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PubMed1995

Demonstration of acquisition of trauma management skills by senior medical students completing the ATLS Program.

OBJECTIVE: To assess the teaching effectiveness of the Advanced Trauma Life Support (ATLS) Program among senior medical students. DESIGN, MATERIALS, AND METHODS: We used objective structured clinical examination (OSCE) and multiple choice question (MCQ) testing to assess 40 senior medical students (20 ATLS and 20 non-ATLS) at the University of Toronto. Pre- and post-ATLS, all students had four 15-minute OSCE stations and a 40-item MCQ test. The pre- and post-ATLS performance for the ATLS and non-ATLS group were compared. MEASUREMENTS AND MAIN RESULTS: Cronbach's reliability coefficients were 0.81 and 0.93 for the pre- and post-ATLS OSCEs. The mean (+/- SD) OSCE scores at the four pre-ATLS OSCE stations were 7.6 +/- 2.8, 7.4 +/- 2.3, 8.3 +/- 2.7, and 10.5 +/- 3.4 for the ATLS group and 6.5 +/- 2.1, 7.0 +/- 2.2, 7.6 +/- 2.5, and 9.6 +/- 3.1 for the non-ATLS group (p = NS). Post-ATLS scores for the four OSCE stations were: 15.5 +/- 1.6, 14.1 +/- 3.2, 12.3 +/- 2.9, and 18.3 +/- 1.0 (ATLS group) and 7.9 +/- 3.5, 6.3 +/- 2.8, 7.6 +/- 2.3, and 10.9 +/- 3.3 (non-ATLS group: p < 0.01). Pre-ATLS MCQ scores were 49 +/- 9 and 52 +/- 8% for the ATLS and non-ATLS groups respectively; the ATLS group increased MCQ scores to 83 +/- 5% and the non-ATLS group did not change (53 +/- 8%). Pre-ATLS scores for adherence to priorities were: 35 +/- 14% (ATLS) and 29 +/- 13% (non-ATLS: p = NS). Post-ATLS scores were 99 +/- 6% (ATLS) and 29 +/- 19% (non-ATLS; p < 0.01). The pre-ATLS organized approach to trauma ratings (range 1 to 5) were: 1.9 +/- 1.5 (ATLS) and 1.6 +/- 0.5 (non-ATLS; p = NS) compared to post-ATLS grades of 4.6 +/- 0.4 (ATLS) and 1.7 +/- 0.5 (non-ATLS: p < 0.01). All 20 students passed the ATLS course. CONCLUSION: Using highly reliable trauma OSCE stations we have demonstrated trauma management skills acquisition by senior medical students after the ATLS course.

Canada↗
PubMed1987

[Overview of ATL (adult T-cell leukemia) research].

ATL is a unique T-cell malignancy first described by Takatsuki and colleagues in 1970s. We estimate that more than 300 patients a year have been detected in the endemic areas of Kyushu, Japan. The surface phenotype of ATL cells characterized by monoclonal antibodies is T3+, T4+, T8-, T11+ and Tac+. In all cases the serum is positive for anti-HTLV-I antibodies and the ATL cells contain the proviral DNA of HTLV-I. Variations in the clinical features of atypical ATL suggested a division of the spectrum of ATL into five types: acute; chronic; smoldering; crisis; and lymphoma. Typical ATL takes an acute course. The survival time is short, with 50% mortality within approximately 5 months. In general a poor prognosis is indicated by the elevation of serum lactate dehydrogenase, calcium, and bilirubin, as well as by high WBC. Smoldering ATL is characterized by the presence of a few abnormal cells (0.5%-3%) in the peripheral blood over a long period. Crisis in chronic or smoldering ATL means the progression of the disease to acute ATL. The lymphoma type of ATL is considered to be a form of T-cell-type non-Hodgkin's lymphoma in which malignant cells contain proviral DNA of HTLV-I. Screening of the sera from healthy adults for presence of the anti-HTLV-I antibodies revealed that 3.6% of healthy individuals in Kumamoto Prefecture, which is located in the middle of Kyushu, were HTLV-I carriers. Family studies showed that the routes of natural infection of HTLV-I are from mother to child and also from husband to wife. The borderline between the healthy carrier state and smoldering ATL remains unclear. Smoldering ATL is frequently diagnosed in patients with fungus infection of the skin, chronic lymphadenopathy, interstitial pneumonitis, chronic renal failure and strongyloidiasis. Five patients with ATL refractory to conventional chemotherapeutic agents were treated with 2'-deoxy-coformycin (DCF), a potent inhibitor of adenosine deaminase. Two patients showed a good response, and three were resistant to DCF. In addition our experiences with a concurrence of lymphoma-type ATL in three sisters and spontaneous remissions in a patients with chronic ATL will be referred.

