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1.
Background
Egg-laying behavior in the nematode C. elegans displays a distinct clustered temporal pattern: egg-laying events occur primarily in bursts or active phases, separated by inactive phases during which eggs are retained. The onset of the active phase can be modeled as a Poisson process with a time constant of approximately 20 minutes, while egg-laying events within an active phase occur with a faster time constant of approximately 20 seconds. Here we propose a cellular model for how the temporal pattern of egg-laying might be generated, based on genetic and cell-biological experiments and statistical analyses. 相似文献2.
Background
Exon skipping oligonucleotides (ESOs) of 2'O-Methyl (2'OMe) and morpholino chemistry have been shown to restore dystrophin expression in muscle fibers from the mdx mouse, and are currently being tested in phase I clinical trials for Duchenne Muscular Dystrophy (DMD). However, ESOs remain limited in their effectiveness because of an inadequate delivery profile. Synthetic cationic copolymers of poly(ethylene imine) (PEI) and poly(ethylene glycol) (PEG) are regarded as effective agents for enhanced delivery of nucleic acids in various applications. 相似文献3.
Background
For a clinical trials unit to run its first model-based, phase I trial, the statistician, chief investigator, and trial manager must all acquire a new set of skills. These trials also require a different approach to funding and data collection.Challenges and discussion
From the statisticians’ viewpoint, we highlight what is needed to move from running rule-based, early-phase trials to running a model-based phase I study as we experienced it in our trials unit located in the United Kingdom. Our example is CHARIOT, a dose-finding trial using the time-to-event continual reassessment method. It consists of three stages and aims to discover the maximum tolerated dose of the combination of radiotherapy, chemotherapy, and the ataxia telangiectasia mutated Rad3-related inhibitor M6620 (previously known as VX-970) in patients with oesophageal cancer. We present the challenges we faced in designing this trial and how we overcame them as a way of demystifying the conduct of a model-based trial in a grant-funded clinical trials unit.Conclusions
Although we appreciate that undertaking model-based trials requires additional time and effort, they are feasible to implement and, once suitable tools such as guiding publications and document templates become available, the design and set-up process will be easier and more efficient.4.
J Geoffrey Chase Fatanah Suhaimi Sophie Penning Jean-Charles Preiser Aaron J Le Compte Jessica Lin Christopher G Pretty Geoffrey M Shaw Katherine T Moorhead Thomas Desaive 《Biomedical engineering online》2010,9(1):84
Background
In-silico virtual patients and trials offer significant advantages in cost, time and safety for designing effective tight glycemic control (TGC) protocols. However, no such method has fully validated the independence of virtual patients (or resulting clinical trial predictions) from the data used to create them. This study uses matched cohorts from a TGC clinical trial to validate virtual patients and in-silico virtual trial models and methods. 相似文献5.
Frank Peters-Klimm Stephen Campbell Thomas Müller-Tasch Dieter Schellberg Goetz Gelbrich Wolfgang Herzog Joachim Szecsenyi 《Trials》2009,10(1):1-16
Background
The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases.Methods
STAMPEDE is an open-label, 5-stage, 6-arm randomised controlled trial using MAMS methodology for men with prostate cancer. It is the first trial of this design to use multiple arms and stages synchronously.Results
The practical and statistical issues faced by STAMPEDE in implementing MAMS methodology are discussed and contrasted with those for traditional trials. These issues include the choice of intermediate and final outcome measures, sample size calculations and the impact of varying the assumptions, the process for moving between trial stages, stopping accrual to each trial arm and overall, and issues around perceived trial complexity.Conclusion
It is possible to use the MAMS design to initiate and undertake large scale cancer trials. The results from STAMPEDE will not be known for some years but the lessons learned from running a MAMS trial are shared in the hope that other researchers will use this exciting and efficient method to perform further randomised controlled trials.Trial registration
ISRCTN78818544, NCT00268476 相似文献6.
