共查询到20条相似文献,搜索用时 31 毫秒
1.
Chenju Yi Ket Yin Goh LikWei Wong Ajeena Ramanujan Kazuhiro Tanaka Sreedharan Sajikumar Carlos F Ibez 《The EMBO journal》2021,40(17)
Correction to: The EMBO Journal (2021) 40: e104450. DOI 10.15252/embj.2020104450 | Published online 1 December 2020The authors correct Figure 6A of this paper. During the revision process, images from p75NTR‐expressing mice were inadvertently used in place of p75NTR knock‐out neurons. The corrected figure, showing lack of p75NTR labeling in knock‐out neurons, along with their corresponding internalized APP, is shown here. This error only concerns the images used to illustrate the quantitative data. It does not affect the analysis itself nor the conclusions derived from it. The authors apologize for this oversight and agree with this corrigendum; no response could be obtained from KT. Figure 6A. Original Figure 6A. Corrected 相似文献
2.
3.
Sheng Niu Jia Wang Bin Bai Lili Wu Anqi Zheng Qian Chen Pei Du Pengcheng Han Yanfang Zhang Yunfei Jia Chengpeng Qiao Jianxun Qi Wenxia Tian HongWei Wang Qihui Wang George Fu Gao 《The EMBO journal》2022,41(1)
Correction to: The EMBO Journal (2021) 40: e107786. DOI 10.15252/embj.2021107786 | Published online 8 June 2021The authors would like to add three references to the paper: Starr et al and Zahradník et al also reported that the Q498H or Q498R mutation has enhanced binding affinity to ACE2; and Liu et al reported on the binding of bat coronavirus to ACE2.Starr et al and Zahradník et al have now been cited in the Discussion section, and the following sentence has been corrected from:“According to our data, the SARS‐CoV‐2 RBD with Q498H increases the binding strength to hACE2 by 5‐fold, suggesting the Q498H mutant is more ready to interact with human receptor than the wildtype and highlighting the necessity for more strict control of virus and virus‐infected animals”.to“Here, according to our data and two recently published papers, the SARS‐CoV‐2 RBD with Q498H or Q498R increases the binding strength to hACE2 (Starr et al, 2020; Zahradník et al, 2021), suggesting the mutant with Q498H or Q498R is more ready to interact with human receptor than the wild type and highlighting the necessity for more strict control of virus and virus‐infected animals”.The Liu et al citation has been added to the following sentence:“In another paper published by our group recently, RaTG13 RBD was found to bind to hACE2 with much lower binding affinity than SARS‐CoV‐2 though RaTG13 displays the highest whole‐genome sequence identity (96.2%) with the SARS‐CoV‐2 (Liu et al, 2021)”.Additionally, the authors have added the GISAID accession IDs to the sequence names of the SARS‐CoV‐2 in two human samples (Discussion section). To make identification unambiguous, the sequence names have been updated from “SA‐lsf‐27 and SA‐lsf‐37” to “GISAID accession ID: EPI_ISL_672581 and EPI_ISL_672589”.Lastly, the authors declare in the Materials and Methods section that all experiments employed SARS‐CoV‐2 pseudovirus in cultured cells. These experiments were performed in a BSL‐2‐level laboratory and approved by Science and Technology Conditions Platform Office, Institute of Microbiology, Chinese Academy of Sciences.These changes are herewith incorporated into the paper. 相似文献
4.
5.
6.
Lennart Greiff Anders Cervin Cecilia Ahlstr?m-Emanuelsson Gun Almqvist Morgan Andersson Jan Dolata Leif Eriksson Edward H?gest?tt Anders K?llén Per Norlén Inga-Lisa Sj?lin Henrik Widegren 《Respiratory research》2012,13(1):53
Background
Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile.Objective
To evaluate the efficacy and safety of intranasal AZD8848.Methods
In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days ( NCT00688779). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. NCT00770003Results
AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30–100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848.Conclusions
Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis.Trial registration
and NCT00688779 as indicated above. NCT00770003相似文献7.
