The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common ...feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
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•GR induction is a common feature of enzalutamide-resistant prostate cancer•GR expression and activity promote resistance to enzalutamide•GR binds and regulates a subset of AR targets in a enzalutamide-insensitive manner•AR inhibition induces high levels of GR in primed prostate cells
Prostate cancer cells that have become resistant to androgen receptor (AR) antagonists escape the AR blockade by turning on expression of the closely related glucocorticoid receptor, which functionally substitutes for AR to drive growth, thus identifying GR as a potential therapeutic target.
During the past 10 years, preclinical studies implicating sustained androgen receptor (AR) signalling as the primary driver of castration-resistant prostate cancer (CRPC) have led to the development ...of novel agents targeting the AR pathway that are now in widespread clinical use. These drugs prolong the survival of patients with late-stage prostate cancer but are not curative. In this Review, we highlight emerging mechanisms of acquired resistance to these contemporary therapies, which fall into the three broad categories of restored AR signalling, AR bypass signalling and complete AR independence. This diverse range of resistance mechanisms presents new challenges for long-term disease control, which may be addressable through early use of combination therapies guided by recent insights from genomic landscape studies of CRPC.
In the context of phase 5 of the Coupled Model Intercomparison Project, most climate simulations use prescribed atmospheric CO₂ concentration and therefore do not interactively include the effect of ...carbon cycle feedbacks. However, the representative concentration pathway 8.5 (RCP8.5) scenario has additionally been run by earth system models with prescribed CO₂ emissions. This paper analyzes the climate projections of 11 earth system models (ESMs) that performed both emission-driven and concentration-driven RCP8.5 simulations. When forced by RCP8.5 CO₂ emissions, models simulate a large spread in atmospheric CO₂; the simulated 2100 concentrations range between 795 and 1145 ppm. Seven out of the 11 ESMs simulate a larger CO₂ (on average by 44 ppm, 985 ± 97 ppm by 2100) and hence higher radiative forcing (by 0.25 W m−2) when driven by CO₂ emissions than for the concentration-driven scenarios (941 ppm). However, most of these models already overestimate the present-day CO₂, with the present-day biases reasonably well correlated with future atmospheric concentrations’ departure from the prescribed concentration. The uncertainty in CO₂ projections is mainly attributable to uncertainties in the response of the land carbon cycle. As a result of simulated higher CO₂ concentrations than in the concentration-driven simulations, temperature projections are generally higher when ESMs are driven with CO₂ emissions. Global surface temperature change by 2100 (relative to present day) increased by 3.9° ± 0.9°C for the emission-driven simulations compared to 3.7° ± 0.7°C in the concentration-driven simulations. Although the lower ends are comparable in both sets of simulations, the highest climate projections are significantly warmer in the emission-driven simulations because of stronger carbon cycle feedbacks.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The terrestrial biosphere currently absorbs about 30% of anthropogenic CO
emissions. This carbon uptake over land results primarily from vegetation's response to increasing atmospheric CO
but other ...factors also play a role. Here we show that since the 1930s increasing population densities and cropland area have decreased global area burned, consistent with the charcoal record and recent satellite-based observations. The associated reduced wildfire emissions from increase in cropland area do not enhance carbon uptake since natural vegetation that is spared burning was deforested anyway. However, reduction in fire CO
emissions due to fire suppression and landscape fragmentation associated with increases in population density is calculated to enhance land carbon uptake by 0.13 Pg C yr
, or ~19% of the global land carbon uptake (0.7 ± 0.6 Pg C yr
), for the 1960-2009 period. These results identify reduction in global wildfire CO
emissions as yet another mechanism that is currently enhancing carbon uptake over land.
Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors ...with
PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a
Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
► Inhibition of the PI3K pathway promotes AR activity ► Androgen blockade activates AKT signaling ► Combined PI3K and AR inhibition is superior to single-agent therapy in PTEN-loss prostate cancer
Evapotranspiration (ET) is critical in linking global water, carbon and energy cycles. However, direct measurement of global terrestrial ET is not feasible. Here, we first reviewed the basic theory ...and state-of-the-art approaches for estimating global terrestrial ET, including remote-sensing-based physical models, machine-learning algorithms and land surface models (LSMs). We then utilized 4 remote-sensing-based physical models, 2 machine-learning algorithms and 14 LSMs to analyze the spatial and temporal variations in global terrestrial ET. The results showed that the ensemble means of annual global terrestrial ET estimated by these three categories of approaches agreed well, with values ranging from 589.6 mm/yr (6.56×10^4 cu.km/yr) to 617.1 mm/yr (6.87×10^4 cu.km/yr). For the period from 1982 to 2011, both the ensembles of remote-sensing-based physical models and machine-learning algorithms suggested increasing trends in global terrestrial ET (0.62 mm/sq.yr with a significance level of p<0.05 and 0.38 mm yr−2 with a significance level of p<0.05, respectively). In contrast, the ensemble mean of the LSMs showed no statistically significant change (0.23 mm/sq.yr, p>0.05), although many of the individual LSMs reproduced an increasing trend. Nevertheless, all 20 models used in this study showed that anthropogenic Earth greening had a positive role in increasing terrestrial ET. The concurrent small interannual variability, i.e., relative stability, found in all estimates of global terrestrial ET, suggests that a potential planetary boundary exists in regulating global terrestrial ET, with the value of this boundary being around 600 mm/yr. Uncertainties among approaches were identified in specific regions, particularly in the Amazon Basin and arid/semiarid regions. Improvements in parameterizing water stress and canopy dynamics, the utilization of new available satellite retrievals and deep-learning methods, and model–data fusion will advance our predictive understanding of global terrestrial ET.
The magnitude and evolution of parameters that characterize feedbacks in the coupled carbon–climate system are compared across nine Earth system models (ESMs). The analysis is based on results from ...biogeochemically, radiatively, and fully coupled simulations in which CO₂ increases at a rate of 1% yr−1. These simulations are part of phase 5 of the Coupled Model Intercomparison Project (CMIP5). The CO₂ fluxes between the atmosphere and underlying land and ocean respond to changes in atmospheric CO₂ concentration and to changes in temperature and other climate variables. The carbon–concentration and carbon–climate feedback parameters characterize the response of the CO₂ flux between the atmosphere and the underlying surface to these changes. Feedback parameters are calculated using two different approaches. The two approaches are equivalent and either may be used to calculate the contribution of the feedback terms to diagnosed cumulative emissions. The contribution of carbon–concentration feedback to diagnosed cumulative emissions that are consistent with the 1% increasing CO₂ concentration scenario is about 4.5 times larger than the carbon–climate feedback. Differences in the modeled responses of the carbon budget to changes in CO₂ and temperature are seen to be 3–4 times larger for the land components compared to the ocean components of participating models. The feedback parameters depend on the state of the system as well the forcing scenario but nevertheless provide insight into the behavior of the coupled carbon–climate system and a useful common framework for comparing models.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ratio of warming to cumulative emissions of carbon dioxide has been shown to be approximately independent of time and emissions scenarios and directly relates emissions to temperature. It is ...therefore a potentially important tool for climate mitigation policy. The transient climate response to cumulative carbon emissions (TCRE), defined as the ratio of global-mean warming to cumulative emissions at CO₂ doubling in a 1% yr−1CO₂ increase experiment, ranges from 0.8 to 2.4 K EgC−1in 15 models from phase 5 of the Coupled Model Intercomparison Project (CMIP5)—a somewhat broader range than that found in a previous generation of carbon–climate models. Using newly available simulations and a new observational temperature dataset to 2010, TCRE is estimated from observations by dividing an observationally constrained estimate of CO₂-attributable warming by an estimate of cumulative carbon emissions to date, yielding an observationally constrained 5%–95% range of 0.7–2.0 K EgC−1.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peak runoff in streams and rivers of the western United States is strongly influenced by melting of accumulated mountain snowpack. A significant decline in this resource has a direct connection to ...streamflow, with substantial economic and societal impacts. Observations and reanalyses indicate that between the 1980s and 2000s, there was a 10-20% loss in the annual maximum amount of water contained in the region's snowpack. Here we show that this loss is consistent with results from a large ensemble of climate simulations forced with natural and anthropogenic changes, but is inconsistent with simulations forced by natural changes alone. A further loss of up to 60% is projected within the next 30 years. Uncertainties in loss estimates depend on the size and the rate of response to continued anthropogenic forcing and the magnitude and phasing of internal decadal variability. The projected losses have serious implications for the hydropower, municipal and agricultural sectors in the region.
The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal ...residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis.
We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point.
utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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