Low elevation of Svalbard glaciers drives high mass loss variability.

Compared to other Arctic ice masses, Svalbard glaciers are low-elevated with flat interior accumulation areas, resulting in a marked peak in their current hypsometry (area-elevation distribution) at  ~450 m above sea level. Since summer melt consistently exceeds winter snowfall, these low-lying glaciers can only survive by refreezing a considerable fraction of surface melt and rain in the porous firn layer covering their accumulation zones. We use a high-resolution climate model to show that modest atmospheric warming in the mid-1980s forced the firn zone to retreat upward by  ~100 m to coincide with the hypsometry peak. This led to a rapid areal reduction of firn cover available for refreezing, and strongly increased runoff from dark, bare ice areas, amplifying mass loss from all elevations. As the firn line fluctuates around the hypsometry peak in the current climate, Svalbard glaciers will continue to lose mass and show high sensitivity to temperature perturbations.

A ß-galactosidase probe for the detection of cellular senescence by mass cytometry.

Mass cytometry (MC) is a powerful method that combines the cellular resolution of flow cytometry with the isotopic resolution of inductively coupled plasma mass spectrometry (ICP-MS). This combination theoretically allows for the simultaneous quantification of >80 different parameters at the single cell level, in turn allowing for the deep profiling of heterogeneous cell populations. The majority of available reagents for MC are antibodies labeled with heavy metal isotopes, allowing for the quantification of static biomarkers. To complement these reagents, we aim to develop small molecule reporters of cellular metabolism that are compatible with MC. Here we report a probe of ß-galactosidase activity capable of detecting cellular senescence. The galactoside probe contains a tellurophene reporter group and, when hydrolyzed, generates a quinone alkide. This reactive alkylating agent forms covalent tellurophene bearing conjugates with local nucleophiles, allowing for the quantification of ß-galactosidase activity in individual cells. Difluoromethyl and monofluoroethyl quinone alkide generating warheads were examined for their activities and compared in vitro and in vivo. We showed that the difluoromethyl derivative gave higher tellurium labelling in vitro and that the quinone methide was more reactive towards thiols than amines. In vivo the difluoromethyl derivative successfully labeled senescent cells with comparable selectivity to the commonly used fluorescent senescence probe C12FDG.

A tipping point in refreezing accelerates mass loss of Greenland's glaciers and ice caps.

Melting of the Greenland ice sheet (GrIS) and its peripheral glaciers and ice caps (GICs) contributes about 43% to contemporary sea level rise. While patterns of GrIS mass loss are well studied, the spatial and temporal evolution of GICs mass loss and the acting processes have remained unclear. Here we use a novel, 1 km surface mass balance product, evaluated against in situ and remote sensing data, to identify 1997 (±5 years) as a tipping point for GICs mass balance. That year marks the onset of a rapid deterioration in the capacity of the GICs firn to refreeze meltwater. Consequently, GICs runoff increases 65% faster than meltwater production, tripling the post-1997 mass loss to 36±16 Gt-1, or ∼14% of the Greenland total. In sharp contrast, the extensive inland firn of the GrIS retains most of its refreezing capacity for now, buffering 22% of the increased meltwater production. This underlines the very different response of the GICs and GrIS to atmospheric warming.

Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity.

BACKGROUND: Autophagy is a survival mechanism that allows recycling of cellular breakdown products, particularly in stressed cells. Here we evaluate the hypotheses that up-regulation of autophagy is a common mechanism of resistance to chemotherapy, and that drug resistance can be reversed by inhibiting autophagy with a proton pump inhibitor. METHODS: We exposed human PC3, LNCaP and MCF7 cells to seven clinically-used chemotherapy drugs ± pantoprazole, examined the up-regulation of autophagy and the effect on cellular proliferation by Western Blots, MTS assay and colony-forming assay. The distribution of drug effects and of autophagy was quantified in LNCaP tumor sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3 and p62. RESULTS: All anticancer drugs led to up-regulation of autophagy in cultured tumor cells. Pantoprazole inhibited the induction of autophagy in a time- and dose-dependent manner, and sensitized cancer cells to the seven anti-cancer drugs. Treatment of LNCaP xenografts with paclitaxel induced both DNA damage and autophagy; autophagy was inhibited and markers of toxicity were increased by pantoprazole. CONCLUSIONS: Induction of autophagy is a general mechanism associated with resistance to anticancer drugs and that its inhibition is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes.

