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  1. Article ; Online: The drug-induced phenotypic landscape of colorectal cancer organoids

    Johannes Betge / Niklas Rindtorff / Jan Sauer / Benedikt Rauscher / Clara Dingert / Haristi Gaitantzi / Frank Herweck / Kauthar Srour-Mhanna / Thilo Miersch / Erica Valentini / Kim E. Boonekamp / Veronika Hauber / Tobias Gutting / Larissa Frank / Sebastian Belle / Timo Gaiser / Inga Buchholz / Ralf Jesenofsky / Nicolai Härtel /
    Tianzuo Zhan / Bernd Fischer / Katja Breitkopf-Heinlein / Elke Burgermeister / Matthias P. Ebert / Michael Boutros

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 15

    Abstract: The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes ... ...

    Abstract The heterogeneity underlying cancer organoid phenotypes is not yet well understood. Here, the authors develop an imaging analysis assay for high throughput phenotypic screening of colorectal organoids that allows to define specific morphological changes that occur following different drug treatments.
    Keywords Science ; Q
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for 2nd line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA)

    Nadja M. Meindl-Beinker / Johannes Betge / Tobias Gutting / Elke Burgermeister / Sebastian Belle / Tianzuo Zhan / Nadine Schulte / Martin Maenz / Matthias P. Ebert / Nicolai Haertel

    BMC Cancer, Vol 19, Iss 1, Pp 1-

    2019  Volume 8

    Abstract: Abstract Background Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous ... ...

    Abstract Abstract Background Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous cell carcinomas. Therefore, we assess combined nivolumab/ipilimumab as 2nd line therapy in elderly ESCC patients. Methods RAMONA is a multicenter open-label phase II trial. The primary objective is to demonstrate a significant survival benefit of nivolumab/ipilimumab in advanced ESCC compared to historical data of standard chemotherapy. Primary endpoint is therefore overall survival (OS). Major secondary objective is the evaluation of tolerability. Time to QoL deterioration will thus be determined as key secondary endpoint. Further secondary endpoints are tumor response, PFS and safety. We aim to recruit a total of n = 75 subjects that have to be > 65 years old. Eligibility is determined by the geriatric status (G8 screening and Deficit Accumulation Frailty Index (DAFI)). A safety assessment will be performed after a 3 cycle run-in phase of nivolumab (240 mg Q2W) to justify escalation for eligible patients to combined nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg Q6W), while the other patients will remain on nivolumab only. RAMONA also includes translational research sub-studies to identify predictive biomarkers, including PD-1 and PD-L1 evaluation at different time points, establishment of organoid cultures and microbiome analyses for response prediction. Discussion The RAMONA trial aims to implement checkpoint inhibitors for elderly patients with advanced ESCC as second line therapy. Novel biomarkers for checkpoint-inhibitor response are analyzed in extensive translational sub-studies. Trial registration EudraCT Number: 2017–002056-86; NCT03416244, registered: 31.1.2018.
    Keywords Esophageal squamous cell cancer ; Elderly ; Comprehensive geriatric assessment ; Checkpoint inhibitors ; Personalized medicine ; Geriatric oncology ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
    Subject code 610 ; 616
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer

    Teresa Friedrich / Michaela Söhn / Tobias Gutting / Klaus-Peter Janssen / Hans-Michael Behrens / Christoph Röcken / Matthias P.A. Ebert / Elke Burgermeister

    EBioMedicine, Vol 8, Iss C, Pp 159-

    2016  Volume 172

    Abstract: Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, ... ...

    Abstract Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p = 0.001; n = 1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments.
    Keywords Docking protein ; DOK ; RAS ; PPAR ; Colorectal cancer ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 616
    Language English
    Publishing date 2016-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA)

    Matthias P Ebert, ProfMD / Nadja M Meindl-Beinker, PhD / Tobias Gutting, MD / Martin Maenz, PhD / Johannes Betge, MD / Nadine Schulte, MD / Tianzuo Zhan, MD / Philip Weidner, MD / Elke Burgermeister, PhD / Ralf Hofheinz, ProfMD / Arndt Vogel, ProfMD / Stefan Angermeier, MD / Claus Bolling, MD / Maike de Wit, ProfMD / Ralf Jakobs, ProfMD / Meinolf Karthaus, ProfMD / Gertraud Stocker, MD / Peter Thuss-Patience, MD / Tobias Leidig, PhD /
    Timo Gaiser, ProfMD / Jakob N Kather, ProfMD / Nicolai Haertel, MD

    The Lancet. Healthy Longevity, Vol 3, Iss 6, Pp e417-e

    a multicentre, open-label phase 2 trial

    2022  Volume 427

    Abstract: Summary: Background: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. ...

    Abstract Summary: Background: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population. Methods: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244. Findings: Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0–76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7–12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3–5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment. Interpretation: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from ...
    Keywords Geriatrics ; RC952-954.6 ; Medicine ; R
    Subject code 616 ; 610
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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