Computational Modeling of the Synergistic Role of GCN2 and HPA Axis in Regulating the Integrated Stress Response in the Central Circadian Timing System.

The circadian timing system and integrated stress response (ISR) systems are fundamental regulatory mechanisms that maintain body homeostasis. The central circadian pacemaker in the suprachiasmatic nucleus (SCN) governs daily rhythms through interactions with peripheral oscillators via the hypothalamus-pituitary-adrenal (HPA) axis. On the other hand, ISR signaling is pivotal for preserving cellular homeostasis in response to physiological changes. Notably, disrupted circadian rhythms are observed in cases of impaired ISR signaling. In this work, we examine the potential interplay between the central circadian system and the ISR, mainly through the SCN and HPA axis. We introduce a semi-mechanistic mathematical model to delineate the suprachiasmatic nucleus (SCN)'s capacity for indirectly perceiving physiological stress through glucocorticoid-mediated feedback from the HPA axis and orchestrating a cellular response via the ISR mechanism. Key components of our investigation include evaluating general control nonderepressible 2 (GCN2) expression in the SCN, the effect of physiological stress stimuli on the HPA axis, and the interconnected feedback between the HPA and SCN. Simulation reveals a critical role for GCN2 in linking ISR with circadian rhythms. Experimental findings have demonstrated that a Gcn2 deletion in mice leads to rapid re-entrainment of the circadian clock following jetlag, as well as to an elongation of the circadian period. These.

A comprehensive quality assurance protocol for electromagnetic tracking in brachytherapy.

BACKGROUND: Electromagnetic tracking (EMT) systems have proven to be a valuable source of information regarding the location and geometry of applicators in patients undergoing brachytherapy (BT). As an important element of an enhanced and individualized pre-treatment verification, EMT can play a pivotal role in detecting treatment errors and uncertainties to increase patient safety. PURPOSE: The purpose of this study is two-fold: to design, develop and test a dedicated measurement protocol for the use of EMT-enabled afterloaders in BT and to collect and compare the data acquired from three different radiation oncology centers in different clinical environments. METHODS: A novel quality assurance (QA) phantom composed of a scaffold with supports to fix the field generator, different BT applicators, and reference sensors (sensor verification tools) was used to assess the precision (jitter error) and accuracy (relative distance errors and target registration error) of the EMT sensor integrated into an afterloader prototype. Measurements were repeated in different environments where EMT measurements are likely to be performed, namely an electromagnetically clean laboratory, a BT suite, an operating room, and, if available, a CT suite and an MRI suite dedicated to BT. RESULTS: The mean positional jitter was consistently under 0.1 mm across all measurement points, with a slight trend of increased jitter at greater distances from the field generator. The mean variability of sensor positioning in the tested tandem and ring gynecological applicator was also below 0.1 mm. The tracking accuracy close to the center of the measurement volume was higher than at its edges. The relative distance error at the center was 0.2-0.3 mm with maximum values reaching 1.2-1.8 mm, but up to 5.5 mm for measurement points close to the edges. In general, similar accuracy results were obtained in the clinical environments and in all investigated institutions (median distance error 0.1-0.4 mm, maximum error 1.0-2.0 mm), however, errors were found to be larger in the CT suite (median distance error up to 1.0 mm, maximum error up to 3.6 mm). CONCLUSION: The presented quality assessment protocol for EMT systems in BT has demonstrated that EMT offers a high-accuracy determination of the applicator/implant geometry even in clinical environments. In addition to that, it has provided valuable insights into the performance of EMT-enabled afterloaders across different radiation oncology centers.

The Physiological and Pharmacological Significance of the Circadian Timing of the HPA Axis: A Mathematical Modeling Approach.

As a potent endogenous regulator of homeostasis, the circadian time-keeping system synchronizes internal physiology to periodic changes in the external environment to enhance survival. Adapting endogenous rhythms to the external time is accomplished hierarchically with the central pacemaker located in the suprachiasmatic nucleus (SCN) signaling the hypothalamus-pituitary-adrenal (HPA) axis to release hormones, notably cortisol, which help maintain the body's circadian rhythm. Given the essential role of HPA-releasing hormones in regulating physiological functions, including immune response, cell cycle, and energy metabolism, their daily variation is critical for the proper function of the circadian timing system. In this review, we focus on cortisol and key fundamental properties of the HPA axis and highlight their importance in controlling circadian dynamics. We demonstrate how systems-driven, mathematical modeling of the HPA axis complements experimental findings, enhances our understanding of complex physiological systems, helps predict potential mechanisms of action, and elucidates the consequences of circadian disruption. Finally, we outline the implications of circadian regulation in the context of personalized chronotherapy. Focusing on the chrono-pharmacology of synthetic glucocorticoids, we review the challenges and opportunities associated with moving toward personalized therapies that capitalize on circadian rhythms.

