To cite this article: Cheong HS, Park S‐M, Kim M‐O, Park J‐S, Lee JY, Byun JY, Park BL, Shin HD, Park C‐S. Genome‐wide methylation profile of nasal polyps: relation to aspirin hypersensitivity in ...asthmatics. Allergy 2011; 66: 637–644.
Background: In addition to the dysregulation of arachidonic acid metabolism in aspirin‐intolerant asthma (AIA), aspirin acetylsalicylic acid (ASA) exerts effects on inflammation and immunity; however, many of these effects are unknown.
Objective: The aim of the study was to evaluate the methylation status of whole genome in blood and polyp tissues with and without aspirin hypersensitivity.
Methods: Genome‐wide DNA methylation levels in nasal polyps and peripheral blood cells were examined by microarray analysis using five subjects with AIA and four subjects with aspirin‐tolerant asthma (ATA).
Results: In the nasal polyps of the patients with AIA, hypermethylation was detected at 332 loci in 296 genes, while hypomethylation was detected at 158 loci in 141 genes. Gene ontologic and pathway enrichment analyses revealed that genes involved in lymphocyte proliferation, cell proliferation, leukocyte activation, cytokine biosynthesis, cytokine secretion, immune responses, inflammation, and immunoglobulin binding were hypomethylated, while genes involved in ectoderm development, hemostasis, wound healing, calcium ion binding, and oxidoreductase activity were hypermethylated. In the arachidonate pathway, PGDS, ALOX5AP, and LTB4R were hypomethylated, whereas PTGES was hypermethylated.
Conclusion: The nasal polyps of patients with AIA have characteristic methylation patterns affecting 337 genes. The genes and pathways identified in this study may be associated with the presence of aspirin hypersensitivity in asthmatics and are therefore attractive targets for future research.
We evaluated whether ELISPOT assay can predict tuberculosis (TB) development in kidney‐transplantation (KT) recipients with a negative tuberculin skin test (TST). All adult patients admitted to a KT ...institute between June 2008 and December 2009 were enrolled; TB development after KT was observed between June 2008 and December 2010. Isoniazid (INH) was given to those patients with positive TST or clinical risk factors for latent TB infection (LTBI). ELISPOT assay was performed on all patients, and TB development after KT was observed by a researcher blinded to the results of ELISPOT. A total of 312 KT recipients including 242 (78%) living‐donor KT were enrolled. Of the 312 patients, 40 (13%) had positive TST or clinical risk factors for LTBI and received INH; none developed TB after KT. Of the remaining 272 patients, 4 (6%) of 71 with positive ELISPOT assay developed TB after KT, whereas none of the 201 patients with negative (n = 171) or indeterminate ELISPOTs (n = 30) developed TB after KT (rate difference between positive and negative/indeterminate ELISPOT, 3.3 per 100 person‐years 95% CI 1.4–5.1, p<0.001). Positive ELISPOT results predict subsequent development of TB in KT recipients in whom LTBI cannot be detected by TST or who lack clinical risk factors for LTBI.
Positive results of an interferon‐gamma releasing assay anticipate the subsequent development of tuberculosis in kidney transplant recipients in whom latent tuberculosis infection cannot be detected by tuberculin skin test or who lack clinical risk factors for latent tuberculosis infection. See editorial by Torre‐Cisneros and Doblas on page 1769.
Aims
To analyse the function of a putative lantibiotic gene cluster of Paenibacillus polymyxa E681 and to characterize its product, paenilan.
Methods and Results
Comparative analysis of the ...lantibiotic gene cluster of E681 revealed that the cluster, consisting of 11 open reading frames, is involved in the biosynthesis of a class I lantibiotic. The pnlA gene encoding the prepeptide PnlA was identified and P. polymyxa strain EPT14 producing only paenilan was constructed by knockout of the other five antibiotic biosynthetic gene clusters of E681. Paenilan was purified from EPT14 culture by solvent partitioning, ODS silica gel chromatography and reversed‐phase preparative HPLC. The molecular mass (2510·10 Da) and structure of paenilan analysed by Nanoelectrospray ionization mass spectrometry (MS) and MS/MS showed that paenilan is a novel class I lantibiotic. Paenilan exhibited antimicrobial activity against Gram‐positive bacteria such as Bacillus cereus, Micrococcus luteus and Paenibacillus durus. The paenilan gene is well‐conserved in different Paenibacillus sp. isolated from globally distant places.
