Recent rapid thinning of West Antarctic ice shelves are believed to be caused by intrusions of warm deep water that induce basal melting and seaward meltwater export. This study uses data from three ...bottom-mounted mooring arrays to show seasonal variability and local forcing for the currents moving into and out of the Dotson ice shelf cavity. A southward flow of warm, salty water had maximum current velocities along the eastern channel slope, while northward outflows of freshened ice shelf meltwater spread at intermediate depth above the western slope. The inflow correlated with the local ocean surface stress curl. At the western slope, meltwater outflows followed the warm influx along the eastern slope with a ~2-3 month delay. Ocean circulation near Dotson Ice Shelf, affected by sea ice distribution and wind, appears to significantly control the inflow of warm water and subsequent ice shelf melting on seasonal time-scales.
There have been concerns about the long-term survival of unicompartmental knee arthroplasty (UKA). This prospective study reports the 15-year survival and ten-year functional outcome of a consecutive ...series of 1000 minimally invasive Phase 3 Oxford medial UKAs (818 patients, 393 men, 48%, 425 women, 52%, mean age 66 years; 32 to 88). These were implanted by two surgeons involved with the design of the prosthesis to treat anteromedial osteoarthritis and spontaneous osteonecrosis of the knee, which are recommended indications. Patients were prospectively identified and followed up independently for a mean of 10.3 years (5.3 to 16.6). At ten years, the mean Oxford Knee Score was 40 (standard deviation (sd) 9; 2 to 48): 79% of knees (349) had an excellent or good outcome. There were 52 implant-related re-operations at a mean of 5.5 years (0.2 to 14.7). The most common reasons for re-operation were arthritis in the lateral compartment (2.5%, 25 knees), bearing dislocation (0.7%, seven knees) and unexplained pain (0.7%, seven knees). When all implant-related re-operations were considered as failures, the ten-year rate of survival was 94% (95% confidence interval (CI) 92 to 96) and the 15-year survival rate 91% (CI 83 to 98). When failure of the implant was the endpoint the 15-year survival was 99% (CI 96 to 100). This is the only large series of minimally invasive UKAs with 15-year survival data. The results support the continued use of minimally invasive UKA for the recommended indications.
Mass loss from the Antarctic Ice Sheet to the ocean has increased in recent decades, largely because the thinning of its floating ice shelves has allowed the outflow of grounded ice to accelerate
. ...Enhanced basal melting of the ice shelves is thought to be the ultimate driver of change
, motivating a recent focus on the processes that control ocean heat transport onto and across the seabed of the Antarctic continental shelf towards the ice
. However, the shoreward heat flux typically far exceeds that required to match observed melt rates
, suggesting that other critical controls exist. Here we show that the depth-independent (barotropic) component of the heat flow towards an ice shelf is blocked by the marked step shape of the ice front, and that only the depth-varying (baroclinic) component, which is typically much smaller, can enter the sub-ice cavity. Our results arise from direct observations of the Getz Ice Shelf system and laboratory experiments on a rotating platform. A similar blocking of the barotropic component may occur in other areas with comparable ice-bathymetry configurations, which may explain why changes in the density structure of the water column have been found to be a better indicator of basal melt rate variability than the heat transported onto the continental shelf
. Representing the step topography of the ice front accurately in models is thus important for simulating ocean heat fluxes and induced melt rates.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We investigated whether increasing levels of tissue hypoxia, measured by the binding of EF5 2-(2-nitro-1- H -imidazol-1-yl)- N -(2,2,3,3,3-pentafluoropropyl) acetamide or by Eppendorf needle ...electrodes, were associated with tumor aggressiveness in
patients with previously untreated glial brain tumors. We hypothesized that more extensive and severe hypoxia would be present
in tumor cells from patients bearing more clinically aggressive tumors. Hypoxia was measured with the 2-nitroimidazole imaging
agent EF5 in 18 patients with supratentorial glial neoplasms. In 12 patients, needle electrode measurements were made intraoperatively.