Personalized medicine and chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: The current review summarizes ongoing developments in personalized medicine and precision medicine in chronic obstructive pulmonary disease (COPD). Our current approach is far away of personalized management algorithms as current recommendations for COPD are largely based on a reductionist disease description, operationally defined by results of spirometry. RECENT FINDINGS: Besides precision medicine developments, a personalized medicine approach in COPD is described based on a holistic approach of the patient and considering illness as the consequence of dynamic interactions within and between multiple interacting and self-adjusting systems. Pulmonary rehabilitation is described as a model of personalized medicine. Largely based on current understanding of inflammatory processes in COPD, targeted interventions in COPD are reviewed. Augmentation therapy for α-1-antitrypsine deficiency is described as model of precision medicine in COPD based in profound understanding of the related genetic endotype. SUMMARY: Future developments of precision medicine in COPD require identification of relevant endotypes combined with proper identification of phenotypes involved in the complex and heterogeneous manifestations of COPD.

Separation of Time Scales in a Quantum Newton's Cradle.

We provide detailed modeling of the Bragg pulse used in quantum Newton's-cradle-like settings or in Bragg spectroscopy experiments for strongly repulsive bosons in one dimension. We reconstruct the postpulse time evolution and study the time-dependent local density profile and momentum distribution by a combination of exact techniques. We further provide a variety of results for finite interaction strengths using a time-dependent Hartree-Fock analysis and bosonization-refermionization techniques. Our results display a clear separation of time scales between rapid and trap-insensitive relaxation immediately after the pulse, followed by slow in-trap periodic behavior.

Complete Generalized Gibbs Ensembles in an Interacting Theory.

In integrable many-particle systems, it is widely believed that the stationary state reached at late times after a quantum quench can be described by a generalized Gibbs ensemble (GGE) constructed from their extensive number of conserved charges. A crucial issue is then to identify a complete set of these charges, enabling the GGE to provide exact steady-state predictions. Here we solve this long-standing problem for the case of the spin-1/2 Heisenberg chain by explicitly constructing a GGE which uniquely fixes the macrostate describing the stationary behavior after a general quantum quench. A crucial ingredient in our method, which readily generalizes to other integrable models, are recently discovered quasilocal charges. As a test, we reproduce the exact postquench steady state of the Néel quench problem obtained previously by means of the Quench Action method.

Glacier mass loss. Dynamic thinning of glaciers on the Southern Antarctic Peninsula.

Growing evidence has demonstrated the importance of ice shelf buttressing on the inland grounded ice, especially if it is resting on bedrock below sea level. Much of the Southern Antarctic Peninsula satisfies this condition and also possesses a bed slope that deepens inland. Such ice sheet geometry is potentially unstable. We use satellite altimetry and gravity observations to show that a major portion of the region has, since 2009, destabilized. Ice mass loss of the marine-terminating glaciers has rapidly accelerated from close to balance in the 2000s to a sustained rate of -56 ± 8 gigatons per year, constituting a major fraction of Antarctica's contribution to rising sea level. The widespread, simultaneous nature of the acceleration, in the absence of a persistent atmospheric forcing, points to an oceanic driving mechanism.

Effect of pantoprazole to enhance activity of docetaxel against human tumour xenografts by inhibiting autophagy.

BACKGROUND: Autophagy allows recycling of cellular components and may facilitate cell survival after chemotherapy. Pantoprazole inhibits proton pumps and is reported to inhibit autophagy. Here we evaluate the effects of pantoprazole to modify cytotoxicity of the anticancer drug docetaxel, and underlying mechanisms. METHODS: Effects of docetaxel±pantoprazole were studied against wild-type and autophagy-deficient PC3 cells and against four human xenografts. Effects of pantoprazole on autophagy were evaluated by quantifying LC3-I, LC3-II and p62 proteins in western blots, and by fluorescent microscopy of cells transfected with RFP-GFP-LC3. The distribution of drug effects and of autophagy was quantified in tumour sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3, Ki67 and LC3/ p62. RESULTS: Pantoprazole increased the toxicity of docetaxel in vitro, increased docetaxel-induced expression of γH2AX and cleaved caspase-3, and decreased Ki67 in tumour sections. Pantoprazole increased growth delay of four human xenografts of low, moderate and high sensitivity to docetaxel, with minimal increase in toxicity. Docetaxel led to increased autophagy throughout tumour sections. Pantoprazole inhibited autophagy, and effects of pantoprazole were reduced against genetically modified cells with decreased ability to undergo autophagy. CONCLUSIONS: Autophagy is a mechanism of resistance to docetaxel chemotherapy that may be modified by pantoprazole to improve therapeutic index.

GRACE, time-varying gravity, Earth system dynamics and climate change.

