The Effect of High-Intensity Interval Exercise on Short-Term Glycaemic Control, Serum Level of Key Mediator in Hypoxia and Pro-Inflammatory Cytokines in Patients with Type 1 Diabetes-An Exploratory Case Study.

Type 1 diabetes (T1D) is associated with hyperglycaemia-induced hypoxia and inflammation. This study assessed the effects of a single bout of high-intensity interval exercise (HIIE) on glycaemia (BG) and serum level of pro-inflammatory cytokines, and an essential mediator of adaptive response to hypoxia in T1D patients. The macronutrient intake was also evaluated. Nine patients suffering from T1D for about 12 years and nine healthy individuals (CG) were enrolled and completed one session of HIIE at the intensity of 120% lactate threshold with a duration of 4 × 5 min intermittent with 5 min rests after each bout of exercise. Capillary and venous blood were withdrawn at rest, immediately after and at 24 h post-HIIE for analysis of BG, hypoxia-inducible factor alpha (HIF-1α), tumour necrosis factor alpha (TNF-α) and vascular-endothelial growth factor (VEGF). Pre-exercise BG was significantly higher in the T1D patients compared to the CG (p = 0.043). HIIE led to a significant decline in T1D patients' BG (p = 0.027) and a tendency for a lower BG at 24 h post-HIIE vs. pre-HIIE. HIF-1α was significantly elevated in the T1D patients compared to CG and there was a trend for HIF-1α to decline, and for VEGF and TNF-α to increase in response to HIIE in the T1D group. Both groups consumed more and less than the recommended amounts of protein and fat, respectively. In the T1D group, a tendency for a higher digestible carbohydrate intake and more frequent hyperglycaemic episodes on the day after HIIE were observed. HIIE was effective in reducing T1D patients' glycaemia and improving short-term glycaemic control. HIIE has the potential to improve adaptive response to hypoxia by elevating the serum level of VEGF. Patients' diet and level of physical activity should be screened on a regular basis, and they should be educated on the glycaemic effects of digestible carbohydrates.

Determinants of daily physical activity limitation in patients with idiopathic pulmonary fibrosis.

The purpose of the study was to determine the level of physical fitness assessed based on the physiological parameters and intensity of daily physical activity (PA) of patients with idiopathic pulmonary fibrosis (IPF). Additionally, we aimed to determine the intensity and duration of exercise that would bring beneficial modifications in the cardio-respiratory system of the patients with IPF. Eighteen patients with IPF (61.7 ± 4.3 years) and fifteen healthy volunteers performed a graded exercise test to exhaustion on a treadmill (Bruce protocol). Spirometry, dyspnea (mMRC, Borg scale) and fatigue (FAS) were measured. Total daily PA (kcal/day, MET) was monitored for seven days. The linear regression of PA (kcal/day) vs. peak oxygen uptake (%pred. peakVO2) was used to determine the intensity of daily PA that should be used in the rehabilitation of the patients with IPF. The average energy expenditure of daily PA of patients with IPF was 147.9 ± 86.4 kcal/day and it was significantly lower compared to healthy individuals. The linear regression indicated that the predicted energy expenditure of daily PA (PAEE) is 280.0 kcal/day, estimated based on VO2peak 100%pred. Therefore, the patients should add about 30 min of exercise of the intensity of 4.5 ± 0.2 kcal (calculated at the anaerobic threshold) or about 3700 steps/day to their daily PA. Diffusion for carbon monoxide and physiological variables of aerobic capacity seem to be the most important determinants of PA limitation in patients with IPF. The method of estimating PAEE should be used to plan training loads in IPF rehabilitation.

Effects of Ni/Co doping on structural and electronic properties of 122 and 112 families of Eu based iron pnictides.

