Naturally occurring flavonoids such as quercetin and genistein possess cancer chemopreventive properties in experimental models. However, adverse effects such as their mutagenicity confound their ...potential clinical usefulness. Furthermore in leukaemia cells some flavonoids cleave the breakpoint cluster region of the mixed lineage leukaemia (MLL) gene as a consequence of inhibition of topoisomerase II. The choice of flavonoids to be developed as cancer chemopreventive agents depends crucially on their safety. Here, we explored safety aspects of the novel flavone tricin, a constituent of rice bran and other grass species, which has recently been found to interfere with murine gastrointestinal carcinogenesis.
Evidence of pathological or morphological changes in liver, lung, heart, spleen, kidney, adrenal gland, pancreas or thymus tissues was studied in mice which received tricin, genistein or quercetin 1,000 mg/kg daily by the oral route on five consecutive days. The ability of tricin (50 microM) to cleave the MLL gene was studied in human leukaemia cells by Southern blotting, and its effect on human topoisomerase II activity was investigated in incubations with supercoiled DNA. The mutagenicity of tricin was assessed in the Salmonella/Escherichia coli assay, and its clastogenicity was adjudged by chromosomal aberrations in Chinese hamster ovary cells and occurrence of micronuclei in bone marrow erythrocytes in Swiss-Webster mice.
Neither tricin, quercetin, or genistein caused pathological or morphological changes in any of the murine tissues studied. Tricin (50 microM) failed to cause MLL gene breakage, and it inhibited topoisomerase II only at 500 microM, but not at 10, 50 or 100 microM. Tricin lacked genotoxic properties in the systems studied here.
The results tentatively suggest that tricin may be considered safe enough for clinical development as a cancer chemopreventive agent.
Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in ...combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.
To describe the dose response relationship and natural history of radiation injury in the Wistar rat and its suitability for use in medical countermeasures (MCM) testing.
In two separate studies, ...male and female rats were exposed to partial body irradiation (PBI) with 5% bone marrow sparing. Animals were X-ray irradiated from 7 to 12 Gy at 7-10 weeks of age. Acute radiation syndrome (ARS) survival at 30 days and delayed effects of acute radiation exposure (DEARE) survival at 182 days were assessed. Radiation effects were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging of lung, whole-body plethysmography, and histopathology.
Rats developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in mortality at doses ≥8Gy in males and ≥8.5 Gy in females. DEARE mortality occurred at doses ≥8Gy for both sexes. Findings indicate lung, kidney, and/or liver injury, and persistent hematological dysregulation, revealing multi-organ injury as a DEARE.
The Wistar rat PBI model is suitable for testing MCMs against hematopoietic and gastrointestinal ARS. DEARE multi-organ injury occurred in both sexes irradiated with 8-9Gy, also suggesting suitability for polypharmacy studies addressing the combination of ARS and DEARE injury.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Assembling contributions from experienced developers, vendors, researchers, and educators, OpenGL Insights presents real-world techniques for intermediate and advanced OpenGL, OpenGL ES, and WebGL ...developers. Focusing on current and emerging techniques for the OpenGL family of APIs, the book demonstrates the breadth and depth of OpenGL. Readers will gain practical skills to solve problems related to performance, rendering, profiling, framework design, and more. Source code, demos, and other material are available on the book's website.
Cigarette smokers have been reported to void urine that is more mutagenic, as measured in the Salmonella/microsome assay, than urine voided by nonsmokers. Several previous studies have attempted to ...correlate indices of tobacco smoke exposure (e.g. nicotine, cotinine, tar intake) with urinary mutagenicity, with conflicting results. These studies generally involved small numbers of smokers and did not carefully control diet, which is known to affect urinary mutagenicity markedly. Our objective was to conduct a controlled study to determine clearly if there were a correlation between urinary nicotine, cotinine, or nicotine + cotinine and urinary mutagenicity and to determine if nicotine or its major metabolite plays a role in the mutagenicity of urine from cigarette smokers. We used a large number of smokers (31), each of whom smoked both a tobacco-burning cigarette and a tobacco-heating cigarette on consecutive weeks, and we prepared and served identical diets to all subjects. Nicotine and cotinine concentrations were determined in small aliquots from urine samples collected over 24 hr, and the remaining urine sample was extracted and concentrated on XAD-2 resin for mutagenicity assays in the Salmonella/microsome test. Nicotine, cotinine, and nicotine + cotinine were statistically correlated with mutagenicity of urine from smokers of the tobacco-burning cigarette, but there was no correlation between nicotine, cotinine, or nicotine + cotinine and mutagenicity of urine from smokers of the tobacco-heating cigarettes. Thus, although urinary nicotine and cotinine concentrations correlate with urinary mutagenicity in smokers of tobacco-burning cigarettes, the present results indicate that nicotine and its metabolite are not responsible for the mutagenicity of smokers' urine.
A preliminary analysis of mRNA transcribed from the N allele at the CSN1S1 locus of the goat Cosenza, G. (Naples Univ., Portici (Italy). Dipartimento di Scienze Zootecniche ed Ispezione degli Alimenti); Ilario, R. (Naples Univ., Portici (Italy). Dipartimento di Scienze Zootecniche ed Ispezione degli Alimenti); Gallo, D. (Naples Univ., Portici (Italy). Dipartimento di Scienze Zootecniche ed Ispezione degli Alimenti) ...
Italian journal of animal science,
01/2003, Letnik:
2, Številka:
1S
Journal Article
Recenzirano
Odprti dostop
Recently a new allele, CSN1S1 N, associated with an apparently null amount of alpha sub(s1) casein, has been identified. Such allele is characterized by the citosine deletion at position 23 of the ...ninth exon of the gene, with consequent formation of a premature termination codon. The preliminary analysis by RT-PCR of transcripts produced by N allele at locus CSN1S1 of goat showed, besides to a product corresponding to a correctly assembled mRNA, at least 10 other transcripts due to an exceptional variability of splicing events.
Recentemente al locus CSN1S1 di capra è stato individuato un nuovo allele, CSN1S1 N, associato a un contenuto apparentemente nullo di caseina alfa inf(s1). Tale allele si caratterizza per la delezione della citosina al 23 nt del nono esone del gene, con conseguente formazione di un codone di terminazione prematuro. L´analisi preliminare per mezzo di RT-PCR dei trascritti prodotti dall´allele N al locus CSN1s1 di capra ha evidenziato, oltre a un prodotto corrispondente a un mRNA correttamente assemblato, almeno altri 10 trascritti, conseguenza di un´eccezionale variabilità di eventi di splicing
Sia nei convegni nazionali, sia all'interno di iniziative locali più circoscritte, la nostra associazione (SIAA) ha creato spazi di confronto sulle diverse sfide professionali con cui il sapere ...antropologico deve misurarsi quando prova ad applicarsi nello spazio pubblico (contesti interdisciplinari, effetto della crisi, collaborazione e mutualismo).
La propensione per lo studio delle specificità culturali ha fatto dell’antropologia una delle discipline direttamente interessate ai processi di mutamento pianificato. L’attenzione per la ...cooperazione internazionale allo sviluppo e alle sue ricadute professionali è stata ben presente nell’antropologia italiana e all’interno dei convegni SIAA, ma il dibattito in seno all’associazione è rimasto per il momento sottodimensionato rispetto a un altro ambito di grande interesse pubblico, la migrazione dai paesi affetti da conflitti e povertà verso l’Europa e al ruolo che gli antropologi possono svolgere nelle politiche di accoglienza.
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