Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.
The purpose of this study was to investigate the impact of Monte Carlo (MC) calculations and optimized dose definitions in stereotactic body radiotherapy (SBRT) for lung cancer patients. We used a retrospective patient review and basic virtual phantom to determine dose prescriptions. Fifty‐three patients underwent SBRT. A basic virtual phantom had a gross tumor volume (GTV) of 10.0 mm with equivalent water density of 1.0 g/cm3, which was surrounded by equivalent lung surrounding the GTV of 0.25 g/cm3. D95 of the planning target volume (PTV) and D99 of the GTV were evaluated with different GTV sizes (5.0 to 30.0 mm) and different lung densities (0.05 to 0.45 g/cm3). Prescribed dose was defined as 95% of the PTV should receive 100% of the dose (48 Gy/4 fractions) using pencil beam (PB) calculation and recalculated using MC calculation. In the patient study, average doses to the D95 of the PTV and D99 of the GTV using the MC calculation plan were 19.9% and 10.2% lower than those by the PB calculation plan, respectively. In the phantom study, decreased doses to the D95 of the PTV and D99 of the GTV using the MC calculation plan were accompanied with changes GTV size from 30.0 to 5.0 mm, which was decreased from 8.4% to 19.6% for the PTV and from 17.4% to 27.5% for the GTV Similar results were seen with changes in lung density from 0. 45 to 0.05 g/cm3, with doses to the D95 of the PTV and D99 of the GTV were decreased from 12.8% to 59.0% and from 7.6% to 44.8%, respectively. The decrease in dose to the PTV with MC calculation was strongly dependent on lung density. We suggest that dose definition to the GTV for lung cancer SBRT be optimized using MC calculation. Our current clinical protocol for lung SBRT is based on a prescribed dose of 44 Gy in 4 fractions to the GTV using MC calculation.PACS number: 87.55.D‐, 87.55.K‐
Summary Background Germline missense mutations in the GJB2 gene that encodes connexin‐26 (Cx26) have recently been found to be the cause of the keratitis–ichthyosis–deafness (KID) syndrome. Objectives To define the GJB2 mutations in three Japanese patients with KID syndrome. Methods Genomic DNA was extracted from peripheral blood and used to amplify the GJB2 gene. Direct sequencing and endonuclease digestion were used for mutation analysis and DNA‐based diagnosis. Results We identified two heterozygous mis‐sense mutations (D50Y, D50N) in the GJB2 gene in three Japanese patients with KID syndrome. All mutations were located on the first extracellular domain of Cx26. Conclusions These data expand the GJB2 mutation database and show that a dominant mutation of Cx26 can cause KID syndrome in Japanese patients.
Radiochromic films are important tools for assessing complex dose distributions. Gafchromic EBT‐XD films have been designed for optimal performance in the 40–4,000 cGy dose range. We investigated the dosimetric characteristics of these films, including their dose‐response, postexposure density growth, and dependence on scanner orientation, beam energy, and dose rate with applications to high‐dose volumetric‐modulated arc therapy (VMAT) verification. A 10 MV beam from a TrueBeam STx linear accelerator was used to irradiate the films with doses in the 0–4,000 cGy range. Postexposure coloration was analyzed at postirradiation times ranging from several minutes to 48 h. The films were also irradiated with 6 MV (dose rate (DR): 600 MU/min), 6 MV flattening filter‐free (FFF) (DR: 1,400 MU/ min), and 10 MV FFF (DR: 2,400 MU/min) beams to determine the energy and dose‐rate dependence. For clinical examinations, we compared the dose distribution measured with EBT‐XD films and calculated by the planning system for four VMAT cases. The red channel of the EBT‐XD film exhibited a wider dynamic range than the green and blue channels. Scanner orientation yielded a variation of ∼3% in the net optical density (OD). The difference between the film front and back scan orientations was negligible, with variation of ∼1.3% in the net OD. The net OD increased sharply within the first 6 hrs after irradiation and gradually afterwards. No significant difference was observed for the beam energy and dose rate, with a variation of ∼1.5% in the net OD. The gamma passing rates (at 3%, 3 mm) between the film‐ measured and treatment planning system (TPS)‐calculated dose distributions under a high dose VMAT plan in the absolute dose mode were more than 98.9%.PACS number(s): 87.56 Fc
We propose that the number of pulmonary metastases that can be safely treated with SBRT is 6 PTVs with a cumulative V20 of 30 % under the restricted respiratory tumor motion using the Air-Bag System(TM). SBRT for pulmonary metastases offers locally effective treatment for recurrent or residual lesions after first line chemotherapy.
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