Showing papers by "St. Jude Children's Research Hospital published in 1981"
TL;DR: Analysis of 34 mutant viruses selected has enabled us to define four antigenic sites on the haemagglutinin molecule that have undergone antigenic drift to a different extent in nature, which implies that the mechanisms responsible for antigenic Drift act selectively on distinct structures of the HA molecule.
Abstract: The recurrence of influenza virus infection in man is attributed primarily to changes occurring in the antigenic structure of the viral surface glycoproteins, especially of the haemagglutinin (HA) molecule1–4. Comparative antigenic analysis5 of epidemic influenza virus strains has allowed the description of ‘strain-specific’ and ‘cross-reactive’ antigenic determinants6–8. However, the interpretation of these findings remained ambiguous, because the specificity of the applied antisera was insufficiently defined and because the antigenic differences among the HA molecules of various epidemic virus strains resulted presumably from a large number of amino acid substitutions9–11. Thus, in characterizing the antigenic structure of the HA molecule, our approach has been (1) to generate a panel of monoclonal anti-HA hybridoma antibodies, (2) to use some of these antibodies to select mutants of the influenza A/PR/8/34 (PR8) virus expressing antigenically altered HA molecules, and (3) to construct an operational antigenic map of the HA molecule by comparative antigenic analysis of the mutant viruses with the monoclonal antibodies. As we report here, analysis of the 34 mutant viruses selected has enabled us to define four antigenic sites on the HA molecule. Our observation that these sites have undergone antigenic drift to a different extent in nature implies that the mechanisms responsible for antigenic drift act selectively on distinct structures of the HA molecule.
442 citations
TL;DR: The A/Seal/Mass/1/80 influenza virus provides the first evidence suggesting that a strain deriving all of its genes from one or more avian influenza viruses can be associated with severe disease in a mammalian population in nature.
222 citations
TL;DR: The effects of the cytochalasins on thrombin-induced actin polymerization in intact cells is studied and it is reported here the first clear evidence that cyto Chalchasins inhibit actin PolymerizationIn intact cells.
Abstract: It has been suggested that the polymerization of actin to form actin filaments is critical for many functions in non-muscle cells including phagocytosis, cell division, secretion and cell motility1,2. In support of this suggestion, many of these functions are inhibited by cytochalasins3 which also inhibit the actin nuclei-induced polymerization of purified actin4–7. Recent studies suggest that the cytochalasins (cytochalasins B, D and E) inhibit polymerization by binding to the growing end of actin filaments and blocking the further addition of monomeric actin molecules4,7–9. If the cytochalasins inhibit cellular contractile functions by a similar mechanism, they could be useful tools in determining whether actin polymerization is required for specific processes within cells. Blood platelets provide an excellent system for testing this as exposure of platelets to thrombin results in a rapid polymerization of actin10,11. We have now studied the effects of the cytochalasins on thrombin-induced actin polymerization and report here the first clear evidence that cytochalasins inhibit actin polymerization in intact cells.
185 citations
TL;DR: In vitro and in vivo studies indicate that calmodulin is part of the linkage between the rise in Ca2+ at fertilization and the turning on of egg metabolism.
169 citations
TL;DR: Stage was the most important prognostic variable, extragonadal tumors were usually advanced at diagnosis, and similarities in the histogenesis, metastatic pattern, and response to therapy, regardless of primary site justify the consideration of childhood malignant GCTs as one group.
Abstract: Fifty-seven patients with malignant germ cell tumors (GCTs) treated at our center between 1962 and 1979 were evaluated to determine 1) the prognostic value of disease stage, tumor histology, primary site, and patient age; 2) results of therapy; and 3) patterns of metastasis. The 35 girls and 22 boys were from 1 week to 18 years old (median 5 yr). Primary sites were ovarian (20), testicular (10), sacrococcygeal (12), retroperitoneal (7), mediastinal (5), and other (3). Cox regression analysis indicated that stage was the most important prognostic variable. Extragonadal tumors were usually advanced at diagnosis, but tumor site did not have prognostic value independent of disease stage. Neither patient age nor tumor histology significantly influenced outcome. Drugs active against malignant GCTs included vincristine, cyclophosphamide, and dactinomycin in combination and vinblastine, bleomycin, and cis-platinum. Radiation alone cured nondisseminated germinomas. The most common sites of metastasis were lungs, liver, central nervous system, and bone; other sites were infrequently involved. We conclude that stage was the most important prognostic variable, extragonadal tumors were usually advanced at diagnosis, and similarities in the histogenesis, metastatic pattern, and response to therapy, regardless of primary site, justify the consideration of childhood malignant GCTs as one group.
