Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.
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PMID:Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. 1087 99

Retinoic acid (RA) has been used to induce the regression of refractory T-cell lymphoma. In vitro and in vivo studies have shown that RA exerts this effect through the induction of apoptosis. This study was designed to investigate the molecular pathway of RA-induced apoptosis in T-lymphoma cell lines.RA-induced apoptosis was verified by morphology, flow cytometry, and DNA ladder analysis. Differential display method using a combination of 12 poly(A)-anchored primers and 20 arbitrary primers was adopted for gene cloning. Total RNAs were extracted from H9 cell line at 0, 6, 12, and 24 hours after All-trans RA (ATRA) treatment and the serial expression patterns of the candidate fragments were recognized. The cloned gene fragments were then analyzed and confirmed by Northern blot analysis on H9 and SR786 cell lines.ATRA-induced apoptosis of T-cell lymphoma was protein synthesis-dependent. The execution or irreversible phase of apoptosis appeared to occur at 6-12 hours of RA treatment. Among the 60,000 arbitrarily displayed bands, 25 of 250 candidate fragments were selected for further cloning and sequencing. A total of 14 clones could be matched to known genes and were categorized into four groups: A) transcription factors: prothymosin, CA150, p78 serine/threonine kinase, IL-1beta-stimulating gene, glucocorticoid receptor, MLN64/CAB1, gastrin-binding protein, and polypeptide from glioblastoma; B) chaperone: 90 kDa heat shock protein; C) ion channel: chloride channel protein 3; and D) cytoskeleton: cytovillin2/ezrin and vimentin. Another two clones of genes were of unrecognized functions. The remaining 11 clones belonged to unmatched or novel genes. The expression of these genes varied, either upregulated or downregulated, in response to ATRA treatment.RA-induced apoptosis may involve a cascade of genes that are related to transcription regulation, stress response, housekeeping, and the execution of apoptosis. The clarification of the RA-induced apoptotic pathway will help us to understand the molecular mechanism of cancer differentiation agents.
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PMID:Retinoic acid-induced apoptotic pathway in T-cell lymphoma: Identification of four groups of genes with differential biological functions. 1114 66

MRI has facilitated diagnostic assessment of the corpus callosum. Diagnostic classification of solitary or multiple lesions of the corpus callosum has not attracted much attention, although signal abnormalities are not uncommon. Our aim was to identify characteristic imaging features of lesions frequently encountered in practice. We reviewed the case histories of 59 patients with lesions shown on MRI. The nature of the lesions was based on clinical features and/or long term follow-up (ischaemic 20, Virchow-Robin spaces 3, diffuse axonal injury 7, multiple sclerosis 11, hydrocephalus 5, acute disseminated encephalomyelitis 5, Marchiafava-Bignami disease 4, lymphoma 2, glioblastoma hamartoma each 1). The location in the sagittal plane, the relationship to the borders of the corpus callosum and midline and the size were documented. The 20 ischaemic lesions were asymmetrical but adjacent to the midline; the latter was involved in new or large lesions. Diffuse axonal injury commonly resulted in large lesions, which tended to be asymmetrical; the midline and borders of the corpus callosum were always involved. Lesions in MS were small, at the lower border of the corpus callosum next to the septum pellucidum, and crossed the midline asymmetrically. Acute disseminated encephalomyelitis and the other perivenous inflammatory diseases caused relatively large, asymmetrical lesions. Hydrocephalus resulted in lesions of the upper part of the corpus callosum, and mostly in its posterior two thirds; they were found in the midline. Lesions in Marchiafava-Bignami disease were large, often symmetrically in the midline in the splenium and did not reach the edge of the corpus callosum.
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PMID:Classification of acquired lesions of the corpus callosum with MRI. 1115 83

Endocannabinoids are lipid mediators thought to modulate central and peripheral neural functions. We report here gas chromatography-electron impact mass spectrometry analysis of human brain, showing that lipid extracts contain anandamide and 2-arachidonoylglycerol (2-AG), the most active endocannabinoids known to date. Human brain also contained the endocannabinoid-like compounds N-oleoylethanolamine, N-palmitoylethanolamine and N-stearoylethanolamine. Anandamide and 2-AG (0.16 +/- 0.05 and 0.10 +/- 0.05 nmol/mg protein, respectively) represented 7.7% and 4.8% of total endocannabinoid-like compounds, respectively. N-Palmitoyethanolamine was the most abundant (50%), followed by N-oleoyl (23.6%) and N-stearoyl (13.9%) ethanolamines. A similar composition in endocannabinoid-like compounds was found in human neuroblastoma CHP100 and lymphoma U937 cells, and also in rat brain. Remarkably, human meningioma specimens showed an approximately six-fold smaller content of all N-acylethanolamines, but not of 2-AG, and a similar decrease was observed in a human glioblastoma. These ex vivo results fully support the purported roles of endocannabinoids in the nervous system.
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PMID:Gas chromatography-mass spectrometry analysis of endogenous cannabinoids in healthy and tumoral human brain and human cells in culture. 1120 22

