The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty ...acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1-FPR2-IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.
Treg cells have been shown to be an important part of immune-homeostasis and IL-2 which is produced upon T cell receptor (TCR)-dependent activation of T lymphocytes has been demonstrated to ...critically participate in Treg development.
To evaluate small molecule inhibitors (SMI) for the identification of novel IL-2/Treg enhancing compounds.
We used TCR-dependent and allergen-specific cytokine secretion of human and mouse T cells, next generation messenger ribonucleic acid sequencing (RNA-Seq) and two different models of allergic airway inflammation to examine lead SMI-compounds.
We show here that the reported 3-phosphoinositide dependent kinase-1 (PDK1) SMI BX-795 increased IL-2 in culture supernatants of Jurkat E6-1 T cells, human peripheral blood mononuclear cells (hPBMC) and allergen-specific mouse T cells upon TCR-dependent and allergen-specific stimulation while concomitantly inhibiting Th2 cytokine secretion. RNA-Seq revealed that the presence of BX-795 during allergen-specific activation of T cells induces a
Treg cell type highly similar to iTreg but lacking Foxp3 expression. When applied in mugwort pollen and house dust mite extract-based models of airway inflammation, BX-795 significantly inhibited Th2 inflammation including expression of Th2 signature transcription factors and cytokines and influx into the lungs of type 2-associated inflammatory cells such as eosinophils.
BX-795 potently uncouples IL-2 production from Th2 inflammation and induces Th-IL-2 cells, which highly resemble induced (i)Tregs. Thus, BX-795 may be a useful new compound for the treatment of allergic diseases.
This paper presents computationally feasible rank-one relaxation algorithms for the efficient simulation of a time-incremental damage model with nonconvex incremental stress potentials in multiple ...spatial dimensions. While the standard model suffers from numerical issues due to the lack of convexity, our experiments showed that the relaxation by rank-one convexification delivering an approximation to the quasiconvex envelope prevents mesh dependence of the solutions of finite element discretizations. By the combination, modification and parallelization of the underlying convexification algorithms, the novel approach becomes computationally feasible. A descent method and a Newton scheme enhanced by step-size control prevent stability issues related to local minima in the energy landscape and the computation of derivatives. Numerical techniques for the construction of continuous derivatives of the approximated rank-one convex envelope are discussed. A series of numerical experiments demonstrates the ability of the computationally relaxed model to capture softening effects and the mesh independence of the computed approximations. An interpretation in terms of microstructural damage evolution is given, based on the rank-one lamination process.
p16and p15, 2 inhibitors of cyclin-dependent kinases, are frequently hypermethylated in hematologic neoplasias. Decitabine, or 5-Aza-2′-deoxycytidine, reverts hypermethylation of these genes in ...vitro, and low-dose decitabine treatment improves cytopenias and blast excess in ∼50% of patients with high-risk myelodysplastic syndrome (MDS). We examined p15and p16 methylation status in bone marrow mononuclear cells from patients with high-risk MDS during treatment with decitabine, using a methylation-sensitive primer extension assay (Ms-SNuPE) to quantitate methylation, and denaturing gradient gel electrophoresis (DGGE) and bisulfite-DNA sequencing to distinguish individually methylated alleles. p15 expression was serially examined in bone marrow biopsies by immunohistochemistry. Hypermethylation in the 5′ p15 gene region was detected in 15 of 23 patients (65%), whereas the 5′ p16 region was unmethylated in all patients. Among 12 patients with hypermethylation sequentially analyzed after at least one course of decitabine treatment, a decrease in p15 methylation occurred in 9 and was associated with clinical response. DGGE and sequence analyses were indicative of hypomethylation induction at individual alleles. Immunohistochemical staining for p15 protein in bone marrow biopsies from 8 patients with p15hypermethylation revealed low or absent expression in 4 patients, which was induced to normal levels during decitabine treatment. In conclusion, frequent, selectivep15hypermethylation was reversed in responding MDS patients following treatment with a methylation inhibitor. The emergence of partially demethylated epigenotypes and re-establishment of normal p15 protein expression following the initial decitabine courses implicate pharmacologic demethylation as a possible mechanism resulting in hematologic response in MDS.
Marshallese adults experience high rates of type 2 diabetes. Previous diabetes self-management education (DSME) interventions among Marshallese were unsuccessful. This study compared the extent to ...which two DSME interventions improved glycemic control, measured on the basis of change in glycated hemoglobin (HbA
).
A two-arm randomized controlled trial compared a standard-model DSME (standard DSME) with a culturally adapted family-model DSME (adapted DSME). Marshallese adults with type 2 diabetes (
= 221) received either standard DSME in a community setting (
= 111) or adapted DSME in a home setting (
= 110). Outcome measures were assessed at baseline, immediately after the intervention, and at 6 and 12 months after the intervention and were examined with adjusted linear mixed-effects regression models.