Elizabeth P. Schlaudecker Mark C. Steinhoff Saad B. Omer Monica M. McNeal Eliza Roy Shams E. Arifeen Caitlin N. Dodd Rubhana Raqib Robert F. Breiman K. Zaman 《PloS one》2013,8(8)
Background
Antenatal immunization of mothers with influenza vaccine increases serum antibodies and reduces the rates of influenza illness in mothers and their infants. We report the effect of antenatal immunization on the levels of specific anti-influenza IgA levels in human breast milk. (ClinicalTrials.gov identifier ; http://clinicaltrials.gov/ct2/show/ NCT00142389). NCT00142389Methods and Findings
The Mother''s Gift study was a prospective, blinded, randomized controlled trial that assigned 340 pregnant Bangladeshi mothers to receive either trivalent inactivated influenza vaccine, or 23-valent pneumococcal polysaccharide vaccine during the third trimester. We evaluated breast milk at birth, 6 weeks, 6 months, and 12 months, and serum at 10 weeks and 12 months. Milk and serum specimens from 57 subjects were assayed for specific IgA antibody to influenza A/New Caledonia (H1N1) using an enzyme-linked immunosorbent assay (ELISA) and a virus neutralization assay, and for total IgA using ELISA. Influenza-specific IgA levels in breast milk were significantly higher in influenza vaccinees than in pneumococcal controls for at least 6 months postpartum (p = 0.04). Geometric mean concentrations ranged from 8.0 to 91.1 ELISA units/ml in vaccinees, versus 2.3 to 13.7 ELISA units/mL in controls. Virus neutralization titers in milk were 1.2 to 3 fold greater in vaccinees, and correlated with influenza-specific IgA levels (r = 0.86). Greater exclusivity of breastfeeding in the first 6 months of life significantly decreased the expected number of respiratory illness with fever episodes in infants of influenza-vaccinated mothers (p = 0.0042) but not in infants of pneumococcal-vaccinated mothers (p = 0.4154).Conclusions
The sustained high levels of actively produced anti-influenza IgA in breast milk and the decreased infant episodes of respiratory illness with fever suggest that breastfeeding may provide local mucosal protection for the infant for at least 6 months. Studies are needed to determine the cellular and immunologic mechanisms of breast milk-mediated protection after antepartum immunization.Trial Registration
ClinicalTrials.gov NCT00142389相似文献8.
Jin Hwa Lee Michael H Cho Craig P Hersh Merry-Lynn N McDonald James D Crapo Per S Bakke Amund Gulsvik Alejandro P Comellas Christine H Wendt David A Lomas Victor Kim Edwin K Silverman 《Respiratory research》2014,15(1)
Background
Chronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population.Methods
We analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis.Results
For CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR = 1.93, P = 4.99 × 10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR = 1.88, P = 4.99 × 10-7).Conclusions
We found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.Trial registration
ClinicalTrials.gov , NCT00608764 NCT00292552Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0113-2) contains supplementary material, which is available to authorized users. 相似文献9.
Geeta A. Thakur Sarojini M. Sengupta Natalie Grizenko Zia Choudhry Ridha Joober 《PloS one》2012,7(11)
Objective
Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.Methods
Children (6–12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.Results
A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z = 3.74, P = 0.0002), behavioral assessments by parents (CBCL, P = 0.00008), as well as restless-impulsive subscale scores on Conners’-teachers (P = 0.006) and parents (P = 0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z = 3.28, P = 0.001), parents (Z = 2.62, P = 0.009), as well as evaluation in the simulated academic environment (Z = 3.58, P = 0.0003).Conclusions
By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information – Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; . NCT00483106相似文献10.
11.
