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Biomedical subjects

J Vincent

Publications and source records attributed to J Vincent.

At least 37 records · Page 2Linked to original sources

Pharmacokinetics of a fluoronaphthyridone, trovafloxacin (CP 99,219), in infants and children following administration of a single intravenous dose of alatrofloxacin.

The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average +/- standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 +/- 1.4 microg/ml. The primary pharmacokinetic parameters (average +/- SD) analyzed were volume of distribution at steady state (1.6 +/- 0.6 liters/kg), clearance (151 +/- 82 ml/h/kg), and half-life (9.8 +/- 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 +/- 10.1 microg. h/ml and the susceptibility (< or =0.5 microg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.

Adolescent↗

A randomized clinical trial comparing concurrent and alternating thoracic irradiation for patients with limited small cell lung carcinoma. "Petites Cellules" Group.

BACKGROUND: Although thoracic radiotherapy is considered to be useful for the treatment of patients with small cell lung carcinoma (SCLC), its optimal administration schedule is still controversial. METHODS: In a multicenter clinical trial, 164 patients with limited SCLC (of whom 156 were eligible for the study) were randomized to receive either concurrent thoracic irradiation, initiated immediately after the second cycle of chemotherapy (Days 30-64) at a dose of 50 grays in 20 fractions, or alternating thoracic irradiation, scheduled in 3 courses between the second, third, fourth, and fifth cycles of chemotherapy with a 7-day rest period after and before chemotherapy at a dose of 20 grays in 8 fractions (Days 36-47 and Days 64-75) and then 15 grays in 6 fractions (Days 92-101). The same chemotherapy regimen (cyclophosphamide-doxorubicin or vindesine-etoposide) was administered every 4 weeks in both groups. RESULTS: Concurrent radiotherapy-induced lung toxicity led to early termination of this trial when a significant difference was observed (6 cases vs. 1, P = 0.05, 2-sided log rank test). Objective response rates were 89% in the 82 patients of the concurrent radiotherapy group and 95% in the 74 patients of the alternating radiotherapy group. Median survival periods were 13.5 and 14.0 months, respectively, with no significant difference between the two survival distributions (P = 0.15, 2-sided log rank test). Toxic deaths due to bone marrow hypoplasia were similar in both groups (3 vs. 2), but mortality due to lung toxicity (pulmonary fibrosis) was more frequent with concurrent radiotherapy (6 patients) than with alternating radiotherapy (1 patient) in long term analysis (P = 0.05, 2-sided log rank test). CONCLUSIONS: Although no statistically significant overall survival difference was observed between the two radiation therapy schedules, the better tolerance of the alternating schedule justifies the choice of this schedule with this chemotherapy regimen, although it may not be applicable to other chemotherapy regimens.

Antineoplastic Combined Chemotherapy Protocols↗

The monoclonal antibody DCGM4 recognizes Langerin, a protein specific of Langerhans cells, and is rapidly internalized from the cell surface.

We generated monoclonal antibody (mAb) DCGM4 by immunization with human dendritic cells (DC) from CD34+ progenitors cultured with granulocyte-macrophage colony-stimulating factor and TNF-alpha. mAb DCGM4 was selected for its reactivity with a cell surface epitope present only on a subset of DC. Reactivity was strongly enhanced by the Langerhans cell (LC) differentiation factor TGF-beta and down-regulated by CD40 ligation. mAb DCGM4 selectively stained LC, hence we propose that the antigen be termed Langerin. mAb DCGM4 also stained intracytoplasmically, but neither colocalized with MHC class II nor with lysosomal LAMP-1 markers. Notably, mAb DCGM4 was rapidly internalized at 37 degrees C, but did not gain access to MHC class II compartments. Finally, Langerin was immunoprecipitated as a 40-kDa protein with a pI of 5.2 - 5.5. mAb DCGM4 will be useful to further characterize Langerin, an LC-restricted molecule involved in routing of cell surface material in immature DC.

Antibodies, Monoclonal↗

Manufacture of strontium-82/rubidium-82 generators and quality control of rubidium-82 chloride for myocardial perfusion imaging in patients using positron emission tomography.

