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Purpose: TOPAS (TOol for PArticle Simulation) is a particle simulation code recently developed with the specific aim of making Monte Carlo simulations user-friendly for research and clinical physicists in the particle therapy community. The authors present a thorough and extensive experimental validation of Monte Carlo simulations performed with TOPAS in a variety of setups relevant for proton therapy applications. The set of validation measurements performed in this work represents an overall end-to-end testing strategy recommended for all clinical centers planning to rely on TOPAS for quality assurance or patient dose calculation and, more generally, for all the institutions using passive-scattering proton therapy systems., Methods: The authors systematically compared TOPAS simulations with measurements that are performed routinely within the quality assurance (QA) program in our institution as well as experiments specifically designed for this validation study. First, the authors compared TOPAS simulations with measurements of depth-dose curves for spread-out Bragg peak (SOBP) fields. Second, absolute dosimetry simulations were benchmarked against measured machine output factors (OFs). Third, the authors simulated and measured 2D dose profiles and analyzed the differences in terms of field flatness and symmetry and usable field size. Fourth, the authors designed a simple experiment using a half-beam shifter to assess the effects of multiple Coulomb scattering, beam divergence, and inverse square attenuation on lateral and longitudinal dose profiles measured and simulated in a water phantom. Fifth, TOPAS' capabilities to simulate time dependent beam delivery was benchmarked against dose rate functions (i.e., dose per unit time vs time) measured at different depths inside an SOBP field. Sixth, simulations of the charge deposited by protons fully stopping in two different types of multilayer Faraday cups (MLFCs) were compared with measurements to benchmark the nuclear interaction models used in the simulations., Results: SOBPs' range and modulation width were reproduced, on average, with an accuracy of +1, -2 and ±3 mm, respectively. OF simulations reproduced measured data within ±3%. Simulated 2D dose-profiles show field flatness and average field radius within ±3% of measured profiles. The field symmetry resulted, on average in ±3% agreement with commissioned profiles. TOPAS accuracy in reproducing measured dose profiles downstream the half beam shifter is better than 2%. Dose rate function simulation reproduced the measurements within ∼2% showing that the four-dimensional modeling of the passively modulation system was implement correctly and millimeter accuracy can be achieved in reproducing measured data. For MLFCs simulations, 2% agreement was found between TOPAS and both sets of experimental measurements. The overall results show that TOPAS simulations are within the clinical accepted tolerances for all QA measurements performed at our institution., Conclusions: Our Monte Carlo simulations reproduced accurately the experimental data acquired through all the measurements performed in this study. Thus, TOPAS can reliably be applied to quality assurance for proton therapy and also as an input for commissioning of commercial treatment planning systems. This work also provides the basis for routine clinical dose calculations in patients for all passive scattering proton therapy centers using TOPAS.

We present a proof of principle study of proton radiography and proton computed tomography (pCT) based on time-resolved dose measurements. We used a prototype, two-dimensional, diode-array detector capable of fast dose rate measurements, to acquire proton radiographic images expressed directly in water equivalent path length (WEPL). The technique is based on the time dependence of the dose distribution delivered by a proton beam traversing a range modulator wheel in passive scattering proton therapy systems. The dose rate produced in the medium by such a system is periodic and has a unique pattern in time at each point along the beam path and thus encodes the WEPL. By measuring the time dose pattern at the point of interest, the WEPL to this point can be decoded. If one measures the time–dose patterns at points on a plane behind the patient for a beam with sufficient energy to penetrate the patient, the obtained 2D distribution of the WEPL forms an image. The technique requires only a 2D dosimeter array and it uses only the clinical beam for a fraction of second with negligible dose to patient. We first evaluated the accuracy of the technique in determining the WEPL for static phantoms aiming at beam range verification of the brain fields of medulloblastoma patients. Accurate beam ranges for these fields can significantly reduce the dose to the cranial skin of the patient and thus the risk of permanent alopecia. Second, we investigated the potential features of the technique for real-time imaging of a moving phantom. Real-time tumor tracking by proton radiography could provide more accurate validations of tumor motion models due to the more sensitive dependence of proton beam on tissue density compared to x-rays. Our radiographic technique is rapid (~100 ms) and simultaneous over the whole field, it can image mobile tumors without the problem of interplay effect inherently challenging for methods based on pencil beams. Third, we present the reconstructed pCT images of a cylindrical phantom containing inserts of different materials. As for all conventional pCT systems, the method illustrated in this work produces tomographic images that are potentially more accurate than x-ray CT in providing maps of proton relative stopping power (RSP) in the patient without the need for converting x-ray Hounsfield units to proton RSP. All phantom tests produced reasonable results, given the currently limited spatial and time resolution of the prototype detector. The dose required to produce one radiographic image, with the current settings, is ~0.7 cGy. Finally, we discuss a series of techniques to improve the resolution and accuracy of radiographic and tomographic images for the future development of a full-scale detector.

Coronary heart disease (CHD) is the leading cause of mortality worldwide. The Chinese medicinal formula Guanxin II has been shown to have a favorable effect in the attenuation of angina. The aim of this study was to compare the pharmacokinetics of ferulic acid (FA), which is a vasorelaxant compound present in Guanxin II, in healthy volunteers and patients with angina pectoris following the administration of Guanxin II. Ex vivo experiments were performed in order to investigate the vasorelaxant effect of FA on the human internal mammary artery (IMA) to provide evidence that it is a bioactive component of Guanxin II. Following the oral administration of Guanxin II, the FA levels in the serum were quantified by a simple and rapid high-performance liquid chromatography (HPLC) method. Treatment with FA (10 -8 -10 -3 M) caused a concentration-dependent relaxation of endothelial IMA rings following precontraction with KCl. Statistically significant differences were identified between the pharmaco-kinetic parameters C max , t 1/2 α, t 1/2 β and t 1/2 Ka of the healthy volunteers and the patients with angina pectoris following the oral administration of Guanxin II. FA is a bioactive compound absorbed from Guanxin II that attenuates angina pectoris, a condition that may modify the pharmacokinetics of FA. Not only do the pharmacokinetic parameters direct the clinical use of Guanxin II, but they may also be useful for exploring the pathology of angina pectoris.

High-quality crystals are key to obtaining accurate three-dimensional structures of proteins using X-ray diffraction techniques. However, obtaining such protein crystals is often a challenge. Several containerless crystallization techniques have been reported to have the ability to improve crystal quality, but it is unknown which is the most favourable way to grow high-quality protein crystals. In this paper, a quality comparison of protein crystals which were grown under three containerless conditions provided by diamagnetic levitation, silicone oil and agarose gel was conducted. A control experiment on a vessel wall was also simultaneously carried out. Seven different proteins were crystallized under the four conditions, and the crystal quality was assessed in terms of the resolution limit, the mosaicity and the Rmerge. It was found that the crystals grown under the three containerless conditions demonstrated better morphology than those of the control. X-ray diffraction data indicated that the quality of the crystals grown under the three containerless conditions was better than that of the control. Of the three containerless crystallization techniques, the diamagnetic levitation technique exhibited the best performance in enhancing crystal quality. This paper is to our knowledge the first report of improvement of crystal quality using a diamagnetic levitation technique. Crystals obtained from agarose gel demonstrated the second best improvement in crystal quality. The study indicated that the diamagnetic levitation technique is indeed a favourable method for growing high-quality protein crystals, and its utilization is thus potentially useful in practical efforts to obtain well diffracting protein crystals.

