The feasibility study of using multiple partial volumetric-modulated arcs therapy in early stage left-sided breast cancer patients.

The purpose of this study was to assess the feasibility of using a multiple partial volumetric-modulated arcs therapy (MP-VMAT) technique on the left breast irradiation and to evaluate the dosimetry and treatment efficiency. Ten patients with left-sided breast cancer who had been treated by whole breast irradiation were selected for the treatment plan evaluation by using six partial volumetric modulated arcs. Each arc consisted of a 50° gantry rotation. The planning target volumes and the normal organs, including the right breast, the bilateral lungs, left ventricle, heart, and unspecified tissue, were contoured on the CT images. Dose-volume histograms were generated and the delivery time for each arc was recorded. The PTV received greater than 95% of the V(95) for all cases, and the maximum dose was within ± 1% of 110% of the prescription dose. The mean homogeneity index (HI) was 10.61 ± 0.99, and mean conformity index (CI) was 1.21 ± 0.03. The mean dose, V(5), V(10), V(25), and V(30) of the heart were 7.61 ± 1.38 Gy, 59.73% ± 15.87%, 24.39%± 6.82%, 2.52%± 1.11%, and 1.57% ± 0.71%, respectively. The volume of the left ventricle receiving 25 Gy was 5.15% ± 2.23%. The total lung mean dose was 5.57 ± 0.36 Gy, with V(5) of 25.39% ± 3.88% and V(20) of 5.66% ± 0.89%. The right breast received a mean dose of 2.13 ± 0.22 Gy, with V(5) of 1.83% ± 1.22% and V(10) of 0.04% ± 0.12%. The mean dose of unspecified tissue was 5.34 ± 0.37 Gy and V(5) was 22.23% ± 1.57%. The volume of the unspecified tissue receiving 50 Gy was 0.50% ± 0.14%. The mean delivery time for each arc was 13.9 seconds. The average MU among ten patients was 511 MU (range 443 to 594 MUs). The MP-VMAT technique for the left-sided breast cancer patients achieved adequate target dose coverage while maintaining low doses to organs-at-risk, and therefore reduced the potential for induction of second malignancy and side effects. The highly efficient treatment delivery would be beneficial for improving patient throughput, providing patient comfort, and achieving precise treatment with the breathing control system.

Isatin-ß-thiosemicarbazones as potent herpes simplex virus inhibitors.

A series of isatin-ß-thiosemicarbazones have been designed and evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a plaque reduction assay. Their cytotoxicity was examined using human rhabdomyosarcoma cells (RD cells). Several derivatives of isatin-ß-thiosemicarbazone exhibited significant and selective antiviral activity with low cytotoxicity. It was found that the thiourea group at thiosemicarbazone and the NH functionality at isatin were essential for their antiherpetic activity. The synthesis and structure-activity relationship studies are presented.

MOSFET dose measurements for proton SOBP beam.

PURPOSE: The aim of this work was to develop a computational scheme for the correction of the LET dependence on the MOSFET response in water phantom dose measurements for a spread-out Bragg peak (SOBP) proton beam. METHODS: The LET dependence of MOSFET was attributed to the stopping power ratio of SiO2 to H2O and to the fractional hole yield in the SiO2 layer. Using literature values for the stopping powers of the continuous slowing down approximation and measured fractional hole yields vs. electric field and LET, formulas were derived for the computation of a dose-weighted correction factor of a SOBP beam. RESULTS: Dose-weighted correction factors were computed for a clinical 190-MeV proton SOBP beam in a high-density polyethylene phantom. By applying correction factors to the SOBP beam, which consisted of weighted monoenergetic Bragg peaks, the MOSFET outputs were predicted and agreed well with the measured MOSFET responses. CONCLUSION: By applying LET dependent correction factors to MOSFET data, quality assurance of dose verification based on MOSFET measurements becomes possible for proton therapy.

Synthesis, activity, and pharmacokinetic properties of a series of conformationally-restricted thiourea analogs as novel hepatitis C virus inhibitors.

A series of novel conformationally-restricted thiourea analogs were designed, synthesized, and evaluated for their anti-HCV activity. Herein we report the synthesis, structure-activity relationships (SARs), and pharmacokinetic properties of this new class of thiourea compounds that showed potent inhibitory activities against HCV in the cell-based subgenomic HCV replicon assay. Among compounds tested, the fluorene compound 4b was found to possess the most potent activity (EC(50)=0.3 microM), lower cytotoxicity (CC(50)>50 microM), and significantly better pharmacokinetic properties compared to its corresponding fluorenone compound 4c.

Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors.

PURPOSE: To investigate how single or fractionated doses of radiation change the microenvironment in transgenic adenocarcinoma of the mouse prostate (TRAMP)-C1 tumors with respect to vascularity, hypoxia, and macrophage infiltrates. EXPERIMENTAL DESIGN: Murine prostate TRAMP-C1 tumors were grown in C57BL/6J mice to 4 mm tumor diameter and were irradiated with either 25 Gy in a single dose or 60 Gy in 15 fractions. Changes in vascularity, hypoxia, and macrophage infiltrates were assessed by immunohistochemistry and molecular assays. RESULTS: Tumor growth was delayed for 1 week after both radiation schedules. Tumor microvascular density (MVD) progressively decreased over a 3-week period to nadirs of 25% and 40% of unirradiated tumors for single or fractionated treatment, respectively. In accord with the decrease in MVDs, mRNA levels of endothelial markers, such as CD31, endoglin, and TIE, decreased over the same time period after irradiation. Central dilated vessels developed surrounded by avascularized hypoxic regions that became infiltrated with aggregates of CD68+ tumor-associated macrophages, reaching a maximum at 3 weeks after irradiation. Necrotic regions decreased and were more dispersed. CONCLUSION: Irradiation of TRAMP-C1 tumors with either single or fractionated doses decreases MVD, leading to the development of disperse chronic hypoxic regions, which are infiltrated with CD68+ tumor-associated macrophages. Approaches to interfere in the development of these effects are promising strategies to enhance the efficacy of cancer radiotherapy.

Four direct measurements of the fine-structure constant 13 billion years ago.

Observations of the redshift z = 7.085 quasar J1120+0641 are used to search for variations of the fine structure constant, α, over the redshift range 5.5 to 7.1. Observations at z = 7.1 probe the physics of the universe at only 0.8 billion years old. These are the most distant direct measurements of α to date and the first measurements using a near-IR spectrograph. A new AI analysis method is employed. Four measurements from the x-shooter spectrograph on the Very Large Telescope (VLT) constrain changes in a relative to the terrestrial value (α0). The weighted mean electromagnetic force in this location in the universe deviates from the terrestrial value by Δα/α = (α z - α0)/α0 = (-2.18 ± 7.27) × 10-5, consistent with no temporal change. Combining these measurements with existing data, we find a spatial variation is preferred over a no-variation model at the 3.9σ level.

Measurement-based Monte Carlo dose calculation system for IMRT pretreatment and on-line transit dose verifications.

The aim of this study was to develop a dose simulation system based on portal dosimetry measurements and the BEAM Monte Carlo code for intensity-modulated (IM) radiotherapy dose verification. This measurement-based Monte Carlo (MBMC) system can perform, within one systematic calculation, both pretreatment and on-line transit dose verifications. BEAMnrc and DOSXYZnrc 2006 were used to simulate radiation transport from the treatment head, through the patient, to the plane of the aS500 electronic portal imaging device (EPID). In order to represent the nonuniform fluence distribution of an IM field within the MBMC simulation, an EPID-measured efficiency map was used to redistribute particle weightings of the simulated phase space distribution of an open field at a plane above a patient/phantom. This efficiency map was obtained by dividing the measured energy fluence distribution of an IM field to that of an open field at the EPID plane. The simulated dose distribution at the midplane of a homogeneous polystyrene phantom was compared to the corresponding distribution obtained from the Eclipse treatment planning system (TPS) for pretreatment verification. It also generated a simulated transit dose distribution to serve as the on-line verification reference for comparison to that measured by the EPID. Two head-and-neck (NPC1 and NPC2) and one prostate cancer fields were tested in this study. To validate the accuracy of the MBMC system, film dosimetry was performed and served as the dosimetry reference. Excellent agreement between the film dosimetry and the MBMC simulation was obtained for pretreatment verification. For all three cases tested, gamma evaluation with 3%/3 mm criteria showed a high pass percentage (> 99.7%) within the area in which the dose was greater than 30% of the maximum dose. In contrast to the TPS, the MBMC system was able to preserve multileaf collimator delivery effects such as the tongue-and-groove effect and interleaf leakage. In the NPC1 field, the TPS showed 16.5% overdose due to the tongue-and-groove effect and 14.6% overdose due to improper leaf stepping. Similarly, in the NPC2 field, the TPS showed 14.1% overdose due to the tongue-and-groove effect and 8.9% overdose due to improper leaf stepping. In the prostate cancer field, the TPS showed 6.8% overdose due to improper leaf stepping. No tongue-and-groove effect was observed for this field. For transit dose verification, agreements among the EPID measurement, the film dosimetry, and the MBMC system were also excellent with a minimum gamma pass percentage of 99.6%.