We describe a protocol to manufacture 82Sr/82Rb generators and 82RbCl for myocardial imaging with PET. The generators are manufactured in 3 stages: (1) preparation of a tin oxide column, (2) leak test of the generator column and (3) loading of the generator with 82Sr. The generators produced sterile and non-pyrogenic 82RbCl for i.v. injection. No significant 82Sr/85Sr breakthroughs were observed after elution with 20 1 of saline. The automated system delivered human doses of 82RbCl accurately.

Chlorides↗

Investigation of cholecystokinin system genes in panic disorder.

There is evidence for the role of the cholecystokinin (CCK) neurotransmitter system in the neurobiology of panic disorder (PD). The CCK receptor agonist, CCK-tetrapeptide (CCK-4) fulfills criteria for a panicogenic agent and there is evidence that PD might be associated with an abnormal function of the CCK system. For example, PD patients show an enhanced sensitivity to CCK-4, and exhibit lower CSF and lymphocyte CCK concentration as compared to healthy controls (reviewed by Bradwejn et al.). Also, untreated PD patients display an increased CCK-4-induced intracellular Ca2+ mobilization in T cells relative to treated PD, depression and schizophrenia. The CCK receptors have been classified into two subtypes: CCK-A and CCK-B. We report here a study of polymorphisms in the CCK pre-pro hormone gene (CCK), CCK-AR, and CCK-BR in DSM-IV panic patients (n = 99) vs controls matched for gender and ethnicity. The CCK polymorphism revealed no association with PD. We identified a new polymorphism for the CCK-A receptor gene, and tested it in our sample, with negative results. A single nucleotide polymorphism has been found in the coding region of the CCK-B receptor gene (CCK-BR) and D Collier (personal communication) identified a highly polymorphic dinucleotide (CT)n microsatellite in the 5' regulatory region. For the CCK-B receptor gene polymorphism, PD patients showed a significant association. Our genetic dissection of the CCK system thus far suggests that the CCK-B receptor gene variation may contribute to the neurobiology of panic disorder.

Alleles↗

Stiripentol: efficacy and tolerability in children with epilepsy.

PURPOSE: Stiripentol (STP) is a new antiepileptic drug (AED) that inhibits cytochrome P450, resulting in increased plasma concentrations of concomitant AEDs. The efficacy and tolerability of STP as an add-on therapy in children were assessed. METHODS: Two hundred twelve patients with refractory epilepsy, aged from 1 month to 20.5 years, received STP either in a single-blind, placebo-controlled trial (108 patients) or in a further open trial (104 other patients selected by epilepsy syndrome for possible efficacy based on the results of the previous trial). RESULTS: Among the 97 patients who could be analyzed for efficacy in the placebo-controlled study, the median seizure frequency was lower at 3 months with STP than with the placebo (p<0.0001); 49% responded to the drug, including 10% who became seizure free. Patients with partial epilepsy had the highest response rate (57%). Results were confirmed in the open study where 68% of the 91 patients receiving STP responded at 3 months. These patients were mainly those with partial epilepsy (73%) who were receiving carbamazepine (CBZ) (75%) as comedication (p<0.001). Ten of the 20 children with severe myoclonic epilepsy in infancy also responded with clobazam (CLB) as comedication. Efficacy was sustained long term in 74% of the 94 patients still receiving STP at a mean 30-month follow-up. Adverse events were reported in 48% of the 212 patients, mainly anorexia and loss of weight, but these events required STP discontinuation in only nine cases. Side effects were minimized in the open trial by optimizing the dose of comedication. CONCLUSIONS: STP seems to be a promising add-on drug, particularly when combined with CBZ in patients with partial childhood epilepsy refractory to vigabatrin (VGB) and with CLB in patients with severe myoclonic epilepsy in infancy.

Adolescent↗

Oral bioavailability and pharmacokinetics of trovafloxacin in patients with AIDS.

Trovafloxacin pharmacokinetics were evaluated in 12 subjects with AIDS. By using a randomized design, single 200-mg doses of oral trovafloxacin and intravenous alatrofloxacin were administered. The mean absolute bioavailability was 91%. The pharmacokinetics of trovafloxacin when administered orally as the active form or intravenously as the prodrug (alatrofloxacin) are not altered in subjects with AIDS compared to those in healthy adults.

