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At least 775 records · Page 43Linked to original sources
PubMed1991

Genetic alteration of p53 in some patients with adult T-cell leukemia.

Abnormalities of p53 mRNA in adult T-cell leukemia (ATL) were analyzed using reverse transcription-polymerase chain reaction-single strand conformation polymorphism analysis. Mutations were present in two of 12 ATL patients studied, but not in 3 cell lines immortalized by human T cell leukemia virus type 1 (HTLV-1) infection in vitro. Direct sequencing analysis of the p53 gene from these two patients revealed missense point mutations at codon 153 (arginine to histidine) or codon 220 (cysteine to tyrosine), respectively. Immunohistochemical analysis revealed the elevated expression of p53 proteins in ATL cells from a patient carrying the mutated p53 gene at codon 158. Neither gross rearrangement of p53 gene nor abnormal size of mRNA for the gene was demonstrated by Southern or Northern blot analyses. Thus, there is a mutated p53 in some patients with ATL. The involvement of abnormalities in some suppressor oncogenes may play a role in the development of ATL.

Base Sequence↗
PubMed1993

Novel interleukin-2 dependent T-cell line derived from adult T-cell leukemia not associated with human T-cell leukemia virus type I.

A novel interleukin-2 (IL-2)-dependent T-cell line, WHN2, was established from a patient with adult T-cell leukemia (ATL) not associated with human T-cell leukemia virus type I (HTLV-I). Neither the original leukemic cells nor the WHN2 cells showed proviral integration in their cellular DNAs by Southern blot analysis. The surface phenotype showed that both the original leukemic cells and the WHN2 cells had a common phenotype of ATL, i.e., positive for CD2, CD4, human leukocyte antigen DR (HLA-DR) and CD25, but negative for CD8, a characteristic of helper/inducer T-cells. Most of the chromosomal abnormalities of the original leukemic cells were maintained in the WHN2 cell line. Furthermore, Southern blot analysis of the T-cell receptor beta-chain gene rearrangement revealed that the original leukemic cells and WHN2 cell line had identical patterns, suggesting that the WHN2 cell line was truly derived from the original leukemic cells. Dose-dependent growth on IL-2 was demonstrated, and at the maximal stimulation, the number of cells doubled within three days. This IL-2-dependent growth was inhibited by the simultaneous existence of anti-IL-2 receptor alpha and beta chain antibodies. These results indicate that the character of the WHN2 cell line is similar to that of the cell lines derived from ATL associated with HTLV-I. Thus, the HTLV-I-negative ATL cell line, WHN2, should be useful in the comparative study of the pathogenesis of ATL associated with or without HTLV-I.

Aged↗
PubMed1993

Aberrant expression of the p53 tumor suppressor gene in adult T-cell leukemia and HTLV-I-infected cells.

By immunoprecipitation analysis, enhanced p53 expression was detected in 3 of 4 adult T-cell leukemia (ATL) cell lines, 1 of 3 HTLV-I-infected cell lines and 1 of 5 fresh ATL samples, compared with phytohemagglutinin-stimulated peripheral blood lymphocytes. Among these 5 high expressers, p53 missense mutations were indicated in 2 ATL cell lines and 1 fresh ATL sample by extensive p53 cDNA and genomic DNA polymerase chain reaction single-strand conformation polymorphism analysis. No mutation was found throughout the entire coding region of the remaining 2 high expressers (1 ATL and 1 HTLV-I-infected cell lines) and low expressers of p53 (2 HTLV-I-infected cell lines). Tax oncoprotein expression was found in these 2 high p53 expressers in which p53 mutation was not present, but not in low p53 expressers or cells carrying this mutation. The levels of p53 mRNA were similar among the samples regardless of p53 levels. Posttranscriptional mechanisms other than missense mutation would thus appear to increase p53 in the Tax-expressing cells but not in cells containing undetectable levels of Tax. No complex formation between p53 and Tax was observed.

Adult↗
PubMed1996

Serial transplantation of adult T cell leukemia cells into severe combined immunodeficient mice.

