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  1. Article ; Online: WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma.

    Rialdi, Alex / Duffy, Mary / Scopton, Alex P / Fonseca, Frank / Zhao, Julia Nanyi / Schwarz, Megan / Molina-Sanchez, Pedro / Mzoughi, Slim / Arceci, Elisa / Abril-Fornaguera, Jordi / Meadows, Austin / Ruiz de Galarreta, Marina / Torre, Denis / Reyes, Kyna / Lim, Yan Ting / Rosemann, Felix / Khan, Zaigham M / Mohammed, Kevin / Wang, Xuedi /
    Yu, Xufen / Lakshmanan, Manikandan / Rajarethinam, Ravisankar / Tan, Soo Yong / Jin, Jian / Villanueva, Augusto / Michailidis, Eleftherios / De Jong, Ype P / Rice, Charles M / Marazzi, Ivan / Hasson, Dan / Llovet, Josep M / Sobota, Radoslaw M / Lujambio, Amaia / Guccione, Ernesto / Dar, Arvin C

    Nature cancer

    2023  Volume 4, Issue 8, Page(s) 1157–1175

    Abstract: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi- ... ...

    Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. β-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant β-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index.
    MeSH term(s) Humans ; Mice ; Animals ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/genetics ; beta Catenin/genetics ; beta Catenin/metabolism ; Liver Neoplasms/drug therapy ; Liver Neoplasms/genetics ; Transcription Factors/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
    Chemical Substances beta Catenin ; Transcription Factors ; Antineoplastic Agents ; Protein Kinase Inhibitors
    Language English
    Publishing date 2023-08-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2662-1347
    ISSN (online) 2662-1347
    DOI 10.1038/s43018-023-00609-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Identification of IGF2 as Genomic Driver and Actionable Therapeutic Target in Hepatoblastoma.

    Abril-Fornaguera, Jordi / Torrens, Laura / Andreu-Oller, Carmen / Carrillo-Reixach, Juan / Rialdi, Alex / Balaseviciute, Ugne / Pinyol, Roser / Montironi, Carla / Haber, Philipp K / Del Río-Álvarez, Álvaro / Domingo-Sàbat, Montserrat / Royo, Laura / Akers, Nicholas K / Willoughby, Catherine E / Peix, Judit / Torres-Martin, Miguel / Puigvehi, Marc / Cairo, Stefano / Childs, Margaret /
    Maibach, Rudolf / Alaggio, Rita / Czauderna, Piotr / Morland, Bruce / Losic, Bojan / Mazzaferro, Vincenzo / Guccione, Ernesto / Sia, Daniela / Armengol, Carolina / Llovet, Josep M

    Molecular cancer therapeutics

    2023  Volume 22, Issue 4, Page(s) 485–498

    Abstract: Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular ... ...

    Abstract Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB. Paired tumor and adjacent tissues from 31 HBs and a validation set of 50 HBs were analyzed using RNA-seq, SNP, and methylation arrays. IGF2 overexpression was identified as the top targetable HB driver, present in 71% of HBs (22/31). IGF2high tumors displayed progenitor cell features and shorter recurrence-free survival. IGF2 overexpression was associated in 91% of cases with fetal promoter hypomethylation, ICR1 deregulation, 11p15.5 loss of heterozygosity or miR483-5p overexpression. The antitumor effect of xentuzumab (a monoclonal antibody targeting IGF1/2) alone or in combination with the conventional therapeutic agent cisplatin was assessed in HB cell lines, in PDX-derived HB organoids and in a xenograft HB murine model. The combination of xentuzumab with cisplatin showed strong synergistic antitumor effects in organoids and in IGF2high cell lines. In mice (n = 55), the combination induced a significant decrease in tumor volume and improved survival compared with cisplatin alone. These results suggest that IGF2 is an HB actionable driver and that, in preclinical models of HB, the combination of IGF1/2 inhibition with cisplatin induces superior antitumor effects than cisplatin monotherapy. Overall, our study provides a rationale for testing IGF2 inhibitors in combination with cisplatin in HB patients with IGF2 overexpression.
    MeSH term(s) Humans ; Animals ; Mice ; Hepatoblastoma/drug therapy ; Hepatoblastoma/genetics ; Hepatoblastoma/pathology ; Cisplatin/pharmacology ; Cisplatin/therapeutic use ; Liver Neoplasms/drug therapy ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; DNA Methylation ; Genomics ; Insulin-Like Growth Factor II/genetics
    Chemical Substances Cisplatin (Q20Q21Q62J) ; IGF2 protein, human ; Insulin-Like Growth Factor II (67763-97-7)
    Language English
    Publishing date 2023-02-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-22-0335
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation.