Acquired Immunodeficiency Syndrome↗

Wingless and Hedgehog pattern Drosophila denticle belts by regulating the production of short-range signals.

The secreted proteins Wingless and Hedgehog are essential to the elaboration of the denticle pattern in the epidermis of Drosophila embryos. We show that signaling by Wingless and Hedgehog regulates the expression of veinlet (rhomboid) and Serrate, two genes expressed in prospective denticle belts. Thus, Serrate and veinlet (rhom) partake in the last layer of the segmentation cascade. Ultimately, Wingless, Hedgehog, Veinlet (an indirect activator of the Egfr) and Serrate (an activator of Notch) are expressed in non-overlapping narrow stripes. The interface between any two stripes allows a reliable prediction of individual denticle types and polarity suggesting that contact-dependent signaling modulates individual cell fates. Attributes of a morphogen can be ascribed to Hedgehog in this system. However, no single morphogen organises the whole denticle pattern.

Animals↗

Separation of proteolytic enzymes originating from Antarctic krill (Euphausia superba) by capillary electrophoresis.

Extracts prepared from Antarctic krill (Euphausia superba), mainly consisting of acidic proteolytic enzymes, have been studied with capillary electrophoretic techniques. Approximately 50 repeatable peaks were obtained with capillary zone electrophoresis on an untreated fused-silica capillary using a phosphate buffer containing anionic and cationic fluorosurfactant additives as separation medium. A faster separation was achieved on a polyvinyl alcohol coated capillary. Quantitative variations of individual proteins regarding different krill enzyme batches were noted. In the krill samples trypsin-like serine proteinase, carboxypeptidase A and carboxypeptidase B were tentatively identified.

Adsorption↗

Hepatobiliary elimination of trovafloxacin and metabolites following single oral doses in healthy volunteers.

Trovafloxacin, a fluoronaphthyridone derivative related to fluoroquinolones, has significant activity against gram-negative and gram-positive pathogens, including penicillin-resistant Streptococcus pneumoniae, anaerobes and atypical organisms, good tissue penetration and a long elimination half-life. Following oral administration, less than 10% of the dose is renally eliminated as unchanged drug. Hepatobiliary elimination of trovafloxacin was examined by comparing the time course and bile and serum concentrations of trovafloxacin and its metabolites following oral administration to three patients with in-dwelling nasobiliary catheters or T-tubes. Following a single 200 mg oral dose, the mean maximum plasma trovafloxacin concentration was 2.0+/-0.4 mg/l, the area under the concentration-time curve 22.0+/-5.5 mg x h/l and the elimination half-life 8.5 h. Values in bile for the same subjects were 27.8+/-9.6 mg/l, 327.7+/-142.9 mg x h/l and 10.7 h. Corresponding values for the N-acetyl metabolite in bile were 3.8+/-3.4 mg/l, 35.3+/-29.8 mg x h/l and 8.3 h. The mean bile : serum ratio of trovafloxacin was 14:9 and consistent with biliary elimination. Serum concentrations of trovafloxacin in this study were similar to those reported in healthy volunteers. Bile concentrations of trovafloxacin substantially exceeded those of the N-acetyl metabolite, suggesting efficient clearance of the metabolite or that hepatic metabolism of trovafloxacin is not extensive.

Administration, Oral↗

Single- and multiple-dose administration, dosing regimens, and pharmacokinetics of trovafloxacin and alatrofloxacin in humans.

A simplified dosing algorithm for trovafloxacin was evaluated following a single-dose infusion of alatrofloxacin at trovafloxacin equivalent doses of 30, 100, 200, 300 and 400 mg (57 subjects), and multiple doses of 200, 300 and 400 mg (30 subjects). Maximum serum concentration and area under the concentration-time curve for trovafloxacin increased with dose. Trovafloxacin clearance (82-85 ml x h/kg) and volume of distribution (1.3-1.6 l/kg) were independent of dose. Infusion of alatrofloxacin at a trovafloxacin equivalent dose of 300 mg at 1, 2 or 3 mg/ml over 1 h did not alter the pharmacokinetics of trovafloxacin. A plot of the weight-adjusted dose of trovafloxacin in individual subjects against the maximum serum concentration following single and multiple dosing, indicated that the maximum serum concentration increased 1 microg/ml for each 1 mg/kg of trovafloxacin administered. Thus, a prior knowledge of the desired serum concentration will permit appropriate dosing without the use of complex nomograms in patients with normal hepatic function.

