Current glioblastoma (GB) small animal models for cranial radiation therapy (RT) use simple single beam technologies, which differ from the advanced conformal image-guided radiation techniques used in clinical practice. This technological disparity presents a major disadvantage for the development of new therapeutic approaches. Hence, we established a F98 GB rat model using magnetic resonance imaging (MRI)-guided three-dimensional (3D)-conformal arc RT with the Small Animal Radiation Research Platform (SARRP). Ten Fischer rats were inoculated with F98 tumor cells. When the tumor reached a volume of approximately 27 mm(3) on T2-weighted MR images, the animals were randomized into a treatment group (n = 5) receiving RT and concomitant temozolomide, and a sham group (n = 5) receiving control injections. For the treated animals, contrast-enhanced T1-weighted MR images were acquired followed by a cone-beam computed tomography (CBCT) on the SARRP system. Both scans were co-registered; MRI was used to define the target whereas CBCT was used for calculating a dose plan (20 Gy, three non-coplanar arc beams, 3 × 3 mm collimator). Tumor volumes were evaluated on follow-up contrast-enhanced T1-weighted MR images. Verification of treatment accuracy with γH2AX immunohistochemical staining was performed. Tumors in the control animals showed rapid proliferation during follow-up, encompassing almost the entire right cerebral hemisphere at day 12-15. Treated animals showed no significant tumor growth from 2 to 9 days post RT. γH2AX results confirmed the accuracy of dose delivery. This model, which is quite similar to the approach in the clinic, is valid for combined RT and chemotherapy of GB in rats.
Bolcaen J, Descamps B, Deblaere K, Boterberg T, Hallaert G, Van den Broecke C, Decrock E, Vral A, Leybaert L, Vanhove C, Goethals I.
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Radiation Research
PTH1-34 blocks radiation-induced osteoblast apoptosis by enhancing DNA repair through canonical Wnt pathway
Focal radiotherapy for cancer patients has detrimental effects on bones within the radiation field and the primary clinical signs of bone damage include the loss of functional osteoblasts. We reported previously that daily injection of parathyroid hormone (PTH, 1-34)...
Invariant natural killer T cells regulate anti-tumor immunity by controlling the population of dendritic cells in tumor and draining lymph nodes
BACKGROUND: Invariant natural killer T (iNKT) cells are CD1d-restricted T cells, which respond rapidly to antigen recognition and promote development of anti-tumor immunity in many tumor models. Surprisingly, we previously found that mice deficient in iNKT cells...
Listeria monocytogenes Dampens the DNA Damage Response.
The DNA damage response (DDR) is an essential signaling pathway that detects DNA lesions, which constantly occur upon either endogenous or exogenous assaults, and maintains genetic integrity. An infection by an invading pathogen is one such assault, but how bacteria impact the cellular DDR is poorly documented. Here, we report that infection with Listeria monocytogenes induces host DNA breaks. Strikingly, the signature response to these breaks is only moderately activated. We uncover the role of the listerial toxin listeriolysin O (LLO) in blocking the signaling response to DNA breaks through degradation of the sensor Mre11. Knocking out or inactivating proteins involved in the DDR promotes bacterial replication showing the importance of this mechanism for the control of infection. Together, our data highlight that bacterial dampening of the DDR is critical for a successful listerial infection.
Ascel Samba-Louaka, Jorge M Pereira, Marie-Anne Nahori, Veronique Villiers, Ludovic Deriano, Mélanie A Hamon and Pascale Cossart
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53BP1 Mediates the Fusion of Mammalian Telomeres Rendered Dysfunctional by DNA-PKcs Loss or Inhibition
Telomere dysfunction promotes genomic instability and carcinogenesis via inappropriate end-to-end chromosomal rearrangements, or telomere fusions. Previous work indicates that the DNA Damage Response (DDR) factor 53BP1 promotes the fusion of telomeres rendered...
Acute Skin Toxicity of Electronic Brachytherapy for Nonmelanoma Skin Cancer
High-dose rate electronic brachytherapy (EBT) using surface applicators allows for convenient hypofractionated treatment of non-melanoma skin cancer (NMSC). However, EBT delivers a higher surface dose as compared to commonly used superficial x-ray or electron...
Economic and Efficacy Analysis of Electron Beam Radiation Therapy and HDR Brachytherapy for Skin Cancer of the Face
Treatment of non-melanoma skin cancers (NMSC) in cosmetically sensitive locations can be challenging. Methods of treatment include different modalities of RT (orthovoltage x-rays, electron-beam RT, high-dose rate [HDR] brachytherapy) and surgical excision, all of...
TGFβ inhibition prior to hypofractionated radiation enhances efficacy in preclinical models
The immune infiltrate in colorectal cancer has been correlated with outcome, such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage. For patients with lower immune infiltrates, overall survival is limited....
Positron Emission Tomography for Pre-Clinical Sub-Volume Dose Escalation
PURPOSE: This dissertation focuses on establishment of pre-clinical methods facilitating the use of PET imaging for selective sub-volume dose escalation. Specifically the problems addressed are 1.) The difficulties associated with comparing multiple PET images, 2.)...