Summary Background Present guidelines are conflicting for patients at high risk of both cardiovascular and gastrointestinal events who continue to require non-steroidal anti-inflammatory drugs ...(NSAIDs). We hypothesised that a cyclooxygenase-2-selective NSAID plus proton-pump inhibitor is superior to a non-selective NSAID plus proton-pump inhibitor for prevention of recurrent ulcer bleeding in concomitant users of aspirin with previous ulcer bleeding. Methods For this industry-independent, double-blind, double-dummy, randomised trial done in one academic hospital in Hong Kong, we screened patients with arthritis and cardiothrombotic diseases who were presenting with upper gastrointestinal bleeding, were on NSAIDs, and require concomitant aspirin. After ulcer healing, an independent staff member randomly assigned (1:1) patients who were negative for Helicobacter pylori with a computer-generated list of random numbers to receive oral administrations of either celecoxib 100 mg twice per day plus esomeprazole 20 mg once per day or naproxen 500 mg twice per day plus esomeprazole 20 mg once per day for 18 months. All patients resumed aspirin 80 mg once per day. Both patients and investigators were masked to their treatments. The primary endpoint was recurrent upper gastrointestinal bleeding within 18 months. The primary endpoint and secondary safety endpoints were analysed in the modified intention-to-treat population. This study was registered with ClinicalTrials.gov , number NCT00153660. Findings Between May 24, 2005, and Nov 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5·6% (95% CI 3·3–9·2) in the celecoxib group and 12·3% (8·8–17·1) in the naproxen group (p=0·008; crude hazard ratio 0·44, 95% CI 0·23–0·82; p=0·010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study. Interpretation In patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib plus proton-pump inhibitor is the preferred treatment to reduce the risk of recurrent upper gastrointestinal bleeding. Naproxen should be avoided despite its perceived cardiovascular safety. Funding The Research Grant Council of Hong Kong.
Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer ...metastasis is unclear. Here, we identified a subpopulation of CD26
+ cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26
+ cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26
+ cells, but not CD26
− cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26
+ cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy.
► Metastatic colorectal cancers contain a subset of CD26
+ cancer stem cells ► Nonmetastatic tumors with CD26
+ CSCs frequently proceed to metastasis ► Isolated CD26
+ CSCs can initiate distant metastasis in a mouse model ► CD26
+ CSCs show enhanced invasiveness and migratory potential
An anti-glitch in a magnetar Archibald, R F; Kaspi, V M; Ng, C-Y ...
Nature (London),
05/2013, Letnik:
497, Številka:
7451
Journal Article
Recenzirano
Magnetars are neutron stars with X-ray and soft γ-ray outbursts thought to be powered by intense internal magnetic fields. Like conventional neutron stars in the form of radio pulsars, magnetars ...exhibit 'glitches' during which angular momentum is believed to be transferred between the solid outer crust and the superfluid component of the inner crust. The several hundred observed glitches in radio pulsars and magnetars have involved a sudden spin-up (increase in the angular velocity) of the star, presumably because the interior superfluid was rotating faster than the crust. Here we report X-ray timing observations of the magnetar 1E 2259+586 (ref. 8), which exhibited a clear 'anti-glitch'--a sudden spin-down. We show that this event, like some previous magnetar spin-up glitches, was accompanied by multiple X-ray radiative changes and a significant spin-down rate change. Such behaviour is not predicted by models of neutron star spin-down and, if of internal origin, is suggestive of differential rotation in the magnetar, supporting the need for a rethinking of glitch theory for all neutron stars.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Clinicians need improved tools to better identify nonacute heart failure with preserved ejection fraction (HFpEF).
The purpose of this study was to derive and validate circulating microRNA signatures ...for nonacute heart failure (HF).
Discovery and validation cohorts (N = 1,710), comprised 903 HF and 807 non-HF patients from Singapore and New Zealand (NZ). MicroRNA biomarker panel discovery in a Singapore cohort (n = 546) was independently validated in a second Singapore cohort (Validation 1; n = 448) and a NZ cohort (Validation 2; n = 716).