Administration, Oral↗

Pharmacokinetics and metabolism of single oral doses of trovafloxacin.

Trovafloxacin, a new fluoronaphthyridone derivative related to fluoroquinolone antimicrobial drugs, has demonstrated the following characteristics: significant gram-positive and gram-negative activity; significant activity against anaerobes and atypical respiratory pathogens; approximately 11-hour elimination half-life, permitting once-daily administration; and good tissue penetration. Because <10% of an orally administered dose is recovered in urine as unchanged drug, the predominant route of trovafloxacin elimination appears to be nonrenal. The two studies described in this review examined the metabolism and excretion of trovafloxacin and compared the time course and concentrations of trovafloxacin and its metabolites in bile to those in serum. In the first study, four healthy male volunteers received a single, oral 200-mg dose of radiolabeled trovafloxacin. In the second study, three patients with indwelling nasobiliary tubes received a single 200-mg dose of trovafloxacin. Samples of blood, urine, bile, and feces were collected. Trovafloxacin in urine and serum was analyzed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection and in bile by HPLC-mass spectroscopy (MS). Levels of the N-acetyl metabolite in bile were determined by HPLC/UV/MS. Metabolites in serum, urine, and feces were determined by reverse-phase HPLC/MS, and radioactivity in these samples was assayed by liquid scintillation counting. In the first study, 63.3% and 23.1% of total radioactivity were recovered in feces and urine, respectively, with most of the radioactivity in urine in the form of the ester glucuronide metabolite (12.8%) and unchanged trovafloxacin (5.9%). Unchanged drug, the N-acetyl metabolite, and the N-sulfate of trovafloxacin accounted for 43.2%, 9.2%, and 3.9%, respectively, of the radioactivity in feces. In the second study, biliary trovafloxacin concentrations were highest between 1.5 and 10 hours postdose, and the maximum concentrations ranged from 18.9 to 37.9 microg/mL. The mean bile:serum ratio of trovafloxacin was 14.9, and the biliary concentration of parent drug was higher than that of its N-acetyl metabolite. In both studies, trovafloxacin was well tolerated, with no discontinuations due to adverse events. The pharmacokinetic profile of trovafloxacin in serum was consistent in healthy subjects and in individuals who had undergone recent hepatobiliary surgery. Trovafloxacin is metabolized primarily by the liver, through phase II metabolism (glucuronidation 13.2%, N-acetylation 10.4%, and N-sulfoconjugation 4.1%); minimal oxidative metabolism was detected. Renal elimination accounted for <10% of the administered dose. The high bile to serum ratio and higher trovafloxacin concentrations relative to metabolite concentrations are consistent with nonrenal elimination. These pharmacokinetic and pharmacodynamic results, together with a broad antimicrobial spectrum, long 11-hour elimination half-life, and low drug-interaction potential, suggest that trovafloxacin may be particularly appropriate for use in the surgical setting.

Administration, Oral↗

Concentrations of trovafloxacin in colonic tissue and peritoneal fluid after intravenous infusion of the prodrug alatrofloxacin in patients undergoing colorectal surgery.

