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1.
J Clin Anesth ; : 109623, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31672417

RESUMO

STUDY OBJECTIVE: To identify the efficacy and safety of haloperidol prophylaxis in adult patients with a high risk for delirium. DESIGN: A meta-analysis with trial sequential analysis of randomized controlled trials. INTERVENTION: A comprehensive search was performed in PubMed, the ISI Web of Knowledge, the Cochrane Library, and Embase databases from inception through to March 2019.Citation screening, data abstraction and quality assessment were performed in duplicate. Meta-analysis with trial sequential analysis (TSA) were used to assess the primary and secondary outcomes. In addition, we used the Grading of Recommendations Assessment Development and Evaluation (GRADE) to evaluate the certainty of the body of evidence. MAIN RESULTS: We appraised 8 RCTs involving 3034 patients that that were in compliance with inclusion and exclusion criterion. Pooled analyses indicated patients receiving haloperidol prophylaxis and placebo or normal saline did not significantly differ in incidence of delirium (relative risk [RR] = 0.90, 95% confidence interval [CI] = 0.70 to 1.15), with TSA inconclusive. Notably, compared with the control group, use of haloperidol significantly decreased the duration of delirium (Mean difference [MD] -0.94; 95% CI -1.82 to -0.06 days), with a marked heterogeneity. Additionally, haloperidol prophylaxis does not significantly affect duration of mechanical ventilation, length of intensive care unit (ICU) stay, length of hospital stay and mortality. In terms of safety profiles, haloperidol was not associated with increased risk for QTc prolongation, extrapyramidal symptoms, or adverse events. GRADE indicated the level of evidence was very low for a benefit from haloperidol prophylaxis. CONCLUSIONS: The results of our meta-analysis suggested the use of prophylactic haloperidol compared with placebo had no beneficial impacts on incidence of delirium, duration of mechanical ventilation, length of intensive care unit (ICU) stay, length of hospital stay and mortality in adult patients. It appeared to have a positive effect on duration of delirium, while with a significant heterogeneity. These findings do not support the routine usage of haloperidol for delirium prevention. TRIAL REGISTRATION: PROSPERO registration number: CRD42018100511. Registered on 17 July 2018.

2.
Opt Express ; 27(22): 31587-31598, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31684390

RESUMO

Most existing experiments on radiative cooling are conducted in dry climates for better performance. However, many important applications require cooling in hot and humid climates. Here we theoretically analyze the temperature reduction and cooling flux at nighttime with the ambient temperature (Tambient) ranging from 0-40  ∘C and the relative humidity (RH) from 0-100%. Our analysis reveals an interesting crossover: for lower (higher) RH, higher (lower) Tambient results in better cooling. Experimentally, we show that radiative cooling of 5  ∘C below ambient can be achieved even at Tambient = 29  ∘C with RH = 100%.

3.
Int J Mol Sci ; 20(21)2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31689978

RESUMO

TLC (TRAM/LAG/CRN8) proteins play important roles in ceramide metabolism and mycotoxin resistance. Herein a comparative genomics analysis of TLCs was performed in 31 plant and 3 species from other kingdoms, with an emphasis mainly on maize. TLCs were conserved across kingdoms and expanded in angiosperms, largely due to whole-genome/segmental duplication (WGD/SD) under purifying selection. Phylogeny reconstruction by maximum-likelihood method uncovered five TLC clades, subsequently named as TRAM/LAG, CLN8, PS-TLC, TM136 and TLCD clades. Each clade of TLCs shared specific transmembrane regions and motif composition. Divisions of conserved motifs to subunits may have occurred in TM136-type TLCs. Focusing on maize, five WGD and two DNA-mediated transposed duplication (TD) pairs were discovered, accounting for 61.11% ZmTLCs. Combined with further expression analysis, significant divergence was found in expression patterns between most maize WGD pairs, indicating subfunctionalization or/and neofunctionalization. Moreover, ZmTLC5, a deduced parental copy in a TD pair, was highly induced under FB1 and fungus pathogen injection and exhibited potential capacity to respond to environmental stimuli. Additionally, population genetics analysis showed that ZmTLC10 in the CLN8-clade may have experienced significant positive selection and differentiated between wild and inbred maize populations. Overall, our results help to decipher the evolutionary history of TLCs in maize and plants, facilitating further functional analysis of them.

