Table of contents

Tissue contrast is a major challenge in the application of computed tomography (CT) and micro-computed tomography (micro-CT) techniques for imaging cancer. Contrast medium is used in order to enhance contrast of certain organs of interest, as well as tumors. Several types of contrast media have been used to assess tumor vasculature, perfusion and angiogenesis in preclinical studies. In general, low molecular weight contrast media have been used to characterize the first pass vascular dynamics of tumors with fast CT systems, while blood pool agents have been preferred to explore the delayed vascular dynamics with micro-CT systems. Together, these approaches provide qualitative, semi-quantitative, and quantitative information of the vascular architecture and vascular functionality of tumors in the preclinical scenario. Herein, we present an overview of contrast media, imaging techniques, image analysis methods, and quantitative parameters that have been used to evaluate tumor angiogenesis in vivo in recent preclinical studies. Preclinical applications on lesion detection and characterization, evaluation of vascular parameters as prognostic and predictive biomarkers, and evaluation of treatment response are also reviewed. These applications have demonstrated the potential of contrast-enhanced x-ray imaging to provide, in a noninvasive manner, a landscape of the spatial and temporal heterogeneity of the angiogenic process underlying tumor development.

Objective: Work stress is identified as the 'health epidemic of 21st century' by WHO because, when left unchecked, it wreaks havoc on human mind and body by accelerating the onset and progression of several health disorders. Hence, the evolution of strategies for early detection of mental stress is pivotal. The study presented here is one step towards the goal of developing a physiological parameter based psychological stress detection scheme which can further be incorporated into a wearable vital signs monitor. Approach: A group of 34 subjects (14 females and 20 males, age: 21.4 ± 1.7 years; mean ± SD) volunteered to participate in a pilot laboratory intervention that emulated real-life job stress scenarios by incorporating stress factors like mental workload, time pressure, performance pressure and social evaluative threat. Electrodermal Activity (EDA), Electrocardiogram (ECG), and Skin Temperature (ST) were monitored throughout the experiment to capture sympathetic activation during stress. Stress response elicitation was validated using salivary cortisol levels. A total of 61 features were extracted from these signals and four classifiers were investigated regarding their ability to detect 'stress' using single and multimodal schemes. A fusion framework that combined the benefits of feature fusion and decision fusion was employed to generate classifier ensembles for multimodal stress detection schemes. As the generated datasets exhibited a class imbalance issue, three separate schemes for class imbalance rectification viz., undersampling, oversampling and SMOTE were investigated concerning their ability to yield the best classification performance. While ECG based performance analysis was restricted to data segments of 300 s duration to conform to international guidelines for short-term HRV analysis, non-overlapping EDA and ST data segments of durations 300 s, 180 s, 60 s, and 30 s were examined to determine the optimum data length that can generate best results. Main Results: EDA gave a superior performance for 60 s windows while ST performed best with data segments of duration 30 s. A comparative study was performed with 25%, 50%, 75% and 90% overlapping data segments as well. However, overlapping did not enhance the performance of the classifiers significantly.While EDA emerged as the best single modality, the highest stress recognition accuracy of 97.13% was yielded by a combination of EDA and ST with data segments of 60 s duration. Furthermore, the differential effect of 'physical' and 'psychological' stressors on EDA and ST was analyzed. Significance: The results clearly suggest that these physiological parameters can not only reliably detect psychological stress but can also discriminate it from physical stress.

The enzyme-less biosensors have grabbed the attention due to the ease of handling them as they can be used in harsh environment besides being economical to use. In the present work, we have shown the synthesis and use of Gold-Graphene oxide (Au-GO) nanocomposites electrodes using glucose-capped Gold nanoparticles (Au NPs) for the enzyme-less biosensing of glucose. Glucose in Au NPs partially reduced GO present in its vicinity as evident from the characterizations, x-ray diffraction, Raman microscopy, UV–vis spectroscopy and Fourier transform infrared spectroscopy. Their structure and morphology were studied using transmission electron microscopy and scanning electron microscopy respectively. The sensitivity of Au-GO nanocomposites electrodes is 25% higher compared to enzymatic GO electrode as evident from the electrochemical measurements. The concentration of gold nanoparticles is varied for nanocomposites to understand their role in the sensing mechanism. Au-GO electrodes showed response for glucose for a wide range of concentration varying from 0.05 mM to 40 mM with linearity between 1 to 10 mM. Also, their selectivity towards glucose among the common interfering agents such as urea, cholesterol, Ascorbic acid, 4-acetaminophenol and citric acid make them suitable candidates as glucose biosensors.

Objective. The primary purpose of this study was to examine the use of the ActiGraph GT9X gyroscope and magnetometer for turn detection and quantifying turn degree during walking and running. The secondary purpose was to examine the effect of varying turn degrees during walking and running on oxygen consumption. Approach. Participants (N = 17) completed pivot trials, straight-line treadmill walking and running (3–6 mph) and four turn conditions (45°, 90°, 135°, and 180°) during over-ground walking and running. Pivot trials were completed for 1 min and walking/running trials were completed for 6 min, both with a turn frequency of 10 turns/min. Data were collected using a GT9X device (right hip) and a Cosmed K4b² (measured oxygen consumption). Raw GT9X gyroscope and magnetometer data were processed through various low-pass filter frequencies (0.25–2.0 Hz). Treadmill and pivot trials were used to develop thresholds for turn detection using gyroscope and magnetometer data and cross-validated using the over-ground trials. Linear mixed models were used to compare actual and estimated number of turns, measured and estimated turn degree, and differences in VO₂ across walking and running speed and turn degree. Main results. Greater than 98% of turns were detected when using gyroscope data filtered at 0.25 Hz and turn degree was estimated within 2.2° of measured turn degree across all speeds. In general, the VO₂ of walking and running increased as the turn degree increased beyond 135°. Significance. The GT9X gyroscope, when filtered at 0.25 Hz can be used to detect the number of turns and estimate turn degree. The magnetometer, when filtered at 0.75 Hz, was useful for detecting the number of turns, however turn detection was more accurate using the gyroscope.