The precise mechanism of the neoplastic cell growth of adult T cell leukemia (ATL) still remains unclear. In the present study, we have succeeded in serial transplantation of ATL cells from a patient into severe combined immunodeficient (SCID) mice. In this model, we found that only a leukemic cell clone from an ATL patient could be successively transplanted into SCID mice, although it was difficult to maintain leukemic cell clones in vitro, suggesting that the microenvironment provided by SCID mice is suitable for leukemic cell growth. We could not detect human T cell leukemia virus type I (HTLV-I) mRNA or interleukin 2 (IL-2) mRNA in either the tumor cells growing in mice or the original leukemic cells. Thus, it appears that neither HTLV-I viral expression nor the IL-2 autocrine mechanism is directly involved in the neoplastic cell growth of fresh ATL cells as well as HTLV-I-infected cell lines, at least in SCID mice. In addition, we could passage frozen cells and obtain a large number of expanded leukemic cells in this model. Such a serial transplantation model, which can avoid the changes in the nature of leukemic cells that are frequently observed in in vitro culture, and which can propagate leukemic cell clones, would be very suitable not only to study the mechanism of neoplastic cell growth, but also to test potential therapeutic agents for ATL.

Aged↗
PubMed2001

Possible involvement of interferon regulatory factor 4 (IRF4) in a clinical subtype of adult T-cell leukemia.

Interferon regulatory factor (IRF) 4 is the lymphoid-specific transcription factor that is required for the proliferation of mitogen-activated T cells. IRF4 has been suggested to be involved in tumorigenesis because the overexpression of IRF4 caused the transformation of Rat-1 fibroblasts in vitro. Here, we show that IRF4 is constitutively expressed in adult T-cell leukemia (ATL)-derived cell lines, which were infected with human T-cell leukemia virus type-I, but hardly expressed the trans-activator protein, Tax. Similarly, constitutive expression of IRF4 was demonstrated in freshly isolated peripheral blood mononuclear cells (PBMC) from patients with either acute or chronic ATL. However, the high-level expression of IRF4 was specifically associated with acute ATL. With mitogen-activated PBMC from healthy donors, cell cycle analyses revealed that the induction of IRF4 occurred prior to cell cycle progression and the cells that had entered the cell cycle were predominantly IRF4-positive cells. In addition, ectopic expression of IRF4 in Rat-1 fibroblasts increased the S and G2 / M phase population significantly. Taken together, our results indicate that IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle, and that IRF4 can be used as a molecular marker of clinical subtype in ATL.

Adult↗
PubMed2004

Integration of human T-cell leukemia virus type 1 in genes of leukemia cells of patients with adult T-cell leukemia.

Adult T-cell leukemia (ATL) occurs after a long latent period of persistent infection by human T-cell leukemia virus type 1 (HTLV-1). However, the mechanism of oncogenesis by HTLV-1 remains to be clarified. It was reported that the incidence curve of ATL versus age was consistent with a multistage carcinogenesis model. Although HTLV-1 is an oncogenic retrovirus, a mechanism of carcinogenesis in ATL by insertional mutagenesis as one step during multistage carcinogenesis has not been considered thus far, because the exact integration sites on the chromosome have not been analyzed. Here we determined the precise HTLV-1 integration sites on the human chromosome, by taking advantage of the recently available human genome database. We isolated 25 integration sites of HTLV-1 from 23 cases of ATL. Interestingly, 13 (52%) of the integration sites were within genes, a rate significantly higher than that expected in the case of random integration (P = 0.043, chi(2) test). These results suggest that preferential integration into genes at the first infection is a characteristic of HTLV-1. However considering that some of the genes are related to the regulation of cell growth, the integration of HTLV-1 into or near growth-related genes might contribute to the clonal selection of HTLV-1-infected cells during multistage carcinogenesis of ATL.

Chromosome Mapping↗
PubMed2004

Identification of differentially expressed molecules in adult T-cell leukemia cells proliferating in vivo.