4.
Med Sci Monit ; 25: 8230-8241, 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31677259

RESUMO

BACKGROUND With the progress in surgical techniques and management of complications, pancreatic resection can be safely performed in experienced hospitals. Pancreatic resection enables surgeons to assess the effect of surgery for metastatic cases, even when there is limited information. In the present study we evaluated the role of primary tumor resection for metastatic pancreatic cancer (mPC) by using the Surveillance, Epidemiology and End Results (SEER) database. MATERIAL AND METHODS Metastatic pancreatic cancer patients treated at our hospital from 2004 to 2015 were identified. The effect of surgery on cancer-specific survival was assessed by restricted mean survival time (RMST) and stabilized inverse probability of treatment weight-adjusted analysis after propensity score matching (PSM). RESULTS A total of 2694 mPC patients were included. Of this population, 365 adults underwent primary tumor resection. After propensity matching, postsurgical patients had longer RMST than non-surgery patients (1: 1 PSM 11.60 months vs. 8.98 months; 1: 2 PSM 11.61 months vs. 9.10 months; p<0.01). Stabilized inverse probability of treatment weight-adjusted analysis yielded similar results (p<0.01). CONCLUSIONS Our study supports the hypothesis that patients with mPC can benefit from primary tumor surgery. However, the surgical inclusion criteria and the appropriate role of surgery, such as its effect on symptom control, quality of life, and the extent to which it prolongs survival for metastatic pancreatic cancer, remain to be completely assessed by well-designed, prospective, randomized clinical trials.

5.
Arterioscler Thromb Vasc Biol ; : ATVBAHA119312707, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597449

RESUMO

OBJECTIVE: Understanding message delivery among vascular cells is essential for deciphering the intercellular communicatios in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene Krüppel-like factor 4 (KLF4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a-induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases. CONCLUSIONS: EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.

6.
Bioengineered ; 10(1): 538-547, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31661653

RESUMO

Buckwheat polysaccharide fractions (BPFs) isolated from seeds of Fagopyrum esculentum have shown extensive immunomodulatory activities including activation of immune system. In this study, the immuno-modulation effects of BPFs on microphages were investigated. The obtained results show that BPFs can activate microphages as indicated by significant increases in the activity of inducible nitric oxide synthase (12.6 ± 1.30 U/mg prot), nuclear factor-kappa B (NF-κB) protein levels, and secretion of nitric oxide (NO) (21.5 ± 1.20 µmol/ml) and tumor necrosis factor-alpha (TNF-α) (71.2 ± 18.20 pg/ml). Moreover, blocking toll-like receptor 4 (TLR4)/NF-κB pathway using a specific antibody to TLR4 or inhibitor of NF-κB led to the significant inhibitory immuno-modulation effect on microphages as indicated by the decrease in the secretion level of NO and TNF-α. It is demonstrated that BPFs can activate microphages and TLR4/NF-κB pathway is involved in the induction of NO and TNF-α in macrophages by BPFs.

7.
Chem Biol Interact ; 314: 108847, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610155

RESUMO

Lead (Pb) is one of the toxic heavy metals that have several toxicological implications including cytotoxicities and oxidative stress. The release of reactive oxygen species (ROS) usually initiates lipid peroxidation and resulting in inflammation and tissue injury. However, the detailed identification of the Pb-produced lipid hydroperoxides has received little attention. Furthermore, the mechanisms behind such effects are less informed. Therefore, this study firstly investigated Pb-produced lipid hydroperoxides in human HepG2 cells using LC/MS. The effects of Pb on the antioxidant enzymes were additionally examined using qPCR and their dependent activities. As a protection trial, the ameliorative effects of rosmarinic (RMA) and ascorbic (ASA) acids on Pb-induced cytotoxicity and oxidative stress and their regulatory effects on Nrf2/Keap1 pathway were investigated. The achieved results confirmed cytotoxicity and oxidative damage of Pb on HepG2 cells. In addition, 20 lipid hydroperoxides (LOOH) were identified including 11 phosphatidylcholine hydroperoxides (PCOOH), 5 triacylglycerol hydroperoxides (TGOOH) and 4 cholesteryl ester hydroperoxides (CEOOH). The most dominant LOOH species were PCOOH 34:2, PCOOH 34:3, PCOOH 38:7, TGOOH 60:14, TGOOH 60:15, CEOOH 18:3 and CEOOH 20:4. Pb significantly downregulated Nrf2-regulated antioxidant enzymes at both the pretranscriptional and functional levels. Co-exposure of HepG2 cells to RMA and ASA significantly reduced Pb-produced adverse outcomes. This protection occurred via activation Nrf2-Keap1 antioxidant pathway.