Graphene is a one-atom thick planar sheet of carbon atoms arranged in a hexagonal crystal lattice. Graphene and related nanomaterials provide a unique biocompatible substrate for the growth of primary and immortalized cardiomyocytes, as well as for the differentiation and maturation of embryonic stem cells into cardiomyocytes. However, the effect of graphene on cardiac ion channels has not been described. The goal of the present study was to determine if culturing cardiomyocytes on graphene alters the properties of cardiac Ca²⁺ channels. For this purpose immortalized H9c2 rat cardiomyocytes were plated either on uncoated glass coverslips or coverslips coated with a monolayer of graphene synthesized with chemical vapor deposition. Cardiomyocytes plated directly on graphene showed no significant change in the density or current versus voltage relationship of the whole-cell Ba²⁺ current (I_Ba) when compared with cells cultured on glass. There was also no difference in the response of I_Ba in the cardiomyocytes to protein kinase A stimulation or to the dihydropyridines BayK 8644 and nisoldipine. Surprisingly, the H9c2 cells grown on graphene displayed a large reduction in the voltage-dependent inactivation of the Ca²⁺ channels. Despite this change, there was no alteration in vasopressin-induced Ca²⁺ transients in the graphene-plated cells. Plating the myocytes on poly-l-lysine- and collagen-coated graphene restored normal inactivation properties to the Ca²⁺ currents. It is concluded that the unique structural and electrical features of graphene alter the biophysical properties of the Ca²⁺ channels.

Background. There are over 33 000 people in the US living with complete tetraplegia due to spinal cord injury (SCI). People with complete tetraplegia rank restoration of hand and arm function as their highest priority, as it would offer greater independence and improved quality of life. In this study, we show that subjects with chronic (>1-year post-injury) C5 or C6 level, motor-complete SCI are able to control a brain computer interface-functional electrical stimulation (BCI-FES) system to enable hand opening and closing. Methods: 8 subjects with C5 or C6 motor-level SCI and 6 uninjured, control subjects participated in 6 sessions of BCI-FES sessions. Electroencephalographic (EEG) signals were acquired using a wireless EEG system and subjects were asked to 'imagine moving their right hand' for motor imagery. Average power was extracted in 5 Hz bins (6–35 Hz) from C3, C1, Cz, C2, and C4 electrodes and input as features to a support vector machine classification algorithm. When 'movement intention' was classified correctly from the motor imagery period, a custom-designed stimulation sequence was delivered to the forearm muscles via surface electrodes to enable opening and closing of the hand. Results: Average online decoding accuracy during the closed-loop BCI-FES sessions was similar for the SCI (74.8% ± 17.76) and the control (75.5% ± 11.94) group. Online decoding accuracies were validated using Monte Carlo simulations that used 30%, 50%, and 70% training data to validate the decoded online accuracy and Wilcoxon rank sum test found no significant differences between the SCI and Control subjects. Conclusions: This study demonstrates that subjects with motor complete, cervical SCI were able to control a BCI-FES system with decoding accuracies similar to healthy controls after minimal BCI-training. Non-invasive BCI-FES systems may have the potential to restore hand function in people with motor-complete SCI to improve their quality of life.

In the present work, Monte Carlo code MCNPX was used to determine the cellular dosimetric parameter; cellular S-values for frequently used radionuclides in targeted radionuclide therapy including ³²P, ⁸⁹Sr, ⁹⁰Y, ^117mSn, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁰Tm, ¹⁷⁷Lu, ¹⁸⁶Re and ¹⁸⁸Re. We considered the effect of some factors such as cell size, radiation subcellular localization and chemical composition on cellular S-values. The cells were defined as two concentric spheres and the radionuclides were assumed to be uniformly distributed in one of the cell compartments including cell surface (CS), cytoplasm (Cy), and nucleus (N). A comparison between MCNPX results with obtained MIRDcell values was performed. Deviations between MCNPX and MIRDcell were found to be less than ∼15% for self-absorption, in the cases of S(C ← C) and S(N ← N) values whereas discrepancies in S-values increased up to ∼22% for C ← CS and ∼28% for N ← Cy and N ← CS. The results showed a significant change with increasing the cell and cell nucleus size. For a given radionuclide, with increasing radii, S-values decreased in all compartments. For a given radius of the cell and nucleus, low energy radionuclides had higher S-values. For all source-target combinations, ¹⁵³Sm and ⁹⁰Y had the highest and lowest S-values, respectively.

The fast dose calculator (FDC), a track-repeating algorithm that was initially developed for proton therapy, has been expanded to include carbon. The purpose of this study was to validate FDC as a dose engine for treatment planning of scanning proton and carbon beams at the Shanghai Proton and Heavy Ion Center (SPHIC). For a complete set of clinical reference beams, the absorbed dose calculated with FDC was compared with that measured. A gamma-index analysis found over 94.6% and 100.0% of the measured points for protons had a gamma-index value smaller than unity for the 1%/1 mm and 1.5%/1.5 mm dose/distance agreement criteria, respectively. For carbon, the passing rates were above 80.6% and 92% with and without ripple filter if the criteria was set to 1%/1 mm. The values increased to 90.0%and 96.0% with the criteria 1.5%/1.5 mm. In conclusion, we found that FDC can serve as an accurate dose calculation engine for the SPHIC.

Purpose: Absolute dose comparison between different methodologies of multichannel dosimetry in pretreatment quality assurance (QA), including highly modulated techniques in a wide range of doses (180 cGy to 1800 cGy). Methods: Several parametric forms for film dosimetry calibration were studied and compared. Then, different algorithms for radiochromic film dosimetry were implemented in Python code. With the objective of comparing these procedures, several IMRT and VMAT plans were irradiated and studied attending to the gamma criterion. A denoising protocol was developed, removing completely Gaussian noise dependency. In addition, spatial resolution dependency was also removed. Results: The algorithms that account for perturbations gave good results in the gamma analysis. The results could not be associated with noise or resolution. The red channel is inadequate for film dosimetry. Conclusions: The studied methodologies offered good agreement with the absolute gamma analysis, even with the 2%, 2 mm criteria. The proposed modifications reduced noise and resolution dependencies and improved the results.

