659 research outputs found
Serial stereotactic biopsy of brainstem lesions in adults improves diagnostic accuracy compared with MRI only.
Objective: The aim of the current prospective study was
to analyse the validity of MRI based diagnosis of
brainstem gliomas which was verified by stereotactic
biopsy and follow-up evaluation as well as to assess
prognostic factors and risk profile.
Methods: Between 1998 and 2007, all consecutive adult
patients with radiologically suspected brainstem glioma
were included. The MRI based diagnosis of the lesions
was made independently by an experienced neuroradiologist.
Histopathological evaluation was performed in all
patients from paraffin embedded specimens obtained by
multimodal image guided stereotactic serial biopsy
technique. Histopathological results were compared with
prior radiological assessment. Length of survival was
estimated with the KaplanâMeier method and prognostic
factors were calculated using the Cox model.
Results: 46 adult patients were included. Histological
evaluation revealed pilocytic astrocytoma (n=2), WHO
grade II glioma (n=14), malignant glioma (n=12),
metastasis (n=7), lymphoma (n=5), cavernoma
(n=1), inflammatory disease (n=2) or no tumour/
gliosis (n=3). Perioperative morbidity was 2.5% (n=1).
There was no permanent morbidity and no mortality. All
patients with ââno tumourââ or ââinflammatory diseaseââ
survived. Patients with low grade glioma and malignant
glioma showed a 1 year survival rate of 75% and 25%,
respectively; the 1 year survival rate for patients with
lymphoma or metastasis was 30%. In the subgroup with a
verified brainstem glioma, negative predictors for length of
survival were higher tumour grade (p=0.002) and
Karnofsky performance score (70 (p=0.004).
Conclusion: Intra-axial brainstem lesions with a radiological
pattern of glioma represent a very heterogeneous
tumour group with completely different outcomes.
Radiological features alone are not reliable for diagnostic
classification. Stereotactic biopsy is a safe method to
obtain a valid tissue diagnosis, which is indispensible for
treatment decision
Genetically modified natural killer cells specifically recognizing the tumor-associated antigens ErbB2/HER2 and EpCAM
The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origin without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92-based therapies, here by transduction with retroviral vectors we have generated genetically modified NK-92 cells expressing chimeric antigen receptors specific either for the tumor-associated ErbB2 (HER2/neu) antigen or the human Epithelial Cell Adhesion Molecule (Ep-CAM). Both antigens are overexpressed by many tumors of epithelial origin. The chimeric antigen receptors consist of either the ErbB2 specific scFv(FRP5) antibody fragment or the Ep-CAM specific scFv(MOC31), a flexible hinge region derived from CD8, and transmembrane and intracellular regions of the CD3 zeta chain. Transduced NK-92-scFv(FRP5)-zeta or NK-92-scFv(MOC31)-zeta cells express high levels of the fusion proteins on the cell surface as determined by FACS analysis. In europium release assays no difference in cytotoxic activity of NK-92 and transduced NK-92 cells towards ErbB2 or Ep-CAM negative targets was found. However, even at low effector to target ratios transduced NK-92 cells specifically and efficiently lysed established ErbB2 or Ep-CAM expressing tumor cells that were completely resistant to cytolytic activity of parental NK-92 cells. Similarly, ErbB2-positive primary breast cancer cells isolated from pleural effusions of patients with recurrent disease were selectively killed by NK-92-scFv(FRP5)-zeta. In an in vivo model in immunodeficient mice treatment with retargeted NK-92-scFv(FRP5)-zeta, but not parental NK-92 cells resulted in markedly delayed growth of ErbB2 transformed cancer cells. These results demonstrate that efficient retargeting of NK-92 cytotoxicity can be achieved, and might allow the generation of potent cell-based therapeutics for the treatment of ErbB2 and Ep-CAM expressing malignancies. This therapeutic approach might be applicable for a large variety of different cancers where suitable cell surface antigens have been identified
Boar rearing: the influence of group vs individual penning from weaning to 27 weeks of age
We compared mating performance and soundness of feet and legs of boars which were reared in group vs individual pens. Individually penned boars consumed more feed from 6 to 12 weeks of age and were heavier at 12 weeks of age. However, individually penned boars also were more unsound and tended to score lower in mating tests.; Swine Day, Manhattan, KS, November 11, 198
Modular total syntheses of thymifodioic/incanic acids
