Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is ...unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A
TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1
) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10
macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10
M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1
myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1
myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1
myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic niche formation and metastasis, and may serve as a potential therapeutic target in human cancer.
The synthesis and structure–activity studies of a series of 6-substituted-4-anilino-1,7-naphthyridine-3-carbonitriles as inhibitors of Tpl2 kinase are described. The early exploratory work described ...here may lead to the discovery of compounds with significant therapeutic potential for treating rheumatoid arthritis and other inflammatory diseases.
Background and purpose
The aim was to describe the clinical, radiological and pathological features of an autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy.
Methods
Data from 19 ...patients with positive GFAP‐immunoglobulin G in cerebrospinal fluid (CSF) were retrospectively analyzed.
Results
The main disease manifestations included myelitis (68.4%), headache (63.2%), abnormal vision (63.2%), fever (52.6%), ataxia (36.8%), psychosis (31.6%), dyskinesia (15.8%), dementia (15.8%) and seizure (10.5%). Seventeen patients had brain abnormalities (89.5%), of which eight (42.1%) revealed the characteristic radial enhancing and laminar patterns. Cortical abnormalities were found in four patients (21.1%). Other abnormalities were found in the hypothalamus, midbrain, pons, medulla cerebellum, meninges and skull. Eleven patients had longitudinally extensive spinal cord lesions. CSF abnormalities were detected in all patients. Pathological examinations of four patients revealed extensive inflammation, with prominent perivascular B cells and T cells. Abundant antibody‐secreting cells were noted in the interstitial and perivascular spaces. Immunohistochemical analysis showed loss of astrocytes and neurons.
Conclusion
The present patients with positive GFAP‐immunoglobulin G are highly similar to autoimmune GFAP astrocytopathy, described in a recent report. The features of the neuropathology and immunopathology of GFAP astrocytopathies were perivascular inflammation and loss of astrocytes and neurons.
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This White Paper presents the science case of an Electron-Ion Collider (EIC), focused on the structure and interactions of gluon-dominated matter, with the intent to articulate it to the broader ...nuclear science community. It was commissioned by the managements of Brookhaven National Laboratory (BNL) and Thomas Jefferson National Accelerator Facility (JLab) with the objective of presenting a summary of scientific opportunities and goals of the EIC as a follow-up to the 2007 NSAC Long Range plan. This document is a culmination of a community-wide effort in nuclear science following a series of workshops on EIC physics over the past decades and, in particular, the focused ten-week program on “Gluons and quark sea at high energies” at the Institute for Nuclear Theory in Fall 2010. It contains a brief description of a few golden physics measurements along with accelerator and detector concepts required to achieve them. It has been benefited profoundly from inputs by the users’ communities of BNL and JLab. This White Paper offers the promise to propel the QCD science program in the US, established with the CEBAF accelerator at JLab and the RHIC collider at BNL, to the next QCD frontier.
From an actual cancer screening service demanders' perspective, we tried to understand the preference on screening frequency and willingness-to-pay for the packaging screening program on common ...cancers and to evaluate its long-term sustainability in urban populations in China.
From 2012 to 2014, a multi-center cross-sectional survey was conducted among the actual screening participants from 13 provinces covered by the Cancer Screening Program in Urban China (CanSPUC). By face-to-face interview, information regarding to preference to screening frequency, willingness-to-pay for packaging screening program, maximum amount on payment and related reasons for unwillingness were investigated.
A total of 31 029 participants were included in this survey, with an average age as (55.2±7.5) years and median annual income per family as 25 000 Chinese Yuan. People's preference to screening frequency varied under different assumptions ( " totally free" and "self-paid" ). When the packaging screening was assumed totally free
To explore the sustainability of cancer screening strategy from potential demander's perspective in Chinese country, we conducted a study on the use of cancer screening services and ...willingness-to-pay among the urban community residents. All the participants of this study had not been on the Cancer Screening Program in Urban China (CanSPUC) or any other national level cancer screening projects.
