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  1. Article ; Online: Psychiatrist experience of remote consultations by telephone in an outpatient psychiatric department during the COVID-19 pandemic.

    Olwill, C / Mc Nally, D / Douglas, L

    Irish journal of psychological medicine

    2020  Volume 38, Issue 2, Page(s) 132–139

    Abstract: Objective: In response to the COVID-19 pandemic, there has been a shift globally from face-to-face consultations to remote consultations. In our department, remote consultations have taken in the form of telephone consultations. In this paper, we set ... ...

    Abstract Objective: In response to the COVID-19 pandemic, there has been a shift globally from face-to-face consultations to remote consultations. In our department, remote consultations have taken in the form of telephone consultations. In this paper, we set out to study a group of Irish psychiatrists' experience of these consultations.
    Methods: We identified recurrent themes in the existing literature on doctors' experience of telephone consultations with a view to determining the applicability of these themes to a group of Irish psychiatrists. A questionnaire was developed based on themes in the literature. This was sent to all psychiatrists working in a busy psychiatric service in Dublin.
    Results: The questionnaire response rate was 72% (n = 26/35). Diagnostic challenges, the effect of phone consultation on the therapeutic alliance, challenges associated with the use of technology and ethical concerns were identified as issues. Flexibility in the working day and convenience were identified as possible benefits to telephone consultations.
    Conclusions: The group that participated in this research study identified a number of challenges to carrying out successful phone consultations. This study highlights the need at our clinical site for interventions to address the issues identified by staff. The findings also highlight the requirement for larger studies with stronger methodologies to determine the generalisability of our results.
    MeSH term(s) COVID-19 ; Humans ; Outpatients ; Pandemics ; Psychiatry ; Remote Consultation ; SARS-CoV-2 ; Telephone
    Keywords covid19
    Language English
    Publishing date 2020-05-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 227751-7
    ISSN 2051-6967 ; 0790-9667
    ISSN (online) 2051-6967
    ISSN 0790-9667
    DOI 10.1017/ipm.2020.51
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  2. Article: Psychiatrist experience of remote consultations by telephone in an outpatient psychiatric department during the COVID-19 pandemic

    Olwill, C / Mc Nally, D / Douglas, L

    Ir J Psychol Med

    Abstract: OBJECTIVE: In response to the COVID-19 pandemic, there has been a shift globally from face-to-face consultations to remote consultations. In our department, remote consultations have taken in the form of telephone consultations. In this paper, we set out ...

    Abstract OBJECTIVE: In response to the COVID-19 pandemic, there has been a shift globally from face-to-face consultations to remote consultations. In our department, remote consultations have taken in the form of telephone consultations. In this paper, we set out to study a group of Irish psychiatrists' experience of these consultations. METHODS: We identified recurrent themes in the existing literature on doctors' experience of telephone consultations with a view to determining the applicability of these themes to a group of Irish psychiatrists. A questionnaire was developed based on themes in the literature. This was sent to all psychiatrists working in a busy psychiatric service in Dublin. RESULTS: The questionnaire response rate was 72% (n = 26/35). Diagnostic challenges, the effect of phone consultation on the therapeutic alliance, challenges associated with the use of technology and ethical concerns were identified as issues. Flexibility in the working day and convenience were identified as possible benefits to telephone consultations. CONCLUSIONS: The group that participated in this research study identified a number of challenges to carrying out successful phone consultations. This study highlights the need at our clinical site for interventions to address the issues identified by staff. The findings also highlight the requirement for larger studies with stronger methodologies to determine the generalisability of our results.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #326215
    Database COVID19

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  3. Article ; Online: Psychiatrist experience of remote consultations by telephone in an outpatient psychiatric department during the COVID-19 pandemic

    Olwill, C. / Mc Nally, D. / Douglas, L.

    Irish Journal of Psychological Medicine

    2020  , Page(s) 1–8

    Abstract: Objective In response to the COVID-19 pandemic, there has been a shift globally from face-to-face consultations to remote consultations. In our department, remote consultations have taken in the form of telephone consultations. In this paper, we set out ... ...

