A chemo-enzymatic pathway to expand cellooligosaccharide chemical space through amine bond introduction.

Enzymatic functionalization of oligosaccharides is a useful and environmentally friendly way to expand their structural chemical space and access to a wider range of applications in the health, food, feed, cosmetics and other sectors. In this work, we first tested the laccase/TEMPO system to generate oxidized forms of cellobiose and methyl ß-D-cellobiose, and obtained high yields of novel anionic disaccharides (>60 %) at pH 6.0. Laccase/TEMPO system was then applied to a mix of cellooligosaccharides and to pure D-cellopentaose. The occurrence of carbonyl and carboxyl groups in the oxidation products was shown by LC-HRMS, MALDI-TOF and reductive amination of the carbonyl groups was attempted with p-toluidine a low molar mass amine to form the Schiff base, then reduced by 2-picoline borane to generate a more stable amine bond. The new grafted products were characterized by LC-HRMS, LC-UV-MS/MS and covalent grafting was evidenced. Next, the same procedure was adopted to successfully graft a dye, the rhodamine 123, larger in size than toluidine. This two-step chemo-enzymatic approach, never reported before, for functionalization of oligosaccharides, offers attractive opportunities to anionic cellooligosaccharides and derived glucoconjugates of interest for biomedical or neutraceutical applications. It also paves the way for more environmentally-friendly cellulose fabric staining procedures.

Complete patient exposure during paediatric brain cancer treatment for photon and proton therapy techniques including imaging procedures.

Background: In radiotherapy, especially when treating children, minimising exposure of healthy tissue can prevent the development of adverse outcomes, including second cancers. In this study we propose a validated Monte Carlo framework to evaluate the complete patient exposure during paediatric brain cancer treatment. Materials and methods: Organ doses were calculated for treatment of a diffuse midline glioma (50.4 Gy with 1.8 Gy per fraction) on a 5-year-old anthropomorphic phantom with 3D-conformal radiotherapy, intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity modulated pencil beam scanning (PBS) proton therapy. Doses from computed tomography (CT) for planning and on-board imaging for positioning (kV-cone beam CT and X-ray imaging) accounted for the estimate of the exposure of the patient including imaging therapeutic dose. For dose calculations we used validated Monte Carlo-based tools (PRIMO, TOPAS, PENELOPE), while lifetime attributable risk (LAR) was estimated from dose-response relationships for cancer induction, proposed by Schneider et al. Results: Out-of-field organ dose equivalent data of proton therapy are lower, with doses between 0.6 mSv (testes) and 120 mSv (thyroid), when compared to photon therapy revealing the highest out-of-field doses for IMRT ranging between 43 mSv (testes) and 575 mSv (thyroid). Dose delivered by CT ranged between 0.01 mSv (testes) and 72 mSv (scapula) while a single imaging positioning ranged between 2 µSv (testes) and 1.3 mSv (thyroid) for CBCT and 0.03 µSv (testes) and 48 µSv (scapula) for X-ray. Adding imaging dose from CT and daily CBCT to the therapeutic demonstrated an important contribution of imaging to the overall radiation burden in the course of treatment, which is subsequently used to predict the LAR, for selected organs. Conclusion: The complete patient exposure during paediatric brain cancer treatment was estimated by combining the results from different Monte Carlo-based dosimetry tools, showing that proton therapy allows significant reduction of the out-of-field doses and secondary cancer risk in selected organs.

End-to-end quality assurance for stereotactic radiotherapy with Fricke-Xylenol orange-Gelatin gel dosimeter and dual-wavelength cone-beam optical CT readout.

PURPOSE: The end-to-end (E2E) quality assurance (QA) test is a unique tool for validating the treatment chain undergone by patients in external radiotherapy. It should be conducted in three dimensions (3D) to get accurate results. This study aims to implement these tests with Fricke-Xylenol orange-Gelatin (FXG) gel dosimeter and a newly developed dual-wavelength reading method on the Vista16™ optical Computed Tomography (CT) scanner (ModusQA) for three treatment techniques in stereotactic radiotherapy, on Novalis (Varian) and CyberKnife (Accuray) linear accelerators. METHODS: The tests were performed in head phantoms. Gel measurements were compared with planned dose distributions and measured by film and ion chamber measurements by plotting isodose curves and dose profiles, and by conducting a 3D local gamma-index analysis (2%/2mm criteria). RESULTS: Gamma passing rates were higher than 95 %. Point dose differences between treatment planning and gel and ion chamber measurements at the isocenter were < 2.3 % for both treatments delivered on the Novalis accelerator, while this difference was higher than 4 % for the treatment delivered on the CyberKnife, highlighting a small overdosing of the tumor volume. A good agreement was observed between gel and film dose profiles. CONCLUSIONS: This study presents the successful implementation of 3D E2E QA tests for stereotactic radiotherapy with FXG gel dosimetry and a dual-wavelength reading method on an optical CT scanner. This dosimetric method provides 3D absolute dose distributions in the 0.25 - 10 Gy dose range with a high spatial resolution and a dose uncertainty of around 2 % (k=1).