Carrier State↗
PubMed1988

Malignant lymphomas in Japan: epidemiological analysis of adult T-cell leukemia/lymphoma (ATL).

The incidence of malignant lymphomas in Japan is relatively low compared to that in western European countries and the United States. However, in limited areas in Japan a specific type of lymphoid malignancy called adult T-cell leukemia/lymphoma (ATL), which is caused by human T-cell leukemia virus type I (HTLV-I), is highly prevalent, and there are also many healthy carriers of HTLV-I in the same areas. A cross-sectional seroepidemiological study of HTLV-I showed that the age-specific proportion of healthy HTLV-I carriers in these ATL-endemic areas increased with age, especially over 40, and was higher in females than in males. Three main routes of HTLV-I transmission are recognized: 1) vertical transmission from mother to child mainly through breast milk; 2) horizontal transmission from man to woman through semen, and; 3) parenteral transmission from carrier donor to non-carrier recipient. The annual incidence rate of ATL among HTLV-I carriers is estimated at 2.0 in males and 0.5 in females, and the cumulative risk for ATL in HTLV-I carriers during a 70-year life span is 1%-5%. Possible risk factors for ATL in addition to HTLV-I infection were considered, i.e. genetic factors, environmental factors, nutritional condition, thymus involution etc., but none of these were found to be clearly associated with ATL. To determine whether there exist particularly susceptible hosts for ATL in the ATL endemic areas, HLA types were examined, but no conclusive results on the positive relationships between HLA types and ATL manifestation or HTLV-I infection were obtained. From follow-up studies on the age-specific distribution of HTLV-I carriers in Japan, it is now speculated that the HTLV-I infection rate might have decreased naturally in the more recent generational cohort groups, even in the ATL-endemic areas. However, ATL in Japan is an important subject for study in the field of cancer epidemiology, and several trial intervention programs for the prevention of ATL, such as controls of vertical transmission from mother to child through breast milk, are now ongoing in the ATL-endemic areas of Japan.

Adult↗
PubMed1995

Molecular detection of pre-ATL state among healthy HTLV-1 carriers in an endemic area of Japan.

Adult T-cell leukemia/lymphoma (ATL) usually develops after age 40 in Japan, suggesting a long latency since HTLV-I is considered to be transmitted mainly from mothers to babies via breast milk. Our previous studies had suggested that HTLV-I carriers who have a monoclonal integration of HTLV-I proviral DNA in the peripheral blood cells, designated pre-ATL, account for about 2% of healthy carriers and are at high risk of developing ATL. Their ages ranged from 32 to 80 (median 57). Nevertheless, many cases of pre-ATL showed a long-lasting carrier state (10-year probability around 90%). In the present investigation we conducted a large-scale molecular detection of monoclonal integration in a population (481 cases) of healthy carriers with ages ranging from 16 to 82 (median 49) for the purpose of clarifying the earliest onset of this pre-ATL state. Southern-blot analysis of DNA extracted from peripheral blood mononuclear cells revealed 6 cases (1.2%) with a monoclonal band. All of these 6 were older than 40; no single positive case was found in 220 carriers under age 40. These results indicate that the molecularly detectable pre-ATL state also develops after a long latency. Thus the pre-ATL state seems to be a subtype of ATL showing an extremely indolent course of disease development, but not merely an early phase of all subtypes of ATL. We propose that, in order to reveal a promoter(s) responsible for the development of ATL from the pre-ATL state, intensive epidemiological investigation of life style, eating habits, occupation and exposure to carcinogens must be conducted on this unique group prone to ATL. It is also important to perform such an epidemiological study on the general population of carriers by paying special attention to the first 3-4 decades of each carrier's life in Japan and by comparing the data with those from carriers in different geographical areas of the world.