Clinical Aspects in Subacute Thyroiditis: A Real-Life Study on 226 Cases in Greece Amid the COVID-19 Pandemic.

PURPOSE: This study aimed to evaluate various therapeutic approaches, identify potential predictive factors for the recurrence and development of hypothyroidism, and examine specific clinical and laboratory characteristics of patients with subacute thyroiditis (SAT) due to SARS-CoV-2 infection. METHODS: We retrospectively analyzed the medical records of 226 patients with confirmed SAT diagnosed from January 2020 to November 2022. RESULTS: The mean age was 48.01 ± 0.75 years, and the F/M ratio was 2.3/1. At the end of the follow-up period, 69 patients (32.1%) had developed hypothyroidism. Treatment duration was significantly shorter with nonsteroidal anti-inflammatory drugs (NSAIDs) (17.40 ± 2.56 days), while time-to-symptom relief was shorter with glucocorticoids (CGs). Recurrence was observed only in those treated with corticosteroid preparations (14.1%). C-reactive protein levels at treatment discontinuation were higher in patients who experienced SAT recurrence, while the coexistence of Hashimoto's thyroiditis was a significant predictive factor for the development of hypothyroidism. The TSH value at the time of treatment withdrawal >4.12 µIU/mL showed optimal sensitivity and specificity for the prediction of permanent hypothyroidism. Regarding COVID-19, 34 patients (15%) experienced related SAT, with similar clinical manifestations of the disease but a higher BMI and shorter time-to-symptom relief. CONCLUSION: In conclusion, GCs administration alleviated acute symptoms earlier during the onset of SAT, whereas NSAIDs had a shorter treatment duration, and both regimens could not prevent the development of delayed hypothyroidism. The clinical characteristics of SAT due to COVID-19 infections were similar to those of typical SAT disease.

The SCN-HPA-Periphery Circadian Timing System: Mathematical Modeling of Clock Synchronization and the Effects of Photoperiod on Jetlag Adaptation.

Synchronizing the circadian timing system (CTS) to external light/dark cycles is crucial for homeostasis maintenance and environmental adaptation. The CTS is organized hierarchically, with the central pacemaker located in the suprachiasmatic nuclei (SCN) generating coherent oscillations that are entrained to light/dark cycles. These oscillations regulate the release of glucocorticoids by the hypothalamus-pituitary-adrenal (HPA) axis, which acts as a systemic entrainer of peripheral clocks throughout the body. The SCN adjusts its network plasticity in response to variations in photoperiod, leading to changes in the rhythmic release of glucocorticoids and ultimately impacting peripheral clocks. However, the effects of photoperiod-induced variations of glucocorticoids on the synchronization of peripheral clocks are not fully understood, and the interaction between jetlag adaption and photoperiod changes is unclear. This study presents a semi-mechanistic mathematical model to investigate how the CTS responds to changes in photoperiod. Specifically, the study focuses on the entrainment properties of a system composed of the SCN, HPA axis, and peripheral clocks. The results show that high-amplitude glucocorticoid rhythms lead to a more coherent phase distribution in the periphery. In addition, our study investigates the effect of photoperiod exposure on jetlag recovery time and phase shift, proposing different interventional strategies for eastward and westward jetlag. The findings suggest that decreasing photic exposure before jetlag during eastward traveling and after jetlag during westward traveling can accelerate jetlag readaptation. The study provides insights into the mechanisms of CTS organization and potential recovery strategies for transitions between time zones and lighting zones.

The clinical significance of low dose biotin supplements (<300µg/day) in the treatment of patients with hypothyroidism: crucial or overestimated?