In discovery, an 8-microRNA panel identified HF with an area under the curve (AUC) 0.96, specificity 0.88, and accuracy 0.89. Corresponding metrics were 0.88, 0.66, and 0.77 in Validation 1, and 0.87, 0.58, and 0.74 in Validation 2. Combining microRNA panels with N-terminal pro–B-type natriuretic peptide (NT-proBNP) clearly improved specificity and accuracy from AUC 0.96, specificity 0.91, and accuracy 0.90 for NT-proBNP alone to corresponding metrics of 0.99, 0.99, and 0.93 in the discovery and 0.97, 0.96, and 0.93 in Validation 1. The 8-microRNA discovery panel distinguished HFpEF from HF with reduced ejection fraction with AUC 0.81, specificity 0.66, and accuracy 0.72. Corresponding metrics were 0.65, 0.41, and 0.56 in Validation 1 and 0.65, 0.41, and 0.62 in Validation 2. For phenotype categorization, combined markers achieved AUC 0.87, specificity 0.75, and accuracy 0.77 in the discovery with corresponding metrics of 0.74, 0.59, and 0.67 in Validation 1 and 0.72, 0.52, and 0.68 in Validation 2, as compared with NT-proBNP alone of AUC 0.71, specificity 0.46, and accuracy 0.62 in the discovery; with corresponding metrics of 0.72, 0.44, and 0.57 in Validation 1 and 0.69, 0.48, and 0.66 in Validation 2. Accordingly, false negative (FN) (81% Singapore and all NZ FN cases were HFpEF) as classified by a guideline-endorsed NT-proBNP ruleout threshold, were correctly reclassified by the 8-microRNA panel in the majority (72% and 88% of FN in Singapore and NZ, respectively) of cases.
Multi-microRNA panels in combination with NT-proBNP are highly discriminatory and improved specificity and accuracy in identifying nonacute HF. These findings suggest potential utility in the identification of nonacute HF, where clinical assessment, imaging, and NT-proBNP may not be definitive, especially in HFpEF.
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Photodissociation of carbon dioxide (CO₂) has long been assumed to proceed exclusively to carbon monoxide (CO) and oxygen atom (O) primary products. However, recent theoretical calculations suggested ...that an exit channel to produce C + O₂ should also be energetically accessible. Here we report the direct experimental evidence for the C + O₂ channel in CO₂ photodissociation near the energetic threshold of the C(³P) + O₂(X³Σg⁻) channel with a yield of 5 ± 2% using vacuum ultraviolet laser pump-probe spectroscopy and velocity-map imaging detection of the C(³PJ) product between 101.5 and 107.2 nanometers. Our results may have implications for nonbiological oxygen production in CO₂-heavy atmospheres.
Incidence of inflammatory bowel disease (IBD) is increasing in Asia, but population-based prevalence data are limited. This study examined IBD incidence and prevalence based on results of a ...territory-wide IBD registry in Hong Kong.
We collected data on 2575 patients with IBD (1541 ulcerative colitis UC, 983 Crohn's disease CD, 51 IBD unclassified) from 1981 to 2014 using hospital and territory-wide administrative coding system. Prevalence and incidence, disease phenotype, surgery, and mortality were analyzed.
Adjusted prevalence of IBD, UC, CD, and IBD unclassified per 100,000 individuals in 2014 were 44.0, 24.5, 18.6, and 0.9, respectively. Age-adjusted incidence of IBD per 100,000 individuals increased from 0.10 (95% confidence interval, 0.06-0.16) in 1985 to 3.12 (95% confidence interval, 2.88-3.38) in 2014. UC:CD incidence ratio reduced from 8.9 to 1.0 over 30 years (P < 0.001). A family history of IBD was reported in 3.0% of patients. Stricturing or penetrating disease was found in 41% and perianal disease in 25% of patients with CD. 5-aminosalicylate use was common in UC (96%) and CD (89%). Cumulative rates of surgery for CD were 20.3% at 1 year and 25.7% at 5 years, and the corresponding rates for UC were 1.8% and 2.1%, respectively. Mortality for CD and UC was not significantly different from the general population.
In a population-based study in Hong Kong, prevalence of IBD is lower than in the west although comparable to that of other East Asian countries. Complicated CD is common. Overall mortality remains low in Asians with IBD.
Pregnant women infected by the pandemic influenza A (H1N1) 2009 virus had more severe disease and higher mortality but its pathogenesis is still unclear.
