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  1. Article ; Online: Grb7 knockout mice develop normally but litters born to knockout females fail to thrive.

    Lofgren, Kristopher A / Kenny, Paraic A

    Developmental dynamics : an official publication of the American Association of Anatomists

    2023  

    Abstract: Background: Growth factor receptor-bound 7 (Grb7) is an adaptor protein involved in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR, and PDGFR pathways. Experimental studies have implicated Grb7 in regulating ... ...

    Abstract Background: Growth factor receptor-bound 7 (Grb7) is an adaptor protein involved in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR, and PDGFR pathways. Experimental studies have implicated Grb7 in regulating cell proliferation, survival, migration, and invasion through its large repertoire of protein-protein interactions.
    Results: Here, we describe the generation and characterization of a Grb7 knockout mouse. These mice are viable and fertile. A lacZ knock-in reporter was used to visualize Grb7 promoter activity patterns in adult tissues, indicating widespread Grb7 expression in glandular epithelium, the central nervous system, and other tissues. The sole defect observed in these animals was a failure of Grb7 knockout females to successfully raise pups to weaning age, a phenotype that was independent of both paternal and pup genotypes.
    Conclusions: These data suggest a regulatory role for Grb7 in mammary lactational physiology.
    Language English
    Publishing date 2023-12-23
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1102541-4
    ISSN 1097-0177 ; 1058-8388
    ISSN (online) 1097-0177
    ISSN 1058-8388
    DOI 10.1002/dvdy.686
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: InferAMP, a python web app for copy number inference from discrete gene-level amplification signals noted in clinical tumor profiling reports.

    Kenny, Paraic A

    F1000Research

    2019  Volume 8, Page(s) 807

    Abstract: As somatic next-generation sequencing gene panel analysis in advanced cancer patients is becoming more routine, oncologists are frequently presented with reports containing lists of genes with increased copy number. Distinguishing which of these ... ...

    Abstract As somatic next-generation sequencing gene panel analysis in advanced cancer patients is becoming more routine, oncologists are frequently presented with reports containing lists of genes with increased copy number. Distinguishing which of these amplified genes, if any, might be driving tumor growth and might thus be worth considering targeting can be challenging. One particular issue is the frequent absence of genomic contextual information in clinical reports, making it very challenging to determine which reported genes might be co-amplified and how large any such amplicons might be. We describe a straightforward Python web app, InferAMP, into which healthcare professionals may enter lists of amplified genes from clinical reports. The tool reports (1) the likely size of amplified genomic regions, (2) which reported genes are co-amplified and (3) which other cancer-relevant genes that were not evaluated in the assay may also be co-amplified in the specimen. The tool is accessible for web queries at http://inferamp.org.
    MeSH term(s) DNA Copy Number Variations ; Gene Amplification ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Software
    Language English
    Publishing date 2019-06-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2699932-8
    ISSN 2046-1402 ; 2046-1402
    ISSN (online) 2046-1402
    ISSN 2046-1402
    DOI 10.12688/f1000research.19541.3
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  3. Article ; Online: InferAMP, a python web app for copy number inference from discrete gene-level amplification signals noted in clinical tumor profiling reports [version 3; peer review

    Paraic A. Kenny

    F1000Research, Vol

    2 approved]

    2019  Volume 8

    Abstract: As somatic next-generation sequencing gene panel analysis in advanced cancer patients is becoming more routine, oncologists are frequently presented with reports containing lists of genes with increased copy number. Distinguishing which of these ... ...

    Abstract As somatic next-generation sequencing gene panel analysis in advanced cancer patients is becoming more routine, oncologists are frequently presented with reports containing lists of genes with increased copy number. Distinguishing which of these amplified genes, if any, might be driving tumor growth and might thus be worth considering targeting can be challenging. One particular issue is the frequent absence of genomic contextual information in clinical reports, making it very challenging to determine which reported genes might be co-amplified and how large any such amplicons might be. We describe a straightforward Python web app, InferAMP, into which healthcare professionals may enter lists of amplified genes from clinical reports. The tool reports (1) the likely size of amplified genomic regions, (2) which reported genes are co-amplified and (3) which other cancer-relevant genes that were not evaluated in the assay may also be co-amplified in the specimen. The tool is accessible for web queries at http://inferamp.org.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2019-09-01T00:00:00Z
    Publisher F1000 Research Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Emergence and onward transmission of a SARS-CoV-2 E484K variant among household contacts of a bamlanivimab-treated patient.

    Sabin, Arick P / Richmond, Craig S / Kenny, Paraic A

    Diagnostic microbiology and infectious disease

    2022  Volume 103, Issue 1, Page(s) 115656

    Abstract: The implementation of monoclonal antibody therapeutics during the COVID-19 pandemic altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for resistant variants. Within-host viral evolution was reported in ... ...

