Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic mastocytosis is characterized by abnormal mast cell proliferation in different organs. The 2001 consensus classification distinguishes in separate categories indolent systemic mastocytosis, systemic mastocytosis with concomitant blood disease, aggressive systemic mastocytosis and mast cell leukemia. Clinical manifestations are caused by tissue infiltration by proliferating mastocytes and by release of mediators. The principal organs affected are the skin, bones, digestive tract, liver, spleen and lymph nodes. Diagnosis of mastocytosis is based on appropriate stains (Giemsa, toluidine blue) and immunophenotype features (tryptase, CD117, also known as c-KIT and stem cell factor receptor). Serum tryptase levels reflect the total mast cell burden. Treatment must prevent release of mast cell mediators (histamine antagonists, cromolyn sodium, corticosteroids, or leukotriene-receptor inhibitors), limit bone involvement (bisphosphonates) and reduce the number of circulating mast cells (interferon, cladribine, or tyrosine kinase inhibitors). Enhanced understanding of the pathogenic mechanisms (mutation of c-kit and platelet-derived growth factor receptor alpha has led to the development of targeted treatments, including new inhibitors of tyrosine kinase and of nuclear factor Kappa B.
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PMID:[Systemic mastocytosis]. 1598 48

Tryptase and chymase are the two major granular proteases present in human mast cell (MC)s. We used oligonucleotide microarray to measure the levels of approximately 22,000 transcripts in cord blood-derived MCs at 4 weeks, 8 weeks, 12 weeks and 18 weeks in culture. Tryptase (TPSB2) was expressed at the highest level among all transcripts and its expression level reached a plateau at 8 weeks. On the other hand, the expression level of chymase (CMAI) doubled every 4-6 weeks. A similar tendency was found at the protein levels with FACS analysis. After filtering the transcripts with MC-specificity, hierarchical clustering analysis identified 494 and 81 transcripts in the same clusters with tryptase and chymase, respectively. MC-specific genes, KIT and HDC were found in the tryptase cluster. In the chymase cluster, a critical suppressor for cell senescence, BMI1 and the several related genes were found, suggesting that chymase expression may be closely related to cell senescence/quiescence events.
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PMID:Identification of tryptase- and chymase-related gene clusters in human mast cells using microarrays. 1643 34

The non-specific background reaction produced in avidin-biotin-based immunohistochemistry, particularly after harsh antigen retrieval procedures, has promoted the use of non-avidin-biotin systems, yet there are few reports comparing the performance of non-avidin-biotin, polymer-based methods. In this study we compare two of these methods, ENVISION+trade mark and ImmPRESS, in animal tissues. We examined the immunoreactivity of 18 antigens in formalin-fixed, paraffin-embedded tissues. Antigens were located in the cytoplasmic membrane (CD11d, CD18 and CD79a), cytoplasm (calretinin, COX-1, COX-2, Glut-1, HepPar 1, KIT, Melan A, tryptase and uroplakin III) or nucleus (MUM-1, PGP 9.5 and thyroid transcription factor 1). We also evaluated three infectious agents (Aspergillus, calicivirus and West Nile virus). The staining with ENVISION+ or ImmPRESS was performed simultaneously for each antigen. The intensity of the reaction and background staining were scored. ImmPRESS yielded similar or higher reaction intensity than ENVISION+trade mark in 16/18 antigens. ImmPRESS produced abundant background with the other two antigens (calretinin and COX-2), which hindered interpretation of the specific reaction. The cost of ImmPRESS was 25% lower than for ENVISION+trade mark. Based on these results, ImmPRESS is a good polymer-based detection system for routine immunohistochemistry.
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PMID:Comparison of two polymer-based immunohistochemical detection systems: ENVISION+ and ImmPRESS. 1720 59

A 20-year-old female horse showed a nodular, firm, focal ulcerated mast cell tumor at the right dorsobuccal face of the tongue. Histologically, the nonencapsulated tumor consisted of dense, infiltrating aggregates of well-differentiated, Cresyl violet-positive mast cells accompanied by numerous eosinophils. Furthermore, they exhibited a strong, diffuse, intracytoplasmatic immunohistochemical signal for tryptase and a faint membrane-associated and perinuclear signal for tyrosine kinase receptor KIT. Confocal laser scanning microscopy confirmed an aberrant spatial colocalization of KIT in the Golgi apparatus, which may be the result of a defective protein processing within the tumor cells. The tumor was not associated with a poor prognosis.
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PMID:Confocal laser scanning analysis of an equine oral mast cell tumor with atypical expression of tyrosine kinase receptor C-KIT. 1731 3