We showed that higher mortality, more severe ...pneumonitis, higher pulmonary viral load, lower peripheral blood T lymphocytes and antibody responses, higher levels of proinflammatory cytokines and chemokines, and worse fetal development occurred in pregnant mice than non-pregnant controls infected by either wild type (clinical isolate) or mouse-adapted mutant virus with D222G substitution in hemagglutinin. These disease-associated changes and the lower respiratory tract involvement were worse in pregnant mice challenged by mutant virus. Though human placental origin JEG-3 cell line could be infected and proinflammatory cytokines or chemokines were elevated in amniotic fluid of some mice, no placental or fetal involvement by virus were detected by culture, real-time reverse transcription polymerase chain reaction or histopathological changes. Dual immunofluorescent staining of viral nucleoprotein and type II alveolar cell marker SP-C protein suggested that the majority of infected alveolar epithelial cells were type II pneumocytes.
The adverse effect of this pandemic virus on maternal and fetal outcome is largely related to the severe pulmonary disease and the indirect effect of inflammatory cytokine spillover into the systemic circulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that ...targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.
ABSTRACT
PSR J1813–1749 is one of the most energetic rotation-powered pulsars known, producing a pulsar wind nebula (PWN) and gamma-ray and TeV emission, but whose spin period is only measurable in ...X-ray. We present analysis of two Chandra data sets that are separated by more than 10 yr and recent NICER data. The long baseline of the Chandra data allows us to derive a pulsar proper motion $\mu _{\rm RA}=(-0.067\pm 0.010)\, \mathrm{ arcsec}\,\mathrm{yr^{-1}}$ and $\mu _{\rm Dec.}=(-0.014\pm 0.007)\, \mathrm{ arcsec}\,\mathrm{yr^{-1}}$ and velocity $v_\perp \approx 900\!-\!1600\, \mathrm{km\, s^{-1}}$ (assuming a distance d = 3–5 kpc), although we cannot exclude a contribution to the change in measured pulsar position due to a change in brightness structure of the PWN very near the pulsar. We model the PWN and pulsar spectra using an absorbed power law and obtain best-fitting absorption $N_{\rm H}=(13.1\pm 0.9)\times 10^{22}\, \mathrm{cm^{-2}}$, photon index Γ = 1.5 ± 0.1, and 0.3–10 keV luminosity $L_{\rm X}\approx 5.4\times 10^{34}\, \mathrm{erg\, s^{-1}}(d/\mbox{ 5 kpc})^2$ for the PWN and Γ = 1.2 ± 0.1 and $L_{\rm X}\approx 9.3\times 10^{33}\, \mathrm{erg\, s^{-1}}(d/\mbox{ 5 kpc})^2$ for PSR J1813–1749. These values do not change between the 2006 and 2016 observations. We use NICER observations from 2019 to obtain a timing model of PSR J1813–1749, with spin frequency ν = 22.35 Hz and spin frequency time derivative $\dot{\nu }=(-6.428\pm 0.003)\times 10^{-11}\, \mathrm{Hz\, s^{-1}}$. We also fit ν measurements from 2009 to 2012 and our 2019 value and find a long-term spin-down rate $\dot{\nu }=(-6.3445\pm 0.0004)\times 10^{-11}\, \mathrm{Hz\, s^{-1}}$. We speculate that the difference in spin-down rates is due to glitch activity or emission mode switching.
In innate immune sensing, the detection of pathogen-associated molecular patterns by recognition receptors typically involve leucine-rich repeats (LRRs). We provide a categorization of 375 human ...LRR-containing proteins, almost half of which lack other identifiable functional domains. We clustered human LRR proteins by first assigning LRRs to LRR classes and then grouping the proteins based on these class assignments, revealing several of the resulting protein groups containing a large number of proteins with certain non-LRR functional domains. In particular, a statistically significant number of LRR proteins in the typical (T) and bacterial + typical (S+T) categories have transmembrane domains, whereas most of the LRR proteins in the cysteine-containing (CC) category contain an F-box domain (which mediates interactions with the E3 ubiquitin ligase complex). Furthermore, by examining the evolutionary profiles of the LRR proteins, we identified a subset of LRR proteins exhibiting strong conservation in fungi and an enrichment for "nucleic acid-binding" function. Expression analysis of LRR genes identifies a subset of pathogen-responsive genes in human primary macrophages infected with pathogenic bacteria. Using functional RNAi, we show that MFHAS1 regulates Toll-like receptor (TLR)-dependent signaling. By using protein interaction network analysis followed by functional RNAi, we identified LRSAM1 as a component of the antibacterial autophagic response.
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