Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase II trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been ...the reference arm in recent phase II and III trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs.
In this open-label, randomized, phase III, noninferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000mg/m2 on days 1 and 8, and oxaliplatin 100mg/m2 on day 1) or XELOX (capecitabine 1000mg/m2, twice daily, on days 1–14 and oxaliplatin 130mg/m2 on day 1) as first-line treatment, given every 3weeks, totaling eight cycles. The primary end point was to prove the noninferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate.
In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5.3months for the GEMOX group and 5.8months for the XELOX group. The 6-month PFS rate was 44.5% for the GEMOX group and 46.7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was −12% to 16%, meeting the criteria for noninferiority of XELOX to GEMOX. There was no difference in objective response (P=0.171) and median overall survival (P=0.131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (P<0.001).
XELOX showed significant noninferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment of BCTs.
This study was registered in ClinicalTrials.gov (number NCT01470443).
Chronic inflammation caused by high glucose and high free fatty acid (FFA) concentrations is a major contributor to the pathogenesis of type 2 diabetes. Recent evidence suggests that activation of ...Toll-like receptor (TLR) signaling induces peripheral insulin resistance and mediates central insulin and leptin resistance. In this study, we investigated the renal effects of TLR4 signaling blockade in type 2 diabetic mice. Eight-week-old db/db mice were treated for 12 weeks with (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (GIT27), which targets macrophages through the inhibition of TLR4- and TLR2/6-mediated signaling pathways. Although GIT27 treatment improved glycemic control and insulin tolerance, which is associated with a lower lipid profile, it did not impact body weight or food consumption. GIT27 treatment also markedly decreased urinary albumin excretion, decreased proinflammatory cytokine synthesis, improved tissue lipid metabolism, induced oxidative stress, and improved glomerulosclerosis compared with the control db/db group. In cultured podocytes and adipocytes, high glucose levels with FFA stimulation increased TLR4 expression and proinflammatory cytokine synthesis, but the effects were abolished by GIT27 treatment. In addition, knockdown of TLR4 expression by stealth small interfering RNA abolished FFA-induced proinflammatory cytokine synthesis in cultured podocytes. In conclusion, our results suggest that GIT27 treatment improves insulin resistance and protects against the renal injury that occurs in type 2 diabetic nephropathy through both metabolic and antiglomerulosclerotic mechanisms. These results suggest that TLR pathway inhibition might play a direct protective role in diabetic kidney disease.
We derive new constraints on the mass of the Milky Way's dark matter halo, based on 2401 rigorously selected blue horizontal-branch halo stars from SDSS DR6. This sample enables construction of the ...full line-of-sight velocity distribution at different galactocentric radii. To interpret these distributions, we compare them to matched mock observations drawn from two different cosmological galaxy formation simulations designed to resemble the Milky Way. This procedure results in an estimate of the Milky Way's circular velocity curve to image60 kpc, which is found to be slightly falling from the adopted value of 220 km s super(-1) at the Sun's location, and implies image M sub(image). The radial dependence of image, derived in statistically independent bins, is found to be consistent with the expectations from an NFW dark matter halo with the established stellar mass components at its center. If we assume that an NFW halo profile of characteristic concentration holds, we can use the observations to estimate the virial mass of the Milky Way's dark matter halo, image M sub(image), which is lower than many previous estimates. We have checked that the particulars of the cosmological simulations are unlikely to introduce systematics larger than the statistical uncertainties. This estimate implies that nearly 40% of the baryons within the virial radius of the Milky Way's dark matter halo reside in the stellar components of our Galaxy. A value for image of only image M sub(image) also (re)opens the question of whether all of the Milky Way's satellite galaxies are on bound orbits.
