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1.
Laura W. Goff Nilay Thakkar Liping Du Emily Chan Benjamin R. Tan Dana B. Cardin Howard L. McLeod Jordan D. Berlin Barbara Zehnbauer Chloe Fournier Joel Picus Andrea Wang-Gillam Wooin Lee A. Craig Lockhart 《PloS one》2014,9(9)
Background
Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking.Methods
In this phase II study ( registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/ NCT00515216), patients with “good risk” TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%). NCT00515216Results
The ORR in genotype-selected patients was 39.1% (9 partial responses out of 23 evaluable patients, 95% CI, 22.2 to 59.2), not achieving the primary objective of improving ORR. An encouraging disease control rate (DCR, consisting of partial responses and stable diseases) of 95.7% was noted and patients with homozygous TSER*2 genotype showed better tumor response.Conclusions
In this first prospective, multi-institutional study in patients with gastric or GEJ cancers, selecting patients with at least one TSER*2 allele did not improve the ORR but led to an encouraging DCR. Further studies are needed to investigate the utility of selecting patients homozygous for the TSER*2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers.Trial Registration
ClinicalTrials.gov NCT00515216相似文献2.
Background
There are little data about adverse effects and immunogenicity of flu vaccine in Asian pregnant women.Methods
This prospective trial () enrolled 46 pregnant women who received a single intramuscular dose of trivalent flu vaccine (AdimFlu-S®) containing 15 mcg of hemagglutinin for each strain/0.5 mL from influenza A (H1N1), influenza A (H3N2), and influenza B after the first trimester. Blood samples were collected at day 0 and 28 after vaccination, and at delivery. Cord blood was also collected. Hemagglutination inhibition (HAI) assays were performed to determine seroprotection and seroconversion rates and fold increase in the HAI geometric mean titer (GMT). NCT01514708Results
Twenty-eight days after vaccination the seroprotection rate against H1N1, H3N2, and influenza B was 91.3%, 84.8% and 56.5%, respectively. The GMT fold increase was 12.8, 8.4, and 4.6 for H1N1, H3N2, and influenza B, respectively. At delivery, both the seroprotection rate (86.4%, 68.2%, and 47.7%) and GMT fold increase (9.4, 5.7 and 3.8) were slightly lower than day 28. The seroprotection rate and GMT fold increase in maternal and cord blood samples were comparable. No significant adverse effects were detected.Conclusions
Trivalent flu vaccine induces a strong immune response in pregnant women and their infants without adverse effects.Trial Registration
Clinical Trials. gov NCT01514708相似文献3.
Bego?a Comin-Anduix Hooman Sazegar Thinle Chodon Douglas Matsunaga Jason Jalil Erika von Euw Helena Escuin-Ordinas Robert Balderas Bartosz Chmielowski Jesus Gomez-Navarro Richard C. Koya Antoni Ribas 《PloS one》2010,5(9)
Background
The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma.Methodology/Principal
Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response.Conclusions/Significance
The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade.Clinical Trial Registration
clinicaltrials.gov; Registration numbers and NCT00090896 NCT00471887相似文献4.
Ishani Ganguli Jamie E. Collins William M. Reichmann Elena Losina Jeffrey N. Katz Christian Arbelaez Laurel A. Donnell-Fink Rochelle P. Walensky 《PloS one》2013,8(1)
Background
HIV infection remains a major US public health concern. While HIV-infected individuals now benefit from earlier diagnosis and improved treatment options, progress is tempered by large numbers of newly diagnosed patients who are lost to follow-up prior to disease confirmation and linkage to care.Methodology
In the randomized, controlled USHER trial, we offered rapid HIV tests to patients presenting to a Boston, MA emergency department. Separate written informed consent was required for confirmatory testing. In a secondary analysis, we compared participants with reactive results who did and did not complete confirmatory testing to identify factors associated with refusal to complete the confirmation protocol.Principal Findings
Thirteen of 62 (21.0%, 95% CI (11.7%, 33.2%)) participants with reactive rapid HIV tests refused confirmation; women, younger participants, African Americans, and those with fewer HIV risks, with lower income, and without primary care doctors were more likely to refuse. We projected that up to four true HIV cases were lost at the confirmation stage.Conclusions
These findings underscore the need to better understand the factors associated with refusal to confirm reactive HIV testing and to identify interventions that will facilitate confirmatory testing and linkage to care among these populations.Trial Registration
ClinicalTrials.gov ; NCT00502944. NCT01258582相似文献5.
