The low-LET radiation contribution to the tumor dose in diffusing alpha-emitters radiation therapy

Diffusing alpha-emitters Radiation Therapy (Alpha DaRT) enables the use of alpha particles for the treatment of solid tumors. It employs interstitial sources carrying a few uCi of Ra-224, designed to release its short-lived progeny, which emit alpha particles, beta, Auger, and conversion electrons, x- and gamma rays. These atoms diffuse around the source and create a lethal high-dose region, measuring a few mm in diameter. Previous studies focused on the alpha dose alone. This work addresses the electron and photon contributed by the diffusing atoms and by the atoms on the source surface, for both a single source and multi-source lattices. This allows to evaluate the low-LET contribution to the dose and demonstrate the sparing of surrounding healthy tissue. The dose is calculated using Monte Carlo codes. We compare the results of a simple line-source to those of a full simulation, which implements a realistic source geometry and the spread of the diffusing atoms. We consider two extreme scenarios: low diffusion and high Pb-212 leakage, and high diffusion and low leakage. The low-LET dose in source lattices is calculated by superposition of single-source contributions. We found that for sources carrying 3 uCi/cm Ra-224 arranged in a hexagonal lattice with 4 mm spacing, the minimal low-LET dose between sources is 18-30 Gy for the two scenarios and is dominated by the beta contribution. The low-LET dose drops below 5 Gy 3 mm away from the lattice. The accuracy of the line-source approximation is 15% for the total low-LET dose over clinically relevant distances (2-4 mm). For 3 uCi/cm Ra-224 sources, the contribution of the low-LET dose can reduce cell survival by up to 2-3 orders of magnitude. Increasing source activities by a factor of 5 can bring the low-LET dose to therapeutic levels leading to a self-boosted configuration, and potentially allowing to increase the lattice spacing.Comment: Submitted to Medical Physic

Initial Safety and Tumor Control Results From a "First-in-Human" Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck.

Purpose Our purpose was to report the feasibility and safety of diffusing alpha-emitter radiation therapy (DaRT), which entails the interstitial implantation of a novel alpha-emitting brachytherapy source, for the treatment of locally advanced and recurrent squamous cancers of the skin and head and neck. Methods and Materials This prospective first-in-human, multicenter clinical study evaluated 31 lesions in 28 patients. The primary objective was to determine the feasibility and safety of this approach, and the secondary objectives were to evaluate the initial tumor response and local progression-free survival. Eligibility criteria included all patients with biopsy-proven squamous cancers of the skin and head and neck with either primary tumors or recurrent/previously treated disease by either surgery or prior external beam radiation therapy; 13 of 31 lesions (42%) had received prior radiation therapy. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. Tumor response was assessed at 30 to 45 days at a follow-up visit using the Response Evaluation Criteria in Solid Tumors, version 1.1. Median follow-up time was 6.7 months. Results Acute toxicity included mostly local pain and erythema at the implantation site followed by swelling and mild skin ulceration. For pain and grade 2 skin ulcerations, 90% of patients had resolution within 3 to 5 weeks. Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); 6 lesions (6/28, 21.4%) manifested a partial response (>30% tumor reduction). Among the 22 lesions with a complete response, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 4.9 months (range, 2.43-5.52 months). The 1-year local progression-free survival probability at the implanted site was 44% overall (confidence interval [CI], 20.3%-64.3%) and 60% (95% CI, 28.61%-81.35%) for complete responders. Overall survival rates at 12 months post-DaRT implantation were 75% (95% CI, 46.14%-89.99%) among all patients and 93% (95% CI, 59.08%-98.96%) among complete responders. Conclusions Alpha-emitter brachytherapy using DaRT achieved significant tumor responses without grade 3 or higher toxicities observed. Longer follow-up observations and larger studies are underway to validate these findings

Diffusing Alpha-Emitters Radiation Therapy in Combination With Temozolomide or Bevacizumab in Human Glioblastoma Multiforme Xenografts

Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of 224Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients

Calcium Handling in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

BACKGROUND: The ability to establish human induced pluripotent stem cells (hiPSCs) by reprogramming of adult fibroblasts and to coax their differentiation into cardiomyocytes opens unique opportunities for cardiovascular regenerative and personalized medicine. In the current study, we investigated the Ca(2+)-handling properties of hiPSCs derived-cardiomyocytes (hiPSC-CMs). METHODOLOGY/PRINCIPAL FINDINGS: RT-PCR and immunocytochemistry experiments identified the expression of key Ca(2+)-handling proteins. Detailed laser confocal Ca(2+) imaging demonstrated spontaneous whole-cell [Ca(2+)](i) transients. These transients required Ca(2+) influx via L-type Ca(2+) channels, as demonstrated by their elimination in the absence of extracellular Ca(2+) or by administration of the L-type Ca(2+) channel blocker nifedipine. The presence of a functional ryanodine receptor (RyR)-mediated sarcoplasmic reticulum (SR) Ca(2+) store, contributing to [Ca(2+)](i) transients, was established by application of caffeine (triggering a rapid increase in cytosolic Ca(2+)) and ryanodine (decreasing [Ca(2+)](i)). Similarly, the importance of Ca(2+) reuptake into the SR via the SR Ca(2+) ATPase (SERCA) pump was demonstrated by the inhibiting effect of its blocker (thapsigargin), which led to [Ca(2+)](i) transients elimination. Finally, the presence of an IP3-releasable Ca(2+) pool in hiPSC-CMs and its contribution to whole-cell [Ca(2+)](i) transients was demonstrated by the inhibitory effects induced by the IP3-receptor blocker 2-Aminoethoxydiphenyl borate (2-APB) and the phospholipase C inhibitor U73122. CONCLUSIONS/SIGNIFICANCE: Our study establishes the presence of a functional, SERCA-sequestering, RyR-mediated SR Ca(2+) store in hiPSC-CMs. Furthermore, it demonstrates the dependency of whole-cell [Ca(2+)](i) transients in hiPSC-CMs on both sarcolemmal Ca(2+) entry via L-type Ca(2+) channels and intracellular store Ca(2+) release

