Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germline p53 mutations have been identified in the Li-Fraumeni syndrome but the role of such mutations in familial leukemia is not established. The p53 gene was examined by single-strand conformation polymorphism analysis of exons 4-8 in 10 families with multiple members affected with leukemia. The diagnoses included acute and chronic leukemias and Hodgkin's disease. Identified in two families were p53 mutations that were nonhereditary. These included a 2-bp deletion in exon 6 found in the lymphoblast DNA of one child whose sibling, cousin, and several adult relatives had acute leukemia. The other nonhereditary p53 mutation was a transition at codon 248 (CGG to CAG, arginine to glutamine) found in the lymphoblasts of a patient with a preleukemic syndrome and acute lymphoblastic leukemia (ALL) whose brother is a long-term survivor of ALL. Thus, p53 mutations were found to occur in two families but both were nonhereditary. Moreover, in the remaining eight families no p53 mutation was identified in the regions of p53 where most mutations have been found in other cancers. Although p53 mutations sometimes may be present, they do not appear to be a primary event responsible for hereditary susceptibility to familial leukemia. This study suggests involvement of other genes or mechanisms.
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PMID:Absence of hereditary p53 mutations in 10 familial leukemia pedigrees. 164 30

We performed analyses of electrolytes, amino acids, albumin, alpha 2-macroglobulin, gamma-globulin and LDH in the lumbar cerebrospinal fluid of children undergoing treatment for acute lymphoblastic leukemia, non-Hodgkin-lymphoma or acute myeloid leukemia. At the time of diagnosis signs of a disturbance of the blood-brain barrier were found in some patients. During induction treatment with L-asparaginase a rise of glutamic acid and a decrease of glutamine occurred. This finding correlated with slowing of the EEG. Treatment with vincristine was associated with a slight drop of sodium and chloride concentration in serum, but not in the cerebrospinal fluid. Central nervous system prophylaxis with cranial irradiation, and to a lesser degree with intravenous medium-dose methotrexate, gave rise to a further deterioration of the blood-brain barrier function as indicated by an increase in albumin, alpha 2-macroglobulin and LDH levels. During radiotherapy the concentration of several amino acids rose, probably due to a disturbance of active carrier mechanisms. Patients with elevated albumin at the end of radiotherapy more often suffered an early leukemia relapse while still on treatment. No other clinical or electroencephalographic correlations of altered barrier function could be found.
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PMID:Electrolytes, amino acids and proteins in lumbar CSF during the treatment of acute leukemia in childhood. 233 48

Owing to the high efficacy of L-asparaginase in the treatment of acute lymphatic leukaemia the enzyme was introduced into the chemotherapy schedules for remission induction of this disease shortly after results of large-scale clinical trials had become available. Since asparaginase monotherapy was associated with a high response rate but short remission duration, the enzyme is currently employed within the framework of combination chemotherapy schedules which achieve treatment response in about 90% and long-term remissions in the majority of patients. Recently initiated clinical trials have still confirmed the eminent value of asparaginase in the combination chemotherapy of acute lymphatic leukaemia and of some subtypes of non-Hodgkin lymphoma, and its important role as an essential component of multimodal treatment protocols. Despite the unique mechanism of action of this cytotoxic substance which shows relative selectivity with regard to the metabolism of malignant cells, some patients experience toxic effects during asparaginase therapy. Immunological reactions toward the foreign protein include enzyme inactivation without any clinical manifestations as well as anaphylactic shock. Severe functional disorders of organ systems result from the impaired homeostasis of the amino acids asparagine and glutamine. The changes affecting the proteins of the coagulation system have considerable clinical impact as they may induce bleeding as well as thromboembolic events and may be associated with life-threatening complications when the central nervous system is involved. Risk factors predisposing to thromboembolic complications are hereditary resistance against activated protein C and any other hereditary thrombophilia. Other organ systems potentially affected by relevant functional disorders are the central nervous system, the liver, and the pancreas, with patients who have a history of pancreatic disorders carrying an especially high risk of developing pancreatitis. Studies on the mechanisms of action and the occurrence of resistance phenomena have shown that a treatment response may only be expected if the malignant cells are unable to increase their asparagine synthetase activity to an extent providing enough asparagine to the cell; one may thus conclude that the enzyme-induced asparagine depletion of the serum constitutes the decisive cytotoxic mechanism. Independent of the asparagine depletion related cytotoxicity however, there are other mechanisms of clinical relevance like induction of apoptosis. Besides this, further influences on signal transduction cannot be excluded. Only few publications have dealt with the question of minimum trough activities to be ensured before each subsequent asparaginase dose in order to maintain uninterrupted asparagine depletion under treatment, and answers to this problem are not definitive. Clinical studies using enzymes from E. coli strains indicate that a trough activity of 100 U/l will suffice for complete asparagine depletion of the fluid body compartments with the preparations studied. These findings have been transferred to enzymes from other E. coli strains as well as those isolated from Erwinia chrysanthemi and to the PEG-conjugated E. coli asparaginases. It might be desirable to countercheck the results for confirmation or correction. The dosage and administration schedule of the various enzyme preparations required for complete asparagine depletion over a period of time have been insufficiently defined. While pharmacokinetic studies showed clinically relevant differences in biological activity and activity half-lives for enzymes from different biological sources, the findings of recently published clinical trials indicate that the therapeutic efficacy is affected when different asparaginase preparations are given by identical therapy schedules. (ABSTRACT TRUNCATED)
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PMID:Use of L-asparaginase in childhood ALL. 976 45