Adolescent↗
PubMed2007

Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax.

Adult T-cell leukemia (ATL) is a highly aggressive mature CD4+ T-cell malignancy that is etiologically associated with human T-lymphotropic virus Type 1 (HTLV-1). ATL is characterized by frequent infiltration of lymph nodes, spleen, liver, skin and gut. Previously, we and others have shown that the majority of ATL cases are strongly positive for CCR4, which may explain the frequent skin invasion of ATL. Here, we examined whether ATL cells express CCR9, which is involved in T-cell homing to the gastrointestinal tract. Human T cell lines carrying HTLV-1 consistently expressed CCR9 together with the HTLV-1-encoded transcriptional activator Tax. Although ATL cells freshly isolated from peripheral blood hardly expressed CCR9, ATL cells cultured for 1 day consistently expressed CCR9 in parallel with the upregulation of Tax. Induction of Tax by Cd2+ in JPX-9, a subline of Jurkat human T cell line carrying Tax under the control of metallothionein promoter, led to upregulation of CCR9. A luciferase reporter gene under the control of the CCR9 promoter was expressed by cotransfection of an expression vector for Tax or in Cd2+-treated JPX-9 cells. Furthermore, immunohistochemical staining demonstrated that ATL cells infiltrating gastrointestinal tract were frequently positive for CCR9. Collectively, CCR9 is inducible in ATL cells expressing Tax and may play a role in the gastrointestinal involvement of ATL.

Adult↗
PubMed2006

Functional and cytoarchitectural spinal cord protection by ATL-146e after ischemia/reperfusion is mediated by adenosine receptor agonism.

BACKGROUND: ATL-146e protects the spinal cord from ischemia/reperfusion injury, presumably via adenosine A(2A) receptor activation, but this relationship remains unproven. We hypothesized that spinal cord functional and cytoarchitectural preservation from ATL-146e would be lost with simultaneous administration of the specific adenosine A(2A) antagonist ZM241385 (ZM), thus proving that adenosine A(2A) receptor activation is responsible for the protective effects of this compound. METHODS: New Zealand White rabbits underwent 45 minutes of infrarenal aortic cross-clamping. Groups (n = 10) included sham, ischemia, ischemia plus ATL-146e (ATL-146E), ischemia plus ZM, or ischemia with both compounds (agonist-antagonist). Tarlov scores were recorded every 12 hours. After 48 hours, the spinal cord was fixed for histology and microtubule-associated protein 2 immunohistochemistry. RESULTS: Tarlov scores at 48 hours were significantly better in the sham and ATL-146E groups (5.0 and 3.9, respectively) compared with the other three groups (all < or =1.3; P < .001). On hematoxylin and eosin, neuronal viability was higher in the sham, ATL-146E, and agonist-antagonist groups compared with the control and ZM groups (P < .05). Microtubule-associated protein 2 expression was preserved in the sham and ATL-146E groups but was lost in the ATL + ZM, ZM241385, and control groups. CONCLUSIONS: ATL-146e preserves the spinal cord in terms of both cytoarchitecture and function after reperfusion of the ischemic spinal cord, but this preservation is not completely blocked by competitive adenosine A(2A) receptor antagonism. Although ATL-146e does seem to partially function through activation of the adenosine A(2A) receptor, the neuroprotective mechanism may not be limited to this particular receptor.

Adenosine A2 Receptor Agonists↗
PubMed2001

An adenosine A2A agonist, ATL-146e, reduces paralysis and apoptosis during rabbit spinal cord reperfusion.

