The current report presents the case of a 43-year-old male suffering from a penile cutaneous horn. A surgical excision of the lesion was performed and histopathology demonstrated hyperkeratosis, dyskeratosis and epithelial hyperplasia. The cutaneous horn progressed to squamous cell carcinoma <1.5 months following surgery and a partial penectomy was conducted. The International Index of Erectile Function 5 questionnaire was used to assess the patient and the score had decreased in the one-month postoperative follow-up compared with that of the preoperative period. These findings indicate that undergoing a partial penectomy on initial diagnosis of a penile cutaneous horn should be considered in order to conserve a greater quantity of the penile tissue and improve the postoperative quality of life.
In this study, we investigated whether PKR protein expression is correlated with mRNA levels and also evaluated molecular biomarkers that are associated with PKR, such as phosphorylated PKR (p-PKR) and phosphorylated eIF2? (p-eIF2?).
Rifampin and carbamazepine have been recommended in the U.S. Food and Drug Administration draft drug interaction guidance as CYP3A4 inducers for clinical drug-drug interaction (DDI) studies. To optimize the dose regimens of these inducers for use in DDI studies, their effect at various doses and dosing durations on the area under the curve (AUC) of multiple probe substrates was simulated using a population-based simulator. A similar assessment of the inducer phenobarbital was also conducted. CYP3A4 induction by all three inducers was previously determined in hepatocytes, and the results were incorporated into simulations. The pharmacokinetics of the three inducers and their associated CYP3A4 drug interactions were predicted and compared with in vivo observations. The predicted C(max) and AUC of all the inducers and substrates correlated closely with those observed clinically. The predicted magnitudes of the DDIs caused by CYP3A4 induction were also in good agreement with the observed clinical results. Comparison of the maximal CYP3A4 induction potential among the three inducers indicated that rifampin is the most potent inducer and is the best choice for clinical CYP3A4 induction DDI studies. Moreover, a near-maximal CYP3A4 DDI was predicted to result from administration of rifampin for approximately 7 days at 450 to 600 mg q.d. or 200 to 300 mg b.i.d. These results suggest optimal dose regimens for clinical trials that maximize the probability of detecting a DDI caused by CYP3A4 induction. The simulation strategy provides the means to predict the induction profiles of compounds in development.
Natural and artificially induced mutants have provided valuable resources for plant genetic studies and crop improvement. In this study, we investigated the genetic and molecular basis of the purple sheath trait in a somaclonal mutant Z418, which was regenerated from a green sheath rice variety C418 through tissue culture. The purple sheath trait in Z418 was heritable and stable based on our 10 years of evaluation. Genetic analysis revealed that the purple sheath trait of the mutant was controlled by a single dominant gene. To map the gene, we scored 89 polymorphic SSRs markers in a F(2) population of 232 plants derived from a cross between Z418 and HX-3, an indica variety with green sheath trait. The gene was initially mapped to the short arm of chromosome 6 between two SSR markers, RPM5 and RM402, with a genetic distance of 1.1 and 10.3 cM, respectively. Thirty-one SSR and indel markers located within the target region were further used to fine-map the gene to a 153-kb interval between two SSR markers (RPM8 and RPM11). The OsC1 gene, which locates within the region and encodes a MYB family transcription factor, was chosen as the candidate gene controlling the purple sheath trait in Z418. Sequencing analysis revealed that OsC1 gene and its transcript in Z418 was 34 bp longer than that in C418. The possible mechanisms for the gene mutation, the developmental and tissue-specific expression of purple anthocyanin pigmentation in Z418, were finally discussed.
Krüppel-Like Factor 4 (KLF4) functions as a tumor suppressor in some cancers, but its molecular mechanism is not clear. Our recent study also showed that the expression of KLF4 is dramatically reduced in primary lung cancer tissues. To investigate the possible role of KLF4 in lung cancer, we stably transfected KLF4 into cells from lung cancer cell lines H322 and A549 to determine the cells invasion ability. Our results showed that ectopic expression of KLF4 extensively suppressed lung cancer cell invasion in Matrigel. This effect was independent of KLF4-mediated p21 up-regulation because ectopic expression of p21 had minimal effect on cell invasion. Our analysis of the expression of 12 genes associated with cell invasion in parental, vector-transfected, and KLF4-transfected cells showed that ectopic expression of KLF4 resulted in extensively repressed expression of secreted protein acidic and rich in cysteine (SPARC), an extracellular matrix protein that plays a role in tumor development and metastasis. Knockdown of SPARC expression in H322 and A549 cells led to suppression of cell invasion, comparable to that observed in KLF4-transfected cells. Moreover, retrovirus-mediated restoration of SPARC expression in KLF4-transfected cells abrogated KLF4-induced anti-invasion activity. Together, our results indicate that KLF4 inhibits lung cancer cell invasion by suppressing SPARC gene expression.
