KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

BACKGROUND: KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC. METHODS: We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients. RESULTS: Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P = 0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P = 0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P = 0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P = 0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P = 0.047) and worse PFS (HR: 0.45, P = 0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P = 0.0005) and PFS (HR: 0.51, P = 0.006) compared with KRAS and BRAF wild-type patients. CONCLUSION: Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs. British Journal of Cancer (2009) 101, 715-721. doi: 10.1038/sj.bjc.6605177 www.bjcancer.com Published online 14 July 2009 (C) 2009 Cancer Research U

Tracking Rapid Permafrost thaw Through Time: Exploring the Potential of Convolutional Neural Network based Models

This paper presents the novel use of convolutional neural network (CNN)-based machine learning models for remotely detecting and monitoring retrogressive thaw slumps (RTS) in high latitude northern permafrost using open-source Sentinel-2 satellite data. RTS are indicative of rapid permafrost thaw (RPT), the accelerated release of greenhouse gases (GHG) and potentially runaway changes in the cryosphere. Attempts to quantify GHG emissions from RTS are inhibited by a lack of information on RTS incidence and area affected. We show that site-specific CNN models can be used to produce time series data on rapid RTS development that allow for the approximation of associated GHG emissions. For the sites assessed we achieve good model precision, recall and F1 values of > 0.8. The short time series studied so far do not reveal clear trends in RTS development. These limitations arise from the low resolution of Sentinel-2 data (10 m) and limited availability and diversity of validated training data. The capability shown here is the first step towards achieving automated monitoring of rapid environmental change in permafrost using satellite data. This work highlights the need for ready access to open-source high resolution satellite data and permafrost field data if the potential of such approaches is to be fully realized

Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes

Histone H3 lysine 4 (H3K4me) methyltransferases and their cofactors are essential for embryonic development and the establishment of gene expression patterns in a cell-specific and heritable manner. However, the importance of such epigenetic marks in maintaining gene expression in adults and in initiating human disease is unclear. Here, we addressed this question using a mouse model in which we could inducibly ablate PAX interacting (with transcription-activation domain) protein 1 (PTIP), a key component of the H3K4me complex, in cardiac cells. Reducing H3K4me3 marks in differentiated cardiomyocytes was sufficient to alter gene expression profiles. One gene regulated by H3K4me3 was Kv channel-interacting protein 2 (Kcnip2), which regulates a cardiac repolarization current that is downregulated in heart failure and functions in arrhythmogenesis. This regulation led to a decreased sodium current and action potential upstroke velocity and significantly prolonged action potential duration (APD). The prolonged APD augmented intracellular calcium and in vivo systolic heart function. Treatment with isoproterenol and caffeine in this mouse model resulted in the generation of premature ventricular beats, a harbinger of lethal ventricular arrhythmias. These results suggest that the maintenance of H3K4me3 marks is necessary for the stability of a transcriptional program in differentiated cells and point to an essential function for H3K4me3 epigenetic marks in cellular homeostasis

Samian Pottery in Britain: Exploring its Distribution and Archaeological Potential

This paper presents some of the results of an English Heritage funded study of the distribution of samian pottery (Terra Sigillata). It aims to highlight the value of samian pottery as a resource for exploring a range of archaeological questions beyond its essential role in providing dating evidence. The work to date has comprised a pilot study designed to assemble an initial database of stratified samian groups, to test methodologies and to explore the character of samian distribution. Some substantive patterns identified from the database are reproduced here and discussed. The opportunity is also taken to clarify baseline trends in the occurrence of samian within Roman pottery assemblages, and to place patterns in the incidence of this ware within the wider context of Roman Britain. A number of other aspects of archaeological value, for instance, the nature of samian from rural sites and the potential use of samian in ritual actions, are also evaluated. A written report and (hardcopy) database were produced in 1997 (Willis 1997b), which presented the results of phase 1 of the survey, with approximately 50 copies circulated for comment. The middle section of the present paper draws on this report. It is hoped that in due course the database will be accessible to all potential users (including excavators, students, curators and academics), for the comparison of samian assemblages from different sites. The database should establish whether there are ‘normal patterns’ of samian occurrence/supply, by region, time, and site type, against which individual site assemblages may be compared. The focus of the pilot study, being funded by English Heritage, has been upon sites within England. However, evidence from sites in Wales and Scotland, both military and civilian, has equal relevance constituting important comparative data. Samian assemblages from these parts of Britain are hence included in the current discussion. Considering the larger canvas, samian work in Britain is part of an international context of study, of what was a widely distributed and imitated material. Specialists in Britain are closely networked with workers elsewhere in western Europe. One of the most fruitful aspects of this liaison is the potential for identifying similarities and differences in the incidence of samian from region to region. It is hoped that the present paper, identifying trends in the British evidence, can contribute to inter-provincial comparisons. This paper has four principal sections. First, the background to the project is outlined, with previous quantitative and comparative studies of samian noted. The second section deals with broad aspects of samian distribution, considering its status during the Roman era, its geographic incidence and its occurrence as a component of pottery groups. Trends in the occurrence of samian types are then examined, while in the final components several areas of special interest are explored. The concluding sections emphasize the main findings and outline the prospects for future work; the manner in which samian information is published in reports is also considered

Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counter-intuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfv\'en waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, $\alpha=2$ as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed $>$600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: pre-flare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that $\alpha = 1.63 \pm 0.03$. This is below the critical threshold, suggesting that Alfv\'en waves are an important driver of coronal heating.Comment: 1,002 authors, 14 pages, 4 figures, 3 tables, published by The Astrophysical Journal on 2023-05-09, volume 948, page 7