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  1. Article ; Online: Cultured Human Foreskin as a Model System for Evaluating Ionizing Radiation-Induced Skin Injury

    Yanick Hippchen / Gargi Tewary / Daniela Jung / Zoé Schmal / Stephan Meessen / Jan Palm / Claudia E. Rübe

    International Journal of Molecular Sciences, Vol 23, Iss 9830, p

    2022  Volume 9830

    Abstract: Purpose: Precise molecular and cellular mechanisms of radiation-induced dermatitis are incompletely understood. Histone variant H2A.J is associated with cellular senescence and modulates senescence-associated secretory phenotype (SASP) after DNA-damaging ...

    Abstract Purpose: Precise molecular and cellular mechanisms of radiation-induced dermatitis are incompletely understood. Histone variant H2A.J is associated with cellular senescence and modulates senescence-associated secretory phenotype (SASP) after DNA-damaging insults, such as ionizing radiation (IR). Using ex vivo irradiated cultured foreskin, H2A.J was analyzed as a biomarker of radiation-induced senescence, potentially initiating the inflammatory cascade of radiation-induced skin injury. Methods: Human foreskin explants were collected from young donors, irradiated ex vivo with 10 Gy, and cultured in air-liquid interphase for up to 72 h. At different time-points after ex vivo IR exposure, the foreskin epidermis was analyzed for proliferation and senescence markers by immunofluorescence and immunohistochemical staining of sectioned tissue. Secretion of cytokines was measured in supernatants by ELISA. Using our mouse model with fractionated in vivo irradiation, H2A.J expression was analyzed in epidermal stem/progenitor cell populations localized in different regions of murine hair follicles (HF). Results: Non-vascularized foreskin explants preserved their tissue homeostasis up to 72 h (even after IR exposure), but already non-irradiated foreskin epithelium expressed high levels of H2A.J in all epidermal layers and secreted high amounts of cytokines. Unexpectedly, no further increase in H2A.J expression and no obvious upregulation of cytokine secretion was observed in the foreskin epidermis after ex vivo IR. Undifferentiated keratinocytes in murine HF regions, by contrast, revealed low H2A.J expression in non-irradiated skin and significant radiation-induced H2A.J upregulations at different time-points after IR exposure. Based on its staining characteristics, we presume that H2A.J may have previously underestimated the importance of the epigenetic regulation of keratinocyte maturation. Conclusions: Cultured foreskin characterized by highly keratinized epithelium and specific immunological features is not an appropriate ...
    Keywords cultured foreskin ; ionizing radiation ; radiation-induced dermatitis ; histone variant H2A.J ; cellular senescence ; senescence-associated secretory phenotype (SASP) ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Feasibility and clinical usefulness of modelling glioblastoma migration in adjuvant radiotherapy

    Sven Knobe / Yvonne Dzierma / Michael Wenske / Christian Berdel / Jochen Fleckenstein / Patrick Melchior / Jan Palm / Frank G. Nuesken / Alexander Hunt / Christian Engwer / Christina Surulescu / Umut Yilmaz / Wolfgang Reith / Christian Rübe

    Zeitschrift für Medizinische Physik, Vol 32, Iss 2, Pp 149-

    2022  Volume 158

    Abstract: Glioblastoma (GBM) is one of the most common primary brain tumours in adults, with a dismal prognosis despite aggressive multimodality treatment by a combination of surgery and adjuvant radiochemotherapy. A detailed knowledge of the spreading of glioma ... ...

    Abstract Glioblastoma (GBM) is one of the most common primary brain tumours in adults, with a dismal prognosis despite aggressive multimodality treatment by a combination of surgery and adjuvant radiochemotherapy. A detailed knowledge of the spreading of glioma cells in the brain might allow for more targeted escalated radiotherapy, aiming to reduce locoregional relapse. Recent years have seen the development of a large variety of mathematical modelling approaches to predict glioma migration.The aim of this study is hence to evaluate the clinical applicability of a detailed micro- and meso-scale mathematical model in radiotherapy. First and foremost, a clinical workflow is established, in which the tumour is automatically segmented as input data and then followed in time mathematically based on the diffusion tensor imaging data. The influence of several free model parameters is individually evaluated, then the full model is retrospectively validated for a collective of 3 GBM patients treated at our institution by varying the most important model parameters to achieve optimum agreement with the tumour development during follow-up. Agreement of the model predictions with the real tumour growth as defined by manual contouring based on the follow-up MRI images is analyzed using the dice coefficient.The tumour evolution over 103-212 days follow-up could be predicted by the model with a dice coefficient better than 60% for all three patients. In all cases, the final tumour volume was overestimated by the model by a factor between 1.05 and 1.47.To evaluate the quality of the agreement between the model predictions and the ground truth, we must keep in mind that our gold standard relies on a single observer's (CB) manually-delineated tumour contours. We therefore decided to add a short validation of the stability and reliability of these contours by an inter-observer analysis including three other experienced radiation oncologists from our department. In total, a dice coefficient between 63% and 89% is achieved between the four ...
    Keywords Bio-mathematical modelling ; Glioblastoma growth and migration ; Tumour segmentation ; Inter observer analysis ; Glioblastoma radiotherapy ; Medical physics. Medical radiology. Nuclear medicine ; R895-920
    Subject code 616
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Increasing genomic instability during cancer therapy in a patient with Li-Fraumeni syndrome