Benedikt Ley Mohammad Shafiul Alam Kamala Thriemer Mohammad Sharif Hossain Mohammad Golam Kibria Sarah Auburn Eugenie Poirot Ric N. Price Wasif Ali Khan 《PloS one》2016,11(4)
BackgroundThe Bangladeshi national treatment guidelines for uncomplicated malaria follow WHO recommendations but without G6PD testing prior to primaquine administration. A prospective observational study was conducted to assess the efficacy of the current antimalarial policy.MethodsPatients with uncomplicated malaria, confirmed by microscopy, attending a health care facility in the Chittagong Hill Tracts, Bangladesh, were treated with artemether-lumefantrine (days 0–2) plus single dose primaquine (0.75mg/kg on day2) for P. falciparum infections, or with chloroquine (days 0–2) plus 14 days primaquine (3.5mg/kg total over 14 days) for P. vivax infections. Hb was measured on days 0, 2 and 9 in all patients and also on days 16 and 30 in patients with P. vivax infection. Participants were followed for 30 days. The study was registered with the clinical trials website ().ResultsBetween September 2014 and February 2015 a total of 181 patients were enrolled (64% P. falciparum, 30% P. vivax and 6% mixed infections). Median parasite clearance times were 22.0 (Interquartile Range, IQR: 15.2–27.3) hours for P. falciparum, 20.0 (IQR: 9.5–22.7) hours for P. vivax and 16.6 (IQR: 10.0–46.0) hours for mixed infections. All participants were afebrile within 48 hours, two patients with P. falciparum infection remained parasitemic at 48 hours. No patient had recurrent parasitaemia within 30 days. Adjusted male median G6PD activity was 7.82U/gHb. One male participant (1/174) had severe G6PD deficiency (<10% activity), five participants (5/174) had mild G6PD deficiency (10–60% activity). The Hb nadir occurred on day 2 prior to primaquine treatment in P. falciparum and P. vivax infected patients; mean fractional fall in Hb was -8.8% (95%CI -6.7% to -11.0%) and -7.4% (95%CI: -4.5 to -10.4%) respectively.ConclusionThe current antimalarial policy remains effective. The prevalence of G6PD deficiency was low. Main contribution to haemolysis in G6PD normal individuals was attributable to acute malaria rather than primaquine administration. NCT02389374
Trial Registration
ClinicalTrials.gov NCT02389374相似文献12.
Henrik N. Kl?verpris Akil Jackson Amanda Handley Peter Hayes Jill Gilmour Lynn Riddell Fabian Chen Mark Atkins Marta Boffito Bruce D. Walker Jim Ackland Mark Sullivan Philip Goulder 《PloS one》2013,8(10)
Background
HIV Gag-specific CD4+ and CD8+ T-cell responses are important for HIV immune control. Pulsing overlapping Gag peptides on autologous lymphocytes (OPAL) has proven immunogenic and effective in reducing viral loads in multiple pigtail macaque studies, warranting clinical evaluation.Methodology
We performed a phase I, single centre, placebo-controlled, double-blinded and dose-escalating study to evaluate the safety and preliminary immunogenicity of a novel therapeutic vaccine approach ‘OPAL-HIV-Gag(c)’. This vaccine is comprised of 120 15mer peptides, overlapping by 11 amino acids, spanning the HIV Gag C clade sequence proteome, pulsed on white blood cells enriched from whole blood using a closed system, followed by intravenous reinfusion. Patients with undetectable HIV viral loads (<50 copies/ml plasma) on HAART received four administrations at week 0, 4, 8 and 12, and were followed up for 12 weeks post-treatment. Twenty-three people were enrolled in four groups: 12 mg (n = 6), 24 mg (n = 7), 48 mg (n = 2) or matching placebo (n = 8) with 18 immunologically evaluable. T-cell immunogenicity was assessed by IFNγ ELIspot and intracellular cytokine staining (ICS).Results
