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PubMed2003

Indolent systemic mast cell disease: immunophenotypic characterization of bone marrow mast cells by flow cytometry.

BACKGROUND: Mast cell disease has a low prevalence and is difficult to diagnose in the absence of the characteristic skin lesions that usually accompany the condition. Extracutaneous involvement is not easy to assess. There are reports in the recent literature on the use of tryptase as a reliable immunohistochemical marker as well as on the study of the immunophenotype of bone marrow mast cells. The latter is of great help for the diagnosis of systemic involvement as, after the skin, the bone marrow is the organ most commonly affected by the disease. OBJECTIVE: We describe two cases of indolent systemic mast cell disease (SMCD) where flow cytometry was used to identify immunophenotypical characteristics of bone marrow mast cells. Recent advances in the application of this technique prove it can be a good diagnostic tool for assessing systemic involvement of the disease. PATIENTS AND METHODS: Two adult subjects with indolent SMCD had multiple clinical symptoms. Cutaneous lesions were the clue to the diagnosis but, subsequently, in the presence of disturbing symptoms, involvement of other organ systems was confirmed. In both cases, the authors used flow cytometry techniques, as described by Escribano et al. (1998) to define the immunophenotype of bone marrow mast cells. RESULTS: Both patients were diagnosed with indolent SMCD with cutaneous and bone marrow involvement. Also, they presented visible clues to the presumptive bone, cardiovascular and nervous system involvement. Gastrointestinal manifestations were documented in one case. CONCLUSIONS: The use of flow cytometry on bone marrow samples from patients with mastocytosis reveals immunophenotypic differences that can serve to allow classification of these subjects in the category of indolent SMCD even though involvement of another organ system may not be thoroughly confirmed.

Aged↗
PubMed2002

Increasing treatment options in indolent non-Hodgkin's lymphoma.

There is currently no standard first-line treatment for indolent non-Hodgkin's lymphoma (NHL) because there is no curative treatment. In asymptomatic patients, treatment with chemotherapy does not improve survival compared with a "watch and wait" approach. Improved treatment strategies, with curative intent, are thus required for indolent NHL. Rituximab is effective and well tolerated in the treatment of indolent NHL and can be considered for asymptomatic patients, where the side effects of chemotherapy may outweigh the benefits. In addition, rituximab does not compromise the use of subsequent chemotherapy in patients who relapse. A study of rituximab monotherapy in patients with low-tumor-burden follicular lymphoma has shown high rates of both clinical remission and molecular remission (clearance of bcl-2-positive cells from blood and/or bone marrow). After 2 years, half the patients relapsed, indicating that improved strategies are still required. Efforts to improve the efficacy of rituximab have included repeated administrations of the antibody and combined administration with chemotherapy or interferon-alpha2a. The optimal role of rituximab in first-line therapy for indolent NHL will be determined through randomized clinical trials.

Antibodies, Monoclonal↗
PubMed2003

First-line and maintenance treatment with rituximab for patients with indolent non-Hodgkin's lymphoma.

The chimeric human-mouse anti-CD20 monoclonal antibody rituximab has durable single-agent activity in patients with relapsed and refractory indolent non-Hodgkin's lymphoma. The focus of this report is a phase II trial evaluating the efficacy of single-agent rituximab as first-line therapy in patients with indolent lymphoma and scheduled maintenance treatment in prolonging duration of remission. Patients received a 4-week course of standard rituximab (375 mg/m(2) intravenously weekly x 4). Those achieving objective response or stable disease then received maintenance courses of standard rituximab every 6 months, for a maximum of four rituximab courses. Of 62 patients entered in the trial, 61% had follicular lymphoma while 39% had small lymphocytic lymphoma (SLL). At 6 weeks, 28 of 60 evaluable patients (47%) had an objective response. The response rate improved to 73% (37% complete response) following maintenance rituximab therapy and was similar in patients with follicular lymphoma and SLL (76% v 70%, respectively). Median progression-free survival for the entire group was 34 months. Single-agent therapy was well tolerated and maintenance rituximab was administered without grade 3/4 toxicity. Because of the higher activity of rituximab in this study compared with previous results in patients with relapsed or refractory SLL, a second phase II trial of identical design but limited to patients with SLL and chronic lymphocytic leukemia was initiated. Forty-four patients entered this second trial and, at present, 27 continue to receive maintenance courses of rituximab. The current response rate is 56% (8% complete responses). In summary, rituximab appears highly active as first-line single-agent therapy for indolent non-Hodgkin's lymphoma and responses may be improved with maintenance courses of rituximab. Results suggest a higher response rate to rituximab when used as first-line compared with second/third-line treatment, particularly in the subset of patients with SLL and chronic lymphocytic leukemia. Further follow-up will provide important information regarding the impact of first-line and maintenance rituximab on progression-free survival in patients with indolent non-Hodgkin's lymphoma.