Studies suggest that anterior beams with in vivo range verification would improve rectal dosimetry in proton therapy for prostate cancer. We investigated whether prostate-rectum spacers would enhance or diminish the benefits of anterior proton beams in these treatments. Twenty milliliters of hydrogel was injected between the prostate and rectum of a cadaver using a transperineal approach. Computed tomography (CT) and magnetic resonance (MR) images were used to generate 7 uniform scanning (US) and 7 single-field uniform dose pencil-beam scanning (PBS) plans with different beam arrangements. Pearson correlations were calculated between rectal, bladder, and femoral head dosimetric outcomes and beam arrangement anterior scores, which characterize the degree to which dose is delivered anteriorly. The overall quality of each plan was compared using a virtual dose-escalation study. For US plans, rectal mean dose was inversely correlated with anterior score, but for PBS plans there was no association between rectal mean dose and anterior score. For both US and PBS plans, full bladder and empty bladder mean doses were correlated with anterior scores. For both US and PBS plans, femoral head mean doses were inversely correlated with anterior score. For US plans and a full bladder, 4 beam arrangements that included an anterior beam tied for the highest maximum prescription dose (MPD). For US plans and an empty bladder, the arrangement with 1 anterior and 2 anterior oblique beams achieved the highest MPD in the virtual dose-escalation study. The dose-escalation study did not differentiate beam arrangements for PBS. All arrangements in the dose-escalation study were limited by bladder constraints except for the arrangement with 2 posterior oblique beams. The benefits of anterior proton beams in the setting of prostate-rectum spacers appear to be proton modality dependent and may not extend to PBS., (Copyright © 2013 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

We used whole exome sequence analysis to investigate a possible genetic etiology for a patient with the phenotype of intrauterine growth restriction, microcephaly, developmental delay, failure to thrive, congenital bilateral hip dysplasia, cerebral and cerebellar atrophy, hydrocephalus, and congenital diaphragmatic hernia (CDH). Whole exome sequencing identified a novel de novo c.2722G > T (p.E908X) mutation in the Myosin Heavy Chain 10 gene (MYH10) which encodes for non-muscle heavy chain II B (NMHC IIB). Mutations in MYH10 have not been previously described in association with human disease. The E908X mutation is located in the coiled-coil region of the protein and is expected to delete the tail domain and disrupt filament assembly. Nonmuscle myosin IIs (NM IIs) are a group of ubiquitously expressed proteins, and NM II B is specifically enriched in neuronal tissue and is thought to be important in neuronal migration. It is also expressed in cardiac myocytes along with NM IIC. Homozygous NMHC II B-/B- mouse knockouts die by embryonic day (E)14.5 with severe cardiac defects (membranous ventricular septal defect and cardiac outflow tract abnormalities) and neurodevelopmental disorders (progressive hydrocephalus and neuronal migrational abnormalities). A heterozygous MYH10 loss of function mutation produces a severe neurologic phenotype and CDH but no apparent cardiac phenotype and suggests that MYH10 may represent a novel gene for brain malformations and/or CDH.

Background: Uremic pruritus is a common and intractable symptom in patients on chronic hemodialysis, but factors associated with the severity of pruritus remain unclear. This study aimed to explore the associations of metabolic factors and dialysis adequacy with the aggravation of pruritus., Methods: We conducted a 5-year prospective cohort study on patients with maintenance hemodialysis. A visual analogue scale (VAS) was used to assess the intensity of pruritus. Patient demographic and clinical characteristics, laboratory parameters, dialysis adequacy (assessed by Kt/V), and pruritus intensity were recorded at baseline and follow-up. Change score analysis of the difference score of VAS between baseline and follow-up was performed using multiple linear regression models. The optimal threshold of Kt/V, which is associated with the aggravation of uremic pruritus, was determined by generalized additive models and receiver operating characteristic analysis., Results: A total of 111 patients completed the study. Linear regression analysis showed that lower Kt/V and use of low-flux dialyzer were significantly associated with the aggravation of pruritus after adjusting for the baseline pruritus intensity and a variety of confounding factors. The optimal threshold value of Kt/V for pruritus was 1.5 suggested by both generalized additive models and receiver operating characteristic analysis., Conclusions: Hemodialysis with the target of Kt/V ≥1.5 and use of high-flux dialyzer may reduce the intensity of pruritus in patients on chronic hemodialysis. Further clinical trials are required to determine the optimal dialysis dose and regimen for uremic pruritus.

Introduction: This study is aimed at determining the incidence, survival rate, life expectancy, quality-adjusted life expectancy (QALE) and prognostic factors in patients with cancer in different organ systems undergoing prolonged mechanical ventilation (PMV)., Methods: We used data from the National Health Insurance Research Database of Taiwan from 1998 to 2007 and linked it with the National Mortality Registry to ascertain mortality. Subjects who received PMV, defined as having undergone mechanical ventilation continuously for longer than 21 days, were enrolled. The incidence of cancer patients requiring PMV was calculated, with the exception of patients with multiple cancers. The life expectancies and QALE of patients with different types of cancer were estimated. Quality-of-life data were taken from a sample of 142 patients who received PMV. A multivariable proportional hazards model was constructed to assess the effect of different prognostic factors, including age, gender, type of cancer, metastasis, comorbidities and hospital levels., Results: Among 9,011 cancer patients receiving mechanical ventilation for more than 7 days, 5,138 undergoing PMV had a median survival of 1.37 months (interquartile range [IQR], 0.50 to 4.57) and a 1-yr survival rate of 14.3% (95% confidence interval [CI], 13.3% to 15.3%). The incidence of PMV was 10.4 per 100 ICU admissions. Head and neck cancer patients seemed to survive the longest. The overall life expectancy was 1.21 years, with estimated QALE ranging from 0.17 to 0.37 quality-adjusted life years for patients with poor and partial cognition, respectively. Cancer of liver (hazard ratio [HR], 1.55; 95% CI, 1.34 to 1.78), lung (HR, 1.45; 95% CI, 1.30 to 1.41) and metastasis (HR, 1.53; 95% CI, 1.42 to 1.65) were found to predict shorter survival independently., Conclusions: Cancer patients requiring PMV had poor long-term outcomes. Palliative care should be considered early in these patients, especially when metastasis has occurred.

Purpose: The α-to-β (α/β) ratio for prostate tumor is likely lower than that for the surrounding normal organs, such as rectum and bladder (≈ 3 Gy). As a result, hypofractionation is expected to improve the therapeutic ratio in prostate radiation therapy. However, with the use of fewer, larger fractions, the accuracy of treatment dose delivery becomes more influenced by the physical uncertainties resulting from motion and radiobiological uncertainties in the α/β ratio of the prostate tumor. The purpose of this study is to evaluate the impact of interfractional motion on treatment dose delivery within the likely range of the tumor α/β ratio., Methods: Serial CT images acquired at simulation and daily treatment for three prostate patients were studied retrospectively. A conventional 3D-conformal proton plan was created for each patient, delivering 25 fractions of 2 Gy to ITV1 (internal target volume, expanded from the prostate and clinically involved seminal vesicles) followed by 14 fractions to ITV2 (expanded from the prostate). The plans were renormalized for a series of hypofractionated protocols of between five and 28 fractions. The fractional doses were computed on daily CT and were mapped onto simulation CT using deformable registration. In each course, the doses from the fractions with the lowest D97% of the ITV2 were summed to approximate the lower limit (worst case) of target coverage. The uncertainty in dose and coverage was estimated as the deviation of the worst case from the nominal plan., Results: For treatments in 28 to five fractions, the uncertainty arising from interfractional motion ranged from ≈ 1% to 4% for V100% and ≈ 2% to 6% for D100% of the ITV2. The uncertainties in V95% and D95% were both minimal (<1%) for all protocols. For tumors with a low α/β of 1.0 Gy, the treatment in five fractions could deliver an additional 21.0 and 17.4 GyEQD2 to 95% and 100% of the ITV2, respectively, compared to that in 28 fractions. This advantage disappeared for tumors with α/β > 2.5 Gy, assuming the worst case for interfractional motion., Conclusions: In hypofractionated proton therapy for prostate cancer, the dosimetric uncertainties due to interfractional motion were minimal for the ITV2 coverage at 95% isodose level and the dose received by 95% of the ITV2. Although hypofractionation could yield an increase in equivalent dose to the target for tumors with low α/β, the gain was cancelled out by the uncertainty due to interfractional motion for tumors with α/β > 2.5 Gy.

Purpose: Dosimetric planning studies have described potential benefits for the use of proton radiation therapy (RT) for locally advanced breast cancer. We report acute toxicities and feasibility of proton delivery for 12 women treated with postmastectomy proton radiation with or without reconstruction., Methods and Materials: Twelve patients were enrolled in an institutional review board-approved prospective clinical trial. The patients were assessed for skin toxicity, fatigue, and radiation pneumonitis during treatment and at 4 and 8 weeks after the completion of therapy. All patients consented to have photographs taken for documentation of skin toxicity., Results: Eleven of 12 patients had left-sided breast cancer. One patient was treated for right-sided breast cancer with bilateral implants. Five women had permanent implants at the time of RT, and 7 did not have immediate reconstruction. All patients completed proton RT to a dose of 50.4 Gy (relative biological effectiveness [RBE]) to the chest wall and 45 to 50.4 Gy (RBE) to the regional lymphatics. No photon or electron component was used. The maximum skin toxicity during radiation was grade 2, according to the Common Terminology Criteria for Adverse Events (CTCAE). The maximum CTCAE fatigue was grade 3. There have been no cases of RT pneumonitis to date., Conclusions: Proton RT for postmastectomy RT is feasible and well tolerated. This treatment may be warranted for selected patients with unfavorable cardiac anatomy, immediate reconstruction, or both that otherwise limits optimal RT delivery using standard methods., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The pH of a solution is an important parameter in crystallization that needs to be controlled in order to ensure success. The actual pH of the crystallization droplet is determined by the combined contribution of the buffers in the screening and protein solutions, although the contribution of the latter to the pH is often ignored. In this study, the effects of the buffer and protein solution pH values on the results of screening are systematically investigated. It was found that these parameters significantly affected the results and thus the following strategy for the selection of appropriate pH values is proposed: (i) when screening with only one protein solution, the pH should be as low, as high or as divergent from the pI as possible for a basic, acidic or neutral protein, respectively, within its stable pH range; (ii) when screening with two protein solutions, the pH values should be well separated from one another; and (iii) when multiple pH values are utilized, an even distribution of pH values is the best approach to increase the success rate of crystallization.