Target communities and populations were selected from the 16 project provinces in China which were on the program between 2014 and 2015, by using the multi-center cross-sectional convenience sampling method. Chi-square was used to compare the rates on the utilization of service and willingness-to-pay across the different subgroups. Logistic progression was conducted to examine factors that associated with the service utilization and willingness-to-pay.
A total of 16 394 participants were included in this study. Among them, 12.1% (1 984/16 394) had ever been on a cancer screening program. Populations with following char
In this study, by analyzing a data set of 2.92 fb-1 of e+e- collision data taken at ps = 3.773 GeV and 106.41×106 ψ(3686) decays taken at √s = 3.686 GeV with the BESIII detector at the BEPCII ...collider, we measure the branching fraction and the partial decay width for ψ(3770) → γχc0 to be B(ψ(3770) → γχc0) = (6.88 ± 0.28 ± 0.67) × 10-3 and ΓΨ(3770) → γχc0 = (187 ± 8 ± 19) keV, respectively. These are the most precise measurements to date.
The effects of milling and compression on the solid-state Maillard reaction between metoclopramide hydrochloride and lactose were investigated. Anhydrous metoclopramide hydrochloride was milled for ...various times, and then mixed with amorphous lactose. The mixtures were stored at 105°C and 0% RH. The reactivity of metoclopramide hydrochloride towards the Maillard reaction increased with milling time, as the result of increased surface area, formation of amorphous content, and creation of defects. Metoclopramide hydrochloride anhydrate and lactose were mixed and the mixtures were compressed into tablets under pressure varied from 70 to 350MPa. Both tablets and mixtures were stored at 105°C and 0% RH for 9days. For all three types of lactose used, spray-dried anhydrous lactose, spray-dried lactose monohydrate, and amorphous lactose, tablets exhibited higher reaction rate toward the Maillard reaction than the powder mixtures. Tablets containing metoclopramide hydrochloride and amorphous lactose prepared at higher pressure showed higher reaction rates than those prepared at lower pressure. This is due to increased contact between reactants and an increased amount of water retained in the tablets.
To discover the relationship between the genotype and antigen serotype of flagellin C among Salmonella strains.
Fragment of Salmonella flagellin C in plasmid pLS408 was cloned, sequenced and compared ...with the corresponding sequence in other strains. Salmonella strains including two typhi strains, one paratyphoid strain, one enteritidis and one typhimurium strain were isolated from outpatients. Genome DNA was purified respectively from these clinical isolates, then the corresponding flagellin C fragment was amplified by polymerase chain reaction,and the amplification products were analyzed by agarose gel electrophoresis.
The cloned fragment includes 582 nucleotides encoding the variable region and partial conservative region of Salmonella flagellin C in plasmid pLS408. With comparison to the corresponding sequences reported previously, there is only a little difference from other strains with the same flagellar serotype in both nucleotide and amino acid level. Specific PCR products were amplified in Salmonella strains with flagellar serotype H-1-d including S. muenchen, typhi and typhimurium, but not in S. paratyphoid C or S. enteritidis strains.
In this experiment, the specificity of nucleotide sequence could be found in flagellin C central variable regions as it exists in flagellar serotypes in Salmonella. It may be helpful to developing a rapid, sensitive, accurate and PCR-based method to detect Salmonella strains with serotype H-1-d.
The CDMS low ionization threshold experiment (CDMSlite) uses cryogenic germanium detectors operated at a relatively high bias voltage to amplify the phonon signal in the search for weakly interacting ...massive particles (WIMPs). Results are presented from the second CDMSlite run with an exposure of 70 kg day, which reached an energy threshold for electron recoils as low as 56 eV. A fiducialization cut reduces backgrounds below those previously reported by CDMSlite. New parameter space for the WIMP-nucleon spin-independent cross section is excluded for WIMP masses between 1.6 and 5.5 GeV/c^{2}.
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