Abstract
Alofanib (RPT835, Ruspharmtech LLC) is a novel selective allosteric inhibitor binding to the extracellular domain of FGFR2. Alofanib had no direct effect on activation of FGFR1 and FGFR3 in ...vitro. Selective effect of the compound may reduce toxicity compared to multi-targeted VEGFR/FGFR or pan-FGFR inhibitors. This study characterizes the organ toxicity of alofanib in Sprague-Dawley rats and Chinchilla rabbits, and the reversibility of any treatment-induced effects.
240 rats and 30 rabbits received alofanib (0-40.5 and 0-21.6 mg/kg/day, respectively) intravenously on a consecutive daily dosing schedule for thirteen weeks. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed.
There was no treatment-related mortality, severe toxicity and significant changes in organs in the thirteen-week study. Alofanib was well-tolerated in vivo. Clinical signs of first injection (8.1 mg/kg) included moderate local irritative reaction and decreased activity during hour in rats. Clinical symptoms of toxicity were not observed over study. Animals were active. Body weight remained stable and it was comparable to vehicle groups. Abnormal electrocardiogram findings and blood pressure changes were not detected. It was notable that in the study, none of the hematologic changes was present at the end of the recovery period. Minimal significant decrease in ALT/AST, slight increase in alkaline phosphatase in male rats and mild increase in urea, decrease in chlorine in female rats were found throughout treatment period. Minimal significant decrease in albumin and chlorine was identified in rabbits. Rate of hyperphosphatemia, an on-target side-effect of pan-FGFR inhibitors, will be presented at the AACR Meeting.
We conclude that toxicity of alofanib was mild in the thirteen-week study. Slight decrease of chlorine in blood was most common side effect. The final conclusion will be made after six-month study. This study was supported by a grant from the Skolkovo Foundation.
Citation Format: Nataliya V. Lapina, Marina V. Melikhova, Olga A. Vakunenkova, Vadim A. Kashuro. Toxicity of selective allosteric FGFR2 inhibition in preclinical studies. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2095.
The paper presents the analysis of the results of application of monofilament suture based on polyhydroxyalkanoates (PHAs) in comparison with suture materials "Vicryl" and "Kaprofil" in experiment ...with Chinchilla rabbits. It was proved that the use of the PHA-based suture is accompanied by minimally pronounced local tissue response.
It is well known that the large caliber vessels, the nutrition of the wall differs in the internal part in comparison to the external one. In the present study we assessed the presence and ...distribution of vascularisation of aortic media in 3 species: lamb, rabbit and chinchilla. Samples were harvested from a group of 3 animals for each species. After histological processing, we stained the sections and assessed the presence and distribution of vasa vasorum. In lamb, blood vessels were present in the media of the first aortic segments (with a larger caliber), and starting with abdominal descending aorta they were absent. In rabbit and chinchilla, blood vessels were not present in tunica media. The present study shows that vasa vasorum are present only in tunica media of arteries exceeding a certain caliber.
The material of Rotundomys (Rodentia, Cricetinae) from the Late Miocene fossiliferous complex of Cerro de los Batallones (Madrid, Spain) is described and compared with all species currently placed in ...the genera Rotundomys and Cricetulodon. Both the morphology and size variation encompassed in the collection of specimens from Batallones suggest they belong to a single taxon different from the other known species of these genera. A new species Rotundomys intimus sp. nov. is, therefore, named for it. A cladistic analysis, which is the first ever published concernig these taxa, has been conducted to clear up the phylogenetic position of the new species. Our results suggest that Rotundomys intimus sp. nov. inserts between R. mundi and R. sabatieri as a relatively primitive taxon inside the clade Rotundomys. The new taxon is more derived than R. mundi in having a transversal connection between the metalophulid and the anterolophulid on some m1 but more primitive than R. sabatieri and the most evolved species of Rotundomys (R. montisrotuni +R.bressanus) in its less developed lophodonty showing distinct cusps, shallower valleys, and the presence of a subdivided anteroloph on the M1. The species of Cricetulodon do not form a monophyletic group. As a member of Rotundomys, Rotundomys intimus sp. nov. is more derived than all of these taxa in its greater lophodonty and the complete loss of the anterior protolophule, mesolophs, and mesolophids.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We combined new sequence data for more than 300 muroid rodent species with our previously published sequences for up to five nuclear and one mitochondrial genes to generate the most widely and ...densely sampled hypothesis of evolutionary relationships across Muroidea. An exhaustive screening procedure for publically available sequences was implemented to avoid the propagation of taxonomic errors that are common to supermatrix studies. The combined data set of carefully screened sequences derived from all available sequences on GenBank with our new data resulted in a robust maximum likelihood phylogeny for 900 of the approximately 1,620 muroids. Several regions that were equivocally resolved in previous studies are now more decisively resolved, and we estimated a chronogram using 28 fossil calibrations for the most integrated age and topological estimates to date. The results were used to update muroid classification and highlight questions needing additional data. We also compared the results of multigene supermatrix studies like this one with the principal published supertrees and concluded that the latter are unreliable for any comparative study in muroids. In addition, we explored diversification patterns as an explanation for why muroid rodents represent one of the most species-rich groups of mammals by detecting evidence for increasing net diversification rates through time across the muroid tree. We suggest the observation of increasing rates may be due to a combination of parallel increases in rate across clades and high average extinction rates. Five increased diversification-rate-shifts were inferred, suggesting that multiple, but perhaps not independent, events have led to the remarkable species diversity in the superfamily. Our results provide a phylogenetic framework for comparative studies that is not highly dependent upon the signal from any one gene.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this article we discuss the reasons why the binomen Cuniculus hernandezi Castro, Lopez y Becerra, 2010, is not an available name according to the rules of the current International Code of ...Zoological Nomenclature (ICZN). Among these reasons are the lack of a precise description of the taxon and the failure to identify a type specimen. In addition, we highlight problems in the research design of the description of the binomen that affect the conclusions regarding the taxonomic distinctiveness between the populations of the Oriental and Central Cordilleras of Colombia.