Flandre P 《PloS one》2011,6(9):e22871
Background
In recent years the “noninferiority” trial has emerged as the new standard design for HIV drug development among antiretroviral patients often with a primary endpoint based on the difference in success rates between the two treatment groups. Different statistical methods have been introduced to provide confidence intervals for that difference. The main objective is to investigate whether the choice of the statistical method changes the conclusion of the trials.Methods
We presented 11 trials published in 2010 using a difference in proportions as the primary endpoint. In these trials, 5 different statistical methods have been used to estimate such confidence intervals. The five methods are described and applied to data from the 11 trials. The noninferiority of the new treatment is not demonstrated if the prespecified noninferiority margin it includes in the confidence interval of the treatment difference.Results
Results indicated that confidence intervals can be quite different according to the method used. In many situations, however, conclusions of the trials are not altered because point estimates of the treatment difference were too far from the prespecified noninferiority margins. Nevertheless, in few trials the use of different statistical methods led to different conclusions. In particular the use of “exact” methods can be very confusing.Conclusion
Statistical methods used to estimate confidence intervals in noninferiority trials have a strong impact on the conclusion of such trials. 相似文献7.
Guojian Liao Jine Li Lei Li Haihua Yang Yuqing Tian Huarong Tan 《Microbial cell factories》2010,9(1):6
Background
Nikkomycins are a group of peptidyl nucleoside antibiotics produced by Streptomyces ansochromogenes. They are competitive inhibitors of chitin synthase and show potent fungicidal, insecticidal, and acaricidal activities. Nikkomycin X and Z are the main components produced by S. ansochromogenes. Generation of a high-producing strain is crucial to scale up nikkomycins production for further clinical trials. 相似文献8.
Jingming Ma Carrie Dykes Tao Wu Yangxin Huang Lisa Demeter Hulin Wu 《BMC bioinformatics》2010,11(1):261
Background
The replication rate (or fitness) between viral variants has been investigated in vivo and in vitro for human immunodeficiency virus (HIV). HIV fitness plays an important role in the development and persistence of drug resistance. The accurate estimation of viral fitness relies on complicated computations based on statistical methods. This calls for tools that are easy to access and intuitive to use for various experiments of viral fitness. 相似文献9.
Federica Volontè Loredano Pollegioni Gianluca Molla Luca Frattini Flavia Marinelli Luciano Piubelli 《BMC biotechnology》2010,10(1):33
Background
Cholesterol oxidase is an alcohol dehydrogenase/oxidase flavoprotein that catalyzes the dehydrogenation of C(3)-OH of cholesterol. It has two major biotechnological applications, i.e. in the determination of serum (and food) cholesterol levels and as biocatalyst providing valuable intermediates for industrial steroid drug production. Cholesterol oxidases of type I are those containing the FAD cofactor tightly but not covalently bound to the protein moiety, whereas type II members contain covalently bound FAD. This is the first report on the over-expression in Escherichia coli of type II cholesterol oxidase from Brevibacterium sterolicum (BCO). 相似文献10.
Cristina Firanescu Paul NM Lohle Jolanda de Vries Caroline A Klazen Job R Juttmann William Clark Willem Jan van Rooij 《Trials》2011,12(1):1-5
Background
Combination of erlotinib and bevacizumab is a promising regimen in advanced non-squamous non-small-cell lung cancer (NSCLC). We are conducting a single arm phase II trial which aims to evaluate the efficacy and safety of this regime as a second- or third-line chemotherapy.Methods
Key eligibility criteria were histologically or cytologically confirmed non-squamous NSCLC, stage III/IV or recurrent NSCLC not indicated radical chemoradiation, prior one or two regimen of chemotherapy, age 20 years or more, and performance status of two or less. The primary endpoint is objective response rate. The secondary endpoints include overall survival, progression-free survival, disease control rate and incidence of adverse events. This trial plans to accrue 80 patients based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35% and a null hypothesis threshold response rate of 20%. A subset analysis according to EGFR mutation status is planned.Discussion
We have presented the design of a single arm phase II trial to evaluate the efficacy and safety of combination of bevacizumab and erlotinib in advanced non-squamous NSCLC patients. In particular we are interested in determining the merit of further development of this regimen and whether prospective patient selection using EGFR gene is necessary in future trials.Trial registration
This trial was registered at the UMIN Clinical Trials Registry as UMIN000004255 (http://www.umin.ac.jp/ctr/index.htm). 相似文献11.
