asp, Gly12Ala, Gly12Asp, Gly12Val, and Gln61His), the last four of which are pathogenic. In conclusion, here we contribute new genetic variation data and provide clinicopathological information pertinent to CRC in Rwanda.
    Type of Medium: Online Resource
    ISSN: 1467-3045
    URL: Article
    DOI: 10.3390/cimb45050277
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2090836-2
    SSG: 12
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