Due to the physical and chemical processes that are involved, interactions of ionizing radiations with cells lead to single- and double-strand breaks (SSB and DSB) and base damage to DNA cells. The damage may kill the cells or may be mis-repaired and lead to genetic diseases and cancers. Track structure Monte Carlo simulation of the DNA damage provides types of the damage and their frequencies. In the present work, to derive initial DNA damage, we used the Geant4-DNA code to simulate the physical, physico-chemical and chemical stages of interactions of incident beams of 100 eV–4.5 keV electrons. By considering the direct damage of electrons and also the indirect hydroxyl radical damage to the DNA, in a simulation, simple and complex damages to SSB and DSB were investigated. Moreover, the yield of damage and the probability of types of DNA damage were evaluated. The results of these calculations were compared with the existing experimental data and the other simulations. For electrons with energies lower than 500 eV, there were differences between our results and published data which are basically due to the existing differences in the physical (electron ionization, excitation cross sections) and chemical models of Geant4-DNA, the chemical processes considered in the simulations, DNA geometry, and the selected parameters for damage threshold as compared to the other codes. In the present work, the effect of the threshold energy of the strand breaks was also evaluated.

Objective. The fast optical signal (FOS), measured with near-infrared spectroscopy (NIRS), has high temporal and competitive spatial resolution which provides an opportunity for a novel brain-computer interface modality. However, the reliability of the FOS has been debated due to its low signal-to-noise ratio. Approach. This study examined the feasibility of automatically classifying the prefrontal FOS response during a visual oddball task. FOS measurements were collected from 15 participants during 3 offline and 2 online sessions. Classification feedback was provided to participants during online sessions. The FOS classification algorithm discriminated between oddball and frequent responses. DC intensity and phase delay FOS measurements were classified individually with both support vector machine (SVM) and linear discriminant analysis (LDA) classifiers. The decisions of these classifiers were combined with a weighted majority vote. Fifteen-trial averages were selected for optimal classification results and the best feature types were found to be the number of zero crossing and the variance. Main results. FOS responses to oddball and frequent images were classified offline with an average balanced accuracy of 62 ± 5% and classified online with an averaged balanced accuracy of 63 ± 6% across all participants. Offline classification accuracies were significantly higher than chance for all participants. Online classification results were significantly above chance in both online sessions for 7 of 14 participants. Event-related potentials (ERPs) were classified using a similar algorithm with an average balanced accuracy of 77 ± 5%, confirming that the prefrontal neuronal response to the visual oddball task could be classified above the level required (>70%) for effective BCI communication. Significance. The FOS classification results demonstrated that automatic classification of the FOS is possible at above-chance levels, however, FOS classification accuracies did not reach the effective BCI communication threshold. Further FOS classification efforts should focus on investigating spectral features as well as adding measurement channels over the fronto-central and parietal areas of the brain.

Nanoparticles have numerous uses in biomedical sciences, and this study addresses the mechanisms responsible for the formation of gold nanoparticles (GNPs) for measuring doses of ionizing radiation used in clinical radiotherapy. GNPs synthesized at various radiation doses were experimentally characterized and two mathematical models were developed to simulate the kinetics of the synthesis process. The first is similar to the Fink-Watzke model and predicts the rate of soluble gold salt conversion to GNPs, and the second model is based on a population balance model and predicts both nanoparticle concentration and size distribution. The model parameters that provided an optimal fit to experimentally gathered data were determined, and both models were able to capture the experimental absorbance time trends, which indicated the formation of gold nanoparticles. The population balance model, however, had the greater predictive power as it captured mean particle size trends that were consistent with experimental measurements.

Protein-based biomaterials with innovative and controlled performance are being sought due to their unique characteristics for use in biomedical fields such as neural implants, drug delivery systems, cell-based therapies and soft tissue engineering. Here, we present a versatile approach for the synthesis of photo-crosslinkable fibroin silk biomaterial with highly tunable mechanical, chemical and biodegradation properties. Unlike the crystalline rich silk fibroin reported previously, the covalently cross-linked fibroin protein photoresist (FPP) via controlled light-induced radical grafting, allows generating a new amorphous biomaterial with tunable properties. It appears that the use of photo-reactive acrylate groups to cross-link FPP induces plasticity that can be tuned by changing the photoinitiator concentration of the film. Tensile strength measurements revealed that elasticity was higher for FPP UV-cross-linked materials with higher concentration of photoinitiator. FTIR and relative humidity measurements showed that hydrophilicity was higher for UV-cross-linked FPP. These materials display stiffness between 0.01–1.5 GPa and tensile strains up to 60%, covering a significant portion of the properties of native soft biomaterials. Besides, in vitro proteolytic degradation of the photocrosslinked FPP films demonstrate a tunable degradation rate over a period ranging from hours to weeks. Those biomaterials have been successfully micropatterned by photolithography techniques across several orders of magnitude (μm to cm) and a systematic study of direct patterning of the fibroin protein to form high fidelity and high-resolution structures has been reported. It was also shown that the fabricated protein features are well suited to cell adhesion. The development of protein-based material with controlled and tunable elasticity that can be easily photo-patterned into centimeter, micrometer and nanometer components will allow a wide range of applications in biomedical fields requesting a natural functional tissue.

We found that the EVs differ in size and light refractive properties which were demonstrated through differences in their light intensity values. The asymmetrical nature of these biological vesicles produces slightly different concentration and size estimates in repeated analyses, but consistent reproducible data measurements can be obtained when several parameters are taken into consideration. In this study, we determined the effects of replicate number, capture time, flow rate and sample dilutions on EV quantification estimates. Individually, each of these factors influences the accuracy and reproducibility of sample readings. These findings have important implications for direct comparisons of samples to assess EV production or depletion. Here we present a practical approach for establishing an EV characterization protocol for anyone wanting to compare EV content among similar biological samples.

Deep learning neural networks have been widely used in general 2D image processing tasks. However, its application to process high-dimensional medical images is impeded by the need to tailor the network for specific considerations on imaging systems and/or biological characteristics, and the high memory/computation cost as the image dimensionality increases. This study aims to design an assembly 2.5D image segmentation framework based on native 2D convolutional neural network (CNN), which is naturally adaptable to problem dimensionality changes in an economical way and intrinsically amicable to parallel processing. In particular, we perform soft segmentation along each 2D fiber using one native 2D CNN, aggregate such decisions based on Bayesian rule, and apply an (optional) polish step to geometrically regularize the raw segmentation. Validation experiments on volumetric CT liver segmentation demonstrate higher segmentation accuracy with pronounced cost-saving benefit, compared to the state-of-the-art 3D CNN and triplanar approaches.