Antibodies, Monoclonal↗
PubMed2000

Synthesis and biological evaluation of indole containing derivatives of thiosemicarbazide and their cyclic 1,2,4-triazole and 1,3,4-thiadiazole analogs.

New indolic derivatives of thiosemicarbazides and some cyclic 1,2,4-triazol-5-thione analogs were synthesized. The newly synthesized compounds as well as some indole containing thiosemicarbazides, 1,2,4-triazoles and 1,3,4- thiadiazoles, which have been reported previously, were investigated for antimicrobial, antifungal and antiphage activity. Certain thiosemicarbazide derivatives and the corresponding cyclic 1,2,4-triazole analogs showed selective antimicrobial or antifungal activity, while they lack any antiphage activity. Antiphage activity was detected for one compound, bearing the 1,3,4-thiadiazole nucleus. The selectively active compounds cover a wide range of lipophilicity. Structure-activity relations show a remarkably similarity in the antimicrobial and antifungal behaviour of the thiosemicarbazides and their cyclic triazo-thien-5-yl analogs, while alpha-naphtyl substitution in the non indolic portion of the molecule is favorable. C5 substitution on the indolic nucleus may also be critical for selective activity.

Anti-Infective Agents↗
PubMed2000

Arabidopsis cytochrome P450s that catalyze the first step of tryptophan-dependent indole-3-acetic acid biosynthesis.

Plants synthesize numerous secondary metabolites that are used as developmental signals or as defense against pathogens. Tryptophan (Trp)-derived secondary metabolites include camalexin, indole glucosinolates, and indole-3-acetic acid (IAA); however, the steps in their synthesis from Trp or its precursors remain unclear. We have identified two Arabidopsis cytochrome P450s (CYP79B2 and CYP79B3) that can convert Trp to indole-3-acetaldoxime (IAOx), a precursor to IAA and indole glucosinolates.

Amino Acid Sequence↗
PubMedDate not supplied

DNA adduct formation of 14 heterocyclic aromatic amines in mouse tissue after oral administration and characterization of the DNA adduct formed by 2-amino-9H-pyrido[2,3-b]indole (AalphaC), analysed by 32P_HPLC.

Heterocyclic aromatic amines (HAAs) are produced during cooking of proteinaceous food such as meat and fish. Humans eating a normal diet are regularly exposed to these food-borne substances. HAAs have proved to be carcinogenic in animals and to induce early lesions in the development of cancer. DNA adduct levels in mouse liver have been measured by 32P-HPLC after oral administration each of 14 different HAAs. The highest DNA adduct levels were detected for 3-amino-1-methyl-5H-pyrido[4,3-b]-indole (Trp-P-2), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 2-amino-9H-pyrido[2,3-b]indole (AalphaC), respectively. To assess a relative risk in a human population, a relative risk index was calculated by combining the DNA adduct levels in mouse liver with human daily intake of heterocyclic amines in a US and in a Swedish population. Such calculations suggest that AalphaC presents the highest risk for humans, e.g. nine-fold higher compared with the most abundant amines in food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP). Therefore, the distribution of DNA adducts in different tissues of mouse was investigated after oral administration of AalphaC. The highest AalphaC-DNA adduct levels were found in liver (137 adducts/10(8) normal nucleotides) followed by heart, kidney, lung, large intestine, small intestine, stomach and spleen, in descending order. To characterize the chemical structure of the major DNA adduct, chemical synthesis was performed. The major DNA adduct from the in vivo experiments was characterized by five different methods. On the basis of these results, the adduct was characterized as N2-(deoxyguanin-8-yl)-2-amino-9H-pyrido [2,3-b]indole. Considering the abundance of AalphaC not only in grilled meat, but also in other products like grilled chicken, vegetables and cigarette smoke and in light of the results of the present study, it is suggested that the human cancer risk for AalphaC might be underestimated.