BACKGROUND: We hypothesized that systemic ATL-146e, an adenosine A(2A) agonist, would decrease spinal cord reperfusion inflammatory stress and inhibit apoptosis and that these effects would correlate with improved neurologic functional outcome. METHODS: Thirty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group of animals (n = 14) received 0.06 microg/kg per minute of ATL-146e infused intravenously for 3 hours, beginning 15 minutes before reperfusion. A second group of animals (n = 16) underwent spinal cord ischemia with saline vehicle alone and served as ischemic controls. Animals (n = 9, 11) from each group survived for 48 hours and assessed for neurologic impairment with the Tarlov (0-5) scoring system. Four animals from each group were humanely killed at the end of the 3-hour treatment period, and the remainder killed after 48 hours' survival. In all animals, lumbar spinal cord tissue specimens were frozen for subsequent Western blot analysis of heat shock protein 70 (HSP 70), and for the p85 fragment of poly (ADP-ribose) polymerase (PARP). Neuronal viability indices were determined at 48 hours with hematoxylin and eosin staining. RESULTS: There was improvement in neurologic function in rabbits receiving ATL-146e (P <.001) compared with ischemic controls. At the end of the 3-hour treatment period there was a 46% (P <.05) decrease in HSP 70 expression in the ATL-146e group compared with the control group, but no difference in PARP expression. At 48 hours, there was no difference between control and ATL-146e groups in HSP 70 expression, but there was a 65% (P <.05) reduction in PARP in the spinal cords of animals that had received ATL-146e. There was a significant improvement in neuronal viability indices in animals receiving ATL-146e compared with ischemic controls (P <.05). CONCLUSIONS: Systemic ATL-146e infusion during reperfusion after spinal cord ischemia results in preservation of hindlimb motor function. There is evidence of decreased spinal cord inflammatory stress immediately after treatment with ATL-146e as indicated by reduced HSP 70 induction. Treatment with ATL-146e is associated with a reduction in neuronal apoptosis as suggested by a substantial decrease in the fragmentation of PARP at 48 hours. These results suggest that inflammation during reperfusion and subsequent apoptosis contribute to paralysis after restoration of blood flow to the ischemic spinal cord.

Animals↗
PubMed1996

Attrition of cognitive and trauma management skills after the Advanced Trauma Life Support (ATLS) course.

OBJECTIVE: To test the attrition of cognitive and trauma management skills among practising physicians after the Advanced Trauma Life Support (ATLS) course. DESIGN, MATERIALS, AND METHODS: Sixty practising physicians who completed the ATLS course had comparative assessment of cognitive skills (with multiple choice questions, MCQ) pre-ATLS, immediately post-ATLS, at 6 months (group A), 2 years (group B), 4 years (group C), and 6 years (group D) after the course. Trauma management skills were also compared using eight Objective Structured Clinical Examination (OSCE) trauma stations completed by the four groups of physicians. MEASUREMENTS AND MAIN RESULTS: Pre-ATLS MCQ scores (54.2 +/- 4.2 to 59.8 +/- 5.3%) and immediately post-ATLS MCQ scores (85.9 +/- 5.1 to 87.7 +/- 5.3%) were similar in all four groups. Follow-up MCQ scores were 77.8 +/- 3.6% at 6 months 70.6. +/- 1.9% at 2 years, 69.4 +/- 1.7% at 4 years, and 68.9 +/- 2.0% at 6 years. OSCE scores out of a maximum of 20 were 16.8 +/- 0.3 at 6 months, 13.9 +/- 0.1 at 2 years, 12.0 +/- 0.1 at 4 years, and 11.9 +/- 0.1 at 6 years. Adherence-to-priorities scores (maximum, 7) were 6.6 +/- 0.2 at 6 months, 6.8 +/- 0.1 at 2 years, 6.6 +/- 0.1 at 4 years, and 6.6 +/- 0.1 at 6 years. Organized-approach scores (maximum, 5) were 4.8 +/- 0.1 at 6 months, 4.6 +/- 0.2 at 2 years, 4.7 +/- 0.2 at 4 years, and 4.6 +/- 0.2 at 6 years. Using the MCQ 80% pass mark criterion, at least 50% of physicians fail by 6 months and all fail this cognitive test thereafter. CONCLUSIONS: Whereas cognitive and trauma management skills decline after the ATLS, these skills are maintained at similar levels between 4 and 6 years after ATLS. A 50% failure rate occurs within 6 months and maximum attrition of cognitive skills occurs within 2 years of ATLS completion. Major principles of adherence to priorities and maintenance of an organized approach to trauma care are preserved for at least 6 years after ATLS.

