Intratumoral immunotherapy of murine pheochromocytoma shows no age-dependent differences in its efficacy

Cancer immunotherapy has shown remarkable clinical progress in recent years. Although age is one of the biggest leading risk factors for cancer development and older adults represent a majority of cancer patients, only a few new cancer immunotherapeutic interventions have been preclinically tested in aged animals. Thus, the lack of preclinical studies focused on age-dependent effect during cancer immunotherapy could lead to different therapeutic outcomes in young and aged animals and future modifications of human clinical trials. Here, we compare the efficacy of previously developed and tested intratumoral immunotherapy, based on the combination of polysaccharide mannan, toll-like receptor ligands, and anti-CD40 antibody (MBTA immunotherapy), in young (6 weeks) and aged (71 weeks) mice bearing experimental pheochromocytoma (PHEO). The presented results point out that despite faster growth of PHEO in aged mice MBTA intratumoral immunotherapy is effective approach without age dependence and could be one of the possible therapeutic interventions to enhance immune response to pheochromocytoma and perhaps other tumor types in aged and young hosts

Mathematical modelling of behavior of filament wound composite structures.

Filament winding technology, composite tubes, shafts, beams and spars, fiber undulation effects were the topics of interest. Analytical models of behavior of filament wound structures were developed. The advantages of the presented analytical methods and numeric algorithms are their mathematical accuracy, fast preparation of data and calculation, and interpretation of results. There are 3 basic models presented. The 1st one is laminate stacking analysis, the condition for data preparation for further modelling and analysis. The 2nd one was specified as a model for fast bending curve analysis and optimization of long non-circular beams like marine masts or wing spars. And the 3rd model was specified as a model for more accurate deformation analysis of thin walled tubes with circular cross section like industrial rollers, driving shafts or hydraulic cylinders under combined load like bending, torsion, axial force, inner pressure and temperature change. The presented models are examples of "the production technology oriented" access of composite laminated beam analysis. The unique and original approach to this development is that models were specified and historically developed during development of production technology of filament winding.Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Late Permian volcanic dykes in the crystalline basement of the Považský Inovec Mts. (Western Carpathians): U–Th–Pb zircon SHRIMP and monazite chemical dating

This paper presents geochronological data for the volcanic dykes located in the northern Považský Inovec Mts. The dykes are up to 5 m thick and tens to hundreds of metres long. They comprise variously inclined and oriented lenses, composed of strongly altered grey-green alkali basalts. Their age was variously interpreted and discussed in the past. Dykes were emplaced into the Tatricum metamorphic rocks, mostly consisting of mica schists and gneisses of the Variscan (early Carboniferous) age. Two different methods, zircon SHRIMP and monazite chemical dating, were applied to determine the age of these dykes. U-Pb SHRIMP dating of magmatic zircons yielded the concordia age of 260.2 ± 1.4 Ma. The Th-U-Pb monazite dating of the same dyke gave the CHIME age of 259 ± 3Ma. Both ages confirm the magmatic crystallization at the boundary of the latest Middle Permian to the Late Permian. Dyke emplacement was coeval with development of the Late Paleozoic sedimentary basin known in the northern Považský Inovec Mts. and could be correlated with other pre-Mesozoic Tethyan regions especially in the Southern Alps

The Significant Reduction or Complete Eradication of Subcutaneous and Metastatic Lesions in a Pheochromocytoma Mouse Model after Immunotherapy Using Mannan-BAM, TLR Ligands, and Anti-CD40

Therapeutic options for metastatic pheochromocytoma/paraganglioma (PHEO/PGL) are limited. Here, we tested an immunotherapeutic approach based on intratumoral injections of mannan-BAM with toll-like receptor ligands into subcutaneous PHEO in a mouse model. This therapy elicited a strong innate immunity-mediated antitumor response and resulted in a significantly lower PHEO volume compared to the phosphate buffered saline (PBS)-treated group and in a significant improvement in mice survival. The cytotoxic effect of neutrophils, as innate immune cells predominantly infiltrating treated tumors, was verified in vitro. Moreover, the combination of mannan-BAM and toll-like receptor ligands with agonistic anti-CD40 was associated with increased mice survival. Subsequent tumor re-challenge also supported adaptive immunity activation, reflected primarily by long-term tumor-specific memory. These results were further verified in metastatic PHEO, where the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 into subcutaneous tumors resulted in significantly less intense bioluminescence signals of liver metastatic lesions induced by tail vein injection compared to the PBS-treated group. Subsequent experiments focusing on the depletion of T cell subpopulations confirmed the crucial role of CD8+ T cells in inhibition of bioluminescence signal intensity of liver metastatic lesions. These data call for a new therapeutic approach in patients with metastatic PHEO/PGL using immunotherapy that initially activates innate immunity followed by an adaptive immune response

Germline SUCLG2 Variants in Patients With Pheochromocytoma and Paraganglioma

International audienceAbstract Background Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors with frequent mutations in genes linked to the tricarboxylic acid cycle. However, no pathogenic variant has been found to date in succinyl-CoA ligase (SUCL), an enzyme that provides substrate for succinate dehydrogenase (SDH; mitochondrial complex II [CII]), a known tumor suppressor in PPGL. Methods A cohort of 352 patients with apparently sporadic PPGL underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health, including the SUCLG2 subunit of SUCL. Gene deletion, succinate levels, and protein levels were assessed in tumors where possible. To confirm the possible mechanism, we used a progenitor cell line, hPheo1, derived from a human pheochromocytoma, and ablated and re-expressed SUCLG2. Results We describe 8 germline variants in the guanosine triphosphate–binding domain of SUCLG2 in 15 patients (15 of 352, 4.3%) with apparently sporadic PPGL. Analysis of SUCLG2-mutated tumors and SUCLG2-deficient hPheo1 cells revealed absence of SUCLG2 protein, decrease in the level of the SDHB subunit of SDH, and faulty assembly of the complex II, resulting in aberrant respiration and elevated succinate accumulation. Conclusions Our study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL. Large-scale sequencing may uncover additional cases harboring SUCLG2 variants and provide more detailed information about their prevalence and penetrance