Millimeter wave-based patient setup verification and motion tracking during radiotherapy.

BACKGROUND: Position verification and motion monitoring are critical for safe and precise radiotherapy (RT). Existing approaches to these tasks based on visible light or x-ray are suboptimal either because they cannot penetrate obstructions to the patient's skin or introduce additional radiation exposure. The low-cost mmWave radar is an ideal solution for these tasks as it can monitor patient position and motion continuously throughout the treatment delivery. PURPOSE: To develop and validate frequency-modulated continuous wave (FMCW) mmWave radars for position verification and motion tracking during RT delivery. METHODS: A 77 GHz FMCW mmWave module was used in this study. Chirp Z Transform-based (CZT) algorithm was developed to process the intermediate frequency (IF) signals. Absolute distances to flat Solid Water slabs and human shape phantoms were measured. The accuracy of absolute distance and relative displacement were evaluated. RESULTS: Without obstruction, mmWave based on the CZT algorithm was able to detect absolute distance within 1 mm for a Solid Water slab that simulated the reflectivity of the human body. Through obstructive materials, the mmWave device was able to detect absolute distance within 5 mm in the worst case and within 3.5 mm in most cases. The CZT algorithm significantly improved the accuracy of absolute distance measurement compared with Fast Fourier Transform (FFT) algorithm and was able to achieve submillimeter displacement accuracy with and without obstructions. The surface-to-skin distance (SSD) measurement accuracy was within 8 mm in the anterior of the phantom. CONCLUSIONS: With the CZT signal processing algorithm, the mmWave radar is able to measure the absolute distance to a flat surface within 1 mm. But the absolute distance measurement to a human shape phantom is as large as 8 mm at some angles. Further improvement is necessary to improve the accuracy of SSD measurement to uneven surfaces by the mmWave radar.

Simulation study of a novel small animal FLASH irradiator (SAFI) with integrated inverse-geometry CT based on circularly distributed kV X-ray sources.

Ultra-high dose rate (UHDR) radiotherapy (RT) or FLASH-RT can potentially reduce normal tissue toxicity. A small animal irradiator that can deliver FLASH-RT treatments similar to clinical RT treatments is needed for pre-clinical studies of FLASH-RT. We designed and simulated a novel small animal FLASH irradiator (SAFI) based on distributed x-ray source technology. The SAFI system comprises a distributed x-ray source with 51 focal spots equally distributed on a 20 cm diameter ring, which are used for both FLASH-RT and onboard micro-CT imaging. Monte Carlo simulation was performed to estimate the dosimetric characteristics of the SAFI treatment beams. The maximum dose rate, which is limited by the power density of the tungsten target, was estimated based on finite-element analysis (FEA). The maximum DC electron beam current density is 2.6 mA/mm2, limited by the tungsten target's linear focal spot power density. At 160 kVp, 51 focal spots, each with a dimension of [Formula: see text] mm2 and 10° anode angle, can produce up to 120 Gy/s maximum DC irradiation at the center of a cylindrical water phantom. We further demonstrate forward and inverse FLASH-RT planning, as well as inverse-geometry micro-CT with circular source array imaging via numerical simulations.

One-Step Regio- and Stereoselective Electrochemical Synthesis of Orexin Receptor Antagonist Oxidative Metabolites.

Synthesis of drug metabolites, which often have complex structures, is an integral step in the evaluation of drug candidate metabolism, pharmacokinetic (PK) properties, and safety profiles. Frequently, such synthetic endeavors entail arduous, multiple-step de novo synthetic routes. Herein, we present the one-step Shono-type electrochemical synthesis of milligrams of chiral α-hydroxyl amide metabolites of two orexin receptor antagonists, MK-8133 and MK-6096, as revealed by a small-scale (pico- to nano-mole level) reaction screening using a lab-built online electrochemistry (EC)/mass spectrometry (MS) (EC/MS) platform. The electrochemical oxidation of MK-8133 and MK-6096 was conducted in aqueous media and found to produce the corresponding α-piperidinols with exclusive regio- and stereoselectivity, as confirmed by high-resolution nuclear magnetic resonance (NMR) characterization of products. Based on density functional theory (DFT) calculations, the exceptional regio- and stereoselectivity for this electrochemical oxidation are governed by more favorable energetics of the transition state, leading to the preferred secondary carbon radical α to the amide group and subsequent steric hindrance associated with the U-shaped conformation of the cation derived from the secondary α-carbon radical, respectively.

