Cancer-associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic ductal adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting ...the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that CAFs exposed to chemotherapy have an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.
A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. ...The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool.
This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured.
Specificity for cancer signal detection was 99.5% 95% confidence interval (CI): 99.0% to 99.8%. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%). Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%).
In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests.
NCT02889978.
•In a validation study, an MCED test identified a diversity of cancer signals with high specificity.•The MCED test predicted the origin of the cancer signal with high accuracy across multiple cancer types.•Results support the use of this MCED test on a population scale as a complement to existing single-cancer screening tests.
Combustion of fuels in the residential sector for cooking and heating results in the emission of aerosol and aerosol precursors impacting air quality, human health, and climate. Residential emissions ...are dominated by the combustion of solid fuels. We use a global aerosol microphysics model to simulate the impact of residential fuel combustion on atmospheric aerosol for the year 2000. The model underestimates black carbon (BC) and organic carbon (OC) mass concentrations observed over Asia, Eastern Europe, and Africa, with better prediction when carbonaceous emissions from the residential sector are doubled. Observed seasonal variability of BC and OC concentrations are better simulated when residential emissions include a seasonal cycle. The largest contributions of residential emissions to annual surface mean particulate matter (PM2.5) concentrations are simulated for East Asia, South Asia, and Eastern Europe. We use a concentration response function to estimate the human health impact due to long-term exposure to ambient PM2.5 from residential emissions. We estimate global annual excess adult (> 30 years of age) premature mortality (due to both cardiopulmonary disease and lung cancer) to be 308 000 (113 300–497 000, 5th to 95th percentile uncertainty range) for monthly varying residential emissions and 517 000 (192 000–827 000) when residential carbonaceous emissions are doubled. Mortality due to residential emissions is greatest in Asia, with China and India accounting for 50 % of simulated global excess mortality. Using an offline radiative transfer model we estimate that residential emissions exert a global annual mean direct radiative effect between −66 and +21 mW m−2, with sensitivity to the residential emission flux and the assumed ratio of BC, OC, and SO2 emissions. Residential emissions exert a global annual mean first aerosol indirect effect of between −52 and −16 mW m−2, which is sensitive to the assumed size distribution of carbonaceous emissions. Overall, our results demonstrate that reducing residential combustion emissions would have substantial benefits for human health through reductions in ambient PM2.5 concentrations.
The volume, extent and age of Arctic sea ice is in decline, yet winter sea ice production appears to have been increasing, despite Arctic warming being most intense during winter. Previous work ...suggests that further warming will at some point lead to a decline in ice production, however a consistent explanation of both rise and fall is hitherto missing. Here, we investigate these driving factors through a simple linear model for ice production. We focus on the Kara and Laptev seas-sometimes referred to as Arctic "ice factories" for their outsized role in ice production, and train the model on internal variability across the Community Earth System Model's Large Ensemble (CESM-LE). The linear model is highly skilful at explaining internal variability and can also explain the forced rise-then-fall of ice production, providing insight into the competing drivers of change. We apply our linear model to the same climate variables from observation-based data; the resulting estimate of ice production over recent decades suggests that, just as in CESM-LE, we are currently passing the peak of ice production in the Kara and Laptev seas.
Sponges are an ancient group of animals that diverged from other metazoans over 600 million years ago. Here we present the draft genome sequence of Amphimedon queenslandica, a demosponge from the ...Great Barrier Reef, and show that it is remarkably similar to other animal genomes in content, structure and organization. Comparative analysis enabled by the sequencing of the sponge genome reveals genomic events linked to the origin and early evolution of animals, including the appearance, expansion and diversification of pan-metazoan transcription factor, signalling pathway and structural genes. This diverse 'toolkit' of genes correlates with critical aspects of all metazoan body plans, and comprises cell cycle control and growth, development, somatic- and germ-cell specification, cell adhesion, innate immunity and allorecognition. Notably, many of the genes associated with the emergence of animals are also implicated in cancer, which arises from defects in basic processes associated with metazoan multicellularity.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Productivity of tree plantations is a function of the supply, capture and efficiency of use of resources, as outlined in the Production Ecology Equation. Species interactions in mixed-species stands ...can influence each of these variables. The importance of resource-use efficiency in determining forest productivity has been clearly demonstrated in monocultures; however, substantial knowledge gaps remain for mixtures. This review examines how the physiology and morphology of a given species can vary depending on whether it grows in a mixture or monoculture. We outline how physiological and morphological shifts within species, resulting from interactions in mixtures, may influence the three variables of the Production Ecology Equation, with an emphasis on nutrient resources nitrogen (N) and phosphorus (P). These include (i) resource availability, including soil nutrient mineralization, N₂ fixation and litter decomposition; (ii) proportion of resources captured, resulting from shifts in spatial, temporal and chemical patterns of root dynamics; (iii) resource-use efficiency. We found that more than 50% of mixed-species studies report a shift to greater above-ground nutrient content of species grown in mixtures compared to monocultures, indicating an increase in the proportion of resources captured from a site. Secondly, a meta-analysis showed that foliar N concentrations significantly increased for a given species in a mixture containing N₂-fixing species, compared to a monoculture, suggesting higher rates of photosynthesis and greater resource-use efficiency. Significant shifts in N- and P-use efficiencies of a given species, when grown in a mixture compared to a monoculture, occurred in over 65% of studies where resource-use efficiency could be calculated. Such shifts can result from changes in canopy photosynthetic capacities, changes in carbon allocation or changes to foliar nutrient residence times of species in a mixture. We recommend that future research focus on individual species' changes, particularly with respect to resource-use efficiency (including nutrients, water and light), when trees are grown in mixtures compared to monocultures. A better understanding of processes responsible for changes to tree productivity in mixed-species tree plantations can improve species, and within-species, selection so that the long-term outcome of mixtures is more predictable.