Time to recurrence was used as an indicator of tumor aggression and was analyzed as a function of EF5 binding, electrode values
and recursive partitioning analysis (RPA) classification. On the basis of EF5 binding, WHO grade 2 tumors were characterized
by modest cellular hypoxia (pO 2 s ≈ 10%) and grade 3 tumors by modest-to-moderate hypoxia (pO 2 s ≈ 10%- 2.5%). Severe hypoxia (≈0.1% oxygen) was present in 5 of 12 grade 4 tumors. A correlation between more rapid tumor
recurrence and hypoxia was demonstrated with EF5 binding, but this relationship was not predicted by Eppendorf measurements.
The liver enzyme cytochrome P450 1A2 (CYP1A2) is responsible for 90% of caffeine metabolism, while caffeine exerts many of its effects via antagonist binding to adenosine A2a receptors (ADORA2A). ...This study aimed to examine whether functional single nucleotide polymorphisms (SNPs) in 1976T > C (ADORA2A; rs5751876) and -163C > A (CYP1A2; rs762551) influence the effect of caffeine on the postprandial glucose (GLU) response to a carbohydrate meal. We report that individuals with the 1976T > C CC, but not CT/TT genotypes display elevated GLU levels after consuming caffeine and carbohydrate (CHO + CAFF) versus carbohydrate only (CHO). The GLU area under the curve (AUC) was also greater during the CHO + CAFF condition compared to the CHO condition in CC, but not the CT/TT genotypes. The -163C > A AC/CC, but not AA, genotypes displayed greater GLU concentrations 60-min post meal during CHO + CAFF versus CHO. Our data suggest that caffeine-induced impairments in postprandial glycaemia are related to 1976T > C and -163C > A SNPs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To develop a map of cell-cell communication mediated by extracellular RNA (exRNA), the NIH Extracellular RNA Communication Consortium created the exRNA Atlas resource (https://exrna-atlas.org). The ...Atlas version 4P1 hosts 5,309 exRNA-seq and exRNA qPCR profiles from 19 studies and a suite of analysis and visualization tools. To analyze variation between profiles, we apply computational deconvolution. The analysis leads to a model with six exRNA cargo types (CT1, CT2, CT3A, CT3B, CT3C, CT4), each detectable in multiple biofluids (serum, plasma, CSF, saliva, urine). Five of the cargo types associate with known vesicular and non-vesicular (lipoprotein and ribonucleoprotein) exRNA carriers. To validate utility of this model, we re-analyze an exercise response study by deconvolution to identify physiologically relevant response pathways that were not detected previously. To enable wide application of this model, as part of the exRNA Atlas resource, we provide tools for deconvolution and analysis of user-provided case-control studies.
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•The exRNA Atlas provides access to human exRNA profiles and web-accessible tools•Atlas analysis reveals six exRNA cargo types present across five human biofluids•Five of the cargo types associate with specific vesicular and non-vesicular carriers•These findings and resources empower studies of extracellular RNA communication
An extracellular RNA atlas from five human biofluids (serum, plasma, cerebrospinal fluid, saliva, and urine) reveals six extracellular RNA cargo types, including both vesicular and non-vesicular carriers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Colorectal cancers (CRCs) are characterized by global hypomethylation and promoter-specific DNA methylation. A subset of CRCs with extensive and co-ordinate patterns of promoter methylation has also ...been identified, termed the CpG-island methylator phenotype. Some genes methylated in CRC are established tumor suppressors; however, for the majority, direct roles in disease initiation or progression have not been established. Herein, we examine functional evidence of specific methylated genes contributing to CRC pathogenesis, focusing on components of commonly deregulated signaling pathways. We also review current knowledge of the mechanisms underpinning promoter methylation in CRC, including genetic events, altered transcription factor binding, and DNA damage. Finally, we summarize clinical trials of DNA methyltransferase inhibitors in CRC, and propose strategies for enhancing their efficacy.
Abstract
Purpose:
Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma. They have also ...demonstrated clinical activity in acute myelogenous leukemia, non–small cell lung cancer, and estrogen receptor–positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherapy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumor type and investigated the mechanism by which it triggers apoptosis.
Experimental Design:
Fifty cancer cell lines from diverse tumor types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway.