HTLV-I is the causative agent of adult T-cell leukemia (ATL). However, the precise mechanism underlying the neoplastic cell growth of ATL remains unclear. In this study, we established a leukemic cell line, termed SYK-11L(+), from tumor cells (S-YU) in an in vivo cell proliferation model of ATL using severe combined immunodeficiency (SCID) mice. Unexpectedly, SYK-11L(+) was found to have no tumorigenicity in SCID mice. Flow cytometric analysis showed that S-YU expressed cell adhesion molecules including CD44, ICAM-1 and OX40, whereas SYK-11L(+) had lost the expression of these molecules. The administration of anti-OX40 monoclonal antibody inhibited the engraftment of S-YU cells into SCID mice, suggesting that OX40 is a potential target for immunotherapy. Significant differences in responsiveness to IL-2 and IL-15 were observed between the two cell types. To better understand the molecular basis of tumorigenicity, cDNA microarray analysis was performed using tumorigenic S-YU and non-tumorigenic SYK-11L(+) cells. We obtained several candidate genes differentially overexpressed in S-YU compared with SYK-11L(+). Interestingly, one such gene, regulator of G protein signaling 1 (RGS1), was shown to be overexpressed in most ATL patients. Further characterization of the differentially expressed molecules, such as OX40 and RGS1, would provide useful information not only to elucidate the mechanism of ATL cell growth in vivo, but also to develop novel molecularly targeted therapies.

Animals↗
PubMed1984

Ultrastructural study of type C virus particles in phytohemagglutinin-stimulated lymphocytes from healthy adults seropositive to adult T-cell leukemia-associated antigens.

PHA-stimulated peripheral lymphocytes from six healthy adults consisting of four family members of an adult T-cell leukemia (ATL) patient and two blood bank donors, seropositive to ATL-associated antigens (ATLA), were all positive for the expression of ATLA and ATL-associated virus (ATLV). These results revealed that anti-ATLA-positive persons were healthy carriers of ATLV and that the numbers of ATLV observed in each culture were more proportional to the percentage of ATLA-positive lymphocytes than anti-ATLA titers of each person. Virus particles detected were C-type in morphology, and essentially similar to those observed in MT-2 and other ATL-related cells, but rather uniform in size, mostly 120-130 nm in diameter. Furthermore, it is of interest that tubuloreticular structures and striated fusiform structures, which were found in fresh or short term cultured ATL cells, were observed in some cultures of lymphocytes from anti-ATLA-positive healthy persons.

Adolescent↗
PubMed1997

Cost-effectiveness of anterotemporal lobectomy in medically intractable complex partial epilepsy.

PURPOSE: The value of high-cost health technologies is being increasingly scrutinized by providers of health care. An understanding of the costs and outcomes of high-technology epilepsy care is required to ensure efficient resource allocation. METHODS: Decision analysis was used to estimate the cost effectiveness of anterotemporal lobectomy (ATL) as compared with standard medical management in medically-intractable epilepsy. Local (Rochester, NY, U.S.A.) cost data were applied to a model of lifetime discounted costs and outcomes of evaluation, ATL, and follow-up in a hypothetical cohort of patients. RESULTS: Base case analysis yielded a marginal cost-effectiveness ratio (MECR) of $15.581/quality-adjusted life year (QALY). Extensive sensitivity analyses identified extreme conditions in which evaluation for ATL was dominant (more effective and less costly) or in which it might be considered not worth the cost (MCER > $50,000/QALY). CONCLUSIONS: Estimates of ATL cost effectiveness fall within a generally acceptable range, even when uncertainty about many model parameters is taken into account. Under assumptions based on available data in the literature, the cost effectiveness of ATL compares favorably with that of other health technologies. Prospective multicenter studies of regional-cost and practice variations; long-term probabilities of year-to-year transitions between seizure outcome states and their effects on quality of life (QOL), and the effect of nonsurgical treatments on seizure control and QOL are needed to provide the critical data to confirm and constrain these estimates.

Anticonvulsants↗
PubMed1998

Prediction of verbal memory loss in individuals after anterior temporal lobectomy.