The OPAL-HIV-Gag(c) peptides were antigenic in vitro in 17/17 subjects. After vaccination with OPAL-HIV-Gag(c), 1/6 subjects at 12 mg and 1/6 subjects at 24 mg dose groups had a 2- and 3-fold increase in ELIspot magnitudes from baseline, respectively, of Gag-specific CD8+ T-cells at week 14, compared to 0/6 subjects in the placebo group. No Gag-specific CD4+ T-cell responses or overall change in Rev, Nef, Tat and CMV specific responses were detected. Marked, transient and self-limiting lymphopenia was observed immediately post-vaccination (4 hours) in OPAL-HIV-Gag(c) but not in placebo recipients, with median fall from 1.72 to 0.67 million lymphocytes/mL for active groups (P<0.001), compared to post-placebo from 1.70 to 1.56 lymphocytes/ml (P = 0.16).Conclusion/Significance
Despite strong immunogenicity observed in several Macaca nemestrina studies using this approach, OPAL-HIV-Gag(c) was not significantly immunogenic in humans and improved methods of generating high-frequency Gag-specific T-cell responses are required.Name of Registry
ClinicalTrials.gov, Registry number: , URL trial registry database: NCT01123915http://www.clinicaltrials.gov/ct2/results?term=OPAL-HIV-1001&Search=Search 相似文献13.
Ammar Al-Chalabi Alexandra Dürr Nicholas W. Wood Michael H. Parkinson Agnes Camuzat Jean-Sébastien Hulot Karen E. Morrison Alan Renton Sigurd D. Sussmuth Bernhard G. Landwehrmeyer Albert Ludolph Yves Agid Alexis Brice P. Nigel Leigh Gilbert Bensimon for the NNIPPS Genetic Study Group 《PloS one》2009,4(9)
Background
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of α-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the α-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson''s disease has identified association of a SNP in SNCA with MSA.Methodology/Findings
We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3–3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6–11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7×10−4). The association with rs3822086 was replicated in the independent samples (P = 0.035).Conclusions/Significance
We report a genetic association between MSA and α-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.Trial Registration
ClinicalTrials.gov . [ NCT00211224] NCT00211224相似文献14.
15.
Azusa Hara Lutgarde Thijs Kei Asayama Lotte Jacobs Ji-Guang Wang Jan A. Staessen 《PloS one》2014,9(8)
Background
In the Systolic Hypertension in Europe trial (), we investigated whether systolic blood pressure variability determines prognosis over and beyond level. NCT02088450Methods
Using a computerised random function and a double-blind design, we randomly allocated 4695 patients (≥60 years) with isolated systolic hypertension (160–219/<95 mm Hg) to active treatment or matching placebo. Active treatment consisted of nitrendipine (10–40 mg/day) with possible addition of enalapril (5–20 mg/day) and/or hydrochlorothiazide (12.5–25.0 mg/day). We assessed whether on-treatment systolic blood pressure level (SBP), visit-to-visit variability independent of the mean (VIM) or within-visit variability (WVV) predicted total (n = 286) or cardiovascular (n = 150) mortality or cardiovascular (n = 347), cerebrovascular (n = 133) or cardiac (n = 217) endpoints.Findings
At 2 years, mean between-group differences were 10.5 mm Hg (p<0.0001) for SBP, 0.29 units (p = 0.20) for VIM, and 0.07 mm Hg (p = 0.47) for WVV. Active treatment reduced (p≤0.048) cardiovascular (−28%), cerebrovascular (−40%) and cardiac (−24%) endpoints. In analyses dichotomised by the median, patients with low vs. high VIM had similar event rates (p≥0.14). Low vs. high WVV was not associated with event rates (p≥0.095), except for total and cardiovascular mortality on active treatment, which were higher with low WVV (p≤0.0003). In multivariable-adjusted Cox models, SBP predicted all endpoints (p≤0.0043), whereas VIM did not predict any (p≥0.058). Except for an inverse association with total mortality (p = 0.042), WVV was not predictive (p≥0.15). Sensitivity analyses, from which we excluded blood pressure readings within 6 months after randomisation, 6 months prior to an event or both were confirmatory.Conclusions
The double-blind placebo-controlled Syst-Eur trial demonstrated that blood-pressure lowering treatment reduces cardiovascular complications by decreasing level but not variability of SBP. Higher blood pressure level, but not higher variability, predicted risk.Trial Registration
ClinicalTrials.gov NCT02088450相似文献16.