Superconductivity in high-temperature superconductors such as cuprates or iron pnictides is typically achieved by hole or electron doping and it is of great interest to understand how doping affects their properties leading to superconductivity. To study it we conducted Fe and As K edge x-ray absorption spectroscopy measurements on several electron doped compounds from the 112 and 122 family of Eu-based iron pnictides. XANES and EXAFS results confirm that dopants are located at expected sites. For both families we found an electron charge redistribution between As and Fe occurring with doping. The changes it caused are stronger in the 112 family and they are bigger at As sites, which indicates that doped charges are predominantly localized on the dopant site. However, the results obtained do not provide clues why Ni doping in 122 family does not lead to occurrence of superconductivity.

Impact of physical functional capacity on quality of life in patients with interstitial lung diseases.

This study aimed to investigate the physical functioning predictors for health-related quality of life (HRQL) decline in patients with idiopathic interstitial fibrosis (IPF), sarcoidosis and other interstitial lung disease (ILD). The study enrolled 52 patients with ILD and 16 healthy individuals. Participants' HRQL was assessed using the 36-item Short-Form Health Survey questionnaire. Spirometry, physical performance, and daily physical activity (PA) were monitored. Patients with IPF showed significantly lower PA compared to patients with other ILD (p = 0.002)and sarcoidosis (p = 0.01). The type of disease aetiology had no significant effect on aerobic capacity, HRQL and fatigue. Patients with ILD showed significant greater fatigue, lower physical functioning and greater physical aspects scores compared to the control group (F=6.0; p = 0.018; F=12.64; p = 0.001, respectively). A significant positive correlation was observed between 6-minute walking distance (6MWD) and the physical domain of HRQL (r = 0.35, p = 0.012) and PA and the physical aspects of HRQL (r = 0.37, p = 0.007). This study revealed that the key predictors for HRQL decline were lower lung function, lower PA and physical performance.

Synthesis of Manganese Zinc Ferrite Nanoparticles in Medical-Grade Silicone for MRI Applications.

The aim of this project is to fabricate hydrogen-rich silicone doped with magnetic nanoparticles for use as a temperature change indicator in magnetic resonance imaging-guided (MRIg) thermal ablations. To avoid clustering, the particles of mixed MnZn ferrite were synthesized directly in a medical-grade silicone polymer solution. The particles were characterized by transmission electron microscopy, powder X-ray diffraction, soft X-ray absorption spectroscopy, vibrating sample magnetometry, temperature-dependent nuclear magnetic resonance relaxometry (20 °C to 60 °C, at 3.0 T), and magnetic resonance imaging (at 3.0 T). Synthesized nanoparticles were the size of 4.4 nm ± 2.1 nm and exhibited superparamagnetic behavior. Bulk silicone material showed a good shape stability within the study's temperature range. Embedded nanoparticles did not influence spin-lattice relaxation, but they shorten the longer component of spin-spin nuclear relaxation times of silicone's protons. However, these protons exhibited an extremely high r2* relaxivity (above 1200 L s-1 mmol-1) due to the presence of particles, with a moderate decrease in the magnetization with temperature. With an increased temperature decrease of r2*, this ferro-silicone can be potentially used as a temperature indicator in high-temperature MRIg ablations (40 °C to 60 °C).

Selective magnetometry of superparamagnetic iron oxide nanoparticles in liquids.

We show that the properties of superparamagnetic iron oxide nanoparticles suspended in liquids can be effectively studied using Magnetic Circular Dichroism in Resonant Inelastic X-ray Scattering. Analysis of the spectral shape and magnetic contrast produced by this experiment enables an assessment of the site distribution and magnetic state of metal ions in the spinel phase. The selective magnetization profile of particles as derived from the field dependence of dichroism empowers an estimation of particle size distribution. Furthermore, the new proposed methodology discriminates sizes that are below the detection limits of X-ray and light scattering probes and that are difficult to spot in TEM.

Cobalt-platinum nanomotors for local gas generation.

