Glycolysis is critical for cancer stem cell reprogramming; however, the underlying regulatory mechanisms remain elusive. Here, we show that pyruvate dehydrogenase kinase 1 (PDK1) is enriched in ...breast cancer stem cells (BCSCs), whereas depletion of PDK1 remarkably diminishes ALDH
subpopulations, decreases stemness-related transcriptional factor expression, and inhibits sphere-formation ability and tumor growth. Conversely, high levels of PDK1 enhance BCSC properties and are correlated with poor overall survival. In mouse xenograft tumor, PDK1 is accumulated in hypoxic regions and activates glycolysis to promote stem-like traits. Moreover, through screening hypoxia-related long non-coding RNAs (lncRNAs) in PDK1-positive tissue, we find that lncRNA H19 is responsible for glycolysis and BCSC maintenance. Furthermore, H19 knockdown decreases PDK1 expression in hypoxia, and ablation of PDK1 counteracts H19-mediated glycolysis and self-renewal ability in vitro and in vivo. Accordingly, H19 and PDK1 expression exhibits strong correlations in primary breast carcinomas. H19 acting as a competitive endogenous RNA sequesters miRNA let-7 to release Hypoxia-inducible factor 1α, leading to an increase in PDK1 expression. Lastly, aspirin markedly attenuates glycolysis and cancer stem-like characteristics by suppressing both H19 and PDK1. Thus, these novel findings demonstrate that the glycolysis gatekeeper PDK1 has a critical role in BCSC reprogramming and provides a potential therapeutic strategy for breast malignancy.
Abstract The magnetic fields in our Milky Way can be revealed by the distribution of Faraday rotation measures (RMs) of radio sources behind the Galaxy and of radio pulsars inside the Galaxy. Based ...on the antisymmetry of the Faraday sky in the inner Galaxy to the Galactic coordinates, the magnetic field toroids above and below the Galactic plane with reversed field directions exist in the Galactic halo and have been included in almost all models for the global magnetic structure in the Milky Way. However, the quantitative parameters—such as the field strength, the scale height, and the scale radius of the toroids—are hard to determine from observational data. It has long been argued that the RM antisymmetry could be dominated by the local contributions of the interstellar medium. Here, we get the local-discounted RM contributions from the RM sky and RMs of pulsars and get the first quantitative estimate of the sizes of the magnetic toroids in the Galactic halo. They are huge, starting from a Galactocentric radius of less than 2 kpc and extending to at least 15 kpc, without field direction reversals. Such magnetic toroids in the Galactic halo should naturally constrain the physical processes in galaxies.
Bimetallic nanoparticles are a class of important electrocatalyst. They exhibit a synergistic effect that critically depends on the surface composition, which determines the surface properties and ...the adsorption/desorption behavior of the reactants and intermediates during catalysis. The surface composition can be varied, as nanoparticles are exposed to certain environments through surface segregation. Thermodynamically, this is caused by a difference in surface energy between the two metals. It may lead to the enrichment of one metal on the surface and the other in the core. The external conditions that influence the surface energy may lead to the variation of the thermodynamic steady state of the particle surface and, thus, offer a chance to vary the surface composition. In this review, the most recent and important progress in surface segregation of bimetallic nanoparticles and its impact in electrocatalysis are introduced. Typical segregation inducements and surface characterization techniques are discussed in detail. It is concluded that surface segregation is a critical issue when designing bimetallic catalysts. It is necessary to explore methods to control it and utilize it as a way towards producing robust, bimetallic electrocatalysts.
Surface segregation of bimetallic nanoparticles may be induced by many factors, such as adsorbates, heat, substrates, and electrochemical reactions. It is a critical issue in bimetallic nanoparticle catalyst engineering. Good control may offer the opportunity to optimize the surface properties of bimetallic nanoparticles, thus promoting their good catalytic performance.
Background
The aim of this study was to assess the immune profile within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), and to investigate the prognostic value of intratumoral ...infiltrating immune/inflammatory cells (IICs) in patients after surgery.