    Nadine Schuler / Jan Palm / Sabine Schmitz / Yvonne Lorat / Claudia E. Rübe

    Clinical and Translational Radiation Oncology, Vol 7, Iss , Pp 71-

    2017  Volume 78

    Abstract: Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder characterized by germline mutations of the p53 tumor-suppressor gene. In response to DNA damage, p53 stimulates protective cellular processes including cell-cycle arrest and ... ...

    Abstract Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder characterized by germline mutations of the p53 tumor-suppressor gene. In response to DNA damage, p53 stimulates protective cellular processes including cell-cycle arrest and apoptosis to prevent aberrant cell proliferation. Current cancer therapies involve agents that damage DNA, which also affect non-cancerous hematopoietic stem/progenitor cells. Here, we report on a child with LFS who developed genomic instability during craniospinal irradiation for metastatic choroid plexus carcinoma (CPC). Case presentation: This previously healthy 4-year-old boy presented with parieto-temporal brain tumor, diagnosed as CPC grade-3. Screening for cancer-predisposing syndrome revealed heterozygous p53 germline mutation, leading to LFS diagnosis. After tumour resection and systemic chemotherapy, entire craniospinal axis was irradiated due to leptomeningeal seeding, resulting in disease stabilization for nearly 12â¯months. Blood lymphocytes of LFS patient (p53-deficient) and age-matched tumor-children (p53-proficient) were collected before, during and after craniospinal irradiation and compared with asymptomatic carriers for identical p53 mutation, not exposed to DNA-damaging treatment. In p53-deficient lymphocytes of LFS patient radiation-induced DNA damage failed to induce cell-cycle arrest or apoptosis. Although DNA repair capacity was not impaired, p53-deficient blood lymphocytes of LFS patient showed significant accumulation of 53BP1-foci during and even several months after irradiation, reflecting persistent DNA damage. Electron microscopy revealed DNA abnormalities ranging from simple unrepaired lesions to chromosomal abnormalities. Metaphase spreads of p53-deficient lymphocytes explored by mFISH revealed high amounts of complex chromosomal aberrations after craniospinal irradiation. Conclusions: Tumor suppressor p53 plays a central role in maintaining genomic stability by promoting cell-cycle checkpoints and apoptosis. Here, we demonstrate that a ...
    Keywords Medical physics. Medical radiology. Nuclear medicine ; R895-920 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
    Language English
    Publishing date 2017-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: DNA-damage foci to detect and characterize DNA repair alterations in children treated for pediatric malignancies.

    Nadine Schuler / Jan Palm / Mareike Kaiser / Dominik Betten / Rhoikos Furtwängler / Christian Rübe / Norbert Graf / Claudia E Rübe

    PLoS ONE, Vol 9, Iss 3, p e

    2014  Volume 91319

    Abstract: Purpose In children diagnosed with cancer, we evaluated the DNA damage foci approach to identify patients with double-strand break (DSB) repair deficiencies, who may overreact to DNA-damaging radio- and chemotherapy. In one patient with Fanconi anemia ( ... ...

    Abstract Purpose In children diagnosed with cancer, we evaluated the DNA damage foci approach to identify patients with double-strand break (DSB) repair deficiencies, who may overreact to DNA-damaging radio- and chemotherapy. In one patient with Fanconi anemia (FA) suffering relapsing squamous cell carcinomas of the oral cavity we also characterized the repair defect in biopsies of skin, mucosa and tumor. Methods and materials In children with histologically confirmed tumors or leukemias and healthy control-children DSB repair was investigated by counting γH2AX-, 53BP1- and pATM-foci in blood lymphocytes at defined time points after ex-vivo irradiation. This DSB repair capacity was correlated with treatment-related normal-tissue responses. For the FA patient the defective repair was also characterized in tissue biopsies by analyzing DNA damage response proteins by light and electron microscopy. Results Between tumor-children and healthy control-children we observed significant differences in mean DSB repair capacity, suggesting that childhood cancer is based on genetic alterations affecting DNA repair. Only 1 out of 4 patients with grade-4 normal-tissue toxicities revealed an impaired DSB repair capacity. The defective DNA repair in FA patient was verified in irradiated blood lymphocytes as well as in non-irradiated mucosa and skin biopsies leading to an excessive accumulation of heterochromatin-associated DSBs in rapidly cycling cells. Conclusions Analyzing human tissues we show that DSB repair alterations predispose to cancer formation at younger ages and affect the susceptibility to normal-tissue toxicities. DNA damage foci analysis of blood and tissue samples allows one to detect and characterize DSB repair deficiencies and enables identification of patients at risk for high-grade toxicities. However, not all treatment-associated normal-tissue toxicities can be explained by DSB repair deficiencies.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616 ; 610
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: In Silico Oncology