Administration, Oral↗
PubMed2003

Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin's lymphoma.

BACKGROUND: The aim of this study was to compare the outcomes of high-dose therapy (HDT) and allogeneic versus autologous hematopoietic stem cell transplantation (SCT) in patients with refractory or recurrent indolent non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: From January 1991 to March 2000, 112 patients underwent HDT followed by either autologous (68 patients) or allogeneic (44 patients) SCT for refractory or recurrent indolent NHL. Prior conventional chemotherapy had failed in all patients. RESULTS: The two groups were similar with respect to age at transplantation, gender, histological subtypes, number of chemotherapy regimens received before transplantation and International Prognostic Index scores. The median time from diagnosis to transplantation was longer in the autologous than in the allogeneic SCT group (46 versus 27 months, P = 0.002). In the allogeneic SCT group the median follow-up time was 53 months (range 21-113), and the overall survival (OS) and disease-free survival (DFS) rates were 49% and 45%, respectively. After a median follow-up time of 71 months (range 22-109), in the autologous SCT group, the OS and DFS rates were 34% and 17%, respectively. Patients who underwent autologous SCT were more likely to have chemosensitive disease (P <0.001) and were more likely to be in complete remission at the time of transplantation (P = 0.001) than those who underwent allogeneic SCT. However, the probability of disease progression was significantly higher in the autologous SCT group than in the allogeneic SCT group (74% versus 19%, P = 0.003). CONCLUSIONS: Patients who undergo HDT with allogeneic SCT for refractory or recurrent indolent NHL have lower relapse rates but higher treatment-related mortality rates than patients who undergo autologous SCT. However, with the development of non-myeloablative preparative regimens, which can decrease treatment-related mortality, patients with recurrent indolent NHL should be considered for controlled trials of allogeneic transplantation if they have a human leukocyte antigen-identical donor.

Adult↗
PubMed2005

Central nervous system involvement in indolent lymphomas.

BACKGROUND: Central nervous system (CNS) involvement, a well-recognized complication of aggressive non-Hodgkin's lymphomas (NHL), has rarely been reported in indolent lymphomas. Large series have reported this complication in 3% of indolent NHLs, generally following histological transformation. PATIENTS AND METHODS: We retrospectively reviewed the disease characteristics and clinical course in seven patients (six females, one male) with indolent B-cell lymphomas who developed CNS involvement during various stages of their illness. RESULTS: The median ages at diagnosis of systemic and CNS lymphoma were 60 and 63 years, respectively. Histologies were: small lymphocytic lymphoma (two), follicular lymphoma grade I (two), follicular lymphoma grade II (two) and unclear low-grade histology (one). There were diverse neurological symptoms. Two patients had parenchymal involvement, three had leptomeningial involvement and two had both. Systemic lymphoma was found in all patients, all but one having bone marrow involvement. Four patients had a transformation to high-grade histology. Six patients were treated with systemic and intra-cerebrospinal fluid chemotherapy, and two received radiotherapy as well. Five patients achieved CNS response. Survival was 1-9 years for treated patients (median 2 years). Three patients died of CNS disease. CONCLUSIONS: CNS involvement is a rare and unexpected complication of indolent NHL, which should be considered in the differential diagnosis of patients presenting with new neurological signs. This condition is treatable and some patients have a long clinical course.

