SETTING: As conclusive data on the performance of interferon-gamma release assays (IGRAs) in paediatric TB are lacking, many guidelines do not recommend their use for TB diagnosis in this population ...in Brazil.OBJECTIVE: To evaluate the performance of an IGRA by investigating its
concordance with the tuberculin skin test (TST) and the role of IGRAs in clinical management and treatment outcomes in children with TB.DESIGN: A historic cohort study was used to evaluate the performance of T-SPOT®.TB (ELISpot) and other tests, such as the TST, in
paediatric patients with or without immunodeficiency who were under investigation for latent tuberculous infection (LTBI) or active tuberculosis (TB).RESULTS: Of 86 paediatric patients evaluated, 41 (48%) were immunocompetent and 45 (52%) immunocompromised. All patients underwent T-SPOT.TB,
while 63 underwent both ELISpot and TST; test results were concordant in 50 patients (79.4%): 22/31 (71%) in immunocompetent (κ = 0.418, P = 0.02) and 28/32 (87.5%) in immunocompromised patients (κ = 0.526, P = 0.003). TB was diagnosed on the basis of the ELISpot
result in 21% (18/86) cases; the contribution of the ELISpot assay was greater in immunocompetent patients than in those who were immunocompromised (13/41, 31.7% vs. 5/45, 11.1%, χ2 P = 0.038).CONCLUSION: ELISpot and TST results were moderately concordant in both
groups of patients. ELISpot contribution was higher among immunocompetent patients than among immunocompromised patients.
In the framework of the EURADOS working group 11, an intercomparison of active neutron survey meters was performed in a pulsed neutron field (PNF). The aim of the exercise was to evaluate the ...performances of various neutron instruments, including commercially available rem-counters, personal dosemeters and instrument prototypes. The measurements took place at the cyclotron of the Helmholtz-Zentrum Berlin für Materialien und Energie GmbH. The cyclotron is routinely used for proton therapy of ocular tumours, but an experimental area is also available. For the therapy the machine accelerates protons to 68MeV. The interaction of the proton beam with a thick tungsten target produces a neutron field with energy up to about 60MeV. One interesting feature of the cyclotron is that the beam can be delivered in bursts, with the possibility to modify in a simple and flexible way the burst length and the ion current. Through this possibility one can obtain radiation bursts of variable duration and intensity. All instruments were placed in a reference position and irradiated with neutrons delivered in bursts of different intensity. The analysis of the instrument response as a function of the burst charge (the total electric charge of the protons in the burst shot onto the tungsten target) permitted to assess for each device the dose underestimation due to the time structure of the radiation field. The personal neutron dosemeters were exposed on a standard PMMA slab phantom and the response linearity was evaluated.
Since the first particle accelerator’s construction in 1931, an exponential spread of these machines occurred worldwide, in different kinds of applications. Nowadays, these are mainly used for ...industrial (60%) and medical (35%) purposes and for scientific research (5%). High energy secondary mixed fields produced by the particle beams interaction with matter imply a complex environmental dosimetry and special radiation protection regulations able to guarantee workers and population safety. In the medical field, this aspect is particularly emphasized in hadrontherapy centres, where high energy charged particles such as protons and carbon ions modify environmental doses, with a significant increase in the neutron contribution. This work proposes a technique to identify points of losses of the primary particle beam around an acceleration ring and has been developed within the radiation protection section at the National Centre for Oncological Hadrontherapy situated in Pavia. In the first part, the radiation field produced by protons and carbon ions interactions with structural materials at different energies was investigated. The main instrument of analysis is the Monte Carlo code for particle transport FLUKA, supported by experimental measurements in the treatment room carried out with the rem counter LUPIN, designed for pulsed neutron fields dosimetry. This first step allowed an analysis of both the angular and energetic instrumental response and a comparison of experimental results with simulations. The second part proposes a description of the technique for beam loss positions reconstruction around the acceleration ring at CNAO based on the application of unfolding codes.
MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated ...the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells.