    Fong, Jia Yi / Pignata, Luca / Goy, Pierre-Alexis / Kawabata, Kimihito Cojin / Lee, Stanley Chun-Wei / Koh, Cheryl M / Musiani, Daniele / Massignani, Enrico / Kotini, Andriana G / Penson, Alex / Wun, Cheng Mun / Shen, Yudao / Schwarz, Megan / Low, Diana Hp / Rialdi, Alexander / Ki, Michelle / Wollmann, Heike / Mzoughi, Slim / Gay, Florence /
    Thompson, Christine / Hart, Timothy / Barbash, Olena / Luciani, Genna M / Szewczyk, Magdalena M / Wouters, Bas J / Delwel, Ruud / Papapetrou, Eirini P / Barsyte-Lovejoy, Dalia / Arrowsmith, Cheryl H / Minden, Mark D / Jin, Jian / Melnick, Ari / Bonaldi, Tiziana / Abdel-Wahab, Omar / Guccione, Ernesto

    Cancer cell

    2019  Volume 36, Issue 2, Page(s) 194–209.e9

    Abstract: Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly ... ...

    Abstract Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Catalysis ; Enzyme Inhibitors/pharmacokinetics ; Enzyme Inhibitors/pharmacology ; Ethylenediamines/pharmacokinetics ; Ethylenediamines/pharmacology ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Humans ; K562 Cells ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Protein-Arginine N-Methyltransferases/antagonists & inhibitors ; Protein-Arginine N-Methyltransferases/genetics ; Protein-Arginine N-Methyltransferases/metabolism ; Pyrroles/pharmacokinetics ; Pyrroles/pharmacology ; RNA Splicing/drug effects ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Repressor Proteins/antagonists & inhibitors ; Repressor Proteins/metabolism ; THP-1 Cells ; Tumor Cells, Cultured ; U937 Cells ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Enzyme Inhibitors ; Ethylenediamines ; MS023 compound ; Pyrroles ; RNA, Neoplasm ; Repressor Proteins ; PRMT1 protein, human (EC 2.1.1.319) ; PRMT5 protein, human (EC 2.1.1.319) ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319)
    Language English
    Publishing date 2019-09-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2019.07.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology.

    Yu, Jia Xin / Craig, Amanda J / Duffy, Mary E / Villacorta-Martin, Carlos / Miguela, Verónica / Ruiz de Galarreta, Marina / Scopton, Alexander P / Silber, Lisa / Maldonado, Andres Y / Rialdi, Alexander / Guccione, Ernesto / Lujambio, Amaia / Villanueva, Augusto / Dar, Arvin C

    Molecular cancer therapeutics

    2019  Volume 18, Issue 9, Page(s) 1506–1519

    Abstract: The approved kinase inhibitors for hepatocellular carcinoma (HCC) are not matched to specific mutations within tumors. This has presented a daunting challenge; without a clear target or mechanism, no straightforward path has existed to guide the ... ...