    Abstract Objective In response to the COVID-19 pandemic, there has been a shift globally from face-to-face consultations to remote consultations. In our department, remote consultations have taken in the form of telephone consultations. In this paper, we set out to study a group of Irish psychiatrists’ experience of these consultations. Methods We identified recurrent themes in the existing literature on doctors’ experience of telephone consultations with a view to determining the applicability of these themes to a group of Irish psychiatrists. A questionnaire was developed based on themes in the literature. This was sent to all psychiatrists working in a busy psychiatric service in Dublin. Results The questionnaire response rate was 72% ( n = 26/35). Diagnostic challenges, the effect of phone consultation on the therapeutic alliance, challenges associated with the use of technology and ethical concerns were identified as issues. Flexibility in the working day and convenience were identified as possible benefits to telephone consultations. Conclusions The group that participated in this research study identified a number of challenges to carrying out successful phone consultations. This study highlights the need at our clinical site for interventions to address the issues identified by staff. The findings also highlight the requirement for larger studies with stronger methodologies to determine the generalisability of our results.
    Keywords Applied Psychology ; History and Philosophy of Science ; Psychiatry and Mental health ; covid19
    Language English
    Publisher Cambridge University Press (CUP)
    Publishing country uk
    Document type Article ; Online
    ZDB-ID 227751-7
    ISSN 0790-9667
    ISSN 0790-9667
    DOI 10.1017/ipm.2020.51
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  4. Article ; Online: The PD-L1/4-1BB Bispecific Antibody-Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner.

    Peper-Gabriel, Janet K / Pavlidou, Marina / Pattarini, Lucia / Morales-Kastresana, Aizea / Jaquin, Thomas J / Gallou, Catherine / Hansbauer, Eva-Maria / Richter, Marleen / Lelievre, Helene / Scholer-Dahirel, Alix / Bossenmaier, Birgit / Sancerne, Celine / Riviere, Matthieu / Grandclaudon, Maximilien / Zettl, Markus / Bel Aiba, Rachida S / Rothe, Christine / Blanc, Veronique / Olwill, Shane A

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2022  Volume 28, Issue 15, Page(s) 3387–3399

    Abstract: Purpose: While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due to resistant or refractory tumors. A combination of checkpoint blockade with further T-cell stimulation ... ...

    Abstract Purpose: While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due to resistant or refractory tumors. A combination of checkpoint blockade with further T-cell stimulation mediated by 4-1BB agonism may increase response rates and durability of response. A bispecific molecule that blocks the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis and localizes 4-1BB costimulation to a PD-L1-positive (PD-L1+) tumor microenvironment (TME) or tumor draining lymph nodes could maximize antitumor immunity and increase the therapeutic window beyond what has been reported for anti-4-1BB mAbs.
    Experimental design: We generated and characterized the PD-L1/4-1BB bispecific molecule PRS-344/S095012 for target binding and functional activity in multiple relevant in vitro assays. Transgenic mice expressing human 4-1BB were transplanted with human PD-L1-expressing murine MC38 cells to assess in vivo antitumoral activity.
    Results: PRS-344/S095012 bound to its targets with high affinity and efficiently blocked the PD-1/PD-L1 pathway, and PRS-344/S095012-mediated 4-1BB costimulation was strictly PD-L1 dependent. We demonstrated a synergistic effect of both pathways on T-cell stimulation with the bispecific PRS-344/S095012 being more potent than the combination of mAbs. PRS-344/S095012 augmented CD4-positive (CD4+) and CD8-positive (CD8+) T-cell effector functions and enhanced antigen-specific T-cell stimulation. Finally, PRS-344/S095012 demonstrated strong antitumoral efficacy in an anti-PD-L1-resistant mouse model in which soluble 4-1BB was detected as an early marker for 4-1BB agonist activity.
    Conclusions: The PD-L1/4-1BB bispecific PRS-344/S095012 efficiently combines checkpoint blockade with a tumor-localized 4-1BB-mediated stimulation burst to antigen-specific T cells, more potent than the combination of mAbs, supporting the advancement of PRS-344/S095012 toward clinical development. See related commentary by Shu et al., p. 3182.
    MeSH term(s) Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; B7-H1 Antigen/metabolism ; CD8-Positive T-Lymphocytes/immunology ; Humans ; Immunologic Factors/therapeutic use ; Immunotherapy ; Mice ; Neoplasms/drug therapy ; Neoplasms/immunology ; Programmed Cell Death 1 Receptor/immunology ; Tumor Microenvironment
    Chemical Substances Antibodies, Monoclonal ; B7-H1 Antigen ; Immunologic Factors ; Programmed Cell Death 1 Receptor
    Language English
    Publishing date 2022-02-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-21-2762
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    Zs.A 4223: Show issues Location:
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  5. Article: Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343.

