Decreasing intensity of open-ocean convection in the Greenland and Iceland seas

The air–sea transfer of heat and fresh water plays a critical role in the global climate system. This is particularly true for the Greenland and Iceland seas, where these fluxes drive ocean convection that contributes to Denmark Strait overflow water, the densest component of the lower limb of the Atlantic Meridional Overturning Circulation (AMOC). Here we show that the wintertime retreat of sea ice in the region, combined with different rates of warming for the atmosphere and sea surface of the Greenland and Iceland seas, has resulted in statistically significant reductions of approximately 20% in the magnitude of the winter air–sea heat fluxes since 1979. We also show that modes of climate variability other than the North Atlantic Oscillation (NAO) are required to fully characterize the regional air–sea interaction. Mixed-layer model simulations imply that further decreases in atmospheric forcing will exceed a threshold for the Greenland Sea whereby convection will become depth limited, reducing the ventilation of mid-depth waters in the Nordic seas. In the Iceland Sea, further reductions have the potential to decrease the supply of the densest overflow waters to the AMOC

Tumour sampling method can significantly influence gene expression profiles derived from neoadjuvant window studies

Patient-matched transcriptomic studies using tumour samples before and after treatment allow inter-patient heterogeneity to be controlled, but tend not to include an untreated comparison. Here, Illumina BeadArray technology was used to measure dynamic changes in gene expression from thirty-seven paired diagnostic core and surgically excised breast cancer biopsies obtained from women receiving no treatment prior to surgery, to determine the impact of sampling method and tumour heterogeneity. Despite a lack of treatment and perhaps surprisingly, consistent changes in gene expression were identified during the diagnosis-surgery interval (48 up, 2 down; Siggenes FDR 0.05) in a manner independent of both subtype and sampling-interval length. Instead, tumour sampling method was seen to directly impact gene expression, with similar effects additionally identified in six published breast cancer datasets. In contrast with previous findings, our data does not support the concept of a significant wounding or immune response following biopsy in the absence of treatment and instead implicates a hypoxic response following the surgical biopsy. Whilst sampling-related gene expression changes are evident in treated samples, they are secondary to those associated with response to treatment. Nonetheless, sampling method remains a potential confounding factor for neoadjuvant study design

Deep Water Warming And Exchange In The Greenland Sea During The Recent Period Of Marginal Winter Convective Activity

No abstracts are to be cited without prior reference to the author.From hydrographic observations in the Greenland Sea over a number of years deep water warming. deep water renewal, and winter convective activity are investigated. It is shown that winter convection was generally weak after the early 1990s, and that - from a basin wide view - only the uppermost l000 m or less are modified by winter convection since then. Because of this long absence of deep winter convection, certain structures of the Greenland Sea hydrography remained intact over a time period of many years. From their changes it is concluded that the persistent deep water warming during the 1990s is caused by a vertical displacement of the water column in the central gyre. as opposed to lateral mixing with deep Arctic Waters. Thereby. bottom water exchange is taking place despite the lack of deep convection. Flushing times of about 30 years arc proroscd and it is suggested to use SF-6 concentrations to trace the pathways of the necessitated bottom water export

Abstract P3-09-04: Genomic landscape of HER2-negative advanced or metastatic breast cancer with PIK3CA gain-of-function mutations

