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Biomedical subjects

H Gelderblom

Publications and source records attributed to H Gelderblom.

At least 19 recordsLinked to original sources

Influence of the cisplatin hydration schedule on topotecan pharmacokinetics.

The study described here was designed to investigate the influence of the hydration schedule of cisplatin on the pharmacokinetics of topotecan. To test this hypothesis, 13 adult cancer patients were treated with intravenous (i.v.) cisplatin followed by i.v. topotecan for 5 days every 3 weeks using a short hydration schedule (SHS) for cisplatin in the first course and a hyper-hydration schedule (HHS) in the second course or vice versa. Topotecan pharmacokinetic analysis was performed in plasma, whole blood and red blood cells in both courses on days 1, 2 and 5. 11 patients received both courses and were pharmacokinetically evaluable. No significant differences between the two studied schedules were noted in the clearances of topotecan on day 1 in the different matrices. However, in both hydration schedules, on average, slightly lower topotecan clearances were observed on both days 2 and 5 compared with day 1 in all of the matrices, while no differences were noted between days 2 and 5. This alteration was independent of the schedule used and was less pronounced than that which has been initially reported for SHS and, overall, will not have clinical consequences.

Adult↗

Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies.

The paclitaxel vehicle Cremophor EL (CrEL) has been shown to selectively inhibit the accumulation of cisplatin in peripheral blood leucocytes, but not in tumour cells in vitro, and we hypothesised that this phenomenon is responsible for the improvement of the therapeutic index of cisplatin observed in combination studies with paclitaxel. Here, we report on studies assessing the interaction between CrEL and cisplatin in a murine model, and involving the potential clinical applicability of CrEL as a protector for cisplatin-associated haematological side-effects. In mice, CrEL (0.17 ml/kg, intravenous (i.v.)) given in combination with cisplatin (10 mg/kg, intraperitoneal (i.p.)) did not change the pharmacokinetics of cisplatin. Cisplatin-induced haematological toxicity, expressed as white blood cells (WBC) at nadir, was significantly reduced by CrEL from 5.05+/-0.95 to 6.50+/-1.31 x 10(9)/l (P=0.0009). Data obtained from cancer patients treated with cisplatin (70 mg/m(2), 3-h i.v.) and topotecan (0.45 or 0.60 mg/m(2)/day x 2) preceded by CrEL (12 ml, 3-h i.v.) (n=6) or without CrEL (n=10) similarly indicated significant differences in the percent decrease in WBC between the groups (46.5+/-18.7 versus 67.2+/-15.0%; P=0.029). Likewise, the percent decrease in platelet count was significantly greater in the absence of CrEL (23.9+/-5.38 versus 73.3+/-15.5%; P=0.0003). Pharmacokinetic parameters of unbound and total cisplatin and of topotecan lactone and total drug were not significantly different from historic control values (P>or=0.245). Overall, this study provides further evidence on the important role of CrEL in the pharmacological and toxicological profile of cisplatin, and implies that reformulation of cisplatin with CrEL for systemic treatment might achieve an improvement of its therapeutic index, particularly in the setting of a weekly dose-dense concept.

Animals↗

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer.

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic. Since preclinical data suggest that Cremophor EL (CrEL), the formulation vehicle of paclitaxel, has a protective effect on haematological toxicity of cisplatin, CrEL was added to the combination cisplatin and topotecan. In this phase I study, escalating doses of oral topotecan administered on day 1, 2, 8, 9, 15, 16, 29, 30, 36, 37, 43, 44 were combined with weekly cisplatin 70 mg m(-2) d(-1) on day 1, 8, 15, 29, 36, 43 (scheme A) or with the presumably less myelotoxic sequence weekly cisplatin day 2, 9, 16, 30, 37, 44 (scheme B). In scheme C, CrEL 12 ml was administered prior to cisplatin in the sequence of Scheme A. 18 patients have received a total of 85 courses. In scheme A 4/10 patients, all treated with topotecan 0.45 mg m(-2) d(-1), experienced DLT: 1 patient had vomiting grade 4, 1 patient had grade 4 neutropenia >5 days, 1 patient had >2 weeks delay due to thrombocytopenia and 1 patient due to neutropenia. Both patients in scheme B (topotecan 0.45 mg m(-2) d(-1)) had DLT due to a delay > 2 weeks because of prolonged haematological toxicity. No DLT was observed in the first 3 patients in scheme C (topotecan 0.45 mg m(-2) d(-1)). However, 2 out of 3 patients treated at dose level topotecan 0.60 mg m(-2)d(-1) in scheme C experienced DLT due to >2 weeks delay because of persistent thrombocytopenia or neutropenia. We conclude that there is a modest clinical effect of CrEL on haematological toxicity for this cisplatin-based combination regimen, which seems to reduce these side effects but does not really enable an increase of the oral topotecan dose.

