Differences in somatic TP53 mutation type in breast tumors by race and receptor status

Purpose: Somatic driver mutations in TP53 are associated with triple-negative breast cancer (TNBC) and poorer outcomes. Breast cancers in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than cancers in non-Hispanic White (NHW) women. Missense driver mutations in TP53 have varied functional impact including loss-of-function (LOF) or gain-of-function (GOF) activity, and dominant negative (DNE) effects. We aimed to determine if there were differences in somatic TP53 mutation types by patient ancestry or TNBC status. Methods: We identified breast cancer datasets with somatic TP53 mutation data, ancestry, age, and hormone receptor status. Mutations were classified for functional impact using published data and type of mutation. We assessed differences using Fisher’s exact test. Results: From 96 breast cancer studies, we identified 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. The distribution of TP53 mutation type was similar by ancestry. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% from AA individuals (p = 0.04). Mutations with DNE activity were positively associated with TNBC (OR 1.37, p = 0.03) and estrogen receptor (ER) negative status (OR 1.38; p = 0.005). Conclusions: Somatic TP53 mutation types did not differ by ancestry overall, but GOF mutations were more common in NHW women than AA women. ER-negative and TNBC tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts and functional studies are needed to further elucidate these findings

Low cycle fatigue of a directionally solidified nickel-based superalloy: Testing, characterisation and modelling

Low cycle fatigue (LCF) of a low-carbon (LC) directionally-solidified (DS) nickel-base superalloy, CM247 LC DS, was investigated using both experimental and computational methods. Strain-controlled LCF tests were conducted at 850°C, with a loading direction either parallel or perpendicular to the solidification direction. Trapezoidal loading-waveforms with 2 s and 200 s dwell times imposed at the minimum and the maximum strains were adopted for the testing. A constant strain range of 2% was maintained throughout the fully-reversed loading conditions (strain ratio R = −1). The observed fatigue life was shorter when the loading direction was perpendicular to the solidification one, indicating an anisotropic material response. It was found that the stress amplitude remained almost constant until final fracture, suggesting limited cyclic hardening/softening. Also, stress relaxation was clearly observed during the dwell period. Scanning Electron Microscopy fractographic analyses showed evidence of similar failure modes in all the specimens. To understand deformation at grain level, crystal plasticity finite element modelling was carried out based on grain textures measured with EBSD. The model simulated the full history of cyclic stress-strain responses. It was particularly revealed that the misorientations between columnar grains resulted in heterogeneous deformation and localised stress concentrations, which became more severe when the loading direction was normal to a solidification direction, explaining the shorter fatigue life observed

The Cholecystectomy As A Day Case (CAAD) Score: A Validated Score of Preoperative Predictors of Successful Day-Case Cholecystectomy Using the CholeS Data Set

Background Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preoperative variables. Methods Data were extracted from a prospectively collected data set of cholecystectomy patients from 166 UK and Irish hospitals (CholeS). Cholecystectomies performed as elective procedures were divided into main (75%) and validation (25%) data sets. Preoperative predictors were identified, and a risk score of failed day case was devised using multivariate logistic regression. Receiver operating curve analysis was used to validate the score in the validation data set. Results Of the 7426 elective cholecystectomies performed, 49% of these were discharged home the same day. Same-day discharge following cholecystectomy was less likely with older patients (OR 0.18, 95% CI 0.15–0.23), higher ASA scores (OR 0.19, 95% CI 0.15–0.23), complicated cholelithiasis (OR 0.38, 95% CI 0.31 to 0.48), male gender (OR 0.66, 95% CI 0.58–0.74), previous acute gallstone-related admissions (OR 0.54, 95% CI 0.48–0.60) and preoperative endoscopic intervention (OR 0.40, 95% CI 0.34–0.47). The CAAD score was developed using these variables. When applied to the validation subgroup, a CAAD score of ≤5 was associated with 80.8% successful day-case cholecystectomy compared with 19.2% associated with a CAAD score >5 (p < 0.001). Conclusions The CAAD score which utilises data readily available from clinic letters and electronic sources can predict same-day discharges following cholecystectomy

Scaling of elastic energy storage in mammalian limb tendons: do small mammals really lose out?

It is widely believed that elastic energy storage is more important in the locomotion of larger mammals. This is based on: (a) comparison of kangaroos with the smaller kangaroo rat; and (b) calculations that predict that the capacity for elastic energy storage relative to body mass increases with size. Here we argue that: (i) data from kangaroos and kangaroo rats cannot be generalized to other mammals; (ii) the elastic energy storage capacity relative to body mass is not indicative of the importance of elastic energy to an animal; and (iii) the contribution of elastic energy to the mechanical work of locomotion will not increase as rapidly with size as the mass-specific energy storage capacity, because larger mammals must do relatively more mechanical work per stride. We predict how the ratio of elastic energy storage to mechanical work will change with size in quadrupedal mammals by combining empirical scaling relationships from the literature. The results suggest that the percentage contribution of elastic energy to the mechanical work of locomotion decreases with size, so that elastic energy is more important in the locomotion of smaller mammals. This now needs to be tested experimentally

PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines

Deletions detected in cytogenetic and loss of heterozygosity (LOH) studies indicate that at least one tumour suppressor gene maps to the long arm of chromosome 10. Previous deletion mapping studies have observed LOH on 10q in about 30% of melanomas analysed. The PTEN gene, mapping to chromosome band 10q23.3, encodes a protein with both lipid and protein phosphatase activity. Somatic mutations and deletions in have been detected in a variety of cell lines and tumours, including melanoma samples. We performed mutation analyses and extensive allelic loss studies to investigate the role this gene plays in melanoma pathogenesis. We found that a total of 34 out of 57 (60%) melanoma cell lines carried hemizygous deletions of chromosome 10q encompassing the PTEN locus. A further three cell lines carried smaller deletions excluding PTEN. Inactivation of both PTEN alleles by exon-specific homozygous deletion or mutation was observed in 13 out of 57 (23%) melanoma cell lines. The mutation spectrum observed does not indicate an important role for ultraviolet radiation in the genesis of these mutations, and evidence from three cell lines supports the acquisition of PTEN aberrations in culture. Ten out of 49 (20%) matched melanoma tumour/normal samples harboured hemizygous deletions of either the whole chromosome or most of the long arm. Mutations within were detected in only one of the 10 tumours demonstrating LOH at 10q23 that were analysed. These results suggest that PTEN inactivation may be important for the propagation of melanoma cells in culture, and that another chromosome 10 tumour suppressor gene may be important for melanoma pathogenesis