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1.
Rev Chir Orthop Reparatrice Appar Mot ; 94(2): 174-8, 2008 Apr.
Article in French | MEDLINE | ID: mdl-18420062

ABSTRACT

We report the case of a child who presented polydactyly with eight triphalangeal fingers, no thumb or radius and ulnar dimelia. Hand, wrist, forearm and elbow function was compromised, particularly due to wrist stiffness in flexion, the absence of forearm pronation supination and severe limitation of elbow motion. In addition, the child underwent surgery for pyloric hypertrophy and also presented a multicystic kidney. We present the clinical, anatomic, electromyographic, genetic and therapeutic aspects of this rare deformity and discuss data presented in the literature.


Subject(s)
Hand Deformities, Congenital , Age Factors , Arm/abnormalities , Arm/diagnostic imaging , Child, Preschool , Follow-Up Studies , Hand Deformities, Congenital/diagnostic imaging , Hand Deformities, Congenital/genetics , Hand Deformities, Congenital/therapy , Humans , Infant , Infant, Newborn , Male , Polydactyly/diagnosis , Polydactyly/diagnostic imaging , Radiography , Radius/abnormalities , Radius/diagnostic imaging , Time Factors , Ulna/abnormalities , Ulna/diagnostic imaging
3.
Biochem Pharmacol ; 34(9): 1537-42, 1985 May 01.
Article in English | MEDLINE | ID: mdl-3994764

ABSTRACT

The expression of epoxide hydrolases was studied in cultured rat hepatocytes and hepatoma cell lines. Styrene 7,8-oxide and benzo[a]pyrene 4,5-oxide were used as substrates for microsomal epoxide hydrolase and trans-stilbene oxide for the cytosolic form of this enzyme. In freshly isolated hepatocytes from control rats, microsomal epoxide hydrolase activity was 7.7 and 10.8 nmoles/mg cellular protein/min with benzo[a]pyrene 4,5-oxide and styrene 7,8-oxide as substrates respectively. This enzyme activity increased by more than 2-fold in hepatocytes after 24 hr in culture and remained elevated throughout 96 hr using both substrates. In cultured hepatocytes from rats pretreated in vivo with phenobarbital, trans-stilbene oxide, 2-acetylaminofluorene and N-hydroxy-2-acetylaminofluorene, both benzo[a]pyrene 4,5-oxide and styrene 7,8-oxide hydrolase activities were increased greater than 1.8 relative to controls. Hepatocytes from 2-acetylaminofluorene-pretreated animals at 24 hr in culture had approximately 9-fold higher activities than control hepatocytes. In marked contrast to microsomal epoxide hydrolase activity, the cytosolic enzyme showed an initial activity of 191 pmoles/mg cellular protein/min in freshly isolated hepatocytes, decreased by 75% after 24 hr in culture, and was barely detectable at 96 hr. A similar trend was apparent in hepatocytes from the pretreated animals. In vitro treatment of hepatocytes with trans-stilbene oxide and phenobarbital increased microsomal epoxide hydrolase, while this activity was refractory to 2-acetylaminofluorene treatment. Styrene 7,8-oxide hydrolase activity was increased in the McA-RH-7777 rat hepatoma cell line by phenobarbital, trans-stilbene oxide and 2-acetylaminofluorene treatment. Similarly, benzo[a]pyrene 4,5-oxide hydrolase activity was also increased in this cell line by treatment with phenobarbital and trans-stilbene oxide but not by 2-acetylaminofluorene. Microsomal epoxide hydrolase activity in rat H4-II-E hepatoma cells was refractory to induction, except by trans-stilbene oxide treatment, which caused a 70% increase in benzo[a]pyrene 4,5-oxide hydrolase activity.


