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  1. Article ; Online: Applying molecular epidemiology in pediatric leukemia.

    Schiffman, Joshua D

    Journal of investigative medicine : the official publication of the American Federation for Clinical Research

    2016  Volume 64, Issue 2, Page(s) 355–360

    Abstract: Molecular epidemiology is the study of genetic and environmental risk for disease, with much effort centered on cancer. Childhood leukemia occurs in nearly a third of all patients newly diagnosed with pediatric cancer. only a small percentage of these ... ...

    Abstract Molecular epidemiology is the study of genetic and environmental risk for disease, with much effort centered on cancer. Childhood leukemia occurs in nearly a third of all patients newly diagnosed with pediatric cancer. only a small percentage of these new cases of childhood leukemia are associated with high penetrant hereditary cancer syndromes. Childhood leukemia, especially acute lymphoblastic leukemia, has been associated with a dysregulated immune system due to delayed infectious exposure at a young age. Identical twins with childhood leukemia suggest that acute lymphoblastic leukemia begins in utero and that the concordant presentation is due to a shared preleukemia subclone via placental transfer. Investigation of single nucleotide polymorphisms within candidate genes find that leukemia risk may be attributed to population-based polymorphisms affecting folate metabolism, xenobiotic metabolism, DNA repair, immunity, and B-cell development. More recently, genome-wide association studies for leukemia risk has led investigators to genes associated with B-cell development. When describing leukemia predisposition due to hereditary cancer syndromes, the following 6 categories become apparent on the basis of biology and clinical presentation: (1) genetic instability/DNA repair syndromes, (2) cell cycle/differentiation syndromes, (3) bone marrow failure syndromes, (4) telomere maintenance syndromes, (5) immunodeficiency syndromes, and (6) transcription factor syndromes and pure familial leukemia. understanding the molecular epidemiology of childhood leukemia can affect the treatment and tumor surveillance strategies for these high risk patients and their family members.
    MeSH term(s) Child ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomic Instability ; Humans ; Inheritance Patterns/genetics ; Leukemia/epidemiology ; Leukemia/genetics ; Molecular Epidemiology
    Language English
    Publishing date 2016-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1217870-6
    ISSN 1708-8267 ; 0009-9279 ; 1081-5589
    ISSN (online) 1708-8267
    ISSN 0009-9279 ; 1081-5589
    DOI 10.1097/JIM.0000000000000204
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The evidence for expanded genetic testing for pediatric patients with cancer.

    Maese, Luke / Schiffman, Joshua D

    Future oncology (London, England)

    2018  Volume 14, Issue 3, Page(s) 187–190

    MeSH term(s) Genetic Association Studies ; Genetic Predisposition to Disease ; Genetic Testing/methods ; Genomics/methods ; Humans ; Neoplasms/diagnosis ; Neoplasms/genetics ; Pediatrics ; Precision Medicine/methods
    Language English
    Publishing date 2018-01-12
    Publishing country England
    Document type Editorial
    ZDB-ID 2184533-5
    ISSN 1744-8301 ; 1479-6694
    ISSN (online) 1744-8301
    ISSN 1479-6694
    DOI 10.2217/fon-2017-0467
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Genome-wide analyses of sarcoma: implications for future treatment options.

    Schiffman, Joshua D

    Future oncology (London, England)

    2013  Volume 9, Issue 3, Page(s) 307–310

    MeSH term(s) Cell Transformation, Neoplastic/genetics ; Gastrointestinal Neoplasms/enzymology ; Gastrointestinal Neoplasms/genetics ; Gastrointestinal Neoplasms/therapy ; Gastrointestinal Stromal Tumors/enzymology ; Gastrointestinal Stromal Tumors/genetics ; Gastrointestinal Stromal Tumors/therapy ; Gene Dosage ; Genome, Human ; Genome-Wide Association Study ; Humans ; Rhabdomyosarcoma/genetics ; Rhabdomyosarcoma/therapy ; Sarcoma/enzymology ; Sarcoma/genetics ; Sarcoma/therapy ; Succinate Dehydrogenase/deficiency ; Translocation, Genetic
    Chemical Substances Succinate Dehydrogenase (EC 1.3.99.1)
    Language English
    Publishing date 2013-03
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2184533-5
    ISSN 1744-8301 ; 1479-6694
    ISSN (online) 1744-8301
    ISSN 1479-6694
    DOI 10.2217/fon.13.1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: ATM and ATR Activation Through Crosstalk Between DNA Damage Response Pathways.

    Fedak, Elizabeth A / Adler, Frederick R / Abegglen, Lisa M / Schiffman, Joshua D

    Bulletin of mathematical biology

    2021  Volume 83, Issue 4, Page(s) 38

    Abstract: Cells losing the ability to self-regulate in response to damage are a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process ...

