Optimization of the Clinical Setting Using Numerical Simulations of the Electromagnetic Field in an Obese Patient Model for Deep Regional Hyperthermia of an 8 MHz Radiofrequency Capacitively Coupled Device in the Pelvis

Background: The purpose of this study was to evaluate the effectiveness of the clinical setting for deep regional hyperthermia of an 8 MHz radiofrequency (RF) capacitively coupled device in the pelvis by using numerical simulations of the electromagnetic field. Methods: A three-dimensional patient model of cervical cancer of the uterus in an obese patient was reconstructed with computed tomography data. The specific absorption rate (SAR) and temperature distributions among the various heating settings were evaluated using numerical simulations. Results: The averaged SAR value of the deep target tumor was similar between with or without overlay boluses (OBs), and that of the subcutaneous fat (SF) at the edges of cooling boluses with OBs was lower than that of the SF without OBs. The use of OBs reduced the overheating of the SF. The 0.5% salt solution in the OB produced the least overheated areas outside the deep target tumor compared with the other concentrations. The insertion of the intergluteal cleft (IGC) bolus could improve the temperature concentration of the deep target tumor. Conclusions: The use of OBs and the salt solution concentration in the OB were important to optimize the temperature distribution. IGC bolus might contribute to temperature optimization. Further studies with individualized numerical simulations in each patient are expected.

The Ilyinetsmeteorite crater - geological structure unique in Europe and a promising destination for international tourism

The Ilyinets meteorite crater is located in Lypovets and Ilyinets districts of Vinnytsia region. It is accessible for examination in quarries near Luhova and Ivanky villages in the Sobok River valley. This site currently has the status of a geological natural landmark of local significance. The crater appeared as a result the impact of a meteorite on Precambrian surface of the Ukrainian Shield 445 million years ago. The impact of the explosion caused the formation of a typical ring structure about 8.5 km diameter and 600-800 m deep. The denudation level in the crater area is estimated at about 300-400 m. Thus, the preserved part of the crater has a diameter of about 3.2 km and is 400 m deep. Target rocks are represented mainly by granitoids of the Haisyn (Sobite) complex. The meteorite crater consists of impactites: shock-melt rocks, impact bombs, allogenic and authigenic breccia (suevite, tagamiteetc). Genesis of impactites is confirmed by the findings of stishovite, koesite, impact-type diamond, the presence of metallic and silicate spherules, planar structures in quartz, feldspars and other characteristic features. Overlap rocks are represented by sporadically distributed Devonian and widespread Quaternary sediments. Their thickness reaches 13 m, and it decreases to 3 m in the Sobok River valley. The Ilyinets meteorite crater is the most representative in Europe because it is easily accessible for examination and study, and available for sampling. Undoubtedly, it is a promising unique geological object that can attract attention of tourists around the world, as well as geoscientists interested in studying unique natural sites and phenomena in Europe and on the Earth in general.

Synthetic Study for Optimizing an Efficient Grid Size for MT and Long Period MT Measurements

<p>While the Ultra Wide-Band Magnetotelluric technology (10,000Hz - 50,000 seconds) covers AMT, MT and LP bends in simultaneously measured time series, many research and exploration projects use dedicated MT (300Hz to 10,000 seconds) or LP (10 seconds - 50,000 seconds) systems. This is usually dictated by available equipment or a traditional approach to deep target studies. Surface anomalies (up to 2-5km) formed by conductive mineral bodies or fault systems considered to be less important and are often completely ignored during deep lithospheric studies. The upper layers conductivity is being estimated and averaged over the whole survey area. As it is very well known, the Magnetotelluric sounding signal measured on the surface represents an apparent resistivity at a depth dependent on frequency and conductivity of averaged ground thickness above. This assumption works generally well in smoothly layered geology, but might integrate an error in estimations and inversions in more complicated situations. In our previous studies we observed an effect of an upward shift of anomalies obtained after inversion of smaller grid size data for long period measurements. This seems to happen when the localized 3D conductive bodies are becoming dominant over the average layer conductivity and it cannot be assumed as a homogeneous thickness. In this study, our intention is analysing the efficient grid size that would be effective for MT band and LP band surveys. To achieve our estimated results, we designed a geoelectrical model that would be typical for Canadian shields with different grid sizes for MT band signal and LP band signals. We did run inversions using ModEM and observed vertical fit of inversion results to an original model.</p>

A Quantitative Systems Pharmacology (QSP) Model to Predict Receptor Occupancy of Bruton's Tyrosine Kinase (BTK) Inhibitors in Peripheral Blood Mononuclear Cells, Bone Marrow and Lymph Nodes of Patients with B-Cell Malignancies

