We report far-infrared and submillimeter observations of supernova 1987A, the star whose explosion was observed on 23 February 1987 in the Large Magellanic Cloud, a galaxy located 160,000 light years ...away. The observations reveal the presence of a population of cold dust grains radiating with a temperature of about 17 to 23 kelvin at a rate of about 220 times the luminosity of the Sun. The intensity and spectral energy distribution of the emission suggest a dust mass of about 0.4 to 0.7 times the mass of the Sun. The radiation must originate from the supernova ejecta and requires the efficient precipitation of all refractory material into dust. Our observations imply that supernovae can produce the large dust masses detected in young galaxies at very high redshifts.
Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, ...we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.
The objective of this study was to evaluate effects of butyrate supplementation on plasma concentration of glucagon-like peptide-2 (GLP-2), apparent total-tract digestibility, and responses to a ...grain challenge of lactating dairy cows fed diets differing in starch content. Eight Holstein cows averaging 58.6 ± 9.96 d in milk (4 primiparous cows fitted with rumen cannula and 4 multiparous intact cows) were blocked by parity and assigned to one of two 4 × 4 Latin squares balanced for carryover effects with a 2 × 2 factorial arrangement of treatments. Treatments were dietary starch content 20.6 vs. 27.5%, respectively, for low starch (LS) and high starch (HS) and butyrate supplementation (butyrate vs. control) with 21-d periods. Butyrate was provided as Gustor BP70 WS (Norel, S.A., Madrid, Spain), containing 70% sodium butyrate and 30% fatty acid mixture, at 2% of dietary dry matter (providing butyrate at 1.1% of dietary dry matter), and control premix contained 70% wheat bran and 30% fatty acid mixture. Feeds, orts, and fecal samples were collected from d 17 to 19 to determine apparent total-tract nutrient digestibility. Blood and rumen fluid samples were collected on d 19. The baseline of dry matter intake (DMI) was determined as average DMI from d 17 to 19 for each cow, and cows were feed-restricted at 60% of the baseline DMI on d 20, and a grain challenge was conducted by providing steam-flaked corn grain at 0.6% of body weight, on an as-fed basis, in addition to each treatment diet on d 21, and blood and ruminal fluid samples were collected. The interaction of dietary starch content by butyrate supplementation was significant for plasma GLP-2 concentration, being greater for cows fed butyrate with the HS diet than those fed the other 3 diets. Cows fed butyrate increased n-butyrate concentration in the ruminal fluid and tended to increase dry matter and organic matter digestibility compared with the control. During the grain challenge, rumen endotoxin concentration increased over time and was higher for cows fed the HS diets compared with those fed LS diets. However, response variables related to inflammation were not affected by the grain challenge. However, serum haptoglobin, lipopolysaccharide-binding protein, and serum amyloid-A concentrations were greater for cows fed butyrate with the LS diet, but not for those fed the HS diet. These results indicate that butyrate supplementation may increase plasma GLP-2 concentration for cows fed HS diets, and total-tract digestibility regardless of dietary starch content. However, butyrate supplementation did not mitigate inflammation in this study.
The time to return to sport from acute hamstring strain injuries is associated with several functional and structural impairments. However, not all previous studies assessed the preinjury level ...before acute hamstring strain injuries directly. The purpose of this study was to examine the associations of the time to return to performance following acute hamstring strain injuries with deficits in running biomechanics, hamstring function and structure in collegiate sprinters by a prospective study.
Using a prospective cohort design, 72 participants were recruited from a collegiate track and field team. At the preinjury assessment, a 60-m running-specific test, passive straight leg raise test and isometric knee flexion strength test were assessed at the beginning of the competitive season for three consecutive years (2017–2019). Afterwards, postinjury examinations were performed only in sprinters with acute hamstring strain injuries.
Twelve sprinters strained their hamstring muscle (incidence rate of hamstring strain injuries: 16.7%); the majority (n = 10) were classified as grades 0–2. The running speed deficit of the running-specific test was associated with the time to return to performance as well as the passive straight leg raise test deficit. In the running-specific test, lower-limb kinetic deficits were more strongly associated with the time to return to performance compared to lower-limb kinematic deficits.
A running-specific test may be considered one of the most convenient and valid tests for assessing rehabilitation progress after acute hamstring strain injuries.