Ni3Sn2/nitrogen-doped graphene composite with chemisorption and electrocatalysis as advanced separator modifying material for lithium sulfur batteries.

Lithium-sulfur batteries have been widely studied because of their advantages of abundant reserves, environmental friendliness, low cost andhighspecific capacity. However, the volume expansionand the low electrical conductivity of sulfur, and the shuttle effect of polysulfides limit their application. Herein,wesynthesizea two-dimensional layered Ni3Sn2/nitrogen-doped graphene (NG) composite asseparator modifying material for lithium-sulfur batteries. The Ni3Sn2formed by dual metal salts Ni(NO3)2·6H2O and SnCl2·2H2O can adsorb polysulfide and catalyze its transformation to improve the electrochemical reaction kinetics. Moreover, the layered NG can not only disperse the Ni3Sn2particles, but alsoensure rapid electron transfer. Therefore, the lithium-sulfur battery with the Ni3Sn2/NG modified separator shows excellent electrochemical performance. At a current rate of 1 C, the lithium-sulfur battery with the Ni3Sn2/NG modified separator can provide a high initial discharge capacity of 1022.1 mAh g-1and maintain a reversible specific capacity of 758.3 mAh g-1after 400 cycles.

A multi-layer strip ionization chamber (MLSIC) device for proton pencil beam scan quality assurance.

Objective. Proton pencil beam scanning (PBS) treatment fields needs to be verified before treatment deliveries to ensure patient safety. In current practice, treatment beam quality assurance (QA) is measured at a few selected depths using film or a 2D detector array, which is insensitive and time-consuming. A QA device that can measure all key dosimetric characteristics of treatment beams spot-by-spot within a single beam delivery is highly desired.Approach. We developed a multi-layer strip ionization chamber (MLSIC) prototype device that comprises of two layers of strip ionization chambers (IC) plates for spot position measurement and 64 layers of plate IC for beam energy measurement. The 768-channel strip ion chamber signals are integrated and sampled at a speed of 3.125 kHz. It has a 25.6 cm × 25.6 cm maximum measurement field size and 2 mm spatial resolution for spot position measurement. The depth resolution and maximum depth were 2.91 mm and 18.6 cm for 1.6 mm thick IC plate, respectively. The relative weight of each spot was determined from total charge by all IC detector channels.Main results. The MLSIC is able to measure ionization currents spot-by-spot. The depth dose measurement has a good agreement with the ground truth measured using a water tank and commercial one-dimensional (1D) multi-layer plate chamber. It can verify the spot position, energy, and relative weight of clinical PBS beams and compared with the treatment plans.Significance. The MLSIC is a highly efficient QA device that can measure the key dosimetric characteristics of proton treatment beams spot-by-spot with a single beam delivery. It may improve the quality and efficiency of clinical proton treatments.

Design and optimization of thin-film tungsten (W)-diamond target for multi-pixel X-ray sources.

BACKGROUND: Emerging multi-pixel X-ray source technology enables new designs for X-ray imaging systems. The power of multi-pixel X-ray sources with a fixed anode is limited by focal spot power density. PURPOSE: The purpose of this study is to optimize the W-diamond target and predict its performance in multi-pixel X-ray sources. METHODS: X-ray intensity and energy deposition in the W-diamond target with different thicknesses of tungsten film and incident electron energies was calculated with the Geant4 Monte Carlo toolkit. COMSOL Multiphysics software was used to analyze the transient and stationary heat transfer in the thin-film W-diamond target. The maximum tube power and X-ray output intensity were predicted for both transmission and reflection target configurations. RESULTS: The maximum focal spot power density was limited by either the graphitization of the diamond substrate or the melting point of the W target. With optimal W-target thickness, the maximum transmission X-ray intensities are about 40%-50% higher than the maximum reflection intensities. Thin-film W-diamond targets allow four to five times more maximum power input and produce six to seven times higher transmission X-ray intensity in continuous mode compared with conventional reflection W thick targets. Depending on the focal spot size, reducing the X-ray pulse duration can further enhance the tube power. CONCLUSIONS: Multi-pixel X-ray sources using this W-diamond target design can produce significantly higher X-ray output than traditional thick tungsten targets without major modification of the tube design.

