Background: Mutations of the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients predict the patients who will respond to EGFR tyrosine kinase inhibitor (TKI) ...treatment. A recent study has suggested that 33% of NSCLC showed primary tumor/metastasis discordance of EGFR expression by immunohistochemistry analysis. We intended to find out whether the EGFR mutations of primary lung cancers are concordant to that of corresponding metastatic tumors. Materials and methods: We analyzed EGFR exons 18–21 from paired primary and metastatic tumors in 67 lung cancer patients who had not received TKI before tissues were sampled. Results: Using the direct sequencing method, 9 of 18 (50%) patients with EGFR mutation-positive primary lung tumors had lost the mutations in metastases. For 26 patients who were EGFR mutation positive in the metastatic tumors, 17 (65%) were negative in the primary tumors. We analyzed these paired tissues with discrepant EGFR mutations by the Scorpion Amplified Refractory Mutation System assay. Finally, the discordant rate reached 27% (18 of 67 cases). Conclusion: EGFR mutations in primary lung tumors do not always reflect the same situation in metastases. Analysis of EGFR mutations in the primary lung tumor would be inadequate for planning the use of TKI for advanced NSCLC.
Abstract
Recent studies suggest that as the trade wind in the Caribbean Sea weakens from summer to fall, conditions become more favorable for the Loop Current in the Gulf of Mexico to shed an ...anticyclonic ring. This idea originated with observations showing a preference for more eddies from summer through fall, and it was confirmed using multidecadal model experiments. Here, the hypothesis is further tested by studying the dynamics of a specific eddy-shedding event in summer 2011 using a model experiment initialized with observation-assimilated reanalysis and forced by reanalysis wind from NCEP. Eddy shedding in July 2011 is shown to follow the weakening of the trade wind and Yucatan transport in late June. The shedding time is significantly earlier than can be explained based on reduced-gravity Rossby wave dynamics. Altimetry and model data are analyzed to show that empirical orthogonal function modes 1 + 2 dominate the reduced-gravity process, while higher modes contain the coupling of the Loop Current with deep layer underneath. The Loop’s westward expansion at incipient shedding induces a deep cyclonic gyre in the eastern Gulf, embedded within which are small cyclones caused by the baroclinic instability of the strongly sheared current north of the Campeche Bank. The associated deep upwelling and upper-layer divergence from these cyclonic circulations accelerate eddy shedding.
Metastasis of the cervical lymph nodes frequently leads to poor survival of patients with oral squamous cell carcinoma (OSCC). The underlying mechanisms of lymph node metastasis are unclear. ...Wingless-type MMTV integration site family, member 5B (WNT5B), one component of the WNT signal pathway, was markedly up-regulated in OSCC sublines with high potential of lymphatic metastasis compared to that in OSCC cells with low nodal metastasis. Increased WNT5B mRNA was demonstrated in human OSCC tissues in comparison with adjacent non-tumorous tissues. Interestingly, the high level of WNT5B protein in serum was associated with lymph node metastasis in OSCC patients. Knockdown of WNT5B expression in OSCC sublines did not affect tumour growth but impaired lymph node metastasis and tumour lymphangiogenesis of orthotopic transplantation. Conditioned medium from WNT5B knockdown cells reduced the tube formation of lymphatic endothelial cells (LECs). In contrast, recombinant WNT5B enhanced the tube formation, permeability and migration of LECs. In LECs stained with phalloidin, the morphology of those treated with recombinant WNT5B changed from flat to spindle-like. Recombinant WNT5B also increased α-smooth muscle actin and inhibited the expression of vascular endothelial-cadherin but retained characteristics of endothelial cells. The results suggest that WNT5B functions in the partial endothelial-mesenchymal transition (EndoMT). Furthermore, WNT5B-induced tube formation was impaired in the LECs following the knockdown of EndoMT-related transcription factor, SNAIL or SLUG. The WNT5B-induced expression of Snail or Slug was abolished by IWR-1-endo and Rac1 inhibitors, which are involved in the WNT/β-catenin and planar cell polarity pathways, respectively. Collectively, the data suggest that WNT5B induces tube formation by regulating the expression of Snail and Slug proteins through activation of canonical and non-canonical WNT signalling pathways.