8.
Aging (Albany NY) ; 11(20): 8860-8878, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31619579

RESUMO

OBJECTIVE: This study is implemented to probe into the function of lncRNA SBF2-AS1 as a competing endogenous RNA (ceRNA) to sponge microRNA-142-3p (miR-142-3p) in modulating TWF1 expression in the gemcitabine resistance of pancreatic cancer. RESULTS: LncRNA SBF2-AS1 was highly expressed in pancreatic cancer tissues and cells. SBF2-AS1 was found to be associated with gemcitabine resistance in pancreatic cancer. Knock-down of SBF2-AS1 inhibited proliferation, epithelial-mesenchymal transition, while promoting apoptosis of gemcitabine resistant pancreatic cancer cells. SBF2-AS1 inhibited the expression of TWF1 by competitively binding with miR-142-3p in pancreatic cancer. CONCLUSION: Our study demonstrates that knock-down of SBF2-AS1 inhibits the expression of TWF1 by competitively binding with miR-142-3p to induce gemcitabine resistance in pancreatic cancer. METHODS: Expression of SBF2-AS1 was tested in pancreatic cancer tissues and cells. Construction of AsPC-1/GEM and PANC-1/GEM cells with low expression of SBF2-AS1 was performed to determine the biological behaviors of drug-resistant cells. AsPC-1 and PANC-1 cells expressing SBF2-AS1 and/or miR-142-3p were constructed and treated with different concentrations of gemcitabine to detect the sensitivity of the cells to gemcitabine. The binding relationship between SBF2-AS1 and miR-142-3p and between miR-142-3p and TWF1 were determined.

9.
Int J Oncol ; 55(6): 1385-1395, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638200

RESUMO

Eukaryotic initiation factor 3c (eIF3C) is involved in the initiation of protein translation. Aberrant eIF3C expression has been reported in different types of human cancer. The present study aimed to assess the role of eIF3C in the malignant behavior of renal cell carcinoma in vitro and in vivo. eIF3C expression was assessed in 16 pairs of renal cell carcinoma (RCC) and matched distant normal tissues, and in RCC cell lines using immunohistochemistry. Subsequently, eIF3C was depleted using lentiviral short hairpin RNA and cell proliferation, cell cycle distribution and apoptosis of these eIF3C­depleted cells were examined. Additionally, tumor cell xenograft assays in nude mice, Affymetrix microarrays and ingenuity pathway analyses were performed. eIF3C expression was upregulated in RCC tissues and cell lines. Depletion of eIF3C reduced tumor cell proliferation and arrested them at the G1 stage, thus promoting their apoptosis in vitro. Depletion of eIF3C also inhibited the formation and growth of tumor cell xenografts in nude mice. In addition, depletion of eIF3C altered the expression levels of 994 differentially expressed genes in RCC cells (516 genes were upregulated and 478 genes were downregulated). The expression levels of phosphorylated­AKT, c­JUN and NFKB inhibitor α were lower in the shorth hairpin RNA eIF3C­transfected RCC cells compared with in the control group. In conclusion, the present study demonstrated that upregulated eIF3C expression contributed to the development and progression of RCC. Future studies should further evaluate whether eIF3C could be used as a potential strategy for RCC targeting therapy.