Abstract Background: Alpelisib and fulvestrant are used as a combination treatment option for postmenopausal PIK3CA-mutated, hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced or metastatic breast cancer (a/mBC) patients. However, despite the presence of activating mutations in PIK3CA, the majority of patients do not derive benefit, or ultimately progress while on alpelisib therapy. Here, we investigate the genomic landscape of PIK3CA-mutated, HER2- a/mBC using next-generation sequencing (NGS) to provide insight into possible mechanisms of therapeutic resistance to alpelisib/fulvestrant and to identify potential targetable pathways. Methods: We utilized the Tempus LENS platform to retrospectively analyze de-identified NGS data from 2,918 a/mBC patients with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq). Mutations identified included germline and/or somatic single nucleotide variants, insertions/deletions and copy number variations (gains defined as ≥8 copies). We used curated clinical data to determine HER2 and hormone receptor (ER/PR) status. Results: Among 2,918 a/mBC patients, we identified somatic mutations in PIK3CA in 782 (26.8%). Within these tumors, 629 (80.4%) had one of the 11 mutations currently included in the alpelisib companion diagnostic, and we focused on this population (here defined as mut-PIK3CA). Of these 629, 546 (86.8%) were HER2-, with 176 (32.3%) and 370 (67.7%) derived from primary and metastatic tumors, respectively. Cases were further classified as HR+ (defined as ER+ or PR+) or triple negative (TNBC). While the majority of mutPIK3CA samples were identified in HR+ disease, 10% of the cases occurred in TNBC. Within the mutPIK3CA cohort, tumor mutational burden high (TMB-H; defined as ≥10 mutations/MB) was detected in 11.5% of samples, while microsatellite instability high (MSI-H) was detected in 0.5%. MSI-H was detected at a higher frequency in TNBC compared to HR+. Overall, the most commonly co-mutated genes among mutPIK3CA, HER2- samples were TP53 (34.6%), CDH1 (21.6%), ESR1 (12.3%), KMT2C (11%), MAP3K1 (9.5%), ARID1A (8.1%), PTEN (6.8%), GATA3 (6.6%), NF1 (5.9%), and TBX3 (5.9%) among others (Table 1); some of these genes have previously been implicated in resistance to endocrine therapy or PI3K inhibitor. In addition, in HR+ disease, metastatic samples had a higher frequency of mutations in genes implicated in endocrine resistance, such as ESR1 (18.7% vs 1.9%), ERBB2 (3.3% vs 2.6%), NF1 (6.8% vs 2.6%), compared to primary tumors. We also identified copy number gains (CNG) in several cell cycle genes, including: CCND1 (15.2%), CDK4 (2.7%), and AURKA (2.6%) (Table 1). Finally, further analyses at the transcript-level are the subject of on-going research. Conclusions: Our study highlights that there is substantial genomic heterogeneity among mutPIK3CA, HER2- a/mBCs. Across a series of comparisons between primary and metastatic samples, as well as HR+ and TNBC subtypes, we identified a number of co-mutations that occur alongside mutPIK3CA and which could be potentially exploited by targeted therapies. Future studies are needed to assess the prognostic/predictive role of these and other candidate gene alterations. Table 1. Genomic features of mutPIK3CA, HER2– a/mBCPrimaryMetastaticTotalAny PIK3CA Mutation1255527782mutPIK3CA2204425629HER2– (n=176)HER2– (n=370)546HR+ HER2– 154 (88%)TNBC 22 (12%)HR+ HER2– 337 (91%)TNBC 33 (9%)TMB-H16 (10.3%)2 (9.1%)41 (12%)4 (12%)63 (11.5%)MSI-H1 (0.6%)1 (4.5%)0 (0%)1 (3.0%)3 (0.5%)Co-mutations (mutPIK3CA): n (%)TP5347 (30.5%)14 (63.6%)101 (30%)27 (81.8%)189 (34.6%)CDH137 (24%)1 (4.5%)75 (22.3%)5 (15.2%)118 (21.6%)KMT2C17 (11%)1 (4.5%)40 (11.9%)2 (6.1%)60 (11%)MAP3K117 (11%)1 (4.5%)31 (9.2%)1 (3%)50 (9.2%)ARID1A15 (9.7%)0 (0%)26 (7.7%)2 (6.1%)43(7.9%)PTEN12 (7.8%)1 (4.5%)21 (6.2%)3 (9.1%)37 (6.8%)GATA311 (7.1%)0 (0%)23 (6.8%)2 (6.1%)35 (6.6%)TBX311 (7.1%)1 (4.5%)19 (5.6%)1 (3%)32 (5.9%)NCOR12 (1.3%)1 (4.5%)18 (5.3%)0 (0%)21 (3.8%)FOXA17 (4.5%)2 (9.1%)10 (3%)1 (3%)20 (3.7%)MAP2K41 (0.6%)1 (4.5%)12 (3.6%)1 (3%)15 (2.7%)ESR13 (1.9%)0 (0%)63 (18.7%)1 (3%)67 (12.3%)PIK3R13 (1.9%)0 (0%)4 (1.2%)0 (0%)7 (1.3%)AKT11 (0.6%)0 (0%)1 (0.6%)0 (0%)2 (0.4%)RB15 (3.2%)1 (4.5%)8 (2.4%)1 (3%)15 (2.7%)NF14 (2.6%)3 (13.6%)23 (6.8%)2 (6.1%)32 (5.9%)ERBB24 (2.6%)4 (18.2%)11 (3.3%)2 (6.1%)21 (3.8%)CCND1 CNG22 (14%)0 (0%)61 (18%)0 (0%)83 (15.2%)AURKA CNG3 (1.9%)0 (0%)11 (3.3%)0 (0%)14 (2.6%)CDK4 CNG5 (3.2%)1 (4.5%)7 (2.1%)1 (3.0%)14 (2.6%)1any somatic variant detected in PIK3CA2somatic PIK3CA mutations among the 11 currently included in the alpelisib companion diagnostic (C420R, E542K, E545A, E545D, E545G, E545K, Q546E, Q546R, H1047L, H1047R, and H1047Y) Citation Format: Jing Xi, Kathleen Harnden, Jingqin Luo, Greg S. Call, Elizabeth Mauer, Karyn Ronski, Cynthia X. Ma, Neil Vasan. Genomic landscape of HER2-negative advanced or metastatic breast cancer with PIK3CA gain-of-function mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-04.</jats:p