•Incidence rate of hamstring strain injuries was 16.7% during competition season.•Majority (83.3%) of injuries was grades 0–2 and the other (16.7%) was grade 3.•Running speed and kinetic deficits relate to time to return to performance.•Altered hamstring strength and flexibility relate to rehabilitation process.•Magnetic resonance image measures may not be related to rehabilitation process.
We present an overview of the HERschel Inventory of The Agents of Galaxy Evolution (HERITAGE) in the Magellanic Clouds project, which is a Herschel Space Observatory open time key program. We ...describe in detail the data processing, particularly for the PACS data, which required some custom steps because of the large angular extent of a single observational unit and overall the large amount of data to be processed as an ensemble. We report total global fluxes for the LMC and SMC and demonstrate their agreement with measurements by prior missions. We describe the point source extraction processing and the criteria used to establish a catalog for each waveband for the HERITAGE program. The 250 mu m band is the most sensitive and the source catalogs for this band have ~25,000 objects for the LMC and ~5500 objects for the SMC.
This paper reports variations of polycyclic aromatic hydrocarbons (PAHs) features that were found in Spitzer Space Telescope spectra of carbon-rich post-asymptotic giant branch (post-AGB) stars in ...the Large Magellanic Cloud (LMC). The paper consists of two parts. The first part describes our Spitzer spectral observing programme of 24 stars including post-AGB candidates. The latter half of this paper presents the analysis of PAH features in 20 carbon-rich post-AGB stars in the LMC, assembled from the Spitzer archive as well as from our own programme. We found that five post-AGB stars showed a broad feature with a peak at 7.7 μm, that had not been classified before. Further, the 10-13 μm PAH spectra were classified into four classes, one of which has three broad peaks at 11.3, 12.3 and 13.3 μm rather than two distinct sharp peaks at 11.3 and 12.7 μm, as commonly found in H ii regions. Our studies suggest that PAHs are gradually processed while the central stars evolve from post-AGB phase to planetary nebulae, changing their composition before PAHs are incorporated into the interstellar medium. Although some metallicity dependence of PAH spectra exists, the evolutionary state of an object is more significant than its metallicity in determining the spectral characteristics of PAHs for LMC and Galactic post-AGB stars.
Summary
Background
Epstein‐Barr virus (EBV)‐associated T/natural‐killer lymphoproliferative disorders form a group of diseases that includes classical and systemic hydroa vacciniforme (HV) and ...hypersensitivity to mosquito bites (HMB). Patients with systemic HV (sHV) and HMB often have a poor prognosis, although little is known about the prognostic factors.
Objectives
To elucidate the prognostic factors of HV and HMB.
Methods
We studied clinicopathological manifestations, routine laboratory findings, anti‐EBV titres, EBV DNA load and EBV‐encoded gene expression, including expression of BZLF1, in 50 patients with classical HV (cHV), sHV, HMB only and HMB with HV (HMB + HV), and further analysed 30 patients who were available for follow‐up.
Results
The median age of disease onset was 5 years (range 1–74). A follow‐up study indicated that fatal outcomes were observed in three of eight patients with sHV, two of six patients with HMB only, and two of five patients with HMB + HV. The main causes of death were complications from haematopoietic stem‐cell transplantation and multiorgan failure. There were no fatalities among the 11 patients with cHV. Univariate analysis revealed two poor prognostic indicators: (i) onset age > 9 years and (ii) the expression of an EBV‐encoded immediate–early gene transcript, BZLF1 mRNA, in the skin lesions (P < 0·001 and P = 0·003, respectively).
Conclusions
No prognostic correlation was observed in EBV‐infected lymphocyte subsets, anti‐EBV antibody titres or EBV DNA load. Late onset and EBV reactivation are both related to more severe phenotypes of the disease, and thus may predict a poor prognosis.
What's already known about this topic?
Epstein–Barr virus‐associated T/natural‐killer lymphoproliferative disorders form a group of diseases that includes classical and systemic hydroa vacciniforme (HV), and hypersensitivity to mosquito bites (HMB).
Patients with systemic HV and HMB usually present with fever, liver damage and haematological abnormalities, and often have a fatal outcome.
What does this study add?