Administration, Oral↗

Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation.

Cremophor EL (CrEL) is a formulation vehicle used for various poorly-water soluble drugs, including the anticancer agent paclitaxel (Taxol). In contrast to earlier reports, CrEL is not an inert vehicle, but exerts a range of biological effects, some of which have important clinical implications. Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy. The pharmacokinetic behaviour of CrEL is dose-independent, although its clearance is highly influenced by duration of the infusion. This is particularly important since CrEL can affect the disposition of various drugs by changing the unbound drug concentration through micellar encapsulation. In addition, it has been shown that CrEL, as an integral component of paclitaxel chemotherapy, modifies the toxicity profile of certain anticancer agents given concomitantly, by mechanisms other than kinetic interference. A clear understanding of the biological and pharmacological role of CrEL is essential to help oncologists avoid side-effects associated with the use of paclitaxel or other agents using this vehicle. With the present development of various new anticancer agents, it is recommended that alternative formulation approaches should be pursued to allow a better control of the toxicity of the treatment and the pharmacological interactions related to the use of CrEL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

The rhesus model of Lyme neuroborreliosis.

Similarity of pathology and disease progression make the non-human primate (NHP) model of Lyme neuroborreliosis appropriate and valuable. In the NHP model of Lyme neuroborreliosis, spirochetal density in the nervous system and other tissues has been measured by polymerase chain reaction and correlated to anti-Borrelia burgdorferi antibody in the serum and cerebrospinal fluid and to inflammation in tissues. Despite the demonstrable presence of Borrelia burgdorferi, the causative agent of Lyme borreliosis, only minor inflammation of the central nervous system occurs, though inflammation can be demonstrated in other tissues. Infected animals also develop anti-Borrelia burgdorferi antibody in the serum, although increased amplitude of antibody is not predictive of higher levels of infection. The NHP model continues to provide important insight into the disease process in humans.

Animals↗

No induction of apoptosis by IFN-beta in human antigen-specific T cells.

Interferon (IFN)-beta, the most effective immunomodulatory treatment for MS, inhibits the proliferation of myelin-specific T cells. We report that IFN-beta moderately enhances the expression of the death receptor, CD95, at the surface of human antigen-specific T cells. However, T-cell apoptosis was not induced by IFNbeta-1a or IFNbeta-1b as assessed by caspase activity or DNA fragmentation. Immunomodulation mediated by IFN-beta does not directly involve apoptotic pathways in human T cells.

Adjuvants, Immunologic↗

Abundant defective viral particles budding from microglia in the course of retroviral spongiform encephalopathy.

A pathogenetic hallmark of retroviral neurodegeneration is the affinity of neurovirulent retroviruses for microglia cells, while degenerating neurons are excluded from retroviral infections. Microglia isolated ex vivo from rats peripherally infected with a neurovirulent retrovirus released abundant mature type C virions; however, infectivity associated with microglia was very low. In microglia, viral transcription was unaffected but envelope proteins were insufficiently cleaved into mature viral proteins and were not detected on the microglia cell surface. These microglia-specific defects in envelope protein translocation and processing not only may have prevented formation of infectious virus particles but also may have caused further cellular defects in microglia with the consequence of indirect neuronal damage. It is conceivable that similar events play a role in neuro-AIDS.

Animals↗

Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

Adult↗

Topotecan lacks third space sequestration.