Tetrahedron beam imaging with a multi-pixel thermionic emission X-ray source and a photon-counting detector: A benchtop experimental study.

PURPOSE: A tetrahedron beam (TB) X-ray system with a linear X-ray source array and a linear detector array positioned orthogonal to each other may overcome the X-ray scattering problem of traditional cone-beam X-ray systems. We developed a TB imaging benchtop system using a linear array X-ray source to demonstrate the principle and benefits of TB imaging. METHODS: A multi-pixel thermionic emission X-ray (MPTEX) source with 48 focal spots in 4-mm spacing was developed in-house. The X-ray beams are collimated to a stack of fan beams that are converged to a 6-mm wide multi-row photon-counting detector (PCD). The data collected with a sequential scan of the sources at a fixed view angle were synthesized to a 2D radiography image by a shift-and-add algorithm. The data collected with a full rotation of the system were reconstructed into 3D TB CT (TBCT) images using an Feldkamp, Davis, and Kress (FDK)-based computed tomography (CT) algorithm modified for the TB geometry. RESULTS: With an 18.8-cm long source array and a 35-cm long detector array, the TB benchtop system provides a 25-cm cross-sectional and 8-cm axial field of view (FOV). The scatter-to-primary ratio (SPR) was approximately 17% for TB, as compared with 120% for cone beam geometry. The TBCT system enables reconstructions in two-dimensional radiography and three-dimensional volumetric CT. The TBCT images were free of "cupping" artifacts and have similar image quality as diagnostic helical CT. CONCLUSIONS: A TB imaging benchtop imaging system was successfully developed with MPTEX source and PCD. Phantom and animal cadaver imaging demonstrated that the TB system can produce satisfactory radiographic X-ray images and 3D CT images with image quality comparable to diagnostic helical CTs.

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties.

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

Recent advances in analytical techniques for high throughput experimentation.

High throughput experimentation is a growing and evolving field that allows to execute dozens to several thousands of experiments per day with relatively limited resources. Through miniaturization, typically a high degree of automation and the use of digital data tools, many parallel reactions or experiments at a time can be run in such workflows. High throughput experimentation also requires fast analytical techniques capable of generating critically important analytical data in line with the increased rate of experimentation. As traditional techniques usually do not deliver the speed required, some unique approaches are required to enable workflows to function as designed. This review covers the recent developments (2019-2020) in this field and was intended to give a comprehensive overview of the current "state-of-the-art."

Diastereoselective FeCl3·6H2O/NaBH4 Reduction of Oxime Ether for the Synthesis of ß-Lactamase Inhibitor Relebactam.

Relebactam, a potent ß-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate 1 suitable for large-scale preparation of relebactam is described. The key steps include a unique highly diastereoselective FeCl3·6H2O/NaBH4 reduction of a chiral oxime ether and chemoselective amidation of the resulting unprotected pipecolic acid. Nuclear magnetic resonance studies and density functional theory calculations were carried out on the substrate-Fe(III) complexes, which shed light on diastereoselective reduction.

Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

Detection of Neutral CO Lost During Ionic Dissociation Using Atmospheric Pressure Thermal Dissociation Mass Spectrometry (APTD-MS).