Adult↗
PubMed1997

Subcellular localization of the major autolysin, ATL and its processed proteins in Staphylococcus aureus.

The Staphylococcus aureus autolysin gene, atl, encodes a unique 138-kDa protein (ATL) with amidase and glucosaminidase domains. ATL has been suggested to undergo proteolytic processing to generate two extracellular peptidoglycan hydrolases, 51-kDa endo-beta-N-acetylglucosaminidase (51-kDa GL) and 62-kDa N-acetylmuramyl-L-alanine amidase (62-kDa AM). To investigate cell-associated bacteriolytic enzymes for atl gene products, proteins were extracted from the cells as follows. The cells were exposed to 3 M LiCl followed by 4% SDS. Thereafter, the cells were disrupted and again extracted with 4% SDS. Whole SDS-stable cell-associated bacteriolytic proteins were extracted without disrupting the cells. Exposure to 3 M LiCl released major 138-, 115-, 85-, 62- and 51-kDa bacteriolytic proteins, and subsequent 4% SDS extraction released major 138- and 115-kDa bacteriolytic proteins. These bacteriolytic proteins were missing in extracts of atl mutant RUSAL2 (S. aureus RN450 atl::Tn551). Immunoblotting studies suggest that these are all atl gene products: the 138-kDa protein is an ATL with a cleaved signal sequence; the 115- and 85-kDa proteins are intermediates; and the 51- and 62-kDa proteins are cell-associated 51-kDa GL and 62-kDa AM, respectively. The trypsin susceptibility of these proteins suggests that they are located outside the cell membrane. Differences in extractability and immunoelectron microscopic studies suggest that atl gene products are associated with cells in two different ways, LiCl extractable and non extractable. We suggest that the 138-kDa ATL undergoes processing through intermediate proteins (115- and 85-kDa proteins) to mature as the active cell cluster-dispersing enzymes 51-kDa GL and 62-kDa AM on the cell surface.

Amino Acid Sequence↗
PubMed2000

Identification of genes associated with the progression of adult T cell leukemia (ATL).

Patients with adult T-cell leukemia/lymphoma (ATL) exhibit a variety of clinical features, and this disease is therefore clinically subclassified into acute, lymphomatous, chronic, and smoldering types. Acute ATL is a typical leukemic form of ATL with rapid progression, and chronic ATL is a less aggressive clinical form allowing long-term survival even without chemotherapy. In the present study, we used fresh peripheral blood mononuclear cells (PBMC) from both types of ATL patients to identify molecules that may contribute to the difference between acute and chronic ATL. Isolated mRNAs expressed differentially between the two types of ATL include a T-cell differentiation antigen (MAL), a lymphoid-specific member of the G-protein-coupled receptor family (EBI-1 / CCR7), a novel human homologue to a subunit (MNLL) of the bovine ubiquinone oxidoreductase complex, and a human fibrinogen-like protein (hpT49). We found that the former three are upregulated in acute ATL and the last is down-regulated in both chronic and acute ATL. We speculate that dysregulation of the genes may account for the malignant features of ATL cells, in terms of growth, energy metabolism, and motility.

Amino Acid Sequence↗
PubMed2000

What do trainees think about advanced trauma life support (ATLS)?

Advanced trauma life support (ATLS) has become a desirable or even essential part of training for many surgeons and anaesthetists, but aspects of the ATLS course have attracted criticism. In the absence of published data on the views of trainees, this study sought their opinions in a structured questionnaire, which was completed by trainees in accident and emergency (A & E) (26), anaesthetic (82), general surgical (26), orthopaedic (42) and other (5) posts in different hospitals (response rate 66%). Of the trainees, 78% had done an ATLS course and, of these, 83% considered ATLS a 'major advantage' or 'essential' for practising their proposed specialty--100% for A & E, 94% for orthopaedics, 92% for general surgery, and 75% for anaesthetics. ATLS was considered a major curriculum vitae (CV) advantage by 94%, 85%, 50%, and 45%, respectively. Over 90% had positive attitudes towards ATLS, and 74% selected 'genuine improvement of management of trauma patients' as the most important reason for doing the course: 93% thought ATLS saved lives. Of the respondents, 83% thought that all existing consultants dealing with trauma patients should have done the course, and 41% thought it offered major advantages to doctors not involved in trauma. Funding problems for ATLS courses had been experienced by 14% trainees. This survey has shown that most trainees view ATLS positively. They believe that it provides genuine practical benefit for patients, and very few regard ATLS primarily as a career advantage or mandate.

