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  1. Article ; Online: Impaired interferon signature in severe COVID-19.

    Gruber, Conor

    Nature reviews. Immunology

    2020  Volume 20, Issue 6, Page(s) 353

    Keywords covid19
    Language English
    Publishing date 2020-04-29
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/s41577-020-0335-0
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  3. Article ; Online: Impaired interferon signature in severe COVID-19

    Gruber, Conor

    Nature Reviews Immunology

    2020  Volume 20, Issue 6, Page(s) 353–353

    Keywords Immunology ; covid19
    Language English
    Publisher Springer Science and Business Media LLC
    Publishing country us
    Document type Article ; Online
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/s41577-020-0335-0
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  4. Article ; Online: Incomplete penetrance in primary immunodeficiency: a skeleton in the closet.

    Gruber, Conor / Bogunovic, Dusan

    Human genetics

    2020  Volume 139, Issue 6-7, Page(s) 745–757

    Abstract: Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand ... ...

    Abstract Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.
    MeSH term(s) Epigenesis, Genetic ; Gene-Environment Interaction ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Mosaicism ; Penetrance ; Primary Immunodeficiency Diseases/genetics ; Primary Immunodeficiency Diseases/immunology ; Primary Immunodeficiency Diseases/pathology
    Language English
    Publishing date 2020-02-17
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 223009-4
    ISSN 1432-1203 ; 0340-6717
    ISSN (online) 1432-1203
    ISSN 0340-6717
    DOI 10.1007/s00439-020-02131-9
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  5. Article ; Online: IL4Rα and IL17A Blockade Rescue Autoinflammation in SOCS1 Haploinsufficiency.

    Gruber, Conor / Lee, Angelica / Buta, Sofija / Khattri, Saakshi / Gottlieb, Alice B / Frost, Jacqueline M / Bowcock, Anne M / Ho, Hsi-En / Bogunovic, Dusan

    Journal of clinical immunology

    2023  Volume 44, Issue 1, Page(s) 36

    Abstract: By inhibition of JAK-STAT signaling, SOCS1 acts as a master regulator of the cytokine response across numerous tissue types and cytokine pathways. Haploinsufficiency of SOCS1 has recently emerged as a monogenic immunodysregulatory disease with marked ... ...

    Abstract By inhibition of JAK-STAT signaling, SOCS1 acts as a master regulator of the cytokine response across numerous tissue types and cytokine pathways. Haploinsufficiency of SOCS1 has recently emerged as a monogenic immunodysregulatory disease with marked clinical variability. Here, we describe a patient with severe dermatitis, recurrent skin infections, and psoriatic arthritis that harbors a novel heterozygous mutation in SOCS1. The variant, c.202_203delAC, generates a frameshift in SOCS1, p.Thr68fsAla*49, which leads to complete loss of protein expression. Unlike WT SOCS1, Thr68fs SOCS1 fails to inhibit JAK-STAT signaling when expressed in vitro. The peripheral immune signature from this patient was marked by a redistribution of monocyte sub-populations and hyper-responsiveness to multiple cytokines. Despite this broad hyper-response across multiple cytokine pathways in SOCS1 haploinsufficiency, the patient's clinical disease was markedly responsive to targeted IL4Rα- and IL17-blocking therapy. In accordance, the mutant allele was unable to regulate IL4Rα signaling. Further, patient cells were unresponsive to IL4/IL13 while on monoclonal antibody therapy. Together, this study reports a novel SOCS1 mutation and suggests that IL4Rα blockade may serve as an unexpected, but fruitful therapeutic target for some patients with SOCS1 haploinsufficiency.
    MeSH term(s) Humans ; Suppressor of Cytokine Signaling 1 Protein/genetics ; Suppressor of Cytokine Signaling 1 Protein/metabolism ; Haploinsufficiency ; Suppressor of Cytokine Signaling Proteins/genetics ; Suppressor of Cytokine Signaling Proteins/metabolism ; Signal Transduction ; Cytokines/metabolism ; Interleukin-17/genetics
    Chemical Substances Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling Proteins ; Cytokines ; SOCS1 protein, human ; IL17A protein, human ; Interleukin-17
    Language English
    Publishing date 2023-12-29
    Publishing country Netherlands
    Document type Case Reports ; Journal Article
    ZDB-ID 779361-3
    ISSN 1573-2592 ; 0271-9142
    ISSN (online) 1573-2592
    ISSN 0271-9142
    DOI 10.1007/s10875-023-01635-z
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  6. Article ; Online: Acquired chemoresistance drives spatial heterogeneity, chemoprotection and collective migration in pancreatic tumor spheroids.