BACKGROUND: Trovafloxacin is a new fourth-generation fluoroquinolone whose pharmacokinetics and in vitro activity suggest that it is well suited for antibiotic prophylaxis in elective colorectal surgery. Alatrofloxacin is a prodrug that is rapidly hydrolyzed to trovafloxacin in the body. METHODS: Twelve patients received a single dose of alatrofloxacin equivalent to 200 mg trovafloxacin by intravenous infusion over 1 hour. Surgery was started at various time points relative to infusion time to allow determination of trovafloxacin concentrations in serum, colonic tissue, and peritoneal fluid as a function of time. RESULTS: The concentration in the earliest colonic tissue sample (1.4 hours after dosing) was 1.4 microg/g. The maximum colonic tissue concentration was 2.8 microg/g in a sample taken 2 hours after dosing. Colonic tissue/serum concentration ratios in samples taken 2-10 hours after the end of infusion ranged from 0.8 to 1.47. Concentrations of trovafloxacin in peritoneal fluid ranged from below the level of quantitation to 2.1 microg/mL at the time of colonic tissue sampling and from below the level of quantitation to 2.5 microg/mL at the time of wound closure. Alatrofloxacin was well tolerated. CONCLUSIONS: After a single intravenous dose of alatrofloxacin equivalent to 200 mg trovafloxacin, trovafloxacin is distributed rapidly into colonic tissue and peritoneal fluids. Tissue concentrations approximate serum concentrations and decline in parallel for up to 10 hours after dosing.

Adult↗

Penetration of trovafloxacin into gynecologic tissues.

BACKGROUND: This randomized open-label study assessed the penetration into gynecologic tissues of trovafloxacin, a new broad-spectrum, fourth-generation fluoroquinolone with in vitro activity against anaerobes, gram-positive, gram-negative, and atypical pathogens. METHODS: Women undergoing hysterectomy or hysterectomy and adnexectomy received 200 mg trovafloxacin orally before surgery as a single dose or as multiple doses. Samples of genital tract tissue and serum were obtained simultaneously during surgery. RESULTS: In the single-dose group, trovafloxacin concentrations in genital tract tissues were measurable for up to 30 hours. Tissue concentrations of trovafloxacin after multiple doses were comparable to those after single doses. Mean tissue: serum concentration ratios after a single dose were greatest in the ovary (1.6 microg/g) and comparable in uterus, myometrium, cervix, and fallopian tubes (0.5 to 0.7 microg/g). Adverse events after a single dose were minor. CONCLUSIONS: A daily dose of 200 mg trovafloxacin produces gynecologic tissue concentrations that persist for up to 30 hours at levels necessary to prevent or treat pelvic infections. This dosing regimen is well tolerated.

Administration, Oral↗

The bioavailability of nasogastric versus tablet-form oral trovafloxacin in healthy subjects.

BACKGROUND: Patients in the hospital, as well as those in home care settings, often require nutritional supplementation with enteral feeding solutions. In addition, patients with serious infections who are clinically unstable often cannot maintain adequate intake by mouth and may require an alternative to oral antibiotic administration. However, delivery of crushed oral formulations of drugs via nasogastric tubes is often carried out without adequate bioavailability data, and this method of administration may not always be equivalent to oral drug delivery. METHODS: In an open-label, randomized, four-period, four-treatment, cross-over study, 24 healthy volunteers were given one dose of each of the following treatments, with a 7-day wash-out between dosing periods: Treatment A: two 100-mg trovafloxacin tablets given orally with 240 mL water; Treatment B: two crushed 100-mg trovafloxacin tablets suspended in water and administered through a nasogastric tube into the stomach; Treatment C: two crushed 100-mg trovafloxacin tablets suspended in water and administered through a nasogastric tube into the duodenum; or Treatment D: two crushed 100-mg trovafloxacin tablets suspended in water and given through a nasogastric tube into the stomach concomitantly with an enteral feeding solution (240 mL full-strength Osmolite). RESULTS: Pharmacokinetic analyses showed that the bioavailability of trovafloxacin after administration of crushed tablets into the stomach with or without concomitant enteral feeding was not significantly different from that of the orally administered whole tablets: the 90% confidence limits of the area under the concentration-time curve (AUC(0-infinity)) for Treatment B versus Treatment A (91.3%, 109.5%) and Treatment D versus Treatment A (91.6%, 109.9%) were well within the bioequivalence criteria of 80% to 125%. Results of analysis of variance (ANOVA) indicated no significant sequence, period, or treatment-by-period interaction effects. Administration of trovafloxacin into the duodenum (Treatment C) resulted in reduced systemic exposure to trovafloxacin, with a 31% decrease in AUC(0-infinity) and a 30% decrease in peak serum concentration (Cmax) compared to oral administration. Time to peak serum concentration (Tmax) was 1.7 hours after oral administration of trovafloxacin and 1.1 hours after administration directly into the stomach or duodenum through a nasogastric tube in the absence of concomitant enteral feeding. All four treatments were well tolerated; no participant discontinued the study due to adverse events and no serious adverse events were reported. CONCLUSIONS: These results showed that administration of crushed trovafloxacin tablets through a nasogastric tube into the stomach, with or without concomitant enteral feeding, achieves absorption and tolerability comparable to those of orally administered trovafloxacin tablets.