Aneuploidy is a characteristic of the majority of human cancers, and recent studies suggest that defects of mitotic checkpoints play a role in carcinogenesis. MAD1L1 is a checkpoint gene, and its dysfunction is associated with chromosomal instability. Rare mutations of this gene have been reported in colon and lung cancers. We examined a total of 44 cell lines (hematopoietic, prostate, osteosarcoma, breast, glioblastoma and lung) and 133 fresh cancer cells (hematopoietic, prostate, breast and glioblastoma) for alterations of MAD1L1 by RT-PCR-SSCP and nucleotide sequencing. Eight mutations consisting of missense, nonsense and frameshift mutations were found, together with a number of nucleotide polymorphisms. All the alterations in cell lines were heterozygous. Frequency of mutations was relatively high in prostate cancer (2/7 cell lines and 2/33 tumor specimens). We placed a mutant truncated MAD1L1, found in a lymphoma sample, into HOS, Ht161 and SJSA cell lines and found that it was less inhibitory than wild type MAD1L1 at decreasing cell proliferation. Co-expression experiments showed that the mutant form had a dominant-negative effect. Furthermore, this mutant impaired the mitotic checkpoint as shown by decreased mitotic indices in HOS cells expressing mutant MAD1L1 after culture with the microtubule-disrupting agent, nocodazole. Our results suggest a pathogenic role of MAD1L1 mutations in various types of human cancer.
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PMID:Mutations in the mitotic check point gene, MAD1L1, in human cancers. 1142 79

Brain tumor incidence has increased over the last 20 years in all age groups, both overall and for specific histologies. Reasons attributed to these increases include increase in lymphoma due to HIV/AIDS, introduction of computed tomography/magnetic resonance imaging, and changes in coding/classification. The purpose of this study was to describe overall and histologic-specific incidence trends in a population-based series of primary benign and malignant brain tumors. Data from the Central Brain Tumor Registry of the United States from 1985 through 1994 were used to determine incidence trends in the broad age groups 0-19, 20-64, and > or = 65 years, both overall and for selected histologies. Poisson regression was used to express trends as average annual percentage change. Overall, incidence increased modestly (annual percentage change 0.9%, 95% confidence interval, 0.4, 1.4). When lymphomas were excluded, this result was not statistically significant (annual percentage change 0.5%, 95% confidence interval, -0.1, 1.1). Specific histologies that were increasing were lymphomas in individuals aged 20 to 64 years and in males aged 65 years or older, ependymomas in the population aged 20 to 64 years, nerve sheath tumors in males, and pituitary tumors in females. Increases that were not specific to any population subgroup were seen for glioblastoma, oligodendrogliomas, and astrocytomas, excluding not otherwise specified (NOS) tumors. Corresponding decreases were noted for NOS, astrocytoma NOS, and glioma NOS. Increasing incidence trends for lymphomas were consistent with previous literature. Improvements in diagnostic technology in addition to changes in classification and coding were likely to be responsible for decreases seen in incidence of NOS subgroups and corresponding increases in glioma subgroups. In contrast, the increases identified for ependymomas, nerve sheath tumors, and pituitary tumors were less likely to be artifacts of improvements in diagnosis, and they warrant further study.
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PMID:Trends in incidence of primary brain tumors in the United States, 1985-1994. 1146 94

Agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beta-tubulin, and monotetrahydrofuran compounds (COBRA compounds), targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization and demonstrated potent cytotoxic activity against cancer cells. COBRA-1 inhibited GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other agents that have shown promise for cancer treatment include phorboxazoles, natural products that are extremely cytostatic towards the National Cancer Institute's panel of 60 tumor cell lines. In standard MTT assays, synthetic phorboxazole A exhibited potent cytotoxicity against NALM-6 acute lymphoblastic leukemia cells (IC50 = 1.7 nM), BT-20 breast cancer cells (IC50 = 3.4 nM), and U373 glioblastoma cells (IC50 = 6.7 nM). Structure-activity studies were reported for seven synthetic analogs of phorboxazole A. Out of these, two showed potent anti-cancer activity. Phorboxazole analog 2 was active against NALM-6 cells (IC50 = 4.8 nM), BT-20 cells (IC50 = 12.6 nM) and U373 cells (IC50 = 27.4 nM), as was analog 3 (NALM-6 IC50 = 5.2 nM, BT-20 IC50 = 11.3 nM, and U373 IC50 = 29.2 nM). Anticancer activity of the phorboxazole analogs was correlated to the presence of certain structural moieties such as portions of the macrolide group, the central oxazole group, and the polyene side chain. The requirement of more than one structural element for activity suggested that at least bimodal interactions of the natural product with key cellular components may occur. Promising anti-mitotic agents with pro-apoptotic activity include inhibitors of the tyrosine kinase BTK. The leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells (IC50 = 17 microM). Consistent with the anti-apoptotic function of BTK, treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.
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PMID:Rationally designed anti-mitotic agents with pro-apoptotic activity. 1156 3