BACKGROUND: In the last decade, the combination of the widespread use of streptavidin-biotin technology and biotin-containing supplements (BCS) in the daily clinical practice, have led to numerous reports of erroneous hormone immunoassay results. However, there are no studies assessing the clinical and biochemical significance of that phenomenon, when treating patients with hypothyroidism. Therefore, a prospective study was designed to investigate the potential alterations in the measurement of thyroid hormone concentrations and clinical consequences in patients with hypothyroidism using low -dose BCS containing less than 300 µg/day. METHODS: Fifty-seven patients on thyroxine supplementation, as a result of hypothyroidism and concurrent use of BCS at a dose <300µg/day for 10 to 60 days were prospectively evaluated. Namely, TSH and free T4 (FT4) concentration measurements were performed, during BC supplementation and 10 days post BCS discontinuation and compared to 31 age-matched patients with supplemented hypothyroidism and without BCS. RESULTS: A statistically significant increase in TSH and decline in FT4 concentrations was observed after BCS discontinuation. However, on clinical grounds, these modifications were minor and led to medication dose adjustment in only 2/57 patients (3.51%) in whom TSH was notably decreased after supplement discontinuation. CONCLUSION: Our study suggests that changes in thyroid hormones profiling, due to supplements containing low dose biotin, are of minimal clinical relevance and in most cases don't occult the need to adjust the thyroxine replacement dose in patients with hypothyroidism. Larger, well-designed trials are required to further evaluate this phenomenon.

Low Dose Monacolin K Combined with Coenzyme Q10, Grape Seed, and Olive Leaf Extracts Lowers LDL Cholesterol in Patients with Mild Dyslipidemia: A Multicenter, Randomized Controlled Trial.

Certain nutraceuticals, mainly containing red yeast rice, might be considered as an alternative therapy to statins in patients with dyslipidemia, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. The aim of this study was to assess the lipid-lowering activity and safety of a dietary supplement containing a low dose of monacolin K combined with coenzyme Q10, grape seed and olive tree leaf extracts in patients with mild hypercholesterolemia. In total, 105 subjects with mild hypercholesterolemia (low-density lipoprotein cholesterol LDL-C levels 140-180 mg/dL) and low CV risk were randomly assigned into three treatment groups: lifestyle modification (LM), LM plus a low dosage of monacolin K (3 mg), and LM plus a high dosage of monacolin K (10 mg) and treated for 8 weeks. The primary endpoint was the reduction of LDL-C and total cholesterol (TC). LDL-C decreased by 26.46% on average (p < 0.001) during treatment with 10 mg of monacolin and by 16.77% on average during treatment with 3 mg of monacolin (p < 0.001). We observed a slight but significant reduction of the triglyceride levels only in the high-dose-treated group (mean -4.25%; 95% CI of mean -11.11 to 2.61). No severe adverse events occurred during the study. Our results confirm the LDL-C-lowering properties of monacolin are clinically meaningful even in lower doses of 3 mg/day.

Design and Validation of Experimental Setup for Cell Spheroid Radiofrequency-Induced Heating.

While hyperthermia has been shown to induce a variety of cytotoxic and sensitizing effects on cancer tissues, the thermal dose-effect relationship is still not well quantified, and it is still unclear how it can be optimally combined with other treatment modalities. Additionally, it is speculated that different methods of applying hyperthermia, such as water bath heating or electromagnetic energy, may have an effect on the resulting biological mechanisms involved in cell death or in sensitizing tumor cells to other oncological treatments. In order to further quantify and characterize hyperthermia treatments on a cellular level, in vitro experiments shifted towards the use of 3D cell spheroids. These are in fact considered a more representative model of the cell environment when compared to 2D cell cultures. In order to perform radiofrequency (RF)-induced heating in vitro, we have recently developed a dedicated electromagnetic field applicator. In this study, using this applicator, we designed and validated an experimental setup which can heat 3D cell spheroids in a conical polypropylene vial, thus providing a reliable instrument for investigating hyperthermia effects at the cellular scale.

Light-induced synchronization of the SCN coupled oscillators and implications for entraining the HPA axis.