The objective of this study was to determine the influence of pleural and ascitic fluid on the pharmacokinetics of the antitumor camptothecin derivative topotecan. Four patients with histological proof of malignant solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of third space volumes. Serial plasma and pleural or ascitic fluid samples were collected during each dosing and analyzed by high-performance liquid chromatography for both the intact lactone form of topotecan and its ring-opened carboxylate form. The apparent topotecan clearance demonstrated substantial interpatient variability but remained unchanged within the same patient in the presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven courses)]. Similarly, terminal half-lives and area under the concentration-time curve ratios of lactone:total drug in plasma were similar between courses within each patient. Topotecan penetration into pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration increased with time after dosing in all patients. The mean ratio of third space topotecan total drug area under the concentration-time curve to that in plasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely administered to patients with pleural effusions or ascites and that there is substantial penetration of topotecan into these third spaces, which may prove beneficial for local antitumor effects.

Adult↗

Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens.

Anticancer drugs still are dosed based on the body-surface area (BSA) of the individual patient, although the BSA is not the main predictor of the clearance for the majority of drugs. The relevance of BSA-based dosing has not been evaluated for topotecan yet. A retrospective pharmacological analysis was performed of kinetic data from four clinical Phase I studies in which topotecan was administered p.o. as a single agent combined with data from a combination study of topotecan and cisplatin. A strong correlation (r = 0.91) was found between the area under the plasma concentration time curve of the lactone and carboxylate forms of topotecan by plotting 326 data sets obtained from 112 patients receiving oral topotecan at dose levels ranging from 0.15-2.70 mg/m2. The intrapatient variability, studied in 47 patients sampled for 3 or more days, for the apparent lactone clearance, ranged from 7.4-69% (mean, 24 +/- 13%; median, 20%). The interpatient variabilities in the lactone clearance, calculated with the data of all studied patients, expressed in liter/h/m2 and in liter/h were 38% and 42%, respectively. In view of the relatively high inter- and intrapatient variabilities in topotecan clearance, in contrast to a variability of only 12% in the BSA of the studied patients, no advantage of BSA-based dosing was found over fixed dose regimens.

Administration, Oral↗

[Primary cerebral highly-malignant B-cell lymphoma of the Burkitt type].

HISTORY AND CLINICAL FINDINGS: A 40-year-old man was admitted with acute onset of positional vertigo, nausea and vomiting. Neurological examination revealed a fatigable nystagmus to the upward ear in positional testing, to the right more than to the left, as well as latent paresis and rigidity of the left arm. INVESTIGATIONS: Magnetic resonance imaging of the brain revealed two space-occupying lesions in the cerebellum and pons. Open biopsy showed a highly malignant B-cell lymphoma of Burkitt type. There was no evidence of acquired or congenital immunodeficiency. As there were no significant abnormalities outside of the CNS, a primary lymphoma in this location was diagnosed. TREATMENT AND COURSE: Chemotherapy with a combination of drugs including methotrexate achieved only partial remission. Subsequent radiotherapy brought about full remission, which has now lasted for over a year. CONCLUSIONS: Treatment of first choice of a primary cerebral lymphoma in an immunocompetent patient is chemotherapy with cerebrospinal fluid-permeable cytostatics. Partial remission should be followed by radiotherapy.

Adult↗

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications.

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios.

Aged↗

In vivo rescue of a silent tax-deficient bovine leukemia virus from a tumor-derived ovine B-cell line by recombination with a retrovirally transduced wild-type tax gene.

The lack of bovine leukemia virus (BLV) expression is a consistent finding in freshly isolated ovine tumor cells and in the B-cell lines derived from these tumors. In order to gain further insight into the mechanisms of BLV silencing in these tumors, we have used the YR2 B-cell line, which was derived from the leukemic cells of a BLV-infected sheep. This cell line contains a single, monoclonally integrated, silent provirus, which cannot be reactivated either by stimulation in vitro or by in vivo injection of the tumor cells or cloned proviral DNA in sheep. Sequence analysis of the tax gene from the YR2 cell line identified two G-to-A transitions (G7924 to A7924 and G8149 to A8149) that result in E-to-K amino acid changes at positions 228 and 303 in the Tax protein. Following retroviral vector-mediated transfer of a wild-type tax gene into YR2 cells, we showed that BLV mRNA, viral proteins, and virions were produced, demonstrating that the cellular factors required for virus expression were present in the original YR2 cell line. Injection of this transduced YR2 cell line in sheep led to the rescue of replication-competent BLV proviruses. The integrated competent proviruses exhibited unique chimeric tax genes, which arose from homologous recombination between the transduced wild-type tax and the YR2-derived tax sequences. Furthermore, in one of these functional recombinant proviruses, only the A8149-to-G8149 reversion was present, providing clear evidence that the defect underlying the silent phenotype in YR2 cells results from a single C-terminal E303-to-K303 amino acid substitution in the BLV Tax protein. Our observations suggest that a single strategically located mutation in tax provides a mechanism for BLV inactivation in B-cell tumors.