Liver transplant is the only curative treatment option for patients with end-stage liver failure, however there are few donor livers available for transplant. Tissue engineering of a human liver would potentially solve the problem of escalating donor shortages. A major challenge presents itself in the form of the hepatic extracellular matrix (ECM); a finely controlled in vivo niche which supports hepatocytes and plays a critical role in the development of liver disease. Polymers and decellularized tissues each provide some of the necessary biological cues for the hepatocytes, however, neither alone has proved sufficient. Equally, the ability to fine tune the microenvironment using bioactive molecules presents researchers with the opportunity to create personalised niches for hepatocytes, representing both normal and diseased phenotypes. This study combines cell derived ECM with a fibronectin vector and electrospun scaffolding techniques to produce a platform for creating customisable ECM microenvironments for hepatocytes (Abstract image). The resulting poly-L-lactic acid-extracellular matrix (PLA-ECM) scaffolds were validated using HepG2 hepatocytes. As expected, statistically significant mechanical differences were observed between the synthetically derived ECM (SD-ECM) scaffolds and normal ECM (N-ECM) scaffolds, confirming that the ECM has been altered by the fibronectin producing vector. The PLA-ECM scaffolds maintained hepatocyte growth and function and influence the gene expression of key hepatic genes. Furthermore, immunohistochemistry showed SD and N-ECMs differed in ratios of Collagen I, Laminin and Fibronectin. Our results demonstrate that hybrid PLA-ECM scaffolds and the synthetic production of ECM provide a viable, translatable platform for customising microenvironments for hepatocytes. This technology offers a potential solution to current obstacles in regenerative medicine, disease modelling and whole organ tissue engineering.

The problem of infertility in animals caused by the abnormality and deficiency of sperms can be solved by Assisted Reproductive Technology (ART). However, the methods of ART require a high quality of sperms to enhance the fertilization rate. In this paper, we focused on investigating the factors that affect the quality of sperms, which were sorted by the simple design of microfluidic devices (MFD). The first factor was associated with the types of polymer, which is used for fabrication. The second factor was related to the distance that sperms swam. The last factor was the temperature that we used for incubating sperms. The results showed that the PDMS MFD was more effective than the SU-8 MFD, and the most suitable distance that the frozen–thawed bull sperms could swim with having less effect of sperm exhaustion was 5 mm. More importantly, we are the first to prove that incubating sperms in the MFD at 37 °C was unnecessary. The percentage of sperm viability for the room temperature (25 °C) was significantly higher than incubation at 37 °C. For this reason, it could be concluded that incubating sperms at 25 °C could be sufficient. This makes it possible to reduce the time consumption and cost of sorting sperms with the MFD as we can eliminate the incubating process and equipment. Moreover, we further assessed the quality of the sperms, which were sorted with PDMS MFD at the channel length 5 mm compared with the pre-sorted sperms. The results revealed that the percentage of progressive motile sperms significantly increased, while the percentage of abnormality significantly reduced. Based on these results, it could be concluded that sorting sperm with a PDMS MFD has a less negative effect on the quality of the sperms.

The pH dependent conductance of the Chitosan/Gelatin and Hydroxy-Ethyl Methacrylate (HEMA)/Gelatin hydrogel based systems was mapped out using a data acquisition system and several aspects of conductance characteristics namely accuracy, response time and sensitivity were compared and discussed. The material characteristics of these sensors were mapped out through FTIR. Specific accuracy tests were designed and conducted and both hydrogel based sensors have been found to give a reasonably predictable outcomes in the physiological pH range (4–10). Although Chitosan/Gelatin sensing systems have been explored with regards to conductivity, to the best of our knowledge, HEMA/Gelatin composite has not yet been explored in this respect. There are observable differences in the conductometric system analysis results of both hydrogels; it has been found that HEMA based hydrogels have a longer response time, but also offer a better sensitivity as compared to Chitosan based conductometric hydrogels. This difference in response may be attributed to the material based characteristics of the conductometric sensing system; the possible underlying mechanisms have also been discussed in this research. Our findings indicate that these conductometric composite hydrogels have the potential to be used in physiological applications; where varying response times are required, a hybrid sensor array comprising of both types of hydrogel sensors may be used; that can utilize the advantages of faster response time in case of Chitosan/Gelatin and better sensitivity in case of HEMA/Gelatin sensors.

An important problem of myocardial SPECT/CT imaging with attenuation correction (AC) is a reduction of radiotracer activity at the apex in reconstructed images. This problem is known as the false apical defect. False apical defects mask real defects and lead to interpretation uncertainties. The aim of the present work is to study this phenomenon to understand the cause of apical defects on AC images. Mathematical modeling and clinical studies are carried out. Special mathematical models were designed to study the effect of the myocardial left ventricle (LV) form and the effect of patient constitution on false apical defects severity. Computer simulations of the SPECT/CT myocardial perfusion imaging procedure with and without attenuation correction were performed. The dependence of apical false defects on the LV form and on the data acquisition scheme was studied. The results of mathematical modeling have shown that the cause of false apical defects is not associated with attenuation correction. Rather, it is related to the LV form, especially to the presence of anatomical apical thinning. The LV form with apical thinning in diastole phase can not be exactly reconstructed by using the standard data acquisition schemes with limited 32 and 60 views. The reconstruction error appears in the rounded apical region in reconstructions with and without attenuation correction. But, in non-AC images, this error is masked by the second error related to the lack of attenuation correction. Interpretation based on the results of two compensating errors cannot be reliable. Taking into account the results obtained, we suggest the following hypothesis: gated systolic AC images can be useful in the interpretations of findings at the apex. This hypothesis was confirmed in preliminary clinical study.