Gain-of-function mutations in the proto-oncogene c-kit have been considered the molecular mechanism of neoplastic proliferation of mast cells. However, the importance of c-kit gene mutations is not well evaluated in canine mast cell tumors (MCTs). In the present study, we established and characterized a mast cell line, HRMC, derived from a dog with MCT. We also examined c-kit mutations in HRMC cells and assessed an inhibitory effect of a tyrosine kinase inhibitor, STI571, on HRMC cells. HRMC cells had cytoplasmic metachromatic granules, chymase and tryptase, and expressed both KIT and FcepsilonRI on the cell surface. HRMC cells contained histamine and released beta-hexosaminidase through FcepsilonRI cross-linking and calcium ionophore stimulation. Nucleotide sequence analysis demonstrated no mutations in an open reading frame of c-kit cDNA and genomic DNA of the juxtamembrane domain of c-kit in HRMC cells. STI571 did not show any inhibitory effects on the proliferation of HRMC cells. These findings clearly demonstrated the existence of c-kit mutations-independent neoplastic canine mast cell proliferation. The growth factor-independent mast cell line established in this study might be valuable to explore novel mechanisms of c-kit mutations-independent neoplastic proliferation of mast cells in dogs.
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PMID:Identification of c-kit mutations-independent neoplastic cell proliferation of canine mast cells. 1868 74

In the World Health Organization classification, one major and four minor criteria are specified for the diagnosis of systemic mastocytosis. We report our experience using these criteria to diagnose systemic mastocytosis involving bone marrow. A total of 59 patients with clinically suspected systemic mastocytosis underwent comprehensive bone marrow examination, including immunophenotyping by immunohistochemistry and/or flow cytometry and molecular studies for KIT exon 17 mutations. Serum tryptase levels were also assessed. Of these 59, 53 (90%) patients met the diagnostic criteria for systemic mastocytosis. In these patients, multifocal dense infiltrates of mast cells, the major criterion, was observed in 36 (68%) patients. Atypical mast cell morphology was observed in 53 (100%), an aberrant immunophenotype was identified in 50 of 52 (96%), KIT mutation was present in 33 of 44 (75%), and an elevated serum tryptase (>20 ng/ml) was detected in 44 of 52 (85%). In the six patients in which bone marrow examination could not confirm systemic mastocytosis, one had systemic mastocytosis involving spleen, one patient had chronic idiopathic myelofibrosis, and four had no specific diagnosis, but systemic mastocytosis was still considered most likely. Of these six patients, atypical mast cell morphology was identified in five, aberrant immunophenotype in five, KIT mutation in two, and elevated serum tryptase in two. None of these cases met the major criteria. We conclude that the World Health Organization criteria are useful for the diagnosis of systemic mastocytosis in bone marrow specimens. The results also show the relative values of traditional morphologic criteria (ie, major criterion) and the results of ancillary testing (ie, minor criteria). However, as illustrated by the case of splenic systemic mastocytosis as well as the patient with chronic idiopathic myelofibrosis, the current World Health Organization system is neither completely sensitive nor specific for systemic mastocytosis.
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PMID:Utility of the World Heath Organization classification criteria for the diagnosis of systemic mastocytosis in bone marrow. 1911 30

Human tryptase is a serine protease expressed in mast-cells. We previously observed that AML blast cells, cultured in vitro from a KIT D816Y patient, give rise to adherent cells with mast-cell like phenotype and tryptase was released in the serum-free medium. To correlate total serum tryptase (ts-try) levels with cytogenetic features and KIT mutational status, we analyzed serum samples from AML patients at diagnosis. In 70 out of 155 patients (45%) we detected elevated ts-try (>15 ng/mL), significantly linked to t(8;21) (P < .001) and inv(16) (P = .007). In patients that achieved complete remission the ts-try decreased to normal values. In 75 patients screened for KIT mutation, we found a clear relationship between elevated ts-try and mutated patients with t(8;21) (P < .001). In conclusion, we propose that checking for ts-try at diagnosis of AML may be a simple tool to select patients to be addressed to KIT mutation screening.
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PMID:Total serum tryptase: a predictive marker for KIT mutation in acute myeloid leukemia. 1940 74