Adult↗
PubMed2001

Comparative quantitative trait loci mapping of aliphatic, indolic and benzylic glucosinolate production in Arabidopsis thaliana leaves and seeds.

Secondary metabolites are a diverse set of plant compounds believed to have numerous functions in plant-environment interactions. Despite this importance, little is known about the regulation of secondary metabolite accumulation. We are studying the regulation of glucosinolates, a large group of secondary metabolites, in Arabidopsis to investigate how secondary metabolism is controlled. We utilized Ler and Cvi, two ecotypes of Arabidopsis that have striking differences in both the types and amounts of glucosinolates that accumulate in the seeds and leaves. QTL analysis identified six loci determining total aliphatic glucosinolate accumulation, six loci controlling total indolic glucosinolate concentration, and three loci regulating benzylic glucosinolate levels. Our results show that two of the loci controlling total aliphatic glucosinolates map to biosynthetic loci that interact epistatically to regulate aliphatic glucosinolate accumulation. In addition to the six loci regulating total indolic glucosinolate concentration, mapping of QTL for the individual indolic glucosinolates identified five additional loci that were specific to subsets of the indolic glucosinolates. These data show that there are a large number of variable loci controlling glucosinolate accumulation in Arabidopsis thaliana.

Amino Acids↗
PubMed2005

Phenols, quinolines, indoles, benzene, and 2-cyclopenten-1-ones are oviductal toxicants in cigarette smoke.

Previously, we showed that pyridines and pyrazines in cigarette smoke inhibit oviductal functioning in vitro in nanomolar and picomolar doses. The purpose of this study was to determine the lowest observable adverse effect levels (LOAELs) of phenols, quinolines, indoles, benzene, and 2-cyclopenten-1-ones found in mainstream smoke solutions on ciliary beat frequency, oocyte pickup rate, and infundibular smooth muscle contraction using the hamster oviduct. After solid phase extraction, mainstream smoke solution fractions were tested in the oviductal assays. The active fractions were analyzed using gas chromatography-mass spectrometry to identify individual chemicals. Using this approach, benzene, eleven phenolic, two indole, two quinoline, and two 2-cyclopenten-1-one derivatives were identified in the active fractions. Commercially available authentic standards of the identified compounds were tested in dose-response studies on hamster oviducts. The LOAELs were determined for each compound using the ciliary beat frequency, oocyte pickup rate, and infundibular smooth muscle contraction rate assays. Indole, the compound with the highest potency, showed inhibition of ciliary beat frequency (10(-13) M), oocyte pickup rate (10(-14) M), and infundibular smooth muscle contraction rate (10(-15) M) in femtomolar doses. All of the other compounds tested, except phenol, which only showed inhibition at millimolar concentrations, were inhibitory in picomolar, nanomolar, or micromolar concentrations. Derivitization of phenol increased its toxicity in the oviductal assays, especially when a methyl or ethyl group was substituted on the fourth position. The indoles, quinolines, and four phenolic compounds had both high potencies and efficacies in the oviductal assays.

Animals↗
PubMed1987

Dynamics of indole-3-acetic acid during germination of Picea abies seeds.

High performance liquid chromatography and combined gas chromatography-mass spectrometry were used to identify indole-3-acetic acid (IAA) and indole-3-ethanol as endogenous constituents of germinating Norway spruce (Picea abies (L.) Karst.) seeds. Indole-3-methanol was tentatively identified by multiple ion monitoring. The free IAA content of the seeds rose from about 20 ng g(-1) to about 60 ng g(-1) (dry weight) during the first five days of germination and thereafter declined to around 20 ng g(-1). Indole-3-acetic acid released by alkaline hydrolysis, which was initially present at about 110 ng g(-1), decreased to 5-10 ng g(-1) during the first week of germination. The IAA content of seed lots differing in germination behavior was investigated. The findings are discussed in relation to the metabolism of IAA in conifer seeds.

