Flights of Holocene marine terraces are useful for reconstructing past earthquakes, but coastal erosion can remove terraces from the landscape, potentially leading to incorrect estimates of ...earthquake magnitude and frequency. Relatively little effort has been afforded to studying terrace erosion processes, and this paper presents the first field evidence that we are aware of documenting terrace erosion rates. Two case studies from New Zealand provide a unique opportunity to observe the beginning and end phases of terrace development. We present downwear and backwear erosion measurements, showing that both sets of processes are important. Micro‐erosion meter measurements from Kaikōura Peninsula, South Island, confirm that downwear processes are modifying new marine terraces that were created when the peninsula was uplifted about 1 m during the 2016 earthquake. Erosion rates were high immediately following uplift as the relatively barren intertidal rock shore platform rapidly transformed into an incipient marine terrace with cover deposits. However, the Kaikōura earthquake uplifted shore platforms only a small distance above the upper tidal limit and ongoing downwear and backwear erosion may begin to remove parts of this terrace in future decades. We explored this prospect with a case study at Māhia Peninsula, North Island, where 100–300 years have elapsed since the last terrace‐forming earthquake. Historical photographs were used to document about 80 years of backwear erosion. Terrace erosion rates have been nearly constant through this period, and extrapolation implies that the terrace will be removed in places by 2030. The erosion data in this paper provide new insights into how terraces can be removed from the landscape, but there are many complicating factors. To help understand these factors we present a new conceptual model of marine terrace creation and destruction for soft‐rock coasts.
Coastal erosion can remove marine terraces from the landscape, complicating interpretation of past earthquakes. We measured terrace erosion rates at two field sites where we had a unique opportunity to study the beginning and end phases of terrace development. Photograph (a) at Kaikōura shows a new marine terrace produced by the 2016 earthquake. Photograph (b) at Mahia shows a narrow terrace that has nearly been removed by erosion.
Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory ...signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.
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2D covalent organic frameworks (2D COFs) are a unique materials platform that combines covalent connectivity, structural regularity, and molecularly precise porosity. However, 2D COFs typically form ...insoluble aggregates, thus limiting their processing via additive manufacturing techniques. In this work, colloidal suspensions of boronate‐ester‐linked 2D COFs are used as a spray‐coating ink to produce large‐area 2D COF thin films. This method is synthetically general, with five different 2D COFs prepared as colloidal inks and subsequently spray‐coated onto a diverse range of substrates. Moreover, this approach enables the deposition of multiple 2D COF materials simultaneously, which is not possible by polymerizing COFs on substrates directly. When combined with stencil masks, spray‐coated 2D COFs are rapidly deposited as thin films larger than 200 cm2 with line resolutions below 50 µm. To demonstrate that this deposition scheme preserves the desirable attributes of 2D COFs, spray‐coated 2D COF thin films are incorporated as the active material in acoustic sensors. These 2D‐COF‐based sensors have a 10 ppb limit‐of‐quantification for trimethylamine, which places them among the most sensitive sensors for meat and seafood spoilage. Overall, this work establishes a scalable additive manufacturing technique that enables the integration of 2D COFs into thin‐film device architectures.
High‐resolution, large‐scale fabrication of 2D covalent organic framework (COF) thin films is achieved by spray‐coating colloidal inks of these materials. Using this additive manufacturing approach, 2D COF thin films are integrated into acoustic sensing platforms. These sensors achieve superlative detection of volatile amines including a limit‐of‐quantification of 10 ppb for trimethylamine, which is a target analyte for the detection of food spoilage.
Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of ...flexible dose adjustments of oral semaglutide with sitagliptin 100 mg.
In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA
of 7·5-9·5% (58-80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA
and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA
of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing.
Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 57% of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA
of 8·3% (SD 0·6%; 67 mmol/mol SD 6·4), a greater proportion of participants achieved an HbA
of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% 134 of 230 vs 25% 60 of 238; and trial product estimand: 63% 123 of 196 vs 28% 52 of 184). The odds of achieving an HbA
of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio OR 4·40, 95% CI 2·89-6·70, p<0·0001; and trial product estimand: 5·54, 3·54-8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: -2·6 kg SE 0·3 vs -0·7 kg SE 0·2, estimated treatment difference ETD -1·9 kg, 95% CI -2·6 to -1·2; p<0·0001; and trial product estimand: -2·9 kg SE 0·3 vs -0·8 kg SE 0·3, ETD -2·2 kg, -2·9 to -1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 21%). Two deaths occurred in the sitagliptin group during the trial.
Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists.
Novo Nordisk A/S.
Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a ...continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.
Women ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0-1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.
Sixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.
Abemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.
https://clinicaltrials.gov/, identifier NCT02057133.
We report new constraints on the size of large extra dimensions from data collected by the MINOS experiment between 2005 and 2012. Our analysis employs a model in which sterile neutrinos arise as ...Kaluza-Klein states in large extra dimensions and thus modify the neutrino oscillation probabilities due to mixing between active and sterile neutrino states. Using Fermilab's NuMI beam exposure of \(10.56 \times 10^{20}\) protons-on-target, we combine muon neutrino charged current and neutral current data sets from the Near and Far Detectors and observe no evidence for deviations from standard three-flavor neutrino oscillations. The ratios of reconstructed energy spectra in the two detectors constrain the size of large extra dimensions to be smaller than \(0.45\,\mu\text{m}\) at 90% C.L. in the limit of a vanishing lightest active neutrino mass. Stronger limits are obtained for non-vanishing masses.
The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new ...susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10
). Most loci harbor biologically plausible candidate genes. We refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37% of father-to-son familial risk, 8% of which can be attributed to the 12 new signals reported here. Our findings substantially increase the number of known TGCT susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT.
Data from the MINOS experiment has been used to search for mixing between muon neutrinos and muon antineutrinos using a time-independent Lorentz-violating formalism derived from the Standard-Model ...Extension (SME). MINOS is uniquely capable of searching for muon neutrino-antineutrino mixing given its long baseline and ability to distinguish between neutrinos and antineutrinos on an event-by-event basis. Neutrino and antineutrino interactions were observed in the MINOS Near and Far Detectors from an exposure of 10.56\(\times10^{20}\) protons-on-target from the NuMI neutrino-optimized beam. No evidence was found for such transitions and new, highly stringent limits were placed on the SME coefficients governing them. We place the first limits on the SME parameters \((c_{L})^{TT}_{\mu\mu} \) and \((c_{L})^{TT}_{\tau\tau}\) at \(-8.4\times10^{-23} < (c_{L})^{TT}_{\mu\mu} < 8.0\times10^{-23}\) and \(-8.0\times10^{-23} < (c_{L})^{TT}_{\tau\tau} < 8.4\times10^{-23}\), and the world's best limits on the \(\tilde{g}^{ZT}_{\mu\overline{\mu}}\) and \(\tilde{g}^{ZT}_{\tau\overline{\tau}}\) parameters at \(|\tilde{g}^{ZT}_{\mu\overline{\mu}}| < 3.3\times 10^{-23}\) and \(|\tilde{g}^{ZT}_{\tau\overline{\tau}}| < 3.3\times 10^{-23}\), all limits quoted at \(3\sigma\).
We report results of a search for oscillations involving a light sterile neutrino over distances of 1.04 and \(735\,\mathrm{km}\) in a \(\nu_{\mu}\)-dominated beam with a peak energy of ...\(3\,\mathrm{GeV}\). The data, from an exposure of \(10.56\times 10^{20}\,\textrm{protons on target}\), are analyzed using a phenomenological model with one sterile neutrino. We constrain the mixing parameters \(\theta_{24}\) and \(\Delta m^{2}_{41}\) and set limits on parameters of the four-dimensional Pontecorvo-Maki-Nakagawa-Sakata matrix, \(|U_{\mu 4}|^{2}\) and \(|U_{\tau 4}|^{2}\), under the assumption that mixing between \(\nu_{e}\) and \(\nu_{s}\) is negligible (\(|U_{e4}|^{2}=0\)). No evidence for \(\nu_{\mu} \to \nu_{s}\) transitions is found and we set a world-leading limit on \(\theta_{24}\) for values of \(\Delta m^{2}_{41} \lesssim 1\,\mathrm{eV}^{2}\).
We have searched for sidereal variations in the rate of antineutrino interactions in the MINOS Near Detector. Using antineutrinos produced by the NuMI beam, we find no statistically significant ...sidereal modulation in the rate. When this result is placed in the context of the Standard Model Extension theory we are able to place upper limits on the coefficients defining the theory. These limits are used in combination with the results from an earlier analysis of MINOS neutrino data to further constrain the coefficients.
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