Design, synthesis, and anti-HCV activity of thiourea compounds.

A series of thiourea derivatives were synthesized and their antiviral activity was evaluated in a cell-based HCV subgenomic replicon assay. SAR studies revealed that the chain length and the position of the alkyl linker largely influenced the in vitro anti-HCV activity of this class of potent antiviral agents. Among this series of compounds synthesized, the thiourea derivative with a six-carbon alkyl linker at the meta-position of the central phenyl ring (10) was identified as the most potent anti-HCV inhibitor (EC(50) = 0.047 microM) with a selectivity index of 596.

Design and synthesis of indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-1-carbothioic acid amide derivatives as novel HCV inhibitors.

An efficient synthetic methodology to provide indole, 2,3-dihydro-indole, and 3,4-dihydro-2H-quinoline-1-carbothioic acid amide derivatives is described. These conformationally restricted heterobicyclic scaffolds were evaluated as a novel class of HCV inhibitors. Introduction of an acyl group at the NH(2) of the thiourea moiety has been found to enhance inhibitory activity. The chain length and the position of the alkyl group on the indoline aromatic ring markedly influenced anti-HCV activity. The indoline scaffold was more potent than the corresponding indole and tetrahydroquinoline scaffolds and analogue 31 displayed excellent activity (EC(50)=510nM) against HCV without significant cytotoxicity (CC(50) >50microM).

Design and efficient synthesis of novel arylthiourea derivatives as potent hepatitis C virus inhibitors.

A novel class of arylthiourea HCV inhibitors bearing various functionalities, such as cyclic urea, cyclic thiourea, urea, and thiourea, on the alkyl linker were designed and synthesized. Herein we report the synthesis and structure-activity relationships (SARs) of this novel class of arylthiourea derivatives that showed potent inhibitory activities against HCV in the cell-based subgenomic HCV replicon assay. Among compounds tested, the new carbazole derivative 64, which has an eight-carbon linkage between the phenyl and carbazole rings and a tolyl group at the N-9 position of carbazole, was found to possess strong anti-HCV activity (EC50=0.031 microM), lower cytotoxicity (CC50 >50 microM), and higher selectivity index (SI >1612) compared to its derivatives.

A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus.

A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1'R,2'S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC50 = 0.003 nM) than daclatasvir (GT1b EC50 = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC50 > 50 µM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.

Predictors of Radiation-Induced Liver Disease in Eastern and Western Patients With Hepatocellular Carcinoma Undergoing Proton Beam Therapy.

PURPOSE: To identify predictors of radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) treated with proton beam therapy (PBT). METHODS: This multicenter study included 136 patients with HCC (eastern, n = 102; western, n = 34) without evidence of intrahepatic tumor progression after PBT. The RILD was defined as ascites with alkaline-phosphatase abnormality, grade ≥3 hepatic toxicity, or Child-Pugh score worsening by ≥2 within 4 months after PBT completion. The proton doses were converted to equivalent doses in 2-GyE fractions. The unirradiated liver volume (ULV) was defined as the absolute liver volume (LV) receiving <1 GyE; the standard liver volume (SLV) was calculated using body surface area. Possible correlations of clinicodosimetric parameters with RILD were examined. RESULTS: The mean pretreatment LV was 85% of SLV, and patients with a history of hepatectomy (P < .001) or hepatitis B virus infection (P = .035) had significantly smaller LV/SLV. Nineteen (14%) patients developed RILD. Multivariate logistic regression analysis identified ULV/SLV (P = .001), gross tumor volume (P = .001), and Child-Pugh classification (P = .002) as independent RILD predictors, and mean liver dose and target-delivered dose were not associated with RILD occurrence. A "volume-response" relationship between ULV/SLV and RILD was consistently observed in both eastern and western cohorts. In Child-Pugh class-A patients whose ULV/SLV were ≥50%, 49.9%-40%, 39.9%-30% and <30%, the RILD incidences were 0%, 6%, 16%, and 39% (P < .001), respectively. For the Child-Pugh class-B group, the RILD incidences in patients with ≥60%, 59.9%-40%, and <40% of ULV/SLV were 0%, 14%, and 83% (P = .006), respectively. CONCLUSIONS: The ULV/SLV, not mean liver dose, independently predicts RILD in patients with HCC undergoing PBT. The relative and absolute contraindications for Child-Pugh class-A patient's ULV/SLV are <50% and <30%, and <60% and <40% for Child-Pugh class-B patients, respectively. Our results indicate that the likelihood of hepatic complications for PBT is dictated by similar metrics as that for surgery.

Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth.

PURPOSE: To investigate the effects of single and fractionated doses of radiation on tumors and tumor-associated macrophages (TAMs), and to elucidate the potential of TAMs to influence tumor growth. METHODS AND MATERIALS: A murine prostate cell line, TRAMP-C1, was grown in C57Bl/6J mice to 4-mm tumor diameter and irradiated with either 25 Gy in a single dose, or 60 Gy in 15 fractions. The tumors were removed at the indicated times and assessed for a variety of markers related to TAM content, activation status, and function. RESULTS: In tumors receiving a single radiation dose, arginase (Arg-I), and cycloxygenase-2 (COX-2) mRNA expression increased as a small transient wave within 24 h and a larger persistent wave starting after 3 days. Inducible nitric oxide synthase (iNOS) mRNA was elevated only after 3 days and continued to increase up to 3 weeks. After fractionated irradiation, Arg-1 and COX-2 mRNA levels increased within 5 days, whereas iNOS was increased only after 10 fractions of irradiation had been given. Increased levels of Arg-I, COX-2, and, to a lesser extent, iNOS protein were found to associate with TAMs 1-2 weeks after tumor irradiation. Function of TAMs were compared by mixing them with TRAMP-C1 cells and injecting them into mice; TRAMP-C1 cells mixed with TAMs from irradiated tumors appeared earlier and grew significantly faster than those mixed with TAMs from unirradiated tumors or TRAMP-C1 alone. CONCLUSIONS: Tumor-associated macrophages in the postirradiated tumor microenvironment express higher levels of Arg-1, COX-2, and iNOS, and promote early tumor growth in vivo.

A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide.

Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC50 = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC50 = 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50 = 4.6 nM), with greater therapeutic index (CC50/EC50 > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats.

Compartmental responses after thoracic irradiation of mice: strain differences.

PURPOSE: To examine and compare the molecular and cellular processes leading to radiation fibrosis and pneumonitis in C57BL/6J and C3H/HeN mice. METHODS AND MATERIALS: At indicated times after various doses of thoracic irradiation, the cell populations obtained by bronchoalveolar lavage of C57BL/6J mice were differentially analyzed by cytology and assessed by RNase protection (RPA) assay for levels of cytokines and related genes. The molecular responses in bronchial alveolar lavage (BAL) populations were compared with those in whole lung of C57BL/6J mice and with those of C3H/HeN mice. The former strain develops late radiation fibrosis, whereas the latter develop subacute radiation pneumonitis. RESULTS: In C57BL/6J mice, a decrease in the total number of BAL cells was found 1 week after 6, 12, or 20 Gy thoracic irradiation with a subsequent dose-dependent increase up to 6 months. After 12 and 20 Gy, large, foamy macrophages and multinucleated cells became evident in BAL at 3 weeks, only to disappear at 4 months and reappear at 6 months. This biphasic response was mirrored by changes expression of mRNA for proinflammatory cytokines and the Mac-1 macrophage-associated antigen. As with BAL, whole lung tissue also showed biphasic cytokine and Mac-1 mRNA responses, but there were striking temporal differences between the two compartments, with changes in whole lung tissue correlating better than BAL with the onset of fibrosis in this strain. The radiation-induced proinflammatory mRNA responses had strain-dependent and strain-independent components. Thoracic irradiation of C3H/HeN induced similar increases in tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha/beta, and interferon (IFN)-gamma mRNA expression in lung as it did in C57BL/6J mice during the "presymptom" phase at 1-2 months. However, immediately preceding and during the pneumonitic time period at 3-4 months, TNF-alpha and IL-1alpha/beta mRNAs were highly upregulated in C3H/HeN mice, which develop pneumonitis, but not in C57BL/6J mice, which do not. At the onset of radiation fibrosis in C57BL/6J mice (5-6 months), irradiated lungs had increased levels of IL-1alpha/beta and IFN-gamma mRNA expression, but the TNF-alpha response was, notably, still muted. CONCLUSIONS: The major molecular and cellular events in lungs of C57BL/6J and C3H/HeN mice, which develop late fibrosis and subacute pneumonitis after thoracic irradiation respectively, take place within the interstitium and are not reflected within BAL populations. The initial proinflammatory responses are similar in the two strains, but later responses reflect the latent time to lesion development. TNF-alpha expression at 3-4 months may be important in radiation-induced pneumonitis, and its downregulation is important in avoiding this radiation-induced complication.

