Lewis Acid-Mediated Friedel-Crafts-Type Formylation of Alkenes with Dichloromethyl Methyl Ether in the Presence of Pyridines.

Various alkenes are formylated with dichloromethyl methyl ether (MOMCl2) by the combined use of SnCl4/2,6-dibromopyridine (B1) or AgOTf/pyridine (B4) via Friedel-Crafts-type reaction. The former reagent combination is mainly applied to α,α-diarylalkenes, while the latter one is applied not only to arylalkenes but also to some alkylalkenes. Vinyl aldehydes are exclusively obtained from alkenes that can possibly afford both allyl and vinyl aldehydes.

Improvement in a post-stroke pediatric patient with hemiplegia: Use of a hand-arm bimanual intensive therapy with hybrid assistive limb.

BACKGROUND: Pediatric stroke is a rare medical condition that often leads to long-lasting motor and cognitive impairments. Although therapies for adults after a stroke are well described, treatments for motor deficits following a pediatric stroke are yet to be investigated. We report a case of pediatric stroke in the chronic phase, in which a combination of novel treatments resulted in a significant improvement in physical function. CASE REPORT: A seven-year-old girl with a left hemispheric cerebral infarction lost almost all right upper extremity motor function. Following onabotulinumtoxinA treatment, she underwent hand-arm bimanual intensive therapy augmented with a hybrid assistive limb for 90 h over 15 days. Evaluation after the training revealed significant improvements in physical function, daily activities, and occupational performance. CONCLUSIONS: This report highlights the importance of innovative combinations of techniques in the treatment of pediatric stroke.

A step-by-step simulation code for estimating yields of water radiolysis species based on electron track-structure mode in the PHITS code.

Objective. Time-dependent yields of chemical products resulting from water radiolysis play a great role in evaluating DNA damage response after exposure to ionizing radiation. Particle and Heavy Ion Transport code System (PHITS) is a general-purpose Monte Carlo simulation code for radiation transport, which simulates atomic interactions originating from discrete energy levels of ionizations and electronic excitations as well as molecular excitations as physical stages. However, no chemical code for simulating water radiolysis products exists in the PHITS package.Approach.Here, we developed a chemical simulation code dedicated to the PHITS code, hereafter calledPHITS-Chemcode, which enables the calculation of theGvalues of water radiolysis species (•OH, eaq-, H2, H2O2etc) by electron beams.Main results.The estimatedGvalues during 1 µs are in agreement with the experimental ones and other simulations. ThisPHITS-Chemcode also simulates the radiolysis in the presence of OH radical scavengers, such as tris(hydroxymethyl)aminomethane and dimethyl sulfoxide. Thank to this feature, the contributions of direct and indirect effects on DNA damage induction under various scavenging capacities can be analyzed.Significance.This chemical code coupled with PHITS could contribute to elucidating the mechanism of radiation effects by connecting physical, physicochemical, and chemical processes.

An Analytical Method for Quantifying the Yields of DNA Double-Strand Breaks Coupled with Strand Breaks by γ-H2AX Focus Formation Assay Based on Track-Structure Simulation.

Complex DNA double-strand break (DSB), which is defined as a DSB coupled with additional strand breaks within 10 bp in this study, induced after ionizing radiation or X-rays, is recognized as fatal damage which can induce cell death with a certain probability. In general, a DSB site inside the nucleus of live cells can be experimentally detected using the γ-H2AX focus formation assay. DSB complexity is believed to be detected by analyzing the focus size using such an assay. However, the relationship between focus size and DSB complexity remains uncertain. In this study, using Monte Carlo (MC) track-structure simulation codes, i.e., an in-house WLTrack code and a Particle and Heavy Ion Transport code System (PHITS), we developed an analytical method for qualifying the DSB complexity induced by photon irradiation from the microscopic image of γ-H2AX foci. First, assuming that events (i.e., ionization and excitation) potentially induce DNA strand breaks, we scored the number of events in a water cube (5.03 × 5.03 × 5.03 nm3) along electron tracks. Second, we obtained the relationship between the number of events and the foci size experimentally measured by the γ-H2AX focus formation assay. Third, using this relationship, we evaluated the degree of DSB complexity induced after photon irradiation for various X-ray spectra using the foci size, and the experimental DSB complexity was compared to the results estimated by the well-verified DNA damage estimation model in the PHITS code. The number of events in a water cube was found to be proportional to foci size, suggesting that the number of events intrinsically related to DSB complexity at the DNA scale. The developed method was applicable to focus data measured for various X-ray spectral situations (i.e., diagnostic kV X-rays and therapeutic MV X-rays). This method would contribute to a precise understanding of the early biological impacts of photon irradiation by means of the γ-H2AX focus formation assay.