A comprehensive investigation was performed to understand the influence of sequence scrambling in peptide ions on peptide identification results. To achieve this, four tandem mass spectrometry datasets with scrambled ions included and with them excluded were analyzed by Crux, X!Tandem, SpectraST, Lutefisk, and PepNovo. While the different algorithms differed in their performance, an increase in the number of correctly identified peptides was generally observed when removing scrambled ions, with the exception of the SpectraST algorithm. However, the variation of the match scores upon removal was unpredictable. Following these investigations, an interpretation was given on how the scrambled ions affect peptide identification. Lastly, a simulated theoretical mass spectral library derived from the NIST peptide Libraries was constructed and searched by SpectraST to study whether scrambled ions in predicted mass spectra could affect peptide identification. Consistent with the peptide library search results, no significant variations for dot product scores as well as peptide identification results were observed when these ions were included in the theoretical MS/MS spectra. From the five adopted algorithms, the SpectraST and Crux provided the most robust results, whereas X!Tandem, PepNovo, and Lutefisk were sensitive to the existence of the scrambled ions, especially the latter two de novo sequencing algorithms.

Background and Purpose: Delivery of post-mastectomy radiation (PMRT) in women with bilateral implants represents a technical challenge, particularly when attempting to cover regional lymph nodes. Intensity modulated proton therapy (IMPT) holds the potential to improve dose delivery and spare non-target tissues. The purpose of this study was to compare IMPT to three-dimensional (3D) conformal radiation following bilateral mastectomy and reconstruction., Materials and Methods: Ten IMPT, 3D conformal photon/electron (P/E), and 3D photon (wide tangent) plans were created for 5 patients with breast cancer, all of whom had bilateral breast implants. Using RTOG guidelines, a physician delineated contours for both target volumes and organs-at-risk. Plans were designed to achieve 95% coverage of all targets (chest wall, IMN, SCV, axilla) to a dose of 50.4 Gy or Gy (RBE) while maximally sparing organs-at-risk., Results: IMPT plans conferred similar target volume coverage with enhanced homogeneity. Both mean heart and lung doses using IMPT were significantly decreased compared to both P/E and wide tangent planning., Conclusions: IMPT provides improved homogeneity to the chest wall and regional lymphatics in the post-mastectomy setting with improved sparing of surrounding normal structures for woman with reconstructed breasts. IMPT may enable women with mastectomy to undergo radiation therapy without the need for delay in breast reconstruction., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The preprocessing of chromatograms is essential to modern chromatography for further qualitative and quantitative analysis, especially when chromatographic instruments are used for herb products analysis involving large number of samples. To accurately compare and analyze the obtained chromatograms, it is necessary to preprocess, especially align retention time shifts. Here moving window fast Fourier transform (FFT) cross-correlation is introduced to perform nonlinear alignment of high-throughput chromatograms. Since elution characteristics of chromatograms will produce local similarity in retention time shifts, moving window procedure seems to be a better substitute of segmentation steps. The retention time shifts can be calculated and accelerated by FFT cross-correlation. The artifacts can be detected and eliminated from the retention time shifts profile since the continuity of moving window procedure. The proposed method is demonstrated in comparison with recursive alignment by FFT on chromatographic datasets from herb products analysis. It is shown that the proposed method can address nonlinear retention time shift problem in chromatograms with the simple moving window procedure, which will not introduce segments size optimization problem. In additional, the parameters are intuitive and easy to adjust, which makes it off-the-shelf toolbox for alignment of chromatograms., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: The delivery of post-mastectomy radiation therapy (PMRT) can be challenging for patients with left sided breast cancer that have undergone mastectomy. This study investigates the use of protons for PMRT in selected patients with unfavorable cardiac anatomy. We also report the first clinical application of protons for these patients., Methods and Materials: Eleven patients were planned with protons, partially wide tangent photon fields (PWTF), and photon/electron (P/E) fields. Plans were generated with the goal of achieving 95% coverage of target volumes while maximally sparing cardiac and pulmonary structures. In addition, we report on two patients with unfavorable cardiac anatomy and IMN involvement that were treated with a mix of proton and standard radiation., Results: PWTF, P/E, and proton plans were generated and compared. Reasonable target volume coverage was achieved with PWTF and P/E fields, but proton therapy achieved superior coverage with a more homogeneous plan. Substantial cardiac and pulmonary sparing was achieved with proton therapy as compared to PWTF and P/E. In the two clinical cases, the delivery of proton radiation with a 7.2 to 9 Gy photon and electron component was feasible and well tolerated. Akimbo positioning was necessary for gantry clearance for one patient; the other was treated on a breast board with standard positioning (arms above her head). LAO field arrangement was used for both patients. Erythema and fatigue were the only noted side effects., Conclusions: Proton RT enables delivery of radiation to the chest wall and regional lymphatics, including the IMN, without compromise of coverage and with improved sparing of surrounding normal structures. This treatment is feasible, however, optimal patient set up may vary and field size is limited without multiple fields/matching.

Background: The introduction of reduced respiratory care may lead to worse long-term outcomes for patients undergoing prolonged mechanical ventilation (PMV) for more than 21 days. The objective of this study was to determine the survival for an integrated system of reduced intensive respiratory care (ISRIRC) by the Taiwan Bureau of National Health Insurance, in patients requiring PMV., Methods: A 10-year retrospective study was performed in a 1,000-bed teaching hospital in Taiwan. A total of 633 consecutive PMV patients transferred from the hospital between 1998 and 2007 were enrolled. Medical records were reviewed to collect the clinical data, which were linked to the National Death Certification Database to ascertain subject survival. Kaplan-Meier estimates were performed, and a Cox proportional hazards model was constructed. We further conducted a corroboration study and retrieved a systematically randomized nationwide sample of PMV subjects with combined septicemia and shock, and compared the survival functions of those who were treated before and after the integrated system, including 228 and 2,677 subjects, respectively., Results: The survival rates at 3 months, 6 months, and 1 year were 60.0%, 44.0%, and 30.0%, respectively. The 1-year survival rates of the subjects before and after ISRIRC were 21.0% and 37.2%, respectively (P = .04). The factors associated with better survival were younger age, absence of cirrhosis, and establishment of the ISRIRC. A comparison of the 4-year survival in the larger random sample of PMV subjects with combined septicemia and shock before and after ISRIRC also showed a significant improvement., Conclusions: With the improvement of PMV technology in the early 2000s, the establishment of ISRIRC seems to be associated with an improved survival rate for subjects under PMV.

The purpose of this study is to investigate whether quality assurance (QA) for cone-beam computed tomography (CBCT) image rotation is necessary in order to ensure the accuracy of CBCT based image-guided radiation therapy (IGRT) and adaptive radiotherapy (ART). Misregistration of angular coordinates during CBCT acquisition may lead to a rotated reconstructed image. If target localization is performed based on this image, an under- or over-dosage of the target volume (TV) and organs at risk (OARs) may occur. Therefore, patient CT image sets were rotated by 1° up to 3° and the treatment plans were recalculated to quantify changes in dose-volume histograms. A computer code in C++ was written to model the TV displacement and overlap area of an ellipse shape at the target and dose prescription levels corresponding to the image rotation. We investigated clinical scenarios in IGRT and ART in order to study the implications of image rotation on dose distributions for: (1) lateral TV and isocenter (SBRT), (2) central TV and isocenter (IMRT), (3) lateral TV and isocenter (IMRT). Mathematical analysis showed the dose coverage of TV depends on its shape, size, location, and orientation relative to the isocenter. Evaluation of three first scenario for θ = 1° showed variations in TV D95 in the context of IGRT and ART when compared to the original plan were within 2.7 ± 2.6% and 7.7 ± 6.9% respectively while variations in the second and third scenarios were less significant (<0.5%) for the angular range evaluated. However a larger degree of variation was found in terms of minimum and maximum doses for target and OARs. The rotation of CBCT image data sets may have significant dosimetric consequences in IGRT and ART. The TV's location relative to isocenter and shape determine the extent of alterations in dose indicators. Our findings suggest that a CBCT QA criterion of 1° would be a reasonable action level to ensure accurate dose delivery.

