The skeleton is the most common metastatic site for breast cancer, with bone metastasis causing pain as well as risk of pathological fractures. Interaction between tumors and the bone ...microenvironment creates a vicious cycle that accelerates both bone destruction and cancer progression. This study is the first to analyze the soluble factors secreted by breast tumor-associated osteoblasts (TAOBs), which are responsible for promoting cancer progression. The addition of CXCL5 (chemokine (C-X-C motif) ligand 5), present in large amounts in TAOB-condition medium (TAOB-CM), mimicked the inductive effect of TAOB-CM on breast cancer epithelial-mesenchymal transition, migration and invasion. In contrast, inhibition of CXCL5 in OBs decreased TAOB-mediated cancer progression. Inducement of MCF-7 and MDA-MB-231 cancer progression by TAOB-derived CXCL5 is associated with increased Raf/MEK/ERK activation, and mitogen- and stress-activated protein kinase 1 (MSK1) and Elk-1 phosphorylation, as well as Snail upregulation. Activation of Elk-1 facilitates recruitment of phosphorylated MSK1, which in turn enhances histone H3 acetylation and phosphorylation (serine 10) of Snail promoter, resulting in Snail enhancement and E-cadherin downregulation. Moreover, mice treated with anti-CXCL5 antibodies showed decreased metastasis of 4T1 breast cancer cells. Our study suggests that inhibition of CXCL5-mediated ERK/Snail signaling is an attractive therapeutic target for treating metastases in breast cancer patients.
Topological semimetals are characterized by symmetry-protected band crossings, which can be preserved in different dimensions in momentum space, forming zero-dimensional nodal points, one-dimensional ...nodal lines, or even two-dimensional nodal surfaces. Materials harboring nodal points and nodal lines have been experimentally verified, whereas experimental evidence of nodal surfaces is still lacking. Here, using angle-resolved photoemission spectroscopy (ARPES), we reveal the coexistence of Dirac nodal surfaces and nodal lines in the bulk electronic structures of ZrSiS. As compared with previous ARPES studies on ZrSiS, we obtained pure bulk states, which enable us to extract unambiguously intrinsic information of the bulk nodal surfaces and nodal lines. Our results show that the nodal lines are the only feature near the Fermi level and constitute the whole Fermi surfaces. We not only prove that the low-energy quasiparticles in ZrSiS are contributed entirely by Dirac fermions but also experimentally realize the nodal surface in topological semimetals.
Summary
Breeding for good meat quality performance while maintaining large body size and desirable carcass traits has been the major challenge for modern swine selective breeding. To address this ...goal, in the present work we studied five related populations produced by two commercial breeds (Berkshire and Duroc) and two Chinese breeds (Licha black pig and Lulai black pig). A single‐trait GWAS performed on 20 body size and carcass traits using a self‐developed China Chip‐1 porcine SNP50K BeadChip identified 11 genome‐wide significant QTL on nine chromosomes and 22 suggestive QTL on 15 chromosomes. For the 11 genome‐wide significant QTL, eight were detected in at least two populations, and the rest were population‐specific and only mapped in Shanxia black pig. Most of the genome‐wide significant QTL were pleiotropic; for example, the QTL around 75.65 Mb on SSC4 was associated with four traits at genome‐wide significance level. After screening the genes within 50 kb of the top SNP for each genome‐wide significant QTL, NR6A1 and VRTN were chosen as candidate genes for vertebrae number; PLAG1 and BMP2 were identified as candidate genes for body size; and MC4R was the strong candidate gene for body weight. The four genes have been reported as candidates for thoracic vertebrae number, lumbar vertebrae number, carcass length and body weight respectively in previous studies. The effects of VRTN on thoracic vertebrae number, carcass length and body length have been verified in Shanxia black pig. Therefore, the VRTN genotype could be used in gene‐assisted selection, and this could accelerate genetic improvement of body size and carcass traits in Shanxia black pig.
To explore the utility of magnetic resonance imaging (MRI) characteristics and whole-lesion apparent diffusion coefficient histogram analysis of brain metastasis from non-small cell lung cancer ...(NSCLC) in the differentiation of epidermal growth factor receptor (EGFR) mutation status.
Forty-eight patients with brain metastases from NSCLC were enrolled in this retrospective study. Patients were subtyped into EGFR mutation (23 cases) and wild-type (25 cases) groups. Whole-lesion histogram metrics were derived from the apparent diffusion coefficient (ADC) maps, and imaging features were evaluated according to conventional MRI. Student's t-test or Mann–Whitney U-test, chi-squared test, and receiver operating characteristic (ROC) curve analysis were performed to discriminate the two groups and to determine the diagnostic efficacy of ADC histogram parameters.