Subject(s)
Epoxide Hydrolases/biosynthesis , Liver Neoplasms, Experimental/enzymology , Liver/enzymology , 2-Acetylaminofluorene/pharmacology , Animals , Cells, Cultured , Enzyme Induction , Hydroxyacetylaminofluorene/pharmacology , Male , Phenobarbital/pharmacology , Rats , Rats, Inbred Strains , Stilbenes/pharmacology
4.
Biochem Biophys Res Commun ; 116(2): 587-92, 1983 Oct 31.
Article in English | MEDLINE | ID: mdl-6686036

ABSTRACT

Microsomal epoxide hydrolase activity, determined using benzpyrene 4,5-oxide and styrene 7,8-oxide, increased in cultured hepatocytes compared to freshly isolated cells. In contrast, cytosolic epoxide hydrolase activity, assayed using trans-stilbene oxide, had decreased 80% by 24 hr and was barely detectable after 96 hr in culture. There was no difference in enzyme activity between freshly isolated hepatocytes and the two rat hepatoma cell lines McA-RH 7777 and H4-II-E, when styrene 7,8-oxide was used as substrate. However, benzpyrene 4,5-oxide hydrolase activity of the McA-RH 7777 and H4-II-E cell lines were 55 and 10%, respectively, of freshly isolated hepatocytes. These results show that hepatoma cell lines provide a suitable system for studying the regulation of both the microsomal and cytosolic epoxide hydrolase enzymes.


Subject(s)
Epoxide Hydrolases/metabolism , Liver Neoplasms, Experimental/enzymology , Microsomes, Liver/enzymology , Animals , Benzopyrenes/metabolism , Cells, Cultured , Cytosol/enzymology , Epoxy Compounds/metabolism , Liver Neoplasms, Experimental/ultrastructure , Male , Molecular Weight , Rats , Rats, Inbred Strains , Time Factors
5.
Toxicol Lett ; 18(1-2): 115-20, 1983 Aug.
Article in English | MEDLINE | ID: mdl-6623533

ABSTRACT

Rabbit liver microsomes N-hydroxylate both 2-acetylaminofluorene (2-AAF) and 2-aminofluorene (2-AF). They also deacetylate N-hydroxy-2-acetylaminofluorene (N-OH-2-AAF). The enzymic activity towards the two substrates is the same but the enzyme has a higher affinity for the arylamide than for the arylamine. With regard to various modifiers added in vitro, rabbit liver microsomal N-hydroxylase behaves like those of rat, hamster and mouse. However, it is less effectively inhibited by the substituted imidazole derivative, Miconazole (MN). None of the enzymic properties of the rabbit liver microsomal N-hydroxylase investigated explains the resistance of this tissue to the carcinogenic effect of 2-AAF.


Subject(s)
2-Acetylaminofluorene/metabolism , Carcinogens/metabolism , Fluorenes/metabolism , Microsomes, Liver/enzymology , Mixed Function Oxygenases/analysis , Animals , Male , Rabbits
6.
Toxicol Lett ; 16(3-4): 339-45, 1983 May.
Article in English | MEDLINE | ID: mdl-6857728

ABSTRACT

As compared to rat liver microsomal arylamide N-hydroxylase both the dog and the human enzymes have lower affinity but higher activity. SKF525A, a well known effector of cytochrome P-450 dependent mixed function oxidases, activates the hepatic N-hydroxylase of all three species. This effect is concentration dependent and tends to plateau at 50 X 10(-6)M. As previously demonstrated with rat liver microsomes, the ring-hydroxylated, non-toxic, metabolites of 2-acetylaminofluorene, interact with the N-hydroxylating enzyme. These interactions are both compound- and species-specific. The most striking differences are seen with the paraphenolic product which activates the rat, does not affect the dog and inhibits the human liver enzyme. In the liver of this last species, that compound is the main metabolite of 2-acetylaminofluorene (2-AAF).


Subject(s)
Microsomes, Liver/enzymology , Mixed Function Oxygenases/metabolism , 2-Acetylaminofluorene/metabolism , Animals , Child , Dogs , Enzyme Activation/drug effects , Humans , In Vitro Techniques , Kinetics , Male , Mixed Function Oxygenases/antagonists & inhibitors , Proadifen/pharmacology , Rats , Rats, Inbred Strains , Species Specificity
7.
Cancer Res ; 42(11): 4712-8, 1982 Nov.
Article in English | MEDLINE | ID: mdl-7127306