PURPOSE: Decreased memory function represents the area of greatest neuropsychological morbidity after anterior temporal lobectomy (ATL), particularly for left ATL candidates. We wished to identify easily derived demographic and neuropsychological predictors of risk of pre- to postoperative memory decline using only information available preoperatively. METHODS: We assessed decline in memory as measured by the California Verbal Learning Test (CVLT) by deriving multiple regression equations using the following measures as independent variables: age at onset, chronological age at time of surgery, sex, Full Scale IQ (FSIQ), level of education, and preoperative memory scores. In all, 203 patients (93 males, 110 females), undergoing ATL (107 left, 96 right) with preoperative and 6-month postoperative testing, were examined. RESULTS: The combination of age, FSIQ, sex, side of surgery and preoperative score was highly predictive (p-values < 0.0001) of postoperative memory scores. Higher postoperative scores were associated with higher preoperative score, younger chronological age, higher FSIQ, female sex, and right side of resection. Reliable change index (RCI) values were used to estimate meaningful decline on the total score across five trials. Logistic regression analysis showed preoperative score and age to be predictors of RCI decline for left-sided resections. Sensitivity of decline (> or =90th centile RCI) prediction was 56%, and specificity was 95%. Validation in 30 patients from a separate population of patients undergoing left ATL produced similar figures. CONCLUSIONS: The derived regression equations can accurately predict verbal memory decline on a list-learning task in approximately 50% of individual patients undergoing ATL, and false-positive prediction errors are very rare.

Age Factors↗
PubMed1998

Contribution of neuropsychological data to the prediction of temporal lobe epilepsy surgery outcome.

PURPOSE: We empirically examined the contribution of neuropsychological data to the prediction of postoperative seizure control relative to base rate information in an existing series of patients undergoing anterior temporal lobectomy (ATL). METHODS: A discriminant function predicting surgery outcome (seizure-free vs. non-seizure-free) was computed separately for samples of patients with left (n = 79) and right (n = 62) temporal lobectomy (LATL, RATL). Predictor variables included 14 measures tapping five neurocognitive domains. The predicted base rates were compared with the actual base rates in the two samples. Finally, overall predictive accuracy was examined in optimal versus suboptimal ATL patients. RESULTS: The base rate of seizure freedom in the LATL group was 74.70%; that in the RATL group was 66.10%. The predictive function for the LATL group achieved a hit rate of 80.00% and a positive predictive power of 92.11%. The function for the RATL group achieved a hit rate of 83.33% and a positive predictive power (PPP) of 89.66%. The overall predictive accuracy for the optimal group was only 55%, but that in the suboptimal group was 72%. CONCLUSIONS: Neuropsychological data used in a multivariate statistical fashion may be able to offer an incremental increase in the prediction of postoperative seizure freedom relative to existing base rates of surgery success in patients with ATL epilepsy. The use of neuropsychological data may be of greatest predictive value in a population of ATL candidates with suboptimal findings with a lower base rate of postoperative seizure freedom, but may actually reduce predictive accuracy in a group of ATL candidates from an optimal population with an already high base rate of surgical success.

Adult↗
PubMed2000

Intracarotid amobarbital procedure and prediction of postoperative memory in patients with left temporal lobe epilepsy and hippocampal sclerosis.

PURPOSE: Although temporal lobe epilepsy (TLE) patients with dominant hemisphere hippocampal sclerosis generally have good cognitive outcome after anterior temporal lobectomy (ATL), a minority of patients experience at least mild post-ATL decline on one or more standardized measures of episodic and semantic memory. The goal of this investigation was to determine whether memory outcome in this group could be predicted from preoperative intracarotid amobarbital procedure (IAP) recognition memory scores. METHODS: Data from 22 left TLE patients were studied retrospectively. All were left hemisphere language dominant and had IAP scores for each hemisphere, a significant degree of pathology-confirmed left hippocampal sclerosis (HS+), and no positive MRI findings other than atrophy. Cognitive outcome status was represented by the number of pre- to post-ATL declines across three tests, as defined by 90th percentile Reliable Change Index (RCI) criteria. RESULTS: Only 14% of the sample exhibited decline on more than one memory test. Low right IAP (left hemisphere injection) scores and relatively high preoperative cognitive ability and age at surgery predicted a greater risk of post-ATL memory decline. CONCLUSIONS: A minority of left TLE HS+ patients experience at least a mild degree of RCI-defined decline in episodic or semantic memory after ATL. The right hemisphere IAP memory score, which reflects the functional reserve of the contralateral hemisphere, can help predict the risk of postoperative memory decline for TLE patients in whom HS+ is likely based on the presence of hippocampal atrophy on MRI or early age of seizure onset.