10.
Science ; 365(6460): 1454-1457, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31604274

RESUMO

A high-conductivity two-dimensional (2D) hole gas, analogous to the ubiquitous 2D electron gas, is desirable in nitride semiconductors for wide-bandgap p-channel transistors. We report the observation of a polarization-induced high-density 2D hole gas in epitaxially grown gallium nitride on aluminium nitride and show that such hole gases can form without acceptor dopants. The measured high 2D hole gas densities of about 5 × 1013 per square centimeters remain unchanged down to cryogenic temperatures and allow some of the lowest p-type sheet resistances among all wide-bandgap semiconductors. The observed results provide a probe for studying the valence band structure and transport properties of wide-bandgap nitride interfaces.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31613769

RESUMO

We present an efficient, trivially parallelizable algorithm to compute offset surfaces of shapes discretized using a dexel data structure. Our algorithm is based on a two-stage sweeping procedure that is simple to implement and efficient, entirely avoiding volumetric distance field computations typical of existing methods. Our construction is based on properties of half-space power diagrams, where each seed is only visible by a half space, which were never used before for the computation of surface offsets. The primary application of our method is interactive modeling for digital fabrication. Our technique enables a user to interactively process high-resolution models. It is also useful in a plethora of other geometry processing tasks requiring fast, approximate offsets, such as topology optimization, collision detection, and skeleton extraction. We present experimental timings, comparisons with previous approaches, and provide a reference implementation in the supplemental material.

12.
Environ Microbiol ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31637819

RESUMO

Ultraviolet-B radiation is known to harm most photosynthetic organisms with the exception of several studies of photosynthetic eukaryotes in which UV-B showed positive effects. In this study, we investigated the effect of acclimation to low UV-B radiation on growth and photosynthesis of the cyanobacterium Nostoc sphaeroides. Exposure to 0.08 W m-2 UV-B plus low visible light for 14 d significantly increased the growth rate and biomass production by 16% and 30%, respectively, compared with those under visible light alone. The UV-B acclimated cells showed an approximately 50% increase in photosynthetic efficiency (α) and photosynthetic capacity (Pmax ), a higher PSI/PSII fluorescence ratio, an increase in PSI content and consequently enhanced cyclic electron flow, relative to those of non-acclimated cells. Both the primary quinone-type acceptor and plastoquinone pool re-oxidation were up-regulated in the UV-B acclimated cells. In parallel, the UV-B acclimated colonies maintained a higher rate of D1 protein synthesis following exposure to elevated intensity of UV-B or visible light, thus functionally mitigating photoinhibition. The present data provide novel insight into photosynthetic acclimation to low UV-B radiation and suggest that UV-B may act as a positive ecological factor for the productivity of some photosynthetic prokaryotes, especially during twilight periods or in shaded environments. This article is protected by copyright. All rights reserved.

13.
Medicine (Baltimore) ; 98(39): e17328, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574868

RESUMO

INTRODUCTION: Gastric leiomyosarcoma (LMS) is a rare malignancy with minimal therapeutic options and has poor prognosis once metastasis develops. PATIENT CONCERNS: A case of gastric LMS with multiple metastases, pain, and progressive anemia 13 months after the initial diagnosis in a 43-year-old woman. DIAGNOSIS: Gastric LMS with liver metastases and multiple retroperitoneal lymphatic metastases. INTERVENTIONS: Minimally invasive therapies of repeated tetrahydropalmatine and oxaliplatin-based transarterial chemoembolization and high-intensity focused ultrasound treatment were performed. OUTCOMES: The treatments resulted in significant pain relief (numerical rating scale from 8-2 points) after the initial treatment, improvement in performance status and quality of life, and a progression-free survival of 4 months after treatment. CONCLUSION: This combined modality palliative treatment approach was well tolerated with noticeable pain relief.


Assuntos
Quimioembolização Terapêutica/métodos , Tratamento por Ondas de Choque Extracorpóreas/métodos , Leiomiossarcoma/patologia , Manejo da Dor/métodos , Dor , Qualidade de Vida , Neoplasias Gástricas/patologia , Adulto , Terapia Combinada/métodos , Feminino , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/fisiopatologia , Neoplasias Hepáticas/secundário , Imagem Multimodal/métodos , Estadiamento de Neoplasias , Dor/diagnóstico , Dor/etiologia , Dor/psicologia , Medição da Dor/métodos , Cuidados Paliativos/métodos , Intervalo Livre de Progressão , Resultado do Tratamento
14.
Food Funct ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31651924

