Vascular endothelial growth factor and cellular chemotaxis: a possible autocrine pathway in adult T-cell leukemia cell invasion.

Our previous report (T. Hayashibara et al., Leukemia, 13: 1634-1635, 1999) revealed a possible link between high plasma vascular endothelial growth factor (VEGF) concentration and leukemic cell invasion in adult T-cell leukemia (ATL). However, the biological mechanism of this link has not been elucidated. The purpose of this study was to address that mechanism. Our present observations showed that VEGF mRNA was expressed in ATL cell lines. The corresponding protein was secreted into the extracellular environment, which suggested that the major source of plasma VEGF is ATL cells themselves. More interestingly, all of the cell lines examined were found to express the mRNA and protein for fms-like tyrosine kinase-1 (Flt-1), which is one of the receptors for VEGF. Cytofluorometric analysis demonstrated the VEGF binding potency of these cells. In clinical specimens, expression of VEGF and Flt-1 mRNAs was detected in all (100%) of 11 and 8 (73%) of 11 ATL patients, respectively. Cytofluorometric analysis revealed that VEGF effectively bound only to Flt-1-expressing cells. These findings are highly suggestive of an autocrine pathway involving VEGF operating in ATL. The proliferation of ATL cell lines was not affected by treatment with an anti-VEGF antibody or exogenous VEGF, which indicated that VEGF has no mitogenic effect on ATL cells. In contrast, we made the interesting finding that treatment with exogenous VEGF enhanced the chemotactic activities of some ATL cell lines, which may play a key role in ATL cell invasion. Collectively, these data lead us to propose a possible autocrine mechanism involving VEGF operating by way of Flt-1, in which ATL cells up-regulate their own chemotaxis to facilitate their invasion into various organs.

De novo acute myeloid leukemia in the elderly; a consistent fraction of long-term survivors by standard-dose chemotherapy.

To clarify the characteristics of de novo acute myeloid leukemia (AML) among the elderly, we reviewed 112 patients over 60 years old (median age 72 years) who were treated at hospitals in Nagasaki Prefecture with a population of 1.5 million between 1987 and 1994. Reclassification of morphological diagnosis revealed that the proportion of M3 was lower but that of M6 and the incidence of cases with trilineage dysplasia (TLD), known as poor prognostic features, were higher in the elderly than in patients less than 60 years old. Similarly, chromosomal data showed a lower frequency of favorable karyotypes such as t(8;21) and t(15;17) in the elderly. The overall survival of all 112 patients was 10.3% at 5 years. Multivariate analysis indicated that good performance status (PS), low WBC at diagnosis, standard dose multi-drug chemotherapy and all-trans retinoic acid (ATRA) treatment for M3 patients, and morphological findings without TLD were significantly correlated with longer survival. Most of the long-term survivors were found among those who received standard dose therapy in this series, although no consensus has been established how to treat elderly AML patients. We propose that a prospective controlled trial is necessary to confirm the role of standard dose chemotherapy for elderly patients with de novo AML.

Tooth eruption in a patient with craniometaphyseal dysplasia: case report.

Craniometaphyseal dysplasia (CMD) is a very rare genetic disorder of bone remodeling caused by osteoclast dysfunction. The clinical and radiographical features of oral findings are presented in a sporadic case of CMD in a child (age 10 years, 7 months). An intraoral examination showed severe malocclusions, including anterior crossbite and deep bite. Furthermore, a radiographic examination showed increased radiopacity of the maxilla and mandibular bones due to hyperostosis and sclerosis of the jaw. There was no root resorption of the canines or molars in the primary dentition, although root formation of the permanent teeth was proceeding. Dental age was calculated to be approximately 1 year, 4 months younger than his chronological age. The eruption speed of the permanent lateral incisors after the gingival emergence was shown to be within normal values, and we discuss whether the canines and premolars in the permanent dentition could erupt or not.

Lactacystin activates FLICE (caspase 8) protease and induces apoptosis in Fas-resistant adult T-cell leukemia cell lines.

Lactacystin (LC) is a specific inhibitor of the proteasome, and has recently been shown to induce apoptosis in certain cell lines. In the present study, we established Fas-resistant adult T-cell leukemia (ATL) cell subclones RSO4 and RST1 from their parental Fas-sensitive cell lines SO4 and ST1, and examined whether LC can overcome Fas resistance. LC completely inhibited proteasome function as determined by a peptidyl-MCA substrate (LLVY-MCA and LLE-MCA), and induced apoptosis in these cell lines irrespective of Fas sensitivity at low concentrations (approximately 10 microM). LC induced the activation of caspase 3 (CPP32/Yama) and caspase 6 proteases in an identical manner to Fas-mediated apoptosis. Moreover, LC induced the activation of caspase 8 (FLICE) protease, which is the initiator of the Fas-mediated apoptotic cascade. Synthesized proteasome inhibitory peptide MG-115 (ZLLnV-CHO) also induced apoptosis in these cell lines. These results indicated that proteasome inhibitors overcome Fas-resistance by bypassing the proximal part of the Fas signal. Inhibition of the proteasome function may be a new strategy for the treatment of ATL.

Fas-resistance in ATL cell lines not associated with HTLV-I or FAP-1 production.