Adult↗
PubMed1984

Phenotypical heterogeneity of Japanese adult T-cell leukaemia.

The leukaemic cells of 11 patients with Japanese adult T-cell leukaemia (ATL) were characterized in terms of phenotype employing various monoclonal antibodies against T-cell surface antigens. The leukaemic cells of all ATL patients except patient no. 11 displayed the phenotype OKT4+/OKT8-. However, the % of OKT3+ cells varied from 3 to 98. In 1 case, cells with phenotype OKT4+/OKT8+, which is characteristic of T-cells at an early stage of differentiation, were found. These results suggest that some ATL cells may be in an immature differentiation stage. Among the 11 patients, 2 with unusual ATL cell phenotypes (1 case with OKT3- cells and 1 case with Ia+/EAC+ cells) showed spontaneous regression of leukaemic cells. Characterization of leukaemic cells from a larger number of ATL patients may demonstrate a significant relationship between cell phenotype and prognosis.

Aged↗
PubMed1990

[Infections in hematological malignancies--clinical analysis of septic patients admitted to the Second Department of Miyazaki Medical College Hospital in the past ten years].

Two hundred and sixty-two patients (actual number 162) of hematological malignancies were admitted to our department from November 1977 to December 1986. Fourty-three of them (16.4%) were demonstrated to be accompanied with sepsis by blood culture. In acute non-lymphocytic leukemias (AML, APL, AMoL) the rate of sepsis was 33.8% (27 patients), while in lymphocytic malignancies (ML, HD, ATL) it was 11.7% (16 patients), particularly being 3.0% in ATL. Among the detected pathogenic microorganisms, gram-negative bacilli were 86.2% in the former and 50.0% in the latter. Especially, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli occupied 58.6% of the total in the former. Laboratory examination, when sepsis occurred, revealed peripheral neutropenia in acute non-lymphocytic leukemias (mean 831/cmm) but not in lymphocytic malignancy (mean 4,420/cmm). And 20 of the 27 cases showed remarkable neutropenia of below 500/cmm in the former. On the other hand in the latter, out of 16 only one with ATL was the case. Hypogammaglobulinemia was one of the characteristic features in lymphocytic malignancies but not in acute non-lymphocytic leukemias. Hypogammaglobulinemia in lymphocytic malignancies might be affected by long-term immunodepressant therapy. Immunologic skin reaction was demonstrated to be decreased in lymphocytic malignancies on admission. From the findings mentioned above, affecting factors to infections may be mainly neutropenia in acute non-lymphocytic leukemias and immunodeficiency in lymphocytic malignancies. And sepsis can occur frequently under neutropenic condition. In ATL both of humoral- and cellular-immunologic disturbance were detected before therapy. But peripheral neutrophil count was maintained to be normal and this could be the reason for the low septic incidence in ATL despite of total immunodepression.

Agammaglobulinemia↗
PubMed1992

[Infectious complications in patients with adult T-cell leukemia].

Between January, 1982, and January, 1992, a total of 112 patients with adult T-cell leukemia (ATL) and 109 patients with non-Hodgkin's lymphoma (NHL) were admitted to our hospital. They were studied for their infectious complications. Infectious complications were seen in 90 patients (80.4%) with ATL, and 51 patients (46.8%) with NHL (p < 0.001). Documented infections were seen in 70 patients (62.5%) with ATL, and 30 patients (27.5%) with NHL (p < 0.001). Pneumonia (p < 0.005), skin infections (p < 0.05), Pneumocystis carinii pneumonia (p < 0.05), fungal infections (p < 0.05), cytomegalovirus infections (p < 0.05) and herpes simplex virus infections (p < 0.01) were identified infections at high risk for patients with ATL. Tuberculosis, listeriosis and salmonella infections were seen only in patients with ATL.

Adolescent↗
PubMed1997

Screening for active toxoplasmosis in patients by DNA hybridization with the ABGTg7 probe in blood samples.