Results:
We show that sensitivity to HDACi across tumor types is predicted by induction of the IE genes FOS, JUN, and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the proapoptotic function of ATF3 is mediated through direct transcriptional repression of the prosurvival factor BCL-XL (BCL2L1). These findings provided the rationale for dual inhibition of HDAC and BCL-XL, which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumor cell types.
Conclusions:
These findings explain the heterogeneous responses of tumor cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types.
Colorectal cancers (CRCs) often display histological features indicative of aberrant differentiation but the molecular underpinnings of this trait and whether it directly drives disease progression ...is unclear. Here, we identify co-ordinate epigenetic inactivation of two epithelial-specific transcription factors, EHF and CDX1, as a mechanism driving differentiation loss in CRCs. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induced extensive chromatin remodelling, transcriptional re-programming, and differentiation along the enterocytic lineage, leading to reduced growth and metastasis. Strikingly, EHF and CDX1 were also able to reprogramme non-colonic epithelial cells to express colonic differentiation markers. By contrast, inactivation of EHF and CDX1 in well-differentiated CRC cells triggered tumour de-differentiation. Mechanistically, we demonstrate that EHF physically interacts with CDX1 via its PNT domain, and that these transcription factors co-operatively drive transcription of the colonic differentiation marker, VIL1. Compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupted normal colonic differentiation and significantly enhanced colorectal tumour progression. These findings thus reveal a novel mechanism driving epithelial de-differentiation and tumour progression in CRC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
10.
A High‐End Estimate of Sea Level Rise for Practitioners Wal, R. S. W.; Nicholls, R. J.; Behar, D. ...
Earth's future,
November 2022, 2022-Nov, 2022-11-00, 20221101, 2022-11, 2022-11-01, Volume:
10, Issue:
11
Journal Article, Web Resource
Peer reviewed
Open access
Sea level rise (SLR) is a long‐lasting consequence of climate change because global anthropogenic warming takes centuries to millennia to equilibrate for the deep ocean and ice sheets. SLR ...projections based on climate models support policy analysis, risk assessment and adaptation planning today, despite their large uncertainties. The central range of the SLR distribution is estimated by process‐based models. However, risk‐averse practitioners often require information about plausible future conditions that lie in the tails of the SLR distribution, which are poorly defined by existing models. Here, a community effort combining scientists and practitioners builds on a framework of discussing physical evidence to quantify high‐end global SLR for practitioners. The approach is complementary to the IPCC AR6 report and provides further physically plausible high‐end scenarios. High‐end estimates for the different SLR components are developed for two climate scenarios at two timescales. For global warming of +2°C in 2100 (RCP2.6/SSP1‐2.6) relative to pre‐industrial values our high‐end global SLR estimates are up to 0.9 m in 2100 and 2.5 m in 2300. Similarly, for a (RCP8.5/SSP5‐8.5), we estimate up to 1.6 m in 2100 and up to 10.4 m in 2300. The large and growing differences between the scenarios beyond 2100 emphasize the long‐term benefits of mitigation. However, even a modest 2°C warming may cause multi‐meter SLR on centennial time scales with profound consequences for coastal areas. Earlier high‐end assessments focused on instability mechanisms in Antarctica, while here we emphasize the importance of the timing of ice shelf collapse around Antarctica. This is highly uncertain due to low understanding of the driving processes. Hence both process understanding and emission scenario control high‐end SLR.
Plain Language Summary
Taking a co‐production approach between scientists and practioners, we provide high‐end sea level rise (SLR) estimates for practitioner application based on an expert evaluation of physical evidence and approaches currently used in policy environments to understand high end risk. We do this for two global warming scenarios, a modest and a strong one, for two time slices 2100 and 2300. The large and growing differences between the scenarios beyond 2100 emphasize the long‐term benefits of mitigation. However, even a modest warming may cause multi‐meter SLR on centennial time scales with profound consequences for coastal areas. Earlier high‐end assessments focused on instability mechanisms in Antarctica, while here we emphasize the importance of the timing of ice shelf collapse around Antarctica as well as how practitioners use high end projections to frame risk. We stress that both emission scenario and limited physical understanding control the outcome.
Key Points
A high‐end estimate of sea level rise in 2100 and 2300
Decisionmaker/practitioner perspective on high‐end
Timing of collapse of ice shelves critical
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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