    Abstract The implementation of monoclonal antibody therapeutics during the COVID-19 pandemic altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for resistant variants. Within-host viral evolution was reported in treated immunocompromised individuals but whether this signifies a real risk of onward transmission is unclear. We used a regional SARS-CoV-2 sequencing program to monitor lineages with clinically relevant variants in identified patients, which facilitated analysis of parameters potentially relevant to new variant emergence. Here we describe a newly acquired spike E484K mutation detected within the B.1.311 lineage. Multiple individuals in 2 households of the same extended family were infected. The timing and patterns of spread were consistent with de novo emergence of this E484K variant in the bamlanivimab-treated index patient. Our study suggests that the selective pressures introduced by the widespread administration of these antibodies may warrant increased genomic surveillance to identify and mitigate spread of therapy-induced variants.
    MeSH term(s) Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; COVID-19 ; Humans ; Mutation ; Pandemics ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus
    Chemical Substances Antibodies, Monoclonal, Humanized ; Antibodies, Neutralizing ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; bamlanivimab (45I6OFJ8QH)
    Language English
    Publishing date 2022-02-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 604920-5
    ISSN 1879-0070 ; 0732-8893
    ISSN (online) 1879-0070
    ISSN 0732-8893
    DOI 10.1016/j.diagmicrobio.2022.115656
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Pan-cancer distribution of cleaved cell-surface amphiregulin, the target of the GMF-1A3 antibody drug conjugate.

    Lofgren, Kristopher A / Reker, Nicolette C / Sreekumar, Sreeja / Kenny, Paraic A

    Antibody therapeutics

    2022  Volume 5, Issue 3, Page(s) 226–231

    Abstract: Amphiregulin is a transmembrane protein which, when cleaved by the TACE/ADAM17 protease, releases a soluble epidermal growth factor receptor ligand domain that promotes proliferation of normal and malignant cells. We previously described a rabbit ... ...

    Abstract Amphiregulin is a transmembrane protein which, when cleaved by the TACE/ADAM17 protease, releases a soluble epidermal growth factor receptor ligand domain that promotes proliferation of normal and malignant cells. We previously described a rabbit monoclonal antibody, GMF-1A3, that selectively recognizes the cell-associated cleaved amphiregulin epitope. Antibody-drug conjugates had anti-tumor activity against human breast cancer xenografts. Several tumor types express amphiregulin, but evidence for a functional requirement for amphiregulin in these malignancies is limited. By directly evaluating amphiregulin cleavage with immunohistochemistry, GMF-1A3 provides a more direct measure of amphiregulin activity. Using 370 specimens from 10 tumor types (as well as normal controls), we demonstrate that cleaved amphiregulin is widely expressed in solid tumors and is especially common (> 50% of cases) in breast, prostate, liver and lung cancer. As a potential companion diagnostic for this antibody-drug conjugate, this assay allows identification of tumors with high levels of the cleaved amphiregulin target.
    Language English
    Publishing date 2022-08-01
    Publishing country United States
    Document type Journal Article
    ISSN 2516-4236
    ISSN (online) 2516-4236
    DOI 10.1093/abt/tbac020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Exceptional Response to Crizotinib in an MET-Amplified Triple-Negative Breast Tumor.

    Parsons, Benjamin M / Meier, David R / Gurda, Grzegorz T / Lofgren, Kristopher A / Kenny, Paraic A

    JCO precision oncology

    2021  Volume 1, Page(s) 1–6

    Language English
    Publishing date 2021-12-31
    Publishing country United States
    Document type Journal Article
    ISSN 2473-4284
    ISSN (online) 2473-4284
    DOI 10.1200/PO.17.00070
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Exceptional Response to Crizotinib With Subsequent Response to Cabozantinib in Metastatic, ROS1-GOPC Fusion-Mutated Breast Cancer.

    O'Neil, Sean R / Weber, Garrett A / Deming, Dustin A / Burkard, Mark E / Kenny, Paraic A / Richmond, Craig S / Parsons, Benjamin M

    JCO precision oncology

    2023  Volume 7, Page(s) e2300174

    MeSH term(s) Humans ; Crizotinib ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins ; Anilides ; Neoplasms ; Golgi Matrix Proteins ; Adaptor Proteins, Signal Transducing
    Chemical Substances cabozantinib (1C39JW444G) ; Crizotinib (53AH36668S) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins ; Anilides ; ROS1 protein, human (EC 2.7.10.1) ; GOPC protein, human ; Golgi Matrix Proteins ; Adaptor Proteins, Signal Transducing
    Language English
    Publishing date 2023-07-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2473-4284
    ISSN (online) 2473-4284
    DOI 10.1200/PO.23.00174
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  8. Article ; Online: Anti-tumor efficacy of an MMAE-conjugated antibody targeting cell surface TACE/ADAM17-cleaved Amphiregulin in breast cancer.

    Lofgren, Kristopher A / Sreekumar, Sreeja / Jenkins, E Charles / Ernzen, Kyle J / Kenny, Paraic A

    Antibody therapeutics

    2021  Volume 4, Issue 4, Page(s) 252–261

    Abstract: Background: The Epidermal Growth Factor Receptor (EGFR) ligand, Amphiregulin (AREG), is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. AREG is a single-pass transmembrane protein ...