Risk stratification of patients with advanced squamous cell carcinoma of cervix treated by radiotherapy alone.

PURPOSE: To identify prognostic factors for local and distant relapse and perform risk stratification for patients with advanced cervical cancer treated with radiotherapy (RT) alone. METHODS AND MATERIALS: A total of 1031 patients with Stage IB-IVA squamous cell carcinoma of the cervix treated with full-course RT but without any chemotherapy were included for analysis. Of these, 311 patients with nonbulky Stage IB-IIA disease were designated the reference group and the other 720 patients were the study group. The associations of stage, squamous cell carcinoma antigen (SCC-ag) level, hemoglobin level, age, cell differentiation, and pelvic lymph node status with treatment failure were evaluated. The independent prognostic factors were identified by multivariate analysis. The study group was further stratified into subgroups using combinations of these risk factors. RESULTS: In the study group, independent risk factors for local relapse were advanced stage and age <45 years. The 5-year local relapse-free survival rate was 86% for patients > or =45 years with bulky Stage IB-IIA or IIB disease, and was even greater, up to 90% if the SCC-ag level was <2. In contrast, it was 65% for patients with Stage IIIB who were <45 years old. The independent risk factors for distant failure were advanced stage, SCC-ag level >2, and positive pelvic lymph nodes. The 5-year distant relapse-free survival rate was 83% for patients with bulky Stage IB-IIA and IIB disease, SCC-ag level <2, and negative lymph nodes and 43% for patients with Stage III, SCC-ag level >2, and positive lymph nodes. CONCLUSION: The risk of treatment failure in advanced-stage cervical cancer patients treated by RT alone can be more precisely predicted by risk stratification. A certain subgroup of patients had better control than the others. The benefit of treating these relatively low-risk patients with additional treatment such as concurrent chemotherapy should be further evaluated in prospective studies or meta-analyses.

Design, synthesis, and antipicornavirus activity of 1-[5-(4-arylphenoxy)alkyl]-3-pyridin-4-ylimidazolidin-2-one derivatives.

A series of pyridylimidazolidinone derivatives was synthesized and tested in vitro against enterovirus 71 (EV71). On the basis of compound 33 (DBPR103), introduction of a methyl group at the 2- or 3-position of the linker between the imidazolidinone and the biphenyl resulted in markedly improved antiviral activity toward EV71 with IC(50) values of 5.0 nM (24b) and 9.3 nM (14a), respectively. Increasing the branched chain to propyl resulted in a progressive decrease in activity, while inserting different heteroatoms entirely rendered the compound only weakly active. The introduction of a bulky group (cyclohexyl, phenyl, or benzyl) led to loss of activity against EV71. The 4-chlorophenyl moiety in 14a was replaced with bioisosteric groups such as oxadiazole (28a-d) or tetrazole (32a,b), dramatically improving anti-EV71 activity and selectivity indices. Compounds 14a, 24b, 28b, 28d, and 32a exhibited a strong activity against lethal EV71, and no apparent cellular toxicity was observed. Three of the more potent imidazolidinone compounds, 14a, 28b, and 32b, were subjected to a large group of picornaviruses to determine their spectrum of antiviral activity.

Depth dose characteristics of proton beams within therapeutic energy range using the particle therapy simulation framework (PTSim) Monte Carlo technique.