Performance of automatic exposure control on dose and image quality: comparison between slot-scanning and flat-panel digital radiography systems.

BACKGROUND: EOSedge™* (EOS Imaging, Paris, France) is an X-ray imaging system using automatic exposure control (AEC) with tube current modulation, in order to optimize dose deposition in patients. PURPOSE: This study aims at characterizing EOSedge organ dose deposition in comparison to a digital radiography (DR) system and the previous EOS system (EOS-1st generation), in relation to their respective image quality levels. METHOD: Organ doses were measured in an anthropomorphic female adult phantom and a 5-year-old pediatric phantom using optically stimulated luminescence (OSL) dosimeters, which were carefully calibrated within the studied energy range. Organ doses were recorded on the EOSedge and the Fuji Visionary DRF (Fujifilm Medical Systems U.S.A., Inc, Lexington, MA). The resulting effective doses were compared to the EOS-1st-generation values present in the literature. Image quality assessment was carried out on end-user images. Quantitative image quality metrics were computed for all tested modalities on a quality assurance phantom. Qualitative assessment of EOSedge image quality was based on anthropomorphic phantom acquisitions against the EOS-1st-generation system, and on clinical images against the tested DR system. RESULTS: For a full-spine exam, and on the female adult phantom (respectively, the pediatric phantom), an effective dose of 92 µSv (respectively, 32 µSv) was obtained on EOSedge, and 572 µSv (respectively, 179 µSv) on the DR system; these values were compared to effective dose values of 290 µSv (respectively, 200 µSv) from the literature on EOS-1st generation, leading to an effective dose reduction factor of 6 with respect to the DR system, and of 3-6 with respect to EOS-1st generation. EOSedge provides the best compromise between contrast-to-noise ratio (CNR) and dose, with more consistent CNR values than the other tested modalities, in a range of attenuation from 10 to 40 cm of poly(methyl methacrylate) (PMMA). Within this range, EOSedge is also comparable to DR for 10 and 20 cm of PMMA, and better than DR for 30 and 40 cm of PMMA, both in terms of spatial resolution and low-contrast detection. The anatomical landmarks of interest in the follow-up of spinal deformities can be detected in all tested modalities. CONCLUSION: Results showed that EOSedge provides significant dose reduction factors for full spine imaging in both adults and children compared to the other tested modalities, without compromising image quality. We believe that this work could help raise awareness on the capabilities of modern X-ray systems, when equipped with appropriate AEC strategies, to perform ultra-low-dose, long-axis images.

Validation of a Monte Carlo Framework for Out-of-Field Dose Calculations in Proton Therapy.

Proton therapy enables to deliver highly conformed dose distributions owing to the characteristic Bragg peak and the finite range of protons. However, during proton therapy, secondary neutrons are created, which can travel long distances and deposit dose in out-of-field volumes. This out-of-field absorbed dose needs to be considered for radiation-induced secondary cancers, which are particularly relevant in the case of pediatric treatments. Unfortunately, no method exists in clinics for the computation of the out-of-field dose distributions in proton therapy. To help overcome this limitation, a computational tool has been developed based on the Monte Carlo code TOPAS. The purpose of this work is to evaluate the accuracy of this tool in comparison to experimental data obtained from an anthropomorphic phantom irradiation. An anthropomorphic phantom of a 5-year-old child (ATOM, CIRS) was irradiated for a brain tumor treatment in an IBA Proteus Plus facility using a pencil beam dedicated nozzle. The treatment consisted of three pencil beam scanning fields employing a lucite range shifter. Proton energies ranged from 100 to 165 MeV. A median dose of 50.4 Gy(RBE) with 1.8 Gy(RBE) per fraction was prescribed to the initial planning target volume (PTV), which was located in the cerebellum. Thermoluminescent detectors (TLDs), namely, Li-7-enriched LiF : Mg, Ti (MTS-7) type, were used to detect gamma radiation, which is produced by nuclear reactions, and secondary as well as recoil protons created out-of-field by secondary neutrons. Li-6-enriched LiF : Mg,Cu,P (MCP-6) was combined with Li-7-enriched MCP-7 to measure thermal neutrons. TLDs were calibrated in Co-60 and reported on absorbed dose in water per target dose (µGy/Gy) as well as thermal neutron dose equivalent per target dose (µSv/Gy). Additionally, bubble detectors for personal neutron dosimetry (BD-PND) were used for measuring neutrons (>50 keV), which were calibrated in a Cf-252 neutron beam to report on neutron dose equivalent dose data. The Monte Carlo code TOPAS (version 3.6) was run using a phase-space file containing 1010 histories reaching an average standard statistical uncertainty of less than 0.2% (coverage factor k = 1) on all voxels scoring more than 50% of the maximum dose. The primary beam was modeled following a Fermi-Eyges description of the spot envelope fitted to measurements. For the Monte Carlo simulation, the chemical composition of the tissues represented in ATOM was employed. The dose was tallied as dose-to-water, and data were normalized to the target dose (physical dose) to report on absorbed doses per target dose (mSv/Gy) or neutron dose equivalent per target dose (µSv/Gy), while also an estimate of the total organ dose was provided for a target dose of 50.4 Gy(RBE). Out-of-field doses showed absorbed doses that were 5 to 6 orders of magnitude lower than the target dose. The discrepancy between TLD data and the corresponding scored values in the Monte Carlo calculations involving proton and gamma contributions was on average 18%. The comparison between the neutron equivalent doses between the Monte Carlo simulation and the measured neutron doses was on average 8%. Organ dose calculations revealed the highest dose for the thyroid, which was 120 mSv, while other organ doses ranged from 18 mSv in the lungs to 0.6 mSv in the testes. The proposed computational method for routine calculation of the out-of-the-field dose in proton therapy produces results that are compatible with the experimental data and allow to calculate out-of-field organ doses during proton therapy.