ABSTRACT

The guinea pig is resistant to the hepatocarcinogenic effects of 2-acetylaminofluorene and 2-aminofluorene. This resistance, however, is not due to the lack of a N-hydroxylating enzyme in the liver which catalyzes the first and rate-limiting step to the activation of these chemicals to proximal carcinogens. It is shown that guinea pig liver microsomes can N-hydroxylate both of these compounds. The N-hydroxylation of 2-acetylaminofluorene but not 2-aminofluorene is inducible by pretreating the guinea pigs with benz(a)anthracene. The microsomal reaction is inhibited by 3-methylcholanthrene, miconazole, or 7,8-benzoflavone, 7-Iodo-2-acetylaminofluorene is N-hydroxylated by guinea pig liver microsomes at approximately the same rate as 2-acetylaminofluorene. The N-hydroxylation of 7-fluoro-2-acetyl-aminofluorene occurs at a much faster rate. The resistance of the guinea pig liver to the carcinogenic effect of the arylamides and arylamines may actually be due to the ability to further convert the N-hydroxylated metabolites to the inactive C7-hydroxylated product. The conversion of N-hydroxy-2-acetylaminofluorene to C7-hydroxy-2-acetylaminofluorene by guinea pig liver microsomes is inhibited by 8-hydroxyquinoline or miconazole. The microsomal metabolic activation of the 7-iodo-2-acetylaminofluorene used to confirm this new metabolic pathway proceeds via a deacetylation step which could explain the resistance of the rat to the carcinogenic effect of that chemical. The high yield of the N-hydroxy-7-fluoro-2-acetylaminofluorene produced by liver microsomes could be responsible for its high carcinogenic potency.


Subject(s)
2-Acetylaminofluorene/analogs & derivatives , Fluorenes/metabolism , Hydroxyacetylaminofluorene/metabolism , Microsomes, Liver/metabolism , Animals , Biotransformation , Chromatography, Gas , Guinea Pigs , Hydroxylation , Kinetics , Male , Mixed Function Oxygenases/metabolism
8.
Chem Biol Interact ; 41(2): 251-64, 1982 Aug.
Article in English | MEDLINE | ID: mdl-6286157

ABSTRACT

Cytochrome P-448 dependent microsomal N-hydroxylases are key enzymes in the metabolic activation of both arylamides and arylamines. Using 2-acetylaminofluorene (2-AAF) and 2-aminofluorene (2-AF) as substrates, the present report compares the biochemical properties of rat, hamster and mouse liver N-hydroxylases. There are marked species differences both in terms of the affinity for the two substrates and in terms of maximum velocity of the enzymes. The rat and hamster liver arylamide N-hydroxylases are induced by pretreatment with 2-AAF which also significantly increases their affinity for the substrate. In mouse liver neither arylamide nor arylamine N-hydroxylases are modified or induced. With 2-AF as substrate, arylamide treatment never enhances N-hydroxylation but it reduces the Km-value of the rat and hamster liver enzymes. Among the effectors tested in vitro, 3-methylcholanthrene (3-MC), 7,8-benzoflavone (BF), benzo[a]pyrene (B[a]P) and miconazole (MN) inhibit hepatic arylamide N-hydroxylase in the submicromolar range. Harman (H) and paraoxon (PX) act in a dose-dependent manner in the micromolar range and metyrapone (MP) is not an inhibitor even at 50-microM concentration. Among the position isomers, 1- and 3-AAF are inhibitors of the N-hydroxylating enzymes whereas 4-AAF is not.


Subject(s)
Microsomes, Liver/enzymology , Mixed Function Oxygenases/metabolism , 2-Acetylaminofluorene/metabolism , Animals , Benzo(a)pyrene , Benzoflavones/pharmacology , Benzopyrenes/pharmacology , Cricetinae , Fluorenes/metabolism , Isomerism , Male , Methylcholanthrene/pharmacology , Metyrapone/pharmacology , Mice , Miconazole/pharmacology , Paraoxon/pharmacology , Rats , Species Specificity , Substrate Specificity
10.
Mol Pharmacol ; 21(2): 449-57, 1982 Mar.
Article in English | MEDLINE | ID: mdl-7099145