Application of a simple DNA damage model developed for electrons to proton irradiation.

Proton beam therapy allows irradiating tumor volumes with reduced side effects on normal tissues with respect to conventional x-ray radiotherapy. Biological effects such as cell killing after proton beam irradiations depend on the proton kinetic energy, which is intrinsically related to early DNA damage induction. As such, DNA damage estimation based on Monte Carlo simulations is a research topic of worldwide interest. Such simulation is a mean of investigating the mechanisms of DNA strand break formations. However, past modellings considering chemical processes and DNA structures require long calculation times. Particle and heavy ion transport system (PHITS) is one of the general-purpose Monte Carlo codes that can simulate track structure of protons, meanwhile cannot handle radical dynamics simulation in liquid water. It also includes a simple model enabling the efficient estimation of DNA damage yields only from the spatial distribution of ionizations and excitations without DNA geometry, which was originally developed for electron track-structure simulations. In this study, we investigated the potential application of the model to protons without any modification. The yields of single-strand breaks, double-strand breaks (DSBs) and the complex DSBs were assessed as functions of the proton kinetic energy. The PHITS-based estimation showed that the DSB yields increased as the linear energy transfer (LET) increased, and reproduced the experimental and simulated yields of various DNA damage types induced by protons with LET up to about 30 keVµm-1. These results suggest that the current DNA damage model implemented in PHITS is sufficient for estimating DNA lesion yields induced after protons irradiation except at very low energies (below 1 MeV). This model contributes to evaluating early biological impacts in radiation therapy.

Impact of the Lorentz force on electron track structure and early DNA damage yields in magnetic resonance-guided radiotherapy.

Magnetic resonance-guided radiotherapy (MRgRT) has been developed and installed in recent decades for external radiotherapy in several clinical facilities. Lorentz forces modulate dose distribution by charged particles in MRgRT; however, the impact of Lorentz forces on low-energy electron track structure and early DNA damage induction remain unclear. In this study, we estimated features of electron track structure and biological effects in a static magnetic field (SMF) using a general-purpose Monte Carlo code, particle and heavy ion transport code system (PHITS) that enables us to simulate low-energy electrons down to 1 meV by track-structure mode. The macroscopic dose distributions by electrons above approximately 300 keV initial energy in liquid water are changed by both perpendicular and parallel SMFs against the incident direction, indicating that the Lorentz force plays an important role in calculating dose within tumours. Meanwhile, DNA damage estimation based on the spatial patterns of atomic interactions indicates that the initial yield of DNA double-strand breaks (DSBs) is independent of the SMF intensity. The DSB induction is predominantly attributed to the secondary electrons below a few tens of eV, of which energy deposition patterns are not considerably affected by the Lorentz force. Our simulation study suggests that treatment planning for MRgRT can be made with consideration of only changed dose distribution.

Track-structure modes in particle and heavy ion transport code system (PHITS): application to radiobiological research.

PURPOSE: In radiation physics, Monte Carlo radiation transport simulations are powerful tools to evaluate the cellular responses after irradiation. When investigating such radiation-induced biological effects, it is essential to perform track structure simulations by explicitly considering each atomic interaction in liquid water at the sub-cellular and DNA scales. The Particle and Heavy-Ion Transport code System (PHITS) is a Monte Carlo code which enables to calculate track structure at DNA scale by employing the track-structure modes for electrons, protons and carbon ions. In this paper, we review the recent development status and future prospects of the track-structure modes in the PHITS code. CONCLUSIONS: To date, the physical features of these modes have been verified using the available experimental data and Monte Carlo simulation results reported in literature. These track-structure modes can be used for calculating microdosimetric distributions to estimate cell survival and for estimating initial DNA damage yields. The use of PHITS track-structure mode is expected not only to clarify the underlying mechanisms of radiation effects but also to predict curative effects in radiation therapy. The results of PHITS simulations coupled with biophysical models will contribute to the radiobiological studies by precisely predicting radiation-induced biological effects based on the Monte Carlo approach.