    Abstract Cells losing the ability to self-regulate in response to damage are a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process would be remarkable if it were based on the total amount of damage in the cell, but because damage detection pathways vary in the rate and intensity with which they promote pro-apoptotic factors, the cell's real challenge is to reconcile dissimilar signals. Crosstalk between repair pathways, crosstalk between pro-apoptotic signaling kinases, and signals induced by damage by-products complicate the process further. The cell's response to [Formula: see text] and UV radiation neatly illustrates this concept. While these forms of radiation produce lesions associated with two different pro-apoptotic signaling kinases, ATM and ATR, recent experiments show that ATM and ATR react to both forms of radiation. To simulate the pro-apoptotic signal induced by [Formula: see text] and UV radiation, we construct a mathematical model that includes three modes of crosstalk between ATM and ATR signaling pathways: positive feedback between ATM/ATR and repair proteins, ATM and ATR mutual upregulation, and changes in lesion topology induced by replication stress or repair. We calibrate the model to agree with 21 experimental claims about ATM and ATR crosstalk. We alter the model by adding or removing specific processes and then examine the effects of each process on ATM/ATR crosstalk by recording which claims the altered model violates. Not only is this the first mathematical model of ATM/ATR crosstalk, it provides a strong argument for treating pro-apoptotic signaling as a holistic effort rather than attributing it to a single dominant kinase.
    MeSH term(s) Apoptosis/radiation effects ; Ataxia Telangiectasia Mutated Proteins/metabolism ; DNA Damage/radiation effects ; DNA Repair/physiology ; Gamma Rays ; Models, Biological ; Neoplasms/physiopathology ; Signal Transduction ; Ultraviolet Rays
    Chemical Substances Atr protein, mouse (EC 2.7.1.-) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
    Language English
    Publishing date 2021-03-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 184905-0
    ISSN 1522-9602 ; 0007-4985 ; 0092-8240
    ISSN (online) 1522-9602
    ISSN 0007-4985 ; 0092-8240
    DOI 10.1007/s11538-021-00868-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Evolutionary determinants of curability in cancer.

    Mansur, Marcela Braga / deSouza, Nandita M / Natrajan, Rachael / Abegglen, Lisa M / Schiffman, Joshua D / Greaves, Mel

    Nature ecology & evolution

    2023  Volume 7, Issue 11, Page(s) 1761–1770

    Abstract: The emergence of drug-resistant cells, most of which have a mutated TP53 gene, prevents curative treatment in most advanced and common metastatic cancers of adults. Yet, a few, rarer malignancies, all of which are TP53 wild type, have high cure rates. In ...

    Abstract The emergence of drug-resistant cells, most of which have a mutated TP53 gene, prevents curative treatment in most advanced and common metastatic cancers of adults. Yet, a few, rarer malignancies, all of which are TP53 wild type, have high cure rates. In this Perspective, we discuss how common features of curable cancers offer insights into the evolutionary and developmental determinants of drug resistance. Acquired loss of TP53 protein function is the most common genetic change in cancer. This probably reflects positive selection in the context of strong ecosystem pressures including microenvironmental hypoxia. Loss of TP53's functions results in multiple fitness benefits and enhanced evolvability of cancer cells. TP53-null cells survive apoptosis, and tolerate potent oncogenic signalling, DNA damage and genetic instability. In addition, critically, they provide an expanded pool of self-renewing, or stem, cells, the primary units of evolutionary selection in cancer, making subsequent adaptation to therapeutic challenge by drug resistance highly probable. The exceptional malignancies that are curable, including the common genetic subtype of childhood acute lymphoblastic leukaemia and testicular seminoma, differ from the common adult cancers in originating prenatally from embryonic or fetal cells that are developmentally primed for TP53-dependent apoptosis. Plus, they have other genetic and phenotypic features that enable dissemination without exposure to selective pressures for TP53 loss, retaining their intrinsic drug hypersensitivity.
    MeSH term(s) Adult ; Humans ; Ecosystem ; Neoplasms/genetics ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/therapeutic use ; Biological Evolution
    Chemical Substances Tumor Suppressor Protein p53
    Language English
    Publishing date 2023-08-24
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2397-334X
    ISSN (online) 2397-334X
    DOI 10.1038/s41559-023-02159-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Hereditary cancer syndromes: if you look, you will find them.