Journal Article↗
PubMed1993

Conjugation of Indole-3-Acetic Acid (IAA) in Wild-Type and IAA-Overprodcing Transgenic Tobacco Plants, and Identification of the Main Conjugates by Frit-Fast Atom Bombardment Liquid Chromatography-Mass Spectrometry.

Transgenic plants overproducing indole-3-acetic acid (IAA) from expression of the Agrobacterium tumefaciens T-DNA IAA biosynthesis genes were used to study the conjugation of IAA. At the 11-node stage, free IAA, as well as ester- and amide-conjugated IAA, was analyzed in wild-type tobacco SR1 and in transgenic plants denoted 35S-iaaM/iaaH (line C) and 35S-iaaM x 35S-iaaH (line X). The transgenic plants contained increased levels of both free and conjugated IAA, and the main increase in IAA conjugates occurred in amide conjugates. Two amide conjugates were identified by fritfast atom bombardment liquid chromatography-mass spectrometry as indole-3-acetylaspartic acid (IAAsp) and indole-3-acetylglutamic acid (IAGlu), and one ester conjugate was identified as indole-3-acetylglucose. IAAsp and IAGlu were also identified as endogenous substances in wild-type plants. In wild-type plants, the percent of total IAA in the free form was significantly higher in young leaves (73 [plus or minus] 7%, SD) than in old leaves (36 [plus or minus] 8%), whereas there was no difference between young (73 [plus or minus] 8%) and old internodes (70 [plus or minus] 9%). In IAA-overproducing transformants, both free and conjugated IAA levels were increased, but the percent free IAA was maintained constant (57 [plus or minus] 10%) for both leaves and internodes, independent of the total IAA level or tissue age. These results suggest that synthesis or transport of IAA conjugates is regulated in the vegetative wild-type plant, and that different organs possess a unique balance between free and conjugated IAA. The IAA-overproducing plant, however, acquires a lower proportion of free IAA in the stem and younger leaves, presumably determined by a higher conjugation in those tissues compared with wild type.

Journal Article↗
PubMed1999

An in vitro system from maize seedlings for tryptophan-independent indole-3-acetic acid biosynthesis

The enzymatic synthesis of indole-3-acetic acid (IAA) from indole by an in vitro preparation from maize (Zea mays L.) that does not use tryptophan (Trp) as an intermediate is described. Light-grown seedlings of normal maize and the maize mutant orange pericarp were shown to contain the necessary enzymes to convert [14C]indole to IAA. The reaction was not inhibited by unlabeled Trp and neither [14C]Trp nor [14C]serine substituted for [14C]indole in this in vitro system. The reaction had a pH optimum greater than 8.0, required a reducing environment, and had an oxidation potential near that of ascorbate. The results obtained with this in vitro enzyme preparation provide strong, additional evidence for the presence of a Trp-independent IAA biosynthesis pathway in plants.

Journal Article↗
PubMed2001

Developmental regulation of indole-3-acetic acid turnover in Scots pine seedlings.

Indole-3-acetic acid (IAA) homeostasis was investigated during seed germination and early seedling growth in Scots pine (Pinus sylvestris). IAA-ester conjugates were initially hydrolyzed in the seed to yield a peak of free IAA prior to initiation of root elongation. Developmental regulation of IAA synthesis was observed, with tryptophan-dependent synthesis being initiated around 4 d and tryptophan-independent synthesis occurring around 7 d after imbibition. Induction of catabolism to yield 2-oxindole-3-acetic acid and irreversible conjugation to indole-3-acetyl-N-aspartic acid was noticed at the same time as de novo synthesis was first detected. As a part of the homeostatic regulation IAA was further metabolized to two new conjugates: glucopyranosyl-1-N-indole-3-acetyl-N-aspartic acid and glucopyranosyl-1-N-indole-3-acetic acid. The initial supply of IAA thus originates from stored pools of IAA-ester conjugates, mainly localized in the embryo itself rather than in the general nutrient storage tissue, the megagametophyte. We have found that de novo synthesis is first induced when the stored pool of conjugated IAA is used up and additional hormone is needed for elongation growth. It is interesting that when de novo synthesis is induced, a distinct induction of catabolic events occurs, indicating that the seedling needs mechanisms to balance synthesis rates for the homeostatic regulation of the IAA pool.