    Abstract The approved kinase inhibitors for hepatocellular carcinoma (HCC) are not matched to specific mutations within tumors. This has presented a daunting challenge; without a clear target or mechanism, no straightforward path has existed to guide the development of improved therapies for HCC. Here, we combine phenotypic screens with a class of conformation-specific kinase inhibitors termed type II to identify a multikinase inhibitor, AD80, with antitumoral activity across a variety of HCC preclinical models, including mouse xenografts. Mass spectrometry profiling found a number of kinases as putative targets for AD80, including several receptor and cytoplasmic protein kinases. Among these, we found p38 gamma and delta as direct targets of AD80. Notably, a closely related analog of AD80 lacking p38δ/γ activity, but retaining several other off-target kinases, lost significant activity in several HCC models. Moreover, forced and sustained MKK6 → p38→ATF2 signaling led to a significant reduction of AD80 activity within HCC cell lines. Together with HCC survival data in The Cancer Genome Atlas and RNA-seq analysis, we suggest p38 delta and gamma as therapeutic targets in HCC and an "AD80 inhibition signature" as identifying those patients with best clinical outcomes.
    MeSH term(s) Animals ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/pathology ; Cell Line, Tumor ; Drug Screening Assays, Antitumor/methods ; Female ; Heterocyclic Compounds, 4 or More Rings/chemistry ; Heterocyclic Compounds, 4 or More Rings/pharmacokinetics ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms/drug therapy ; Liver Neoplasms/pathology ; Male ; Mice, Inbred C57BL ; Mice, Nude ; Mitogen-Activated Protein Kinase 12/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 12/chemistry ; Mitogen-Activated Protein Kinase 13/antagonists & inhibitors ; Mitogen-Activated Protein Kinase 13/chemistry ; Phenotype ; Polypharmacology ; Xenograft Model Antitumor Assays/methods
    Chemical Substances AD80 compound ; Heterocyclic Compounds, 4 or More Rings ; Mitogen-Activated Protein Kinase 12 (EC 2.7.1.-) ; Mitogen-Activated Protein Kinase 13 (EC 2.7.1.-)
    Language English
    Publishing date 2019-06-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-18-0571
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Influenza virus infection causes global RNAPII termination defects.

    Zhao, Nan / Sebastiano, Vittorio / Moshkina, Natasha / Mena, Nacho / Hultquist, Judd / Jimenez-Morales, David / Ma, Yixuan / Rialdi, Alex / Albrecht, Randy / Fenouil, Romain / Sánchez-Aparicio, Maria Teresa / Ayllon, Juan / Ravisankar, Sweta / Haddad, Bahareh / Ho, Jessica Sook Yuin / Low, Diana / Jin, Jian / Yurchenko, Vyacheslav / Prinjha, Rab K /
    Tarakhovsky, Alexander / Squatrito, Massimo / Pinto, Dalila / Allette, Kimaada / Byun, Minji / Smith, Melissa Laird / Sebra, Robert / Guccione, Ernesto / Tumpey, Terrence / Krogan, Nevan / Greenbaum, Benjamin / van Bakel, Harm / García-Sastre, Adolfo / Marazzi, Ivan

    Nature structural & molecular biology

    2018  Volume 25, Issue 9, Page(s) 885–893

    Abstract: Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection ... ...

    Abstract Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3' ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3' extensions and host-gene fusions) that ultimately cause global transcriptional downregulation of physiological transcripts, an effect influencing antiviral response and virulence. This phenomenon occurs with multiple strains of IAV, is dependent on influenza NS1 protein, and can be modulated by SUMOylation of an intrinsically disordered region (IDR) of NS1 expressed by the 1918 pandemic IAV strain. Our data identify a strategy used by IAV to suppress host gene expression and indicate that polymorphisms in IDRs of viral proteins can affect the outcome of an infection.
    MeSH term(s) Humans ; Influenza A virus/pathogenicity ; Influenza A virus/physiology ; Influenza, Human/genetics ; RNA Polymerase II/genetics ; Terminator Regions, Genetic/genetics ; Virulence
    Chemical Substances RNA Polymerase II (EC 2.7.7.-)
    Language English
    Publishing date 2018-09-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-018-0124-7
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    Zs.A 4101: Show issues Location:
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  6. Article ; Online: Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.

    Rialdi, Alex / Campisi, Laura / Zhao, Nan / Lagda, Arvin Cesar / Pietzsch, Colette / Ho, Jessica Sook Yuin / Martinez-Gil, Luis / Fenouil, Romain / Chen, Xiaoting / Edwards, Megan / Metreveli, Giorgi / Jordan, Stefan / Peralta, Zuleyma / Munoz-Fontela, Cesar / Bouvier, Nicole / Merad, Miriam / Jin, Jian / Weirauch, Matthew / Heinz, Sven /
    Benner, Chris / van Bakel, Harm / Basler, Christopher / García-Sastre, Adolfo / Bukreyev, Alexander / Marazzi, Ivan

    Science (New York, N.Y.)

    2016  Volume 352, Issue 6289, Page(s) aad7993

    Abstract: The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of ... ...