Elucidation of ion dissociation patterns is particularly important to structural analysis by mass spectrometry (MS). However, typically, only the charged fragments from an ion dissociation event are detected in tandem MS experiments; neutrals are not identified. In recent years, we have developed an atmospheric pressure thermal dissociation (APTD) technique that can be applied to dissociate ions at atmosphere pressure and thus provide one way to characterize neutral fragments. In this paper, we focus on the detection of neutral CO resulting from amino acid and peptide ion dissociation. In the first set of experiments, several protonated amino acids (e.g., + 1 ion of phenylalanine) were found to undergo loss of a neutral (s) of total mass 46 Da, a process leading to iminium ion formation. We successfully detected the neutral species CO by using a CO sensor, UV-Vis and MS analysis following selective CO trapping with a rhodium complex. The capture of CO from dissociation of protonated amino acids supports the assignment of the loss of 46 Da to neutral losses of CO and H2O, rather than loss of formaldehyde or dihydroxycarbene, other possible fragmentation pathways that have been subject of debate for a long time. In a second experiment, we used the APTD method in combination with the CO detection technique, to demonstrate the formation of CO in the conversion of b ions to a ions during peptide ion dissociations. These results showed the potential of APTD in the elucidation of ion dissociation mechanisms, using simple home-built apparatus. Graphical Abstract ᅟ.

A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions.

Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. 31P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)2/(R,R)-QuinoxP* pre-catalyst to form the active bis-phosphine mono-oxide-Pd(0) catalyst with competitive formation of a less active (R,R)-QuinoxP*·PdBr2 complex. Based on these detailed mechanistic studies, a new series of bis-phosphine mono-oxides (BPMO)-ligated Pd(ii) pre-catalysts have been rationally developed that allow for reliable and complete catalyst activation which should have general utility in academic and industrial settings.

Synthesis of Verubecestat, a BACE1 Inhibitor for the Treatment of Alzheimer's Disease.

Verubecestat is an inhibitor of ß-secretase being evaluated for the treatment of Alzheimer's disease. The first-generation route relies on an amide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies. The second-generation route replaces this with a copper-catalyzed C-N coupling, allowing for more direct access to the target. Other features of the new route include a diastereoselective Mannich-type addition into an Ellman sulfinyl ketimine and a late-stage guanidinylation.

Capture of reactive monophosphine-ligated palladium(0) intermediates by mass spectrometry.

A long-sought-after reactive monophosphine-ligated palladium(0) intermediate, Pd(0)L (L = phosphine ligand), was detected for the first time from the activation of the Buchwald precatalyst with base. The detection was enabled using desorption electrospray ionization mass spectrometry (DESI-MS) in combination with online reaction monitoring. The subsequent oxidative addition of Pd(0)L with aryl halide and C-N coupling with amine via reductive elimination was also probed using DESI-MS.

Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C-N Coupling with Chiral Bisphosphine Mono-oxides.

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

Remote Meta-C-H Activation Using a Pyridine-Based Template: Achieving Site-Selectivity via the Recognition of Distance and Geometry.

The pyridyl group has been extensively employed to direct transition-metal-catalyzed C-H activation reactions in the past half-century. The typical cyclic transition states involved in these cyclometalation processes have only enabled the activation of ortho-C-H bonds. Here, we report that pyridine is adapted to direct meta-C-H activation of benzyl and phenyl ethyl alcohols through engineering the distance and geometry of a directing template. This template takes advantage of a stronger σ-coordinating pyridine to recruit Pd catalysts to the desired site for functionalization. The U-shaped structure accommodates the otherwise highly strained cyclophane-like transition state. This development illustrates the potential of achieving site selectivity in C-H activation via the recognition of distal and geometric relationship between existing functional groups and multiple C-H bonds in organic molecules.

Correction to "Remote Meta-C-H Activation Using a Pyridine-Based Template: Achieving Site-Selectivity via the Recognition of Distance and Geometry".

[This corrects the article DOI: 10.1021/acscentsci.5b00312.].

4-(2,3-Dimeth-oxy-phen-yl)-1H-pyrrole-3-carbonitrile.

The asymmetric unit of the title compound, C(13)H(12)N(2)O(2), obtained in a search for analogs of the fungicide fludioxonil [systematic name: 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile], contains two independent mol-ecules, A and B. The benzene and pyrrole rings are inclined to each other at 38.5 (1) and 29.3 (1)° in mol-ecules A and B, respectively. In the crystal, bifurcated N-H⋯(O,O) hydrogen bonds link A mol-ecules into chains along [001], while B mol-ecules are linked into layers parallel to the bc plane via bifurcated N-H⋯(N,N) hydrogen bonds.