Absorption↗

The pharmacokinetic effects of coadministration of morphine and trovafloxacin in healthy subjects.

BACKGROUND: Morphine and antibiotics are frequently coadministered in the surgical setting. These agents may interact, reducing the efficacy of the antibiotic or increasing the toxicity of morphine. It is therefore important to determine whether antibiotics that might be used for surgical prophylaxis have the potential to change the pharmacokinetics of morphine. It is equally important to learn whether morphine affects the plasma levels of antibiotics and thus may potentially influence their efficacy or tolerability. METHODS: This open, randomized, placebo-controlled, three-treatment, three-period cross-over study enrolled 19 healthy volunteers. Oral trovafloxacin (200 mg), a novel fluoroquinolone antibiotic, and intravenous morphine (0.15 mg/kg) were coadministered, and the effects on the pharmacokinetics of each drug and on changes in the pharmacologic action of morphine, estimated from its effects on respiratory rate and level of sedation, were examined. RESULTS: When trovafloxacin was coadministered with morphine, the half-life of trovafloxacin was unchanged; however, the ratio of the area under the serum concentration versus time curve (AUC(0-infinity)) estimates for trovafloxacin/morphine versus trovafloxacin/placebo was 63.8% (95% confidence interval [CI], 40.7% to 100.3%), indicating a 36% reduction in the bioavailability of trovafloxacin. The ratio of the mean maximum serum concentration (Cmax) estimates of trovafloxacin for the two treatments was 53.8% (95% CI: 36.1% to 80.1%), indicating a 46% reduction in Cmax. The time to Cmax was delayed by 4 hours. With trovafloxacin coadministration, there were no statistically significant changes in either the mean relative bioavailability of morphine or that of its metabolite, 6beta-glucuronide-morphine. Coadministration of trovafloxacin did not exacerbate the reduction in respiratory rate or increase the number of side effects associated with morphine administration. CONCLUSIONS: Coadministration of trovafloxacin and morphine reduces the bioavailability and maximum serum concentrations of trovafloxacin. However, elimination of oral trovafloxacin is not impaired, suggesting that the efficacy of trovafloxacin could be maintained in many patients who receive concomitant morphine. Morphine plasma levels and pharmacologic effects are not significantly altered by coadministration of trovafloxacin. Despite their similar metabolic pathways, the trovafloxacin/morphine combination neither exacerbates the respiratory depressant effects of morphine nor increases the frequency of side effects when compared with placebo/morphine treatment. These results suggest that the efficacy of trovafloxacin may be maintained when coadministered with morphine. Concurrent administration of trovafloxacin and morphine is unlikely to alter the pharmacologic effects of morphine.

Adolescent↗

A novel lysosome-associated membrane glycoprotein, DC-LAMP, induced upon DC maturation, is transiently expressed in MHC class II compartment.

We have identified a novel lysosome-associated membrane glycoprotein localized on chromosome 3q26.3-q27, DC-LAMP, which is homologous to CD68. DC-LAMP mRNA is present only in lymphoid organs and DC. A specific MAb detects the protein exclusively in interdigitating dendritic cells. Expression of DC-LAMP increases progressively during in vitro DC differentiation, but sharply upon activation with LPS, TNFalpha, or CD40L. Confocal microscopy confirmed the lysosomal distribution of the protein. Furthermore, DC-LAMP was found in the MHC class II compartment immediately before the translocation of MHC class II molecules to the cell surface, after which it concentrates into perinuclear lysosomes. This suggests that DC-LAMP might change the lysosome function after the transfer of peptide-MHC class II molecules to the surface of DC.

Amino Acid Sequence↗