EGFR mutation group had more multiple brain metastases, less peritumoural brain oedema (PTBO), and lower peritumoural brain oedema index (PTBO-I) than EGFR wild-type group (all p<0.05). In addition, 90th and 75th percentiles of ADC and maximum ADC in the EGFR mutation group were significantly higher than in the EGFR wild-type group (all p<0.05). Ninetieth percentile of ADC had the highest area under the curve (AUC; 0.711), and it was found to outperform 75th percentile of ADC (AUC, 0.662; p=0.039) and maximum ADC (AUC, 0.681).
Whole-lesion ADC histogram analysis and MRI features of brain metastasis from NSCLC are expected to be potential biomarkers to non-invasively differentiate the EGFR mutation status.
The extension of the cosmic-ray spectrum beyond 1 petaelectronvolt (PeV; 10
electronvolts) indicates the existence of the so-called PeVatrons-cosmic-ray factories that accelerate particles to PeV ...energies. We need to locate and identify such objects to find the origin of Galactic cosmic rays
. The principal signature of both electron and proton PeVatrons is ultrahigh-energy (exceeding 100 TeV) γ radiation. Evidence of the presence of a proton PeVatron has been found in the Galactic Centre, according to the detection of a hard-spectrum radiation extending to 0.04 PeV (ref.
). Although γ-rays with energies slightly higher than 0.1 PeV have been reported from a few objects in the Galactic plane
, unbiased identification and in-depth exploration of PeVatrons requires detection of γ-rays with energies well above 0.1 PeV. Here we report the detection of more than 530 photons at energies above 100 teraelectronvolts and up to 1.4 PeV from 12 ultrahigh-energy γ-ray sources with a statistical significance greater than seven standard deviations. Despite having several potential counterparts in their proximity, including pulsar wind nebulae, supernova remnants and star-forming regions, the PeVatrons responsible for the ultrahigh-energy γ-rays have not yet been firmly localized and identified (except for the Crab Nebula), leaving open the origin of these extreme accelerators.
The 3D printed bulk samples fabricated by selective laser melting (SLM) of the additive manufacturing technique are usually considered to be 3D isotropic in microstructures and mechanical responses. ...This study systematically investigates the anisotropic responses in terms of hardness and electrochemical resistance for the X-, Y- and Z-planes of the SLM Ti-6Al-4V bulk samples fabricated with the zigzag laser path strategy. Results show that all SLM planes exhibit no significant difference in Young's modulus compared to the mechanically rolled plate. However, the X-plane, referred to the cross-sectional plane perpendicular to the laser moving direction, is found ~20% lower hardness and the lowest corrosion resistance compared to the Y- and Z-planes. The underlying reasoning is researched and discussed. The microstructure observations indicate that artifact holes are induced in the X-plane due to un-uniform laser intensity distribution between two neighboring printing lines. Alternatively, the Y- and Z-planes exhibit dense morphology due to multiple heating while zigzag scanning. Experimental results also indicate that the SLM materials exhibit higher corrosion resistance than the commercial rolled materials.
Aims/hypothesis
Arctigenin is a natural compound that had never been previously demonstrated to have a glucose-lowering effect. Here it was found to activate AMP-activated protein kinase (AMPK), and ...the mechanism by which this occurred, as well as the effects on glucose and lipid metabolism were investigated.
Methods
2-Deoxyglucose uptake and AMPK phosphorylation were examined in L6 myotubes and isolated skeletal muscle. Gluconeogenesis and lipid synthesis were evaluated in rat primary hepatocytes. The acute and chronic effects of arctigenin on metabolic abnormalities were observed in C57BL/6J and
ob
/
ob
mice. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye, JC-1. Analysis of respiration of L6 myotubes or isolated mitochondria was conducted in a channel oxygen system.
Results
Arctigenin increased AMPK phosphorylation and stimulated glucose uptake in L6 myotubes and isolated skeletal muscles. In primary hepatocytes, it decreased gluconeogenesis and lipid synthesis. The enhancement of glucose uptake and suppression of hepatic gluconeogenesis and lipid synthesis by arctigenin were prevented by blockade of AMPK activation. The respiration of L6 myotubes or isolated mitochondria was inhibited by arctigenin with a specific effect on respiratory complex I. A single oral dose of arctigenin reduced gluconeogenesis in C57BL/6J mice. Chronic oral administration of arctigenin lowered blood glucose and improved lipid metabolism in
ob
/
ob
mice.
Conclusions/interpretation
This study demonstrates a new role for arctigenin as a potent indirect activator of AMPK via inhibition of respiratory complex I, with beneficial effects on metabolic disorders in
ob
/
ob
mice. This highlights the potential value of arctigenin as a possible treatment of type 2 diabetes.