The aim of this work was to develop and incorporate a simple knowledge-based planning (KBP) tool into the volumetric modulated arc therapy (VMAT) treatment plan production process and to determine whether the tool improved plan quality and consistency. A study of 92 existing clinical prostate VMAT plans showed correlation between the proportion of organ at risk (OAR) overlapping with the planning target volume (PTV) and various OAR volume-doses of clinical interest. Simple linear models were generated that predicted the achievable rectum and bladder volume-doses according to the fraction of OAR volume overlapping with the PTV. The models were integrated into the planning process via a script using the Eclipse scripting application programming interface (ESAPI). The script's impact on plan quality was evaluated by comparing the plans before and after script implementation using the parameter d = achieved volume-dose—predicted volume-dose, the amount by which the achieved volume-dose exceeded the predicted value. All OAR volume-doses investigated demonstrated smaller d and reduced variability following script implementation. The largest reductions in d value were observed for bladder V_60Gy and V_50Gy, which reduced from 2.9 ± 2.3 to 0.5 ± 1.6, and 4.9 ± 4.7 to 1.5 ± 3.4 respectively. Variability was most significantly improved for rectum V_50Gy, for which the standard deviation was reduced from 7.2 to 3.8% following script implementation. A survey of the treatment planners found that the majority believed the script helped to improve the quality and consistency of their plans (57%) and save time (86%).

At epidemic proportions worldwide, one in four persons now has cancer, and this statistic will change to one in two persons in near future. An important step in the fight against cancer is its early and accurate detection. This calls for affordable, quick and easy diagnostic methods. Standard pathological detection of cancer involves microscopic examination of morphological changes using stained biopsy samples, but this method is prone to human error and misdiagnosis. A tissue is a spatially heterogeneous medium with fractal properties owing to self-similarity in mass distribution. With the progress of cancer, this tissue heterogeneity changes owing to more mass accumulation and rearrangement of intracellular macromolecules like DNA, RNA, and lipids. Recently, commercially available tissue microarray (TMA) samples have gained significant attention in research studies, as the array of numerous tissue samples of different cases of a disease on a glass slide allows ease of conducting comprehensive studies. The present study uses optical transmission imaging to analyze the fractal dimension of colon TMA samples of 5 μm thickness and 1.5 mm diameter to correctly distinguish different stages of colon cancer. Results of this specialized analysis are also supported by entropy and spatial correlation length analysis. The application of this method of cancer diagnostics is discussed.

Preservation of acellular matrices represents a big challenge for the improvement of tissue engineering. In this work, a new method to preserve over time a decellularized esophageal scaffolds was explored. Dried and sterile acellular esophagi were obtained with a combined treatment of ethanol and a subsequent supercritical CO₂ drying. Preservation of the extracellular matrix architecture, collagen content, and mechanical properties up to 6 months demonstrated the efficiency of the methodology with implications in natural scaffold storage. In vitro support of mesenchymal stem cells showed a promising indication to the further use of the technology in pre-clinical and clinical application.

Nowadays, brain-computer interfaces (BCI) are designed to do the desired action only by analyzing brain signals. Taking the advantages of computers, these systems have higher reliability and speed than conventional mankind approaches. In a typical BCI system, the stimulation is applied and at the same time, the participants' brain signals are recorded. The system then performs the desired action by decoding the brain responses. One of the most important stimuli is a rapid serial visual presentation (RSVP). This study dealt with the problem of automatic classification of the target/non-target images with different presentation rates at RSVP events using electroencephalogram (EEG) data. In the present work, we propose a combined dual-tree complex wavelet transform (DTCWT) and Poincare plot indices to robustly characterize and classify EEG responses elicited during an RSVP experiment. Additionally, a robust classification scheme was developed by taking advantage of feature selection algorithms and a probabilistic neural network (PNN). The features were classified into six categories, including target/non-target events displayed at the rate of 5 Hz (C1/C2), target/non-target events displayed at the rate of 6 Hz (C3/C4), and target/non-target events displayed at the rate of 10 Hz (C5/C6) using one vs. all strategy. The framework was evaluated using EEG time-series from an RSVP task database available at Physionet. The data were collected from eight channels while target and non-target pictures were shown in different displaying rates, including 5, 6, and 10 Hz. The results showed the robust maximum average classification rates in the range of 81.5 to 83.33% for all feature selection strategies. In conclusion, the proposed framework paved the way for designing a reliable BCI system for target detection and classification.

Purpose: 2-[¹⁸F] fluoro-2-deoxy-d-glucose is a positron emitting isotope, which emits 511 keV γ-rays through annihilation process. These γ-rays can induce a variety of DNA damages in animal tissues. It is known that during PET-CT procedure most tissues irradiated with 4–9 mGy absorbed dose and 6–10 mSv whole body effective dose. The biological effects including DNA damages with different dose of fluorine 18 (¹⁸F) is still the part of observation and recent research. After knowing the ¹⁸F mediated DNA damage and its repair using time dependent radiation dose study in in-vitro cellular model may clear the understanding of radiation absorbed dose and their side effects including genotoxic effects at specific point of time. Methods: to check the early and late apoptosis in irradiated peripheral blood mononuclear cells (PBMCs), annexin V FITC tagged microscopic imaging was examined. To detect DNA double-strand breaks (DSBs), apoptosis and DNA repair, comet assay and γ-H2AX assay was used. BrdU incorporation assay was also performed to label the fragmented DNA. Results: significant amount of apoptotic cells were observed in PBMC after being irradiated for 120 min with absorbed dose of 8.22 mGy. The appearance of comets and number of foci are increasing in the cells irradiated with 8.22 mGy for 120 min and the amount of FITC tagged BrdU stain percentage confirms the presence of DSBs and apoptosis for longer exposure time (120 min). In DNA repair study, 24 h is the necessary time to repair the damaged cells. Conclusions: our time- and dose- dependent study shows that radiation induced DSBs generation and cell apoptosis at low dose radiation of ¹⁸F. ¹⁸F has the capacity to damage DNA and induce apoptosis only if the cells are exposed for the longer period of time. However, all the damages are repaired within 24 h.

