Perturbations of radiation field caused by titanium dental implants in pencil proton beam therapy.

The aim of this study was to investigate the absorbed dose and the linear energy transfer (LET) of a scanning proton pencil beam at the Proton Therapy Center Czech, applied to phantoms containing metal implants. We investigated two different phantoms composed of commonly used metals with a known chemical composition. Two rectangular phantoms consisted of water-equivalent environment material with a 65 mm thickness surrounding the 2, 5, 10 and 15 mm inserts of grade-2 and grade-5 Titanium. Track-etched detectors (TEDs) were placed behind the phantoms to gather the data. The measured LET spectra behind the implants were compared with Monte Carlo simulations using the Geant4 toolkit, version 10.03.p01. The simulations were used to provide additional information regarding the contribution of each type of particles to the LET spectra (protons, alpha particles, deuteron, neutrons, photons, and electrons) and to estimate the LET spectra above the TED's detection threshold. We used two different beam energies to study the most pertinent irradiation scenarios, one in the Bragg curve plateau and one at the maximum. The measurement of the LET spectra behind phantoms irradiated with a proton beam in the plateau region of the Bragg curve led to the detection of numerous particles with a very high LET. Lateral dose enhancement at the border between implants and the plastic material was detected when the phantoms were exposed to a proton beam and the data were recorded in the Bragg peak maximum. In this area, the dose increased 13 times for grade-2 Ti and 12 times for grade-5 Ti. The performed experimental study highlights the effect of dental implants on the LET spectra and absorbed dose when a proton pencil beam is crossing high-density titanium.

In Vitro Cytotoxicity of Zinc Fructoborate, a Novel Zinc-Boron Active Natural Complex.

In recent years, the role of zinc in biological systems has been a subject of intense research. Zinc is required for multiple metabolic processes as a structural, regulatory, or catalytic ion. The objective of this study, was to assess the toxicity profile of a newly synthesized zinc-boron molecule on cultured cells. Zinc fructoborate, at different levels of concentration, was tested for its impact on the Vero kidney cell line (ATCC® CCL-81™) using the MTT assay. The compound exhibited a low cytotoxic effect on the cell line. Thus, our study demonstrates that the zinc fructoborate could become a promising dietary supplement molecule.

Validation of the EUMASS Core Set for medical evaluation of work disability.

OBJECTIVE: To perform a content validation of the EUMASS Core Set across six European social insurance systems. The EUMASS Core Set contains 20 categories to describe the functional (in-) capacity of claimants for disability benefits. METHODS: We performed an exploratory, cross-sectional study. We used the EUMASS Core Set, added scales to rate the relevance of the 20 categories and added additional questions concerning comprehensiveness, usefulness and sufficiency of the instrument. Medical examiners from European countries filled in this instrument in 10 consecutive claim assessments. RESULTS: Forty-eight medical examiners in six different countries evaluated 446 claimants. The medical examiners used all categories to describe the claimants' functional (in-) capacity. Medical examiners missed 41 different categories, often mental functions (n = 17). They rated the instrument as useful in 68.4% and as sufficient in 63.2% of the claims. Perceived usefulness varied among countries, but not among disease groups. Perceived sufficiency varied among countries and disease groups. CONCLUSION: The EUMASS Core Set is promising for reporting about functional (in-) capacities. It contains relevant categories for disability evaluation among countries and disease groups. Adding more mental functions might make it more applicable. Medical examiners found it useful and sufficient to evaluate functional (in-) capacity. Implications for Rehabilitation In medical reports of evaluation of work disability, reporting about functional capacity is often unstructured in free text, making the reports difficult to understand. The EUMASS Core Set contains common definitions for expressing functional capacity and is expected to support taking decisions, to improve the quality of decisions and to allow national and international comparisons. Our study suggests the EUMASS core set to be comprehensive, useful and sufficient to express functional capacity in disability evaluation.

The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation.

The t(6;9)-positive acute myeloid leukemia (AML) is classified as a separate clinical entity because of its early onset and poor prognosis. The hallmark of t(6;9) AML is the expression of the DEK/CAN fusion protein. The leukemogenic potential of DEK/CAN has been called into question, because it was shown to be unable to block the differentiation of hematopoietic progenitors. We found that DEK/CAN initiated leukemia from a small subpopulation within the hematopoietic stem cell (HSC) population expressing a surface marker pattern of long-term (LT) HSC. The propagation of established DEK/CAN-positive leukemia was not restricted to the LT-HSC population, but occurred even from more mature and heterogeneous cell populations. This finding indicates that in DEK/CAN-induced leukemia, there is a difference between 'leukemia-initiating cells' (L-ICs) and 'leukemia-maintaining cells' (L-MCs). In contrast to the L-IC cells represented by a very rare subpopulation of LT-HSC, the L-MC seem to be represented by a larger and phenotypically heterogeneous cell population.