Methods
Eighteen phenotypic markers representing 11 types of IIC and the protein products of genes TP53, CDKN2A/p16 and SMAD4/DPC4 were assessed by immunohistochemistry of specimens from patients with pancreatic cancer. The expression of IICs and the mutational status of the genes were correlated with tumour recurrence and survival, and results were validated in an independent cohort.
Results
CD15+ neutrophils, CD20+ B cells and CD206+ tumour‐associated macrophages were seen frequently in tumours, and their presence was associated with reduced survival in a cohort of 79 patients. Expression of CD4+ T helper cells, CD8+ cytotoxic T lymphocytes and CD117+ mast cells was associated with a favourable prognosis. A weighted Cox regression recurrence‐predictive model was constructed that showed good correlation of IICs and gene mutations. A combination of CD15, CD206, CD117 and Smad4 expression was independently associated with overall (hazard ratio (HR) 3·63, 95 per cent c.i. 2·18 to 6·04; P < 0·001) and recurrence‐free (HR 2·93, 1·81 to 4·75; P < 0·001) survival. These findings were validated in an independent cohort (151 patients) and in 54 tissue samples obtained by preoperative endoscopic ultrasound‐guided fine‐needle aspiration.
Conclusion
PDAC has a unique immunosuppressive phenotype that is associated with characteristic gene mutations, disease recurrence and survival after pancreatectomy.
Surgical relevance
The immune microenvironment plays a critical role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is associated with mutations in major driver genes, including KRAS, TP53, CDKN2A/p16 and SMAD4/DPC4.
This study shows that the microenvironment of PDAC has a unique immunosuppressive phenotype, which may be driven by oncogene mutations. Patients with PDAC with a highly immunosuppressive profile tended to have poor postoperative survival. A model including three intratumoral infiltrating immune markers (CD15+, CD206+ and CD117+) and a SMAD4 mutation can be used to predict recurrence and survival in patients after surgery for PDAC.
Immunosuppressive phenotype has poor prognosis
The clean energy carrier, hydrogen, if efficiently produced by water electrolysis using renewable energy input, would revolutionize the energy landscape. It is the sluggish oxygen evolution reaction ...(OER) at the anode of water electrolyzer that limits the overall efficiency. The large spinel oxide family is widely studied due to their low cost and promising OER activity. As the distribution of transition metal (TM) cations in octahedral and tetrahedral site is an important variable controlling the electronic structure of spinel oxides, the TM geometric effect on OER is discussed. The dominant role of octahedral sites is found experimentally and explained by computational studies. The redox‐active TM locating at octahedral site guarantees an effective interaction with the oxygen at OER conditions. In addition, the adjacent octahedral centers in spinel act cooperatively in promoting the fast OER kinetics. In remarkable contrast, the isolated tetrahedral TM centers in spinel prohibit the OER mediated by dual‐metal sites. Furthermore, various spinel oxides preferentially expose octahedral‐occupied cations on the surface, making the octahedral cations easily accessible to the reactants. The future perspectives and challenges in advancing fundamental understanding and developing robust spinel catalysts are discussed.
The octahedral unit is the key site for engineering better spinel oxide catalysts for the oxygen evolution reaction (OER) due to the effective interaction between oxygen and octahedral‐occupied transition metal, the fast OER kinetics by dual‐metal sites (adjacent octahedral transition metal) mediation, and the preferential exposure of octahedral cations on the surface of spinel oxides.
Projection imaging has been employed widely in many areas, such as x-ray radiography, due to its penetration power and ballistic geometry of their paths. However, its resolution limit remains a major ...challenge, caused by the conflict of source intensity and source size associated with image blurriness. A simple yet robust scheme has been proposed here to solve the problem. An unconventional square aperture, rather than the usual circular beam, is constructed, which allows for the straightforward deciphering of a blurred spot, to unravel hundreds originally hidden pixels. With numerical verification and experimental demonstration, our proposal is expected to benefit multiple disciplines, not limited to x-ray imaging.