The suprachiasmatic nucleus (SCN) synchronizes the physiological rhythms to the external light-dark cycle and tunes the dynamics of circadian rhythms to photoperiod fluctuations. Changes in the neuronal network topologies are suggested to cause adaptation of the SCN in different photoperiods, resulting in the broader phase distribution of neuron activities in long photoperiods (LP) compared to short photoperiods (SP). Regulated by the SCN output, the level of glucocorticoids is elevated in short photoperiod, which is associated with peak disease incidence. The underlying coupling mechanisms of the SCN and the interplay between the SCN and the HPA axis have yet to be fully elucidated. In this work, we propose a mathematical model including a multiple-cellular SCN compartment and the HPA axis to investigate the properties of the circadian timing system under photoperiod changes. Our model predicts that the probability-dependent network is more energy-efficient than the distance-dependent network. Coupling the SCN network by intra-subpopulation and inter-subpopulation forces, we identified the negative correlation between robustness and plasticity of the oscillatory network. The HPA rhythms were predicted to be strongly entrained to the SCN rhythms with a pro-inflammatory high-amplitude glucocorticoid profile under SP. The fast temporal topology switch of the SCN network was predicted to enhance synchronization when the synchronization is not complete. These synchronization and circadian dynamics alterations might govern the seasonal variation of disease incidence and its symptom severity.

Patient-derived breast model repository, a tool for hyperthermia treatment planning and applicator design.

OBJECTIVE: The addition of hyperthermia in the treatment of intact breast cancer with the aim to improve local response is currently in a research phase. First, optimal hyperthermia devices need to be developed, for which a diverse, anatomically and pathologically accurate set of patient models is necessary. METHODS: To investigate the effects of inter-subject variations on hyperthermia treatment plans, we generated a repository of 22 anatomically and pathologically diverse patient models based on MR images of breast cancer patients. Hyperthermia treatment plans were generated for the 22 models using a generic theoretical phased array hyperthermia applicator. RESULTS: Good temperature coverage was achieved in the vast majority of the models, with median values for T10 = 43.5°C (41.9-43.8°C), T50 = 42.5°C (41.3-43.3°C), and T90 = 41.3°C (39.8-42.6°C) under the condition that the maximum temperature increase in the patient is limited to 44°C. CONCLUSIONS: For future development of hyperthermia devices and treatment methods, a repository with a sufficiently large number of representative patient models, such as the one provided in this study, should be used to ensure applicability to a wide variety of patients. This repository is therefore made publicly available.

Towards a comprehensive assessment of QSP models: what would it take?

Quantitative Systems Pharmacology (QSP) has emerged as a powerful ensemble of approaches aiming at developing integrated mathematical and computational models elucidating the complex interactions between pharmacology, physiology, and disease. As the field grows and matures its applications expand beyond the boundaries of research and development and slowly enter the decision making and regulatory arenas. However, widespread acceptance and eventual adoption of a new modeling approach requires assessment criteria and quantifiable metrics that establish credibility and increase confidence in model predictions. QSP aims to provide an integrated understanding of pathology in the context of therapeutic interventions. Because of its ambitious nature and the fact that QSP emerged in an uncoordinated manner as a result of activities distributed across organizations and academic institutions, high entropy characterizes the tools, methods, and computational methodologies and approaches used. The eventual acceptance of QSP model predictions as supporting material for an application to a regulatory agency will require that two key aspects are considered: (1) increase confidence in the QSP framework, which drives standardization and assessment; and (2) careful articulation of the expectations. Both rely heavily on our ability to rigorously and consistently assess QSP models. In this manuscript, we wish to discuss the meaning and purpose of such an assessment in the context of QSP model development and elaborate on the differentiating features of QSP that render such an endeavor challenging. We argue that QSP establishes a conceptual, integrative framework rather than a specific and well-defined computational methodology. QSP elicits the use of a wide variety of modeling and computational methodologies optimized with respect to specific applications and available data modalities, which exceed the data structures employed by chemometrics and PK/PD models. While the range of options fosters creativity and promises to substantially advance our ability to design pharmaceutical interventions rationally and optimally, our expectations of QSP models need to be clearly articulated and agreed on, with assessment emphasizing the scope of QSP studies rather than the methods used. Nevertheless, QSP should not be considered an independent approach, rather one of many in the broader continuum of computational models.

In silico evaluation of adverse eddy current effects in preclinical tests of magnetic hyperthermia.