Abstract
Topological superconductors (TSCs) are unconventional superconductors with bulk superconducting gap and in-gap Majorana states on the boundary that may be used as topological qubits for ...quantum computation. Despite their importance in both fundamental research and applications, natural TSCs are very rare. Here, combining state of the art synchrotron and laser-based angle-resolved photoemission spectroscopy, we investigated a stoichiometric transition metal dichalcogenide (TMD), 2M-WS
2
with a superconducting transition temperature of 8.8 K (the highest among all TMDs in the natural form up to date) and observed distinctive topological surface states (TSSs). Furthermore, in the superconducting state, we found that the TSSs acquired a nodeless superconducting gap with similar magnitude as that of the bulk states. These discoveries not only evidence 2M-WS
2
as an intrinsic TSC without the need of sensitive composition tuning or sophisticated heterostructures fabrication, but also provide an ideal platform for device applications thanks to its van der Waals layered structure.
This study evaluated maintenance treatment with niraparib, a potent inhibitor of poly(ADP-ribose) polymerase 1/2, in patients with platinum-sensitive recurrent ovarian cancer.
In this phase III, ...double-blind, placebo-controlled study conducted at 30 centers in China, adults with platinum-sensitive recurrent ovarian cancer who had responded to their most recent platinum-containing chemotherapy were randomized 2 : 1 to receive oral niraparib (300 mg/day) or matched placebo until disease progression or unacceptable toxicity (NCT03705156). Following a protocol amendment, patients with a bodyweight <77 kg or a platelet count <150 × 103/μl received 200 mg/day, and all other patients 300 mg/day, as an individualized starting dose (ISD). Randomization was carried out by an interactive web response system and stratified by BRCA mutation, time to recurrence following penultimate chemotherapy, and response to most recent chemotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review.
Between 26 September 2017 and 2 February 2019, 265 patients were randomized to receive niraparib (n = 177) or placebo (n = 88); 249 patients received an ISD (300 mg, n = 14; 200 mg, n = 235) as per protocol. In the intention-to-treat population, median PFS was significantly longer for patients receiving niraparib versus placebo: 18.3 95% confidence interval (CI), 10.9-not evaluable versus 5.4 (95% CI, 3.7-5.7) months hazard ratio (HR) = 0.32; 95% CI, 0.23-0.45; P < 0.0001, and a similar PFS benefit was observed in patients receiving an ISD, regardless of BRCA mutation status. Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively; the most common events were neutrophil count decreased (20.3% versus 8.0%) and anemia (14.7% versus 2.3%).
Niraparib maintenance treatment reduced the risk of disease progression or death by 68% and prolonged PFS compared to placebo in patients with platinum-sensitive recurrent ovarian cancer. Individualized niraparib dosing is effective and safe and should be considered standard practice in this setting.
•Chinese patients with platinum-sensitive recurrent ovarian cancer received maintenance niraparib (n = 177) or placebo (n = 88).•Median PFS was longer for niraparib versus placebo: 18.3 versus 5.4 months (HR = 0.32; 95% CI, 0.23-0.45; P < 0.0001).•Niraparib had a similar PFS benefit for 249 patients receiving individualized dosing based on bodyweight and platelet count.•Grade ≥3 treatment-emergent adverse events occurred in 50.8% and 19.3% of patients who received niraparib and placebo, respectively.•In the niraparib group, Grade ≥3 platelet count decreased/thrombocytopenia occurred in 11.3% of patients.
Previous mass screening studies have shown that IgA antibodies against Epstein–Barr Virus (EBV) can facilitate early detection of nasopharyngeal carcinoma (NPC), but the impact of EBV-antibody ...screening for NPC-specific mortality remains unknown.
A prospective, cluster randomized, controlled trial for NPC screening (PRO-NPC-001) was conducted in 3 selected towns of Zhongshan City and 13 selected towns of Sihui City in southern China beginning in 2008. Serum samples of the screening group were tested for two previously selected anti-EBV antibodies. Subjects with serological medium risk were subsequently retested annually for 3 years, and those with serological high risk were referred to otorhinolaryngologists for diagnostic check-up. An interim analysis was carried out to evaluate the primary end points of the NPC-specific mortality and the early diagnostic rate, and the secondary end point of the NPC incidence, through linkage with the database of Zhongshan City.
Among 70 296 total subjects, 29 413 screened participants (41.8% of the total subjects) in the screening group and 50 636 in the control group, 153 (43.3 per 100 000 person-year), 62 (55.3 per 100 000 person-year) and 99 (33.1 per 100 000 person-year) NPC cases were identified. The early diagnostic rates of NPC were significantly higher in the participants (79.0%, P < 0.0001) and the screening group (45.9%, P < 0.0001) compared with the control group (20.6%). Although no differences were found between NPC-specific mortality of the screening group and the control group relative risk (RR)= 0.82, 95% confidence interval (CI) 0.37–1.79, lower NPC-specific mortality was noticed among participants from the screening group versus the control group (RR = 0.22, 95% CI 0.09–0.49).
IgA antibodies against EBV can identify high-risk population and was effective in screening for early asymptomatic NPC. Although the mortality reduction was not significant in the primary end point, we noted encouraging evidence of a mortality reduction in screening participants in this interim analysis.
NCT00941538.
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