Biotransformation↗
PubMed1972

Polar Indole-3-acetic Acid Diffusion in Nonliving and Model Systems.

Polar indole-3-acetic acid movement was observed in killed plant segments and in artificial model systems. The polar diffusion of indole-3-acetic acid was observed in tissue killed by chemical or physical means in an agar-plant system and in a multicelled Plexiglas dialysis chamber containing hypocotyl tissue gradients or gradients of anion exchange material.It was suggested that polar indole-3-acetic acid movement in excised segments may be a reflection of the diffusion of indole-3-acetic acid through asymmetric gradients of materials with binding characteristics somewhat similar to ion exchange.

Journal Article↗
PubMed1973

Indole-3-ethanol Oxidase: Kinetics, Inhibition, and Regulation by Auxins.

We report the further characterization of indole-3-ethanol oxidase from cucumber seedlings. The effects of various inhibitors suggest that the enzyme may be a flavoprotein with a metal ion and sulfhydryl groups required for full activity. Indole-3-acetaldehyde, a product of the reaction, inhibits the enzyme. This inhibition is overcome by O(2) but not by indole-3-ethanol, indicating that the kinetic mechanism of the enzyme is a ping-pong Bi-Bi. The enzyme undergoes cooperative interactions with indoleethanol, yielding Hill coefficients as high as 2.96. Gibberellins are without effect on the enzyme, but it is inhibited by several acidic indoles possessing growth-promoting activity and by two synthetic auxins, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. Increasing concentrations of indoleacetic acid (IAA) brought about a slight reduction in the indoleethanol concentration producing halfmaximal velocity. Increasing levels of indoleethanol decreased the concentration of IAA required for half-maximal inhibition. At low concentrations of indoleethanol, low levels of IAA activated rather than inhibited. The effect of IAA was not overcome at higher levels of indoleethanol. These results may be interpreted as showing that IAA is a noncompetitive inhibitor which binds to that conformation of the enzyme which also binds indoleethanol. The significance of these interactions for the regulation of IAA biosynthesis is discussed.

Journal Article↗
PubMed1983

Purification and Characterization of a New Indole Oxygenase from the Leaves of Tecoma stans L.

A new indole oxygenase from the leaves of Tecoma stans was isolated and purified to homogenity. The purified enzyme system catalyzes the conversion of indole to anthranilic acid. It is optimally active at pH 5.2 and 30 degrees C. Two moles of oxygen are consumed and one mole of anthranilic acid is formed for every mole of indole oxidized. Dialysis resulted in complete loss of the activity. The inactive enzyme could be reactivated by the addition of concentrated dialysate. The enzyme is not inhibited by copper-specific chelators, non-heme iron chelators or atebrin. It is not a cuproflavoprotein, unlike the other indole oxygenases and oxidases.

Journal Article↗
PubMed1983

Analysis of Indole-3-acetic Acid Metabolism in Zea mays Using Deuterium Oxide as a Tracer.

A method using deuterium oxide (D(2)O) as a tracer was used to study indole-3-acetic acid (IAA) metabolism in Zea mays seedlings. Seeds were imbibed and grown for 4 days in 30% D(2)O in the dark. IAA was then isolated from roots and shoots and analyzed for deuterium content by mass spectrometry. We found that a significant portion of the IAA isolated from plants had incorporated deuterium at nonexchangeable sites of the indole ring. This indicates that some of the IAA in the germinating seedling is made via de novo indole synthesis. Moreover, we found that the deuterium content of IAA was 2.6 times greater in shoots than in roots. These results indicate that at least some of the IAA in roots and shoots came from different biosynthetic pathways. It appears that the fraction of IAA produced via de novo indole synthesis is greater in shoots than in roots.

Journal Article↗