Neutron stars are not only of astrophysical interest, but are also of great interest to nuclear physicists because their attributes can be used to determine the properties of the dense matter in ...their cores. One of the most informative approaches for determining the equation of state (EoS) of this dense matter is to measure both a star's equatorial circumferential radius Re and its gravitational mass M. Here we report estimates of the mass and radius of the isolated 205.53 Hz millisecond pulsar PSR J0030+0451 obtained using a Bayesian inference approach to analyze its energy-dependent thermal X-ray waveform, which was observed using the Neutron Star Interior Composition Explorer (NICER). This approach is thought to be less subject to systematic errors than other approaches for estimating neutron star radii. We explored a variety of emission patterns on the stellar surface. Our best-fit model has three oval, uniform-temperature emitting spots and provides an excellent description of the pulse waveform observed using NICER. The radius and mass estimates given by this model are km and (68%). The independent analysis reported in the companion paper by Riley et al. explores different emitting spot models, but finds spot shapes and locations and estimates of Re and M that are consistent with those found in this work. We show that our measurements of Re and M for PSR J0030+0451 improve the astrophysical constraints on the EoS of cold, catalyzed matter above nuclear saturation density.
Can of Clinical Genetics, Maastricht University Medical Centre, Maastricht kisspeptin and its analogues regulate the motility of human decidual stromal cells and what intracellular signaling pathways ...are involved?
Kisspeptin analogue-mediated cell motility in human decidual stromal cells via the focal adhesion kinase (FAK)-steroid receptor coactivator (Src) pathway suggesting that kisspeptin may modulate embryo implantation and decidual programming in human pregnancy.
The extravillous trophoblast invades the maternal decidua during embryo implantation and placentation. The motile behavior and invasive potential of decidual stromal cells regulate embryo implantation and programming of human pregnancy.
Human decidual stromal cells were isolated from healthy women undergoing elective termination of a normal pregnancy at 6- to 12-week gestation, after informed consent.
Kisspeptin analogues were synthetic peptides. Cell motility was estimated by an invasion and migration assay. Immunoblot analysis was performed to investigate the expression of kisspeptin receptor and the effects of kisspeptin analogues on the phosphorylation of FAK and Src. Small interfering RNAs (siRNAs) were used to knock down the expression of kisspeptin receptor, FAK, Src, matrix metallo-proteinases (MMPs) 2 and 9, and extracellular signal-regulated protein kinase (ERK) 1/2.
The kisspeptin receptor was expressed in human decidual stromal cells. Kisspeptin agonist decreased, but antagonist increased, cell motility. Kisspeptin agonist decreased the phosphorylation of FAK and Src tyrosine kinases, whereas antagonist increased it. These effects on phosphorylation were abolished by kisspeptin receptor siRNA. The activation of cell motility by kisspeptin analogues was suppressed by siRNA knockdown of endogenous FAK (decreased 66%), Src (decreased 60%), kisspeptin receptor (decreased 26%), MMP-2 (decreased 36%), MMP-9 (decreased 23%), and ERK 1/2 inhibitor (decreased 27%).
Human decidual stromal cells were obtained from women having terminations after 6-12 weeks of pregnancy and differences in timing could affect their properties.
Kisspeptin acting within the endometrium has a potential modulatory role on embryo implantation and decidual programming of human pregnancy.
This work was supported by grant NSC-104-2314-B-182A-146-MY2 (to H.-M.W.) from the Ministry of Science and Technology, Taiwan, and grants CMRPG3E0401 and CMRPG3E0402 (to H.-M.W.). This work was also supported by grants from the Canadian Institutes of Health Research to P.C.K.L. P.C.K.L. is the recipient of a Child & Family Research Institute Distinguished Investigator Award. The authors have no conflicts of interest to disclose.
N/A.
Although the link between inflammation and cancer initiation is well established, its role in metastatic diseases, the primary cause of cancer deaths, has been poorly explored. Our previous studies ...identified a population of metastasis-associated macrophages (MAMs) recruited to the lung that promote tumor cell seeding and growth. Here we show that FMS-like tyrosine kinase 1 (Flt1, also known as VEGFR1) labels a subset of macrophages in human breast cancers that are significantly enriched in metastatic sites. In mouse models of breast cancer pulmonary metastasis, MAMs uniquely express FLT1. Using several genetic models, we show that macrophage FLT1 signaling is critical for metastasis. FLT1 inhibition does not affect MAM recruitment to metastatic lesions but regulates a set of inflammatory response genes, including colony-stimulating factor 1 (CSF1), a central regulator of macrophage biology. Using a gain-of-function approach, we show that CSF1-mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity of FLT1-inhibited MAMs. Thus, CSF1 is epistatic to FLT1, establishing a link between FLT1 and inflammatory responses within breast tumor metastases. Importantly, FLT1 inhibition reduces tumor metastatic efficiency even after initial seeding, suggesting that these pathways represent therapeutic targets in metastatic disease.