Summary
New variants of porcine epidemic diarrhoea virus (PEDV), which emerged in Taiwan in late 2013, have caused a high morbidity and mortality in neonatal piglets. To investigate the molecular ...characteristics of the spike (S) gene of the emerging Taiwan PEDV strains for a better understanding of the genetic diversity and relationship among the Taiwan new variants and the global PEDVs, full‐length S genes of PEDVs from nine 1–7 day‐old piglets from three pig farms in the central and southern Taiwan were sequenced and analysed. The result of phylogenetic analysis of the S gene showed that all the Taiwan PEDV strains were closely related to the non‐S INDEL strains from US, Canada and China, suggesting a common ancestor for these strains. As compared with the historic PEDVs and CV777‐based vaccine strains, the nine Taiwan PEDV variants shared almost the same genetic signatures as the global non‐S INDEL strains, including a series of insertions, deletions and mutations in the amino terminal as well as identical mutations in the neutralizing epitopes of the S gene. The high similarity of the S protein among the Taiwan and the globally emerged non‐S INDEL PEDV strains suggests that the Taiwan new variants may share similar pathogenesis and immunogenicity as the global outbreak variants. The development of a novel vaccine based on the Taiwan or the global non‐S INDEL strains may be contributive to the control of the current global porcine epidemic diarrhoea outbreaks.
Summary
Background: Chronic antigen exposure and/or ageing increases the frequency of T‐box expressed in T cells (T‐bet)‐expressing B‐lymphocytes in mice. The frequency and significance of B‐cell ...T‐bet expression during chronic hepatitis C (HCV) infection in human subjects has never been described. Methods: Healthy controls, cirrhotic and noncirrhotic HCV‐infected patients, and non‐HCV patients with cirrhosis were recruited. Peripheral blood mononuclear cells were phenotyped for expression of T‐bet and related markers by flow cytometry. In a subset of patients who underwent antiviral therapy and were cured of HCV infection (sustained virological response), the dynamics of T‐bet expression in B cells was monitored. After cure, convalescent B cells were tested for T‐bet expression after re‐exposure to infected plasma or recombinant HCV proteins. Results: Forty‐nine patients including 11 healthy donors, 30 hepatitis C‐infected individuals (nine with liver cancer, 13 with cirrhosis, eight without cirrhosis) and eight patients with cirrhosis due to non‐HCV‐related cause were recruited. We found that B cells in patients with chronic HCV exhibited increased frequency of T‐bet+ B cells relative to noninfected individuals (median 11.5% v. 2.2%, P<.0001) but that there were no significant differences between noncirrhotic, cirrhotic and cancer‐bearing infected individuals. T‐Bet+ B cells expressed higher levels of CD95, CXCR3, CD11c, CD267 and FcRL5 compared to T‐bet− B cells and predominantly exhibit a tissue‐like memory CD27−CD21− phenotype independent of HCV infection. T‐bet+ B cells in HCV‐infected patients were more frequently class‐switched IgD−IgG+ (40.4% vs. 26.4%, P=.012). Resolution of HCV infection with direct‐acting antiviral (DAA) therapy leads to a marked reduction in the frequency of T‐bet+ B cells (median 14.1% pretreatment v. 6.7% end of treatment v. 6.1% SVR12, P≤.01). Re‐exposure of convalescent (cured) B cells to viremic plasma and recombinant HCV E2 protein led to re‐expression of T‐bet. Conclusion: Chronic antigenemia in chronic HCV infection induces and maintains an antigen‐specific T‐bet+ B cell. These B cells share markers with tissue‐like memory B cells. Antigen‐driven T‐bet expression may be a critical suppressor of B‐cell activation in chronic HCV infection.
ABSTRACT
The association of two IceCube detections, the IceCube-170922A event and a neutrino flare, with the blazar TXS 0506+056, has paved the way for the multimessenger quest for cosmic ...accelerators. IceCube has observed many other neutrinos but their origin remains unknown. To better understand the reason for the apparent lack of neutrino counterparts, we have extended the comprehensive dissection of the sky area performed for the IceCube-170922A event to all 70 public IceCube high-energy neutrinos that are well reconstructed and off the Galactic plane. Using the multifrequency data available through the Open Universe platform, we have identified numerous candidate counterparts of IceCube events. We report here the classification of all the γ-ray blazars found and the results of subsequent statistical tests. In addition, we have checked the 4LAC, 3FHL, and 3HSP catalogues for potential counterparts. Following the dissection of all areas associated with IceCube neutrinos, we evaluate the data using a likelihood-ratio test and find a $3.23\, \sigma$ (post-trial) excess of HBLs and IBLs with a best fit of 15 ± 3.6 signal sources. This result, together with previous findings, consistently points to a growing evidence for a connection between IceCube neutrinos and blazars, the most energetic particle accelerators known in the Universe.