The toxicity of the antifouling biocides Irgarol 1051, Diuron, Chlorothalonil, Dichlofluanid, Sea-nine 211, Copper pyrithione, Zinc pyrithione, Ziram and Zineb were evaluated on Nitzschia pungens and ...Artemia larvae. Results showed that EC50 for Irgarol 1051 was 0.586μgl−1 was the strongest effect on N. pungens following by Copper pyrithione (4.908μgl−1), Ziram (5.421μgl−1), Zinc pyrithione (5.513μgl−1), Diuron (6.640μgl−1), Zineb (232.249μgl−1), Sea-nine 211(267.368μgl−1), Chlorothalonil (360.963μgl−1) and Dichlofluanid (377.010μgl−1) in 96h. In Artemia larvae, the biocides were evaluated the LC50 for larval survivals at 48h. Sea-nine 211 and Copper pyrithione were 0.318 and 0.319mgl−1. Chlorothalonil, Zinc pyrithione and Ziram were 2.683, 3.147 and 4.778mgl−1. Irgarol 1051, Diuron, Zineb and Dichlofluanid were 9.734, 30.573, 41.170 and 154.944mgl−1. These results provide baseline data concerning the toxicity of antifouling biocides against marine environment.
•Nine antifouling biocides were investigated toxicological response•Two species (Nitzschia pungens and Artemia larvae) were used to assess•Results showed comparable for ecological risk using antifouling paint
Yes-associated protein 1 (YAP1) is a multifunctional protein that can interact with different transcription factors to activate gene expression. The role of YAP1 in tumorigenesis is unclear. We aimed ...to investigate the functional role of YAP1 in tumorigenesis of gastric cancer.
YAP1 expression in gastric adenocarcinoma was evaluated. The biological function was determined by proliferation assay, colony formation, cell invasion, and flow cytometric analysis through knocking down or ectopic expressing YAP1 in gastric cancer cell lines coupled with in vivo study. The possible downstream effectors of YAP1 were investigated by expression microarray.
YAP1 protein expression was upregulated in gastric cancer. Nuclear accumulation of YAP1 was associated with poor disease-specific survival (P = 0.021), especially in patients with early-stage diseases (P < 0.001). Knockdown YAP1 resulted in a significant reduction in proliferation, anchorage-dependent colony formation, cell invasion, and cell motility. Ectopic YAP1 expression promoted anchorage-independent colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK (mitogen-activated protein kinase) pathway by YAP1. We confirmed a constitutive activation of RAF/MEK/ERK (extracellular signal-regulated kinase) in YAP1-expressing MKN45 cells and further showed that YAP1 enhanced serum/epidermal growth factor-induced c-Fos expression in gastric cancer cells.
Our findings supported that YAP1 exhibits oncogenic property in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early-response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer.
The contamination of microplastics in aquatic environment is regarded as a serious threat to ecosystem especially to aquatic environment. Microplastic pollution associated problems including their ...bioaccumulation and ecological risks have become a major concern of the public and scientific community. The removal of microplastics from their discharge points is an effective way to mitigate the adverse effects of microplastic pollution, hence has been the central of the research in this realm. Presently, most of the commonly used water or wastewater treatment technologies are capable of removing microplastic to certain extent, although they are not intentionally installed for this reason. Nevertheless, recognizing the adverse effects posed by microplastic pollution, more efforts are still desired to enhance the current microplastic removal technologies. With their structural multifunctionalities and flexibility, nanomaterials have been increasingly used for water and wastewater treatment to improve the treatment efficiency. Particularly, the unique features of nanomaterials have been harnessed in synthesizing high performance adsorbent and photocatalyst for microplastic removal from aqueous environment. This review looks into the potentials of nanomaterials in offering constructive solutions to resolve the bottlenecks and enhance the efficiencies of the existing materials used for microplastic removal. The current efforts and research direction of which studies can dedicate to improve microplastic removal from water environment with the augmentation of nanomaterial-enabled strategies are discussed. The progresses made to date have witnessed the benefits of harnessing the structural and dimensional advantages of nanomaterials to enhance the efficiency of existing microplastic treatment processes to achieve a more sustainable microplastic cleanup.
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•The potentials of nanomaterials for microplastic remediation are reviewed.•Various nanomaterial-enabled removal techniques are discussed.•Nanomaterials overcome the limitations of bulk materials in microplastic remediation.•The challenges and way forward are presented.