Conclusions
The lantibiotic gene cluster of P. polymyxa E681 was analysed and its product, a novel and useful lantibiotic named paenilan that inhibits the growth of some Gram‐positive bacteria, was characterized.
Significance and Impact of the Study
Paenibacillus species are a good source of new lantibiotics, and the conservation of the paenilan gene among Paenibacillus sp. implies paenilan has an important function(s) for their survival.
Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with ...non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440 and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.
Abstract
Objectives
This study examines differences in the mental and physical health of the U.S. population during the early stages of the COVID-19 pandemic among 3 groups: noncaregivers, short-term ...caregivers (1 year or less), and long-term caregivers (greater than 1 year).
Methods
Data from the Understanding America Study are used to describe group differences in reports of psychological distress and somatic symptoms. Logistic and negative binomial regression models are used to examine whether these differences persist after adjusting for demographic, socioeconomic, and prepandemic health conditions. To understand within-group differences in caregiving demands, the intensity of care provided by short-term and long-term caregivers, as well as selected patients’ health conditions are summarized.
Results
Adults’ mental and physical health varied substantially by caregiver status. Caregivers continued to fare worse than noncaregivers in terms of mental health and fatigue, and long-term caregivers were more likely to report headache, body aches, and abdominal discomfort than both short-term caregivers and noncaregivers, net of controls. The nature of caregiving differed between short-term and long-term caregivers, with the latter more likely to provide greater hours of care, and to be looking after patients with permanent medical conditions.
Discussion
Efforts to understand and mitigate the impact of the pandemic on population health should include caregivers, whose mental and physical health were already vulnerable before COVID-19.
Abstract
The crystal structure, cryogenic magnetic properties, and magnetocaloric performance of double perovskite Eu
2
NiMnO
6
(ENMO), Gd
2
NiMnO
6
(GNMO), and Tb
2
NiMnO
6
(TNMO) ceramic powder ...samples synthesized by solid-state method have been investigated. X-ray diffraction structural investigation reveal that all compounds crystallize in the monoclinic structure with a P2
1
/n space group. A ferromagnetic to paramagnetic (FM-PM) second-order phase transition occurred in ENMO, GNMO, and TNMO at 143, 130, and 112 K, respectively. Maximum magnetic entropy changes and relative cooling power with a 5 T applied magnetic field are determined to be 3.2, 3.8, 3.5 J/kgK and 150, 182, 176 J/kg for the investigated samples, respectively. The change in structural, magnetic, and magnetocaloric effect attributed to the superexchange mechanism of Ni
2+
–O–Mn
3+
and Ni
2+
–O–Mn
4+
. The various atomic sizes of Eu, Gd, and Tb affect the ratio of Mn
4+
/Mn
3+
, which is responsible for the considerable change in properties of double perovskite.
Summary Objective The objectives were to investigate the in vivo effects of treatment with rebamipide on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA) ...and to explore its mode of action. Materials and methods OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA). Oral administration of rebamipide was initiated on the day of MIA injection, 3 or 7 days after. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. We analyzed the samples macroscopically and histomorphologically, and used immunohistochemistry to investigate the expression of matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), hypoxia-inducible factor-2α (HIF-2α), inducible nitric oxide synthase (iNOS), and nitrotyrosine in knee joints. Real-time quantitative reverse transcription–polymerase chain reaction was used to quantify the mRNA for catabolic and anticatabolic factors in human OA chondrocytes. Results Rebamipide showed an antinociceptive property and attenuated cartilage degeneration. Rebamipide reduced the expression of MMP-13, IL-1β, HIF-2α, iNOS, and nitrotyrosine in OA cartilage in a dose-dependent manner. Nitrotyrosine expression in the subchondral bone region was decreased in the rebamipide-treated joints. mRNA expression of MMP-1, -3, and -13, and ADAMTS5 was attenuated in IL-1β-stimulated human OA chondrocytes. By contrast, rebamipide induced the mRNA expression of tissue inhibitor of metalloproteinase-1 and -3. Conclusion The results show the inhibitory effects of rebamipide on pain production and cartilage degeneration in experimentally induced OA. The suppression of oxidative damage and the restoration of extracellular matrix homeostasis of articular chondrocyte suggest that rebamipide is a potential therapeutic strategy for OA.
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