Animals↗

Disposition of [G-(3)H]paclitaxel and cremophor EL in a patient with severely impaired renal function.

In the present work, we studied the pharmacokinetics and metabolic disposition of [G-(3)H]paclitaxel in a female patient with recurrent ovarian cancer and severe renal impairment (creatinine clearance: approximately 20 ml/min) due to chronic hypertension and prior cisplatin treatment. During six 3-weekly courses of paclitaxel at a dose level of 157.5 mg/m(2) (viz. a 10% dose reduction), the renal function remained stable. Pharmacokinetic evaluation revealed a reproducible and surprisingly high paclitaxel area under the plasma concentration-time curve of 26.0 +/- 1.11 microM.h (mean +/- S.D.; n = 6; c.v. = 4.29%), and a terminal disposition half-life of approximately 29 h. Both parameters are substantially increased ( approximately 1.5-fold) when compared with kinetic data obtained from patients with normal renal function. The cumulative urinary excretion of the parent drug was consistently low and averaged 1.58 +/- 0.417% (+/- S.D.) of the dose. Total fecal excretion (measured in one course) was 52.9% of the delivered radioactivity, and mainly comprised known mono- and dihydroxylated metabolites, with unchanged paclitaxel accounting for only 6.18%. The plasma area under the plasma concentration-time curve of the paclitaxel vehicle Cremophor EL, which can profoundly alter the kinetics of paclitaxel, was 114.9 +/- 5.39 microl.h/ml, and not different from historic data in patients with normal or mild renal dysfunction. Urinary excretion of Cremophor EL was less than 0.1% of the total amount administered. These data indicate that the substantial increase in systemic exposure of the patient to paclitaxel relates to decreased renal metabolism and/or urinary elimination of polar radioactive species, most likely lacking an intact taxane ring fragment.

Aged↗

Human herpesvirus type 7 in blood donors: detection by the polymerase chain reaction.

In order to evaluate the prevalence of human herpesvirus type 7 (HHV-7) in adult blood donors oral lavage fluid, buffy coat, and urine samples from 112 persons were examined by the polymerase chain reaction (PCR) at one time point. In addition, 11 donors were studied longitudinally over 11 weeks. When the results of the initial and the longitudinal study were combined HHV-7 DNA was found in samples from 109 of 112 (97.3%) adult blood donors. On the basis of different sensitivity levels of the first and the nested PCR differences were detected in the viral DNA load in the samples. It was found that lavage fluid regularly carried significantly higher DNA concentrations than buffy coat. Out of 112 donors, 102 (91.1%) and 8 (7.1%) were positive in the first, less sensitive PCR in lavage fluid and buffy coat, respectively (P < .0001). After nested PCR, 107 (95.5%) and 74 (66.1%) were positive in lavage fluid and buffy coat, respectively (P < .0001). Urine samples were found positive only sporadically. The longitudinal study showed that the oral lavage fluid of most of the donors consistently carried HHV-7 over up to 53 weeks, whereas buffy coat samples were positive less often. In conclusion, HHV-7 is found frequently in adult blood donors in the oral lavage fluid and buffy coat, which are, therefore, potential sources of HHV-7 transmission.

Adult↗

Oral manifestations of alpha-mannosidosis: report of a case with ultrastructural findings.

Alpha-mannosidosis is a rare storage disease with distinct biochemical, clinical, histological and ultrastructural features. The oro-facial findings in a 26-year-old man are described. Gingival and oral mucosal hyperplasias were studied using histology and transmission electron microscopy (TEM). The TEM findings were comparable to those of other tissues examined in previous reports, consisting of histiocytic cells containing storage vacuoles with fine reticulo-granular material.

