Safety and Efficacy of FIT039 for Verruca Vulgaris: A Placebo-Controlled, Phase I/II Randomized Controlled Trial

TRIAL DESIGN: Human papillomavirus infection causes verruca vulgaris. CDK9 inhibitor FIT039 inhibits DNA virus proliferation in animal models. We conducted a multicenter, single-blind, placebo-controlled, randomized phase I/II clinical trial evaluating the safety and efficacy of FIT039 against verruca vulgaris. METHODS: Target lesions were treated with liquid nitrogen once, and a FIT039 patch or placebo patch was applied for 14 days. The primary endpoint was lesion disappearance. The secondary endpoints were safety and changes in dimension, cross-sectional area, and the number of petechial lesions. RESULTS: A total of 24 participants were randomly allocated to the FIT039 (n = 13, median age, 54 years) and placebo (n = 11, median age, 62 years) groups. Verruca vulgaris did not disappear. FIT039 decreased the dimension to 76% of the initial value on day 29, followed by an increase to 98% on day 57. Placebo showed a monotonic increase to 107% on day 57. Changes in the cross-sectional area and petechiae number were comparable between the groups. CONCLUSIONS: No drug-related adverse reactions occurred. FIT039 efficacy was not determined in this study

Functional roles of Aves class-specific cis-regulatory elements on macroevolution of bird-specific features

Unlike microevolutionary processes, little is known about the genetic basis of macroevolutionary processes. One of these magnificent examples is the transition from non-avian dinosaurs to birds that has created numerous evolutionary innovations such as self-powered flight and its associated wings with flight feathers. By analysing 48 bird genomes, we identified millions of avian-specific highly conserved elements (ASHCEs) that predominantly (>99%) reside in non-coding regions. Many ASHCEs show differential histone modifications that may participate in regulation of limb development. Comparative embryonic gene expression analyses across tetrapod species suggest ASHCE-associated genes have unique roles in developing avian limbs. In particular, we demonstrate how the ASHCE driven avian-specific expression of gene Sim1 driven by ASHCE may be associated with the evolution and development of flight feathers. Together, these findings demonstrate regulatory roles of ASHCEs in the creation of avian-specific traits, and further highlight the importance of cis-regulatory rewiring during macroevolutionary changes

Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial

<p>Abstract</p> <p>Background</p> <p>Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and advanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required.</p> <p>Methods/Design</p> <p>This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 (¹²⁵I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with ¹²⁵I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during ¹²⁵I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.</p> <p>The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events.</p> <p>Discussion</p> <p>To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa.</p> <p>Trial registration</p> <p>UMIN000003992</p

Occurrence patterns of facilitation by shade along a water gradient are mediated by species traits

In disturbed habitats, shade often has facilitative effects on plants by ameliorating water and thermal stresses. Facilitation by shade tends to increase as water availability decreases. At the same time, several studies have suggested that facilitation by shade is not affected by water status or collapses under extremely dry conditions. We hypothesized that traits of beneficiary plants, specifically, the flexibility in the allocation of biomass between shoots and roots, would mediate variation in the relationship between facilitation by shade and water status. To test this hypothesis, we examined the responses of two bog species to shade under various water conditions in a post-mined peatland. The seeds of Rhynchospora alba and Moliniopsis japonica were sown under three water levels (dry: 53% peat water content, wet: 77%, and control: 71%) x two shading levels (50% shaded and unshaded). The survival, biomass, and biomass allocation between the shoots and roots of the two species were monitored for two years. Shade increased the survival and biomass of both species. However, the facilitation of R. alba by shade was independent of water level, whereas the strength of the facilitative effects on M. japonica increased as water content decreased. R. alba preferentially allocated biomass to roots under dry conditions and was highly drought tolerant. M. japonica did not alter the allocation of its biomass in response to either shade or water level and was drought intolerant. Our results suggest that flexibility in biomass allocation of beneficiary plants mediates occurrence patterns of facilitation by shade along a water gradient. The facilitation of species with inflexible biomass allocation by shade through the amelioration of water stress increases as water availability decreases, whereas the facilitation of species with flexible biomass allocation is independent of water status. Such species-specific facilitation would promote the coexistence of diverse species in a community. (C) 2014 Elsevier Masson SAS. All rights reserved

Relationships between the developments of seedbank, standing vegetation and litter in a post-mined peatland

To clarify seedbank developmental pattern and its determinants, we examined relationships between seedbank, standing vegetation, and litter in a post-mined peatland on Sarobetsu Mire, northern Japan. In late fall 2006 and early summer 2007, peat was sampled from four vegetation types, and litter was also sampled from two of the four vegetation where thick litter was accumulated. Seed germination tests were performed by the samples in a glasshouse. The results were compared to the standing vegetation and litter accumulation. Seed density and species richness in seedbank gradually increased with increasing vegetation cover. Seeds in surface layer germinated more in fall than in summer. In vegetation with thick litter, small seeds, such as Drosera rotundifolia and Gentiana triflora, germinated more from peat than from litter in summer, probably due to the downward movement. Seed density in litter decreased from fall to the next summer. Moliniopsis japonica and Rhynchospora alba developed short-term persistent seedbank, whereas D. rotundifolia and G. triflora preserved long-term persistent seedbank in peat covered with thick litter. Seedbank development follows the development of the standing vegetation with litter. Litter derived from the standing vegetation is a prime determinant on the seedbank composition and development, by acting as seed trap and keeping seed dormancy

Flight feather development: its early specialization during embryogenesis

Abstract Background Flight feathers, a type of feather that is unique to extant/extinct birds and some non-avian dinosaurs, are the most evolutionally advanced type of feather. In general, feather types are formed in the second or later generation of feathers at the first and following molting, and the first molting begins at around two weeks post hatching in chicken. However, it has been stated in some previous reports that the first molting from the natal down feathers to the flight feathers is much earlier than that for other feather types, suggesting that flight feather formation starts as an embryonic event. The aim of this study was to determine the inception of flight feather morphogenesis and to identify embryological processes specific to flight feathers in contrast to those of down feathers. Results We found that the second generation of feather that shows a flight feather-type arrangement has already started developing by chick embryonic day 18, deep in the skin of the flight feather-forming region. This was confirmed by shh gene expression that shows barb pattern, and the expression pattern revealed that the second generation of feather development in the flight feather-forming region seems to start by embryonic day 14. The first stage at which we detected a specific morphology of the feather bud in the flight feather-forming region was embryonic day 11, when internal invagination of the feather bud starts, while the external morphology of the feather bud is radial down-type. Conclusion The morphogenesis for the flight feather, the most advanced type of feather, has been drastically modified from the beginning of feather morphogenesis, suggesting that early modification of the embryonic morphogenetic process may have played a crucial role in the morphological evolution of this key innovation. Co-optation of molecular cues for axial morphogenesis in limb skeletal development may be able to modify morphogenesis of the feather bud, giving rise to flight feather-specific morphogenesis of traits