A 2-aminothiazole derivative 1 was developed as a potential inhibitor of the oncology target AKT, a serine/threonine kinase. When incubated in rat and human liver microsomes in the presence of NADPH, 1 underwent significant metabolic activation on its 2-aminothiazole ring, leading to substantial covalent protein binding. Upon addition of glutathione, covalent binding was reduced significantly, and multiple glutathione adducts were detected. Novel metabolites from the in vitro incubates were characterized by LC-MS and NMR to discern the mechanism of bioactivation. An in silico model was developed based on the proposed mechanism and was employed to predict bioactivation in 23 structural analogues. The predictions were confirmed empirically for the bioactivation liability, in vitro, by LC-MS methods screening for glutathione incorporation. New compounds were identified with a low propensity for bioactivation.
Understanding the evolutionary mechanisms that maintain genetic variation in natural populations is one of the fundamental goals of evolutionary biology. There is growing evidence that genotype-by-environment interaction (G x E) can maintain additive genetic variance (V (A)), but we lack information on the relative performance of genotypes under the competitive situations encountered in the field. Competing genotypes may influence each other, and this interaction is also subject to selection through indirect genetic effects (IGE). Here, we explore how genotypes perform when interacting and evaluate IGE in order to understand its influence on V (A) for sexually-selected traits in the lesser waxmoth, Achroia grisella. We found that inter-genotype differences and crossover interactions under joint rearing are equal to or greater than values when reared separately. A focal genotype exhibited different performances when jointly reared with various genotypes-suggesting that IGE may be responsible for the increased levels of crossover and differences in performance observed. We suggest that some genotypes are superior competitors for food acquisition in the larval stage, and that these differences influence the development and evolution of other genotypes through IGE. We reaffirm the role of G x E in maintaining V (A) and note the general importance of IGE in studies of evolutionary mechanisms.
Motesanib diphosphate is a novel, investigational, highly selective oral inhibitor of the receptor tyrosine kinases vascular endothelial growth factor receptors 1, 2, and 3, the platelet-derived growth factor receptor, and the stem cell factor receptor (Kit). The in vitro metabolic profiles of [(14)C]motesanib were examined by using microsomes and hepatocytes from preclinical species and humans. Several oxidative metabolites were observed and characterized by tandem mass spectrometry, nuclear magnetic resonance spectroscopy, and coinjection with authentic standards. Cytochrome P450 (P450) 3A4 is the major isozyme involved in the oxidative biotransformation of motesanib, but the CYP2D6 and CYP1A isozymes also make minor contributions. In hepatocyte incubations, oxidative and conjugative pathways were observed for all species examined, and indoline N-glucuronidation was the dominant pathway. Three less common and novel phase II conjugates of the indoline nitrogen were detected in hepatocytes and in microsomes supplemented with specific cofactors, including N-carbamoyl glucuronide, N-glucose, and N-linked beta-N-acetylglucosamine. An N-glucuronide metabolite was the most frequently observed phase II conjugate in liver microsomes of all species, whereas the N-acetylglucosamine conjugate was observed only in monkey liver microsomes. Incubations with recombinant human UDP-glucuronosyltransferases (UGTs) and inhibition by the UGT1A4 and UGT1A1 substrates/inhibitors imipramine and bilirubin suggested that UGT1A4 is the major UGT isozyme catalyzing the N-glucuronidation of motesanib, with a minor contribution from UGT1A1. The in vitro metabolic profiles were similar between the human and preclinical species examined. All metabolites found in humans were also detected in other species.
Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.
We report the first described non-plant family of TRIMs (terminal-repeat retrotransposons in miniature), which are small nonautonomous LTR retrotransposons, from the whole-genome sequence of the red harvester ant, Pogonomyrmex barbatus (Hymenoptera: Myrmicinae). Members of this retrotransposon family, named PbTRIM, have typical features of plant TRIMs in length and structure, although they share no overall sequence similarity. PbTRIM elements and their solo-LTRs are abundant in the host genome and exhibit an uneven distribution pattern. Elements are preferentially inserted into TA-rich regions with ATAT as the most common pattern of target site duplication (TSD). PbTRIM is most likely mobile as indicated by the young age of many complete elements, the high degree of sequence similarity among elements at different genomic locations, the abundance of elements in the host genome, and the presence of 4-bp target site duplications (TSDs) flanking the elements and solo-LTRs. Many PbTRIM elements and their solo-LTRs are located within or near genes, suggesting their potential roles in restructuring the host genes and genome. Database search, PCR and sequencing analysis revealed the presence of homologous PbTRIM elements in other ant species. The high sequence similarity between elements from distantly related ant species, the incongruence between the phylogenies of PbTRIM and its hosts, and the patchy distribution of the retroelement within the Myrmicinae subfamily indicate possible horizontal transfer events of the retroelement.
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