Background
Recent circadian clock studies using gene expression microarray in two different tissues of mouse have revealed not all circadian-related genes are synchronized in phase or peak expression times across tissues in vivo. Instead, some circadian-related genes may be delayed by 4–8 hrs in peak expression in one tissue relative to the other. These interesting biological observations prompt a statistical question regarding how to distinguish the synchronized genes from genes that are systematically lagged in phase/peak expression time across two tissues. 相似文献12.
Background
Most differentiating cells are arrested in G1-phase of the cell cycle and this proliferative quiescence appears important to allow differentiation programmes to be executed. An example occurs in the Drosophila eye imaginal disc, where all cells are synchronized and arrested in G1 phase prior to making a fate choice either to initiate the first round of photoreceptor differentiation or to re-enter one terminal mitosis. 相似文献13.
Donald A Yergeau Clair M Kelley Emin Kuliyev Haiqing Zhu Amy K Sater Dan E Wells Paul E Mead 《BMC developmental biology》2010,10(1):11
Background
The Class II DNA transposons are mobile genetic elements that move DNA sequence from one position in the genome to another. We have previously demonstrated that the naturally occurring Tol2 element from Oryzias latipes efficiently integrates its corresponding non-autonomous transposable element into the genome of the diploid frog, Xenopus tropicalis. Tol2 transposons are stable in the frog genome and are transmitted to the offspring at the expected Mendelian frequency. 相似文献14.
15.
Beneficial effect of Burdock complex on asymptomatic Helicobacter pylori‐infected subjects: A randomized,double‐blind placebo‐controlled clinical trial
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Chi‐Hua Yen Hui‐Fang Chiu Su‐Yu Huang Yan‐Ying Lu Yi‐Chun Han You‐Cheng Shen Kamesh Venkatakrishnan Chin‐Kun Wang 《Helicobacter》2018,23(3)
Background
Burdock complex (BC) constitutes of burdock (Arctium lappa), angelica (Angelica sinensis), gromwell (Lithospermum erythrorhizon), and sesame (Sesamum indicum) oil, which are commonly used in traditional Chinese medicine (TCM) for treating various disorders. This study intended to examine the anti‐H. pylori activity of BC on AGS cell model as well as in asymptomatic H. pylori‐infected subjects.Materials and Methods
AGS cell incubated with H. pylori and treated with BC to evaluate the minimum inhibition concentration (MIC), cell viability (MTT) anti‐adhesion activity, and inflammatory markers. In case of clinical trial, H. pylori‐positive subjects (urea breath test [UBT] >10%, n = 36) were enrolled and requested to intake BC (n = 19) or placebo (n = 17) for 8 weeks. Antioxidant capacity, total phenol, UBT, inflammatory markers were analyzed at the initial, 4th, 8th, and 10th weeks. Moreover, the endoscopic examination was carried out on baseline and 10th week.Results
In vitro studies showed that BC treatment significantly inhibited (P < .05) the inflammatory markers and adhesion of H. pylori to AGS cell. However, H. pylori‐infected subject ingested with BC for 8 weeks significantly decreased (P < .05) the UBT value, inflammatory markers with improved antioxidant activity, and phenolic levels as compared to placebo. Also, consumption of BC considerably healed the ulcer wound.Conclusion
Overall, the BC could attenuate H. pylori infection by inhibiting H. pylori adhesion and subsequent inflammatory response on the gastric epithelial cell (AGS) as well as clinically ameliorated UBT, antioxidant capacity, and alleviated inflammation to display its anti‐H. pylori activity. 相似文献16.