    Hinner, Marlon J / Aiba, Rachida Siham Bel / Jaquin, Thomas J / Berger, Sven / Dürr, Manuela Carola / Schlosser, Corinna / Allersdorfer, Andrea / Wiedenmann, Alexander / Matschiner, Gabriele / Schüler, Julia / Moebius, Ulrich / Rothe, Christine / Matis, Louis / Olwill, Shane Anthony

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2019  Volume 25, Issue 19, Page(s) 5878–5889

    Abstract: Purpose: 4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. To overcome limitations of current 4-1BB-targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to ... ...

    Abstract Purpose: 4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. To overcome limitations of current 4-1BB-targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation.
    Experimental design: PRS-343 was generated by the genetic fusion of 4-1BB-specific Anticalin proteins to a variant of trastuzumab with an engineered IgG4 isotype. Its activity was characterized using a panel of
    Results: PRS-343 targets 4-1BB and HER2 with high affinity and binds both targets simultaneously. 4-1BB-expressing T cells are efficiently costimulated when incubated with PRS-343 in the presence of cancer cells expressing HER2, as evidenced by increased production of proinflammatory cytokines (IL2, GM-CSF, TNFα, and IFNγ). In a humanized mouse model engrafted with HER2-positive SK-OV-3 tumor cells and human peripheral blood mononuclear cells, PRS-343 leads to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. In IND-enabling studies, PRS-343 was found to be well tolerated, with no overt toxicity and no relevant drug-related toxicologic findings.
    Conclusions: PRS-343 facilitates tumor-localized targeting of T cells by bispecific engagement of HER2 and 4-1BB. This approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity compared with current monospecific approaches. The reported data led to initiation of a phase I clinical trial with this first-in-class molecule.
    MeSH term(s) Animals ; Antibodies, Bispecific ; Humans ; Lymphocyte Activation ; Lymphocytes, Tumor-Infiltrating ; Mice ; Neoplasms ; T-Lymphocytes ; Tumor Necrosis Factor Receptor Superfamily, Member 9
    Chemical Substances Antibodies, Bispecific ; Tumor Necrosis Factor Receptor Superfamily, Member 9
    Language English
    Publishing date 2019-05-28
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-18-3654
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  6. Article ; Online: Application of the Enfer chemiluminescent multiplex ELISA system for the detection of Mycobacterium bovis infection in goats.

    Shuralev, Eduard / Quinn, Padraig / Doyle, Mairead / Duignan, Anthony / Kwok, Hang Fai / Bezos, Javier / Olwill, Shane A / Gormley, Eamonn / Aranaz, Alicia / Good, Margaret / Davis, William C / Clarke, John / Whelan, Clare

    Veterinary microbiology

    2012  Volume 154, Issue 3-4, Page(s) 292–297

    Abstract: A study was conducted to optimise a multiplex serological immunoassay for use in identification of goats infected with Mycobacterium bovis. To assess assay specificity, 31 goats with a history of being free from M. bovis infection were used. To determine ...