136 citations
TL;DR: In this paper, the authors determined retrospectively the frequency and risk of hyperglycemia in 421 children with leukemia who had received L-asparaginase and prednisone as part of their remission induction therapy.
112 citations
TL;DR: A kinetically based sequence of chemotherapy seems to produce a high rate of complete remissions in children with disseminated neuroblastoma, and to consolidate this gain into curative treatment will require a continuation therapy to prevent the emergence of drug‐resistant disease.
Abstract: When 70 children with disseminated neuroblastoma were treated for 4 months with a course of cyclophosphamide and doxorubicin (Adriamycin) 35 (52%) of 68 assessable patients achieved complete remissions, 13 had partial responses, and 20 had either less than a 50% regression of tumor or evidence of tumor progression. Of the 35 children with complete responses, three received local irradiation, but for the remainder, chemotherapy alone provided rapid control of tumor growth. Drug-induced toxicity caused the hospitalization of four of 17 infants and five of 52 older children, but was related to only two of the eight deaths that occurred during treatment. Infants less than 1 year of age were more likely to achieve a complete remission than were older children. That 52% of these patients achieved complete remissions represents a marked improvement over the 22% response rate for patients seen between 1962 and 1974. Of 35 patients with complete responses, 15 have survived, contrasted with only four of 33 patients achieving less than a complete response. Median survival for patients achieving a partial response was 14.4 months, compared to 8.4 months for patients not achieving a response. A kinetically based sequence of chemotherapy seems to produce a high rate of complete remissions in children with disseminated neuroblastoma. To consolidate this gain into curative treatment will require a continuation therapy to prevent the emergence of drug-resistant disease.
95 citations
TL;DR: It was shown that CDDP‐induced hypomagnesemia is the result of excessive renal loss and is severe enough to interfere with the normal parathormone response to hypocalcemia.
Abstract: Cis-dichlorodiammineplatinum (CDDP) and VM26, both of which have been proven efficient in treating neuroblastoma, were combined in a sequential schedule and administered to 22 children with disseminated neuroblastomas resistant to treatment with cyclophosphamide and doxorubicin (Adriamycin). During this same study, 14 children were prospectively evaluated for the effect of CDDP on magnesium metabolism and the effect of the induced hypomagnesemia on parathyroid function. Complete or partial tumor responses were achieved in six and nine cases, respectively and were of prolonged duration (longer than six months) in eight of the 15 responding. It was also shown that CDDP-induced hypomagnesemia is the result of excessive renal loss and is severe enough to interfere with the normal parathormone response to hypocalcemia.
94 citations
TL;DR: Data presented are consistent with the concept that independent sites on the HN molecule may be involved in attachment to host cells and neuraminidase activity, and the possibility that a single active site may beinvolved in both activities has not been excluded.
83 citations
TL;DR: Teenage girls with acute lymphoblastic leukemia whose leukemia cells were near-haploid may represent a unique subgroup of ALL with a poor prognosis, and cytogenetic analysis and flow cytometric analysis of DNA content are included in initial evaluation of patients with ALL.
81 citations
TL;DR: It is suggested that sequence changes in the region comprising residues 142 to 146 of HA1 affect an important antigenic site on the hemagglutinin molecule, but how these changes affect the antigenic properties, or whether this region actually forms part of the antigenIC site is not known.
TL;DR: Modifications to the actin filament content of cell lysates can be assayed by inhibition of DNase I activity and a computer is used for direct data acquisition and analysis of the linear portion of the reaction curve.
TL;DR: It is suggested that a complete molecule of polypeptide P is not required for the synthesis or modification of viral mRNA, and that polypePTide L and/or SP may be responsible for some or all of these activities.
TL;DR: In this article, human saliva was fractionated to determine the components required for production and accumulation of the antimicrobial oxidizing agent, hypothiocyanite ion (OSCN-).
Abstract: Human saliva was fractionated to determine the components required for production and accumulation of the antimicrobial oxidizing agent, hypothiocyanite ion (OSCN-). The required components were: 1) peroxidase activity and thiocyanate ion (SCN -), 2) the saliva sediment, which produced hydrogen peroxide (H 2O2) in the presence of oxygen and a divalent cation, and 3) heatstable factors of the saliva supernatant. The supernatant factors were separated into high- and low-mol wt fractions. The high-mol wt fraction contained both peptide and carbohydrate, and its activity was partially inhibited by proteolytic treatment. The low-mol wt fraction contained carbohydrate and could be replaced by a number of mono- and di-saccharides. Glucosamine and N-acetyl glucosamine were the most effective, whereas neutral sugars such as sucrose were less effective. Sucrose competed with glucosamine, so that lower levels of OSCN- were obtained with increasing amounts of sucrose. The sugars stimulated production of H202 by the s...