A simple LC-MS/MS method was developed for determination and pharmacokinetic study of Epothilone B in rat plasma.Plasma sample pretreatment involved a one-step liquid-liquid extraction of 100 µL plasma. The chromatographic separation was carried out on a Agilent Zobax SB C18 column with a mobile phase consisting of 10 mmol/L ammonium acetate-acetonitrile (35:65, v/v) at a flow rate of 0.2 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by SRM via electro spray ionization source with positive mode.The standard curve for Epothilone B was linear over the concentration range of 1-100 ng/mL with a lower limit of quantification of 0.5 ng/mL. The intra- and inter-day precision (relative standard deviation) values were not higher than 15% and the accuracy (relative error) was < 10% at 3 quality control levels. Pharmacokinetic parameters were as follows: t1/2, 3.56 (1.12) h; AUC0-24 h, 295.7 (65.3) ng · h/mL and AUC0-∞, 339.2 (87.4) ng · h/mL, CL, 5.77 (0.67) mL/h; MRT, 7.55 (2.41) h, respectively.This simple, fast and highly sensitive method was fully validated and successfully applied to a preclinical pharmacokinetic study of Epothilone B in rats after i. v. administration., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To explore the role of microRNA-92a (miR-92a) in evaluating endothelium damage induced by percutaneous coronary intervention (PCI)., Methods: A case control study was prospectively conducted. Fifty-eight patients with ST-segment elevation acute myocardial infarction (STEAMI) received PCI were enrolled. MiR-92a expression in circulation was determined on the next day after PCI (reverse transcription-polymerase chain reaction). The correlation between miR-92a expression in circulation and PCI influence factors, such as inflation pressure, duration of balloon inflation and length of culprit atheromatous plaque were explored., Results: MiR-92a was lower in inflation pressure 11-19 atm (1 atm=101.325 kPa) group [n=43, mean -0.36, 95% confidence interval (95%CI) -0.60 to -0.12] than inflation pressure ≤10 atm group (n=11, mean 1.16, 95%CI 0.80 to 1.52, P<0.01) and ≥ 20 atm group (n=4, mean 0.26, 95%CI 0.26 to 0.26, P=0.1); and also lower in duration of balloon inflation 6-7 seconds group (n=24, mean -0.42, 95%CI -0.83 to -0.01) than in duration of balloon inflation ≤ 5 seconds group (n=9, mean 0.63, 95%CI 0.49 to 0.78, P=0.03) and ≥ 8 seconds group (n=25, mean 0.45, 95%CI 0.10 to 0.80, P<0.001); lower in implanted stent length ≤30 mm (n=31, mean -0.48, 95%CI -0.80 to -0.16) than those >30 mm (n=27, mean 0.16, 95%CI 0.01 to 0.32, P<0.01). A significantly negative correlation was found between inflation pressure and duration of balloon inflation. (r=-0.48, P<0.001)., Conclusions: There is a relationship between circulating miR-92a, inflation pressure and duration of balloon inflation. Circulating miR-92a could be used to evaluate the endothelium injury induced by PCI, and be used as a new target of prevention and treatment of endothelial dysfunction following revascularization.

The identification of interactions between drugs and target proteins plays a key role in the process of genomic drug discovery. It is both consuming and costly to determine drug-target interactions by experiments alone. Therefore, there is an urgent need to develop new in silico prediction approaches capable of identifying these potential drug-target interactions in a timely manner. In this article, we aim at extending current structure-activity relationship (SAR) methodology to fulfill such requirements. In some sense, a drug-target interaction can be regarded as an event or property triggered by many influence factors from drugs and target proteins. Thus, each interaction pair can be represented theoretically by using these factors which are based on the structural and physicochemical properties simultaneously from drugs and proteins. To realize this, drug molecules are encoded with MACCS substructure fingerings representing existence of certain functional groups or fragments; and proteins are encoded with some biochemical and physicochemical properties. Four classes of drug-target interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models with support vector machines (SVMs). The SVM models gave prediction accuracy of 90.31%, 88.91%, 84.68% and 83.74% for four datasets, respectively. In conclusion, the results demonstrate the ability of our proposed method to predict the drug-target interactions, and show a general compatibility between the new scheme and current SAR methodology. They open the way to a host of new investigations on the diversity analysis and prediction of drug-target interactions., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: This study took advantage of a large population-based database of the Taiwan National Health Insurance (NHI) to investigate the epidemiology of idiopathic pulmonary fibrosis (IPF) in Taiwan., Methods: This is a retrospective cohort study based on secondary analysis of prospectively collected data in the NHI system and governmental data on death registry in Taiwan during 1997-2007. By using the broad and narrow definitions for IPF, we estimated incidence and prevalence rates of IPF, and its associated clinical outcomes., Results: The estimates of annual IPF incidence rates became more stable after 2000, ranging between 0.9 and 1.6 cases per 100,000 persons. The prevalence rates became more than twofold from 2000 to 2007 (from 2.8 to 6.4 cases per 100,000 persons for the broad definition, and from 2.0 to 4.9 cases per 100,000 persons for the narrow definition). Men of age older than 75 years had markedly higher incidence and prevalence rates than other groups. Around 40% of all incidences and about 30% of prevalent cases occurred in this population group. The median survival time after IPF diagnosis was 0.9 year (interquartile range (IQR), 0.2-2.5 years) and 0.7 year (IQR, 0.1-2.3 years) for the broad and narrow definitions, respectively. Progression of IPF was the leading cause of death, followed by cancer., Conclusions: In Taiwan, elderly men were the major group suffering from IPF. Survival time was short after IPF diagnosis, and the poor survival was largely attributable to quick IPF progression after diagnosis., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in- and out-of-field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields.

Background/aims: The timing for the management of gallstones pancreatitis remains a contentious issue. Various scholars have their own achievement in in regards to this issue., Methodology: We reviewed our hospital charts from Jan 2007 to December 2010 and made a comparative study about early and delayed LC for mild to moderate gallstone pancreatitis in 80 patients., Results: Successful management was obtained in all patients. Out of 80 patients, 54 had underwent for early LC within 48 hours and 26 delayed LC (6-8 weeks)., Conclusions: Our study reveals that early cholecystectomy has nice outcomes in terms of shorter hospital stay and expenses. Proper consultation should be taken from radiological colleague if CBD dilations are >6 mm and contraction of gallbladder appears on imaging modalities. Comorbid conditions, past history of cholecystitis cannot be avoided for proper surgical outcomes. Postoperative complications can be deterred by early LC for mild gallstone pancreatitis. However, large volume studies are essential from different places to answer the debated topic of which management protocol is justifiable for the management of mild to moderate gall stone pancreatitis.

It was proposed recently that time-resolved dose measurements during proton therapy treatment by passively scattered beams may be used for in vivo range verification. The method was shown to work accurately in a water tank. In this paper, we further evaluated the potential of the method for more clinically relevant situations where proton beams must pass through regions with significant tissue heterogeneities. Specifically, we considered prostate treatment where the use of anterior or anterior- oblique fields was recently proposed in order to reduce rectal dose by taking advantage of the sharp distal fall-off of the Bragg peak. These beam portals pass through various parts of pubic bone and potential air cavities in the bladder and bowels. Using blocks of materials with densities equivalent to bone, air, etc, arranged in the water tank in relevant configurations, we tested the robustness of the method against range shifting and range mixing. In the former, the beam range is changed uniformly by changes in tissue density in the beam path, while in the latter, variations in tissue heterogeneities across the beam cross section causes the mixing of beam energies downstream, as often occurs when the beam travels along the interface of materials with significantly different densities. We demonstrated that in the region of interest, the method can measure water-equivalent path length with accuracy better than ±0.5 mm for pure range shifting and still reasonable accuracy for range mixing between close beam energies. In situations with range mixing between significantly different beam energies, the dose rate profiles may be simulated for verifying the beam range. We also found that the above performances can be obtained with very small amount of dose (<0.5 cGy), if silicon diodes are used as detectors. This makes the method suitable for in vivo range verification prior to each treatment delivery.