ABSTRACT

3-Methycholantrene, benzoanthracene, benzo[e]pyrene, and pyrene induce N-hydroxylase activity and modify the enzyme by increasing its apparent Km. As exemplified by the effect of 3-methylcholanthrene, the polycyclic aromatic hydrocarbons also induce other mixed-function oxidases such as aryl hydrocarbon hydroxylase and the various arylamide C-hydroxylases. Acute or chronic pretreatment of rats with acetylaminofluorenes induces N-hydroxylase and modifies the enzyme affinity by decreasing its apparent Km. Among the various-position isomers, 4-acetylaminofluorene is completely inactive and 2-acetylaminofluorene is the most potent. Its effect is both dose- and time dependent, and it seems to be specific for N-hydroxylase, the same pretreatment having no effect on arylhydrocarbon hydroxylase or arylamide C-hydroxylases. After simultaneous treatment of rats with 3-methylcholanthrene and 2-acetylaminofluorene, even though N-hydroxylase activity as measured on hepatic microsomes in vitro is significantly induced, the urinary excretion of N-hydroxy-2-acetylaminofluorene is significantly reduced over a 24-hr period. This observation is discussed in relationship to the well-known inhibitory effect of 3-methylcholanthrene on the hepatocarcinogenicity of 2-acetylaminofluorene.


Subject(s)
Aryl Hydrocarbon Hydroxylases/biosynthesis , Microsomes, Liver/enzymology , 2-Acetylaminofluorene/metabolism , Animals , Benzopyrene Hydroxylase/metabolism , Biotransformation , Chromatography, Gas , Enzyme Induction/drug effects , Fluorenes/pharmacology , In Vitro Techniques , Male , Phenobarbital/pharmacology , Rats , Rats, Inbred Strains , p-Aminohippuric Acid/pharmacology
11.
Carcinogenesis ; 3(11): 1325-9, 1982.
Article in English | MEDLINE | ID: mdl-7151250

ABSTRACT

3-Methylcholanthrene (3-MC) pretreatment induces the liver microsomal 2-acetylaminofluorene (2-AAF) N-hydroxylase activity of C57BL6 responsive mice. The same pretreatment modifies this enzyme by significantly increasing its apparent Km value which, moreover, becomes protein concentration dependent. After 3-MC induction, the C57BL6 mouse liver microsomal 2-AAF N-hydroxylase is activated by paraoxon and 8-hydroxyquinoline. This last chemical does not, however, inhibit the microsomal metabolism of N-hydroxy-2-acetylaminofluorene (N-OH-2-AAF) as it does in the presence of guinea pig liver microsomes. The hypothesis is formulated that 3-MC pretreatment of C57BL6 mice induces not only cytochrome P448 dependent mixed function oxidase but also the synthesis of a microsomal protein which reversibly binds 2-AAF. Mutagenicity data are presented which corroborate this hypothesis. As in guinea pig liver microsomes, N-OH-2-AAF is further metabolized by both C57BL6 and DBA2 mouse liver microsomes. This metabolism is not inhibited by NaF which acts as an inhibitor of microsomal arylamidase. This is a possible contributing reason why 2-AAF is only weakly carcinogenic for mice.


Subject(s)
2-Acetylaminofluorene/metabolism , Aryl Hydrocarbon Hydroxylases/biosynthesis , Methylcholanthrene/pharmacology , Microsomes, Liver/enzymology , Animals , Enzyme Induction/drug effects , Guinea Pigs , Hydroxyacetylaminofluorene/metabolism , Hydroxylation , Kinetics , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Species Specificity
12.
Toxicol Lett ; 7(6): 385-92, 1981 Mar.
Article in English | MEDLINE | ID: mdl-7018023

ABSTRACT

Pretreatment of rat, hamster or mouse by 3-methylcholanthrene (3-MC) largely induces the liver microsomal N-hydroxylase activity. The same pretreatment given simultaneously with 2-acetylaminofluorene (2-AAF) inhibits the hepatocarcinogenicity in the rat but not in the hamster. The present report compared the in vivo and in vitro effects of 3-MC on liver microsomal N-hydroxylation and liver microsome-mediated mutagenicity of 2-AAF in hamster, rat and mouse. The induction of hamster or mouse liver microsomal N-hydroxylase activity correlated well with the increase in the microsome-mediated mutagenicity of 2-AAF. With rat, however, even though the N-hydroxylase activity is largely enhanced, microsome-mediated mutagenicity is significantly reduced after pretreatment with 3-MC. Such a reduction parallels a decrease in enzyme affinity. Added in vitro to the incubation medium, 3-MC (microM concentration) inhibits both the N-hydroxylase activity and the microsome-mediated mutagenicity of 2-AAF. Those data are discussed in relationship with the biological interactions between 3-MC and 2-AAF.