The first total synthesis of the bioactive natural product 2,6-(E,E)-thymifodioic acid, also called incanic acid, and its stereoisomers is described. An unified, iterative and modular strategy was envisioned, achieving the synthesis of the goals products after five reaction steps in an overall yield ranging from 8% to 16%. The key step is a non-expensive easy to perform HornerâWadsworthâEmmons condensation.Fil: Ălvarez MĂ©ndez, Sergio J.. Universidad de la Laguna. Departamento de QuĂmica OrgĂĄnica. Instituto Universitario de Bio-OrgĂĄnica "Antonio GonzĂĄlez"; EspañaFil: Saad, JosĂ© Roberto. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - San Luis. Instituto de Investigaciones en TecnologĂa QuĂmica. Universidad Nacional de San Luis. Facultad de QuĂmica, BioquĂmica y Farmacia. Instituto de Investigaciones en TecnologĂa QuĂmica; ArgentinaFil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - San Luis. Instituto de Investigaciones en TecnologĂa QuĂmica. Universidad Nacional de San Luis. Facultad de QuĂmica, BioquĂmica y Farmacia. Instituto de Investigaciones en TecnologĂa QuĂmica; ArgentinaFil: MartĂn, VĂctor S.. Universidad de la Laguna. Departamento de QuĂmica OrgĂĄnica. Instituto Universitario de Bio-OrgĂĄnica "Antonio GonzĂĄlez"; EspañaFil: GarcĂa, Celina. Universidad de la Laguna. Departamento de QuĂmica OrgĂĄnica. Instituto Universitario de Bio-OrgĂĄnica "Antonio GonzĂĄlez"; Españ
A comparative assessment of biomass ash preparation methods using X-ray fluorescence and wet chemical analysis
X-ray fluorescence (XRF) spectroscopy is a rapid method used to determine the composition of biomass ash, but the accuracy of the method is sensitive to various factors including ash preparation methods. In this study different types of biomass ash were examined by using wet chemical analysis (WCA) and compared with the respective XRF results. The biomass ash was initially prepared in accordance with the European Standard method at 550 °C. At this low combustion temperature the amount of residual unburned carbon is significant. To eliminate this, the ashes were heated at higher temperatures: a batch of twenty biomass ashes were heated at 850 °C and a batch of five heated to 815 °C. At these higher temperatures there may be loss of inorganic components by vaporisation. Variation in these effects may lead to unreliable results. The relationship between XRF and WCA results are given by regression equations. The ashes processed at 815 °C show better agreement between the two analysis methods
Derivatives of grindelic acid: from a non-active natural diterpene to synthetic antitumor derivatives
Using several reactions that include homologations and asymmetric epoxidations as well as Ugi and Huisgen couplings, we generated a small focused library of new derivatives from the labdane-type diterpene grindelic acid. These compounds were evaluated as cytotoxic agents against a panel of five human solid tumor cell lines (HBL-100, HeLa, SW1573, T-47D, and WiDr). The presence of the diamide functionalizations enhanced the cytotoxic effect. N-benzyl-N-(1-(benzylamino)-2-methyl-1-oxopropan-2-yl)grindelicamide, proved to be the most active product in all cell lines tested, with values of 0.95 (± 0.38) ÎŒM against HBL-100 cells.Fil: Reta, Guillermo Federico. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico San Luis. Instituto de Investigaciones En TecnologĂa QuĂmica; ArgentinaFil: Chiaramello, Alejandra Ilda. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico San Luis. Instituto de Investigaciones en TecnologĂa QuĂmica; ArgentinaFil: GarcĂa, Celina. Universidad de la Laguna. Departamento de QuĂmica OrgĂĄnica. Instituto Universitario de Bio-orgĂĄnica "Antonio Gonzalez"; EspañaFil: LeĂłn, Leticia G.. Universidad de la Laguna. Departamento de QuĂmica OrgĂĄnica. Instituto Universitario de Bio-orgĂĄnica "Antonio Gonzalez"; EspañaFil: MartĂn, Victor S.. Universidad de la Laguna. Departamento de QuĂmica OrgĂĄnica. Instituto Universitario de Bio-orgĂĄnica "Antonio Gonzalez"; EspañaFil: PadrĂłn, JosĂ© M.. Universidad de la Laguna. Departamento de QuĂmica OrgĂĄnica. Instituto Universitario de Bio-orgĂĄnica "Antonio Gonzalez"; EspañaFil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico San Luis. Instituto de Investigaciones En TecnologĂa QuĂmica; ArgentinaFil: Donadel, Osvaldo Juan. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico San Luis. Instituto de Investigaciones En TecnologĂa QuĂmica; Argentin
Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma
Background aims
Natural killer (NK) cells can rapidly respond to transformed and stressed cells and represent an important effector cell type for adoptive immunotherapy. In addition to donor-derived primary NK cells, continuously expanding cytotoxic cell lines such as NK-92 are being developed for clinical applications.