Bimetallic Co-Pt nanorods exhibit an enhanced capacity for the production of gas from liquid-phase chemicals. Based on the systematic structural and magnetic characterization we discuss potential applications of these hybrid nanostructures for localized fuel generation in microdevices. Experimental proof of the feasibility for controlling the rate of catalytic reaction via external magnetic stimuli is shown. This unique functionality makes these hybrids promising candidates for optimizing the energy conversion rate in microfluidics fuel cells.

Comparison of the Effectiveness of High-Intensity Interval Training in Hypoxia and Normoxia in Healthy Male Volunteers: A Pilot Study.

AIMS: The study investigated the effect of high-intensity interval training in hypoxia and normoxia on serum concentrations of proangiogenic factors, nitric oxide, and inflammatory responses in healthy male volunteers. METHODS: Twelve physically active male subjects completed a high-intensity interval training (HIIT) in normoxia (NorTr) and in normobaric hypoxia (HypTr) (FiO2 = 15.2%). The effects of HIIT in hypoxia and normoxia on maximal oxygen uptake, hypoxia-inducible factor-1-alpha, vascular endothelial growth factor, nitric oxide, and cytokines were analyzed. RESULTS: HIIT in hypoxia significantly increases maximal oxygen uptake (p=0.01) levels compared to pretraining levels. Serum hypoxia-inducible factor-1 (p=0.01) and nitric oxide levels (p=0.05), vascular endothelial growth factor (p=0.04), and transforming growth factor-ß (p=0.01) levels were increased in response to exercise test after hypoxic training. There was no effect of training conditions for serum baseline angiogenic factors and cytokines (p > 0.05) with higher HIF-1α and NO levels after hypoxic training compared to normoxic training (F = 9.1; p < 0.01 and F = 5.7; p < 0.05, respectively). CONCLUSIONS: High-intensity interval training in hypoxia seems to induce beneficial adaptations to exercise mediated via a significant increase in the serum concentrations of proangiogenic factors and serum nitric oxide levels compared to the same training regimen in normoxia.

Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel.

PURPOSE: To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing. EXPERIMENTAL DESIGN: Pan-cancer MSI detection using Guardant360 was analytically validated according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated. RESULTS: cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit. CONCLUSIONS: cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.See related commentary by Wang and Ajani, p. 6887.

A Hybrid System for Magnetic Hyperthermia and Drug Delivery: SPION Functionalized by Curcumin Conjugate.

Cancer is among the leading causes of death worldwide, thus there is a constant demand for new solutions, which may increase the effectiveness of anti-cancer therapies. We have designed and successfully obtained a novel, bifunctional, hybrid system composed of colloidally stabilized superparamagnetic iron oxide nanoparticles (SPION) and curcumin containing water-soluble conjugate with potential application in anticancer hyperthermia and as nanocarriers of curcumin. The obtained nanoparticulate system was thoroughly studied in respect to the size, morphology, surface charge, magnetic properties as well as some biological functions. The results revealed that the obtained nanoparticles, ca. 50 nm in diameter, were the agglomerates of primary particles with the magnetic, iron oxide cores of ca. 13 nm, separated by a thin layer of the applied cationic derivative of chitosan. These agglomerates were further coated with a thin layer of the sodium alginate conjugate of curcumin and the presence of both polymers was confirmed using thermogravimetry. The system was also proven to be applicable in magnetic hyperthermia induced by the oscillating magnetic field. A high specific absorption rate (SAR) of 280 [W/g] was registered. The nanoparticles were shown to be effectively uptaken by model cells. They were found also to be nontoxic in the therapeutically relevant concentration in in vitro studies. The obtained results indicate the high application potential of the new hybrid system in combination of magnetic hyperthermia with delivery of curcumin active agent.

Statistical motion modelling for robust evaluation of clinically delivered accumulated dose distributions after curative radiotherapy of locally advanced prostate cancer.