Attitude of Health Personnel↗
PubMed1989

[Expressions of 2H4 and 4B4 antigens on ATL cells].

We studied the expression of 2H4 and 4B4 on the surfaces of leukemia cells from 17 patients with adult T-cell leukemia (ATL) as well as of cells belonging to 2 T-cell lines derived from ATL patients. The effects of the supernatants obtained from culture fluids of the ATL cells and the T-cell lines on IgG production of a human B-cell line, CESS cells, were also examined. On the surfaces of the ATL cells from 15 out of 17 cases and of the cells of 2 T-cell lines 4B4 obviously existed at higher percentage than 2H4 and more than 80% of ATL cells from 16 out of these 17 cases showed the expression of T4 (CD4). These findings revealed that the most of ATL cells had a helper-inducer phenotype. Supernatants (Sups) of culture fluids of ATL cells from 4 patients and those of 2 T-cell lines were added at various concentrations to the CESS cells. In only 1 Sup from ATL patient enhanced the IgG production of the CESS cells at lower concentration. However, other 5 Sups suppressed the IgG production of the CESS cells in proportion to the increase of Sup added. These results showed that phenotypical type of ATL cells does not always correspond to their functions, and the ATL cells may produce humoral factors that regulate B cell functions.

Adult↗
PubMedDate not supplied

Association between ATL and non-hematopoietic neoplasms.

A high incidence of multiple primary neoplasms has been observed in our patients with ATL in comparison to persons with other forms of hematologic malignancy who we have observed during the past 23 years (1963-1985). Five of 15 patients with ATL (33.3 per cent) have had at least one other associated neoplasm in comparison to only 44 of 1156 patients with other forms of hematological malignancy (3.8 per cent). The incidence figures for secondary neoplasms associated with the other hematologic malignancies were 4.3 per cent (16/370) for acute non-lymphocytic leukemia (ANLL), 2.2 per cent (2/90) for acute lymphocytic leukemia (ALL), 4.8 per cent (1/21) for acute unclassifiable leukemia, 2.2 per cent (5/225) for chronic myelogenous leukemia, 4.7 per cent (2/43) for chronic lymphocytic leukemia, 5.9 per cent (8/136) for malignant monoclonal gammopathy and 3.7 per cent (10/271) for malignant lymphoma. The incidence of multiple neoplasms in patients with ATL in comparison to those with other hematological malignancies was statistically significant (p < 0.01 or p < 0.001). The neoplasms associated with ATL have been adenocarcinoma of the thyroid or stomach, and squamous cell carcinoma of the larynx, lip or lung. We identified ATL-derived factor (ADF) in the cytoplasm of the secondary neoplasms of the ATL patients by means of indirect immunofluoroscopy and immunohistochemical techniques utilizing anti-ADF antibody. We also identified ras p21 products in these neoplasms by means of p21 ras monoclonal antibody studies. The possibility that HTLV-I was the cause of the secondary neoplasms thus was investigated. HTLV-I provirus genome was not found in all the six cases of non-ATL leukemic cells of the patients with anti-HTLV-I antibodies as determined by means of Southern blot analysis utilizing pX DNA probe. These findings suggest that there is some association between ATL cells and pre-malignant cells through ADF or other unknown factors in the activation of ras oncogenes. Subsequent suppression of host immune defence mechanisms in ATL patients permits evolution of the secondary neoplasms.

Adenocarcinoma↗
PubMed1999

Detection of inducible nitric oxide synthase (iNOS) mRNA by RT-PCR in ATL patients and HTLV-I infected cell lines: clinical features and apoptosis by NOS inhibitor.