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6.
Jaime Altcheh Guillermo Moscatelli Guido Mastrantonio Samanta Moroni Norberto Giglio Maria Elena Marson Griselda Ballering Margarita Bisio Gideon Koren Facundo García-Bournissen 《PLoS neglected tropical diseases》2014,8(5)
Introduction
Chagas disease, caused by the parasite Trypanosoma cruzi, can lead to long term cardiac morbidity. Treatment of children with benznidazole is effective, but no pediatric pharmacokinetics data are available and clinical pharmacology information on the drug is scarce.Patients and Methods
Prospective population pharmacokinetic (PK) cohort study in children 2–12 years old with Chagas disease treated with oral benznidazole 5–8 mg/kg/day BID for 60 days. (clinicaltrials.gov #). NCT00699387Results
Forty children were enrolled in the study. Mean age was 7.3 years. A total of 117 samples were obtained from 38 patients for PK analysis. A one compartment model best fit the data. Weight-corrected clearance rate (CL/F) showed a good correlation with age, with younger patients having a significantly higher CL/F than older children and adults. Simulated median steady-state benznidazole concentrations, based on model parameters, were lower for children in our study than for adults and lowest for children under 7 years of age. Treatment was efficacious in the 37 patients who completed the treatment course, and well tolerated, with few, and mild, adverse drug reactions (ADRs).Discussion
Observed benznidazole plasma concentrations in children were markedly lower than those previously reported in adults (treated with comparable mg/kg doses), possibly due to a higher CL/F in smaller children. These lower blood concentrations were nevertheless associated to a high therapeutic response in our cohort. Unlike adults, children have few adverse reactions to the drug, suggesting that there may be a direct correlation between drug concentrations and incidence of ADRs. Our results suggest that studies with lower doses in adults may be warranted.Trial Registration
ClinicalTrails.gov NCT00699387相似文献7.
Roberto Esposito Franco Cilli Valentina Pieramico Antonio Ferretti Antonella Macchia Marco Tommasi Aristide Saggino Domenico Ciavardelli Antonietta Manna Riccardo Navarra Filippo Cieri Liborio Stuppia Armando Tartaro Stefano L. Sensi 《PloS one》2013,8(7)
Background
There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects.Methodology
A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances with the Raven’s Advanced Progressive Matrices II set (APM) before and three hours after administration of drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; ; http://clinicaltrials.gov/ct2/show/ NCT01684306. NCT01684306Principal Findings
Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs-fMRI showed that the drug produces a statistically significant increased activation of Frontal Parietal Control (FPC; p<0.04) and Dorsal Attention (DAN; p<0.04) networks. No modifications in structural connectivity were observed.Conclusions and Significance
Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these effects.Trial Registration
ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/ NCT01684306. NCT01684306相似文献8.
《PloS one》2013,8(3)
Background
Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI).Methodology
We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns.Results
ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC).Conclusions
ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted.Trial Registration
Pactr.org PACTR2010020001771828 http://www.pactr.org/ Pactr.org PACTR201008000221638 http://www.pactr.org/ ClinicalTrials.gov NCT01373879 ClinicalTrials.gov NCT01373879 NCT01379430 NCT01379430相似文献9.
Chen Wang Zhenguo Zhai Yuanhua Yang Yadong Yuan Zhaozhong Cheng Lirong Liang Huaping Dai Kewu Huang Weixuan Lu Zhonghe Zhang Xiansheng Cheng Ying H Shen China Venous Thromboembolism Study Group 《Respiratory research》2009,10(1):128
Backgrounds
Urokinase (UK) 2 200 U/kg·h for 12 hours infusion(UK-12 h)is an ACCP recommended regimen in treating acute pulmonary embolism (PE). It is unclear whether this dose and time can be reduced further. We compared the efficacy and safety of 20, 000 U/kg for 2 hours (UK-2 h) with the UK-12 h regime in selected PE patients.Methods
A randomized trial involving 129 patients was conducted. Patients with acute PE were randomly assigned to receive either UK-12 h (n = 70), or UK-2 h (n = 59). The efficacy was determined by the improvement of right heart dysfunction and perfusion defect at 24 h and 14 d post UK treatment. The bleeding incidence, death rate and PE recurrence were also evaluated.Results
Similarly significant improvements in right heart dysfunction and lung perfusion defects were observed in both groups. Overall bleeding incidents were low in both groups. Major bleeding directly associated with UK infusion occurred in one patient in the UK-2 h group and one in the UK-12 h group. Mortality rates were low, with one reported fatal recurrent in the UK-12 h group and none in the UK-2 h group. When the rate of bleeding, death and PE recurrence were compared separately in the hemodynamic instability and the massive anatomic obstruction subgroups, no significant difference was found.Conclusions
The UK-2 h regimen exhibits similar efficacy and safety as the UK-12 h regimen for acute PE.Trial Registration
Clinical trial registered with http://clinicaltrials.gov/ct2/show/ (Identifier: NCT00799968) NCT 00799968相似文献10.