We report the potential use of a specific Toxoplasma gondii DNA probe (ABGTg7). We applied a dot blot hybridization assay to blood samples for the diagnosis of cerebral toxoplasmosis (CT), acute toxoplasmic lymphadenopathy (ATL), and disseminated toxoplasmosis in transplant recipients (TRs). We studied a total of 84 individuals: 38 patients and 46 controls. We found positive hybridization signals for 12 (66.7%) of 18 patients with confirmed CT, 9 (52.9%) of 17 patients with ATL, and 2 (66.7%) of 3 TRs. PCR assays were performed in parallel for patients with ATL, resulting in T. gondii DNA detection for 10 patients (58.8%). A comparative study between dot blot and PCR assays performed with the blood of mice that had been experimentally infected with tachyzoites gave similar results: 60 and 70% positive results, respectively. Finally, the sum of positive values obtained by both DNA tests (dot blot assay plus PCR) increased the rate of positivity for ATL patients to 76.4%. These results demonstrate that the T. gondii ABGTg7 repetitive DNA element is an additional useful resource for diagnosing Toxoplasma parasitemia in patients with CT and ATL and in TRs. Thus, our ABGTg7-based dot blot test may lead to an improvement in T. gondii detection methods in patients with acute toxoplasmosis.

Animals↗
PubMed2004

Repression of tax expression is associated both with resistance of human T-cell leukemia virus type 1-infected T cells to killing by tax-specific cytotoxic T lymphocytes and with impaired tumorigenicity in a rat model.

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Although the viral transactivation factor, Tax, has been known to have apparent transforming ability, the exact function of Tax in ATL development is still not clear. To understand the role of Tax in ATL development, we introduced short-interfering RNAs (siRNAs) against Tax in a rat HTLV-1-infected T-cell line. Our results demonstrated that expression of siRNA targeting Tax successfully downregulated Tax expression. Repression of Tax expression was associated with resistance of the HTLV-1-infected T cells to Tax-specific cytotoxic-T-lymphocyte killing. This may be due to the direct effect of decreased Tax expression, because the Tax siRNA did not alter the expression of MHC-I, CD80, or CD86. Furthermore, T cells with Tax downregulation appeared to lose the ability to develop tumors in T-cell-deficient nude rats, in which the parental HTLV-1-infected cells induce ATL-like lymphoproliferative disease. These results indicated the importance of Tax both for activating host immune response against the virus and for maintaining the growth ability of infected cells in vivo. Our results provide insights into the mechanisms how the host immune system can survey and inhibit the growth of HTLV-1-infected cells during the long latent period before the onset of ATL.

Animals↗
PubMed2005

Resistance to Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and constitutive expression of Apo2L/TRAIL in human T-cell leukemia virus type 1-infected T-cell lines.

Adult T-cell leukemia (ATL), a CD4+-T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1), is difficult to cure, and novel treatments are urgently needed. Apo2 ligand (Apo2L; also tumor necrosis factor-related apoptosis-inducing ligand [TRAIL]) has been implicated in antitumor therapy. We found that HTLV-1-infected T-cell lines and primary ATL cells were more resistant to Apo2L-induced apoptosis than uninfected cells. Interestingly, HTLV-1-infected T-cell lines and primary ATL cells constitutively expressed Apo2L mRNA. Inducible expression of the viral oncoprotein Tax in a T-cell line up-regulated Apo2L mRNA. Analysis of the Apo2L promoter revealed that this gene is activated by Tax via the activation of NF-kappaB. The sensitivity to Apo2L was not correlated with expression levels of Apo2L receptors, intracellular regulators of apoptosis (FLICE-inhibitory protein and active Akt). NF-kappaB plays a crucial role in the pathogenesis and survival of ATL cells. The resistance to Apo2L-induced apoptosis was reversed by N-acetyl-L-leucinyl-L-leucinyl-lLnorleucinal (LLnL), an NF-kappaB inhibitor. LLnL significantly induced the Apo2L receptors DR4 and DR5. Our results suggest that the constitutive activation of NF-kappaB is essential for Apo2L gene induction and protection against Apo2L-induced apoptosis and that suppression of NF-kappaB may be a useful adjunct in clinical use of Apo2L against ATL.

Apoptosis↗