Various tumors have been reported to express an inducible form of nitric oxide synthase (iNOS), and nitric oxide (NO) may affect the clinicopathological features of these tumors. Previously, Burkitt's lymphoma and Epstein-Barr virus (EBV)-infected cells were shown to express iNOS constitutively at a low level. We analyzed iNOS expression by the reverse transcriptase-polymerase reaction method (RT-PCR) in eight HTLV-I-infected cell lines (five were ATL-derived lines and there were in vitro transformed lines), nine ATL patients (three were chronic, two were acute, and four were lymphoma type), and an HTLV-I-negative T cell line (CEM). In four ATL derived and in all three in vitro transformed cell lines, iNOS was expressed constitutively, but it was not expressed in CEM cells. Four out of nine ATL patients also showed iNOS expression. The expression of iNOS was found in all subtypes of ATL. Three of four iNOS-positive patients had infiltration of ATL cells to organs such as skin, lung, or liver. In NOS inhibitor (NG-monomethyl-L-arginine: L-NMMA)-containing medium, an iNOS-positive ATL cell line (K3T) showed growth inhibition and DNA ladder. Although only a limited number of patients was analyzed, our results suggest that NO may be involved in the invasive character of ATL cells. The NOS inhibitor can induce apoptosis in an ATL cell line, as it does in EBV-infected cell lines.

Apoptosis↗
PubMed2002

Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL).

Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to purine synthesis inhibitors and/or methionine starvation. We reported previously that the MTAP gene is deleted in adult T cell leukemia (ATL) cells. In the present study, we expanded our series and used a real-time quantitative PCR assay for accurate diagnosis of the deletion and nine of 65 primary ATL samples (13.8%) were MTAP negative. In spite of this low incidence, ATL cells showed significantly higher sensitivity to L-alanosine, an inhibitor of de novo adenosine monophosphate (AMP) synthesis, than normal lymphocytes, suggesting that the MTAP gene is inactivated not only by deletion but also by other mechanisms. Indeed, a real-time quantitative RT-PCR assay disclosed that primary ATL cells had significantly lower MTAP mRNA expression than normal lymphocytes. Since MTAP-negative ATL cell lines also showed much higher sensitivity to L-alanosine than MTAP-positive ATL cell lines, we used these cell lines to investigate whether it is possible to develop selective therapy targeting MTAP deficiency. A substrate of MTAP, methylthioadenosine (MTA) or its substitutes rescued concanavalin A (Con A)-activated normal lymphocyte proliferation from L-alanosine toxicity. All the compounds except 5'-deoxyadenosine, however, also caused the undesirable rescue of MTAP-negative ATL cell lines. 5'-Deoxyadenosine had the desired ability to rescue hematopoietic progenitor cells without rescuing ATL cell lines. These results support the rationale for a chemotherapy regimen of L-alanosine combined with 5'-deoxyadenosine rescue in MTAP-deficient ATL.

Adenosine Monophosphate↗
PubMed1982

A retrovirus from human leukemia cell lines: its isolation, characterization, and implication in human adult T-cell leukemia (ATL).

We have tried to isolate a retrovirus from adult T-cell leukemia (ATL) which is a new clinical entity of T-cell malignancy. This disease shows a peculiar geographic clustering of patient birthplaces in the southwestern part of Japan. A retrovirus was isolated from the T-cell line, MT-2, which was established from cord lymphocytes cocultivated with leukemic cells from an ATL patient and characterized by: (a) density of 1.152-1.155 g/ml in sucrose gradient; (b) reverse transcriptase activity; (c) specific protein components; (d) RNA labeled with 3H-uridine, and (e) specific DNA complementary with viral RNA. The retrovirus was named adult T-cell leukemia virus (ATLV). Complementary DNA (cDNA) prepared by the endogenous reaction of detergent-treated virions hybridized with 35S RNA in MT-2 cells and another ATL cell line, MT-1, and this 35S RNA was inducible with IUDR treatment of the MT-1 cells, indicating that ATLV is a typical retrovirus containing 35S RNA as the genome. However, the cDNA did not show any detectable hybridization with cellular RNA of other human cell lines unrelated to ATL. The ATLV proviral DNA was detected in the chromosomal DNA of MT-1 and MT-2 cell lines as well well as in fresh peripheral blood cells of all five patients with ATL tested; however, it was not found in those of three healthy adults. Furthermore, sera from the patients reacted with one component of the ATLV protein, but normal sera did not. These sera and all other sera from ATL patients were previously shown to react with antigen(s) in leukemic cells of ATL, and the antigen(s) also reacted with sera from about 25% of the healthy adults in the endemic area, but not in the non-endemic area. These close associations of ATLV proviral DNA and proteins with ATL are direct evidence strongly suggesting the involvement of the retrovirus, ATLV, in the leukemogenesis of human ATL.