Summary
Bisphosphonates have been used for the treatment of postmenopausal osteoporosis since the early 1990s and studies show that compliant patients experience a lower fracture rate. This cohort ...study showed that the compliance of Taiwanese patients was poor and the refracture risk was related to compliance with bisphosphonate therapy.
Introduction
Bisphosphonates are potent inhibitors of osteoclast activity, and reduce bone turnover by inhibiting bone resorption. According to Taiwanese reimbursement guidelines, patients with osteoporosis-related fractures are eligible for bisphosphonate treatment. This study aimed to elucidate the relationship of refracture risk with compliance/persistence with bisphosphonate therapy in Taiwan.
Methods
This was a retrospective, administrative, database analysis measuring the adherence status and impact of poor adherence to bisphosphonate therapy in Taiwan. Study data derived from the National Health Insurance Research Database (NHIRD) were used to assemble a cohort of all osteoporosis patients who initiated bisphosphonate treatment between January 1, 2004, and December 31, 2005. Patients were followed until death, end of registration in NHIRD, or end of study period (December 31, 2006), whichever occurred first. Compliance was calculated as medication possession ratio (MPR; sum of days of supply of osteoporosis medications divided by follow-up duration).
Results
The refracture rates for osteoporosis patients were 5.15 %, 7.36 %, and 8.49 % in the first, second, and third year, respectively, and were significantly lower for patients with >80 % compliance than with <80 % compliance (
p
< 0.05). Nearly 50 % patients were noncompliant (MPR < 80 %) at 3 months, and only around 30 % patients were adherent at 1 year. Refracture risk increased with MPR < 80 %, age, and co-morbidities like diabetes mellitus or dementia. Patients with concomitant statin medication had significantly lower refracture risk.
Conclusions
The compliance of Taiwanese patients with osteoporosis medication is poor, and refracture risk is related to compliance with bisphosphonate therapy.
ObjectivesFor eligible patient groups, hospital-at-home (HaH) programmes have been shown to deliver equivalent patient outcomes with cost reduction compared with standard care. This study aims to ...establish a benchmark of inpatient admissions that could potentially be substituted by HaH services.DesignDescriptive retrospective cohort study.SettingAcademic tertiary hospital in Singapore.Participants124 253 medical admissions over 20 months (January 2016 to August 2017).Primary and secondary outcome measuresThe primary measure was the proportion of hospitalised patients who may be eligible for HaH, based on eligibility criteria adapted for the Singapore context. The secondary measures were the utilisation patterns and outcomes of these patients.ResultsApplying generalised eligibility criteria to the retrospective dataset showed that 53.0% of 124 253 medical admissions fitted the eligibility criteria for HaH based on administrative data. 46.8% of such patients had a length of stay <48 hours (‘short-stay’) and 53.1% had a length of stay ≥48 hours (‘medium-stay’). The mortality rate and the 30-day readmission rate were lower in the ‘short-stay’ cohort (0.6%, 12.8%) compared with the ‘medium-stay’ cohort (0.7%, 20.3%). The key services used by both groups were: parenteral drug administration, blood investigations, imaging procedures and consultations with allied health professionals.ConclusionsUp to 53.0% of medical admissions receive care elements that HaH programmes could provide. Applying estimates of functional limitations and patient preferences, we propose a target of ~18% of inpatient medical admissions to be substituted by HaH services. The methodology adopted in this paper is a reproducible approach to characterise potential patients and service utilisation requirements when developing such programmes.
Dendritic cells (DC) are specialized sentinel cells that bridge the innate and adaptive immune response and play a crucial role in shaping the adaptive immune response. Vitamin D, a known ...epidemiological risk factor for the development of several autoimmune diseases, influences the development of dendritic cells. Consequently, vitamin D metabolites are frequently used in protocols to develop therapeutic dendritic cell therapies for autoimmune diseases. However, the mechanisms by which vitamin D modulates DC function remain poorly understood. We investigated the effects of vitamin D on murine CD11c
+
bone marrow derived DC (BMDC) function by analyzing global gene expression in CD11c
+
BMDC generated in the presence (VitD-CD11c
+
BMDC) or absence (Veh-CD11c
+
BMDC) of the active vitamin D metabolite, 1,25-dihydroxyvitamin D
3
(1,25(OH)
2
D
3
). Seven genes were significantly increased in expression in both immature and LPS-matured VitD-CD11c
+
BMDC, one of which was CD31, a member of the immunoglobulin superfamily. Gene knockdown of CD31 enhanced the ability of VitD-CD11c
+
BMDC to prime naïve CD4
+
T cells
in vitro
; conversely, increased expression of CD31 on vehicle treated CD11c
+
BMDC restrained their T cell priming abilities. Time-lapse imaging of BMDC and CD4
+
T cells during
in vitro
priming revealed that CD31 reduced the BMDC–T cell interaction time. Finally, we confirmed a similar effect of 1,25(OH)
2
D
3
on human CD34
+
cell-derived CD11c
+
DC, whereby DC generated in the presence of 1,25(OH)
2
D
3
had increased CD31 expression. In summary, we show that both mouse and human DC generated in the presence of 1,25(OH)
2
D
3
upregulate CD31 expression, resulting in a reduced ability to prime CD4
+
T cells by impairing a stable cell-cell contact.