Participants in the adapted DSME arm showed significantly greater declines in mean HbA
immediately (-0.61% 95% CI -1.19, -0.03;
= 0.038) and 12 months (-0.77% 95% CI -1.38, -0.17;
= 0.013) after the intervention than those in the standard DSME arm. Within the adapted DSME arm, participants had significant reductions in mean HbA
from baseline to immediately after the intervention (-1.18% 95% CI -1.55, -0.81), to 6 months (-0.67% 95% CI -1.06, -0.28), and to 12 months (-0.87% 95% CI -1.28, -0.46) (
< 0.001 for all). Participants in the standard DSME arm had significant reductions in mean HbA
from baseline to immediately after the intervention (-0.55% 95% CI -0.93, -0.17;
= 0.005).
Participants receiving the adapted DSME showed significantly greater reductions in mean HbA
immediately after and 12 months after the intervention than the reductions among those receiving standard DSME. This study adds to the body of research that shows the potential effectiveness of culturally adapted DSME that includes participants' family members.
The brief history of relaxation in continuum mechanics ranges from early application of non-convex plasticity and phase transition formulations to small and large strain continuum damage mechanics. ...However, relaxed continuum damage mechanics formulations are still limited in the following sense that their material response lack to model strain softening and the convexification of the non-convex incremental stress potential is computationally costly. This paper presents a reduced model for relaxed continuum damage mechanics at finite strains which includes strain softening by a fiber-specific damage in the microsphere approach. Computational efficiency is achieved by novel adaptive algorithms for the fast convexification of the one-dimensional fiber material model. The algorithms are benchmarked against state-of-the-art methods, and the choice of quadrature schemes for the microsphere approach is discussed. This contribution is finalized by a mesh independence test.
Patients with the connective tissue disorder Ehlers-Danlos syndrome (EDS) often suffer from fatigue, excessive daytime sleepiness and impaired quality of life. Obstructive sleep apnoea (OSA) may be ...an underlying cause for these symptoms but its prevalence in this population is unclear.
In this prospective parallel-cohort study, we included 100 adult patients with EDS (46% hypermobile-type, 35% classical-type and 19% other), which were one-to-one matched to 100 healthy adult controls according to sex, age, weight and height. Participants underwent structured interviews (including short-form 36) and level-3 respiratory polygraphy. OSA was defined as apnoea-hypopnea index ≥5/hour. Photographic craniofacial phenotyping was conducted in a subgroup. Conditional logistic regression was used to compare the prevalence of OSA.
In patients with EDS, OSA prevalence was 32% versus 6% in the matched control group (OR 5.3 (95% CI 2.5 to 11.2); p<0.001). The EDS group reported impaired quality of life in all dimensions (p<0.05) and significantly higher excessive daytime sleepiness measured by the Epworth Sleepiness Scale (median (quartiles) 11 (7-14) vs 7 (5-10); p<0.001). OSA severity was positively associated with daytime sleepiness and lower quality of life in the EDS group. There was no evidence of a difference between the two study groups in terms of craniofacial phenotypes.
The prevalence of OSA is higher in patients with EDS than in a matched control group. This is of clinical relevance as it is associated with fatigue, excessive daytime sleepiness and impaired quality of life. Further studies are needed to assess the clinical benefit of OSA treatment in patients with EDS.
NCT02435745.
This article illustrates how a collaborative research process can successfully engage an underserved minority community to address health disparities. Pacific Islanders, including the Marshallese, ...are one of the fastest growing US populations. They face significant health disparities, including extremely high rates of type 2 diabetes. This article describes the engagement process of designing patient‐centered outcomes research with Marshallese stakeholders, highlighting the specific influences of their input on a randomized control trial to address diabetes. Over 18 months, an interdisciplinary research team used community‐based participatory principles to conduct patient‐engaged outcomes research that involved 31 stakeholders in all aspects of research design, from defining the research question to making decisions about budgets and staffing. This required academic researcher flexibility, but yielded a design linking scientific methodology with community wisdom.
Abstract Purpose To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with ...metastatic colorectal cancer (mCRC). Patients and methods A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m2 , 5-fluorouracil 2000 mg/m2 , folinic acid 500 mg/m2 weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m2 applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS). Results A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm hazard ratio = 1.14; 95% confidence interval (CI) 0.94–1.37; P = 0.178. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio = 1.08, P = 0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P = 0.001). Most frequent grades 1–4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3–4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P = 0.006) Conclusion mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.
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