    Schiffman, Joshua D

    Pediatric blood & cancer

    2011  Volume 58, Issue 1, Page(s) 5–6

    MeSH term(s) Genetic Predisposition to Disease ; Genetic Testing ; Humans ; Neoplastic Syndromes, Hereditary/diagnosis ; Neoplastic Syndromes, Hereditary/genetics
    Language English
    Publishing date 2011-09-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2131448-2
    ISSN 1545-5017 ; 1545-5009
    ISSN (online) 1545-5017
    ISSN 1545-5009
    DOI 10.1002/pbc.23336
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: 50 Years Ago in TheJournal ofPediatrics: Multiple Cutaneous Cancers in Children: The Nevoid Basal Cell Carcinoma Syndrome.

    Garfield, Kinley / Schiffman, Joshua D

    The Journal of pediatrics

    2016  Volume 174, Page(s) 239

    MeSH term(s) Basal Cell Nevus Syndrome/genetics ; Basal Cell Nevus Syndrome/history ; Child ; Genetic Predisposition to Disease/history ; History, 20th Century ; Humans ; Mutation ; Pediatrics/history ; Skin/pathology ; Skin Neoplasms/genetics ; Skin Neoplasms/history ; Skin Neoplasms/pathology
    Language English
    Publishing date 2016-06-21
    Publishing country United States
    Document type Classical Article ; Historical Article ; Journal Article
    ZDB-ID 3102-1
    ISSN 1097-6833 ; 0022-3476
    ISSN (online) 1097-6833
    ISSN 0022-3476
    DOI 10.1016/j.jpeds.2016.01.062
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: No child left behind in SDHB testing for paragangliomas and pheochromocytomas.

    Schiffman, Joshua D

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology

    2011  Volume 29, Issue 31, Page(s) 4070–4072

    MeSH term(s) Adrenal Gland Neoplasms/genetics ; Adrenal Gland Neoplasms/pathology ; Female ; Genetic Testing ; Germ-Line Mutation ; Humans ; Male ; Paraganglioma/genetics ; Pheochromocytoma/genetics ; Succinate Dehydrogenase/genetics
    Chemical Substances SDHB protein, human (EC 1.3.5.1) ; Succinate Dehydrogenase (EC 1.3.99.1)
    Language English
    Publishing date 2011-11-01
    Publishing country United States
    Document type Comment ; Editorial
    ZDB-ID 604914-x
    ISSN 1527-7755 ; 0732-183X
    ISSN (online) 1527-7755
    ISSN 0732-183X
    DOI 10.1200/JCO.2011.37.8695
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Germ Cell Mosaicism: A Rare Cause of Li-Fraumeni Recurrence Among Siblings.

    Donovan, Lauren N / Kohlmann, Wendy / Snow, Angela K / Neklason, Deborah W / Schiffman, Joshua D / Maese, Luke

    JCO precision oncology

    2020  Volume 4

    Language English
    Publishing date 2020-06-16
    Publishing country United States
    Document type Case Reports
    ISSN 2473-4284
    ISSN (online) 2473-4284
    DOI 10.1200/PO.20.00064
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Discussing and managing hematologic germ line variants.

    Kohlmann, Wendy / Schiffman, Joshua D

    Hematology. American Society of Hematology. Education Program

    2016  Volume 2016, Issue 1, Page(s) 309–315

    Abstract: With the introduction of genomic technologies, more hereditary cancer syndromes with hematologic malignancies are being described. Up to 10% of hematologic malignancies in children and adults may be the result of an underlying inherited genetic risk. ... ...

    Abstract With the introduction of genomic technologies, more hereditary cancer syndromes with hematologic malignancies are being described. Up to 10% of hematologic malignancies in children and adults may be the result of an underlying inherited genetic risk. Managing these patients with hereditary hematologic malignancies, including familial leukemia, remains a clinical challenge because there is little information about these relatively rare disorders. This article covers some of the issues related to the diagnosis and interpretation of variants associated with hereditary hematologic malignancies, including the importance of an accurate family history in interpreting genetic variants associated with disease. The challenges of screening other family members and offering the most appropriate early malignancy detection is also discussed. We now have a good opportunity to better define hereditary cancer syndromes with associated hematologic malignancies and contribute to clinically effective guidelines.
    MeSH term(s) Adolescent ; Adult ; Child ; Child, Preschool ; Germ-Line Mutation ; Hematologic Neoplasms/genetics ; Hematologic Neoplasms/metabolism ; Hematologic Neoplasms/therapy ; Humans ; Neoplastic Syndromes, Hereditary/genetics ; Neoplastic Syndromes, Hereditary/metabolism ; Neoplastic Syndromes, Hereditary/therapy
    Language English
    Publishing date 2016-11-30
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 1520-4383
    ISSN (online) 1520-4383
    DOI 10.1182/asheducation-2016.1.309
    Database MEDical Literature Analysis and Retrieval System OnLINE

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