We report an Elizabethkingia anophelis case cluster associated with contaminated aerators and tap water in a children's intensive care unit in Singapore in 2017. We demonstrate a likely transmission ...route for E. anophelis to patients through acquisition of the bacteria on hands of healthcare workers via handwashing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
It is important to understand the temporal trend of the paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load to estimate the transmission potential of children in ...schools and communities. We determined the differences in SARS-CoV-2 viral load dynamics between nasopharyngeal samples of infected asymptomatic and symptomatic children. Serial cycle threshold values of SARS-CoV-2 from the nasopharynx of a cohort of infected children were collected for analysis. Among 17 infected children, 10 (58.8%) were symptomatic. Symptomatic children, when compared to asymptomatic children, had higher viral loads (mean cycle threshold on day 7 of illness 28.6 vs. 36.7, P = 0.02). Peak SARS-CoV-2 viral loads occurred around day 2 of illness in infected children. Although we were unable to directly demonstrate infectivity, the detection of significant amount of virus in the upper airway of asymptomatic children suggest that they have the potential to shed and transmit SARS-CoV-2. Our study highlights the importance of contact tracing and screening for SARS-CoV-2 in children with epidemiological risk factors regardless of their symptom status, in order to improve containment of the virus in the community, including educational settings.
The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are ...significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes.
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•Cancer alters circulating monocytic populations and their transcriptomes•Tumor-associated macrophages show tissue-specific programming•Tumor-associated macrophages’ gene signature correlates with poor clinical outcome•Tumor-associated macrophages enhance cancer cells malignancy through CCL8
Cassetta et al. identify a breast cancer tumor-associated macrophage (TAM) transcriptome that is different from those of monocytes and tissue-resident macrophages, and which is associated with shorter disease-specific survival, and they demonstrate crosstalk between tumor cells and TAMs via SIGLEC1, CCL8, and CSF1.
BackgroundMetastatic breast cancer is a leading cause of cancer-related death in women worldwide. Infusion of natural killer (NK) cells is an emerging immunotherapy for such malignant tumors, ...although elimination of the immunosuppressive tumor environment is required to improve its efficacy. The effects of this “metastatic” tumor environment on NK cells, however, remain largely unknown. Previous studies, including our own, have demonstrated that metastasis-associated macrophages (MAMs) are one of the most abundant immune cell types in the metastatic tumor niche in mouse models of metastatic breast cancer. We thus investigated the effects of MAMs on antitumor functions of NK cells in the metastatic tumor microenvironment.MethodsMAMs were isolated from the tumor-bearing lung of C57BL/6 mice intravenously injected with E0771-LG mouse mammary tumor cells. The effects of MAMs on NK cell cytotoxicity towards E0771-LG cells were evaluated in vitro by real-time fluorescence microscopy. The effects of MAM depletion on NK cell activation, maturation, and accumulation in the metastatic lung were evaluated by flow cytometry (CD69, CD11b, CD27) and in situ hybridization (Ncr1) using colony-stimulating factor 1 (CSF-1) receptor conditional knockout (Csf1r-cKO) mice. Finally, metastatic tumor loads in the chest region of mice were determined by bioluminescence imaging in order to evaluate the effect of MAM depletion on therapeutic efficacy of endogenous and adoptively transferred NK cells in suppressing metastatic tumor growth.ResultsMAMs isolated from the metastatic lung suppressed NK cell-induced tumor cell apoptosis in vitro via membrane-bound transforming growth factor β (TGF-β) dependent mechanisms. In the tumor-challenged mice, depletion of MAMs increased the percentage of activated (CD69+) and mature (CD11b+CD27–) NK cells and the number of Ncr1+ NK cells as well as NK cell-mediated tumor rejection in the metastatic site. Moreover, MAM depletion or TGF-β receptor antagonist treatment significantly enhanced the therapeutic efficacy of NK cell infusion in suppressing early metastatic tumor outgrowth.ConclusionThis study demonstrates that MAMs are a main negative regulator of NK cell function within the metastatic tumor niche, and MAM targeting is an attractive strategy to improve NK cell-based immunotherapy for metastatic breast cancer.
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