Purpose: To report the early outcomes for children with high-risk neuroblastoma treated with proton radiotherapy (RT) and to compare the dose distributions for intensity-modulated photon RT (IMRT), three-dimensional conformal proton RT (3D-CPT), and intensity-modulated proton RT to the postoperative tumor bed., Methods and Materials: All patients with high-risk (International Neuroblastoma Staging System Stage III or IV) neuroblastoma treated between 2005 and 2010 at our institution were included. All patients received induction chemotherapy, surgical resection of residual disease, high-dose chemotherapy with stem cell rescue, and adjuvant 3D-CPT to the primary tumor sites. The patients were followed with clinical examinations, imaging, and laboratory testing every 6 months to monitor disease control and side effects. IMRT, 3D-CPT, and intensity-modulated proton RT plans were generated and compared for a representative case of adjuvant RT to the primary tumor bed followed by a boost., Results: Nine patients were treated with 3D-CPT. The median age at diagnosis was 2 years (range 10 months to 4 years), and all patients had Stage IV disease. All patients had unfavorable histologic characteristics (poorly differentiated histologic features in 8, N-Myc amplification in 6, and 1p/11q chromosomal abnormalities in 4). The median tumor size at diagnosis was 11.4 cm (range 7-16) in maximal dimension. At a median follow-up of 38 months (range 11-70), there were no local failures. Four patients developed distant failure, and, of these, two died of disease. Acute side effects included Grade 1 skin erythema in 5 patients and Grade 2 anorexia in 2 patients. Although comparable target coverage was achieved with all three modalities, proton therapy achieved substantial normal tissue sparing compared with IMRT. Intensity-modulated proton RT allowed additional sparing of the kidneys, lungs, and heart., Conclusions: Preliminary outcomes reveal excellent local control with proton therapy for high-risk neuroblastoma, although distant failures continu to occur. Dosimetric comparisons demonstrate the advantage of proton RT compared with IMRT in this setting, allowing more conformal treatment and better normal tissue sparing., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To investigate the failure of internal fixation on displaced femoral neck fractures in adults under fifty-five years old retrospectively inorder to pay more attention to the treatment of these fractures., Methods: From Junary 2007 to June 2010,18 failed cases of internal fixation on displaced femoral neck fractures in adults under fifty-five years old were treated,there were 13 males and 5 females with an average age of (48.0 +/- 6.0) years old ranging from 27 to 55. Among them, 17 patients were treated with cannulated screws and 1 patient was treated with intramedullary nail; 16 patients were diagnosed as osteonecrosis and 2 patients as osteonecrosis associated with nonunion., Results: The average time from internal fixation to failure was 23 months (ranged, 8 to 32 months). The quality of fracture reduction in Garden index was poor. The Harris Hip Score was (56.0 +/- 12.5) (ranged,33 to 80). Eight cases of osteonecrosis and 2 cases of nonunion combinated osteonecrosis were received total hip arthroplasty. Hip resurfacing arthroplasty were performed for other 5 osteonecrosis. Because of no evident clinical symptoms,the other 3 cases received conservative treatment. The patients with total hip arthroplasty and hip resurfacing arthroplasty were followed-up for 34 months ranging from 12 to 53 months. After operation,the Harris score was (94.0 +/- 3.0) ranged 89 to 96., Conclusion: Osteonecrosis is a common complication after internal fixation on displaced femoral neck fracture in adults under fifty-five years old. More attention should be paid to the treatment of displaced femoral neck fracture in those patients.

Purpose: To characterize and quantify multiorgan respiration-induced motion in the abdomen in liver and pancreatic cancer patients., Methods and Materials: Four-dimensional computed tomography scans were acquired for 18 patients treated for abdominal tumors. Contours of multiple abdominal organs were drawn by the radiation oncologist at one respiratory phase; these contours were propagated to other respiratory phases by deformable registration. Three-dimensional organ models were generated from the resulting contours at each phase. Motions of the bounding box and center of mass were extracted and analyzed for the clinical target volume and organs at risk., Results: On average, the center of mass motion for liver clinical target volumes was 9.7 mm (SD 5 mm) in the superior-inferior direction, with a range of 3 to 18 mm; for pancreatic tumors, the average was 5 mm (SD 1 mm) m with a range of 3 to 7 mm. Abdominal organs move in unison, but with varying amplitudes. Gating near exhale (T40-T60) reduces the range of motion by a factor of ∼10., Conclusion: We have used deformable registration to calculate the trajectories of abdominal organs in four dimensions, based on center of mass and bounding box motion metrics. Our results are compared with previously reported studies. Possible reasons for differences are discussed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: We performed a treatment planning study to demonstrate the potential dosimetric benefits of anterior-oriented fields for prostate irradiation by proton beam. A novel in vivo beam range control method shows millimeter accuracy, suggesting that such fields could be safely used to spare the rectum given the sharp distal penumbra of protons., Methods and Materials: Ten prostate patients treated with water-filled endorectal balloon were selected. Bilateral fields were planned following the conventional treatment protocol. Three anterior-oriented fields (0, +30, -30°) were planned, with the range compensators manually adjusted to improve rectal sparing. Dose distributions to the clinical target volume, rectum, anterior rectal wall (ARW), bladder, bladder wall (BW), and femoral heads were compared for: A) equally weighted bilateral fields, B) a single straight anterior field, and C) two equally weighted anterior-oblique fields., Results: The anterior-oriented fields required much less beam energy, ∼10 cm water equivalent path length less than lateral fields. For ARW, the V(95%) for Plans A, B, and C were 39%, 8%, and 6%, respectively; the corresponding V(80%) were 59%, 27%, and 26%, respectively (p = 0.002 when Plan A was compared with B or C). Plan B irradiated a larger volume of BW than did Plan A by 3% at V(95%), 11% at V(80%), and 16% at V(50%) (p = 0.002), whereas Plan C differs little from Plan A for BW at these dose levels. The femoral heads received ∼40% of the prescription dose in Plan A, but negligible dose in Plans B and C., Conclusions: Compared to lateral fields, anterior-oriented fields can significantly reduce dose to the ARW, particularly at high dose levels. These fields alone, or in combination with lateral fields, allow for the possibility of either reducing treatment toxicity at current prescription doses or further dose escalation in the treatment of prostate cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: This study investigated prognosis among patients under prolonged mechanical ventilation (PMV) through exploring the following issues: (1) post-PMV survival rates, (2) factors associated with survival after PMV, and (3) the number of days alive free of hospital stays requiring mechanical ventilation (MV) care after PMV., Methods: This is a retrospective cohort study based on secondary analysis of prospectively collected data in the national health insurance system and governmental data on death registry in Taiwan. It used data for a nationally representative sample of 25,482 patients becoming under PMV (> = 21 days) during 1998-2003. We calculated survival rates for the 4 years after PMV, and adopted logistic regression to construct prediction models for 3-month, 6-month, 1-year, and 2-year survival, with data of 1998-2002 for model estimation and the 2003 data for examination of model performance. We estimated the number of days alive free of hospital stays requiring MV care in the immediate 4-year period after PMV, and contrasted patients who had low survival probability with all PMV patients., Results: Among these patients, the 3-month survival rate was 51.4%, and the 1-year survival rate was 31.9%. Common health conditions with significant associations with poor survival included neoplasm, acute and unspecific renal failure, chronic renal failure, non-alcoholic liver disease, shock and septicaemia (odd ratio < 0.7, p < 0.05). During a 4-year follow-up period for patients of year 2003, the mean number of days free of hospital stays requiring MV was 66.0 in those with a predicted 6-month survival rate < 10%, and 111.3 in those with a predicted 2-year survival rate < 10%. In contrast, the mean number of days was 256.9 in the whole sample of patients in 2003., Conclusions: Neoplasm, acute and unspecific renal failure, shock, chronic renal failure, septicemia, and non-alcoholic liver disease are significantly associated with lower survival among PMV patients. Patients with anticipated death in a near future tend to spend most of the rest of their life staying in hospital using MV services. This calls for further research into assessing PMV care need among patients at different prognosis stages of diseases listed above.