Background: Bruton tyrosine kinase (BTK) is a key component of the B-cell receptor signaling pathway. The BTK inhibitors ibrutinib and acalabrutinib have been approved for the treatment of various B-cell malignancies. Zanubrutinib is a potent and highly specific next-generation BTK inhibitor currently in Phase 3 clinical testing. Achieving complete and sustained target engagement with respect to BTK receptor occupancy is thought to be an important factor for attaining deeper and durable clinical responses with the BTK inhibitors. Testing for BTK occupancy in peripheral blood mononuclear cells (PBMC) can be assessed in clinical studies. However, it is difficult to sample deep target tissues such as bone marrow (BM) and lymph nodes (LN) in patients to assess receptor occupancy. The objectives of this work were (1) to develop a QSP model to describe and predict the BTK receptor occupancy in PBMC, BM and LN after dosing with these BTK inhibitors in patients with B-cell malignancies, (2) to understand the impact of different dosing regimens (once daily (QD) v/s twice daily (BID)) on BTK receptor occupancy. Methods: A mathematical model was developed that describes: (1) pharmacokinetics (PK) of BTK inhibitors; (2) intracellular concentration of BTK inhibitors in PBMC, BM and LN; (3) binding of BTK inhibitors with BTK including competition with ATP and (4) BTK degradation/turnover rate. This QSP model includes ibrutinib with its metabolite PCI-45227, acalabrutinib with its metabolite ACP-5862, and zanubrutinib. Previously developed minimal Physiologically-based Pharmacokinetic (PBPK) models were used to reproduce PK of BTK inhibitors. Intracellular concentrations of BTK inhibitors were described in the model in accordance with PBPK equations for small molecules (Rodgers and Rowland. J Pharm Sci. 2006) and on the basis of their physico-chemical properties. Parameters and interindividual variability in parameter values were taken from previously developed models and estimated using experimental data. Sensitivity analyses using key model parameters such as BTK degradation/turnover rate were performed. The model was validated using available in vitro and clinical data on BTK occupancy. Results: The QSP model accurately described the observed clinical data on PK of BTK inhibitors during treatment with different doses and regimens of ibrutinib, acalabrutinib and zanubrutinib. There was good agreement between model prediction and observed BTK occupancy in PBMC and LN (Figure 1 and Figure 2). Zanubrutinib (160 mg BID) was predicted to result in higher median BTK occupancy with less variability in both PBMC and LN than ibrutinib (420 mg QD, 560 mg QD) and acalabrutinib (100 mg BID). In the absence of clinical BTK occupancy data in BM, the model predicted that steady-state trough BTK occupancy in BM were also predicted to be higher after zanubrutinib 160 mg BID administration, than those after ibrutinib 560 mg or 420 mg QD administration, and after acalabrutinib 100 mg BID administration. These differences are attributed to the PK properties (higher AUC and fraction unbound in plasma), binding properties to BTK (Kd, inactivation rate constant), and higher lipophilicity for zanubrutinib. The model predicted that 160 mg BID of zanubrutinib resulted in higher median trough BTK occupancy than 320 mg QD with less variability which is consistent with the observed clinical data (Figure 3). Conclusions: A QSP model was successfully developed and validated, which predicted higher median BTK occupancy with less variability for zanubrutinib in PBMC, BM and LN than ibrutinib and acalabrutinib. A BID dosing regimen produces higher BTK occupancy than a QD regimen over the dosing interval. Ongoing clinical trials with 160 mg BID zanubrutinib will help to determine if improved BTK occupancy in these peripheral and deep target tissues translate into improvements in clinical outcomes. Disclosures Sahasranaman: BeiGene: Employment, Equity Ownership. Demin:BeiGene USA, Inc.: Consultancy; InSysBio LLC: Employment. Shchelokov:InSysBio LLC: Employment; BeiGene USA, Inc.: Consultancy. Musatova:BeiGene USA, Inc.: Consultancy; InSysBio LLC: Employment. Budha:BeiGene Ltd.: Employment, Equity Ownership. Ou:BeiGene: Employment.

TWO-STAGES TECHNIWUE OF TO FULL WAVEFORM INVERSION: FROM NEAR SURFACE TO DEEP TARGET GEOLOGICAL STRUCTURES

Full Waveform Inversion in its traditional formulation is nothing else but finding the minimum of the objective functional, that characterizes L2 difference between acquired and simulated wave fields. The accumulated experience proves the necessity of the following conditions for correct recovery of the wave propagation velocity: • The presence of low time frequencies in the data; • Information about near surface structure of the media. We modify the traditional L2 objective functional on thy base of decomposition of the model space. This modification weakens the requirements for the presence of low time frequencies.

Can transcranial electric stimulation with multiple electrodes reach deep targets?

To reach a deep target in the brain with transcranial electric stimulation (TES), currents have to pass also through the cortical surface. Thus, it is generally thought that TES cannot achieve focal deep brain stimulation. Recent efforts with interfering waveforms and pulsed stimulation have argued that one can achieve deeper or more intense stimulation in the brain. Here we argue that conventional transcranial stimulation with multiple current sources is just as effective as these new approaches. The conventional multi-electrode approach can be numerically optimized to maximize intensity or focality at a desired target location. Using such optimal electrode configurations we find in a detailed and realistic head model that deep targets may in fact be strongly stimulated, with cerebrospinal fluid guiding currents deep into the brain.