    Abstract A study was conducted to optimise a multiplex serological immunoassay for use in identification of goats infected with Mycobacterium bovis. To assess assay specificity, 31 goats with a history of being free from M. bovis infection were used. To determine assay sensitivity, 180 Single Intradermal Comparative Tuberculin test (SICTT) positive goats were recruited. Additionally, 286 SICTT negative goats classed as potentially exposed animals present in the same positive herds were also included in the study. The results of the assay demonstrated a specificity of 100%. The multiplex assay detected 57/60 SICTT (95.0%) positive animals in one M. bovis infected herd and 120/120 (100%) in a second herd. In a separate experiment, 28 M. caprae culture confirmed infected goats from Spain were assayed, of which 24 (85.7%) were found positive in the test. The results show that inclusion of an antibody based assay can improve the ability to identify M. bovis and M. caprae infected goats. With further development and validation the multiplex assay may prove to be a useful tool for control of M. bovis and M. caprae infection in goats.
    MeSH term(s) Animals ; Enzyme-Linked Immunosorbent Assay/methods ; Enzyme-Linked Immunosorbent Assay/veterinary ; Goats/blood ; Goats/virology ; Luminescence ; Mycobacterium bovis ; Sensitivity and Specificity ; Spain ; Tuberculin Test/veterinary ; Tuberculosis/microbiology ; Tuberculosis/veterinary
    Language English
    Publishing date 2012-01-27
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 753154-0
    ISSN 1873-2542 ; 0378-1135
    ISSN (online) 1873-2542
    ISSN 0378-1135
    DOI 10.1016/j.vetmic.2011.07.028
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  7. Article ; Online: Inhibition of Cathepsin S by Fsn0503 enhances the efficacy of chemotherapy in colorectal carcinomas.

    Burden, Roberta E / Gormley, Julie A / Kuehn, Diana / Ward, Claire / Kwok, Hang Fai / Gazdoiu, Mihaela / McClurg, Angela / Jaquin, Thomas J / Johnston, James A / Scott, Christopher J / Olwill, Shane A

    Biochimie

    2012  Volume 94, Issue 2, Page(s) 487–493

    Abstract: Cathepsin S is a lysosomal cysteine protease implicated in tumourigenesis with key roles in invasion and angiogenesis. We have previously shown that the specific inhibition of Cathepsin S using a monoclonal antibody (Fsn0503) blocks colorectal carcinoma ... ...

    Abstract Cathepsin S is a lysosomal cysteine protease implicated in tumourigenesis with key roles in invasion and angiogenesis. We have previously shown that the specific inhibition of Cathepsin S using a monoclonal antibody (Fsn0503) blocks colorectal carcinoma tumour growth and angiogenesis in vivo. We investigated whether Cathepsin S expression levels were affected by chemotherapy in human cancer cell lines by RT-PCR. Using colorectal xenograft models, we examined the therapeutic benefit of Cathepsin S inhibition using Fsn0503 in combination with a metronomic dosing regimen of CPT-11. We analysed the effects of the combination therapy on tumour progression and on tumour vascularisation by immunohistochemical staining of tumours. Cathepsin S expression levels are upregulated in HCT116, LoVo, Colo205 cell lines and HUVECs after exposure to CPT-11 in vitro. The administration of Fsn0503 in combination with CPT-11 significantly attenuated tumour growth in comparison to CPT-11 alone in colorectal HCT116 xenograft models. Furthermore, analysis of tumour vascularisation revealed that this was also significantly disrupted by the combination treatment. These results show that the combination of Cathepsin S inhibition with CPT-11 enhances the therapeutic effect of the chemotherapy. This rationale may have clinical application in the treatment of colorectal cancer upon further evaluation.
    MeSH term(s) Animals ; Antibodies, Monoclonal/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Camptothecin/administration & dosage ; Camptothecin/analogs & derivatives ; Cathepsins/antagonists & inhibitors ; Cathepsins/genetics ; Cathepsins/metabolism ; Cell Line, Tumor ; Colon/blood supply ; Colon/drug effects ; Colon/pathology ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/enzymology ; Colorectal Neoplasms/pathology ; Cysteine Proteinase Inhibitors/administration & dosage ; Gene Expression/drug effects ; Humans ; Mice ; Mice, Nude ; Neovascularization, Pathologic ; Treatment Outcome ; Xenograft Model Antitumor Assays
    Chemical Substances Antibodies, Monoclonal ; Cysteine Proteinase Inhibitors ; irinotecan (7673326042) ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27) ; Camptothecin (XT3Z54Z28A)
    Language English
    Publishing date 2012-02
    Publishing country France
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120345-9
    ISSN 1638-6183 ; 0300-9084
    ISSN (online) 1638-6183
    ISSN 0300-9084
    DOI 10.1016/j.biochi.2011.08.017
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  8. Article ; Online: A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity.