Our patients with classical HV showed a favourable prognosis, while approximately one‐third of the patients with systemic HV or HMB died during the 10‐year follow‐up.
Late onset (over 9 years of age) and an EBV reactivation signal (BZLF1 mRNA expression) were both related to more severe phenotypes of the disease, and a poor prognosis.
Aims. The spatial structure of the emission lines and continuum over the 50″ extent of the nearby, O-rich, PN NGC 7009 (Saturn Nebula) have been observed with the MUSE integral field spectrograph on ...the ESO Very Large Telescope. This study concentrates on maps of line emission and their interpretation in terms of physical conditions. Methods. MUSE Science Verification data, in <0.6″ seeing, have been reduced and analysed as maps of emission lines and continuum over the wavelength range 4750–9350 Å. The dust extinction, the electron densities and temperatures of various phases of the ionized gas, abundances of species from low to high ionization and some total abundances are determined using standard techniques. Results. Emission line maps over the bright shells are presented, from neutral to the highest ionization available (He II and Mn V). For collisionally excited lines (CELs), maps of electron temperature (Te from N II and S III) and density (Ne from S II and Cl III) are available and for optical recombination lines (ORLs) temperature (from the Paschen jump and ratio of He I lines) and density (from high Paschen lines). These estimates are compared: for the first time, maps of the differences in CEL and ORL Te’s have been derived, and correspondingly a map of t2 between a CEL and ORL temperature, showing considerable detail. Total abundances of only He and O were formed, the latter using three ionization correction factors. However, the map of He/H is not flat, departing by ~2% from a constant value, with remnants corresponding to ionization structures. An integrated spectrum over an area of 2340 arcsec2 was also formed and compared to 1D photoionization models. Conclusions. The spatial variation of a range of nebular parameters illustrates the complexity of the ionized media in NGC 7009. These MUSE data are very rich with detections of hundreds of lines over areas of hundreds of arcsec2 and follow-on studies are outlined.
Tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant mutations of epidermal growth factor receptor (EGFR) are associated with lung adenocarcinoma. EGFR mutants were previously shown to exhibit ...ligand-independent activation. We have previously demonstrated that pulmonary surfactant protein D (SP-D, SFTPD) suppressed wild-type EGFR signaling by blocking ligand binding to EGFR. We herein demonstrate that SFTPD downregulates ligand-independent signaling in cells harboring EGFR mutations such as TKI-sensitive exon 19 deletion (Ex19del) and L858R mutation as well as TKI-resistant T790M mutation, subsequently suppressing cellular growth and motility. Lectin blotting and ligand blotting in lung cancer cell lines suggested that EGFR mutants express oligomannose-type N-glycans and interact with SFTPD directly. Cross-linking assay indicated that SFTPD inhibits ligand-independent dimerization of EGFR mutants. We also demonstrated that SFTPD reduced dimerization-independent phosphorylation of Ex19del and T790M EGFR mutants using point mutations that disrupted the asymmetric dimer interface. It was confirmed that SFTPD augmented the viability-suppressing effects of EGFR-TKIs. Furthermore, retrospective analysis of 121 patients with lung adenocarcinoma to examine associations between serum SFTPD levels and clinical outcome indicated that in TKI-treated patients with lung cancer harboring EGFR mutations, including Ex19del or L858R, high serum SFTPD levels correlated with a lower number of distant metastases and prolonged overall survival and progression-free survival. These findings suggest that SFTPD downregulates both TKI-sensitive and -resistant EGFR mutant signaling, and SFTPD level is correlated with clinical outcome. These findings illustrate the use of serum SFTPD level as a potential marker to estimate the efficacy of EGFR-TKIs.
Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies ...suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients.
We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan–Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4.
Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001).
First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.
•Anti-PD-1 plus anti-CTLA-4 antibody therapy (PD1 + CTLA4) is an option for patients with advanced mucosal melanoma (MCM).•Data on the efficacy of PD1 + CTLA4 compared with PD-1 monotherapy (PD1) for MCM, however, are limited.•We retrospectively analyzed data from 329 Japanese patients with advanced MCM treated with PD1 or PD1 + CTLA4.•No significant differences in objective response rate, progression-free survival, or overall survival were observed.•Immune-related adverse events resulting in treatment cessation were higher in the PD1 + CTLA4 group.
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