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931.
Background
The United States (US) Food and Drug Administration (FDA) approves new drugs based on sponsor-submitted clinical trials. The publication status of these trials in the medical literature and factors associated with publication have not been evaluated. We sought to determine the proportion of trials submitted to the FDA in support of newly approved drugs that are published in biomedical journals that a typical clinician, consumer, or policy maker living in the US would reasonably search.Methods and Findings
We conducted a cohort study of trials supporting new drugs approved between 1998 and 2000, as described in FDA medical and statistical review documents and the FDA approved drug label. We determined publication status and time from approval to full publication in the medical literature at 2 and 5 y by searching PubMed and other databases through 01 August 2006. We then evaluated trial characteristics associated with publication. We identified 909 trials supporting 90 approved drugs in the FDA reviews, of which 43% (394/909) were published. Among the subset of trials described in the FDA-approved drug label and classified as “pivotal trials” for our analysis, 76% (257/340) were published. In multivariable logistic regression for all trials 5 y postapproval, likelihood of publication correlated with statistically significant results (odds ratio [OR] 3.03, 95% confidence interval [CI] 1.78–5.17); larger sample sizes (OR 1.33 per 2-fold increase in sample size, 95% CI 1.17–1.52); and pivotal status (OR 5.31, 95% CI 3.30–8.55). In multivariable logistic regression for only the pivotal trials 5 y postapproval, likelihood of publication correlated with statistically significant results (OR 2.96, 95% CI 1.24–7.06) and larger sample sizes (OR 1.47 per 2-fold increase in sample size, 95% CI 1.15–1.88). Statistically significant results and larger sample sizes were also predictive of publication at 2 y postapproval and in multivariable Cox proportional models for all trials and the subset of pivotal trials.Conclusions
Over half of all supporting trials for FDA-approved drugs remained unpublished ≥ 5 y after approval. Pivotal trials and trials with statistically significant results and larger sample sizes are more likely to be published. Selective reporting of trial results exists for commonly marketed drugs. Our data provide a baseline for evaluating publication bias as the new FDA Amendments Act comes into force mandating basic results reporting of clinical trials. 相似文献932.
de Aquino TM Liesen AP da Silva RE Lima VT Carvalho CS de Faria AR de Araújo JM de Lima JG Alves AJ de Melo EJ Góes AJ 《Bioorganic & medicinal chemistry》2008,16(1):446-456
In the present communication, a new series of 2-[(phenylmethylene)hydrazono]-4-oxo-3-phenyl-5-thiazolidineacetic acids (2a-p) have been synthesized. Benzaldehyde 4-phenyl-3-thiosemicarbazones substituted (1a-p) were also obtained and used as intermediate to give the title compounds. All synthesized compounds were characterized by IR, (1)H and (13)C NMR. The in vitro anti-Toxoplasma gondii activity of 1a-p and 2a-p was evaluated. The 4-thiazolidinones (2a-p) were screened for their in vitro antimicrobial activity. For anti-Toxoplasma gondii activity, in general, all compounds promoted decreases in the percentage of infected cells leading to parasite elimination. These effects on intracellular parasites also caused a decrease in the mean number of tachyzoites. In addition, most of the 4-thiazolidinones showed more effective toxicity against intracellular parasites, with IC(50) values ranging from 0.05 to 1 mM. According to results of antimicrobial activity, compounds 2f, 2l, and 2p showed best activity against Mycobacterium luteus, 2c was more active against Mycobacterium tuberculosis, and 2g, 2l, and 2n showed same activity as nistatin (standard drug) against Candida sp. (4249). 相似文献
933.
Goeminne A Berg M McNaughton M Bal G Surpateanu G Van der Veken P De Prol S Versées W Steyaert J Haemers A Augustyns K 《Bioorganic & medicinal chemistry》2008,16(14):6752-6763
A key enzyme within the purine salvage pathway of parasites, nucleoside hydrolase, is proposed as a good target for new antiparasitic drugs. We have developed N-arylmethyl-iminoribitol derivatives as a novel class of inhibitors against a purine specific nucleoside hydrolase from Trypanosoma vivax. Several of our inhibitors exhibited low nanomolar activity, with 1,4-dideoxy-1,4-imino-N-(8-quinolinyl)methyl-d-ribitol (UAMC-00115, K(i) 10.8nM), N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.1nM), and N-(9-deazahypoxanthin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.4nM) being the three most active compounds. Docking studies of the most active inhibitors revealed several important interactions with the enzyme. Among these interactions are aromatic stacking of the nucleobase mimic with two Trp-residues, and hydrogen bonds between the hydroxyl groups of the inhibitors and amino acid residues in the active site. During the course of these docking studies we also identified a strong interaction between the Asp40 residue from the enzyme and the inhibitor. This is an interaction which has not previously been considered as being important. 相似文献
934.
935.
