Supraglacial debris affects glacier mass balance as a thin layer enhances surface melting, while a thick layer reduces it. While many glaciers are debris‐covered, global glacier models do not account ...for debris because its thickness is unknown. We provide the first globally distributed debris thickness estimates using a novel approach combining sub‐debris melt and surface temperature inversion methods. Results are evaluated against observations from 22 glaciers. We find the median global debris thickness is ∼0.15 ± 0.06 m. In all regions, the net effect of accounting for debris is a reduction in sub‐debris melt, on average, by 37%, which can impact regional mass balance by up to 0.40 m water equivalent (w.e.) yr‐1. We also find recent observations of similar thinning rates over debris‐covered and clean ice glacier tongues is primarily due to differences in ice dynamics. Our results demonstrate the importance of accounting for debris in glacier modeling efforts.
Plain Language Summary
Many glaciers around the world have a layer of debris (boulders, rocks, and sand) covering the underlying ice over much of the glacier surface, yet global glacier models do not account for debris because the debris thickness is unknown. Here we provide the first estimates of debris thickness for debris‐covered glaciers globally and show the debris substantially reduces regional glacier mass loss. We also find that recent observations that debris‐covered and clean ice glaciers are thinning at similar speeds is primarily due to differences in how glaciers flow. Our results fundamentally advance our ability to account for debris in glacier reconstructions, landscape evolution models, hazard assessments, and glacier projections of glacier runoff and their contribution to sea‐level rise.
Key Points
We produce the first distributed global debris thickness estimates
Accounting for debris significantly reduces regional glacier mass loss
The similar thinning rates of debris‐covered and clean ice glaciers in High Mountain Asia is primarily caused by differences in ice dynamics
Fifteen children with spinal muscular atrophy type 1 received gene-replacement therapy with a single dose of adeno-associated virus containing SMN. In marked contrast to well-characterized historical ...cohorts, all the patients survived at least 20 months and most reached motor milestones.
Colorectal cancers with
BRAF
mutations have an aggressive natural history and are often resistant to therapy. A treatment regimen that combined BRAF inhibition, MET inhibition, and blocking of EGFR ...signaling resulted in a response rate of 26% and a median overall survival of 9 months.
Polydimethylsiloxane‐based self‐healing is achieved through the tin‐catalyzed polycondensation of phase‐separated droplets. The catalyst is released into the crack plane when microcapsules containing ...a tin compound are ruptured by the advancing crack (see figure). This system greatly extends the capability of self‐healing polymers by introducing a new, stable healing chemistry into a structural polymer matrix and may provide a route to self‐healing in harsh and corrosive environments.
Summary Background The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was ...designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. Methods In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00442637. Findings Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36–57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56–0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 23% patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. Interpretation Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. Funding Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, with astrocytes implicated as contributing substantially to motor neuron death in familial (F)ALS. However, the proposed role of ...astrocytes in the pathology of ALS derives in part from rodent models of FALS based upon dominant mutations within the superoxide dismutase 1 (SOD1) gene, which account for <2% of all ALS cases. Their role in sporadic (S)ALS, which affects >90% of ALS patients, remains to be established. Using astrocytes generated from postmortem tissue from both FALS and SALS patients, we show that astrocytes derived from both patient groups are similarly toxic to motor neurons. We also demonstrate that SOD1 is a viable target for SALS, as its knockdown significantly attenuates astrocyte-mediated toxicity toward motor neurons. Our data highlight astrocytes as a non-cell autonomous component in SALS and provide an in vitro model system to investigate common disease mechanisms and evaluate potential therapies for SALS and FALS.
SiC/SiC composites reinforced with 3rd generation SiC fibers (Hi-Nicalon S and Tyranno SA3 fibers) are promising candidates for thermomechanical applications in high technology industries. Both ...composites exhibited a pseudo-ductile mechanical behavior but the HNS/PyC/SiC composite reaches higher failure strains than TSA3/PyC/SiC ones. The mechanical behavior of SiC/SiC composites is linked to the way PyC is bonded to the fiber surface. Analyses have shown that these interactions and the Fiber/Matrix debonding behavior depend strongly on the nature of the carbon on the SiC fiber surface, which is different according to the SiC fiber. In order to understand the mechanism governing the chemical adhesion at the PyC/SiC fiber interface, the formation, the chemistry and the structure of the surface carbon layer were studied. Understanding the origin of this carbon has allowed elucidating the local interaction mechanisms of the studied SiC/SiC composites.
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number ...(CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
Spinal muscular atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease is caused by low abundance of the survival of motor neuron (SMN) protein leading ...to motor neuron degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) of self-complementary adeno-associated virus-9 carrying the human SMN cDNA (scAAV9-SMN) resulted in widespread transgene expression in spinal cord motor neurons in SMA mice as well as nonhuman primates and complete rescue of the disease phenotype in mice. Here, we evaluated the dosing and efficacy of scAAV9-SMN delivered directly to the cerebral spinal fluid (CSF) via single injection. We found widespread transgene expression throughout the spinal cord in mice and nonhuman primates when using a 10 times lower dose compared to the IV application. Interestingly, in nonhuman primates, lower doses than in mice can be used for similar motor neuron targeting efficiency. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate spreading of the vector. We present a detailed analysis of transduction levels throughout the brain, brainstem, and spinal cord of nonhuman primates, providing new guidance for translation toward therapy for a wide range of neurodegenerative disorders.
Previous studies have suggested that overexpression of the oncogenic protein epithelial membrane protein-2 (EMP2) correlates with endometrial carcinoma progression and ultimately poor survival from ...disease. To understand the role of EMP2 in the etiology of disease, gene analysis was performed to show transcripts that are reciprocally regulated by EMP2 levels. In particular, EMP2 expression correlates with and helps regulate the expression of several cancer stem cell associated markers including aldehyde dehydrogenase 1 (ALDH1). ALDH expression significantly promotes tumor initiation and correlates with the levels of EMP2 expression in both patient samples and tumor cell lines. As therapy against cancer stem cells in endometrial cancer is lacking, the ability of anti-EMP2 IgG1 therapy to reduce primary and secondary tumor formation using xenograft HEC1A models was determined. Anti-EMP2 IgG1 reduced the expression and activity of ALDH and correspondingly reduced both primary and secondary tumor load. Our results collectively suggest that anti-EMP2 therapy may be a novel method of reducing endometrial cancer stem cells.
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