    Olwill, Shane A / Joffroy, Christian / Gille, Hendrik / Vigna, Elisa / Matschiner, Gabriele / Allersdorfer, Andrea / Lunde, Bradley M / Jaworski, Jakub / Burrows, James F / Chiriaco, Cristina / Christian, Hans Jürgen / Hülsmeyer, Martin / Trentmann, Stefan / Jensen, Kristian / Hohlbaum, Andreas M / Audoly, Laurent

    Molecular cancer therapeutics

    2013  Volume 12, Issue 11, Page(s) 2459–2471

    Abstract: Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. ...

    Abstract Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.
    MeSH term(s) Amino Acid Sequence ; Animals ; Binding Sites/drug effects ; CHO Cells ; Cell Line, Tumor ; Cricetulus ; Dose-Response Relationship, Drug ; Epitope Mapping ; Female ; HT29 Cells ; Hepatocyte Growth Factor/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Ligands ; Lipocalins/pharmacology ; Lipocalins/therapeutic use ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms, Experimental/drug therapy ; Neoplasms, Experimental/pathology ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proteins/pharmacology ; Proteins/therapeutic use ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
    Chemical Substances Ligands ; Lipocalins ; PRS-110 ; Protein Kinase Inhibitors ; Proteins ; Hepatocyte Growth Factor (67256-21-7) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
    Language English
    Publishing date 2013-09-03
    Publishing country United States
    Document type Journal Article ; 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-13-0318
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    Zs.A 5750: Show issues Location:
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  9. Article ; Online: The role of Cathepsin S as a marker of prognosis and predictor of chemotherapy benefit in adjuvant CRC: a pilot study.

    Gormley, J A / Hegarty, S M / O'Grady, A / Stevenson, M R / Burden, R E / Barrett, H L / Scott, C J / Johnston, J A / Wilson, R H / Kay, E W / Johnston, P G / Olwill, S A

    British journal of cancer

    2011  Volume 105, Issue 10, Page(s) 1487–1494

    Abstract: Background: The aim of this pilot retrospective study was to investigate the immunohistochemical expression of Cathepsin S (CatS) in three cohorts of colorectal cancer (CRC) patients (n=560).: Methods: Prevalence and association with ... ...

    Abstract Background: The aim of this pilot retrospective study was to investigate the immunohistochemical expression of Cathepsin S (CatS) in three cohorts of colorectal cancer (CRC) patients (n=560).
    Methods: Prevalence and association with histopathological variables were assessed across all cohorts. Association with clinical outcomes was investigated in the Northern Ireland Adjuvant Chemotherapy Trial cohort (n=211), where stage II/III CRC patients were randomised between surgery-alone or surgery with adjuvant fluorouracil/folinic acid (FU/FA) treatment.
    Results: Greater than 95% of tumours had detectable CatS expression with significantly increased staining in tumours compared with matched normal colon (P>0.001). Increasing CatS was associated with reduced recurrence-free survival (RFS; P=0.03) among patients treated with surgery alone. Adjuvant FU/FA significantly improved RFS (hazard ratio (HR), 0.33; 95% CI, 0.12-0.89) and overall survival (OS; HR, 0.25; 95% CI, 0.08-0.81) among 36 patients with high CatS. Treatment did not benefit the 66 patients with low CatS, with a RFS HR of 1.34 (95% CI, 0.60-3.19) and OS HR of 1.33 (95% CI, 0.56-3.15). Interaction between CatS and treatment status was significant for RFS (P=0.02) and OS (P=0.04) in a multivariate model adjusted for known prognostic markers.
    Conclusion: These results signify that CatS may be an important prognostic biomarker and predictive of response to adjuvant FU/FA in CRC.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biomarkers, Tumor/metabolism ; Cathepsins/metabolism ; Chemotherapy, Adjuvant ; Cohort Studies ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/enzymology ; Colorectal Neoplasms/surgery ; Female ; Fluorouracil/administration & dosage ; Humans ; Immunohistochemistry ; Leucovorin/administration & dosage ; Male ; Middle Aged ; Pilot Projects ; Prognosis
    Chemical Substances Biomarkers, Tumor ; Cathepsins (EC 3.4.-) ; cathepsin S (EC 3.4.22.27) ; Leucovorin (Q573I9DVLP) ; Fluorouracil (U3P01618RT)
    Language English
    Publishing date 2011-10-11
    Publishing country England
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 80075-2
    ISSN 1532-1827 ; 0007-0920
    ISSN (online) 1532-1827
    ISSN 0007-0920
    DOI 10.1038/bjc.2011.408
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  10. Article ; Online: In vivo visualization of MET tumor expression and anticalin biodistribution with the MET-specific anticalin 89Zr-PRS-110 PET tracer.