Phenotypic subtypes of acute lymphoblastic leukemia associated with different nuclear chromatin texture 总被引:1,自引:0,他引:1
Mello MR Metze K Adam RL Pereira FG Magalhães MG Machado CG Lorand-Metze I 《Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology》2008,30(2):92-98
OBJECTIVE: To determine if phenotypic subtypes of acute lymphoblastic leukemia (ALL) are associated with different nuclear textures. STUDY DESIGN: In 49 newly diagnosed patients, diagnostic work-up was made by routinely Giemsa-stained smears and immunophenotyping. B-precursor ALL was further subdivided by European Group for the Immunological Classification of Leukemias criteria. T-ALL was analyzed as a whole group. One hundred nuclear images were acquired; standard morphometric variables and texture features derived from the co-occurrence matrix were calculated. RESULTS: In T-ALL, nuclei presented higher mean and minimal gray levels and higher local homogeneity and angular second moment but lower entropy values, contrast, diagonal moment and cluster prominence than did nuclei in B-derived ALL. In T-ALL, peripheral blood (PB) leukocyte count showed significant positive correlation with minimal gray level and inverse correlation with nuclear area. In B-ALL, peripheral leukocyte count showed positive correlation with mean fluorescence intensity of CD45. In T-ALL but not in B-ALL, inverse correlation existed among age and PB leukocyte count and mean gray levels, and direct correlation existed with nuclear area and mean optical density. CONCLUSION: ALL of B- or T-origin presented significant differences in nuclear texture features, probably reflecting different molecular events associated with cell differentiation, gene methylation pattern, apoptosis, and lineage-specific functional events. 相似文献
936.
de Oliveira RM Lia EN Guimarães RM Bocca AL Cavalcante Neto FF da Silva TA 《Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology》2008,30(2):113-118
OBJECTIVE: To analyze cytomorphologically the buccal mucosa of patients with Alzheimer's disease (AD). STUDY DESIGN: Brush biopsies were obtained from 10 patients with AD and 9 age-matched controls without neurologic symptoms from 3 distinct oral sites. RESULTS: A significant reduction in partially keratinized intermediate (red) cells was observed in the buccal mucosa of the AD group. In the AD group, parabasal cells from the floor of the mouth (p = 0.017) and buccal mucosa (p = 0.058) and red cells,from the tongue dorsum (p = 0.013) and buccal mucosa (p = 0.002), exhibited significantly greater nuclear areas. With regard to the nuclear to cytoplasmic (N:C) ratio, intermediate (red) cells from the buccal mucosa and tongue dorsum of AD individuals showed a decrease in this parameter (p <0.0001), while superficial (yellow) cells (from buccal mucosa) (p= 0.042) and parabasal (blue) cells (from the tongue dorsum) (p = 0.003) exhibited an increased N:C ratio. No significant differences were detected in the cells from the floor of the mouth. CONCLUSIONS: Our findings indicate that cytologic and cytometric changes were detectable in the exfoliative cytology of the buccal mucosa and tongue in the AD group. 相似文献
937.
In a previous study, the conserved arginine residue at position 306 of Streptomyces clavuligerus deacetoxycephalsoporin C synthase (scDAOCS), when mutated to leucine, resulted in 191% increase in converting ampicillin to its expanded cephalosporin moiety compared with that of the wild-type enzyme. However, the role of this residue in eliciting the improved enzymatic activity is not well understood. In this study, probing the molecular basis of amino acid substitutions at position 306 has underscored its importance for engineering various improvements in the ring expansion activity. Structural modeling using SwissPdbViewer revealed that R306 is surrounded by a hydrophobic cleft formed by residues Y184, L186, W297, I298, and V303. Hence, the improved activity achieved by the R306L mutation was probably because of better hydrophobic packing in this region. To evaluate the role of amino acids at position 306 of scDAOCS and its influence on the molecular status of the enzyme at this locality, alteration to 18 other amino acids was done by site-directed mutagenesis. The effects of each substitution on the enzyme activity were determined by bioassay using penicillin substrates: ampicillin, penicillin G, phenethicillin, and carbenicillin. Results obtained showed a drastic reduction in enzyme activity when R306 was replaced with charged or polar residues, thus emphasizing the importance of hydrophobic packing around this site. The bioassay results also illustrated that apart from leucine, substitutions to nonpolar residues, isoleucine and methionine, were able to improve the ampicillin conversion activity of scDAOCS by 168 and 113% of the wild-type enzyme activity, respectively. Similar trend of effects from each mutation was also observed for penicillin G, phenethicillin, and carbenicillin conversions. The enhanced enzyme activities were supported by spectrophotometric assay indicating that all these mutants have lower K(m) values (R306L: 1.09 mM; R306I: 2.64 mM; R306M: 5.68 mM) than the wild-type enzyme (8.33 mM), resulting in improvement in the enzyme's substrate binding affinity. Hence, this mutational study of amino acids situated at 306 of scDAOCS has provided a better understanding of the significance of specific amino acid residues at this position which can improve its ring-expansion activity when given a plethora of beta-lactam substrates to generate corresponding, possibly new, cephalosporins. 相似文献
938.