BACKGROUND AND PURPOSE: Planned doses are used as surrogate for the actually delivered dose in radiotherapy. We have estimated the delivered dose in a dose-escalation trial of locally advanced prostate cancer by statistical dose-accumulation and by DVH-summation, and compared to planned dose. MATERIALS AND METHOD: Prescribed dose-escalation to the prostate was 67.5 Gy/25fr., corresponding to 81GyEQD2 assuming α/ß = 1.5. The 21 patients had three targets (i.e. CTV67.5 + 2 mm, CTV60 + 5 mm, CTV50 + 10 mm) irradiated by a simultaneous-integrated-boost technique. Analysis was based on 213 CT scans and 5-years of follow-up. For statistical dose-accumulation, we modelled 10000 possible treatment courses based on planned dose and deformation-vector-fields from contour-based registration. For DVH-summation we recalculated dose on repeat-CTs and estimated median D98%/EUD. Groups with/without disease recurrence were compared. RESULTS: Discrepancies between planned and accumulated dose were mostly seen for CTV67.5, where under-dosage was found at different locations in the prostate in 12/21 patients. Delivered dose-escalation (D98%) was on average 73.9GyEQD2 (range: 68.3-78.7GyEQD2). No significant difference in accumulated-D98% was found in patients with (n = 8) and without (n = 13) recurrence (p > 0.05). Average D98%/EUD with statistical dose-accumulation vs DVH-summation was significantly different in CTV60, CTV50, rectum and bladder but not in CTV67.5. CONCLUSION: The planned dose escalation was not received by more than half-of-the patients. Robustness of the prostate target (CTV67.5) should therefore be better prioritized in these patients given the low toxicity profile. Estimates of delivered dose were less conservative for dose-accumulation due to interaction of random organ motion with the dose matrix.

Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies.

Purpose: To analytically and clinically validate a circulating cell-free tumor DNA sequencing test for comprehensive tumor genotyping and demonstrate its clinical feasibility.Experimental Design: Analytic validation was conducted according to established principles and guidelines. Blood-to-blood clinical validation comprised blinded external comparison with clinical droplet digital PCR across 222 consecutive biomarker-positive clinical samples. Blood-to-tissue clinical validation comprised comparison of digital sequencing calls to those documented in the medical record of 543 consecutive lung cancer patients. Clinical experience was reported from 10,593 consecutive clinical samples.Results: Digital sequencing technology enabled variant detection down to 0.02% to 0.04% allelic fraction/2.12 copies with ≤0.3%/2.24-2.76 copies 95% limits of detection while maintaining high specificity [prevalence-adjusted positive predictive values (PPV) >98%]. Clinical validation using orthogonal plasma- and tissue-based clinical genotyping across >750 patients demonstrated high accuracy and specificity [positive percent agreement (PPAs) and negative percent agreement (NPAs) >99% and PPVs 92%-100%]. Clinical use in 10,593 advanced adult solid tumor patients demonstrated high feasibility (>99.6% technical success rate) and clinical sensitivity (85.9%), with high potential actionability (16.7% with FDA-approved on-label treatment options; 72.0% with treatment or trial recommendations), particularly in non-small cell lung cancer, where 34.5% of patient samples comprised a directly targetable standard-of-care biomarker.Conclusions: High concordance with orthogonal clinical plasma- and tissue-based genotyping methods supports the clinical accuracy of digital sequencing across all four types of targetable genomic alterations. Digital sequencing's clinical applicability is further supported by high rates of technical success and biomarker target discovery. Clin Cancer Res; 24(15); 3539-49. ©2018 AACR.

Pushing up the magnetisation values for iron oxide nanoparticles via zinc doping: X-ray studies on the particle's sub-nano structure of different synthesis routes.