BACKGROUND AND OBJECTIVE: Magnetic hyperthermia is an oncological therapy that employs magnetic nanoparticles activated by alternating current (AC) magnetic fields with frequencies between 50 kHz and 1 MHz, to release heat in a diseased tissue and produce a local temperature increase of about 5 °C. To assess the treatment efficacy, in vivo tests on murine models (mice and rats) are typically performed. However, these are often carried out without satisfying the biophysical constraints on the electromagnetic (EM) field exposure, with consequent generation of hot spots and undesirable heating of healthy tissues. Here, we investigate possible adverse eddy current effects, to estimate AC magnetic field parameters (frequency and amplitude) that can potentially guarantee safe animal tests of magnetic hyperthermia. METHODS: The analysis is performed through in silico modelling by means of finite element simulation tools, specifically developed to study eddy current effects in computational animal models, during magnetic hyperthermia treatments. The numerical tools enable us to locally evaluate the specific absorption rate (SAR) and the produced temperature increase, under different field exposure conditions. RESULTS: The simulation outcomes demonstrate that in mice with weight lower than 30 g the thermal effects induced by AC magnetic fields are very weak, also when slightly overcoming the Hergt-Dutz limit, that is the product of the magnetic field amplitude and frequency should be lower than 5·109 A/(m·s). Conversely, we observe significant temperature increases in 500 g rats, amplified when the field is applied transversally to the body longitudinal axis. A strong mitigation of side-effects can be achieved by introducing water boluses or by applying focused fields. CONCLUSIONS: The developed physics-based modelling approach has proved to be a useful predictive tool for the optimization of preclinical tests of magnetic hyperthermia, allowing the identification of proper EM field conditions and the design of setups that guarantee safe levels of field exposure during animal treatments. In such contest, the obtained results can be considered as valid indicators to assess reference levels for animal testing of biomedical techniques that involve EM fields, like magnetic hyperthermia, thus complying with the Directive 2010/63/EU on the protection of animals used for scientific purposes.

Design and Characterization of an RF Applicator for In Vitro Tests of Electromagnetic Hyperthermia.

The evaluation of the biological effects of therapeutic hyperthermia in oncology and the precise quantification of thermal dose, when heating is coupled with radiotherapy or chemotherapy, are active fields of research. The reliable measurement of hyperthermia effects on cells and tissues requires a strong control of the delivered power and of the induced temperature rise. To this aim, we have developed a radiofrequency (RF) electromagnetic applicator operating at 434 MHz, specifically engineered for in vitro tests on 3D cell cultures. The applicator has been designed with the aid of an extensive modelling analysis, which combines electromagnetic and thermal simulations. The heating performance of the built prototype has been validated by means of temperature measurements carried out on tissue-mimicking phantoms and aimed at monitoring both spatial and temporal temperature variations. The experimental results demonstrate the capability of the RF applicator to produce a well-focused heating, with the possibility of modulating the duration of the heating transient and controlling the temperature rise in a specific target region, by simply tuning the effectively supplied power.

Does seasonality of the microbiota contribute to the seasonality of acute gout flare?

Gout, the most common inflammatory arthritis worldwide, is an auto-inflammatory metabolic disease that leads to monosodium urate crystal deposition. Hyperuricaemia is a significant risk factor for the development of gout; however, hyperuricaemia alone is not sufficient to induce gout.Gout flares have circadian rhythms. Gout flares vary during the day and have strong seasonality, with flares being more common in the spring. The reasons for the predominance of flares in the spring are unclear since serum urate (SU) levels show seasonal variation; however, SU levels are highest in the summer.Immune function varies significantly throughout the year, with enhanced immune responses increasing during the winter. In addition, chronic disruption of circadian rhythms is associated with metabolic syndrome and diseases driven by metabolism. The most telling example relates to Xanthine oxidase (XOD/XDH). The analysis of XOD/XDH established its circadian regulation and demonstrated that inhibition of the activity of XOD is characterised by distinct, crossregulating diurnal/seasonal patterns of activity.The gastrointestinal microbiota of gout patients is highly distinct from healthy individuals. In a small series of gout patients, Bacteroides caccae and Bacteroides xylanisolvens were found to be enriched. Bacteroidales levels were highest during the spring and summer, and loading values were highest in the spring.Our review discusses gout's circadian rhythm and seasonality, possible influences of the microbiome on gout due to our new knowledge that Bacteroidales levels were highest during spring when gout is most common, and potential opportunities for treatment based on our current understanding of this interaction.