A
bstract
Limits on the cross section for weakly interacting massive particles (WIMPs) elastic scattering on nuclei in NaI(Tl) detectors at the Yangyang Underground Laboratory are obtained from a ...2967.4 kg·day data exposure. The nuclei recoiling from the scattering process are identified by the pulse shape of the scintillation light signals that they produce. The data are consistent with a no nuclear-recoil hypothesis, and WIMP-mass-dependent 90% confidence-level upper-limits are set on WIMP-nuclei elastic scattering cross sections. These limits partially exclude the DAMA/LIBRA allowed region for WIMP-sodium interactions with the same NaI(Tl) target material. The 90% confidence level upper limit on the WIMP-nucleon spin-independent cross section is 3.26×10
−4
pb for a WIMP mass of 10 GeV/c
2
.
Ammoniated aerosols are important for urban air quality, but emissions of the key precursor NH3 are not well quantified. Mobile laboratory observations are used to characterize fleet-integrated NH3 ...emissions in six cities in the U.S. and China. Vehicle NH3:CO2 emission ratios in the U.S. are similar between cities (0.33–0.40 ppbv/ppmv, 15% uncertainty) despite differences in fleet composition, climate, and fuel composition. While Beijing, China has a comparable emission ratio (0.36 ppbv/ppmv) to the U.S. cities, less developed Chinese cities show higher emission ratios (0.44 and 0.55 ppbv/ppmv). If the vehicle CO2 inventories are accurate, NH3 emissions from U.S. vehicles (0.26 ± 0.07 Tg/yr) are more than twice those of the National Emission Inventory (0.12 Tg/yr), while Chinese NH3 vehicle emissions (0.09 ± 0.02 Tg/yr) are similar to a bottom-up inventory. Vehicle NH3 emissions are greater than agricultural emissions in counties containing near half of the U.S. population and require reconsideration in urban air quality models due to their colocation with other aerosol precursors and the uncertainties regarding NH3 losses from upwind agricultural sources. Ammonia emissions in developing cities are especially important because of their high emission ratios and rapid motorizations.
Increasing evidence on the impact of the different wavelengths of sunlight on the skin demonstrates the need for tailored recommendations of sunscreen according to skin phototype and dermatoses, ...which is now possible due to advances in the filters and formulations of sunscreens. A selective literature search was performed by an international expert panel, focusing on the type of sunscreen to recommend for photoaging, skin cancers, photodermatoses, pigmentary disorders and skin inflammatory disorders. Protection against ultraviolet (UV)B is especially important for light skin as there is a high risk of sunburn, DNA damage and skin cancers. Darker skin may be naturally better protected against UVB but is more prone to hyperpigmentation induced by visible light (VL) and UVA. Protection against UVA, VL and infrared A can be helpful for all skin phototypes as they penetrate deeply and cause photoaging. Long‐wave UVA1 plays a critical role in pigmentation, photoaging, skin cancer, DNA damage and photodermatoses. Adapting the formulation and texture of the sunscreen to the type of skin and dermatoses is also essential. Practical recommendations on the type of sunscreen to prescribe are provided to support the clinician in daily practice.
Nuclear fusion is one of the most attractive alternatives to carbon-dependent energy sources1. Harnessing energy from nuclear fusion in a large reactor scale, however, still presents many scientific ...challenges despite the many years of research and steady advances in magnetic confinement approaches. State-of-the-art magnetic fusion devices cannot yet achieve a sustainable fusion performance, which requires a high temperature above 100 million kelvin and sufficient control of instabilities to ensure steady-state operation on the order oftens of seconds2,3. Here we report experiments at the Korea Superconducting Tokamak Advanced Research4 device producing a plasma fusion regime that satisfies most ofthe above requirements: thanks to abundant fast ions stabilizing the core plasma turbulence, we generate plasmas at a temperature of 100 million kelvin lasting up to 20 seconds without plasma edge instabilities or impurity accumulation. A low plasma density combined with a moderate input power for operation is key to establishing this regime by preserving a high fraction of fast ions. This regime is rarely subject to disruption and can be sustained reliably even without a sophisticated control, and thus represents a promising path towards commercial fusion reactors.
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