    Thege, Fredrik I / Cardle, Ian I / Gruber, Conor N / Siemann, Megan J / Cong, Sophie / Wittmann, Katharina / Love, Justin / Kirby, Brian J

    PloS one

    2022  Volume 17, Issue 5, Page(s) e0267882

    Abstract: Tumors display rich cellular heterogeneity and typically consist of multiple co-existing clones with distinct genotypic and phenotypic characteristics. The acquisition of resistance to chemotherapy has been shown to contribute to the development of ... ...

    Abstract Tumors display rich cellular heterogeneity and typically consist of multiple co-existing clones with distinct genotypic and phenotypic characteristics. The acquisition of resistance to chemotherapy has been shown to contribute to the development of aggressive cancer traits, such as increased migration, invasion and stemness. It has been hypothesized that collective cellular behavior and cooperation of cancer cell populations may directly contribute to disease progression and lack of response to treatment. Here we show that the spontaneous emergence of chemoresistance in a cancer cell population exposed to the selective pressure of a chemotherapeutic agent can result in the emergence of collective cell behavior, including cell-sorting, chemoprotection and collective migration. We derived several gemcitabine resistant subclones from the human pancreatic cancer cell line BxPC3 and determined that the observed chemoresistance was driven of a focal amplification of the chr11p15.4 genomic region, resulting in over-expression of the ribonucleotide reductase (RNR) subunit RRM1. Interestingly, these subclones display a rich cell-sorting behavior when cultured as mixed tumor spheroids. Furthermore, we show that chemoresistant cells are able to exert a chemoprotective effect on non-resistant cells in spheroid co-culture, whereas no protective effect is seen in conventional 2D culture. We also demonstrate that the co-culture of resistant and non-resistant cells leads to collective migration where resistant cells enable migration of otherwise non-migratory cells.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Coculture Techniques ; Drug Resistance, Neoplasm/genetics ; Humans ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Spheroids, Cellular/metabolism
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2022-05-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0267882
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  7. Article ; Online: Rationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma.

    Oh, Danielle H / Ma, Xiao / Hogg, Simon J / He, Jackson / Kearney, Conor / Brasacchio, Daniella / Susanto, Olivia / Maher, Belinda / Jennings, Ian G / Newbold, Andrea / Fraser, Peter / Gruber, Emily / Kats, Lev M / Gregory, Gareth P / Johnstone, Ricky W / Thompson, Philip E / Shortt, Jake

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 36, Page(s) e2306414120

    Abstract: Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis ( ...

    Abstract Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis (
    MeSH term(s) Humans ; Phosphatidylinositol 3-Kinases ; Phosphatidylinositol 3-Kinase ; Aggression ; Epigenomics ; Lymphoma/drug therapy ; Phosphoinositide-3 Kinase Inhibitors
    Chemical Substances Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Phosphoinositide-3 Kinase Inhibitors
    Language English
    Publishing date 2023-08-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2306414120
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    Zs.A 1148: Show issues Location:
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  8. Article ; Online: ISG15 deficiency restricts HIV-1 infection.

    Jurczyszak, Denise / Manganaro, Lara / Buta, Sofija / Gruber, Conor / Martin-Fernandez, Marta / Taft, Justin / Patel, Roosheel S / Cipolla, Melissa / Alshammary, Hala / Mulder, Lubbertus C F / Sachidanandam, Ravi / Bogunovic, Dusan / Simon, Viviana

    PLoS pathogens

    2022  Volume 18, Issue 3, Page(s) e1010405

    Abstract: Type I interferons (IFN-Is) are a group of potent inflammatory and antiviral cytokines. They induce IFN stimulated genes (ISGs), which act as proinflammatory mediators, antiviral effectors, and negative regulators of the IFN-I signaling cascade itself. ... ...

    Abstract Type I interferons (IFN-Is) are a group of potent inflammatory and antiviral cytokines. They induce IFN stimulated genes (ISGs), which act as proinflammatory mediators, antiviral effectors, and negative regulators of the IFN-I signaling cascade itself. One such regulator is interferon stimulated gene 15 (ISG15). Humans with complete ISG15 deficiency express persistently elevated levels of ISGs, and consequently, exhibit broad spectrum resistance to viral infection. Here, we demonstrate that IFN-I primed fibroblasts derived from ISG15-deficient individuals are more resistant to infection with single-cycle HIV-1 compared to healthy control fibroblasts. Complementation with both wild-type (WT) ISG15 and ISG15ΔGG (incapable of ISGylation while retaining negative regulation activity) was sufficient to reverse this phenotype, restoring susceptibility to infection to levels comparable to WT cells. Furthermore, CRISPR-edited ISG15ko primary CD4+ T cells were less susceptible to HIV-1 infection compared to cells treated with non-targeting controls. Transcriptome analysis of these CRISPR-edited ISG15ko primary CD4+ T cells recapitulated the ISG signatures of ISG15 deficient patients. Taken together, we document that the increased broad-spectrum viral resistance in ISG15-deficiency also extends to HIV-1 and is driven by a combination of T-cell-specific ISGs, with both known and unknown functions, predicted to target HIV-1 replication at multiple steps.
    MeSH term(s) Antiviral Agents/pharmacology ; Cytokines/genetics ; HIV Infections/genetics ; HIV-1 ; Humans ; Interferon Type I ; Ubiquitins/genetics
    Chemical Substances Antiviral Agents ; Cytokines ; Interferon Type I ; Ubiquitins ; ISG15 protein, human (60267-61-0)
    Language English
    Publishing date 2022-03-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1010405
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  9. Article ; Online: A case of methimazole-induced chronic arthritis masquerading as seronegative rheumatoid arthritis.