A Novel Framework for the Optimization of Simultaneous ThermoBrachyTherapy.

In high-dose-rate brachytherapy (HDR-BT) for prostate cancer treatment, interstitial hyperthermia (IHT) is applied to sensitize the tumor to the radiation (RT) dose, aiming at a more efficient treatment. Simultaneous application of HDR-BT and IHT is anticipated to provide maximum radiosensitization of the tumor. With this rationale, the ThermoBrachyTherapy applicators have been designed and developed, enabling simultaneous irradiation and heating. In this research, we present a method to optimize the three-dimensional temperature distribution for simultaneous HDR-BT and IHT based on the resulting equivalent physical dose (EQDphys) of the combined treatment. First, the temperature resulting from each electrode is precomputed. Then, for a given set of electrode settings and a precomputed radiation dose, the EQDphys is calculated based on the temperature-dependent linear-quadratic model. Finally, the optimum set of electrode settings is found through an optimization algorithm. The method is applied on implant geometries and anatomical data of 10 previously irradiated patients, using reported thermoradiobiological parameters and physical doses. We found that an equal equivalent dose coverage of the target can be achieved with a physical RT dose reduction of 20% together with a significantly lower EQDphys to the organs at risk (p-value < 0.001), even in the least favorable scenarios. As a result, simultaneous ThermoBrachyTherapy could lead to a relevant therapeutic benefit for patients with prostate cancer.

Can dysglycemia in OGTT be predicted by baseline parameters in patients with PCOS?

Background: Polycystic ovary syndrome (PCOS) is considered a risk factor for the development of type 2 diabetes mellitus (T2DM). However, which is the most appropriate way to evaluate dysglycemia in women with PCOS and who are at increased risk are as yet unclear. Aim of the study: To determine the prevalence of T2DM, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) in PCOS women and potential factors to identify those at risk. Subjects and methods: The oral glucose tolerance test (OGTT), biochemical/hormonal profile, and ovarian ultrasound data from 1614 Caucasian women with PCOS and 362 controls were analyzed in this cross-sectional multicenter study. The data were categorized according to age and BMI. Results: Dysglycemia (T2DM, IGT, and IFG according to World Health Organization criteria) was more frequent in the PCOS group compared to controls: 2.2% vs 0.8%, P = 0.04; 9.5% vs 7.4%, P = 0.038; 14.2% vs 9.1%, P = 0.002, respectively. OGTT was essential for T2DM diagnosis, since in 88% of them basal glucose values were inconclusive for diagnosis. The presence of either T2DM or IFG was irrespective of age (P = 0.54) and BMI (P = 0.32), although the latter was associated with IGT (P = 0.021). There was no impact of age and BMI status on the prevalence of T2DM or IFG. Regression analysis revealed a role for age, BMI, fat deposition, androgens, and insulin resistance for dysglycemia. However, none of the factors prevailed as a useful marker employed in clinical practice. Conclusions: One-third of our cohort of PCOS women with either T2DM or IGT displayed normal fasting glucose values but without confirming any specific predictor for dysglycemic condition. Hence, the evaluation of glycemic status using OGTT in all women with PCOS is strongly supported.

Two heads are better than one: current landscape of integrating QSP and machine learning : An ISoP QSP SIG white paper by the working group on the integration of quantitative systems pharmacology and machine learning.

Quantitative systems pharmacology (QSP) modeling is applied to address essential questions in drug development, such as the mechanism of action of a therapeutic agent and the progression of disease. Meanwhile, machine learning (ML) approaches also contribute to answering these questions via the analysis of multi-layer 'omics' data such as gene expression, proteomics, metabolomics, and high-throughput imaging. Furthermore, ML approaches can also be applied to aspects of QSP modeling. Both approaches are powerful tools and there is considerable interest in integrating QSP modeling and ML. So far, a few successful implementations have been carried out from which we have learned about how each approach can overcome unique limitations of the other. The QSP + ML working group of the International Society of Pharmacometrics QSP Special Interest Group was convened in September, 2019 to identify and begin realizing new opportunities in QSP and ML integration. The working group, which comprises 21 members representing 18 academic and industry organizations, has identified four categories of current research activity which will be described herein together with case studies of applications to drug development decision making. The working group also concluded that the integration of QSP and ML is still in its early stages of moving from evaluating available technical tools to building case studies. This paper reports on this fast-moving field and serves as a foundation for future codification of best practices.