Oligomerization inhibition, combined with allosteric inhibition, abrogates the transformation potential of T315I-positive BCR/ABL.

The t(9;22) translocation leads to the formation of the chimeric bcr/abl fusion gene, which encodes the BCR/ABL fusion protein. In contrast to its physiological counterpart c-ABL, the BCR/ABL kinase is constitutively activated, inducing the leukemic phenotype. The N-terminus of c-ABL (Cap region) contributes to the regulation of its kinase function. It is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain known as the myristoyl-binding pocket in a process called 'capping', which results in an auto-inhibited conformation. Because the cap region is replaced by the N-terminus of BCR, the BCR/ABL 'escapes' this auto-inhibition. Allosteric inhibition by myristate 'mimics', such as GNF-2, is able to inhibit unmutated BCR/ABL, but not the BCR/ABL that harbors the 'gatekeeper' mutation T315I. In this study, we analyzed the possibility of increasing the efficacy of allosteric inhibition by blocking BCR/ABL oligomerization. We showed that inhibition of oligomerization was able to not only increase the efficacy of GNF-2 on unmutated BCR/ABL, but also overcome the resistance of BCR/ABL-T315I to allosteric inhibition. These results strongly suggest that the response to allosteric inhibition by GNF-2 is inversely related to the degree of oligomerization of BCR/ABL. In summary, our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants represented by the combination of oligomerization and allosteric inhibitors.

The gatekeeper mutation T315I confers resistance against small molecules by increasing or restoring the ABL-kinase activity accompanied by aberrant transphosphorylation of endogenous BCR, even in loss-of-function mutants of BCR/ABL.

In Philadelphia chromosome-positive (Ph+) leukemia BCR/ABL induces the leukemic phenotype. Targeted inhibition of BCR/ABL by kinase inhibitors leads to complete remission. However, patients with advanced Ph+ leukemia relapse and acquire resistance, mainly due to point mutations in BCR/ABL. The 'gatekeeper mutation' T315I is responsible for a general resistance to small molecules. It seems not only to decrease the affinity for kinase inhibitors, but to also confer additional features to the leukemogenic potential of BCR/ABL. To determine the role of T315I in resistance to the inhibition of oligomerization and in the leukemogenic potential of BCR/ABL, we investigated its influence on loss-of-function mutants with regard to the capacity to mediate factor independence. Here, we show that T315I (i) requires autophosphorylation at tyrosine 177 in the BCR-portion to mediate resistance against the inhibition of oligomerization; (ii) restores the capacity to mediate factor-independent growth of loss-of-function mutants due to an increase in or activation of ABL-kinase; (iii) leads to phosphorylation of endogenous BCR, suggesting aberrant substrate activation by BCR/ABL harboring the T315I mutation. These data show that T315I confers additional leukemogenic activity to BCR/ABL, which might explain the clinical behavior of patients with BCR/ABL-T315I-positive blasts.

Determination of blood serum protein reactivity in children with behavior disturbances.

The researches were carried out on two groups of children: normals and with behavior disturbances. The serum cationic state was determined by an original method, using heparin as cautions exchanger in physiological pH, and the protein reactivity; the electrophoretic mobility of serum proteins at pH 7.4; total soduim and serum proteins. The obtained results show that serum proteins in children with behavior disturbances differ from those of normals, having: 1) smaller number of serotonin-fixing sites, 2) higher strength interaction between the serotonin and proteins, 3) lower resistance to the denaturant agents which has as a consequence the increase of cationic activity in the serum, and an increased electrophoretic mobility. The data are discussed and interpreted as perturbations in the electrolytes exchange (Na+, especially) in the integration centres of the autonomic functions.

Atypical juvenile neurolipidosis. Ultrastructural study of a cerebral biopsy.

The description is given of a structural and ultrastructural aspect of a cerebral biopsy specimen collected from a 17-year-old patient, with very frequent convulsive seizures, dementia, motor aphasia and spastic tetraparesis. The disease started at the age of 9 years and evolved very slowly. The morphologic diagnosis was neurolopidosis, the ultrastructural one was atypical juvenile lipofuscinosis, the electron microscopic aspect being identical to that of another 3 cases published in the literature: highly polymorphous membranogranulovesicular cytosomes.