Cancer cells acquire several traits that allow for their survival and progression, including the ability to evade the host immune response. However, the mechanisms by which cancer cells evade host ...immune responses remain largely elusive. Here we study the phenomena of immune evasion in malignant melanoma cells. We find that the tumor suppressor phosphatase and tensin homolog (PTEN) is an important regulator of the host immune response against melanoma cells. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, conditioned media from PTEN-deficient, patient-derived short-term melanoma cultures and established melanoma cell lines blocked the production of the interleukin-12 (IL-12) in human monocyte-derived dendritic cells. Inhibition of IL-12 production was rescued by restoring PTEN or using neutralizing antibodies against the immunosuppressive cytokines. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response. Finally, to establish the clinical significance of our results, we analyzed malignant melanoma patient samples with or without brisk host responses. These analyses confirmed that PTEN loss is associated with a higher percentage of malignant melanoma samples with non-brisk host responses compared with samples with brisk host responses. Collectively, these results establish that PTEN functions as a melanoma tumor suppressor in part by regulating the host immune response against melanoma cells and highlight the importance of assessing PTEN status before recruiting melanoma patients for immunotherapies.
Over the past four decades, amplified warming in the Arctic has led to numerous consequences. Of particular relevance, negative anomalies of snow and sea ice cover, glacier retreat, and the extended ...melt of Greenland combined with increasing temperature at double the rate of the rest of the planet have been observed in the Arctic. Several studies have suggested that another response to the current arctic warming could be an increase in rain-on-snow (ROS) events followed by subsequent freezing and the creation of ice layers. We use recently developed detection algorithms of ROS and ice events using passive microwave retrieval approaches to examine the spatial and temporal trends in rain-on-snow and ice layer creation for 18 islands across the Canadian Arctic Archipelago (CAA) over the last two decades. Results show that both icing and ROS event occurrence tripled between the periods of 1979–1995 and 1996–2011, with very active years in winters 1993–1994, 1998–1999 and 2002–2003. The areas with the most combined occurrences are the Boothia Peninsula and Axel Heiberg, Cornwallis, Banks and Victoria Islands. We then compare the rain-on-snow and icing events to Peary caribou estimates to test whether the algorithms can detect weather events associated with population declines. There has been an important reduction in population numbers of Peary caribou, the northernmost caribou population in Canada, over the last three generations. The major hypothesis for the decline is that severe weather events lead to more difficult winter grazing conditions. The comparison with the Peary caribou population estimates suggest that caribou numbers decrease with increased occurrence of ROS and icing events, where 3–4 ROS events and 1–2 icing events in one winter season are sufficient to have a negative impact on Peary caribou.
•Passive microwaves can be used to monitor ROS and ice layers in snow.•An increase in ROS occurrence has been observed since 1979 in the Arctic.•An increase in ice layer occurrence has been observed since 1979 in the Arctic.•Peary population numbers are impacted by ROS and ice layers.
18 days of MERLIN data and 42 h of A-array VLA data at 1.4 GHz have been combined to image a 10-arcmin field centred on the Hubble Deep Field (HDF). This area also includes the Hubble Flanking Fields ...(HFF). A complete sample of 92 radio sources with S1.4 > 40 μJy was detected using the VLA data alone and then imaged with the MERLIN+VLA combination. The combined images offer (i) higher angular resolution (synthesized beams of diameter 0.2–0.5 arcsec), (ii) improved astrometric accuracy, and (iii) improved sensitivity compared with VLA-only data. The images are amongst the most sensitive yet made at 1.4 GHz, with rms noise levels of 3.3 μJy beam−1 in the 0.2-arcsec images. Virtually all the sources are resolved, with angular sizes in the range 0.2 to 3 arcsec. The central 3-arcmin square was imaged separately to search for sources down to 27 μJy. No additional sources were detected, indicating that sources fainter than 40 μJy are heavily resolved with MERLIN and must have typical angular sizes > 0.5 arcsec. Radio sources associated with compact galaxies have been used to align the HDF, the HFF and a larger CFHT optical field to the radio-based International Celestial Reference Frame. The HST optical fields have been registered to <50 mas in the HDF itself, and to ≤150 mas in the outer parts of the HFF. We find a statistical association of very faint (≥2 μJy) radio sources with optically bright HDF galaxies down to ∼23 mag. Of the 92 radio sources above 40 μJy, ∼85 per cent are identified with galaxies brighter than I= 25 mag; the remaining 15 per cent are associated with optically faint systems close to or beyond the HFF (or even the HDF) limit. The high astrometric accuracy and the ability of radio waves to penetrate obscuring dust have led to the correct identification of several very red, optically faint systems, including the the strongest submillimetre source in the HDF, HDF 850.1. On the basis of their radio structures and spectra, 72 per cent (66 sources) can be classified as starburst or active galactic nucleus-type systems; the remainder are unclassified. The proportion of starburst systems increases with decreasing flux density; below 100 μJy > 70 per cent of the sources are starburst-type systems associated with major disc galaxies in the redshift range 0.3–1.3. Chandra detections are associated with 55 of the 92 radio sources, but their X-ray flux densities do not appear to be correlated with the radio flux densities or morphologies. The most recent submillimetre results on the HDF and HFF do not provide any unambiguous identifications with these latest radio data, except for HDF 850.1, but suggest at least three strong candidates.
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