Subject(s)
2-Acetylaminofluorene/pharmacology , Methylcholanthrene/pharmacology , Microsomes, Liver/physiology , Mutagens , Animals , Cricetinae , Drug Interactions , In Vitro Techniques , Mice , Mixed Function Oxygenases/pharmacology , Rats , Salmonella typhimurium/genetics , Species Specificity
15.
Cancer Res ; 40(10): 3540-6, 1980 Oct.
Article in English | MEDLINE | ID: mdl-7438040

ABSTRACT

By applying a new and highly sensitive assay for measuring N-hydroxy metabolites, the biochemical properties of the microsomal N-hydroxylase from control and 3-methylcholanthrene-treated rat and hamster liver have been analyzed, and the following conclusions have been drawn. (a) Due to a difference in enzyme affinity, the metabolic activation of acetylaminofluorene is more pronounced than that of aminofluorene, a fact which correlates with the difference in the carcinogenic potency of the two compounds. (b) Arylamine N-hydroxylase differs qualitatively as well as quantitatively from arylamide N- hydroxylase mainly in terms of sensitivity to various in vitro inhibitors. (c) 7,8-Benzoflavone and 3-methylcholanthrene are strong inhibitors of liver microsomal N-hydroxylases. This effect could partly explain the inhibition of the hepatic tumorigenicity of acetylaminofluorene in animals simultaneously fed 3-methylcholanthrene. (d) The metabolism of acetylaminofluorene proceeds via both ring- (C-1, C-3, C-5, or C-7) and N-hydroxylation. There is clear reciprocal interaction between these various microsomal pathways. (e) The apparent increase in Km following pretreatment of the rat with 3-methylcholanthrene is due to competitive inhibition of the N-hydroxylase by some of the C-hydroxy metabolites. This effect is not seen in hamster liver.


Subject(s)
2-Acetylaminofluorene/metabolism , Aryl Hydrocarbon Hydroxylases/metabolism , Microsomes, Liver/enzymology , 2-Acetylaminofluorene/pharmacology , Animals , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Benzoflavones/pharmacology , Cricetinae , Enzyme Activation/drug effects , Enzyme Induction , Kinetics , Mesocricetus , Methylcholanthrene/pharmacology , Paraoxon/pharmacology , Rats
16.
Xenobiotica ; 10(7-8): 565-71, 1980.
Article in English | MEDLINE | ID: mdl-7445523

ABSTRACT

1. Ag.l.c. assay for N-hydroxy-2-acetamidofluorene has been modified to measure both N-hydroxy-2-acetamidofluorene and N-hydroxy-2-aminofluorene. 2. Like guinea-pig, monkey N-hydroxylates both 2-aminofluorene and 2-acetamido-fluorene. The N-hydroxy metabolites are rapidly further metabolized even in the presence of inhibitors of deacetylase. The exact nature of this further metabolism is still unknown. Preliminary evidence indicates that, at least in the guinea-pig, 7-hydroxy-2-acetamidofluorene may be a metabolite of N-hydroxy-2-acetmidofluorene. 3. 3-Methylcholanthrene, 7,8-benzoflavone and miconazole, which have been shown to inhibit guinea-pig liver microsomal N-hydroxylase, do not significantly inhibit the monkey liver enzyme. 4. 2-Acetamidofluorene, which inhibits the guinea-pig liver microsomal N-hydroxylation of 2-aminofluorene in vitro, activates the enzyme from monkey liver. This activation, which is dose-dependent, appears to be allosteric. 5. Both guinea-pig and monkey are more efficient in N-hydroxylating 2-aminofluorene than 2-acetamidofluorene. The affinity (in term of apparent KM) of the guinea-pig liver enzyme is 4 times greater than the affinity of the monkey liver enzyme.