    Terwisscha van Scheltinga, Anton G T / Lub-de Hooge, Marjolijn N / Hinner, Marlon J / Verheijen, Remy B / Allersdorfer, Andrea / Hülsmeyer, Martin / Nagengast, Wouter B / Schröder, Carolien P / Kosterink, Jos G W / de Vries, Elisabeth G E / Audoly, Laurent / Olwill, Shane A

    Journal of nuclear medicine : official publication, Society of Nuclear Medicine

    2014  Volume 55, Issue 4, Page(s) 665–671

    Abstract: ... 110) were injected into BALB/c mice bearing high MET-expressing H441 non-small cell lung cancer ...

    Abstract Unlabelled: Anticalins are a novel class of biopharmaceuticals, displaying highly desirable attributes as imaging agents. The anticalin PRS-110 was rationally engineered to target the oncogene MET with high affinity and specificity. The aim of this study was to visualize MET expression and analyze biodistribution of (89)Zr-labeled PRS-110 in human tumor-bearing mice.
    Methods: (89)Zr-PRS-110 was generated. For biodistribution studies (96 h after injection of tracer) 10 μg of (89)Zr-PRS-110 (with 0-490 μg of unlabeled PRS-110) were injected into BALB/c mice bearing high MET-expressing H441 non-small cell lung cancer xenografts. Further characterization with PET imaging was performed at 6, 24, 48, and 96 h after injection of 50 μg of (89)Zr-PRS-110 into mice bearing H441, primary glioblastoma U87-MG (intermediate MET), or ovarian cancer A2780 (low MET) xenografts. Drug distribution was also analyzed ex vivo using fluorescently labeled PRS-110.
    Results: Biodistribution analyses showed a dose-dependent tumor uptake of (89)Zr-PRS-110, with the highest fractional tumor uptake at 10 μg of (89)Zr-PRS-110, with no unlabeled PRS-110. Small-animal PET imaging supported by biodistribution data revealed specific tumor uptake of (89)Zr-PRS-110 in the MET-expressing H441 and U87-MG tumors whereas the MET-negative A2780 tumor model showed a lower uptake similar to a non-MET binder anticalin control. Tumor uptake increased up to 24 h after tracer injection and remained high, whereas uptake in other organs decreased over time. Ex vivo fluorescence revealed intracellular presence of PRS-110.
    Conclusion: (89)Zr-PRS-110 specifically accumulates in MET-expressing tumors in a receptor density-dependent manner. PET imaging provides real-time noninvasive information about PRS-110 distribution and tumor accumulation in preclinical models.
    MeSH term(s) Animals ; Antibodies, Monoclonal, Humanized ; Bevacizumab ; Binding, Competitive ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Isotope Labeling ; Lipocalins ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Proteins ; Proto-Oncogene Proteins c-met/biosynthesis ; Quality Control ; Radiopharmaceuticals ; Tissue Distribution ; Xenograft Model Antitumor Assays
    Chemical Substances Antibodies, Monoclonal, Humanized ; Lipocalins ; PRS-110 ; Proteins ; Radiopharmaceuticals ; Bevacizumab (2S9ZZM9Q9V) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
    Language English
    Publishing date 2014-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80272-4
    ISSN 1535-5667 ; 0097-9058 ; 0161-5505 ; 0022-3123
    ISSN (online) 1535-5667
    ISSN 0097-9058 ; 0161-5505 ; 0022-3123
    DOI 10.2967/jnumed.113.124941
    Database MEDical Literature Analysis and Retrieval System OnLINE

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