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3D printing is a promising solution for the production of bespoke phantoms and phantom components, for radiotherapy dosimetry and quality assurance (QA) purposes. This proof-of-concept study investigated the use of a dual-head printer to deposit two different filaments (polylactic acid (PLA) and StoneFil PLA-concrete (Formfutura BV, Nijmegen, Netherlands)) at several different in-fill densities, to achieve quasi-simultaneous 3D printing of muscle-, lung- and bone-equivalent media. A Raise 3D Pro 3D printer (Raise 3D Technologies Inc, Irvine, USA) was used to print one thoracic and one cranial phantom slab. Analysis using in-house 3D print QA software showed that the two humanoid phantom slabs geometrically matched the stereolithography (STL) files on which they were based, within 0.3 mm, except in one area of the thoracic slab that was affected by thermal warping by up to 3.4 mm. The 3D printed muscle, lung and bone materials in the two humanoid phantom slabs were approximately radiologically-equivalent to human muscle, lung and bone. In particular, the use of StoneFil with a nominally constant in-fill density of 100% resulted in regions that were approximately inner-bone-equivalent, at kV and MV energies. These regions were bounded by walls that were substantially denser than inner bone, although generally not dense enough to be truly cortical-bone-equivalent. This proof-of-concept study demonstrated a method by which multiple tissue-equivalent materials (eg. muscle-, lung- and bone-equivalent media) can be deposited within one 3D print, allowing complex phantom components to be fabricated efficiently in a clinical setting.

The increase in complexity of treatment plans over time through modalities such as intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) has often not been met with an increase in capability of the secondary dose calculation checking systems typically used to verify the treatment planning system. Monte Carlo (MC) codes such as EGSnrc have become easily available and are capable of performing calculations of highly complex radiotherapy treatments. This educational note demonstrates a method for implementing and using a fully automated system for performing and analysing full MC calculations of conformal, IMRT and VMAT radiotherapy plans. Example calculations were based on BEAMnrc/DOSXYZnrc and are performed automatically after either uploading exported plan DICOM data through a Python-based web interface, or exporting DICOM data to a monitored network location. This note demonstrates how completed MC calculations can then be analysed using an automatically generated dose point comparison report, or easily re-imported back into the treatment planning system. Agreement between the TPS and MC calculation was an improvement on agreement between RadCalc and the TPS, with differences ranging from 1.2 to 5.5% between RadCalc and the treatment planning system (TPS), and 0.1–1.7% between MC and TPS. Comparison of the dose-volume histogram (DVH) parameters Dmean, D98%, D2%, and Dmax for the example VMAT plans showed agreement for the mean planning target volume dose within 0.25%, D98% and D2% generally within 1% with the exception of a brain case, and Dmax within 1%. Overall, this note provides a demonstration of a system that has been integrated well into existing clinical workflow, and has been shown to be a valuable additional tool in the secondary checking of treatment plan calculations.

Given the existing literature on the subject, there is obviously a need for specific advice on quality assurance (QA) tolerances for departments using or implementing 3D printed bolus for radiotherapy treatments. With a view to providing initial suggested QA tolerances for 3D printed bolus, this study evaluated the dosimetric effects of changes in bolus geometry and density, for a particularly common and challenging clinical situation: specifically, volumetric modulated arc therapy (VMAT) treatment of the nose. Film-based dose verification measurements demonstrated that both the AAA and the AXB algorithms used by the Varian Eclipse treatment planning system (Varian Medical Systems, Palo Alto, USA) were capable of providing sufficiently accurate dose calculations to allow this planning system to be used to evaluate the effects of bolus errors on dose distributions from VMAT treatments of the nose. Thereafter, the AAA and AXB algorithms were used to calculate the dosimetric effects of applying a range of simulated errors to the design of a virtual bolus, to identify QA tolerances that could be used to avoid clinically significant effects from common printing errors. Results were generally consistent, whether the treatment target was superficial and treated with counter-rotating coplanar arcs or more-penetrating and treated with noncoplanar arcs, and whether the dose was calculated using the AAA algorithm or the AXB algorithm. The results of this study suggest the following QA tolerances are advisable, when 3D printed bolus is fabricated for use in photon VMAT treatments of the nose: bolus relative electron density variation within ±5% (although an action level at ±10% may be permissible); bolus thickness variation within ±1 mm (or 0.5 mm variation on opposite sides); and air gap between bolus and skin ≤5 mm. These tolerances should be investigated for validity with respect to other treatment modalities and anatomical sites. This study provides a set of baselines for future comparisons and a useful method for identifying additional or alternative 3D printed bolus QA tolerances.

Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8 + T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM. Uveal melanoma is highly metastatic and unresponsive to checkpoint immunotherapy. Here, the authors present single-cell transcriptomics of 59,915 cells in 8 primary and 3 metastatic samples, highlighting the diversity of the tumour microenvironment.

This research tested the impact of how group members appraise their collective history on in-group identification and group-based action in the African context. Across three experiments ( N s = 950; 270; and 259) with Nigerian participants, we tested whether the effect of historical representations–specifically the valence of the in-group’s collective history–on in-group engagement, in turn, depends on whether that history is also appraised as subjectively important. In Study 1, findings from exploratory moderated-mediation analyses indicated that the appraised negative valence of African history was associated with an increase in identification and group-based action when African history was appraised as unimportant (history-as-contrast). Conversely, the appraised positive valence of African history was also associated with an increase in identification and group-based action when African history was also appraised as important (history-as-inspiration). Studies 2a and 2b then orthogonally manipulated the valence and subjective importance of African history. However, findings from Studies 2a and 2b did not replicate those of Study 1. Altogether, our findings suggest that the relationship between historical representations of groups and in-group identification and group-based action in the present is more complex than previously acknowledged.

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors. Analysis of signatures of hypoxia in more than 8,000 tumors from 19 cancer types identifies hypoxia-driven mutation signatures and dysregulation of microRNAs.

OBJECTIVE: To compare portion size (PS) estimates, perceived energy density (ED) and anticipated consumption guilt (ACG) for healthier vs standard foods. METHODS: Three pairs of isoenergy dense (kJ per 100 g) foods—healthier vs standard cereals, drinks and coleslaws—were selected. For each food, subjects served an appropriate PS for themselves and estimated its ED. Subjects also rated their ACG about eating the food on a scale of 1 (not at all guilty) to 5 (very guilty). RESULTS: Subjects ( n= 186) estimated larger portions of the healthier coleslaw than that of the standard version, and perceived all healthier foods to be lower in ED than their standard alternatives, despite being isoenergy dense. Higher ACG was associated with the standard foods. Portion estimates were generally larger than recommendations and the ED of the foods was underestimated. CONCLUSIONS: The larger portions selected for the ‘reduced fat’ food in association with lower perceived ED and ACG suggests that such nutrition claims could be promoting inappropriate PS selection and consumption behaviour. Consumer education on appropriate portions is warranted to correct such misconceptions.

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations ( BRCA2 -mutant PCa). We show that BRCA2 -mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2 -mutant PCa shows genomic and epigenomic dysregulation of the MED12L / MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2 -mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2 -mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment. Men that carrier BRCA2 germline mutations are at risk of developing prostate cancer. Here, the authors analyse the genomes of prostate cancer from these individuals and demonstrate increased genomic instability in comparison to sporadic prostate cancer.

Historical representation of collective identity offer means of influencing the extent to which group members engage in activities in line with the collective interests of their group vs. their own individual interests. This research tested the effect of different historical representations of the African people on Africans' perceptions of African social identity and engagement in identity management strategies across two studies. In Study 1 (N = 162), we tested the effect of two historical representations: positive (prestigious precolonial African history and resistance to the colonial power) and negative (inhumane practices of precolonial Africans). In Study 2 (N = 431), we tested the effect of two historical representations: positive (prestigious precolonial African history) and negative factual (inhuman practices of precolonial Africans) while also making salient the ubiquitous historical representation of the African people (negative colonial-perspective) across all history conditions. We predicted that positive (vs. negative) historical representation would lead to more positive perceptions of African identity, which in turn would predict more collectively-oriented identity management strategies. Altogether, results provided no support for these predictions. We highlight methodological (and by extension theoretical) features-such as, psychological reactance and outgroup audience effect-which may have limited the effect of the manipulations to help inform the interpretation of the null findings obtained. We conclude by discussing other limitations and the theoretical implications of our work, before pointing out various avenues for future research to help us better test, and understand, the role of historical representation in the African context.

We consider how different choices of kinetic energy in Hamiltonian Monte Carlo affect algorithm performance. To this end, we introduce two quantities which can be easily evaluated, the composite gradient and the implicit noise. Results are established on integrator stability and geometric convergence, and we show that choices of kinetic energy that result in heavy-tailed momentum distributions can exhibit an undesirable negligible moves property, which we define. A general efficiency-robustness trade-off is outlined, and implementations which rely on approximate gradients are also discussed. Two numerical studies illustrate our theoretical findings, showing that the standard choice which results in a Gaussian momentum distribution is not always optimal in terms of either robustness or efficiency.