BACKGROUND: The stopping power and range tables published by the National Institute of Standards and Technology (NIST) were obtained by assuming continuous slowing down approximation (CSDA). This study examined more detail depth dose characteristics of ideal proton beams using the particle therapy simulation framework (PTSim) Monte Carlo technique. METHODS: Simulation for parallel broad field geometry (PBFG) was replaced by the pencil beam geometry (PBG) for improved simulation efficiency. Depth dose distributions (Bragg peak, BP) for beam energies from 69.44 to 230.71 MeV at 5 mm range interval were obtained. This study used seven parameters, Rpeak, R90, R80, R50, full width at half maximum (FWHM), W(80-20), and peak-to-entrance ratio to represent BP characteristics. The resulting energy-range relationships were fitted into third order polynomial formulae. In addition, initial beam energy spreads at 0-1% (1σ) of the mean incident energies at 70, 110, 150, 190, and 230 MeV were added into the simulation to uncover their impact on BP shapes. RESULTS: The study results reveal deeper penetration, broader FWHM and decreased peak-to-entrance dose ratio at increasing beam energy. Study results for beams with initial energy spreads show that R 80 can be a good indicator to characterize initial mean energy. They also suggest FWHM is more sensitive than the width of 80-to-20% distal fall-off in finding initial energy spread. CONCLUSION: Detail depth dose characteristics for monoenergetic proton beams and beams with initial energy spreads within therapeutic energy ranges were reported. These data can serve as a good reference for a clinical practitioner in their daily practice.

MCNPX simulation of proton dose distributions in a water phantom.

BACKGROUND: This study presents the Monte Carlo N-Particles Transport Code, Extension (MCNPX) simulation of proton dose distributions in a water phantom. METHODS: In this study, fluence and dose distributions from an incident proton pencil beam were calculated as a function of depth in a water phantom. Moreover, lateral dose distributions were also studied to understand the deviation among different MC simulations and the pencil beam algorithm. MCNPX codes were used to model the transport and interactions of particles in the water phantom using its built-in "repeated structures" feature. Mesh Tally was used in which the track lengths were distributed in a defined cell and then converted into doses and fluences. Two different scenarios were studied including a proton equilibrium case and a proton disequilibrium case. RESULTS: For the proton equilibrium case, proton fluence and dose in depths beyond the Bragg peak were slightly perturbed by the choice of the simulated particle types. The dose from secondary particles was about three orders smaller, but its simulation consumed significant computing time. This suggests that the simulation of secondary particles may only be necessary for radiation safety issues for proton therapy. For the proton disequilibrium case, the impacts of different multiple Coulomb scattering (MCS) models were studied. Depth dose distributions of a 70 MeV proton pencil beam in a water phantom obtained from MCNPX, Geometry and Track, version 4, and the pencil beam algorithm showed significant deviations between each other, because of different MCS models used. CONCLUSIONS: Careful modelling of MCS is necessary when proton disequilibrium exists.

Design, synthesis, and structure-activity relationship of pyridyl imidazolidinones: a novel class of potent and selective human enterovirus 71 inhibitors.

When skeletons of Win compounds were used as templates, computer-assisted drug design led to the identification of a novel series of imidazolidinone derivatives with significant antiviral activity against enterovirus 71 (EV 71), the infection of which had resulted in about 80 fatalities during the 1998 epidemic outbreak in Taiwan. In addition to inhibiting all the genotypes (A, B, and C) of EV 71 in the submicromolar to low micromolar range, compounds 1 and 8 were extensively evaluated against a variety of viruses, showing potent activity against coxsackievirus A9 (IC(50) = 0.47-0.55 microM) and coxsackievirus A24 (IC(50) = 0.47-0.55 microM) as well as moderate activity against enterovirus 68 (IC(50) = 2.13 microM) and echovirus 9 (IC(50) = 2.6 microM). Our SAR studies revealed that imidazolidinone analogues with an aryl substituent at the para position of the phenoxyl ring, such as compounds 20, 21, 27, 57, 58, and 61, in general exhibited the highest activity against EV 71. Among them, compound 20 and its corresponding hydrochloride salt 57, in terms of potency and selectivity index, appear to be the most promising candidates in this series for further development of anti-EV-71 agents. Preliminary results of the study on the mode of action by a time-course experiment suggest that test compounds 1 and 8 can effectively inhibit the virus replication at the early stages, referring to virus attachment or uncoating. This indicates that the surface protein may be the target for this type of compounds.