11.
Uzma N. Sarwar Laura Novik Mary E. Enama Sarah A. Plummer Richard A. Koup Martha C. Nason Robert T. Bailer Adrian B. McDermott Mario Roederer John R. Mascola Julie E. Ledgerwood Barney S. Graham the VRC study team 《PloS one》2014,9(9)
Background
Needle-free delivery improves the immunogenicity of DNA vaccines but is also associated with more local reactogenicity. Here we report the first comparison of Biojector and needle administration of a candidate rAd5 HIV vaccine.Methods
Thirty-one adults, 18–55 years, 20 naive and 11 prior rAd5 vaccine recipients were randomized to receive single rAd5 vaccine via needle or Biojector IM injection at 1010 PU in a Phase I open label clinical trial. Solicited reactogenicity was collected for 5 days; clinical safety and immunogenicity follow-up was continued for 24 weeks.Results
Overall, injections by either method were well tolerated. There were no serious adverse events. Frequency of any local reactogenicity was 16/16 (100%) for Biojector compared to 11/15 (73%) for needle injections. There was no difference in HIV Env-specific antibody response between Biojector and needle delivery. Env-specific antibody responses were more than 10-fold higher in subjects receiving a booster dose of rAd5 vaccine than after a single dose delivered by either method regardless of interval between prime and boost.Conclusions
Biojector delivery did not improve antibody responses to the rAd5 vaccine compared to needle administration. Homologous boosting with rAd5 gene-based vectors can boost insert-specific antibody responses despite pre-existing vector-specific immunity.Trial Registration
Clinicaltrials.gov NCT00709605 NCT00709605相似文献12.
Mayu O. Frank Julia Kaufman Suyan Tian Mayte Suárez-Fari?as Salina Parveen Nathalie E. Blachère Michael J. Morris Susan Slovin Howard I. Scher Matthew L. Albert Robert B. Darnell 《PloS one》2010,5(9)
Background
Studies of patients with paraneoplastic neurologic disorders (PND) have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC) vaccine.Methods and Findings
We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH) responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002), decrease in prostate specific antigen (PSA) slope (p = 0.016), and a two-fold increase in PSA doubling time (p = 0.003) were identified when we compared data before and after vaccination.Conclusions
An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine. (ClinicalTrials.gov number ). NCT00289341Trial Registration
ClinicalTrials.gov NCT00289341相似文献13.
Rajkumar Venkatramani Marcio Malogolowkin Tom B. Davidson William May Richard Sposto Leo Mascarenhas 《PloS one》2013,8(7)
Background
To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of irinotecan administered in combination with vincristine, temozolomide and bevacizumab in children with refractory solid tumors.Methods
The study design included two dose levels (DL) of irinotecan given intravenously once daily for 5 consecutive days (DL1: 30 mg/m2, and DL2: 50 mg/m2), combined with vincristine 1.5 mg/m2 on days 1 and 8, temozolomide 100 mg/m2 on days 1-5, and bevacizumab 15mg/kg on day 1, administered every 21 days for a maximum of 12 cycles.Results
Thirteen patients were enrolled and 12 were evaluable for toxicity Dose limiting toxicity observed included grade 3 hyperbilirubinemia in 1 of 6 patients on DL1, and grade 3 colitis in 1 of 6 patients on DL2. DL 2 was the determined MTD. A total of 87 cycles were administered. Myelosuppression was mild. Grade 1-2 diarrhea occurred in the majority of cycles with grade 3 diarrhea occurring in only one cycle. Grade 2 hypertension developed in two patients. Severe hemorrhage, intestinal perforation, posterior leukoencephalopathy or growth plate abnormalities were not observed. Objective responses were noted in three Wilms tumor patients and one each of medulloblastoma and hepatocellular carcinoma. Five patients completed all 12 cycles of protocol therapy.Conclusions
Irinotecan 50 mg/m2/day for 5 days was the MTD when combined with vincristine, temozolomide and bevacizumab administered on a 21 day schedule. Encouraging anti-tumor activity was noted.Trial Registration
ClinicalTrials.gov; ; http://clinicaltrials.gov/show/ NCT00993044 NCT00993044相似文献14.