Evidence of EGR1 as a differentially expressed gene among proliferative skin diseases

Hyperproliferative epidermal disorders range from benign hyperplasias such as psoriasis to basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), the two most common cancers in the US. While they all arise from the epidermis, these diseases differ dramatically in biological behavior and their underlying gene expression patterns have not been compared. We thus examined mRNA transcript levels in these disorders to identify and further characterize differentially expressed genes. Transcript expression patterns distinguish these disorders and identify EGR1, among other genes, whose epidermal expression is decreased in BCC and SCC but is elevated in psoriasis. Egr-1 inhibits growth of benign and malignant epidermal cells in vitro and appears to suppress both Cdc25A expression and Cdk2 dephosphorylation. These data indicate that gene expression profiling can differentiate epidermal hyperproliferative diseases and suggest that Egr-1 may play a role in preventing uncontrolled epidermal growth

Marine cold-air outbreaks in the future: an assessment of IPCC AR4 model results for the Northern Hemisphere

For many locations around the globe some of the most severe weather is associated with outbreaks of cold air over relatively warm oceans, referred to here as marine cold-air outbreaks (MCAOs). Drawing on empirical evidence, an MCAO indicator is defined here as the difference between the skin potential temperature, which over open ocean is the sea surface potential temperature, and the potential temperature at 700 hPa. Rare MCAOs are defined as the 95th percentile of this indicator. Climate model data that have been provided as part of the Intergovernmental Panel on Climate Change (IPCC) Assessment Report Four (AR4) were used to assess the models' projections for the twenty-first century and their ability to represent the observed climatology of MCAOs. The ensemble average of the models broadly captures the observed spatial distribution of the strength of MCAOs. However, there are some significant differences between the models and observations, which are mainly associated with simulated biases of the underlying sea ice, such as excessive sea-ice extent over the Barents Sea in most of the models. The future changes of the strength of MCAOs vary significantly across the Northern Hemisphere. The largest projected weakening of MCAOs is over the Labrador Sea. Over the Nordic seas the main region of strong MCAOs will move north and weaken slightly as it moves away from the warm tongue of the Gulf Stream in the Norwegian Sea. Over the Sea of Japan there is projected to be only a small weakening of MCAOs. The implications of the results for mesoscale weather systems that are associated with MCAOs, namely polar lows and arctic fronts, are discussed