Monte Carlo-based software for 3D personalized dose calculations in image-guided radiotherapy.

BACKGROUND AND PURPOSE: Image-guided radiotherapy (IGRT) involves frequent in-room imaging sessions contributing to additional patient irradiation. The present work provided patient-specific dosimetric data related to different imaging protocols and anatomical sites. MATERIAL AND METHODS: We developed a Monte Carlo based software able to calculate 3D personalized dose distributions for five imaging devices delivering kV-CBCT (Elekta and Varian linacs), MV-CT (Tomotherapy machines) and 2D-kV stereoscopic images from BrainLab and Accuray. Our study reported the dose distributions calculated for pelvis, head and neck and breast cases based on dose volume histograms for several organs at risk. RESULTS: 2D-kV imaging provided the minimum dose with less than 1 mGy per image pair. For a single kV-CBCT and MV-CT, median dose to organs were respectively around 30 mGy and 15 mGy for the pelvis, around 7 mGy and 10 mGy for the head and neck and around 5 mGy and 15 mGy for the breast. While MV-CT dose varied sparsely with tissues, dose from kV imaging was around 1.7 times higher in bones than in soft tissue. Daily kV-CBCT along 40 sessions of prostate radiotherapy delivered up to 3.5 Gy to the femoral heads. The dose level for head and neck and breast appeared to be lower than 0.4 Gy for every organ in case of a daily imaging session. CONCLUSIONS: This study showed the dosimetric impact of IGRT procedures. Acquisition parameters should therefore be chosen wisely depending on the clinical purposes and tailored to morphology. Indeed, imaging dose could be reduced up to a factor 10 with optimized protocols.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide.

A strategy for the assembly of the entire carbon backbone of a stereoisomer of the antitumor marine natural product hemicalide has been investigated. The devised convergent approach relies on Horner-Wadsworth-Emmons and Julia-Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 double bonds, respectively, an aldol reaction to create the C27-C28 bond, and a Suzuki-Miyaura cross-coupling as the endgame to form the C15-C16 bond.

Elaboration of Sterically Hindered δ-Lactones through Ring-Closing Metathesis: Application to the Synthesis of the C1-C27 Fragment of Hemicalide.

The synthesis of the C1-C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted δ-lactone framework.

Synthetic Studies toward the C32-C46 Segment of Hemicalide. Assignment of the Relative Configuration of the C36-C42 Subunit.

The synthesis of five diastereomeric model compounds incorporating the C32-C46 segment of the antitumor marine natural product hemicalide has been achieved through a convergent approach relying on the 1,4-addition of an alkenyl boronate to an α,ß-unsaturated δ-lactone followed by α-hydroxylation of an enolate and a Julia-Kocienski olefination. Comparison of the (1)H and (13)C NMR data of the model compounds with those of hemicalide enabled the assignment of the relative configuration of the C36-C42 subunit.

Au-catalyzed formation of functionalized quinolines from 2-alkynyl arylazide derivatives.

A new method for converting 2-alkynyl arylazide derivatives into functionalized polysubstituted quinolines following a gold-catalyzed 1,3-acetoxy shift/cyclization/1,2-group shift sequence has been developed. This transformation proceeds under mild reaction conditions, is efficient, and tolerates a large variety of functional groups.