Background
Today, a large proportion of early abortions are medical terminations, in accordance to the woman''s choice. Intrauterine contraceptives (IUC) provide highly effective, reversible, long-acting contraception. However, the effects of timing of IUC insertion after medical abortion are not known.Methods
Women undergoing medical abortion with mifepristone and misoprostol up to 63 days gestation and opting for IUC were randomised to early insertion (day 5–9 after mifepristone) or delayed (routine) insertion (at 3–4 weeks after mifepristone). The primary outcome was the rate of IUC expulsion at six months after IUC insertion.Results
A total of 129 women were randomized, and 116 women had a successful IUC insertion. There was no difference in expulsion rate between early (9.7%) vs. delayed (7.4%) IUC insertion (risk difference −9.2–13.4). Furthermore, 1.5% of women randomized to early and 11.5% to delayed insertion did not attend the follow up (proportion difference 10.0%, 95% CI: 1.8–20.6%, p = 0.015), and a higher proportion of women (41%) had had unprotected intercourse prior to returning for insertion in the delayed group compared with the early group (16%) (p = 0.015). Adverse events were rare and did not differ between the groups.Conclusions
Early insertion of IUC after medical abortion was safe and well tolerated with no increased incidence for expulsions or complications. Women were more likely to return for the IUC insertion if scheduled early after the abortion, and less likely to have had an unprotected intercourse prior to the IUC insertion. Early insertion should be offered as a routine for women undergoing first trimester medical abortion.Trial Registration
ClinicalTrials.gov NCT01537562相似文献15.
Gregory M. Lucas Bernadette Anna Mullen Noya Galai Richard D. Moore Katie Cook Mary E. McCaul Sheldon Glass Krisann K. Oursler Cynthia Rand 《PloS one》2013,8(7)
Background
Data regarding the efficacy of directly administered antiretroviral therapy (DAART) are mixed. Opioid treatment programs (OTPs) provide a convenient framework for DAART. In a randomized controlled trial, we compared DAART and self-administered therapy (SAT) among HIV-infected subjects attending five OTPs in Baltimore, MD.Methods
HIV-infected individuals attending OTPs were eligible if they were not taking antiretroviral therapy (ART) or were virologically failing ART at last clinical assessment. In subjects assigned to DAART, we observed one ART dose per weekday at the OTP for up to 12 months. SAT subjects administered ART at home. The primary efficacy comparison was the between-arm difference in the average proportions with HIV RNA <50 copies/mL during the intervention phase (3-, 6-, and 12-month study visits), using a logistic regression model accounting for intra-person correlation due to repeated observations. Adherence was measured with electronic monitors in both arms.Results
We randomized 55 and 52 subjects from five Baltimore OTPs to DAART and SAT, respectively. The average proportions with HIV RNA <50 copies/mL during the intervention phase were 0.51 in DAART and 0.40 in SAT (difference 0.11, 95% CI: −0.020 to 0.24). There were no significant differences between arms in electronically-measured adherence, average CD4 cell increase from baseline, average change in log10 HIV RNA from baseline, opportunistic conditions, hospitalizations, mortality, or the development of new drug resistance mutations.Conclusions
In this randomized trial, we found little evidence that DAART provided clinical benefits compared to SAT among HIV-infected subjects attending OTPs.Trial Registration
ClinicalTrails.gov NCT00279110?term =  NCT00279110&rank = 1 NCT00279110相似文献16.
Paul W Jones James F Donohue Jerry Nedelman Steve Pascoe Gregory Pinault Cheryl Lassen 《Respiratory research》2011,12(1):161
Background
Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV1) are correlated with changes in patient-reported outcomes.Methods
Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George''s Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of ΔFEV1. Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use.Results
With increasing positive ΔFEV1, TDI and ΔSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort-level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV1 was associated with improved TDI (0.46 units), ΔSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between ΔFEV1 and outcomes.Conclusions
These results suggest that larger improvements in FEV1 are likely to be associated with larger patient-reported benefits across a range of clinical outcomes.Trial Registration
ClinicalTrials.gov , NCT00393458, and NCT00463567 NCT00624286相似文献17.
