Microdosimetric quantities of an accelerator-based neutron source used for boron neutron capture therapy measured using a gas-filled proportional counter

Boron neutron capture therapy (BNCT) is an emerging radiation treatment modality, exhibiting the potential to selectively destroy cancer cells. Currently, BNCT is conducted using a nuclear reactor. However, the future trend is to move toward an accelerator-based system for use in hospital environments. A typical BNCT radiation field has several different types of radiation. The beam quality should be quantified to accurately determine the dose to be delivered to the target. This study utilized a tissue equivalent proportional counter (TEPC) to measure microdosimetric and macrodosimetric quantities of an accelerator-based neutron source. The micro- and macro-dosimetric quantities measured with the TEPC were compared with those obtained via the the particle and heavy ion transport code system (PHITS) Monte Carlo simulation. The absorbed dose from events >20 keV/μm measured free in air for a 1-h irradiation was calculated as 1.31 ± 0.02 Gy. The simulated result was 1.41 ± 0.07 Gy. The measured and calculated values exhibit good agreement. The relative biological effectiveness (RBE) that was evaluated from the measured microdosimetric spectrum was calculated as 3.7 ± 0.02, similar to the simulated value of 3.8 ± 0.1. These results showed the PHITS Monte Carlo simulation can simulate both micro- and macro-dosimetric quantities accurately. The RBE was calculated using a single-response function, and the results were compared with those of several other institutes that used a similar method. However, care must be taken when using such a single-response function for clinical application, as it is only valid for low doses. For clinical dose ranges (i.e., high doses), multievent distribution inside the target needs to be considered

Development and evaluation of dose calculation algorithm with a combination of Monte Carlo and point-kernel methods for boron neutron capture therapy

We developed a 'hybrid algorithm' that combines the Monte Carlo (MC) and point-kernel methods for fast dose calculation in boron neutron capture therapy. The objectives of this study were to experimentally verify the hybrid algorithm and to verify the calculation accuracy and time of a 'complementary approach' adopting both the hybrid algorithm and the full-energy MC method. In the latter verification, the results were compared with those obtained using the full-energy MC method alone. In the hybrid algorithm, the moderation process of neutrons is simulated using only the MC method, and the thermalization process is modeled as a kernel. The thermal neutron fluxes calculated using only this algorithm were compared with those measured in a cubic phantom. In addition, a complementary approach was used for dose calculation in a geometry simulating the head region, and its computation time and accuracy were verified. The experimental verification indicated that the thermal neutron fluxes calculated using only the hybrid algorithm reproduced the measured values at depths exceeding a few centimeters, whereas they overestimated those at shallower depths. Compared with the calculation using only the full-energy MC method, the complementary approach reduced the computation time by approximately half, maintaining nearly same accuracy. When focusing on the calculation only using the hybrid algorithm only for the boron dose attributed to the reaction of thermal neutrons, the computation time was expected to reduce by 95% compared with the calculation using only the full-energy MC method. In conclusion, modeling the thermalization process as a kernel was effective for reducing the computation time

Intensity-modulated irradiation for superficial tumors by overlapping irradiation fields using intensity modulators in accelerator-based BNCT

The distribution of the thermal neutron flux has a significant impact on the treatment efficacy. We developed an irradiation method of overlapping irradiation fields using intensity modulators for the treatment of superficial tumors with the aim of expanding the indications for accelerator-based boron neutron capture therapy (BNCT). The shape of the intensity modulator was determined and Monte Carlo simulations were carried out to determine the uniformity of the resulting thermal neutron flux distribution. The intensity modulators were then fabricated and irradiation tests were conducted, which resulted in the formation of a uniform thermal neutron flux distribution. Finally, an evaluation of the tumor dose distribution showed that when two irradiation fields overlapped, the minimum tumor dose was 27.4 Gy-eq, which was higher than the tumor control dose of 20 Gy-eq. Furthermore, it was found that the uniformity of the treatment was improved 47% as compared to the treatment that uses a single irradiation field. This clearly demonstrates the effectiveness of this technique and the possibility of expanding the indications to superficially located tumors