Methods
To enhance their therapeutic utility for the treatment of B-cell malignancies, we engineered NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors (CARs) that target CD19 and contain human CD3ζ (CAR 63.z), composite CD28-CD3ζ or CD137-CD3ζ signaling domains (CARs 63.28.z and 63.137.z).
Results
Exposure of CD19-positive targets to CAR NK-92 cells resulted in formation of conjugates between NK and cancer cells, NK-cell degranulation and selective cytotoxicity toward established B-cell leukemia and lymphoma cells. Likewise, the CAR NK cells displayed targeted cell killing of primary pre-B-ALL blasts that were resistant to parental NK-92. Although all three CAR NK-92 cell variants were functionally active, NK-92/63.137.z cells were less effective than NK-92/63.z and NK-92/63.28.z in cell killing and cytokine production, pointing to differential effects of the costimulatory CD28 and CD137 domains. In a Raji B-cell lymphoma model in NOD-SCID IL2R Îłnull mice, treatment with NK-92/63.z cells, but not parental NK-92 cells, inhibited disease progression, indicating that selective cytotoxicity was retained in vivo.
Conclusions
Our data demonstrate that it is feasible to generate CAR-engineered NK-92 cells with potent and selective antitumor activity. These cells may become clinically useful as a continuously expandable off-the-shelf cell therapeutic agent
Association of pre-radiotherapy tumour burden and overall survival in newly diagnosed glioblastoma adjusted for MGMT promoter methylation status
PURPOSE: We retrospectively evaluated the association between postoperative pre-radiotherapy tumour burden and overall survival (OS) adjusted for the prognostic value of O-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with newly diagnosed glioblastoma treated with radio-/chemotherapy with temozolomide.
MATERIALS AND METHODS: Patients were included from the CENTRIC (EORTC 26071-22072) and CORE trials if postoperative magnetic resonance imaging scans were available within a timeframe of up to 4weeks before radiotherapy, including both pre- and post-contrast T1w images and at least one T2w sequence (T2w or T2w-FLAIR). Postoperative (residual) pre-radiotherapy contrast-enhanced tumour (CET) volumes and non-enhanced T2w abnormalities (NT2A) tissue volumes were obtained by three-dimensional segmentation. Cox proportional hazard models and Kaplan Meier estimates were used to assess the association of pre-radiotherapy CET/NT2A volume with OS adjusted for known prognostic factors (age, performance status, MGMT status).
RESULTS: 408 tumour (of which 270 MGMT methylated) segmentations were included. Median OS in patients with MGMT methylated tumours was 117 weeks versus 61weeks in MGMT unmethylated tumours (p < 0.001). When stratified for MGMT methylation status, higher CET volume (HR 1.020; 95% confidence interval CI [1.013-1.027]; p < 0.001) and older age (HR 1.664; 95% CI [1.214-2.281]; p = 0.002) were significantly associated with shorter OS while NT2A volume and performance status were not.
CONCLUSION: Pre-radiotherapy CET volume was strongly associated with OS in patients receiving radio-/chemotherapy for newly diagnosed glioblastoma stratified by MGMT promoter methylation status
- âŠ