We examined the types of Epstein-Barr virus-associated nuclear antigen-1 (EBNA-1) gene carboxy (C)-terminal mutations occurring in Hodgkin's disease (HD) and reactive tissues from two different geographic regions. Previously reported EBNA-1 C-terminal region amino acid sequence variants, based on the amino acid at codon 487, include Prototype (P)-ala, which is found in the B95.8-derived prototype virus, P-thr, Variant (V)-leu, V-val, and V-pro. Using polymerase chain reaction (PCR) to amplify portions of the EBNA-1 gene, followed by DNA sequencing, we found a single EBNA-1 gene sequence variant in each tissue, whether reactive or neoplastic and whether from Brazil or the United States. Variant EBNA-1 gene sequences were more common in both neoplastic and non-neoplastic tissues from different geographic areas than the so-called prototype sequence. In the 17 Brazilian HD cases, 4 cases had P-thr variants and 13 had V-leu variants. In the six reactive tissues from Brazil, one had a P-ala variant, two had P-thr variants, and three had V-leu variants. In the 12 American HD cases, 2 had P-ala variants, 6 had P-thr variants, and 4 had V-leu variants. The 11 American reactive tissues included 2 P-ala variants, 5 P-thr variants, and 4 V-leu variants. In both countries, there were similar variant EBNA-1 sequences present in normal tissues and HD cases. Compared with the P-ala and P-thr cases, the V-leu cases were more likely to have the 30-bp latent membrane protein 1 (LMP1) gene deletion (P = 0.0075). In addition, cases of HD with the V-leu were statistically associated with a substitution of asparagine for glutamine at codon 322 of the C-terminal portion of the LMP1 gene. Our results suggest that any variation in EBNA-1 gene sequence is caused by a polymorphism present in pre-existing viral strains in the underlying population, and not a mutation occurring during oncogenesis.
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PMID:EBNA-1 gene sequences in Brazilian and American patients with Hodgkin's disease. 1038 19

FAS germline mutations have been associated with the development of autoimmune lymphoproliferative syndrome (ALPS). Occurrence of Hodgkin lymphoma (HL) has been reported in 2 families with ALPS. In both families an uncle of the index patient developed HL. A 15-year-old boy with autoimmune thrombopenia, lymphadenopathy, and splenomegaly for 6 years was studied. In an axillary lymph node biopsy nodular lymphocyte predominant (NLP) HL was diagnosed; in the areas between the nodules a proliferation of double-negative blastic T cells were present, suggestive of ALPS. Analysis for the presence of a FAS gene mutation using the denaturing gradient gel electrophoresis technique indicated a mutation in exon 9. Direct sequence analysis revealed a mutation causing a substitution of arginine with glutamine at codon 234. Because ALPS and NLP HL are both highly infrequent conditions, the occurrence in at least 3 families suggests a causative relationship between germline FAS gene mutations and NLP HL.
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PMID:Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma. 1183 May 7