Development of optimization method for uniform dose distribution on superficial tumor in an accelerator-based boron neutron capture therapy system

To treat superficial tumors using accelerator-based boron neutron capture therapy (ABBNCT), a technique was investigated, based on which, a single-neutron modulator was placed inside a collimator and was irradiated with thermal neutrons. In large tumors, the dose was reduced at their edges. The objective was to generate a uniform and therapeutic intensity dose distribution. In this study, we developed a method for optimizing the shape of the intensity modulator and irradiation time ratio to generate a uniform dose distribution to treat superficial tumors of various shapes. A computational tool was developed, which performed Monte Carlo simulations using 424 different source combinations. We determined the shape of the intensity modulator with the highest minimum tumor dose. The homogeneity index (HI), which evaluates uniformity, was also derived. To evaluate the efficacy of this method, the dose distribution of a tumor with a diameter of 100 mm and thickness of 10 mm was evaluated. Furthermore, irradiation experiments were conducted using an ABBNCT system. The thermal neutron flux distribution outcomes that have considerable impacts on the tumor’s dose confirmed a good agreement between experiments and calculations. Moreover, the minimum tumor dose and HI improved by 20 and 36%, respectively, compared with the irradiation case wherein a single-neutron modulator was used. The proposed method improves the minimum tumor volume and uniformity. The results demonstrate the method’s efficacy in ABBNCT for the treatment of superficial tumors

Critical contribution of MCL-1 in EMT-associated chemo-resistance in A549 non-small-cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the leading causes of death in all lung cancer patients due to its metastatic spread. Even though cisplatin treatment after surgical resection of the primary tumor has been established as a standard chemotherapy for residual disease including metastatic spread, NSCLC often acquires a resistance against chemotherapy, and metastatic disease is often observed. Amongst many potential mechanisms, epithelial-to-mesenchymal transition (EMT) has been considered as an important process in acquiring both metastatic spread and chemo-resistance of NSCLC. In this study, we identified MCL-1 as a critical molecule for chemoresistance in A549 cells associated with TGF-β-induced EMT. Importantly, downregulation of MCL-1 by siRNA or inhibition of MCL-1 with pan-BCL2 inhibitor to inhibit MCL-1 was able to overcome the EMT-associated chemo-resistance in A549 cells. Collectively, MCL-1 can be a new therapeutic target for overcoming EMT-associated chemo-resistance in NSCLC patients in the context of post-operative chemotherapies

Role of p53 mutation in the effect of boron neutron capture therapy on oral squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Boron neutron capture therapy (BNCT) is a selective radiotherapy, being effective for the treatment of even advanced malignancies in head and neck regions as well as brain tumors and skin melanomas. To clarify the role of p53 gene, the effect of BNCT on oral squamous cell carcinoma (SCC) cells showing either wild- (SAS/neo) or mutant-type (SAS/mp53) p53 was examined.</p> <p>Methods</p> <p>Cells were exposed to neutron beams in the presence of boronophenylalanine (BPA) at Kyoto University Research Reactor. Treated cells were monitored for modulations in colony formation, proliferation, cell cycle, and expression of cell cycle-associated proteins.</p> <p>Results</p> <p>When SAS/neo and SAS/mp53 cells were subjected to BNCT, more suppressive effects on colony formation and cell viability were observed in SAS/neo compared with SAS/mp53 cells. Cell cycle arrest at the G1 checkpoint was observed in SAS/neo, but not in SAS/mp53. Apoptotic cells increased from 6 h after BNCT in SAS/neo and 48 h in SAS/mp53 cells. The expression of p21 was induced in SAS/neo only, but G2 arrest-associated proteins including Wee1, cdc2, and cyclin B1 were altered in both cell lines.</p> <p>Conclusion</p> <p>These results indicate that oral SCC cells with mutant-type are more resistant to BNCT than those with wild-type p53, and that the lack of G1 arrest and related apoptosis may contribute to the resistance. At a physical dose affecting the cell cycle, BNCT inhibits oral SCC cells in p53-dependent and -independent manners.</p