A Simplified Cluster Analysis of Electron Track Structure for Estimating Complex DNA Damage Yields.

Complex DNA damage, defined as at least two vicinal lesions within 10-20 base pairs (bp), induced after exposure to ionizing radiation, is recognized as fatal damage to human tissue. Due to the difficulty of directly measuring the aggregation of DNA damage at the nano-meter scale, many cluster analyses of inelastic interactions based on Monte Carlo simulation for radiation track structure in liquid water have been conducted to evaluate DNA damage. Meanwhile, the experimental technique to detect complex DNA damage has evolved in recent decades, so both approaches with simulation and experiment get used for investigating complex DNA damage. During this study, we propose a simplified cluster analysis of ionization and electronic excitation events within 10 bp based on track structure for estimating complex DNA damage yields for electron and X-ray irradiations. We then compare the computational results with the experimental complex DNA damage coupled with base damage (BD) measured by enzymatic cleavage and atomic force microscopy (AFM). The computational results agree well with experimental fractions of complex damage yields, i.e., single and double strand breaks (SSBs, DSBs) and complex BD, when the yield ratio of BD/SSB is assumed to be 1.3. Considering the comparison of complex DSB yields, i.e., DSB + BD and DSB + 2BD, between simulation and experimental data, we find that the aggregation degree of the events along electron tracks reflects the complexity of induced DNA damage, showing 43.5% of DSB induced after 70 kVp X-ray irradiation can be classified as a complex form coupled with BD. The present simulation enables us to quantify the type of complex damage which cannot be measured through in vitro experiments and helps us to interpret the experimental detection efficiency for complex BD measured by AFM. This simple model for estimating complex DNA damage yields contributes to the precise understanding of the DNA damage complexity induced after X-ray and electron irradiations.

Track Structure Study for Energy Dependency of Electrons and X-rays on DNA Double-Strand Break Induction.

Radiation weighting factor wR for photons and electrons has been defined as unity independently of the energy of the particles. However, the biological effects depend on the incident energies according to in vitro experimental data. In this study, we have quantified the energy concentration along electron tracks in terms of dose-mean lineal energy (yD) on chromosome (micro-meter) and DNA (nano-meter) order scales by Monte Carlo simulations, and evaluated the impact of photon energies on DNA double-strand break (DNA-DSB) induction from an experimental study of irradiated cells. Our simulation result shows that the yD values for diagnostic X-rays (60-250 kVp) are higher than that for therapeutic X-rays (linac 6 MV), which agrees well with the tissue equivalent proportional counter (TEPC) measurements. The relation between the yD values and the numbers of γ-H2AX foci for various photon energy spectra suggests that low energy X-rays induce DNA-DSB more efficiently than higher energy X-rays even at the same absorbed dose (e.g., 1.0 Gy). The relative biological effectiveness based on DNA-DSBs number (RBEDSB) is proportionally enhanced as the yD value increases, demonstrating that the biological impact of the photon irradiation depends on energy concentration along radiation tracks of electrons produced in the bio-tissues. Ultimately, our study implies that the value of wR for photons varies depending on their energies.

Acylation of Alkenes with the Aid of AlCl3 and 2,6-Dibromopyridine.

Friedel-Crafts-type acylation of alkenes with acyl chlorides has been successfully conducted with a wide substrate scope by the combined use of AlCl3 and 2,6-dibromopyridine. Trisubstituted alkenes afford allylketones or vinylketones depending on the presence or absence of hydrogen atom(s) at the ß-position to the acylation site, while monosubstituted alkenes exclusively afford vinylketones.

Intensity Modulated Radiation Fields Induce Protective Effects and Reduce Importance of Dose-Rate Effects.