Jerzy Wielbo Dominika Kidaj Piotr Koper Agnieszka Kubik-Komar Anna Skorupska 《Central European Journal of Biology》2012,7(1):13-24
Background
Rhizobium leguminosarum bv. viciae (Rlv) is a soil bacterium which can form nitrogen-fixing symbiotic relationships with leguminous plants. Numerous rhizobial strains found in soils compete with each other. Competition can occur both during the saprophytic growth phase in the rhizosphere and inside plant tissues, during the symbiotic phase. Competition is important as it may affect the composition of rhizobial populations present in the soil and in the root nodules of plants. 相似文献17.
Thomas M. Lampinen Keith Chan Robert S. Remis Maraki Fikre Merid Melanie Rusch Jean Vincelette Ken Logue Vladimir Popovic Michel Alary Martin T. Schechter Robert S. Hogg 《CMAJ》2005,172(4):479-483
Background
Phase I and phase II HIV-1 vaccine trials have revealed increases in risky sexual activity among study subjects during the trials, perhaps because the subjects believe that the vaccine being tested is efficacious; subjects may thus suffer harm from their participation. We evaluated the sexual behaviour of Canadian men who have sex with men (MSM) who participated in the phase III Vax004 trial of an HIV-1 vaccine.Methods
Using self-reports of sexual behaviours during the 6 months before trial entry as a baseline, we determined changes in reported sexual behaviour after 6, 12 and 18 months of participation in the trial.Results
Of 291 HIV-seronegative MSM enrolled from July to October 1999, 260 (89%) completed 18 months of follow-up, 19 (7%) experienced seroconversion, and 12 (4%) did not complete follow-up. Unprotected receptive anal intercourse during the previous 6 months with partners whose HIV-1 serostatus was positive or unknown was reported by 21% of men at enrolment and by 27% at any point during 18 months of follow-up. No increase in this behaviour from baseline was reported by participants, including among men who were motivated to enrol because of expected protection from HIV-1 infection, men who believed they had received the vaccine, men who believed that the vaccine had greater than 50% efficacy, or men who believed that they had received the vaccine and that vaccine efficacy was greater than 50%.Interpretation
MSM can be successfully enrolled in HIV-1 vaccine efficacy trials without evident increases in those sexual behaviours most associated with HIV-1 risk.Development of preventive HIV-1 vaccines requires clinical trials that effectively recruit, enrol and retain high-risk subjects, including men who have sex with men (MSM). Since candidate vaccines may prove to have little or no efficacy, these trials must also strive to minimize harms associated with participation. A major concern has been that trial participants might believe vaccination affords some protection and therefore increase their sexual risk-taking.1,2 This concern derives in part from increases in unprotected anal intercourse observed during phase I and phase II vaccine trials. For example, self-reports of unprotected insertive anal intercourse during the previous 6 months increased among 44 gay men enrolled in San Francisco trials, from 9% at enrolment to 20% at the 12-month assessment; however, the HIV status of sexual partners was not assessed.1 The world''s first phase III trial to evaluate a candidate preventive HIV-1 vaccine was recently completed in North America and Europe.2 A consortium sponsored by the Canadian Network for Vaccines and Immunotherapeutics of Cancer and Chronic Viral Diseases (CANVAC) was formed to assess participation, retention and change in sexual risk behaviour at trial sites in this country. We report here the Canadian experience in this trial through 18 months of follow-up and assess trends in high-risk sexual behaviour reported by participants. 相似文献18.
Background
The origin of vertebrate retroviruses (Retroviridae) is yet to be thoroughly investigated, but due to their similarity and identical gag-pol (and env) genome structure, it is accepted that they evolve from Ty3/Gypsy LTR retroelements the retrotransposons and retroviruses of plants, fungi and animals. These 2 groups of LTR retroelements code for 3 proteins rarely studied due to the high variability – gag polyprotein, protease and GPY/F module. In relation to 3 previously proposed Retroviridae classes I, II and II, investigation of the above proteins conclusively uncovers important insights regarding the ancient history of Ty3/Gypsy and Retroviridae LTR retroelements. 相似文献19.
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