The maximum magnetisation (saturation magnetisation) obtainable for iron oxide nanoparticles can be increased by doping the nanocrystals with non-magnetic elements such as zinc. Herein, we closely study how only slightly different synthesis approaches towards such doped nanoparticles strongly influence the resulting sub-nano/atomic structure. We compare two co-precipitation approaches, where we only vary the base (NaOH versus NH3), and a thermal decomposition route. These methods are the most commonly applied ones for synthesising doped iron oxide nanoparticles. The measurable magnetisation change upon zinc doping is about the same for all systems. However, the sub-nano structure, which we studied with Mössbauer and X-ray absorption near edge spectroscopy, differs tremendously. We found evidence that a much more complex picture has to be drawn regarding what happens upon Zn doping compared to what textbooks tell us about the mechanism. Our work demonstrates that it is crucial to study the obtained structures very precisely when "playing" with the atomic order in iron oxide nanocrystals.

Validation of a virtual source model for Monte Carlo dose calculations of a flattening filter free linac.

PURPOSE: A linac delivering intensity-modulated radiotherapy (IMRT) can benefit from a flattening filter free (FFF) design which offers higher dose rates and reduced accelerator head scatter than for conventional (flattened) delivery. This reduction in scatter simplifies beam modeling, and combining a Monte Carlo dose engine with a FFF accelerator could potentially increase dose calculation accuracy. The objective of this work was to model a FFF machine using an adapted version of a previously published virtual source model (VSM) for Monte Carlo calculations and to verify its accuracy. METHODS: An Elekta Synergy linear accelerator operating at 6 MV has been modified to enable irradiation both with and without the flattening filter (FF). The VSM has been incorporated into a commercially available treatment planning system (Monaco™ v 3.1) as VSM 1.6. Dosimetric data were measured to commission the treatment planning system (TPS) and the VSM adapted to account for the lack of angular differential absorption and general beam hardening. The model was then tested using standard water phantom measurements and also by creating IMRT plans for a range of clinical cases. RESULTS: The results show that the VSM implementation handles the FFF beams very well, with an uncertainty between measurement and calculation of <1% which is comparable to conventional flattened beams. All IMRT beams passed standard quality assurance tests with >95% of all points passing gamma analysis (γ < 1) using a 3%/3 mm tolerance. CONCLUSIONS: The virtual source model for flattened beams was successfully adapted to a flattening filter free beam production. Water phantom and patient specific QA measurements show excellent results, and comparisons of IMRT plans generated in conventional and FFF mode are underway to assess dosimetric uncertainties and possible improvements in dose calculation and delivery.

Monte Carlo vs. pencil beam based optimization of stereotactic lung IMRT.

BACKGROUND: The purpose of the present study is to compare finite size pencil beam (fsPB) and Monte Carlo (MC) based optimization of lung intensity-modulated stereotactic radiotherapy (lung IMSRT). MATERIALS AND METHODS: A fsPB and a MC algorithm as implemented in a biological IMRT planning system were validated by film measurements in a static lung phantom. Then, they were applied for static lung IMSRT planning based on three different geometrical patient models (one phase static CT, density overwrite one phase static CT, average CT) of the same patient. Both 6 and 15 MV beam energies were used. The resulting treatment plans were compared by how well they fulfilled the prescribed optimization constraints both for the dose distributions calculated on the static patient models and for the accumulated dose, recalculated with MC on each of 8 CTs of a 4DCT set. RESULTS: In the phantom measurements, the MC dose engine showed discrepancies < 2%, while the fsPB dose engine showed discrepancies of up to 8% in the presence of lateral electron disequilibrium in the target. In the patient plan optimization, this translates into violations of organ at risk constraints and unpredictable target doses for the fsPB optimized plans. For the 4D MC recalculated dose distribution, MC optimized plans always underestimate the target doses, but the organ at risk doses were comparable. The results depend on the static patient model, and the smallest discrepancy was found for the MC optimized plan on the density overwrite one phase static CT model. CONCLUSIONS: It is feasible to employ the MC dose engine for optimization of lung IMSRT and the plans are superior to fsPB. Use of static patient models introduces a bias in the MC dose distribution compared to the 4D MC recalculated dose, but this bias is predictable and therefore MC based optimization on static patient models is considered safe.