Objective: To investigate the modulatory function of statin therapy on circulating microRNA-92a (miR-92a) in patients with coronary heart disease (CHD), and to evaluate the possibility of miR-92a as a new target of treatment for endothelial dysfunction., Methods: A case control study was conducted. Prevalence of abnormal blood fat content, statin treatment rate, and attainment rate of low density lipoprotein-cholesterol (LDL-C) lowered to expected level in 236 patients with CHD were analyzed. Relationship between statin therapy in patients with type 2 diabetes mellitus (DM), and level of LDL-C and circulating miR-92a expression was analyzed by multivariate general linear factorial analysis. The incidence of acute coronary syndrome (ACS) was compared in patients with CHD receiving statin therapy in all groups., Results: Prevalence of abnormal LDL-C was 95.7% (112/117) in CHD patients of non-statin therapy group, and 47.5% (112/236) of patients with CHD who should receive statin therapy but did not. Attainment rate of lowering of LDL-C to expected level in statin therapy group was 27.7% (33/119). LDL-C level (mmol/L) was significantly lower in statin therapy group than that in non-statin therapy group (2.457 ± 0.802 vs. 3.218 ± 1.130, Z = -9.760, P = 0.001), and incidence of ACS was significantly lower in statin therapy group than that in non-statin therapy group [33.6% vs. 71.8%, χ(2) = 34.491, P = 0.001]. There was no significant difference in incidence of ACS between patients with or without attaining the expected low value of LDL-C in statin therapy group [33.3% vs. 33.7%,χ(2) = 0.002, P = 0.968]. Circulating miR-92a expression was significantly higher in patients with stable angina pectoris (SAP) complicated with DM than those without DM (0.492 vs. -0.121, Z = -3.038, P = 0.002). It was found that statin therapy could down regulate miR-92a expression in patients with SAP complicated with DM as compared with that with non-statin therapy (0.419 vs. 0.687, Z = 1.289, P = 0.072). There was no significant difference in circulating miR-92a expression between statin therapy and non-statin therapy in patients with SAP without co-existing DM (-0.032 vs. -0.198, Z = -0.614, P = 0.539). Multivariate general linear factorial analysis showed that statin therapy was the major influential factor on LDL-C level in patients with CHD (F = 22.863, P = 0.001), and complicating DM was the major influential factor on circulating miR-92a expression in patients with SAP (F = 9.641, P = 0.003)., Conclusion: Regulation of circulating miR-92a expression may be considered as a new clinical target for statin treating endothelial dysfunction in patients with CHD.

Purpose: Given concerns of excess malignancies following adjuvant radiation for seminoma, we evaluated photon and proton beam therapy (PBT) treatment plans to assess dose distributions to organs at risk and model rates of second cancers., Materials and Methods: Ten stage I seminoma patients who were treated with conventional para-aortic AP-PA photon radiation to 25.5 Gy at Massachusetts General Hospital had PBT plans generated (AP-PA, PA alone). Dose differences to critical organs were examined. Risks of second primary malignancies were calculated., Results: PBT plans were superior to photons in limiting dose to organs at risk. PBT decreased dose by 46% (8.2 Gy) and 64% (10.2 Gy) to the stomach and large bowel, respectively (p<0.01). Notably, PBT was found to avert 300 excess second cancers among 10,000 men treated at a median age of 39 and surviving to 75 (p<0.01)., Conclusions: In this study, the use of protons provided a favorable dose distribution with an ability to limit unnecessary exposure to critical normal structures in the treatment of early-stage seminoma. It is expected that this will translate into decreased acute toxicity and reduced risk of second cancers, for which prospective studies are warranted., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate the expressions of Bcl-2 and Beclin-1 in pancreatic cancer and analyze the correlation between them., Methods: The pancreatic tissue samples were collected from each 6 cases of pancreatic cancer, pancreatic exocrine benign tumor, chronic pancreatitis and normal pancreas and marked as group A, group B, group C and group D, respectively. The mRNA expression levels of Bcl-2 and Beclin-1 were detected by real-time fluorescence quantitative PCR and the protein expression levels of Bcl-2 and Beclin-1 were detected through immunohistochemistry., Results: The expression levels of Bcl-2 mRNA and protein, were the lowest in group D and the highest in group A (P < 0.05). The expression levels of Beclin-1 mRNA and protein in group A were significantly lower than those in group B and group D (P < 0.05). However, the expression levels of Beclin-1 between group A and group C were not significantly different (P > 0.05). The correlation coefficient between Bcl-2 and Beclin-1 protein expression in pancreatic cancer is--0.827 (P = 0. 042)., Conclusion: Compared with normal pancreatic tissue, pancreatic cancer had Bcl-2 expression upregulated and Beclin-1 expression downregulated. The increased anti-apoptotic effect of Bcl-2 and the decreased autophagic effect of Beclin-1 may collaboratively contribute to the occurrence of pancreatic cancer.

Although the melting of ice is the most ubiquitous phase transition, (pre)melting and the quasi-liquid layer remain a matter of debate, and little is known about the relationship between the thermodynamic properties of ice nanocrystals and their size and dimensionality. Here, we model analytically the size- and dimensionality-dependent melting temperature, premelting temperature, and melting enthalpy of hydrogen-bonded ice nanocrystals. These three thermodynamic parameters are found to increase with increasing size and dimensionality where the size effect is principle while the dimensionality effect is secondary, and the size dependence of premelting temperature almost follows the same trend as that of melting temperature. The model predictions correspond to the available molecular dynamic simulation and experimental results of ice nanoparticles and nanowires. These agreements enable us to determine theoretically the thickness of the quasi-liquid layer for the first time, which is found to be not constant but slightly increase with increasing size and thus accounts for the occurrence of different reported thicknesses of the quasi-liquid layer., (© 2012 American Chemical Society)

Chromatography has been extensively applied in many fields, such as metabolomics and quality control of herbal medicines. Preprocessing, especially peak alignment, is a time-consuming task prior to the extraction of useful information from the datasets by chemometrics and statistics. To accurately and rapidly align shift peaks among one-dimensional chromatograms, multiscale peak alignment (MSPA) is presented in this research. Peaks of each chromatogram were detected based on continuous wavelet transform (CWT) and aligned against a reference chromatogram from large to small scale gradually, and the aligning procedure is accelerated by fast Fourier transform cross correlation. The presented method was compared with two widely used alignment methods on chromatographic dataset, which demonstrates that MSPA can preserve the shapes of peaks and has an excellent speed during alignment. Furthermore, MSPA method is robust and not sensitive to noise and baseline. MSPA was implemented and is available at http://code.google.com/p/mspa., (Copyright © 2011. Published by Elsevier B.V.)

The aim of this study was to evaluate the bioequivalence of a new generic formulation of bicalutamide 50-mg tablets (test) and the available branded formulation (reference) to comply with regulatory criteria for marketing of the test product in China. This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in 40 healthy male volunteers and consisted of separate fasting and fed phases. A single oral dose of the test or reference formulation was followed by a 6-week washout period, after which subjects received the alternative formulation. Blood samples were collected before dosing and at 0.5, 1, 2, 4, 8, 12, 15, 24, 30, 36, 48, 72, 144, 288, 432 and 576 h after dosing. Plasma samples were separated and assayed for bicalutamide using a selective and sensitive HPLC method with UV detection. The fasting and fed states pharmacokinetic parameters AUC0-576 h, AUC0-∞, Cmax, tmax and t1/2 were determined from plasma concentration-time profile of both formulations. The formulations were considered bioequivalent when the 90% CIs of the geometric mean ratios (test:reference) for Cmax and AUC0-576 h were within the regulatory range of 80-125%. There were no significant increases in bicalutamide Cmax, AUC0-576 h or tmax for either formulation in the fed phase compared with the fasting phase. In both the fasting and fed portions of the study, the 90% CIs for the ratio (test:reference) of log-transformed Cmax and AUC0-576 h were within the acceptance range for bioequivalence., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Patients who require prolonged mechanical ventilation (PMV) are increasing and producing financial burdens worldwide. This study determines the cost per QALY (quality-adjusted life year), out-of-pocket expenses, and lifetime costs for PMV patients stratified by underlying diseases and cognition levels., Methods: A nationwide sample of 50,481 patients with continual mechanical ventilation for more than 21 days was collected during 1997-2007. After stratifying the patients according to specific diagnoses, a latent class analysis (LCA) was performed to categorise PMV patients with multiple co-morbidities into several homogeneous groups. The survival functions were estimated for individual groups using the Kaplan-Meier method and extrapolated to 300 months through a semi-parametric method. The survival functions were adjusted using an EQ-5D utility value derived from a convenience sample of 142 PMV patients to estimate quality-adjusted life expectancies (QALE). Another convenience sample of 165 patients was used to estimate the out-of-pocket expenses. The lifetime expenditures paid by the single-payer National Health Insurance (NHI) system and patients' families were estimated by multiplying average monthly expenditures by the survival probabilities and summing the values over lifetime., Results: PMV therapy costs more than 100,000 U.S. dollars (USD) per QALY for all patients with poor cognition. For patients with partial cognition, PMV therapy costs less than 56,000 USD per QALY for those with liver cirrhosis, intracranial or spinal cord injuries, and 57,000-69,000 USD for patients with multiple co-morbidities under age of 65. The average lifetime cost of PMV was usually below 56,000 USD. The out-of-pocket expenses were often more than one-third of the total cost of treatment., Conclusions: PMV treatment for patients with poor cognition would cost more than 5 times Taiwan's GDP (gross domestic products), or less cost-effective. The out-of-pocket expenses for PMV provision should also be considered in policy decision.