Physiological Properties of Rod Photoreceptor Cells in Green-sensitive Cone Pigment Knock-in Mice

Rod and cone photoreceptor cells that are responsible for scotopic and photopic vision, respectively, exhibit photoresponses different from each other and contain similar phototransduction proteins with distinctive molecular properties. To investigate the contribution of the different molecular properties of visual pigments to the responses of the photoreceptor cells, we have generated knock-in mice in which rod visual pigment (rhodopsin) was replaced with mouse green-sensitive cone visual pigment (mouse green). The mouse green was successfully transported to the rod outer segments, though the expression of mouse green in homozygous retina was ∼11% of rhodopsin in wild-type retina. Single-cell recordings of wild-type and homozygous rods suggested that the flash sensitivity and the single-photon responses from mouse green were three to fourfold lower than those from rhodopsin after correction for the differences in cell volume and levels of several signal transduction proteins. Subsequent measurements using heterozygous rods expressing both mouse green and rhodopsin E122Q mutant, where these pigments in the same rod cells can be selectively irradiated due to their distinctive absorption maxima, clearly showed that the photoresponse of mouse green was threefold lower than that of rhodopsin. Noise analysis indicated that the rate of thermal activations of mouse green was 1.7 × 10−7 s−1, about 860-fold higher than that of rhodopsin. The increase in thermal activation of mouse green relative to that of rhodopsin results in only 4% reduction of rod photosensitivity for bright lights, but would instead be expected to severely affect the visual threshold under dim-light conditions. Therefore, the abilities of rhodopsin to generate a large single photon response and to retain high thermal stability in darkness are factors that have been necessary for the evolution of scotopic vision

Prophylactic effects of isomaltodextrin in a Balb/c mouse model of egg allergy

The aim of this study was to evaluate the potential effects of isomaltodextrin (IMD), a dietary saccharide polymer derived from enzymatically produced from starch, on the ability to alter immune response (IR) bias to hen egg ovalbumin (Ova) induced allergic inflammation in mice. Groups of Balb/c mice were pre-treated with various doses of IMD in drinking water (1.0, 2.5, and 5.0% w/v) for 6 weeks and subsequently sensitized to the Ova together with continuous administration of IMD. To evaluate changes in immune response bias, immunoglobulin isotype-associated antibody activity, concentrations of type 1 and 2 cytokines and the percentage of T-regulatory cells (T-regs) in blood were measured. Clinical signs of allergy were assessed after oral challenge with Ova. Treatment with IMD did not significantly alter the frequency of clinical signs, however there was a trend in the overall reduction of clinical signs. Effect on IR bias was observed in the treatment groups as reflected by reduction in a type 1-biased phenotype as evident by decrease in isotype-specific IgE, IgG and increase in IL-12 cytokine production and a high proportion of Tregs. This study revealed that IMD could be a useful prophylactic candidate for alteration of allergic IR bias in mice and an immunestimulator for reducing egg induced allergic reactions

Design, Synthesis, and Biological Applications of Boron-Containing Polyamine and Sugar Derivatives

Boron (B), an element that is present in ultratrace amounts in animal cells and tissues, is expected to be useful in many scientific fields. We have found the hydrolysis of C–B bond in phenylboronic acid-pendant cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) and the full decomposition of ortho-carborane attached with cyclen and ethylenediamines in aqueous solution at neutral pH upon complexation with intracellular metals. The change in the chemical shift of the 11B signals in 11B-NMR spectra of these boron-containing metal chelators can be applied to the magnetic resonance imaging (MRI) of metal ions in solutions and in living cells