Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients.

BackgroundGender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied.MethodsForty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974-2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients.ResultsOur murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations.ConclusionsAlthough our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance

Correction factors to convert microdosimetry measurements in silicon to tissue in \u3csup\u3e12\u3c/sup\u3eC ion therapy

Silicon microdosimetry is a promising technology for heavy ion therapy (HIT) quality assurance, because of its sub-mm spatial resolution and capability to determine radiation effects at a cellular level in a mixed radiation field. A drawback of silicon is not being tissue-equivalent, thus the need to convert the detector response obtained in silicon to tissue. This paper presents a method for converting silicon microdosimetric spectra to tissue for a therapeutic 12C beam, based on Monte Carlo simulations. The energy deposition spectra in a 10 μm sized silicon cylindrical sensitive volume (SV) were found to be equivalent to those measured in a tissue SV, with the same shape, but with dimensions scaled by a factor κ equal to 0.57 and 0.54 for muscle and water, respectively. A low energy correction factor was determined to account for the enhanced response in silicon at low energy depositions, produced by electrons. The concept of the mean path length (lPath) to calculate the lineal energy was introduced as an alternative to the mean chord length (l) because it was found that adopting Cauchy\u27s formula for the (l) was not appropriate for the radiation field typical of HIT as it is very directional (lPath) can be determined based on the peak of the lineal energy distribution produced by the incident carbon beam. Furthermore it was demonstrated that the thickness of the SV along the direction of the incident 12C ion beam can be adopted as (lPath). The tissue equivalence conversion method and (lPath) were adopted to determine the RBE10, calculated using a modified microdosimetric kinetic model, applied to the microdosimetric spectra resulting from the simulation study. Comparison of the RBE10 along the Bragg peak to experimental TEPC measurements at HIMAC, NIRS, showed good agreement. Such agreement demonstrates the validity of the developed tissue equivalence correction factors and of the determination of (lPath)

Impacts of fallow conditions, compost and silicate fertilizer on soil nematode community in salt–affected paddy rice fields in acid sulfate and alluvial soils in the Mekong Delta, Vietnam

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)Avoidance of intensive rice cultivation (IRC) and soil amendments are potential practices to enhance soil properties. There is only limited information on the effects of reduced IRC and its mixture with compost or silicate fertilizer (Si) on the soil nematode community in salt–affected soils. This study aimed to assess the shifts of soil nematode community by reducing a rice crop from triple rice system (RRR) to a double rice system and mixed with compost or Si in paddy fields in acid sulfate soil (ASS) and alluvial soil (AL) in the Mekong Delta, Vietnam. Field experiments were designed with four treatments in four replicates, including RRR and a proposed system of double–rice followed by a fallow (FRR) and with 3 Mg ha–1 crop−1 compost or 100 kg ha–1 crop−1 Si. Soils were collected at harvest after the 2 year experiment, reflecting the fifth and third consecutive rice crop in RRR and FRR system, respectively. Results showed that reduced IRC gave a significant reduction in abundance of plant–parasitic nematodes (PPN), dominated by Hirschmanniella and increased abundance bacterivorous nematodes when mixed to compost and silicate fertilizer in ASS. In addition, reduced IRC increased nematode biodiversity Hill’s indices and reduced herbivorous footprint in ASS. Proposed system having compost or Si had strongly increased in bacterivorous and omnivorous footprints. Particularly, reduced IRC mixture with Si increased abundance of Rhabdolaimus, Mesodorylaimus and Aquatides, metabolic footprints (structure footprint, bacterivorous, omnivorous and predator) and diversity Hill’s N1 index in ASS. Our results highlighted that reduced IRC was a beneficial practice for decreasing abundance of PPN in salt-affected soils and increasing abundance of FLN in ASS. IRC mixture with compost or Si had potential in structuring the nematode communities with increasing biodiversity, trophic structure, and metabolic footprintsPeer reviewedFinal Accepted Versio

Experimental studies with two novel silicon detectors for the development of time-of-flight spectrometry of laser-accelerated proton beams

Laser-accelerated proton beams exhibit remarkably different beam characteristics as compared to conventionally accelerated ion beams. About 105 to 107 particles per MeV and msr are accelerated quasi-instantaneously within about 1 ps. The resulting energy spectrum typically shows an exponentially decaying distribution. Our planned approach to determine the energy spectrum of the particles generated in each pulse is to exploit the time-of-flight (TOF) difference of protons with different kinetic energies at 1 m distance from the laser-target interaction. This requires fast and sensitive detectors. We therefore tested two prototype silicon detectors, developed at the Centre for Medical Radiation Physics at the University of Wollongong with a current amplifier, regarding their suitability for TOF-spectrometry in terms of sensitivity and timing properties. For the latter, we illuminated the detectors with short laser pulses, measured the signal current and compared it to the signal of a fast photodiode. The comparison revealed that the timing properties of both prototypes are not yet sufficient for our purpose. In contrast, our results regarding the detectors\u27 sensitivity are promising. The lowest detectable proton flux at 10 MeV was found to be 25 protons per ns on the detector. With this sensitivity and with a smaller pixelation of the detectors, the timing properties can be improved for new prototypes, making them potential candidates for TOF-spectrometry of laser-accelerated particle beams