Salvador B Delgadillo MO Sáenz P García JA Simón-Mateo C 《Molecular plant-microbe interactions : MPMI》2008,21(1):20-29
Plum pox virus (PPV) is a member of the genus Potyvirus that is able to infect a large variety of plant species, including trees of the genus Prunus, its natural host. When some PPV isolates are propagated for an extended time in herbaceous plants, their ability to infect trees is reduced. The molecular basis of this change in host infectivity is poorly understood. We report the construction of hybrid viruses from cDNA clones of two D-strain isolates of PPV, PPV-D and PPV-R, which differ in their host range. PPV-D can infect GF305 peach seedlings efficiently, however, it is unable to infect Nicotiana clevelandii plants. Conversely, PPV-R infects N. clevelandii, but not GF305 peach seedlings. The analyses of the hybrid viruses showed that, although determinants of PPV pathogenicity are extensively spread throughout the PPV genome, the 3' terminal region of the PPV-R genome, including the 3' noncoding region and the coding regions for the coat protein (CP), NIb, and part of NIa protein, is sufficient to confer infectivity of N. clevelandii in a PPV-D background. Our data demonstrate a high concentration of amino acid substitutions in the CP and a host-specific effect of a deletion at the N terminus of this protein in PPV pathogenicity in peach and N. clevelandii infectivity experiments. These results suggest that relevant host specificity determinants are located in the N-terminal region of the CP. The analyses of the PPV-R and PPV-D chimeras also showed that key host-specific pathogenicity determinants lie in the 5' terminal third of the PPV genome, a region that spans proteins P1, HCPro, and P3. The selection of mutations in only a few specific residues in proteins P1, P3, and 6K1 after partial adaptation of a chimeric virus (BD-GFP) to N. clevelandii further suggests a relevant role for these proteins in host adaptation. 相似文献
939.
Darren C. J. Yeo Peter K. L. Ng Neil Cumberlidge Célio Magalhães Savel R. Daniels Martha R. Campos 《Hydrobiologia》2008,595(1):275-286
An assessment of the global freshwater crab diversity is presented. A total of 1,476 species in 14 families are currently
known from all zoogeographical regions (except Antarctica), including 1,306 species in eight exclusively freshwater families
(Pseudothelphusidae, Trichodactylidae, Potamonautidae, Deckeniidae, Platythelphusidae, Potamidae, Gecarcinucidae and Parathelphusidae).
Estimates of true freshwater crab diversity including likely numbers of undescribed taxa suggest that the field remains largely
in a “discovery” phase. Main ideas on the origins, diversification, and phylogeny of true freshwater crabs are briefly discussed.
The economic importance of freshwater crabs is also highlighted.
Guest editors: E. V. Balian, C. Lévêque, H. Segers & K. Martens
Freshwater Animal Diversity Assessment 相似文献
940.
In the 1990s a sharp decrease in nitrogen loading occurred in Estonian rivers, bringing about a reduction of the nitrogen-to-phosphorus ratio (N:P ratio) in the large shallow lakes, Peipsi (3,555 km2, mean depth 7.1 m) and Võrtsjärv (270 km2, 2.8 m). The average mass ratio of total nitrogen (TN) and total phosphorus (TP) in Võrtsjärv (45) was about twice as high as that in Peipsi (22). In Peipsi, the N2-fixing Gloeotrichia echinulata, Aphanizomenon flos-aquae and Anabaena species prevailed in the summer phytoplankton, while in Võrtsjärv the dominant cyanobacteria were Limnothrix planktonica, L. redekei and Planktolyngbya limnetica, which cannot fix N2; the main N2-fixing taxa Aphanizomenon skujae and Anabaena sp. seldom gained dominance. In May–October the critical TN:TP mass ratio, below which N2-fixing cyanobacteria (Nfix) achieved high biomasses, was ~40 in Võrtsjärv and ~30 in Peipsi. The percentages of both total cyanobacteria (CY) and Nfix (CY% and Nfix%) in Peipsi achieved their maximum values at an N:P mass ratio at or below 20 for both TN:TP and Nmin:SRP. In Võrtsjärv, the TN:TP supporting a high Nfix% was between 30 and 40 and the Nmin:SRP supporting this high percentage was in the same range as that in Peipsi (<20), though the maximum Nfix% values in Võrtsjärv (69%) were much lower than in Peipsi (96%). The Nmin:SRP ratio explained 77% of the variability in Nfix% in May–October. The temperature dependence of Nfix% approximated to the maximum function type, with an upper limiting value at a certain water temperature, and this was most distinct in May–October. The critical TN:TP ratios obtained from our study (roughly 30 for Peipsi and 40 for Võrtsjärv) are much higher than the Redfield N:P mass ratio routinely considered (7). Our results represent valuable guidelines for creating effective management strategies for large shallow lakes. They provide a basis for stressing the urgent need to decrease phosphorus loading and to keep the in-lake P concentration low, and not to implement nitrogen reduction measures without a simultaneous decrease of phosphorus concentration. 相似文献