Mahamadou S. Sissoko Abdoulaye Dabo Hamidou Traoré Mouctar Diallo Boubacar Traoré Drissa Konaté Boubacar Niaré Moussa Diakité Bourama Kamaté Abdrahamane Traoré Aboudramane Bathily Amadou Tapily Ousmane B. Touré Sarah Cauwenbergh Herwig F. Jansen Ogobara K. Doumbo 《PloS one》2009,4(10)
Background
This study was conducted to determine the efficacy of the antimalarial artemisinin-based combination therapy (ACT) artesunate +sulfamethoxypyrazine/pyrimethamine (As+SMP), administered in doses used for malaria, to treat Schistosoma haematobium in school aged children.Methodology/Principal Findings
The study was conducted in Djalakorodji, a peri-urban area of Bamako, Mali, using a double blind setup in which As+SMP was compared with praziquantel (PZQ). Urine samples were examined for Schistosoma haematobium on days −1, 0, 28 and 29. Detection of haematuria, and haematological and biochemical exams were conducted on day 0 and day 28. Clinical exams were performed on days 0, 1, 2, and 28. A total of 800 children were included in the trial. The cure rate obtained without viability testing was 43.9% in the As+SMP group versus 53% in the PZQ group (Chi2 = 6.44, p = 0.011). Egg reduction rates were 95.6% with PZQ in comparison with 92.8% with As+SMP, p = 0.096. The proportion of participants who experienced adverse events related to the medication was 0.5% (2/400) in As+SMP treated children compared to 2.3% (9/399) in the PZQ group (p = 0.033). Abdominal pain and vomiting were the most frequent adverse events in both treatment arms. All adverse events were categorized as mild.Conclusions/Significance
The study demonstrates that PZQ was more effective than As+SMP for treating Schistosoma haematobium. However, the safety and tolerability profile of As+SMP was similar to that seen with PZQ. Our findings suggest that further investigations seem justifiable to determine the dose/efficacy/safety pattern of As+SMP in the treatment of Schistosoma infections.Trial Registration
ClinicalTrials.gov NCT00510159http://clinicaltrials.gov/ct2/show/NCT00510159 相似文献17.
Otto Metzger-Filho Aurélie Catteau Stefan Michiels Marc Buyse Michail Ignatiadis Kamal S. Saini Evandro de Azambuja Virginie Fasolo Sihem Naji Jean Luc Canon Paul Delrée Michel Coibion Pino Cusumano Veronique Jossa Jean Pierre Kains Denis Larsimont Vincent Richard Daniel Faverly Nathalie Cornez Peter Vuylsteke Brigitte Vanderschueren Hélène Peyro-Saint-Paul Martine Piccart Christos Sotiriou 《PloS one》2013,8(8)
Purpose
Genomic Grade Index (GGI) is a 97-gene signature that improves histologic grade (HG) classification in invasive breast carcinoma. In this prospective study we sought to evaluate the feasibility of performing GGI in routine clinical practice and its impact on treatment recommendations.Methods
Patients with pT1pT2 or operable pT3, N0-3 invasive breast carcinoma were recruited from 8 centers in Belgium. Fresh surgical samples were sent at room temperature in the MapQuant Dx™ PathKit for centralized genomic analysis. Genomic profiles were determined using Affymetrix U133 Plus 2.0 and GGI calculated using the MapQuant Dx® protocol, which defines tumors as low or high Genomic Grade (GG-1 and GG-3 respectively).Results
180 pts were recruited and 155 were eligible. The MapQuant test was performed in 142 cases and GGI was obtained in 78% of cases (n=111). Reasons for failures were 15 samples with <30% of invasive tumor cells (11%), 15 with insufficient RNA quality (10%), and 1 failed hybridization (<1%). For tumors with an available representative sample (≥ 30% inv. tumor cells) (n=127), the success rate was 87.5%. GGI reclassified 69% of the 54 HG2 tumors as GG-1 (54%) or GG-3 (46%). Changes in treatment recommendations occurred mainly in the subset of HG2 tumors reclassified into GG-3, with increased use of chemotherapy in this subset.Conclusion
The use of GGI is feasible in routine clinical practice and impacts treatment decisions in early-stage breast cancer.Trial Registration
ClinicalTrials.gov , NCT01916837http://clinicaltrials.gov/ct2/show/ NCT01916837 相似文献18.