    Eleni Kolokotroni / Dimitra Dionysiou / Christian Veith / Yoo-Jin Kim / Jörg Sabczynski / Astrid Franz / Aleksandar Grgic / Jan Palm / Rainer M Bohle / Georgios Stamatakos

    PLoS Computational Biology, Vol 12, Iss 9, p e

    Quantification of the In Vivo Antitumor Efficacy of Cisplatin-Based Doublet Therapy in Non-Small Cell Lung Cancer (NSCLC) through a Multiscale Mechanistic Model.

    2016  Volume 1005093

    Abstract: The 5-year survival of non-small cell lung cancer patients can be as low as 1% in advanced stages. For patients with resectable disease, the successful choice of preoperative chemotherapy is critical to eliminate micrometastasis and improve operability. ... ...

    Abstract The 5-year survival of non-small cell lung cancer patients can be as low as 1% in advanced stages. For patients with resectable disease, the successful choice of preoperative chemotherapy is critical to eliminate micrometastasis and improve operability. In silico experimentations can suggest the optimal treatment protocol for each patient based on their own multiscale data. A determinant for reliable predictions is the a priori estimation of the drugs' cytotoxic efficacy on cancer cells for a given treatment. In the present work a mechanistic model of cancer response to treatment is applied for the estimation of a plausible value range of the cell killing efficacy of various cisplatin-based doublet regimens. Among others, the model incorporates the cancer related mechanism of uncontrolled proliferation, population heterogeneity, hypoxia and treatment resistance. The methodology is based on the provision of tumor volumetric data at two time points, before and after or during treatment. It takes into account the effect of tumor microenvironment and cell repopulation on treatment outcome. A thorough sensitivity analysis based on one-factor-at-a-time and latin hypercube sampling/partial rank correlation coefficient approaches has established the volume growth rate and the growth fraction at diagnosis as key features for more accurate estimates. The methodology is applied on the retrospective data of thirteen patients with non-small cell lung cancer who received cisplatin in combination with gemcitabine, vinorelbine or docetaxel in the neoadjuvant context. The selection of model input values has been guided by a comprehensive literature survey on cancer-specific proliferation kinetics. The latin hypercube sampling has been recruited to compensate for patient-specific uncertainties. Concluding, the present work provides a quantitative framework for the estimation of the in-vivo cell-killing ability of various chemotherapies. Correlation studies of such estimates with the molecular profile of patients could serve as a basis for reliable personalized predictions.
    Keywords Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2016-09-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Cytokine plasma levels

    Claudia E Rübe / Jan Palm / Michael Erren / Jochen Fleckenstein / Jochem König / Klaus Remberger / Christian Rübe

    PLoS ONE, Vol 3, Iss 8, p e

    reliable predictors for radiation pneumonitis?

    2008  Volume 2898

    Abstract: Background Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting ... ...

    Abstract Background Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. However, cytokines are produced not only in normal lung tissue after irradiation, but are also over-expressed in tumour cells of NSCLC specimens. This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-alpha, IL-1beta, IL-6 and TGF-beta1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC. Methodology/principal findings In 52 NSCLC patients (stage I-III) cytokine plasma levels were investigated by ELISA before and weekly during RT, during follow-up (1/3/6/9 months after RT), and at the onset of RP. Tumour biopsies were immunohistochemically stained for IL-6 and TGF-beta1, and immunoreactivity was quantified (grade 1-4). RP was evaluated according to LENT-SOMA scale. Tumour response was assessed according to RECIST criteria by chest-CT during follow-up. In our clinical study 21 out of 52 patients developed RP (grade I/II/III/IV: 11/3/6/1 patients). Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence. In most patients IL-6 and TGF-beta1 plasma levels were already elevated before RT and correlated significantly with the IL-6 and TGF-beta1 production in corresponding tumour biopsies. Moreover, IL-6 and TGF-beta1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients. Conclusions/significance The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP. In contrast, the clear correlations of IL-6 and TGF-beta1 plasma levels with the cytokine production in corresponding tumour biopsies and with the individual tumour responses suggest that the tumour is the major source of circulating cytokines in patients receiving RT for advanced NSCLC.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2008-08-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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