TL;DR: The working hypothesis for identification of the thrombin receptor on platelets is that interaction ofThrombin with its receptor involves a hydrolytic event.
Abstract: The molecular mechanism by which a-thrombin activates platelets remains an essentially unsolved problem in hemostasis. Interaction of thrombin with the platelet plasma membrane is sufficient to trigger this event since a-thrombin covalently coupled to agarose beads will activate plate1ets.l The active site of thrombin plays a critical role since active-site-inhibited thrombin (by diisopropyl fluorophosphate [DFP], phenylmethanesulfonyl fluoride [PMSF], and l-chloro3-tosylarnido-7-amino-~-Zheptanone [TLCK]) will not activate platelet^.^-^ Further, a number of proteases, such as trypsin,zo papain,s and thrombocytin,?, 8 whose cleavage specificity overlaps that of a-thrombin, will activate platelets. Our working hypothesis for identification of the thrombin receptor on platelets is that interaction of thrombin with its receptor involves a hydrolytic event. Despite the evidence for a simple hydrolytic mechanism, other aspects of thrombin-platelet interaction suggest a classical agonist-receptor equilibrium 8 . 9 in that the amount of dense body secretion is proportional to thrombin concent r a t i ~ n . ~ , lo Binding analyses employing 1251-labeled a-thrombin indicate -500 high-affinity binding sites with a K,% of -1 nM and -50,000 low-affinity binding sites with a K, of -100 nM.34, 11-13 Although the precise relationship between the two types of binding sites remains ~ n c l e a r , ~ . l4 binding to both classes of sites is freely reversible with koff 2 S ~ C ' . ~ . l5 In contrast, if thrombin is reacted with an excess of platelets, the rate of appearance of catalytically active thrombin may be calculated from the data of Detwiler and Feinman to occur with a first-order rate constant of ~ e c l . ~ Binding analyses using lZ5Ilabeled, active-site-inhibited a-thrombin (by DFP, PMSF and TLCK) yield the same number of binding sites and binding affinities as observed with native a-thr~mbin.~. 4, l 6 This competition for binding is not reflected in the functional response of platelets, since inhibited thrombin, even in a 1000-fold excess, is without effect on, or enhances, the subsequent response of platelets to catalytically active thr~mbin .~ , 5 . 6
TL;DR: The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial, and the ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion, apparently a function of two independent first-order processes for renal clearance of parent drug and cis platin metabolites.
Abstract: The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m2 (11) or 90 mg/m2 (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m2 dosages were adequately described by a biexponential equation. The mean (±SE) serum T1/2α of total platinum was 0.42 (±0.10) h and the mean (±SE) T1/2β was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K12) that is about six times the rate of transport out of tissues (K21). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m2 and 35.8 (±13.6) ml/min/m2 for the 30 mg/m2 and 90 mg/m2 groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m2 for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m2 for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.
TL;DR: Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs, with activity for head and neck tumors, that were introduced into clinical use in the past ten years.
Abstract: Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs with activity for head and neck tumors. Introduced into clinical use in the past ten years, bleomycin is used primarily in the chemotherapy of squamous cell carcinomas, lymphomas, and testicular carcinoma, while cisplatin is effective against testicular and ovarian carcinoma, head and neck cancer, bladder cancer, and neuroblastoma. Bleomycin is rapidly excreted renally (T 1/2 beta = 2-4 hr) although enzymatic inactivation also occurs in many tissues. Cisplatin is nonenzymatically converted to highly protein-bound metabolites, which then undergo renal elimination, but total body clearance occurs much more slowly than with bleomycin (T 1/2 beta = 40-50 hr). Both agents have acute and chronic toxicities; the acute toxicities are generally reversible but cause a great deal of patient discomfort, while the chronic toxicities are often irreversible and dose-limiting. For bleomycin, the acute toxicities are mucocutaneous and pyretic, while severe nausea and vomiting represent the major acute toxicities of cisplatin therapy. Cumulative dose-related pulmonary toxicity is the most serious chronic toxicity of bleomycin. The clinical, radiographic, and pathologic presentations are nonspecific, although identification of high-risk patients may be possible with serial pulmonary function tests. Cumulative nephrotoxicity occurs with cisplatin use and its incidence and severity can be reduced by maintaining adequate hydration and diuresis during and following administration of the drug.