Eric D. Bateman Kenneth R. Chapman Dave Singh Anthony D. D’Urzo Eduard Molins Anne Leselbaum Esther Garcia Gil 《Respiratory research》2015,16(1)
Background
The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT).Methods
Patients ≥40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1 ≥30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg, aclidinium 400 μg, formoterol 12 μg or placebo via Genuair™/Pressair®. Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed.Results
The pooled intent-to-treat population included 3394 patients. Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p < 0.05). Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies (all p < 0.05). The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo (p < 0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo (p < 0.01) and aclidinium (p < 0.05). Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo (all p < 0.05) but not the monotherapies. Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium (p < 0.01).Conclusions
Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD. Furthermore, aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo.Trial registration
and NCT01462942 (ClinicalTrials.gov) NCT01437397Electronic supplementary material
The online version of this article (doi:10.1186/s12931-015-0250-2) contains supplementary material, which is available to authorized users. 相似文献19.
DNA polymerases (Pols) ε and δ perform the bulk of yeast leading- and lagging-strand DNA synthesis. Both Pols possess intrinsic proofreading exonucleases that edit errors during polymerization. Rare errors that elude proofreading are extended into duplex DNA and excised by the mismatch repair (MMR) system. Strains that lack Pol proofreading or MMR exhibit a 10- to 100-fold increase in spontaneous mutation rate (mutator phenotype), and inactivation of both Pol δ proofreading (pol3-01) and MMR is lethal due to replication error-induced extinction (EEX). It is unclear whether a similar synthetic lethal relationship exists between defects in Pol ε proofreading (pol2-4) and MMR. Using a plasmid-shuffling strategy in haploid Saccharomyces cerevisiae, we observed synthetic lethality of pol2-4 with alleles that completely abrogate MMR (msh2Δ, mlh1Δ, msh3Δ msh6Δ, or pms1Δ mlh3Δ) but not with partial MMR loss (msh3Δ, msh6Δ, pms1Δ, or mlh3Δ), indicating that high levels of unrepaired Pol ε errors drive extinction. However, variants that escape this error-induced extinction (eex mutants) frequently emerged. Five percent of pol2-4 msh2Δ eex mutants encoded second-site changes in Pol ε that reduced the pol2-4 mutator phenotype between 3- and 23-fold. The remaining eex alleles were extragenic to pol2-4. The locations of antimutator amino-acid changes in Pol ε and their effects on mutation spectra suggest multiple mechanisms of mutator suppression. Our data indicate that unrepaired leading- and lagging-strand polymerase errors drive extinction within a few cell divisions and suggest that there are polymerase-specific pathways of mutator suppression. The prevalence of suppressors extragenic to the Pol ε gene suggests that factors in addition to proofreading and MMR influence leading-strand DNA replication fidelity. 相似文献
20.
Daniel H. Johnson Deborah Sutherland Edward P. Acosta Husamettin Erdem Danielle Richardson David W. Haas 《PloS one》2013,8(12)