Mastocytosis, an unusual disorder of bone marrow-derived, clonally transformed hematopoietic progenitor cells, exhibits a broad spectrum of clinical and morphologic features ranging from a self-limiting benign disorder (ie, juvenile cutaneous mastocytosis) to highly aggressive neoplasms like mast cell leukemia. Principally, mastocytosis should be divided in 2 main subentities: cutaneous mastocytosis and systemic mastocytosis mainly involving the bone marrow. Mastocytosis is a morphologic diagnosis and should not be diagnosed on the basis of clinical findings alone. Pathologists need to be aware of the disease and its mimickers. Application of the defined diagnostic criteria can confirm or exclude mastocytosis in most cases. Use of antibodies against tryptase, CD117 (KIT), and CD25 is recommended in every suspected case. Because most cases of systemic mastocytosis show a very low degree of infiltration of the bone marrow, antitryptase and anti-CD117 are of major importance for screening and quantification of mast cells, in particular to detect even small compact infiltrates as the only major diagnostic criterion for mastocytosis. Expression of CD25 on mast cells is defined as a minor diagnostic criterion and is usually seen only in mastocytosis but not in reactive states of mast cell hyperplasia.
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PMID:Mastocytosis: an unusual clonal disorder of bone marrow-derived hematopoietic progenitor cells. 1968 20

We describe a case of systemic mastocytosis associated with myelodysplastic syndrome. The bone marrow showed multifocal clusters of mast cells and myeloid dysplasia. Sequencing of the KIT DNA revealed a point mutation at codon 816 including a substitution of valine for aspartic acid (D816V). The patient's tumor did not respond to imatinib; however, interferon-alpha reduced the bone marrow mast cells and serum total tryptase. The patient remains alive at one year after the diagnosis without disease progression.
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PMID:Successful treatment of KIT D816V-positive, imatinib-resistant systemic mastocytosis with interferon-alpha. 1991 99

Diagnosis of systemic mastocytosis (SM) is mainly based on the morphological demonstration of compact mast cell infiltrates in various tissue sites. In almost all patients such infiltrates are detected in the bone marrow. Reliable immunohistochemical markers for the diagnosis and grading of SM have been established, but various differential diagnoses including myeloproliferative neoplasms, basophilic and eosinophilic leukemias may be very difficult to delineate. Even more challenging is the recognition of hematological neoplasms with signs of mast cell differentiation but not fulfilling diagnostic criteria for SM, especially the rare myelomastocytic leukemia. It is also important to separate the reactive state of mast cell hyperplasia from indolent variants of SM, especially those with a very low degree of bone marrow infiltration and absence of compact mast cell infiltrates. When the lymphocytic component of the SM infiltrate is very prominent, SM may be confused with an indolent lymphoma, especially lymphoplasmacytic lymphoma which almost always shows a marked reactive increase in mast cells. In aggressive and leukemic variants of SM, mast cells may be very atypical and devoid of metachromatic granules. This hypogranulation can be regarded as cellular atypia and may lead to the misdiagnosis aspect of monocytic leukemia or histiocytic neoplasm. Regarding immunohistochemical anomalies, mast cells in aggressive and leukemic SM have been found to express CD30 (Ki1-antigen). Thus, anaplastic large cell lymphoma or Hodgkin's disease may first be considered rather than SM. There is increasing evidence that most patients with long-standing adult-type urticaria pigmentosa-like skin lesions have in fact indolent SM. Therefore, such skin lesions are an important clue to the correct diagnosis in these patients. However, in aggressive or leukemic SM skin lesions are usually absent and then the correct diagnosis relies on an appropriate investigation of bone marrow biopsy specimens using both SM-related immunohistochemical markers (tryptase, KIT, CD25, CD30) but also markers excluding potential differential diagnoses. Investigation for presence of the activating KIT point mutation D816V is very helpful to establish a correct diagnosis of SM in all the difficult cases exhibiting a low degree of bone marrow infiltration or puzzling morphological findings.
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PMID:Differential diagnoses of systemic mastocytosis in routinely processed bone marrow biopsy specimens: a review. 2061 12


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