TL;DR: Signs of leukoencephalopathy appeared in 11 children (nine without CNS leukemia) after 4-15 months of IV MTX alone, and included lethargy, seizures, spasticity, paresis, drooling, and dementia.
Abstract: From 1972-1974, 228 children began treatment for acute lymphocytic leukemia and were prospectively assessed for neurologic complications. After CNS irradiation (2,400 rad) and intrathecal methotrexate (MTX), they received weekly intravenous maintenance therapy with MTX alone (40-60 mg/m2; 20 patients) or MTX (10-30 mg/m2) with other drugs (208 patients). Signs of leukoencephalopathy appeared in 11 children (nine without CNS leukemia) after 4-15 months of IV MTX alone, and included lethargy, seizures, spasticity, paresis, drooling, and dementia. Before or during the clinical onset, EEG frequencies slowed (all ten patients tested). Radionuclide scans showed periventricular accumulation of 99mTc (9/11 patients) and remained abnormal for greater than or equal to six months in eight patients. Cranial computed tomograms or neuropathology findings (five patients each) demonstrated leukoencephalopathy (nine patients) and radiation-related microangiopathy (ten patients). Severe neurologic and neuropsychologic dysfunctions were present in four long-term survivors.
TL;DR: It was found that cleavage of P was accompanied by a concomitant loss of RNA synthetic activity implicating P in the synthesis of viral RNA.
TL;DR: Filamentous muscle actin aggregated blood platelets while G-actin was ineffective and this aggregation could be blocked by ATP suggesting a possible role of actin-bound ADP in this process.
TL;DR: Five viruses isolated from hunter-killed doves in Tennessee, U.S.A. in 1975 were shown to be related paramyxoviruses which represent a new serologically distinct group of avian paramyxOViruses, and this subtype should be designated as PMV-7 in the current system of nomenclature.
Abstract: Five viruses isolated from 114 hunter-killed doves (Columba species) in Tennessee, U.S.A. in 1975 were shown to be related paramyxoviruses which represent a new serologically distinct group of avian paramyxoviruses. We propose that this subtype be designated as PMV-7 in the current system of nomenclature.
TL;DR: The separate crystallization of antigen and Fab fragment opens the way to map, for the first time, the complementary surfaces of an antigen-antibody complex.
TL;DR: The rationale for pharmacokinetic monitoring of aminoglycosides is critically reviewed and it is suggested that for optimal antibacterial effect, peak serum gentamicin concentrations should exceed 5 μg/ml, despite the fact that these concentrations are indirect measures of the concentration of drug at the site of infection.
Abstract: The rationale for pharmacokinetic monitoring of aminoglycosides is critically reviewed. Retrospective studies suggest that for optimal antibacterial effect, peak serum gentamicin concentrations should exceed 5 μg/ml, despite the fact that these concentrations are indirect measures of the concentration of drug at the site of infection. When quantitative results of antimicrobial susceptibility are known (e.g. MIC or MBC), limited data suggest that for most infections, the peak serum aminoglycoside concentration should exceed the minimum inhibitory concentration by four-fold. However, the optimal duration for which the serum concentration should exceed the MIC or MBC during each dosing interval and the detrimental effect of prolonged subinhibitory drug concentrations have not been evaluated. Furthermore, the immunological competence of the host and the pathogenicity of the infecting organism are important factors in achieving antibacterial response.
Using serum creatinine as an indirect and relatively late indicator of nephrotoxicity, nadir gentamicin concentrations greater than 2 μg/ml may predispose patients to develop nephrotoxicity. In addition, recent information indicates that patients who accumulate excessive amounts of aminoglycosides In their tissues may be at higher risk for developing nephrotoxicity; these patients may be identified based on the extent of accumulation in their nadir concentrations with continuous dosing. The aminoglycosides diffuse into the inner ear fluids slowly and diffuse out with a half-life of decline in inner ear fluid concentrations slower than that in serum. High transient peak serum concentrations probably do not contribute significantly to the risk of ototoxicity. However, there is evidence from early clinical trials, studies using continuous infusions of aminoglycosides, and animal studies indicating that elevated nadir serum concentrations relate to the development of ototoxicity.