Continuous observations of temporal variations in the Earth's gravity field have recently become available at an unprecedented resolution of a few hundreds of kilometers. The gravity field is a product of the Earth's mass distribution, and these data-provided by the satellites of the Gravity Recovery And Climate Experiment (GRACE)-can be used to study the exchange of mass both within the Earth and at its surface. Since the launch of the mission in 2002, GRACE data has evolved from being an experimental measurement needing validation from ground truth, to a respected tool for Earth scientists representing a fixed bound on the total change and is now an important tool to help unravel the complex dynamics of the Earth system and climate change. In this review, we present the mission concept and its theoretical background, discuss the data and give an overview of the major advances GRACE has provided in Earth science, with a focus on hydrology, solid Earth sciences, glaciology and oceanography.

Quenching the anisotropic heisenberg chain: exact solution and generalized Gibbs ensemble predictions.

We study quenches in integrable spin-1/2 chains in which we evolve the ground state of the antiferromagnetic Ising model with the anisotropic Heisenberg Hamiltonian. For this nontrivially interacting situation, an application of the first-principles-based quench-action method allows us to give an exact description of the postquench steady state in the thermodynamic limit. We show that a generalized Gibbs ensemble, implemented using all known local conserved charges, fails to reproduce the exact quench-action steady state and to correctly predict postquench equilibrium expectation values of physical observables. This is supported by numerical linked-cluster calculations within the diagonal ensemble in the thermodynamic limit.

Hypoxia signaling and the metastatic phenotype.

Conditions of poor oxygenation (hypoxia) are present in the majority of solid human tumors and are associated with poor patient prognosis due to both hypoxia-mediated resistance to treatment, and to hypoxia induced biological changes that promote increased malignancy, including metastasis. Tumor cells respond to hypoxia by activating several oxygen-sensitive signaling pathways that include the hypoxia inducible factor 1/2 (HIF1/2) signalling pathways and the unfolded protein response (UPR), which alter gene expression to promote adaptation and survival during hypoxic conditions. Furthermore, these hypoxia responsive pathways can lead to changes in gene expression and cellular phenotype that influence the potential of cancer cells to metastasize. However, the hypoxia-induced signaling events that promote tumor metastasis are still relatively poorly understood. Previous studies have largely focused on the contribution of the HIF signaling pathway to hypoxia-mediated metastasis. However, recent evidence demonstrates that hypoxic activation of the UPR is also an important mediator of metastasis.

Independent and functional validation of a multi-tumour-type proliferation signature.

BACKGROUND: Previously we demonstrated that an mRNA signature reflecting cellular proliferation had strong prognostic value. As clinical applicability of signatures can be controversial, we sought to improve our marker's clinical utility by validating its biological relevance, reproducibility in independent data sets and applicability using an independent technique. METHODS: To facilitate signature evaluation with quantitative PCR (qPCR) a novel computational procedure was used to reduce the number of signature genes without significant information loss. These genes were validated in different human cancer cell lines upon serum starvation and in a 168 xenografts panel. Analyses were then extended to breast cancer and non-small-cell lung cancer (NSCLC) patient cohorts. RESULTS: Expression of the qPCR-based signature was dramatically decreased under starvation conditions and inversely correlated with tumour volume doubling time in xenografts. The signature validated in breast cancer (hazard ratio (HR)=1.63, P<0.001, n=1820) and NSCLC adenocarcinoma (HR=1.64, P<0.001, n=639) microarray data sets. Lastly, qPCR in a node-negative, non-adjuvantly treated breast cancer cohort (n=129) showed that patients assigned to the high-proliferation group had worse disease-free survival (HR=2.25, P<0.05). CONCLUSION: We have developed and validated a qPCR-based proliferation signature. This test might be used in the clinic to select (early-stage) patients for specific treatments that target proliferation.

Regulatory functions of ubiquitin in diverse DNA damage responses.

In recent years there has been intense investigation and rapid progress in our understanding of the cellular responses to various types of endogenous and exogenous DNA damage that ensure genetic stability. These studies have identified numerous roles for ubiquitylation, the post-translational modification of proteins with single ubiquitin or poly-ubiquitin chains. Initially discovered for its role in targeting proteins for degradation in the proteasome, ubiquitylation functions in a variety of regulatory roles to co-ordinate the recruitment and activity of a large number of protein complexes required for recovery from DNA damage. This includes the identification of essential DNA damage response genes that encode proteins directly involved in the ubiquitylation process itself, proteins that are targets for ubiquitylation, proteins that contain ubiquitin binding domains, as well as proteins involved in the de-ubiquitylation process. This review will focus on the regulatory functions of ubiquitylation in three distinct DNA damage responses that involve ubiquitin modification of proliferating cell nuclear antigen (PCNA) in DNA damage tolerance, the core histone H2A and its variant H2AX in double strand break repair (DSBR) and the Fanconi anaemia (FA) proteins FANCD2 and FANCI in cross link repair.