The protein structural entries grew far slower than the sequence entries. This is partly due to the bottleneck in obtaining diffraction quality protein crystals for structural determination using X-ray crystallography. The first step to achieve protein crystallization is to find out suitable chemical reagents. However, it is not an easy task. Exhausting trial and error tests of numerous combinations of different reagents mixed with the protein solution are usually necessary to screen out the pursuing crystallization conditions. Therefore, any attempts to help find suitable reagents for protein crystallization are helpful. In this paper, an analysis of the relationship between the protein sequence similarity and the crystallization reagents according to the information from the existing databases is presented. We extracted information of reagents and sequences from the Biological Macromolecule Crystallization Database (BMCD) and the Protein Data Bank (PDB) database, classified the proteins into different clusters according to the sequence similarity, and statistically analyzed the relationship between the sequence similarity and the crystallization reagents. The results showed that there is a pronounced positive correlation between them. Therefore, according to the correlation, prediction of feasible chemical reagents that are suitable to be used in crystallization screens for a specific protein is possible.

Background: Prolonged mechanical ventilation (PMV) is increasingly common worldwide, consuming enormous healthcare resources. Factors that modify PMV outcome are still obscure., Methods: We selected patients without preceding mechanical ventilation within the one past year and who developed PMV during index admission in Taiwan's National Health Insurance (NHI) system during 1998-2007 for comparison of mortality and resource use. They were divided into three groups: (1) patients with end-stage renal diseases (ESRD) before the index admission for PMV onset; (2) patients with dialysis-requiring acute kidney injury (AKI-dialysis) during the hospitalization course; and (3) patients without AKI or with non dialysis-requiring AKI during the hospitalization course (non-AKI). We used a random-effects logistic regression model to identify factors associated with mortality., Results: Compared with the other two groups, patients with AKI-dialysis had significantly longer mechanical ventilation, more frequent use of vasopressors, longer intensive care unit/hospital stay and higher inpatient expenditures during the index admission. Relative to non-AKI patients, patients with AKI-dialysis had an elevated mortality hazard; the adjusted relative risk ratios were 1.51 (95% confidence interval [CI]:1.46-1.56), 1.27 (95% CI: 1.23-1.32), and 1.10 (95% CI: 1.08-1.12) for mortality rates at discharge, 3 months, and 4 years after PMV, respectively. Patients with AKI-dialysis also consumed significantly higher total in-patient expenditure than the other two patient groups (p<0.001)., Conclusions: Among patients that need PMV care during an admission, the presence of de novo AKI requiring dialysis significantly increased short and long term mortality, and demand for health care resources.

Objective: To examine the expression of circulating microRNA-92a (miR-92a) in patients with ST-segment elevation myocardial infarction (STEMI), and the impact of percutaneous coronary intervention (PCI) on such expression., Methods: The level of circulating miR-92a was measured in three groups of patients: 58 STEMI patients received PCI, 24 STEMI patients received no PCI, and 116 patients with stable angina pectoris (SAP) without PCI., Results: On the day next to admission, STEMI patients received no PCI were found to have higher level of circulating miR-92a as compared to SAP patients without PCI (0.2869 ± 0.8167 vs. -0.0555 ± 0.9855, F = 2.438, P = 0.121). Twenty-four hours after the PCI, the level of circulating miR-92a in STEMI patients received the procedure was lower than those without it (-0.0324 ± 0.9563 vs. 0.2869 ± 0.8167, F = 2.054, P = 0.156). The SAP patients (without PCI) had higher survival rate as compared to the STEMI patients without PCI (100.0% vs. 75.0% P = 0.001), and the survival rate in STEMI patients received PCI was higher than those without it (89.7% vs. 75.0%, P = 0.088)., Conclusions: In STEMI patients, the expression of circulating miR-92a is up-regulated. PCI therapy may suppress such up-regulation. Survival rate is higher in patients showing down-regulation of miR-92a. Our data suggest that miR-92a might have potential for diagnosis and therapeutic application in the prevention and treatment of STEMI.

Purpose: To evaluate whether pretreatment carcinoembryonic antigen (CEA) levels have a prognostic role in patients after definitive radiotherapy for squamous cell carcinoma (SCC) of the uterine cervix., Methods and Materials: A retrospective study of 550 patients was performed. The SCC antigen (SCC-Ag) and CEA levels were regarded as elevated when they were ≥2 and ≥5 ng/mL, respectively. A total of 208 patients underwent concurrent chemoradiotherapy (CCRT). The Kaplan-Meier method was used to calculate the distant metastasis (DM), local failure (LF), disease-free survival (DFS), and overall survival (OS) rates. Multivariate analysis was performed using the Cox proportional hazards model. The hazard ratio (HR) with 95% confidence interval (CI) was evaluated for the risk of a poor prognosis., Results: Compared with the patients with normal CEA/SCC-Ag levels, CEA levels ≥10 ng/mL but without elevated SCC-Ag levels was an independent factor for LF (HR, 51.81; 95% CI, 11.51-233.23; p < .001), DM (HR, 6.04; 95% CI, 1.58-23.01; p = .008), DFS (HR, 10.17; 95% CI, 3.18-32.56; p < .001), and OS (HR, 5.75; 95% CI, 1.82-18.18; p = .003) after RT alone. However, no significant role for CEA was noted in patients with SCC-Ag levels ≥2 ng/mL. In patients undergoing CCRT, a CEA level ≥10 ng/mL was an independent factor for LF (HR, 2.50; 95% CI, 1.01-6.21; p = .047), DM (HR, 3.41; 95% CI, 1.56-7.46; p = .002), DFS (HR, 2.73; 95% CI, 1.39-5.36; p = .003), and OS (HR, 3.93; 95% CI 1.99-7.75; p < .001). A SCC-Ag level of ≥40 ng/mL was another prognostic factor for DM, DFS, and OS in patients undergoing not only CCRT, but also RT alone. The 5-year OS rate for CCRT patients with CEA <10 ng/mL and ≥10 ng/mL was 75.3% and 35.8%, respectively (p < .001). CCRT was an independent factor for better OS (HR, 0.69; 95% CI, 0.50-0.97; p = .034)., Conclusion: Pretreatment CEA levels in patients with SCC of the uterine cervix provide complementary information for predicting LF, DM, DFS, and OS, except for in patients with abnormal SCC-Ag levels before RT alone. More aggressive therapy might be advisable for patients with CEA levels of ≥10 ng/mL., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Large amounts of data from high-throughput metabolomics experiments become commonly more and more complex, which brings an enormous amount of challenges to existing statistical modeling. Thus there is a need to develop statistically efficient approach for mining the underlying metabolite information contained by metabolomics data under investigation. In the work, we developed a novel kernel Fisher discriminant analysis (KFDA) algorithm by constructing an informative kernel based on decision tree ensemble. The constructed kernel can effectively encode the similarities of metabolomics samples between informative metabolites/biomarkers in specific parts of the measurement space. Simultaneously, informative metabolites or potential biomarkers can be successfully discovered by variable importance ranking in the process of building kernel. Moreover, KFDA can also deal with nonlinear relationship in the metabolomics data by such a kernel to some extent. Finally, two real metabolomics datasets together with a simulated data were used to demonstrate the performance of the proposed approach through the comparison of different approaches., (Copyright © 2011. Published by Elsevier B.V.)

Objectives: This study aimed to address whether hydroxyethyl starch (HES) is beneficial for intra-abdominal pressure (IAP) in severe acute pancreatitis (SAP) in early stages., Methods: Forty-one patients with SAP were randomized to HES group (n = 20) and the Ringer's lactate (RL) group (n = 21). The groups received 6% HES 130/0.4 for 8 days and RL solution without colloid, respectively. The primary end point was the IAP. The secondary end points were fluid balance, major organ complications, the Acute Physiology and Chronic Heath Evaluation II score, and the serum levels of C-reactive protein, interleukin-6, and interleukin-8., Results: The characteristics of baseline data were similar in the 2 groups. In the HES group, the IAP was significantly lower in 2 to 7 days, and fewer patients received mechanical ventilation (15.0% vs 47.6%). A negative fluid balance was observed earlier in the HES group than in the RL group (2.5 ± 2.2 vs 4.0 ± 2.5 days)., Conclusions: Fluid resuscitation with HES in the early stages of SAP can decrease the risk of intra-abdominal hypertension and reduce the use of mechanical ventilation.