Richard A. Koup Mario Roederer Laurie Lamoreaux Jennifer Fischer Laura Novik Martha C. Nason Brenda D. Larkin Mary E. Enama Julie E. Ledgerwood Robert T. Bailer John R. Mascola Gary J. Nabel Barney S. Graham the VRC VRC Study Teams 《PloS one》2010,5(2)
Background
Induction of HIV-1-specific T-cell responses relevant to diverse subtypes is a major goal of HIV vaccine development. Prime-boost regimens using heterologous gene-based vaccine vectors have induced potent, polyfunctional T cell responses in preclinical studies.Methods
The first opportunity to evaluate the immunogenicity of DNA priming followed by recombinant adenovirus serotype 5 (rAd5) boosting was as open-label rollover trials in subjects who had been enrolled in prior studies of HIV-1 specific DNA vaccines. All subjects underwent apheresis before and after rAd5 boosting to characterize in depth the T cell and antibody response induced by the heterologous DNA/rAd5 prime-boost combination.Results
rAd5 boosting was well-tolerated with no serious adverse events. Compared to DNA or rAd5 vaccine alone, sequential DNA/rAd5 administration induced 7-fold higher magnitude Env-biased HIV-1-specific CD8+ T-cell responses and 100-fold greater antibody titers measured by ELISA. There was no significant neutralizing antibody activity against primary isolates. Vaccine-elicited CD4+ and CD8+ T-cells expressed multiple functions and were predominantly long-term (CD127+) central or effector memory T cells and that persisted in blood for >6 months. Epitopes mapped in Gag and Env demonstrated partial cross-clade recognition.Conclusion
Heterologous prime-boost using vector-based gene delivery of vaccine antigens is a potent immunization strategy for inducing both antibody and T-cell responses.Trial Registration
ClinicalTrails.gov , NCT00102089 NCT00108654相似文献18.
Stephen I Rennard Peter MA Calverley Udo M Goehring Dirk Bredenbr?ker Fernando J Martinez 《Respiratory research》2011,12(1):18
Background
As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further.Methods
The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset.Results
The pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%).Conclusions
This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment.Trials registration
ClinicalTrials.gov identifiers: and NCT00076089. NCT00430729相似文献19.
Ingeborg A. Brouwer Johanna M. Geleijnse Veronique M. Klaasen Liesbeth A. Smit Erik J. Giltay Janette de Goede Annemieke C. Heijboer Daan Kromhout Martijn B. Katan 《PloS one》2013,8(12)
Background
Alpha linolenic acid (ALA) is the major omega-3 fatty acid in the diet. Evidence on health effects of ALA is not conclusive, but some observational studies found an increased risk of prostate cancer with higher intake of ALA. We examined the effect of ALA supplementation on serum concentrations of prostate-specific antigen (PSA), a biomarker for prostate cancer.Methods
The Alpha Omega Trial (ClinicalTrials.gov Identifier: ) was a double-blind, placebo-controlled trial of ALA and the fish fatty acids eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) on the recurrence of cardiovascular disease, using a 2×2 factorial design. Blood was collected at the start and the end of the intervention period. The present analysis included 1622 patients with a history of a myocardial infarction, aged 60–80 years with an initial PSA concentration <4 ng/mL. They received either 2 g per day of ALA or placebo in margarine spreads for 40 months. T-tests and logistic regression were used to assess the effects of ALA supplementation on changes in serum PSA (both continuously and as a dichotomous outcome, cut-off point: >4 ng/mL). NCT00127452Findings
Mean serum PSA increased by 0.42 ng/mL on placebo (n = 815) and by 0.52 ng/mL on ALA (n = 807), a difference of 0.10 (95% confidence interval: −0.02 to 0.22) ng/mL (P = 0·12). The odds ratio for PSA rising above 4 ng/mL on ALA versus placebo was 1.15 (95% CI: 0.84–1.58).Interpretation
An additional amount of 2 g of ALA per day increased PSA by 0.10 ng/mL, but the confidence interval ranged from −0.02 to 0.22 ng/mL and included no effect. Therefore, more studies are needed to establish whether or not ALA intake has a clinically significant effect on PSA or prostate cancer.Trial registration information
ClinicalTrials.gov; Identifier: . URL: http://www.clinicaltrials.gov/ct2/show/ NCT00127452. NCT00127452相似文献20.
Nawar Diar Bakerly Ashley Woodcock John P. New J. Martin Gibson Wei Wu David Leather J?rgen Vestbo 《Respiratory research》2015,16(1)