L-shell x-ray fluorescence (LXRF) is a non-invasive approach to lead (Pb) concentration measurements in human bone. The method is based on the detection of the characteristic x-ray photons of Pb at 10.5 and 12.6 keV and experimental studies were designed to perform in vivo human bone Pb measurements. In later studies, however, the initial LXRF methodology was shown to have poor accuracy and precision. In a recent publication, we investigated an optimal grazing-incidence position (OGIP) approach using a sub-millimeter x-ray beam from an integrated x-ray tube and polycapillary x-ray lens table-top system. The OGIP method effectively reduced the x-ray scatter and produced a Pb detection limit of ∼5 μg/g for a 2 mm soft tissue phantom thickness. In this study, the OGIP methodology was improved by using 10 s x-ray spectra acquisitions at sequential positions 0.5 mm apart. The measured Sr K_α peak height versus position data was used to spectroscopically identify the bone phantom and the OGIP. The data was fitted with the analytical convolution between a Gaussian and an exponential decay. The position corresponding to the maximum of the fitted convolution function was then selected as the OGIP. Four phantom sets were used. A cylindrical plaster-of-Paris bone phantom doped with Pb in a concentration of 74 μg/g was used as a bare bone phantom or with one of the three overlying polyoxymethylene cylindrical shell soft tissue phantoms of 1, 2, and 3 mm thickness. The reproducibility of the OGIP method was assessed in five independent trials using each of the four phantom sets. The coefficient of variation (COV) percentage values of the Sr K_α peak height measurements were below 5%. The new procedure decreased by more than threefold the duration and radiation dose of the earlier approach.

We report the use of reflection-mode terahertz (THz) imaging in a transgenic mouse model of breast cancer. Unlike tumor xenografts that are grown from established cell lines, these tumors were spontaneously generated in the mammary fat pad of mice, and are a better representation of human breast cancer. THz imaging results from 7 tumors that recapitulate the compartmental complexity of breast cancer are presented here. Imaging was first performed on freshly excised tumors within an hour of excision and then repeated after fixation with formalin and paraffin. These THz images were then compared with histopathology to determine reflection-mode signals from specific regions within tumor. Our results demonstrate that the THz signal was consistently higher in cancerous tissue compared with fat, muscle, and fibrous tissue. Almost all tumors presented in this work demonstrated advanced stages where cancer infiltrated other tissues like fat and fibrous stroma. As the first known THz investigation in a transgenic model, these results hold promise for THz imaging at different stages of breast cancer.

Tissue invasion and metastasis are leading causes of death among cancer patients due to cells escaping from the primary tumor and invading distant sites. To better understand these phenomena and develop efficient therapeutic regimens against different types of malignancies, there is a need for exclusive cellular and molecular examination of migrating cells. In this study, aggressive brain cancer cells, G55, migrating through confined microchannels were directly extracted and used for subsequent proteomic analysis via Western Blot and/or immunostaining quantification. The method was based on an engineered Polydimethylsiloxane microchannel platform that facilitated the exclusive extraction of migrating cells and their contents while preventing non-migrating (or proliferating—denoted as 2D) cell contamination. The migrating cells in physical confinement of the microchannels were exclusively examined for their protein expression. They were found with increased expression of Vimentin, approximately 2.5-fold higher than 2D cells. On the other hand, the migrating cells showed significantly decreased β3-Tubulin and Met signal compared to 2D cells. The differences in biomarker expression between migrating cells and non-migrating cells revealed by this study provided an insight into key features of cancer invasion and metastasis. The successful outcome of this research suggests improved targets for ceasing different types of malignancies.

The Hyperion II^D PET insert is the first scanner using fully digital silicon photomultipliers for simultaneous PET/MR imaging of small animals up to rabbit size. In this work, we evaluate the PET performance based on the National Eletrical Manufacturers Association (NEMA) NU 4-2008 standard, whose standardized measurement protocols allow comparison of different small-animal PET scanners. The Hyperion II^D small-animal PET/MR insert comprises three rings of 20 detector stacks with pixelated scintillator arrays with a crystal pitch of 1 mm, read out with digital silicon photomultipliers. The scanner has a large ring diameter of 209.6 mm and an axial field of view of 96.7 mm. We evaluated the spatial resolution, energy resolution, time resolution and sensitivity by scanning a ²²Na point source. The count rates and scatter fractions were measured for a wide range of ¹⁸F activity inside a mouse-sized scatter phantom. We evaluated the image quality using the mouse-sized image quality phantom specified in the NEMA NU4 standard, filled with ¹⁸F. Additionally, we verified the in-vivo imaging capabilities by performing a simultaneous PET/MRI scan of a mouse injected with ¹⁸F-FDG. We processed all measurement data with an energy window of 250 keV to 625 keV and a coincidence time window of 2 ns. The filtered-backprojection reconstruction of the point source has a full width at half maximum (FWHM) of 1.7 mm near the isocenter and degrades to 2.5 mm at a radial distance of 50 mm. The scanner's average energy resolution is 12.7% (ΔE/E FWHM) and the coincidence resolution time is 609 ps. The peak absolute sensitivity is 4.0% and the true and noise-equivalent count rates reach their peak at an activity of 46 MBq with 483 kcps and 407 kcps, respectively, with a scatter fraction of 13%. The iterative reconstruction of the image quality phantom has a uniformity of 3.7%, and recovery coefficients from 0.29, 0.91 and 0.94 for rod diameters of 1 mm, 3 mm and 5 mm, respectively. After application of scatter and attenuation corrections, the air- and water-filled cold regions have spill-over ratios of 6.3% and 5.4%, respectively. The Hyperion II^D PET/MR insert provides state-of-the-art PET performance while enabling simultaneous PET/MRI acquisition of small animals up to rabbit size.

A high-performance method is suspension microbead arrays which facilitate HER2 recognition for rapid prognosis in its preliminary stages before cancer reaches to its metastases level or first prevalence of tumor growth. To achieve this goal, we synthesized gelatin microbeads by oil in water (o/w) emulsion method and the size and stability of micro-particles were optimized with different concentrations of glutaraldehyde. The non-toxicity of microbeads was proved by MTT assay. Then the Herceptin was immobilized on the microbeads surface by carbodiimide coupling method. FITC was used as a fluorescent marker for recognizing HER2 receptors on SKBr3 cancer cells (clinical sample) and the recognition was tracked by flow cytometry. Results showed significant discrimination between SKBr3 cancer cells sample concerning HER2 negative cancer cells as a control sample.