    Abstract The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. We identified topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against influenza and Ebola viruses as well as bacterial products. Therapeutic pharmacological inhibition of Top1 protected mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life-threatening infections characterized by an acutely exacerbated immune response.
    MeSH term(s) Animals ; Azepines/pharmacology ; Azepines/therapeutic use ; Camptothecin/pharmacology ; Camptothecin/therapeutic use ; DNA Topoisomerases, Type I/metabolism ; Ebolavirus ; Flavonoids/pharmacology ; Flavonoids/therapeutic use ; Gene Expression Regulation/drug effects ; HEK293 Cells ; Hemorrhagic Fever, Ebola/drug therapy ; Host-Pathogen Interactions/drug effects ; Host-Pathogen Interactions/genetics ; Humans ; Immunity, Innate ; Inflammation/drug therapy ; Inflammation/genetics ; Inflammation/microbiology ; Influenza A virus ; Interferon-beta/immunology ; Mice ; Mice, Inbred C57BL ; Piperidines/pharmacology ; Piperidines/therapeutic use ; Positive Transcriptional Elongation Factor B/antagonists & inhibitors ; RNA Polymerase II/metabolism ; Sendai virus ; Staphylococcal Infections/drug therapy ; Staphylococcus aureus ; Topoisomerase I Inhibitors/pharmacology ; Topoisomerase I Inhibitors/therapeutic use ; Topotecan/therapeutic use ; Transcription, Genetic/drug effects ; Triazoles/pharmacology ; Triazoles/therapeutic use
    Chemical Substances (+)-JQ1 compound ; Azepines ; Flavonoids ; Piperidines ; Topoisomerase I Inhibitors ; Triazoles ; alvocidib (45AD6X575G) ; Interferon-beta (77238-31-4) ; Topotecan (7M7YKX2N15) ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; RNA Polymerase II (EC 2.7.7.-) ; DNA Topoisomerases, Type I (EC 5.99.1.2) ; Camptothecin (XT3Z54Z28A)
    Language English
    Publishing date 2016-05-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aad7993
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  7. Article: Influences of Maternal Stress during Pregnancy on the Epi/genome: Comparison of Placenta and Umbilical Cord Blood.

    Chen, Jia / Li, Qian / Rialdi, Alexender / Mystal, Elana / Ly, Jenny / Finik, Jackie / Davey, Taira / Lambertini, Luca / Nomura, Yoko

    Journal of depression & anxiety

    2014  Volume 3, Issue 2

    Abstract: Background: Maternal stress during pregnancy is one of the major adverse environmental factors in utero that is capable of influencing health outcomes of the offspring throughout life. Both genetic and epigenetic processes are susceptible to ... ...

    Abstract Background: Maternal stress during pregnancy is one of the major adverse environmental factors in utero that is capable of influencing health outcomes of the offspring throughout life. Both genetic and epigenetic processes are susceptible to environmental insults in utero and are potential biomarkers of the experienced environment including maternal stress.
    Methods: We profiled expression level of six genes in hypothalamic pituitary adrenal (HPA) axis functioning (HSD11B2, SLC6A4, NR3C1, NR3C2, CRHR1 and CRHR2), two imprinted genes (IGF2 and H19) and one neurodevelopmental gene (EGR1), from 49 pairs of placenta and umbilical cord blood (UCB) samples from a birth cohort. We also assessed global methylation levels by LUminometric Methylation Assay (LUMA) and methylation at the imprinting control region (ICR) of IGF2/H19.
    Results: Little correlations between paired placenta and UCB were observed except H19 expression (r = 0.31, P = 0.04) and IGF2/H19 ICR methylation (r = 0.43, P = 0.01); gene expression levels were significantly higher (P < 0.001) in placenta than UCB except CRHR1 and CRHR2, which were unexpressed in placenta. Maternal stress correlated higher levels of HPA genes and lower levels of EGR1 and LUMA, but only in placenta. Positive association between maternal stress and IGF2/H19 ICR methylation was present in both placenta and UCB.
    Conclusions: Our findings support the notion that adverse in utero environment, as measured by antenatal maternal stress, depression and anxiety, can be observed in the epi/genome of the relevant tissues, i.e. placenta and UCBs, leading to development of molecular markers for assessing in utero adversities.
    Language English
    Publishing date 2014-02-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2765350-X
    ISSN 2167-1044
    ISSN 2167-1044
    DOI 10.4172/2167-1044.1000152
    Database MEDical Literature Analysis and Retrieval System OnLINE

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