Cobalt spinel oxides are a class of promising transition metal (TM) oxides for catalyzing oxygen evolution reaction (OER). Their catalytic activity depends on the electronic structure. In a spinel ...oxide lattice, each oxygen anion is shared amongst its four nearest transition metal cations, of which one is located within the tetrahedral interstices and the remaining three cations are in the octahedral interstices. This work uncovered the influence of oxygen anion charge distribution on the electronic structure of the redox‐active building block Co−O. The charge of oxygen anion tends to shift toward the octahedral‐occupied Co instead of tetrahedral‐occupied Co, which hence produces strong orbital interaction between octahedral Co and O. Thus, the OER activity can be promoted by pushing more Co into the octahedral site or shifting the oxygen charge towards the redox‐active metal center in CoO6 octahedra.
The oxygen evolution activity of Co‐based spinel oxides is dominated by the catalytically critical TMO6 octahedra. Pushing more active Co into octahedral sites and shifting the oxygen charge to octahedral Co significantly enhance the activity.
Background and purpose
Neutrophils, a pivotal immune responder to ischaemic brain insult, have been involved in neuroplasticity and increase after stroke. Recombinant tissue plasminogen activator ...(r‐tPA), a promising treatment improving neuroplasticity, promotes neutrophil degranulation. However, the dynamic profile of neutrophils after r‐tPA treatment and their effect on neurological recovery after stroke are not well studied.
Methods
Cell counts of neutrophils, lymphocytes and their ratio (NLR) were measured on admission and 24 h after r‐tPA infusion in 372 consecutively recruited acute ischaemic stroke patients (mean age 64 years). Death or major disability at 3 months after stroke was diagnosed based on the modified Rankin Scale (mRS ≥ 3) obtained by neurologists who were blinded to any hospital records. The longitudinal associations of percentage increase in neutrophils, lymphocytes and the NLR with death or major disability were examined by logistic regression adjusting for covariates including neurological deficits at baseline.
Results
Neutrophils exhibited a steeper increase after r‐tPA infusion in patients with death or major disability than in those without (P < 0.001). A 10% increase in neutrophils after r‐tPA infusion was associated with an 83% increased risk for death or major disability within 3 months after stroke onset odds ratio (OR) 1.99, P = 0.009. Increased neutrophils at 24 h after r‐tPA (OR 6.30, P < 0.001 after log transformation) but not on admission significantly predicted increased risks for death or major disability within 3 months after stroke onset. A similar phenomenon was also observed for the NLR.
Conclusions
A dynamic increase in neutrophils after stroke significantly predicts 3‐month death or major disability in acute ischaemic stroke patients receiving r‐tPA treatment.
This Letter reports a measurement of the flux and energy spectrum of electron antineutrinos from six 2.9 GWth nuclear reactors with six detectors deployed in two near (effective baselines 512 and 561 ...m) and one far (1579 m) underground experimental halls in the Daya Bay experiment. Using 217 days of data, 296 721 and 41 589 inverse β decay (IBD) candidates were detected in the near and far halls, respectively. The measured IBD yield is (1.55±0.04) ×10(-18) cm(2) GW(-1) day(-1) or (5.92±0.14) ×10(-43) cm(2) fission(-1). This flux measurement is consistent with previous short-baseline reactor antineutrino experiments and is 0.946±0.022 (0.991±0.023) relative to the flux predicted with the Huber-Mueller (ILL-Vogel) fissile antineutrino model. The measured IBD positron energy spectrum deviates from both spectral predictions by more than 2σ over the full energy range with a local significance of up to ∼4σ between 4-6 MeV. A reactor antineutrino spectrum of IBD reactions is extracted from the measured positron energy spectrum for model-independent predictions.
Colorectal cancer (CRC) results from the accumulation of genetic alterations, and somatic copy number alterations (CNAs) are crucial for the development of CRC. Genome-wide survey of CNAs provides ...opportunities for identifying cancer driver genes in an unbiased manner. The detection of aberrant CNAs may provide novel markers for the early diagnosis and personalized treatment of CRC. A major challenge in array-based profiling of CNAs is to distinguish the alterations that play causative roles from the random alterations that accumulate during colorectal carcinogenesis. In this view, we systematically discuss the frequent CNAs in CRC, focusing on functional genes that have potential diagnostic, prognostic and therapeutic significance.
PDF