Currently, the most commonly used estimate of metabolic activity during clinical positron emission tomography (PET) is standardized uptake value (SUV) obtained from ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) captured in cancer cells. Although SUV is evaluated after corrections for the injected dose, weight, and other such parameters, the entire injected dose is inappropriate for this calculation because some FDG is excreted in urine. Therefore, the injected dose warrants correction by assessment of urinary radioactivity in patients before PET to enhance the accuracy of FDG calculation. However, this is not typically performed in clinical practice owing to secondary effects of radioactive contamination in hospitals and radiation exposure risk to the attending staff. Therefore, we aimed to develop a remote method for the measurement of urinary radioactivity in FDG-PET patients. Urinary radioactivity was estimated in a toilet bowl using gamma-ray distribution obtained with a Compton camera. The gamma-ray events from the toilet bowl per unit time (5 s) facilitated radioactivity calculation. Between 0 and 40 MBq, deviation of our detector from the linearity for radioactivity was <8.3%. The accuracy of radioactive assessment was ±11% for a 5-s measurement of 19.7 MBq ¹⁸F-FDG. Overall, we obtained 75 samples (45 males and 30 females). Our results revealed that excretion of FDG in the urine per person varied between 1.9% and 15.6% of the injected dose (range, 225–305 MBq). Urinary radioactivity can be evaluated before PET using a Compton camera. SUV determination in clinical context could be enhanced by considering urinary radioactivity for corrections caused by individual differences in radioactivity.

Background and objective: Mapping different point sets onto each other is a frequent problem in many fields of science. In radiation therapy, for example, electromagnetic tracking allows to measure the spatial location of radiation sources inside the treatment volume without external registration. The various source loci form point sets, with concomitant subsets, which refer to different coordinate systems when data is collected during different treatment sessions. We present a toolbox, called MDSLAB, which allows to unify a given point set and its reference point set. Methods: The toolbox relies on multi-dimensional scaling and the estimation of principal coordinates only from observed distances between pairs of points in each set. Deviations between the principal coordinates, i.e. the data projections, are quantified and their histograms analyzed employing a Hartigan dip test. Observed uni- or bimodal, asymmetric distributions of distance deviations are approximated by α-stable distributions. Results: We illustrate the working of the toolbox with an application to data collected during high dose rate brachytherapy. Sensor dwell positions inside catheters, implanted into a female breast, are collected, their distance matrices estimated and their underlying principal coordinates computed by diagonalizing the related kernel matrix. Considering the projections of the data onto their principal axes, distance deviations are quantified, their underlying distributions determined and approximated by heavy-tailed distributions. Tools, either images or whole animations, are developed to visualize the spatial dwell positions of the sensors, which map out the catheter shapes before any radiation treatment is started. Distance deviation histograms are also visualized and fit to α-stable distributions. Conclusion: MDSLAB provides a convenient tool to register point sets which are collected in different coordinate systems but whose relative distances should be identical, ideally. In practice, however, they mostly differ and MDSLAB allows to quantify such deviations and analyze their statistics as well as conveniently visualize them in images or movies.

The transmission line matrix (TLM) method is developed to efficiently solve the bioheat transfer with phase change in freeze-thaw cryoablation. This new design of three dimensional TLM model with an automatic time stepping is based on hyperbolic heat transfer model. It is able to consider many factors such as temperature-dependant thermophysical properties during phase change, blood perfusion and latent heat release/absorption. Thermal analysis of heat transfer in the cryotreated tissue is detailed; with special emphases on lethal temperature isotherms with respect to the cooling rates and duration of freeze-thaw cycle. The basic numerical model is validated through available experimental data on skeletal muscle of rabbit hind-limbs.

Thermal therapy is an efficient, cost-effective method for treating different types of cancers and hence flexible, light weight, biocompatible heating materials with low power consumption are of utmost importance. Partially reduced flexible, robust and bio-compatible thick graphene oxide films with, mostly edge functionalized Polymethyl methacrylate (PMMA) and in situ grown silver nanoparticles were prepared using simple soak and dry strategy. Larger distribution of silver nanoparticles with a mean diameter of 2.5 nm were anchored towards the edges of these thick films. The electrothermal (Joule heating) performance were found to increase in the presence of silver nanoparticles due to decrease in sheet resistance (0.33 × 10⁴ Ωm) and increase in electron-phonon interaction. These free-standing, flexible films exhibited stable Joule heating behavior under repeated voltage on/off cycles. In-vitro studies performed on breast cancer cells in the presence of the prepared films, with an external applied voltage of 10 V_DC, shows 67% cell death. This work proves the potentiality of thick heterogeneous (partially) reduced graphene oxide films towards site specific destruction of solid tumors by utilizing its Joule heating properties.

The Accuray CyberKnife® system provides radiotherapy for the treatment of moving lung tumors, thanks to the use of the Xsight® Lung Tracking technology for monitoring the motion of the target. However, there are situations in which this technology is not able to properly track the target. Thus, the aim of the proposed work is to study the accuracy of the dose delivery process while using the Xsight® Spine Tracking technology, which helps to overcome the aforementioned issue. The CIRS Dynamic Thorax Phantom was used to simulate the motion of a spherical target (diameter 2 cm), which moves along the craniocaudal direction (motion 3 cm). Monte Carlo algorithm calculated PTV and ITV treatment plans for isocentric and non-isocentric irradiation methods. Ionization Chamber and Film Dosimetry measurements were performed to study the accuracy of the dose delivery process to the center, and to the periphery of the tumor. Results obtained through the implementation of the PTV treatment plans were used as a baseline to analyze the accuracy of dose delivery for ITV plans. Although results indicated a decrease for the dose delivered compared to the planned one, the dose delivered was not lower than the prescribed one in any of the studied cases.

The purpose was to compare unilateral exercise-induced changes in arterial occlusion pressure between the exercising and non-exercising arm. Participants had arterial occlusion pressure measured before and after exercise in: both arms simultaneously (Double AOP), the exercise limb only (Exercise AOP), and the non-exercise limb only (Non-exercise AOP). The blood flow restriction exercise protocol included four sets of biceps curls to failure in the dominant arm using 30% of one-repetition maximum and applying 40% of pre-exercise arterial occlusion pressure using a 5 cm nylon cuff. The change in arterial occlusion pressure from pre to post-exercise did not differ between the exercise limb [mean change (95%CI) = 27 (20, 33) mmHg] and non-exercise limb [mean change (95%CI) = 24 (18, 31) mmHg] during Double AOP (p=.325). When comparing the changes observed for each arm during Double AOP to their respective control conditions, there were no differences for the exercising arm [p = .554, mean change (95%CI) of Exercise AOP = 28 (20, 33) mmHg] or the non-exercise arm [p = .147, mean change (95%CI) of Non-exercise AOP = 18 (13, 23) mmHg]. The cardiovascular response to blood flow restriction, as measured by arterial occlusion pressure changes does not seem to be limb specific during unilateral exercise.