Development of phylogenetic methods that do not rely on fossils for the study of evolutionary processes through time have revolutionized the field of evolutionary biology and resulted in an ...unprecedented expansion of our knowledge about the tree of life. These methods have helped to shed light on the macroevolution of many taxonomic groups such as the placentals (Mammalia). However, despite the increase of studies addressing the diversification patterns of organisms, no synthesis has addressed the case of the most diversified mammalian clade: the Rodentia.
Here we present a rodent maximum likelihood phylogeny inferred from a molecular supermatrix. It is based on 11 mitochondrial and nuclear genes that covers 1,265 species, i.e., respectively 56% and 81% of the known specific and generic rodent diversity. The inferred topology recovered all Rodentia clades proposed by recent molecular works. A relaxed molecular clock dating approach provided a time framework for speciation events. We found that the Myomorpha clade shows a greater degree of variation in diversification rates than Sciuroidea, Caviomorpha, Castorimorpha and Anomaluromorpha. We identified a number of shifts in diversification rates within the major clades: two in Castorimorpha, three in Ctenohystrica, 6 within the squirrel-related clade and 24 in the Myomorpha clade. The majority of these shifts occurred within the most recent familial rodent radiations: the Cricetidae and Muridae clades. Using the topological imbalances and the time line we discuss the potential role of different diversification factors that might have shaped the rodents radiation.
The present glimpse on the diversification pattern of rodents can be used for further comparative meta-analyses. Muroid lineages have a greater degree of variation in their diversification rates than any other rodent group. Different topological signatures suggest distinct diversification processes among rodent lineages. In particular, Muroidea and Sciuroidea display widespread distribution and have undergone evolutionary and adaptive radiation on most of the continents. Our results show that rodents experienced shifts in diversification rate regularly through the Tertiary, but at different periods for each clade. A comparison between the rodent fossil record and our results suggest that extinction led to the loss of diversification signal for most of the Paleogene nodes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction: The use of super(99m)Tc-macroggregated albumin for lung perfusion imaging is well established in nuclear medicine. However, there have been safety concerns over the use of blood-derived ...products because of potential contamination by infective agents, for example, Variant Creutzfeldt Jakob Disease. Preliminary work has indicated that Tc(CO) sub(5) I is primarily taken up in the lungs following intravenous administration. The aim of this study was to evaluate the biodistribution and pharmacokinetics of super(99m)Tc(CO) sub(5)I and its potential as a lung perfusion agent. Methods: super(99m)Tc(CO) sub(5)I was synthesized by carbonylation of super(99m)TcO sub(4)_ at 160 atm of CO at 170 degree C in the presence of HI for 40 min. Radiochemical purity was determined by HPLC using super(99)Tc(CO) sub(5)I as a reference. super(99m)Tc(CO) sub(5)I was administered by ear-vein injection to three chinchilla rabbits, and dynamic images were acquired using a gamma camera (Siemens E-cam) over 20 min. Imaging studies were also performed with super(99m)Tc-labeled macroaggregated albumin ( super(99m)Tc-MAA) and super(99m)TcO sub(4)_ for comparison. super(99m)Tc(CO) sub(5)I was administered intravenously to Sprague-Dawley rats, and tissue distribution studies were obtained at 15 min and 1 h postinjection. Comparative studies were performed using super(99m)Tc-MAA. Results: Radiochemical purity, assessed by HPLC, was 98%. The retention time was similar to that of super(99)Tc(CO) sub(5)I. The dynamic images showed that 70% of super(99m)Tc(CO) sub(5)I appeared promptly in the lungs and remained constant for at least 20 min. In contrast, super(99m)Tc04- rapidly washed out of the lungs after administration. As expected super(99m)Tc-MAA showed 90% lung accumulation. The percentage of injected dose per gram of organ plus or minus S.D. at 1 h for super(99m)Tc(CO) sub(5)I was as follows: blood, 0.22 plus or minus 0.02; lung, 12.8 plus or minus 2.87; liver, 0.8 plus or minus 0.15; heart, 0.15 plus or minus 0.01; kidney, 0.47 plus or minus 0.08. The percentage of injected dose per organ plus or minus S.D. at 1 h was as follows: lung, 22.47 plus or minus 2.31; liver, 10.53 plus or minus 1.8; heart, 0.18 plus or minus 0.01; kidney, 1.2 plus or minus 0.17. Tissue distribution studies with super(99m)Tc-MAA showed 100% lung uptake. Conclusion: super(99m)Tc(CO) sub(5)I was synthesized with a high radiochemical purity and showed a high accumulation in the lungs. Further work on the mechanism and optimization of lune uptake of super(99m)Tc-tentacarbonyl complexes is warranted.
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