Robust prognostic value of a knowledge-based proliferation signature across large patient microarray studies spanning different cancer types.

Tumour proliferation is one of the main biological phenotypes limiting cure in oncology. Extensive research is being performed to unravel the key players in this process. To exploit the potential of published gene expression data, creation of a signature for proliferation can provide valuable information on tumour status, prognosis and prediction. This will help individualizing treatment and should result in better tumour control, and more rapid and cost-effective research and development. From in vitro published microarray studies, two proliferation signatures were compiled. The prognostic value of these signatures was tested in five large clinical microarray data sets. More than 1000 patients with breast, renal or lung cancer were included. One of the signatures (110 genes) had significant prognostic value in all data sets. Stratifying patients in groups resulted in a clear difference in survival (P-values <0.05). Multivariate Cox-regression analyses showed that this signature added substantial value to the clinical factors used for prognosis. Further patient stratification was compared to patient stratification with several well-known published signatures. Contingency tables and Cramer's V statistics indicated that these primarily identify the same patients as the proliferation signature does. The proliferation signature is a strong prognostic factor, with the potential to be converted into a predictive test. Furthermore, evidence is provided that supports the idea that many published signatures track the same biological processes and that proliferation is one of them.

Poorer outcome in stromal HIF-2 alpha- and CA9-positive colorectal adenocarcinomas is associated with wild-type TP53 but not with BNIP3 promoter hypermethylation or apoptosis.

Stromal expression of hypoxia inducible factor 2 alpha (HIF-2 alpha) and carbonic anhydrase 9 (CA9) are associated with a poorer prognosis in colorectal cancer (CRC). Tumour cell death, regulated by a hypoxic stromal microenvironment, could be of importance in this respect. Therefore, we correlated apoptosis, TP53 mutational status and BNIP3 promoter hypermethylation of CRC cells with HIF-2 alpha- and CA9-related poor outcome. In a series of 195 CRCs, TP53 mutations in exons 5-8 were analysed by direct sequencing, and promoter hypermethylation of BNIP3 was determined by methylation-specific PCR. Expressions of HIF-2 alpha, CA9, p53, BNIP3 and M30 were analysed immunohistochemically. Poorer survival of HIF-2 alpha and CA9 stromal-positive CRCs was associated with wild-type TP53 (P=0.001 and P=0.0391), but not with BNIP3 methylation. Furthermore, apoptotic levels were independent of the TP53 status, but lower in unmethylated BNIP3 CRCs (P=0.004). It appears that wild-type TP53 in CRC cells favours the progression of tumours expressing markers for hypoxia in their stroma, rather than in the epithelial compartment. Preserved BNIP3 function in CRC cells lowers apoptosis, and may thus be involved in alternative cell death pathways, such as autophagic cell death. However, BNIP3 silencing in tumour cells does not impact on hypoxia-driven poorer prognosis. These results suggest that the biology of CRC cells can be modified by alterations in the tumour microenvironment under conditions of tumour hypoxia.

Dose- and time-dependent changes in gene expression in human glioma cells after low radiation doses.

We have used DNA microarrays to identify changes in gene expression in cells of the radioresistant human glioma cell lines T98G and U373 after low radiation doses (0.2-2 Gy). Using Bayesian linear models, we have identified a set of genes that respond to low doses of radiation; furthermore, a hypothesis-driven approach to data analysis has allowed us to identify groups of genes with defined non-linear dose responses. Specifically, one of the cell lines we have examined (T98G) shows increased radiosensitivity at low doses (low-dose hyper-radiosensitivity, HRS); thus we have also assessed sets of genes whose dose response mirrors this survival pattern. We have also investigated a time course for induction of genes over the period when the DNA damage response is expected to occur. We have validated these data using quantitative PCR and also compared genes up-regulated in array data to genes present in the polysomal RNA fraction after irradiation. Several of the radioresponsive genes that we describe code for proteins that may have an impact on the outcome of irradiation in these cells, including RAS homologues and kinases involved in checkpoint signaling, so understanding their differential regulation may suggest new ways of altering radioresistance. From a clinical perspective these data may also suggest novel targets that are specifically up-regulated in gliomas during radiotherapy treatments.