Simultaneous ThermoBrachytherapy: Electromagnetic Simulation Methods for Fast and Accurate Adaptive Treatment Planning.

The combination of interstitial hyperthermia treatment (IHT) with high dose rate brachytherapy (HDR-BT) can improve clinical outcomes since it highly enhances the efficiency of cell kill, especially when applied simultaneously. Therefore, we have developed the ThermoBrachy applicators. To effectively apply optimal targeted IHT, treatment planning is considered essential. However, treatment planning in IHT is rarely applied as it is regarded as difficult to accurately calculate the deposited energy in the tissue in a short enough time for clinical practice. In this study, we investigated various time-efficient methods for fast computation of the electromagnetic (EM) energy deposition resulting from the ThermoBrachy applicators. Initially, we investigated the use of an electro-quasistatic solver. Next, we extended our investigation to the application of geometric simplifications. Furthermore, we investigated the validity of the superpositioning principle, which can enable adaptive treatment plan optimization without the need for continuous recomputation of the EM field. Finally, we evaluated the accuracy of the methods by comparing them to the golden standard Finite-Difference Time-Domain calculation method using gamma-index analysis. The simplifications considerably reduced the computation time needed, improving from >12 h to a few seconds. All investigated methods showed excellent agreement with the golden standard by showing a >99% passing rate with 1%/0.5 mm Dose Difference and Distance-to-Agreement criteria. These results allow the proposed electromagnetic simulation method to be used for fast and accurate adaptive treatment planning.

Teaching computational systems biology with an eye on quantitative systems pharmacology at the undergraduate level: Why do it, who would take it, and what should we teach?

Computational systems biology (CSB) is a field that emerged primarily as the product of research activities. As such, it grew in several directions in a distributed and uncoordinated manner making the area appealing and fascinating. The idea of not having to follow a specific path but instead creating one fueled innovation. As the field matured, several interdisciplinary graduate programs emerged attempting to educate future generations of computational systems biologists. These educational initiatives coordinated the dissemination of information across student populations that had already decided to specialize in this field. However, we are now entering an era where CSB, having established itself as a valuable research discipline, is attempting the next major step: Entering undergraduate curricula. As interesting as this endeavor may sound, it has several difficulties, mainly because the field is not uniformly defined. In this manuscript, we argue that this diversity is a significant advantage and that several incarnations of an undergraduate-level CSB biology course could, and should, be developed tailored to programmatic needs. In this manuscript, we share our experiences creating a course as part of a Biomedical Engineering program.

Design of the novel ThermoBrachy applicators enabling simultaneous interstitial hyperthermia and high dose rate brachytherapy.

OBJECTIVE: In High Dose Rate Brachytherapy for prostate cancer there is a need for a new way of increasing cancer cell kill in combination with a stable dose to the organs at risk. In this study, we propose a novel ThermoBrachy applicator that offers the unique ability to apply interstitial hyperthermia while simultaneously serving as an afterloading catheter for high dose rate brachytherapy for prostate cancer. This approach achieves a higher thermal enhancement ratio than in sequential application of radiation and hyperthermia and has the potential to decrease the overall treatment time. METHODS: The new applicator uses the principle of capacitively coupled electrodes. We performed a proof of concept experiment to demostrate the feasibility of the proposed applicator. Moreover, we used electromagnetic and thermal simulations to evaluate the power needs and temperature homogeneity in different tissues. Furthermore we investigated whether dynamic phase and amplitude adaptation can be used to improve longitudinal temperature control. RESULTS: Simulations demonstrate that the electrodes achieve good temperature homogeneity in a homogenous phantom when following current applicator spacing guidelines. Furthermore, we demonstrate that by dynamic phase and amplitude adaptation provides a great advancement for further adaptability of the heating pattern. CONCLUSIONS: This newly designed ThermoBrachy applicator has the potential to revise the interest in interstitial thermobrachytherapy, since the simultaneous application of radiation and hyperthermia enables maximum thermal enhancement and at maximum efficiency for patient and organization.