Rapid response to the M_w 4.9 earthquake of November 11, 2019 in Le Teil, Lower Rhône Valley, France

On November 11, 2019, a Mw 4.9 earthquake hit the region close to Montelimar (lower Rhône Valley, France), on the eastern margin of the Massif Central close to the external part of the Alps. Occuring in a moderate seismicity area, this earthquake is remarkable for its very shallow focal depth (between 1 and 3 km), its magnitude, and the moderate to large damages it produced in several villages. InSAR interferograms indicated a shallow rupture about 4 km long reaching the surface and the reactivation of the ancient NE-SW La Rouviere normal fault in reverse faulting in agreement with the present-day E-W compressional tectonics. The peculiarity of this earthquake together with a poor coverage of the epicentral region by permanent seismological and geodetic stations triggered the mobilisation of the French post-seismic unit and the broad French scientific community from various institutions, with the deployment of geophysical instruments (seismological and geodesic stations), geological field surveys, and field evaluation of the intensity of the earthquake. Within 7 days after the mainshock, 47 seismological stations were deployed in the epicentral area to improve the Le Teil aftershocks locations relative to the French permanent seismological network (RESIF), monitor the temporal and spatial evolution of microearthquakes close to the fault plane and temporal evolution of the seismic response of 3 damaged historical buildings, and to study suspected site effects and their influence in the distribution of seismic damage. This seismological dataset, completed by data owned by different institutions, was integrated in a homogeneous archive and distributed through FDSN web services by the RESIF data center. This dataset, together with observations of surface rupture evidences, geologic, geodetic and satellite data, will help to unravel the causes and rupture mechanism of this earthquake, and contribute to account in seismic hazard assessment for earthquakes along the major regional Cévenne fault system in a context of present-day compressional tectonics

Effectiveness of Autologous Tissue Grafts on Soft Tissue Ingrowth in Patients Following Partial Root Extraction with Socket Shield: A Retrospective Analysis of a Case Series

Abstract Purpose: There is little knowledge about healing patterns for the socket with an intentionally retained root fragment: a socket shield. The clinical observation is soft tissue ingrowth next to the socket shield. The aim of this study was to evaluate the effectiveness of autologous grafting matrices in preventing soft tissue ingrowth. Materials and methods: Patient data from a private clinic were searched for sockets with a socket shield left to heal with blood clot or grafted with autologous materials: autologous platelet- rich fibrin (PRF), scraped particulate bone, cortical tuberosity bone plate, or particulate dentin and covered with PRF membranes. The included sites were exposed by the flap 4 months after the first surgery, and soft tissue ingrowth depth and width next to the root fragment were measured by a scaled probe and documented. Results: Evaluation of 34 sites showed the greatest depth of soft tissue ingrowth in the nongrafted sockets (6.0 ± 0.0 mm). Grafting with PRF plugs (depth of 2.3 ± 0.2 mm) or particulate bone (depth of 2.7 ± 0.6 mm) decreased soft tissue ingrowth. Grafting with particulate dentin or cortical tuberosity bone plate resulted in a soft tissue ingrowth depth of only 1 mm, yielding the best clinical outcome. Radiography confirmed those findings. Conclusion: Autologous dentin particulate or tuberosity cortical bone plate is most effective for preventing soft tissue ingrowth

Numerical Simulations of Large Martian Impact Ripples

Ripples made from unimodal fine sands can grow much larger on Mars than on Earth, reaching wavelengths of 1–3 m and heights exceeding 1 dm. Smaller decimeter-wavelength ripples can be superimposed on them. Classification and origins of these bedforms have been debated. They have been interpreted as analogous to subaqueous ripples on Earth, or as aeolian impact ripples with a range of grain sizes that reach large maximum sizes on Mars. This study uses a mathematical model to evaluate the formation of large Martian ripples as aeolian impact ripples to further investigate this hypothesis. The model parameters were computed using COMSALT for 100 µm grains under shear velocity of 0.65 m/s, which is a reasonable shear velocity for sand transport on Mars according to recent estimations of threshold Martian winds. The numerical experiments utilize a large grid 8 m long. Experiments also evaluate the development of secondary small ripples between the large ripples from random perturbations. The numerical simulations show the evolution of ripple wavelength and height. According to the results, the time scale for the formation of the large ripples is about 2–3 years, which is a much longer time scale compared to terrestrial impact ripples. Small secondary ripples develop only if the space between the large ripples is sufficiently large