There is considerable interpatient variability in the peak serum concentration, even when identical dosages based on body weight or surface area are administered. Similarly, the half-life for decline In serum concentrations is highly variable from patient to patient, even in patients with stable normal renal function. Absorption after intramuscular administration is reliable in most patients, although critically ill patients may experience erratic absorption. The distribution of aminoglycosides is altered in obese patients because of differences in extracellular fluid content between fat and other tissues. Maintaining serum aminoglycoside concentrations in the desired therapeutic range is difficult in patients with impaired renal function, and frequent monitoring of serum concentrations is essential in these patients. Neonates, infants and children differ from adults in their ability to eliminate aminoglycosides and in their central volume of distribution. Fever, state of hydration, “third-spaces”, and concurrent penicillin therapy may also affect the pharmacokinetics of the aminoglycosides. Diseases which affect some of the factors mentioned above (e.g. burns) may cause unpredictable changes in pharmacokinetic behavior.
The approach at St. Jude Children's Research Hospital to pharmacokinetic monitoring of aminoglycoside therapy in children with cancer is presented. This method accounts for tissue accumulation, and allows for dosage adjustments using individualized pharmacokinetic values.
TL;DR: The results suggest that (A) the thrombin receptor in human platelets is different from the ristocetin or ristOCetin-von Willebrand factor receptor and (B) the 74,000 dalton glycoprotein may be a physiologic receptor of throm bin in human Platelets.
TL;DR: 5 children with sickle cell anemia and priapism are managed successfully by creation of a fistula between the glans penis and the corpora cavernosa, which includes early shunting should initial nonoperative treatment fail.
TL;DR: In this paper, the histopathologic and anatomoclinical features of 211 cases of non-Hodgkin's lymphoma (NHL) were reviewed and each case reclassified according to Lukes-Collins, Kiel and Rappaport criteria.
Abstract: The histopathologic and anatomoclinical features of 211 cases of non-Hodgkin's lymphoma (NHL) were reviewed and each case reclassified according to Lukes-Collins, Kiel and Rappaport criteria. Immunologic determination of cell phenotype in 63 cases as well as assessments of immunoglobulin and lysozyme by immunoperoxidase in 48 cases, permitted a precise definition of cell lineage on a functional basis and showed a high degree of predictability of immunologic phenotype of lymphoma cells by conventional morphology. The results of immunologic cell typing and immunoperoxidase studies were consistent with functional schema of Lukes-Collins and Kiel. “True” histiocytic proliferations, (9 cases) showed biologically different behavior from malignant lymphoma (ML), by a high incidence of extralymphatic (skin and soft tissue) presentation, rapid course, and frequent conversion to histiocytic leukemia. Fifty-two percent of studied ML cases were categorized morphologically as B-cell line proliferations, 36.7% as T-cell line and 6.9% as undefined group (ML “U” type). The ratio of T-cell to B-cell malignancies was 1∶1.4. The convoluted type lymphoma was characterized by a high incidence (70%) of anterior mediastinal presentation, high incidence (over 60%) of hematologic and CNS involvement, and a high probability of testicular relapse, especially late. In contrast to malignancies of the T-cell line, B-cell proliferations tended to be localized below the diaphragm, and the most common anatomic location of lymphoma growth appeared to be the gastrointestinal tract, where small and large noncleaved follicular center cell types predominated. The nodular lymphoid hyperplasia in the vicinity of intestinal lymphoma and lack of secretory component within enterocytes were other substantial findings in abdominal B-cell malignancies. Among immunoblastic proliferations, the B-cell type was found to predominate over T-cell and was characterized as highly aggressive disease with a relatively common marrow infiltration. A low anatomic stage of disease and a favorable outcome were closely related to small cleaved type of follicular center cell lymphoma, which comprised only 1.5% of the patients studied. The less defined and morphologically heterogeneous group formed ML “U”, which in over 95% of patients converted to acute lymphocytic leukemia. This joint analysis of “primary leukemic” and “non-leukemic” NHL patients disclosed striking differences in anatomic presentation and natural history of disease between T, B and null cell proliferations versus related cytologic types.
TL;DR: Analysis of the density of the DNA synthesized after a shiftup in the presence of BUdR and FUdR suggested that residual viral DNA synthesis represented chain elongation, and not initiation of new rounds of DNA replication, and that the defective protein was therefore involved in the initiation process.
TL;DR: These affinity and photoaffinity crosslinking results are interpreted as evidence that the “backside” of yeast iso-1-cytochrome c interacts with subunit III of yeast cytochrome oxidase.
TL;DR: A pharmacokinetic basis is established for previous clinical observations indicating sustained serum methotrexate concentrations in patients with GI obstructions and the utility of physiological pharmacokinetics models in assessing the potential effects of clinical variables on drug disposition is exemplified.