Novel Dedifferentiated Liposarcoma Xenograft Models Reveal PTEN Down-Regulation as a Malignant Signature and Response to PI3K Pathway Inhibition

Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care

3D silicon microdosimetry and RBE study using C-12 ion of different energies

This paper presents a new version of the 3D mesa "bridge" microdosimeter comprised of an array of 4248 silicon cells fabricated on 10 µm thick silicon-on-insulator substrate. This microdosimeter has been designed to overcome limitations existing in previous generation silicon microdosimeters and it provides well-defined sensitive volumes and high spatial resolution. The charge collection characteristics of the new 3D mesa microdosimeter were investigated using the ANSTO heavy ion microprobe, utilizing 5.5 MeV He2+ ions. Measurement of microdosimetric quantities allowed for the determination of the Relative Biological Effectiveness of 290 MeV/u and 350 MeV/u 12C heavy ion therapy beams at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. The microdosimetric RBE obtained showed good agreement with the tissue-equivalent proportional counter. Utilizing the high spatial resolution of the SOI microdosimeter, the LET spectra for 70 MeV 12C+6 ions, like those present at the distal edge of 290 and 350 MeV/u beams, were obtained as the ions passed through thin layers of polyethylene film. This microdosimeter can provide useful information about the lineal energy transfer (LET) spectra downstream of the protective layers used for shielding of electronic devices for single event upset prediction

Predicting the Biological Effects of Human Salivary Gland Tumour Cells for Scanned 4He-, 12C-, 16O-, and 20Ne-Ion Beams Using an SOI Microdosimeter

Experimental microdosimetry along with the microdosimetric kinetic (MK) model can be utilized to predict the biological effects of ions. To predict the relative biological effectiveness (RBE) of ions and the survival fraction (SF) of human salivary gland tumour (HSGc-C5) cells, microdosimetric quantities measured by a silicon-on-insulator (SOI) MicroPlus-mushroom microdosimeter along the spread-out Bragg peak (SOBP) delivered by pencil beam scanning of 4He, 12C, 16O, and 20Ne ions were used. The MK model parameters of HSGc-C5 cells were obtained from the best fit of the calculated SF for the different linear energy transfer (LET) of these ions and the formerly reported in vitro SF for the same LET and ions used for calculations. For a cube-shaped target of 10 × 10 × 6 cm3, treatment plans for 4He, 12C, 16O, and 20Ne ions were produced with proprietary treatment planning software (TPS) aiming for 10% SF of HSGc-C5 cells over the target volume and were delivered to a polymethyl methacrylate (PMMA) phantom. Afterwards, the saturation-corrected dose-mean lineal energy derived based on the measured microdosimetry spectra, along with the physical dose at various depths in PMMA phantoms, was used for the estimation of the SF, RBE, and RBE-weighted dose using the MK model. The predicted SF, RBE, and the RBE-weighted dose agreed with what was planned by the TPS within 3% at most depths for these ions.publishedVersio

Thin Silicon Microdosimeter utilizing 3D MEMS Fabrication Technology: Charge Collection Study and its application in mixed radiation fields

New 10-μm-thick silicon microdosimeters utilizing 3-D technology have been developed and investigated in this paper. The TCAD simulations were carried out to understand the electrical properties of the microdosimeters\u27 design. A charge collection study of the devices was performed using 5.5-MeV He2+ ions which were raster scanned over the surface of the detectors and the charge collection median energy maps were obtained and the detection yield was also evaluated. The devices were tested in a 290 MeV/u carbon ion beam at the Heavy Ion Medical Accelerator in Chiba (HIMAC) in Japan. Based on the microdosimetric measurements, the quality factor and dose equivalent out of field were obtained in a mixed radiation field mimicking the radiation environment for spacecraft in deep space

Social Contact Patterns in Vietnam and Implications for the Control of Infectious Diseases

BACKGROUND: The spread of infectious diseases from person to person is determined by the frequency and nature of contacts between infected and susceptible members of the population. Although there is a long history of using mathematical models to understand these transmission dynamics, there are still remarkably little empirical data on contact behaviors with which to parameterize these models. Even starker is the almost complete absence of data from developing countries. We sought to address this knowledge gap by conducting a household based social contact diary in rural Vietnam. METHODS AND FINDINGS: A diary based survey of social contact patterns was conducted in a household-structured community cohort in North Vietnam in 2007. We used generalized estimating equations to model the number of contacts while taking into account the household sampling design, and used weighting to balance the household size and age distribution towards the Vietnamese population. We recorded 6675 contacts from 865 participants in 264 different households and found that mixing patterns were assortative by age but were more homogenous than observed in a recent European study. We also observed that physical contacts were more concentrated in the home setting in Vietnam than in Europe but the overall level of physical contact was lower. A model of individual versus household vaccination strategies revealed no difference between strategies in the impact on R(0). CONCLUSIONS AND SIGNIFICANCE: This work is the first to estimate contact patterns relevant to the spread of infections transmitted from person to person by non-sexual routes in a developing country setting. The results show interesting similarities and differences from European data and demonstrate the importance of context specific data