In advanced radiotherapy, intensity modulated radiation fields and complex dose-delivery are utilized to prescribe higher doses to tumours. Here, we investigated the impact of modulated radiation fields on radio-sensitivity and cell recovery during dose delivery. We generated experimental survival data after single-dose, split-dose and fractionated irradiation in normal human skin fibroblast cells (AGO1522) and human prostate cancer cells (DU145). The dose was delivered to either 50% of the area of a T25 flask containing the cells (half-field) or 100% of the flask (uniform-field). We also modelled the impact of dose-rate effects and intercellular signalling on cell-killing. Applying the model to the survival data, it is found that (i) in-field cell survival under half-field exposure is higher than uniform-field exposure for the same delivered dose; (ii) the importance of sub-lethal damage repair (SLDR) in AGO1522 cells is reduced under half-field exposure; (iii) the yield of initial DNA lesions measured with half-field exposure is smaller than that with uniform-field exposure. These results suggest that increased cell survival under half-field exposure is predominantly attributed not to rescue effects (increased SLDR) but protective effects (reduced induction of initial DNA lesions). In support of these protective effects, the reduced DNA damage leads to modulation of cell-cycle dynamics, i.e., less G1 arrest 6 h after irradiation. These findings provide a new understanding of the impact of dose-rate effects and protective effects measured after modulated field irradiation.

Estimation of the radiation-induced DNA double-strand breaks number by considering cell cycle and absorbed dose per cell nucleus.

DNA double-strand breaks (DSBs) are thought to be the main cause of cell death after irradiation. In this study, we estimated the probability distribution of the number of DSBs per cell nucleus by considering the DNA amount in a cell nucleus (which depends on the cell cycle) and the statistical variation in the energy imparted to the cell nucleus by X-ray irradiation. The probability estimation of DSB induction was made following these procedures: (i) making use of the Chinese Hamster Ovary (CHO)-K1 cell line as the target example, the amounts of DNA per nucleus in the logarithmic and the plateau phases of the growth curve were measured by flow cytometry with propidium iodide (PI) dyeing; (ii) the probability distribution of the DSB number per cell nucleus for each phase after irradiation with 1.0 Gy of 200 kVp X-rays was measured by means of γ-H2AX immunofluorescent staining; (iii) the distribution of the cell-specific energy deposition via secondary electrons produced by the incident X-rays was calculated by WLTrack (in-house Monte Carlo code); (iv) according to a mathematical model for estimating the DSB number per nucleus, we deduced the induction probability density of DSBs based on the measured DNA amount (depending on the cell cycle) and the calculated dose per nucleus. The model exhibited DSB induction probabilities in good agreement with the experimental results for the two phases, suggesting that the DNA amount (depending on the cell cycle) and the statistical variation in the local energy deposition are essential for estimating the DSB induction probability after X-ray exposure.

Investigation of dose-rate effects and cell-cycle distribution under protracted exposure to ionizing radiation for various dose-rates.

During exposure to ionizing radiation, sub-lethal damage repair (SLDR) competes with DNA damage induction in cultured cells. By virtue of SLDR, cell survival increases with decrease of dose-rate, so-called dose-rate effects (DREs). Here, we focused on a wide dose-rate range and investigated the change of cell-cycle distribution during X-ray protracted exposure and dose-response curves via hybrid analysis with a combination of in vitro experiments and mathematical modelling. In the course of flow-cytometric cell-cycle analysis and clonogenic assays, we found the following responses in CHO-K1 cells: (1) The fraction of cells in S phase gradually increases during 6 h exposure at 3.0 Gy/h, which leads to radio-resistance. (2) Slight cell accumulation in S and G2/M phases is observed after exposure at 6.0 Gy/h for more than 10 hours. This suggests that an increase of SLDR rate for cells in S phase during irradiation may be a reproducible factor to describe changes in the dose-response curve at dose-rates of 3.0 and 6.0 Gy/h. By re-evaluating cell survival for various dose-rates of 0.186-60.0 Gy/h considering experimental-based DNA content and SLDR, it is suggested that the change of S phase fraction during irradiation modulates the dose-response curve and is possibly responsible for some inverse DREs.