    Gruber, Conor N / Finzel, Kathleen / Gruber, Barry L

    Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases

    2014  Volume 20, Issue 4, Page(s) 229–232

    Abstract: We report a 40-year-old woman with onset of oligoarthritis shortly after initiating treatment with methimazole for Graves disease. Over the course of 7 years, her arthritis became progressively severe, leading to a diagnosis of seronegative rheumatoid ... ...

    Abstract We report a 40-year-old woman with onset of oligoarthritis shortly after initiating treatment with methimazole for Graves disease. Over the course of 7 years, her arthritis became progressively severe, leading to a diagnosis of seronegative rheumatoid arthritis. Treatment with disease-modifying antirheumatic agents and surgical intervention was contemplated. Ultrasound and magnetic resonance imaging revealed exuberant synovitis, involving right elbow and knees. Upon withdrawal of methimazole, prompt resolution of all signs and symptoms of arthritis was observed within several weeks. Following a MEDLINE search of available literature concerning antithyroid drug-induced arthritis, it is evident that this case represents the lengthiest duration of inflammatory arthropathy ever described in a patient that nonetheless was rapidly reversible with discontinuation of methimazole.
    MeSH term(s) Adult ; Antithyroid Agents/adverse effects ; Arthritis, Rheumatoid/chemically induced ; Arthritis, Rheumatoid/diagnosis ; Chronic Disease ; Diagnosis, Differential ; Female ; Graves Disease/drug therapy ; Humans ; Methimazole/adverse effects
    Chemical Substances Antithyroid Agents ; Methimazole (554Z48XN5E)
    Language English
    Publishing date 2014-06
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 1283266-2
    ISSN 1536-7355 ; 1076-1608
    ISSN (online) 1536-7355
    ISSN 1076-1608
    DOI 10.1097/RHU.0000000000000104
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    Zs.A 4815: Show issues Location:
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  10. Article ; Online: Acquired chemoresistance drives spatial heterogeneity, chemoprotection and collective migration in pancreatic tumor spheroids.

    Fredrik I Thege / Ian I Cardle / Conor N Gruber / Megan J Siemann / Sophie Cong / Katharina Wittmann / Justin Love / Brian J Kirby

    PLoS ONE, Vol 17, Iss 5, p e

    2022  Volume 0267882

    Abstract: Tumors display rich cellular heterogeneity and typically consist of multiple co-existing clones with distinct genotypic and phenotypic characteristics. The acquisition of resistance to chemotherapy has been shown to contribute to the development of ... ...

    Abstract Tumors display rich cellular heterogeneity and typically consist of multiple co-existing clones with distinct genotypic and phenotypic characteristics. The acquisition of resistance to chemotherapy has been shown to contribute to the development of aggressive cancer traits, such as increased migration, invasion and stemness. It has been hypothesized that collective cellular behavior and cooperation of cancer cell populations may directly contribute to disease progression and lack of response to treatment. Here we show that the spontaneous emergence of chemoresistance in a cancer cell population exposed to the selective pressure of a chemotherapeutic agent can result in the emergence of collective cell behavior, including cell-sorting, chemoprotection and collective migration. We derived several gemcitabine resistant subclones from the human pancreatic cancer cell line BxPC3 and determined that the observed chemoresistance was driven of a focal amplification of the chr11p15.4 genomic region, resulting in over-expression of the ribonucleotide reductase (RNR) subunit RRM1. Interestingly, these subclones display a rich cell-sorting behavior when cultured as mixed tumor spheroids. Furthermore, we show that chemoresistant cells are able to exert a chemoprotective effect on non-resistant cells in spheroid co-culture, whereas no protective effect is seen in conventional 2D culture. We also demonstrate that the co-culture of resistant and non-resistant cells leads to collective migration where resistant cells enable migration of otherwise non-migratory cells.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
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