Adult↗
PubMed2006

The ATL gene family from Arabidopsis thaliana and Oryza sativa comprises a large number of putative ubiquitin ligases of the RING-H2 type.

Ubiquitin ligases play an important regulatory role in the control of protein degradation processes via the ubiquitin/26S proteasome pathway in eukaryotes. These enzymes participate in substrate specification and mediate the transfer of ubiquitin to target proteins. A large number of ubiquitin ligases are predicted in the eukaryotes whose genomes have been sequenced; in Arabidopsis thaliana more than 1300 genes are thought to encode ubiquitin ligases. At least three classes of ubiquitin ligases are present in Arabidopsis, one of which comprises about 470 RING zinc-finger domain proteins. Within this class we have characterized the ATL family that encodes a RING-H2 finger. We identified 80 members of this family in A. thaliana and 121 in Oryza sativa. About 60% of the rice ATLs are clustered with A. thaliana ATLs, and in many cases the gene products showed sequence similarities beyond the ATL's conserved features, suggesting that they could be orthologous genes. Ninety percent of the ATLs are intronless genes, suggesting that the structure of the basic ATL protein may have evolved as a functional module. We carried out a survey of T-DNA insertions in 30% of the Arabidopsis ATL genes and screened for possible phenotypes. Four of these genes are likely to be essential for viability, since homozygous plants for the T-DNA insertion were not recovered. One of them, ATL8, is mainly expressed in young siliques, suggesting a role during embryogenesis. We also recovered a line carrying a T-DNA insertion in ATL43 that showed an ABA-insensitive phenotype, suggesting a role of this gene in the ABA response. The organization of ATLs in Arabidopsis and rice in this study will be a valuable comprehensive guide for this multigene family.

Arabidopsis↗
PubMed2006

A selective adenosine A2A receptor agonist, ATL-146e, prevents concanavalin A-induced acute liver injury in mice.

BACKGROUND AND AIMS: Concanavalin A (Con A) activates T lymphocytes and induces CD4+ T cell-mediated hepatic injury in mice. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6), are critical mediators in this experimental model. Activation of adenosine A2A receptors reduces the production of various pro-inflammatory cytokines and suppresses T cell activation. A selective adenosine A2A receptor agonist (ATL-146e) has been shown to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP (cAMP) in leukocytes. The aim of the present study was to determine whether ATL-146e could ameliorate Con A-induced hepatic injury, reduction of pro-inflammatory cytokine production. METHODS: Balb/c mice were injected with 25mg/kg Con A with or without a single injection of ATL-146e (0.5-50 microg/kg), 5 min prior to Con A administration. Liver enzymes, histology, and serum levels of tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 were examined. We also assessed the effects of ATL-146e on pro-inflammatory cytokine production with CD4+ T cell. RESULTS: Pretreatment with ATL-146e significantly reduced serum levels of liver enzymes (P<0.001). The serum pro-inflammatory cytokines were all increased after Con A administration and reduced to near normal levels by ATL-146e. ATL-146e also inhibited CD4+ T cell pro-inflammatory cytokine production. CONCLUSION: A selective adenosine A2A receptor agonist, ATL-146e, can prevent concanavalin A-induced hepatic injury that is presumably mediated by its anti-inflammatory properties.

Adenosine A2 Receptor Agonists↗