Although two-thirds of tumors occurring in the central nervous system (CNS) are primary neoplasms, only 10% of positive cerebrospinal fluid (CSF) specimens are from primary CNS tumors. In this study, we reviewed the cytologic findings of 21 positive CSF specimens from primary CNS tumors. A computer search identified 21 cases of positive CSF specimens from patients with primary CNS tumors from the archives. Follow-up included review of medical charts and histologic correlation. The specimens were from 20 patients (9 females and 11 males). Their ages ranged from 6-83 yr, old with a mean of 30 yr. The cases included 9 medulloblastomas, 7 gliomas (3 glioblastoma multiformes, 2 anaplastic astrocytomas, and 2 ependymomas), 2 germinomas, 2 non-Hodgkin's large B-cell lymphomas, and 1 ganglioneurocytoma. Two cases were classified as suspicious and the remaining as positive for malignancy. Immunocytochemistry was employed in 3 cases to support the cytologic diagnosis. These cases included one large-cell lymphoma (leukocyte-common antigen-positive), one germinoma (placental alkaline phosphatase-positive), and the ganglioneurocytoma (neuron-specific enolase- and synaptophysin-positive). There were no false-positive cases. Our results suggest that positive CSF cytology in patients with a primary CNS tumor is a reliable indicator of malignancy and reflects leptomeningeal involvement. The use of immunocytochemistry is helpful in confirming the cytologic impression in some cases.
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PMID:Cytology of primary central nervous system neoplasms in cerebrospinal fluid specimens. 1193 64

The Neuropathology Study Group of the Korean Society of Pathologists conducted a nationwide collection of central nervous system (CNS) tumors to evaluate the relative frequency in Korea of CNS tumors belonging to the revised World Health Organization (WHO) classification categories. A total of 3221 histologically proven cases of CNS tumors were collected from 13 institutes between 1997 and 1998. All the cases were classified according to the revised WHO histological types and analyzed for the relative frequency, the distribution of age and sex, and location of tumors. The most frequent type of CNS tumors in Korea was meningiomas, followed by pituitary adenoma, glioblastoma, astrocytoma, and schwannoma. Among the pediatric CNS tumors, pilocytic astrocytoma, medulloblastoma, craniopharyngioma, germ cell tumors, and ependymomas were common types of tumors. Compared with a previous nationwide study, the rates for neuronal/glial tumors, glioblastoma, malignant lymphoma, and cystic lesion were increased, and the rate of embryonal tumors was decreased. The overall male to female ratio was 0.9: 1, which may be attributed to the greater number of female-predominate meningiomas and pituitary adenoma. Compared with Western countries, Koreans had higher rates of pituitary adenoma and meningiomas and lower rate of gliomas. The relative frequency of CNS tumors among Koreans is very similar to that reported in Taiwan. The occurrence rates for various subtypes of CNS tumors in Korea are distinct from those in the United States and Europe and similar in many ways to those in Asian and Mexican population.
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PMID:Tumors of the central nervous system in Korea: a multicenter study of 3221 cases. 1206 32

The initial identification of the ALK gene, expressed as C-terminal part of the transforming fusion protein NPM-ALK in the t(2;5)(p23;q35) lymphoma-associated chromosomal translocation, revealed a novel receptor tyrosine kinase (RTK). In order to expand the knowledge on ALK expression in the human system, we examined a panel of human cell lines for ALK expression and found that transcription is completely repressed in cell lines of entodermal origin (0/21). Furthermore, full length receptor expression is absent in cell lines of the hematopoietic system with the exception of t(2;5)-associated anaplastic large cell lymphomas lines (ALCL), which are known to express chimeric NPM-ALK mRNA. Cell lines established from solid tumors of ectodermal origin, including melanoma and breast carcinoma, exhibited widespread mRNA expression of the ALK receptor at a broad range (53/64), an association which was found to be strongest in cell lines derived from neuroblastoma (6/6), glioblastoma (8/8) as well as in cell lines established from Ewing sarcoma (4/4) and retinoblastomas (2/2). Because of the reported involvement of neutrophin tyrosine kinase receptors in autocrine differentiation in neuroblastomas, we analyzed cell lines positive for full length or chimeric ALK protein for the presence of phoshotyrosine residues within the intracellular region of ALK. While the constitutive activation of chimeric NPM-ALK molecules could be shown, no evidence was found for induced or constitutively activated ALK receptors in neuroblastoma, melanoma or breast carcinoma cell lines. Although the receptor could be shown to be consistently expressed with exclusive specificity in tissues developed from the ectoderm, our results do not support any involvement of ALK in the stimulation of tumorigenic cell growth or differentiation so far, indicating that ALK expression is a physiologic rather than a pathologic phenomenon.
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PMID:Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines. 1211 86


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