For small, early-stage or otherwise non-palpable breast tumors, surgeons rely on localization technologies to accurately find and remove the tumor tissue during breast conserving surgery. However, current widely accepted localization technologies either use painful and logistically challenging guidewires, or complex radioactive iodine sources. We have developed an implantable magnetic marker, intended to mark the location of a breast tumor, that can be detected during surgery using a clinical handheld magnetic susceptometry system. Here, we report on the development and optimization of this magnetic marker, focusing on the material, shape and various material assemblies. It was found that the effects of magnetic shape anisotropy may decrease localization precision. This can be circumvented by combining multiple isotropic magnetic elements separated from one another. A final optimized prototype was constructed and compared to a commercially available magnetic marker. Finally, the technology was tested in an ex vivo surgical setting on tissue to assess radiological visibility and surgical feasibility. The marker was successfully detected and removed in all ex vivo sessions, and the technology was found feasible.

Objective; To establish the performance of several drive and measurement patterns in EIT imaging of neural activity in peripheral nerve, which involves large impedance changes in the nerve's anisotropic length axis. Approach; Twelve drive and measurement electrode patterns are compared using a finite element (FE) four-cylindrical shell model of a peripheral nerve and a 32 channel dual-ring nerve cuff. The central layer of the FE model contains impedance changes representative of neural activity of −0.30 in length axis and −8.8 × 10⁻⁴ in the radial axis. Six of the electrode patterns generate longitudinal drive current, which runs parallel to the anisotropic axis, while the remaining six patterns generate transverse drive current, which runs perpendicular to the anisotropic axis. Main results; Of the twelve patterns evaluated, transverse current patterns produce higher resolution than longitudinal current patterns but are also more susceptible to noise and errors, and exhibit poorer sensitivity to impedance changes in central sample locations. Three of the six longitudinal current patterns considered can reconstruct fascicle level impedance changes with up to 0.2 mV noise and error, which corresponds to between −5.5 and +0.18 dB of the normalised signal standard deviation. Reducing the spacing between the two electrode rings in all longitudinal current patterns reduced the signal to error ratio across all depth locations of the sample. Significance; Electrode patterns which target the large impedance change in the anisotropic length axis can provide improved robustness against noise and errors, which is a critical step towards real time EIT imaging of neural activity in peripheral nerve.

Objective: Commercial devices for pneumatic compressive treatment of the limbs generally provide predefined stereotyped compressive profiles. The possibility to deliver compressive stimuli with a customizable pressure profile would be useful to differently probe the vascular reactivity to muscle compression (MC) and improve the understanding of MC-induced hyperemia. Aim of this study was the realization of a novel pneumatic system capable of generating adjustable and stable compressive conditions, preceding and following a 'standard' MC stimulus. Approach: A custom-made pneumatic system specifically built to this purpose is tested and characterized in 10 subjects. Three different compressive patterns were delivered to the leg: (1) a constant level: 50 mmHg for 50 s; (2) MC: 200 mmHg for 1 s; (3) a complex profile: 20 mmHg for 50 s, 200 mmHg for 1 s, 50 mmHg for 50 s. Main results: The implemented system allowed to deliver graded compressions to the limb characterized by fast transitions (0 to 200 mmHg in 0.5 ± 0.07 s) and stable plateau levels (50.4 ± 0.5 mmHg). Significance: A new, low-cost, pneumatic prototype has been presented and tested in the present study allowing to deliver compressive stimuli with pre-and post-compressions of adjustable level. This device has been conceived for research purposes and may find application in therapeutic compressive treatments.

Introduction: MRI is an emerging method in obesity research for the quantification of fat content in various body regions. The aim of this study was to determine the accuracy of MR fat-water imaging and MR spectroscopy for fat quantification at 1.5 T in oil-in-water phantoms. Material and Methods: Oil-in-water emulsions were fabricated over the entire range of lipid content (0%–100%). Relative lipid content was then assessed by two-point Dixon MRI, multi-echo Dixon MRI and single-voxel proton MR spectroscopy (SV-MRS) with localization by both stimulated echo acquisition (STEAM) and point-resolved spectroscopy (PRESS). Linear regression and Bland-Altman analyses were used for statistical evaluation of the results. Results: Agreement between MR-derived measures of lipid content and nominal values in phantoms was generally good. Agreement for two-point Dixon was moderate only (R² = 0.75) here, especially for lipid contents between 30% and 70%. For multi-echo Dixon, STEAM and PRESS MRS, the coefficients of determination were very high (rounded R² = 0.98 for all). Discussion: In conclusion, this work complements previous studies of MR-based fat quantification at 1.5 T and shows that multi-echo Dixon MRI and MR spectroscopy provide close results over the full range of lipid contents.

Contrast agents have been employed in radiography for more than 80 years and computed tomography (CT) for more than 50 years. These high atomic number agents increase photoelectric interaction thereby reducing photon intensity projected through the contrast agent containing structure to improve image contrast. A wide variety of contrast agents have been examined over the years, however, iodine and barium containing agents make up the majority of applications. Other agents may become available which may find utility due to reduced toxicity, better imaging characteristics or dose reduction. The purpose of this work is to develop a frame work to evaluate current and future CT contrast agents as they apply to CT enhancement of the head including CTA. The model used we have called the CT Contrast Agent Evaluation Model (CAEM) and allows the determination of the minimum effective concentration (MEC). The MEC is that concentration that provides a contrast-to-noise ratio (CNR) of one for a radiation dose of one centigray (cGy). The MEC can be examined as kilovoltage and filtration are varied allowing for optimized combinations. The approach taken in the model was to first compute x-ray tube spectra for the desired kilovoltage/filter combination. Next, projection data was computed through a cylindrical phantom with a central contrast containing target. Noise was applied to projection data based on photon counting. The application of filtered back projection to the noisy projection data could be used to compute a simulated image from which image CNR could be determined. This process was simplified by computing the CNR of the projection data and correcting for propagation of error using an empirically derived correction factor. The radiation exposure in air at the target can be accurately estimated from the computed x-ray spectra and used to determine dose. The computed CNR and dose were validated by direct measure using a clinical scanner.