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Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumor material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumor showed a mutant expression pattern (including subclonal): overexpression, null or cytoplasmic. The presence of pathogenic mutations was determined by next generation sequencing (NGS). Abnormal p53 expression was observed in 131/408 (32%) tumors. The most common abnormal p53 IHC pattern was overexpression (n = 89, 68%), followed by null (n = 12, 9%) and cytoplasmic (n = 3, 2%). Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLE mutations and/or MMRd (n = 22/27; p < 0.001). Agreement between p53 IHC and TP53 NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Excluding POLEmut and MMRd EC, as per the WHO-endorsed algorithm, increased the accuracy to 94.5% with sensitivity and specificity of 95.0% and 94.1%, respectively. Our data shows that awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC. No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns. Our data support use of the WHO-endorsed algorithm and combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC).

The tumour suppressor PTEN is a key negative regulator of the PI3K-Akt pathway, and is frequently either reduced or lost in human tumours. Murine genetic studies have confirmed that reduction of Pten promotes tumourigenesis in multiple organs, and demonstrated dependency of tumour development on the activation of downstream components such as Akt. Insulin-like growth factors (IGFs) act via IGF1R to activate the PI3K-Akt pathway, and are commonly upregulated in cancer. A context-dependent interplay between IGFs and PTEN exists in normal tissue and tumours; increased IGF2 ligand supply induces Pten expression creating an autoregulatory negative feedback loop, whereas complete loss of PTEN may either cooperate with IGF overexpression in tumour promotion, or result in desensitisation to IGF ligand. However, it remains unknown whether neoplasia associated with Pten loss is dependent on upstream IGF ligand supply in vivo. We evaluated this by generation of [Pten.sup.+/-] mice with differing allelic dosage of Igf1, an imprinted gene encoding the potent embryonic and tumour growth factor Igf2. We show that biallelic Igf1 supply potentiates a previously unreported [Pten.sup.+/-] placental phenotype and results in strain-dependent cardiac hyperplasia and neonatal lethality. Importantly, we also show that the effects of Pten loss in vivo are modified by Igf1 supply, as lack of Igf1 results in extended survival and delayed tumour development while biallelic supply is associated with reduced lifespan and accelerated neoplasia in females. Furthermore, we demonstrate that reduction of PTEN protein to heterozygote levels in human MCF7 cells is associated with increased proliferation in response to IGF2, and does not result in desensitisation to IGF2 signalling. These data indicate that the effects of Pten loss at heterozygote levels commonly observed in human tumours are modified by Igf2 ligand, and emphasise the importance of the evaluation of upstream pathways in tumours with Pten loss.

The National Ignition Facility (NIF) relies on a suite of nuclear diagnostics to measure the neutronic output of experiments. Neutron time-of-flight (NTOF) and neutron activation diagnostics (NAD) provide performance metrics of absolute neutron yield and neutron spectral content: spectral width and non-thermal content, from which implosion physical quantities of temperature and scattering mass are inferred. Spatially-distributed flange- mounted NADs (FNAD) measure, with nearly identical systematic uncertainties, primary DT neutron emission to infer a whole-sky neutron field. An automated FNAD system is being developed. A magnetic recoil spectrometer (MRS) shares few systematics with comparable NTOF and NAD devices, and as such is deployed for independent measurement of the primary neutronic quantities. The gas-Cherenkov Gamma Reaction History (GRH) instrument records four energy channels of time-resolved gamma emission to measure nuclear bang time and burn width, as well as to infer carbon areal density in experiments utilizing plastic or diamond capsules. A neutron imaging system (NIS) takes two images of the neutron source, typically gated to create coregistered 13-15 MeV primary and 6-12 MeV downscattered images. The radiochemical analysis of gaseous samples (RAGS) instrument pumps target chamber gas to a chemical reaction and fractionation system configured with gamma counters, allowing measurement of radionuclides with half-lives as short as 8 seconds. Solid radiochemistry collectors (SRC) with backing NAD foils collect target debris, where activated materials from the target assembly are used as indicators of neutron spectrum content, and also serve as the primary diagnostic for nuclear forensic science experiments. Particle time-of-flight (PTOF) measures compression-bang time using DT- or DD-neutrons, as well as shock bang-time using D3He-protons for implosions with lower x-ray background. In concert, these diagnostics serve to measure the basic and advanced quantities required to understand NIF experimental results.