Adult↗

Herpesvirus type 6 in patients undergoing bone marrow transplantation: serologic features and detection by polymerase chain reaction.

To evaluate the potential role of human herpesvirus type 6 (HHV-6) infection in patients after bone marrow transplantation (BMT) we sequentially analyzed buffy coat leukocytes, oral lavage fluid, and urine from 57 patients for the presence of HHV-6 DNA by polymerase chain reaction (PCR) before and after 60 BMTs. Twenty-four patients undergoing autologous BMT and 36 with allogeneic BMT were studied. Thirty-six patients (60%) were PCR positive in one or more tests. The majority of PCR-positive patients had positive results only sporadically, in 1 (n = 23) or 2 weeks (n = 5). Six patients were positive in 3 to 5 weeks. In 2 patients, we found a high frequency of positive tests, in 7 of 7 and 10 of 10 weeks analyzed. Twenty-four patients (40%) remained PCR negative throughout the post-BMT period. There was a significant correlation between the results of HHV-6 PCR and the occurrence of acute graft-versus-host disease (aGVHD). In grade II-IV, 6 of 8 (75%) patients had 2 or more positive PCR tests, compared with 5 of 25 (20%) patients without or with grade I aGVHD (P = .01). There was no difference in the outcome of PCR tests with respect to the type of BMT or pre-BMT HHV-6 enzyme-linked immunosorbent assay titers. Restriction enzyme analysis of PCR amplificates from 18 patients showed HHV-6 variant B in 16 (88.9%) and variant A in 2 cases (11.1%). We conclude that HHV-6 DNA can be detected in 60% of the patients after BMT. HHV-6 DNA can be detected more frequently in patients with moderate and severe aGVHD than in patients without aGVHD or with mild aGVHD.

Adolescent↗

Human adenovirus type 41 contains two fibers.

DNA sequencing of the subgroup F human adenovirus serotype 41 (TAK, Ad41) fiber gene revealed the presence of two adjacent open reading frames encoding information for proteins with molecular weights of 60.6 kDa and 41.4 kDa (Pieniazek, et al; Nucleic Acids Res. 18: p. 1901, 1990). In this paper, various approaches were used to characterize the two proteins and determine whether both fibers were expressed in infected cells as well as on viral particles. We initially used a reverse transcriptase-polymerase chain reaction with primers for the short and long fiber genes to amplify mRNA from Ad41 infected HEp-2 cells at 48 h post-infection. Two distinct DNA bands; one slightly larger than 1.1 kbp and the other at about 1.7 kbp were identified. Second, we used polyclonal anti-Ad41 virion and monoclonal anti-Ad5 fiber antibodies to demonstrate that at both 24 and 36 h post-infection, Ad41 expressed two fiber proteins of the expected size. Specifically, by SDS-PAGE, one fiber (short) had a molecular weight of 40 kDa, while the other (long) had a molecular weight of 60 kDa. Third, by electron microscopy, two sizes of fibers were released from CsCl purified virions, both having a characteristic adenovirus morphology, with a knob at one end. The long fiber measured 315A in length and the short fiber was 250A long. These measurements are consistent with the two Ad41 fibers being encoded by the above open reading frames. We also performed a computer search to compare fiber sequences from other human adenovirus serotypes with that of the Ad41 short and long fiber proteins. The primary structure of both Ad41 fibers were found to be similar in that they contained tail, shaft and knob regions. Further, the tail region of both fibers (amino acids 1-42) showed a 74% overall homology to each other and contained the Ad conserved sequence NH2-F-N-P-V-Y-P-Y-COOH. An interesting difference, however, was observed in the shaft region where the long fiber (amino acids 43-389) had twenty-two 16-amino acid repeat motifs, while the short fiber (amino acids 43-233) had only twelve. Finally, we noted that the long fiber knob region was about 15% longer than that of the short fiber, and showed little overall homology. In conclusion, human adenovirus subgroup F (type 41) virions appear to differ from those of all other human adenoviruses (subgenera A-E) in that they contain two fiber genes and correspondingly, two different sized fibers.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenoviruses, Human↗