Subject(s)
2-Acetylaminofluorene/metabolism , Carcinogens , Fluorenes/metabolism , Microsomes, Liver/metabolism , Animals , Benzoflavones , Drug Resistance , Guinea Pigs , Hydroxylation , Macaca mulatta , Male , Methylcholanthrene/pharmacology , Miconazole/pharmacology
17.
Cancer Lett ; 9(2): 123-31, 1980 Apr.
Article in English | MEDLINE | ID: mdl-7379042

ABSTRACT

Many reports in the literature have indicated that the guinea-pig is resistant to the carcinogenic effect of N-2-fluorenylacetamide (2FAA); this refractoriness has been attributed to its lack of N-hydroxylating enzymes. The present communication, however, supports the results of contradictory reports which demonstrate that guinea-pig liver microsomes are in fact able to N-hydroxylate both 2-fluorenamine and 2FAA. The guinea-pig N-hydroxylase activity toward 2-fluorenamine is found to be even greater than the reported activity in the rat and hamster. It is similarly inhibited by 3-methylcholanthrene (3MC), 7,8-benzoflavone (7,8 BF) or miconazole. Activity toward N-2-fluorenacetamide is present in the microsomal preparation from the control guinea-pig. There is slight activation by SKF525A, paraoxon (PX) or sodium fluoride. Under optimum conditions, in the presence of both paraoxon and sodium fluoride, activity is equivalent to that of rat liver microsomal enzymes.


Subject(s)
2-Acetylaminofluorene/metabolism , Carcinogens/metabolism , Fluorenes/metabolism , Guinea Pigs/metabolism , Microsomes, Liver/metabolism , Animals , Aryl Hydrocarbon Hydroxylases/metabolism , Benzoflavones/pharmacology , Hydroxylation , Male , Methylcholanthrene/pharmacology , Mixed Function Oxygenases/metabolism , Paraoxon/metabolism , Sodium Fluoride/metabolism
18.
Toxicol Lett ; 5(1): 61-7, 1980 Jan.
Article in English | MEDLINE | ID: mdl-7376201

ABSTRACT

The kinetic properties of the N-hydroxylation of 2-acetylaminofluorene (2-AAF) are studied with microsomal preparations of livers from both control and 3-methylcholanthrene (3-MC)-pretreated rats and hamsters. The level of basal enzymatic activity is higher in hamster than in rat liver; 3-MC induces the activity in both animals. When added in vitro to incubation mixture, 3-MC competitively inhibits the N-hydroxylase activity. When fed to rats simultaneously with 2-AAF, 3-MC suppresses the carcinogenicity of the acetylated arylamine by inhibiting the first step in its activation pathway. Hamster tissues are not protected by this pretreatment because the level of N-hydroxylase activity is too high.


Subject(s)
2-Acetylaminofluorene/antagonists & inhibitors , Carcinogens/metabolism , Methylcholanthrene/pharmacology , Microsomes, Liver/enzymology , Mixed Function Oxygenases/analysis , Animals , Cricetinae , In Vitro Techniques , Kinetics , Male , Mixed Function Oxygenases/antagonists & inhibitors , Rats , Species Specificity
20.
Arch Toxicol Suppl ; (1): 291-4, 1978.
Article in English | MEDLINE | ID: mdl-277117

ABSTRACT

N-hydroxylation represents the first and limiting step in the metabolic pathway leading to the carcinogenic activity of aromatic amines and amides. Using a method recently developed by the same authors (Analytical Biochemistry, in press), the effects of pretreatment of male adult rats with N-2-acetylaminofluorene (2AAF), N-4-acetylaminofluorene (4AAF), N-4-acetyl-aminobiphenyl, (4-AABP), and phenobarbital (PB), on the kinetic parameters of the N-hydroxylase activity have been evaluated and compared. Our resutls clearly demonstrate that both hepatocarcinogenic amides, 2-AAF and 4-AABP very significantly increase the affinity of the activating enzyme towards both substrates; on the other hand, 4-AAF and PB, which are non-carcinogenic compounds slightly decrease the affinity of the enzyme. In conclusion, the carcinogenic aromatic amides seem to specifically modify the catalytic properties of the enzyme responsible for their own metabolic activation.


Subject(s)
Amides/pharmacology , Carcinogens/pharmacology , Mixed Function Oxygenases/metabolism , 2-Acetylaminofluorene/pharmacology , Aminobiphenyl Compounds/pharmacology , Animals , Kinetics , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Phenobarbital/pharmacology , Rats
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