    Abstract Background: The Epidermal Growth Factor Receptor (EGFR) ligand, Amphiregulin (AREG), is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. AREG is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized.
    Methods: Using phage display, we identified antibodies that selectively recognize the residual transmembrane stalk of cleaved AREG. Conjugation with fluorescence labels and monomethyl auristatin E (MMAE) was used to study their intracellular trafficking and anti-cancer effects, respectively.
    Results: We report the development of an antibody-drug conjugate (ADC), GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved AREG, providing a novel means of targeting cells with high rates of AREG shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved AREG. Antibodies conjugated with MMAE were cytotoxic
    Conclusions: This ADC targeting AREG has potential utility in the treatment of breast and other tumors in which proteolytic AREG shedding is a frequent event.
    Language English
    Publishing date 2021-11-10
    Publishing country United States
    Document type Journal Article
    ISSN 2516-4236
    ISSN (online) 2516-4236
    DOI 10.1093/abt/tbab026
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  9. Article ; Online: Acquisition and onward transmission of a SARS-CoV-2 E484K variant among household contacts of a bamlanivimab-treated patient

    Sabin, Arick P / Richmond, Craig S / Kenny, Paraic A

    medRxiv

    Abstract: The implementation of monoclonal antibody therapeutics during the COVID19 pandemic has altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for variants resistant to one or more monoclonal antibodies and ... ...

    Abstract The implementation of monoclonal antibody therapeutics during the COVID19 pandemic has altered the selective pressures encountered by SARS-CoV-2, raising the possibility of selection for variants resistant to one or more monoclonal antibodies and subsequent transmission into the wider population. Early studies indicated that monoclonal antibody treatment in immunocompromised individuals could result in within-host viral evolution preferentially affecting epitopes recognized by these antibodies, although whether this signifies a real risk of transmissible antibody resistant virus is unclear. In this study we have taken advantage of a regional SARS-CoV-2 genomic surveillance program encompassing regions in Wisconsin, Minnesota and Iowa to monitor the introduction or de novo emergence of SARS-Cov-2 lineages with clinically relevant variants. Here we describe a newly acquired E484K mutation in the SARS-CoV-2 spike protein detected within the B.1.311 lineage. Multiple individuals in two related households were infected. The timing and patterns of subsequent spread were consistent with de novo emergence of this E484K variant in the initially affected individual who had been treated with bamlanivimab monotherapy. The subsequent transmission to close contacts occurred several days after the resolution of symptoms and the end of this patient9s quarantine period. Our study suggest that the selective pressures introduced by the now widespread administration of these antibodies may warrant increased genomic surveillance to identify and mitigate spread of therapy-induced variants.
    Keywords covid19
    Language English
    Publishing date 2021-10-05
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2021.10.02.21264415
    Database COVID19

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  10. Article ; Online: Optimized infection control practices augment the robust protective effect of vaccination for ESRD patients during a hemodialysis facility SARS-CoV-2 outbreak.

    Meller, Megan E / Pfaff, Bridget L / Borgert, Andrew J / Richmond, Craig S / Athas, Deena M / Kenny, Paraic A / Sabin, Arick P

    American journal of infection control

    2022  Volume 50, Issue 10, Page(s) 1118–1124

    Abstract: Background: While dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate infection and transmission risks within dialysis facilities. We describe an outbreak of 14 cases ... ...

    Abstract Background: While dialysis patients are at greater risk of serious SARS-CoV-2 complications, stringent infection prevention measures can help mitigate infection and transmission risks within dialysis facilities. We describe an outbreak of 14 cases diagnosed in a hospital-based outpatient ESRD facility over 13 days in the second quarter of 2021, and our coordinated use of epidemiology, viral genome sequencing, and infection control practices to quickly end the transmission cycle.
    Methods: Symptomatic patients and staff members were diagnosed by RT-PCR. Facility-wide screening utilized SARS-CoV-2 antigen tests. SARS-CoV-2 genome sequences were obtained from residual diagnostic specimens.
    Results: Of the 106 patients receiving dialysis in the facility, 10 were diagnosed with SARS-CoV-2 infection, as was 1 patient support person. Of 3 positive staff members, 2 were unvaccinated and had provided care for 6 and 4 of the affected patients, respectively. Sequencing demonstrated that all cases in the cluster shared an identical B.1.1.7./Alpha substrain. Attack rates were greatest among unvaccinated patients and staff. Vaccine effectiveness was 88% among patients.
    Conclusions: Prompt recognition of an infection cluster and rapid intervention efforts successfully ended the outbreak. Alongside consistent adherence to core infection prevention measures, vaccination was highly effective in reducing disease incidence and morbidity in this vulnerable population.
    MeSH term(s) COVID-19/epidemiology ; COVID-19/prevention & control ; Disease Outbreaks/prevention & control ; Humans ; Infection Control ; Kidney Failure, Chronic/complications ; Kidney Failure, Chronic/therapy ; Renal Dialysis/adverse effects ; SARS-CoV-2 ; Vaccination
    Language English
    Publishing date 2022-07-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392362-9
    ISSN 1527-3296 ; 0196-6553
    ISSN (online) 1527-3296
    ISSN 0196-6553
    DOI 10.1016/j.ajic.2022.06.025
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