RESUMO

Previous studies have shown that 7S protein is the active ingredient responsible for the plasma cholesterol-lowering activity of soybean. It is hypothesized that isoflavones in soybean could enhance the blood cholesterol-lowering activity of 7S protein. Forty-eight hamsters were divided into six groups and fed a non-cholesterol diet or one of the five high-cholesterol diets containing 12.1% 7S protein with 0-15.62 mg g-1 isoflavones. The results showed that addition of isoflavones in diets dose-dependently enhanced the plasma total cholesterol-lowering activity of 7S protein. Addition of isoflavones in 7S protein-based diets significantly reduced hepatic cholesterol accumulation by 12.6-26.1%, compared with the high cholesterol control diet. Isoflavones could also facilitate excretion of neutral sterols in a dose-dependent manner. Supplementation of isoflavones in diets favourably modulated mRNA expression and the protein mass of HMG-CoA reductase. It was concluded that the enhancing effect of isoflavones on the blood cholesterol-lowering activity of 7S protein was mediated by inhibiting the cholesterol absorption and de novo cholesterol synthesis in hypercholesterolemic hamsters.

15.
J Hematol Oncol ; 12(1): 103, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623653

RESUMO

BACKGROUND: Circular RNAs (circRNAs) represent a type of endogenous noncoding RNAs that are generated by back-splicing events and favor repetitive sequences. Recent studies have reported that cancer-associated chromosomal translocations could juxtapose distant complementary repetitive intronic sequences, resulting in the aberrant formation of circRNAs. However, among the reported fusion genes, only a small number of circRNAs were found to originate from fusion regions during gene translocation. We question if circRNAs could also originate from fusion partners during gene translocation. METHODS: Firstly, we designed divergent primers for qRT-PCR to identify a circRNA circAF4 in AF4 gene and investigated the expression pattern in different types of leukemia samples. Secondly, we designed two small interfering RNAs specially targeting the back-spliced junction point of circAF4 for functional studies. CCK8 cell proliferation and cell cycle assay were performed, and a NOD-SCID mouse model was used to investigate the contribution of circAF4 in leukemogenesis. Finally, luciferase reporter assay, AGO2 RNA immunoprecipitation (RIP), and RNA Fluorescent in Situ Hybridization (FISH) were performed to confirm the relationship of miR-128-3p, circAF4, and MLL-AF4 expression. RESULTS: We discovered a circRNA, named circAF4, originating from the AF4 gene, a partner of the MLL fusion gene in MLL-AF4 leukemia. We showed that circAF4 plays an oncogenic role in MLL-AF4 leukemia and promotes leukemogenesis in vitro and in vivo. More importantly, knockdown of circAF4 increases the leukemic cell apoptosis rate in MLL-AF4 leukemia cells, while no effect was observed in leukemia cells that do not carry the MLL-AF4 translocation. Mechanically, circAF4 can act as a miR-128-3p sponge, thereby releasing its inhibition on MLL-AF4 expression. We finally analyzed most of the MLL fusion genes loci and found that a number of circRNAs could originate from these partners, suggesting the potential roles of fusion gene partner-originating circRNAs (named as FP-circRNAs) in leukemia with chromosomal translocations. CONCLUSION: Our findings demonstrate that the abnormal elevated expression of circAF4 regulates the cell growth via the circAF4/miR-128-3p/MLL-AF4 axis, which could contribute to leukemogenesis, suggesting that circAF4 may be a novel therapeutic target of MLL-AF4 leukemia.

16.
Phys Rev E ; 100(3-1): 033111, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31640031

RESUMO

Adhesion dynamics of cells is of great value to biological systems and adhesion-based biomedical applications. Although adhesion of a single cell or capsule has been widely studied, physical insights into the adhesion dynamics of aggregates containing two or more cells remain elusive. In this paper, we numerically investigate the dynamic adhesion of a deformable cell pair to a flat substrate under shear flow. Specifically, the immersed boundary-lattice Boltzmann method is utilized as the flow solver, and the stochastic receptor-ligand kinetics model is implemented to recover cell-substrate and cell-cell adhesive interactions. Special attention is paid to the roles of the cell deformability and adhesion strengths in cellular motion. Four distinct adhesion states, namely, rolling, tumbling, firm adhesion, and detachment, are identified and presented in phase diagrams as a function of the adhesion strengths for cell pairs with different deformabilities. The simulation results suggest that both the cell-cell and cell-substrate adhesion strengths act as the resistance to the rolling motion, and dominate the transition among various adhesion states. The cell deformability not only enhances the resistance effect, but also contributes to detachment or fast tumbling of the cell pair. These findings enrich the understanding of adhesion dynamics of cell aggregates, which could shed light on complex adhesion processes and provide instructions in developing adhesion-based applications.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31641952