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The purpose of this study was to establish the phospho-specific flow cytometry (phospho-flow) to detect the phosphorylated signaling proteins of leukemia cells and to evaluate its useful value in leukemia study. The bone marrow of leukemia children was collected, and treated by phospho-flow of extracted mononuclear cells (MNC) and phospho-flow of directly fixed bone marrow (BM) respectively. In phospho-flow of extracted MNC, the MNC extracted from BM were fixed and permeabilized, then were cultured with P-AKT and P-ERK1/2, finally were analyzed by flow cytometry. In phospho-flow of directly fixed BM, the BM was treated with fixation/lysis buffer and 90% methanol, then were incubated with the surface CD antibody, P-AKT and P-ERK1/2, finally the treated BM cells were analyzed by flow cytometry. The results showed that the positive rates of P-AKT and P-ERK1/2 in MNC treated by phospho-flow of extracted MNC of 26 leukemia children were 46.2% and 30.8% respectively, while the positive rates of P-AKT and P-ERK1/2 in BM treated by phospho-flow of directly fixed BM were 50.0% and 38.5% respectively. The comparison of positive rates of P-AKT and P-ERK1/2 between the 2 treatment protocol showed no difference (p > 0.05). It is concluded that the phospho-flow of directly fixed BM established by our laboratory can be used to analyze the signaling proteins of leukemia cells.

Purpose: To quantify interfractional anatomical variations and their dosimetric impact during the course of fractionated proton therapy (PT) of prostate cancer and to assess the robustness of the current treatment planning techniques., Methods: Simulation and daily in-room CT scans from ten prostate carcinoma patients were analyzed. PT treatment plans (78 Gy in 39 fractions of 2 Gy) were created on the simulation CT, delivering 25 fractions to PTV1 (expanded from prostate and seminal vesicles), followed by 14 boost fractions to PTV2 (expanded from prostate). Plans were subsequently applied to daily CT, with beams aligned to the prostate center in the sagittal plane. For five patients having a sufficiently large daily imaging volume, structure contours were manually drawn, and plans were evaluated for all CT sets. For the other five patients, the plans were evaluated for six selected fractions. The daily CT was matched to the simulation CT through deformable registration. The registration accuracy was validated for each fraction, and the three patients with a large number of accurately registered fractions were used for dose accumulation., Results: In individual fractions, the coverage of the prostate, seminal vesicles, and PTV1 was generally maintained at the corresponding prescription dose. For PTV2, the volume covered by the fractional prescription dose of 2 Gy (i.e., V2) was, on average, reduced by less than 3% compared to the simulation plan. Among the 225 (39 x 5 + 6 x 5) fractions examined, 15 showed a V2 reduction larger than 5%, of which ten were caused by a large variation in rectal gas, and five were due to a prostate shift in the craniocaudal direction. The fractional dose to the anterior rectal wall was found to increase for one patient who had large rectal gas volume in 25 of the 39 fractions, and another who experienced significant prostate volume reduction during the treatment. The fractional bladder dose generally increased with decreasing fullness. In the total accumulated dose for the three patients after excluding a few fractions with inaccurate registration due to a large amount of rectal gas (a condition inconsistent with RTOG protocol), 98.5%, 96.6%, and 98.2% of the PTV2 received the prescription dose of 78 Gy. The V75 and V70 of the anterior rectal wall and bladder both remained within tolerance., Conclusions: The results confirm that the PT planning techniques and dose constraints used at our institution ensure that target coverage to the prescription dose is maintained in the presence of interfractional anatomical variations. Dose coverage in individual fractions can be compromised, and normal tissue dose increased, due to deviations in the bladder and rectal volume compared to the simulation plans or progressive changes in the prostate volume during the treatment. Deviations from the plan can be reduced with efforts aimed at maintaining consistent daily patient anatomy.

Objective: To study the clinical significance of Toll-like receptor 4 (TLR4) in children with severe sepsis., Methods: A prospective control study was performed. All cases were enrolled from pediatric department of the First Affiliated Hospital of Guangzhou Medical College, and they were divided into severe sepsis group (14 patients) who were diagnosed to have severe sepsis or septic shock in intensive care unit (ICU), pneumonia group (10 cases) with diagnosis of bronchial pneumonia, and healthy control group (10 healthy children). Venous blood samples of 2 ml were collected at admission, the level of TLR4 was detected by flow cytometry .At the same time, the changes in serum interleukin (IL-6, IL-10 ) and tumor necrosis factor-α (TNF-α) levels were determined by enzyme linked immunoadsorbent assay (ELISA)., Results: In severe sepsis group, the contents of TLR4 [(71.56±15.32)%], IL-6 [(1.98±1.55) ng/L], IL-10 [(88.20±61.23) ng/L] and TNF-α [(104.08±85.36) ng/L] were significantly higher than those in pneumonia group [(50.07±26.36)%, (0.93±0.16) ng/L, (41.42±7.02) ng/L, (48.96±6.40) ng/L] and healthy control group [(39.43±17.43)%, (0.94±0.43) ng/L,(43.73±22.68) ng/L, ( 49.94± 18.47) ng/L, all P<0.05). But there was no significant difference in the contents of TLR4, IL-6, IL-10 and TNF-α between pneumonia group and healthy control group (all P>0.05)., Conclusion: This study suggests that TLR4 might be critically involved in the development of sepsis, and changes in TLR4 expression are parallel with levels of proinflammatory cytokines, including IL-6, TNF-α, and IL-10. The combination of TLR4 and proinflammatory cytokines would serve as the predictive parameters in early diagnosis and severity evaluation of sepsis in children.

Purpose: To quantify daily variations in the anatomy of patients undergoing radiation therapy for prostate carcinoma, to estimate their effect on dose distribution, and to evaluate the effectiveness of current standard planning and setup approaches employed in proton therapy., Methods: We used series of computed tomography data, which included the pretreatment scan, and between 21 and 43 in-room scans acquired on different treatment days, from 10 patients treated with intensity-modulated radiation therapy at Morristown Memorial Hospital. Variations in femur rotation angles, thickness of subcutaneous adipose tissue, and physical depth to the distal surface of the prostate for lateral beam arrangement were recorded. Proton dose distributions were planned with the standard approach. Daily variations in the location of the prescription isodose were evaluated., Results: In all 10 datasets, substantial variation was observed in the lateral tissue thickness (standard deviation of 1.7-3.6 mm for individual patients, variations of >5 mm from the planning computed tomography observed in all series), and femur rotation angle (standard deviation between 1.3° and 4.8°, with the maximum excursion exceeding 10° in 6 of 10 datasets). Shifts in the position of treated volume (98% isodose) were correlated with the variations in the lateral tissue thickness., Conclusions: Analysis suggests that, combined with image-guided setup verification, the range compensator expansion technique prevents loss of dose to target from femur rotation and soft-tissue deformation, in the majority of cases. Anatomic changes coupled with the uncertainties of particle penetration in tissue restrict possibilities for margin reduction in proton therapy of prostate cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Nowadays, Monte Carlo models of proton therapy treatment heads are being used to improve beam delivery systems and to calculate the radiation field for patient dose calculations. The achievable accuracy of the model depends on the exact knowledge of the treatment head geometry and time structure, the material characteristics, and the underlying physics. This work aimed at studying the uncertainties in treatment head simulations for passive scattering proton therapy. The sensitivities of spread-out Bragg peak (SOBP) dose distributions on material densities, mean ionization potentials, initial proton beam energy spread and spot size were investigated. An improved understanding of the nature of these parameters may help to improve agreement between calculated and measured SOBP dose distributions and to ensure that the range, modulation width, and uniformity are within clinical tolerance levels. Furthermore, we present a method to make small corrections to the uniformity of spread-out Bragg peaks by utilizing the time structure of the beam delivery. In addition, we re-commissioned the models of the two proton treatment heads located at our facility using the aforementioned correction methods presented in this paper.

Objective: To explore the molecular mechanism of interleukin cytokines IL-6, IL-17, IL-23, IL-23R in the onset of acute pancreatitis in rats pancreatitis models., Methods: Thirty six SD rats were randomized into 3 groups: control group, model group, and intervention group (n = 12). The rats in model group and intervention group were induced by intraperitoneal injection of 1-arginine, and those in intervention group were treated by tail intravenous administration of drugs at the same time. Then the rats were sacrified at 3rd, 6th, and 12th h. after the modeling. The levels of IL-6 ,IL-17, IL-23, IL-23R in blood, pancreas, lung and kidney were checked by ELISA., Results: The IL-6 levels of serum, pancreas, lung and kidney in AP Model group were obviously higher than those in the control group and intervention group. This trend increased with time. Similarly, the levels of IL-17 and IL-23 in AP group were obviously higher than those in the control group and intervention group. Compared with the control and intervention group, AP group showed higher IL-23R levels in serum, pancreas, but lower IL-23R levels in lung and kidney., Conclusion: IL-23 is a mediator involved in the formation of IL-17 and IL-6, they all can promote acute pancreatitis.