Summary
Due to the huge gap in the care of patients with osteoporosis and fragility fractures, we aimed to explore the effectiveness of the osteoporosis liaison service (OLS) in osteoporosis care. We ...found that OLS can improve osteoporosis care, including increasing medication compliance, increasing calcium/vitamin D/protein intake, and reducing fall rate.
Introduction
A significant gap exists in the care of patients with osteoporosis and fragility fractures. This study aimed to evaluate 1-year outcomes of an osteoporosis liaison service (OLS) program that includes two independent components: medication management services (MMS) to improve medication adherence and fracture liaison services (FLS) for secondary prevention.
Methods
Patients with new hip fracture or untreated vertebral fractures enrolled in the FLS program (
n
= 600), and those with osteoporosis medication management issues but not necessarily fragility fractures enrolled in the MMS program (
n
= 499) were included. To evaluate outcomes, care coordinators assessed baseline items adapted from the 13 Best Practices Framework (BPF) standards of the International Osteoporosis Foundation, with telephone follow-up every 4 months for 1 year.
Results
Mean age of this cohort was 76.2 ± 10.3 years, 78.8% were female. After 1-year participation in the program, all patients had received bone mineral density tests, and medication adherence for the entire cohort at 12 months was 91.9 ± 19.6%, with significant improvement in fall rates (23.4% reduction), exercise rates (16.8% increase), calcium intake (26.5% increase), vitamin D intake (26.4% increase), and adequate protein intake (17.3% increase) (all
p
< 0.05). After 1-year OLS program, the overall rates of mortality, incident fracture, and falls were 6.6%, 4.0%, and 24.3%, respectively.
Conclusions
The OLS program is associated with improved osteoporosis care, including increased medication adherence, calcium/vitamin D and protein intake, and reduced fall rate.
It is first shown that wind in the Gulf of Mexico can delay the shedding of Loop Current eddies. A time-dependent, three-dimensional numerical experiment forced by a spatially and temporally constant ...westward wind stress within the Gulf is analyzed and then is compared with an otherwise identical no-wind run, and the result is confirmed with reduced-gravity experiments. It is shown that the wind produces westward transports over the northern and southern shelves of the Gulf, convergence in the west, and a returned (i.e., eastward) upper-layer flow over the deep central basin toward the Loop Current. The theory from T. Pichevin and D. Nof is then used to explain that the returned flow constitutes a zonal momentum flux that delays eddy shedding. Mass-balance analysis shows that wind also forces larger Loop Current and rings (because the delayed shedding allows more mass to be accumulated in them) and produces more efficient mass exchange between the Gulf and the Caribbean Sea. It is shown that eddies alone (without wind stress curl) can force a boundary current and downward flow in the western Gulf and a corresponding deep flow from the western Gulf to the eastern Gulf.
Abstract
Spin-valley locking in monolayer transition metal dichalcogenides has attracted enormous interest, since it offers potential for valleytronic and optoelectronic applications. Such an exotic ...electronic state has sparsely been seen in bulk materials. Here, we report spin-valley locking in a Dirac semimetal BaMnSb
2
. This is revealed by comprehensive studies using first principles calculations, tight-binding and effective model analyses, angle-resolved photoemission spectroscopy measurements. Moreover, this material also exhibits a stacked quantum Hall effect (QHE). The spin-valley degeneracy extracted from the QHE is close to 2. This result, together with the Landau level spin splitting, further confirms the spin-valley locking picture. In the extreme quantum limit, we also observed a plateau in the
z
-axis resistance, suggestive of a two-dimensional chiral surface state present in the quantum Hall state. These findings establish BaMnSb
2
as a rare platform for exploring coupled spin and valley physics in bulk single crystals and accessing 3D interacting topological states.
Many applications proposed for graphene require multiple sheets be assembled into a monolithic structure. The ability to maintain structural integrity upon large deformation is essential to ensure a ...macroscopic material which functions reliably. However, it has remained a great challenge to achieve high elasticity in three-dimensional graphene networks. Here we report that the marriage of graphene chemistry with ice physics can lead to the formation of ultralight and superelastic graphene-based cellular monoliths. Mimicking the hierarchical structure of natural cork, the resulting materials can sustain their structural integrity under a load of >50,000 times their own weight and can rapidly recover from >80% compression. The unique biomimetic hierarchical structure also provides this new class of elastomers with exceptionally high energy absorption capability and good electrical conductivity. The successful synthesis of such fascinating materials paves the way to explore the application of graphene in a self-supporting, structurally adaptive and 3D macroscopic form.
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