RESUMO

INTRODUCTION: The Patient-Oriented Eczema Measure (POEM) assesses patient-reported frequency of atopic dermatitis (AD) symptoms, while the Children's Dermatology Life Quality Index (CDLQI) measures the impact of skin disease on health-related quality of life (HRQoL) in children. There is currently no threshold for clinically meaningful within-person change in POEM or CDLQI scores in adolescents. Here we empirically derive within-person thresholds of meaningful within-person change in POEM and CDLQI scores in adolescents with moderate-to-severe AD. METHODS: Data were used from a phase 3, randomized, double-blind, placebo-controlled trial of dupilumab in adolescents (aged ≥ 12 to < 18 years) with moderate-to-severe AD. Anchor-based methods were employed using the mean change in POEM and CDLQI scores from baseline to week 16 linked with a 1-point improvement in Patient Global Assessment of Disease (PGAD), a score of "a little better" on the Patient Global Assessment of Treatment effect (PGAT), a 50-74% improvement from baseline in the Eczema Area and Severity Index (EASI-50-74), and a 1-point improvement in Investigator's Global Assessment (IGA) score. RESULTS: A mean change of - 7.8 and - 5.6 in the POEM score was associated with PGAD and PGAT anchors, respectively. EASI-50-74 was associated with a mean change in POEM score of - 8.2, while the IGA anchor was associated with a mean change of - 7.9 in POEM score. The mean changes in CDLQI score associated with PGAD and PGAT anchors were - 6.4 and - 6.6, respectively, while CDLQI mean scores changed by - 8.3 and - 8.0 for the EASI and IGA anchors, respectively. CONCLUSION: In adolescents (aged ≥ 12 to < 18 years) with moderate-to-severe AD, a within-person change of 6-8 points in POEM and CDLQI scores, independently, can be considered a reasonable responder threshold for clinically meaningful change in each of the two scales, respectively. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03054428. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc.

19.
Nat Protoc ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619811

RESUMO

RNA-chromatin interactions represent an important aspect of the transcriptional regulation of genes and transposable elements. However, analyses of chromatin-associated RNAs (caRNAs) are often limited to one caRNA at a time. Here, we describe the iMARGI (in situ mapping of RNA-genome interactome) technique, which is used to discover caRNAs and reveal their respective genomic interaction loci. iMARGI starts with in situ crosslinking and genome fragmentation, followed by converting each proximal RNA-DNA pair into an RNA-linker-DNA chimeric sequence. These chimeric sequences are subsequently converted into a sequencing library suitable for paired-end sequencing. A standardized bioinformatic software package, iMARGI-Docker, is provided to decode the paired-end sequencing data into caRNA-DNA interactions. Compared to its predecessor MARGI (mapping RNA-genome interactions), the number of input cells for iMARGI is 3-5 million (a 100-fold reduction), experimental time is reduced, and clear checkpoints have been established. It takes a few hours a day and a total of 8 d to complete the construction of an iMARGI sequencing library and 1 d to carry out data processing with iMARGI-Docker.

20.
Gastroenterology ; 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31593702

RESUMO

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin 4 (IL4) receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. METHODS: We performed a phase 2 study of adults with active EoE (2 dysphagia episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015 through November 9, 2016 at 14 sites. Subjects were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg; n=23) or placebo (n=24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann dysphagia instrument patient-reported outcome (SDI-PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. RESULTS: The mean SDI-PRO score was 6.4 when the study began. In the dupilumab group, SDI-PRO scores were reduced by a mean value of 3.0 at week 10 compared with vs a mean reduction of 1.3 in the placebo group (P=.0304) At week 12, dupilumab reduced peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P<.0001 compared with baseline), the EoE-HSS severity score by 68.3% (P<.0001 vs baseline), and the endoscopic reference score by 1.6 (P=.0006 compared with baseline. Dupilumab increased esophageal distensibility by 18% compared with baseline (P<.0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). CONCLUSIONS: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features, compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov no: NCT02379052.

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