Integrated Modelling of Cell Responses after Irradiation for DNA-Targeted Effects and Non-Targeted Effects.

Intercellular communication after ionizing radiation exposure, so-called non-targeted effects (NTEs), reduces cell survival. Here we describe an integrated cell-killing model considering NTEs and DNA damage along radiation particle tracks, known as DNA-targeted effects (TEs) based on repair kinetics of DNA damage. The proposed model was applied to a series of experimental data, i.e., signal concentration, DNA damage kinetics, cell survival curve and medium transfer bystander effects (MTBEs). To reproduce the experimental data, the model considers the following assumptions: (i) the linear-quadratic (LQ) function as absorbed dose to express the hit probability to emit cell-killing signals, (ii) the potentially repair of DNA lesions induced by NTEs, and (iii) lower efficiency of repair for the damage in NTEs than that in TEs. By comparing the model results with experimental data, we found that signal-induced DNA damage and lower repair efficiency in non-hit cells are responsible for NTE-related repair kinetics of DNA damage, cell survival curve with low-dose hyper-radiosensitivity (HRS) and MTBEs. From the standpoint of modelling, the integrated cell-killing model with the LQ relation and a different repair function for NTEs provide a reasonable signal-emission probability and a new estimation of low-dose HRS linked to DNA repair efficiency.

Modeling cell survival and change in amount of DNA during protracted irradiation.

Hyper-radiosensitivity (HRS) is a well-known bioresponse under low-dose or low-dose-rate exposures. Although disorder of the DNA repair function, non-targeted effects and accumulation of cells in G2 have been experimentally observed, the mechanism for inducing HRS by long-term irradiation is still unclear. On the basis of biological experiments and a theoretical study, we have shown that change in the amount of DNA associated with accumulation of cells in G2 enhances radiosensitivity. To demonstrate continuous irradiation with 250 kVp X-rays, we adopted a fractionated regimen of 0.186 or 1.00 Gy per fraction at intervals of 1 h (i.e. 0.186 Gy/h, 1.00 Gy/h on average) to Chinese Hamster Ovary (CHO)-K1 cells. The change in the amount of DNA during irradiation was quantified by flow cytometric analysis with propidium iodide (PI). Concurrently, we attempted a theoretical evaluation of the DNA damage by using a microdosimetric-kinetic (MK) model that was modified to incorporate the change in the amount of DNA. Our experimental results showed that the fraction of the cells in G2/M phase increased by 6.7% with 0.186 Gy/h and by 22.1% with 1.00 Gy/h after the 12th irradiation. The MK model considering the change in amount of DNA during the irradiation exhibited a higher radiosensitivity at a high dose range, which could account for the experimental clonogenic survival. The theoretical results suggest that HRS in the high dose range is associated with an increase in the total amount of DNA during irradiation.

[Development of a Lead-covered Case for a Wireless X-ray Output Analyzer to Perform CT Half-value Layer Measurements].

Measurement of the half-value layer (HVL) is a difficult task in computed tomography (CT) , because a nonrotating X-ray tube must be used. The purpose of this study is to develop a lead-covered case, which enables HVL measurements with a rotating CT X-ray tube. The lead-covered case was manufactured from acrylic and lead plates, which are 3 mm thick and have a slit. The slit-detector distance can be selected between 14 mm and 122 mm. HVL measurements were performed using a wireless X-ray output analyzer "Piranha." We used the following exposure conditions: tube voltages of 80, 100, and 120 kV; a tube current of 550 mA; and an exposure time of 1.0 s. The HVLs were measured by using the following two methods: (a) Nonrotating method-a conventional method that uses the nonrotating exposure mode. (b) Rotating method-a new method that uses the lead-covered case and the rotating exposure mode. As a result, when the slit-detector distance was 58 mm, the HVL values obtained by the nonrotating and rotating methods were 4.38 and 4.24 mmAl at 80 kV, 5.51 and 5.37 mmAl at 100 kV, 6.61 and 6.48 mmAl at 120 kV, respectively. A lead-covered case, which enables the measurement of the HVL in a rotating X-ray tube, was developed. The case is useful in measuring the HVLs at facilities that cannot fix the X-ray tube.