Survival of patients affected by Multiple Myeloma (MM), a B-cell tumor of malignant plasma cells, has dramatically improved, owing to the recent introduction of the proteasome inhibitor (PI) ...Bortezomib and of the immunomodulatory drugs (IMiDs). This major advance originates from accumulating knowledge on MM biology, leading to the development of drugs targeting not only MM cells, but also their microenvironment. Indeed, the disease develops as a result of genetic abnormalities and of reciprocal interactions between MM cells and the permissive BM microenvironment, which delivers growth- and pro-survival signals and confers resistance to drugs. As for solid tumors, bone marrow (BM) angiogenesis is emerging as a critical component of MM development and progression, and hence as an attractive therapeutic target for the disease. The patho-physiology of MM associated angiogenesis is complex and involves a plethora of soluble factors, cellular players and mechanisms. Moreover, the hypoxic microenvironment inside the BM might significantly contribute to the induction and maintenance of a pro-angiogenic profile, given the well-known role of hypoxia in promoting angiogenesis in all its forms. Here we present an overview of the literature focusing on the mechanisms implicated in the "angiogenic switch", which corresponds to the transition from the avascular to the vascular phase of the disease. We also review evidence on the anti-angiogenic effects of PI and IMiDs, which substantially contribute to their anti-MM activity. Finally, we summarize possible caveats and perspectives about antiangiogenic strategies that could be addressed to improve the efficacy of treatments for MM patients.
A new method for improving REM counter performance in Pulsed Neutron Fields (PNFs) has been developed. This method uses an analysis of the build-up of space charge in the counter to compensate for an ...underestimation of Ambient Dose Equivalent (H*(10)) in intense pulsed fields. It was applied to three sets of experimental data acquired using the LUPIN-II REM counter device, which is designed for use in PNFs. The data was acquired using the cyclotron at Helmholtz-Zentrum Berlin für Materialien und Energie GmbH (HZB), at the HiRadMat facility at CERN and at the ‘Elettra Sincrotrone Trieste’ (ELETTRA), Italy. A comparison of the data with and without this compensation method is used to highlight its effectiveness. The LUPIN-II performance, which has already been shown to be able to cope with fields of up to hundreds of nSv/burst, is improved by at least one order of magnitude, with further potential for improvement.
Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated ...the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.
Tuberculosis (TB) infection was evaluated in Brazilian immunocompetent children and adolescents exposed and unexposed (control group) to adults with active pulmonary TB. Both groups were analysed by ...clinical and radiological assessment, TST, QFT-IT and T-SPOT.TB. The three tests were repeated after 8 weeks in the TB-exposed group if results were initially negative. Individuals with latent tuberculosis infection (LTBI) were treated and tests were repeated after treatment. Fifty-nine TB-exposed and 42 controls were evaluated. Rate of infection was 69·5% and 9·5% for the exposed and control groups, respectively. The exposed group infection rate was 61% assessed by TST, 57·6% by T-SPOT.TB, and 59·3%, by QFT-IT. No active TB was diagnosed. Agreement between the three tests was 83·1% and 92·8% in the exposed and control groups, respectively. In the exposed group, T-SPOT.TB added four TB diagnoses 16%, 95% confidence interval (CI) 1·6–30·4 and QFT-IT added three TB diagnoses (12%, 95% CI 0–24·7) in 25 individuals with negative tuberculin skin test (TST). Risk factors associated to TB infection were contact with an adult with active TB 0–60 days: odds ratio (OR) 6·9; >60 days: OR 27·0 and sleeping in the same room as an adult with active TB (OR 5·2). In Brazilian immunocompetent children and adolescents, TST had a similar performance to interferon-gamma release assays and detected a high rate of LTBI.
SSNTDs (solid-state nuclear track detectors), primarily made from PADC (poly(allyl diglycol carbonate)), are attractive detectors for dosimetric purposes. SSNTDs are more similar to human tissue than ...other passive detectors and the measurement of the track parameters provides information about the energy deposition of the incident particle. This paper describes a method for LET measurement based on the measurements of the major and minor axes of the track opening. The method was experimentally tested using alpha particles with energies ranging from 4.2MeV to 6MeV. The experimental results show that PADC can measure the total energy lost by a particle along a path of length Δx divided by the length itself, a quantity strictly related to the LET.
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