A preventive role for human T-cell leukemia virus type-I (HTLV-I) and Fas-associated phosphatase-1 (FAP-1) in Fas-mediated apoptosis has been reported in HTLV-I-infected cells. In the present study, we examined whether these molecules increased during the acquisition of Fas-resistance in adult T-cell leukemia (ATL) cell lines. SO4, ST1 and KK1 are Fas-sensitive ATL cell lines, and produce small amounts of HTLV-I in vitro. Although their subclones RSO4 and RST1 are completely Fas-resistant, they produced an equivalent amount of HTLV-I to SO4 and ST1. Moreover, FAP-1 mRNA was not detected in these cell lines irrespective of Fas sensitivity. Thus, Fas resistance in ATL cells was not directly associated with the increased production of HTLV-I or FAP-1.

An Ancient Chemosensory Mechanism Brings New Life to Coral Reefs.

The first scleractinians, progenitors of modern corals, began to appear 240 million years ago; by the late Jurassic (150 Ma) most families of modern corals had evolved and begun forming reefs (1, 2). Mechanisms controlling the recruitment of new corals to sustain these structures are, however, poorly understood (3). Corals, like many marine invertebrates, begin life as soft-bodied larvae that are dispersed in the plankton (3, 4). As the first step in developing a calcified coral colony, the larva must settle out of the plankton onto a suitable substratum and metamorphose to the single calcified polyp stage cemented to the reef (3, 5). Our analyses of the metamorphic requirements of larvae in divergent coral families surprised us by revealing the existence of a common chemosensory mechanism that is required to bring larvae out of the plankton and onto the reef. This mechanism appears to be quite old, predating both the phylogenetic divergence of these coral families and the development of different modes of coral reproduction.

Clinical significance of tissue polypeptide antigen in serum of acute nonlymphocytic leukemia.

Tissue polypeptide antigen (TPA) in serum was measured at diagnosis in 27 patients with acute nonlymphocytic leukemia (ANLL) (1 FAB M0, 1 M1, 10 M2, 7 M3, 5 M4, 1 M5, 1 M6 and 1 MU). Statistical analysis disclosed a close correlation of TPA level with age (P < 0.01), hemoglobin level (P < 0.05), therapeutic response (P < 0.01) and the length of survival after the initial diagnosis (P < 0.02). A significant difference in TPA level was present between patients with complete remission and those with poor response. To our knowledge, this is the first report to prove a correlation of TPA level with therapeutic response and the length of survival in ANLL.

Clinical significance of serum thymidine kinase in adult T-cell leukaemia and acute myeloid leukaemia.

To clarify the clinical and biological significance of serum thymidine kinase (TK) in adult T-cell leukaemia (ATL) associated with human lymphotropic virus type-I (HTLV-I) and in acute myeloid leukaemia (AML), TK was measured in 52 patients with ATL (acute ATL, 35 patients; lymphoma ATL, two patients; chronic ATL, 12 patients; smouldering ATL, three patients), and in 27 patients with AML (one FAB MO, one M1, 10 M2, seven M3, five M4, one M5, one M6, one MU). In ATL patients, statistical analysis disclosed a close correlation between TK level and the leucocyte count (P < 0.01), and absolute number of abnormal lymphocytes (P < 0.01). However, no correlation was observed between serum lactic dehydrogenase (LDH) level and these items. Concerning the therapeutic response, a statistical difference was present in TK between complete remission and no response (P < 0.05), but not in LDH. We also investigated a significant inverse correlation between TK level as well as LDH level and the length of survival after the initial diagnosis (P < 0.01). In AML patients a close correlation of TK level with the count of leucocytes (P < 0.01), percentage of blasts in the blood (P < 0.05), therapeutic response (P < 0.01) and the length of survival after the initial diagnosis (P < 0.05) was present. Therefore the TK level may indicate the aggressiveness of leukaemic cells and predict the response to the chemotherapy and the length of survival in ATL and AML.

A statistical study of calcifying epithelioma, focusing on the sites of origin.

We statistically investigated 396 lesions taken from 355 cases of calcifying epithelioma. The distribution of these lesions did not correlate with the density of the hair follicles, but it was in accord with the distribution of intermediate hairs, such as those in the hair border. This relationship may have etiologic significance.

Binding of the amino-terminal region of myosin alkali 1 light chain to actin and its effect on actin-myosin interaction.

The role of the amino-terminal region of myosin alkali 1 light chain (A1) in the interaction between actin and myosin subfragment-1 (S-1) was explored. Papain digestion of skeletal myosin filaments produced S-1 whose A1 was found to lose the basic 13 amino-terminal amino acid residues (A1'). We obtained three types of papain S-1 isoenzymes differing in their alkali light chain content: recombined papain S-1 (A1), papain S-1 (A1'), and papain S-1 (A2). Both the maximum turnover rate (Vmax) and the dissociation constant (Km) for actin-activated papain S-1 (A1') ATPase activity were similar to those for papain S-1 (A2) and remarkably larger than those for recombined papain S-1 (A1). The 13 amino-terminal residue peptide of A1 (N-pep) was isolated and characterized. 1H-NMR spectroscopy suggested that the N-pep was relatively immobilized in the presence of actin filaments. A cross-linking study suggested that N-pep binds to actin. The addition of N-pep to acto-S-1 (A1) made Km and Vmax for the actin-activated ATPase activity close to those for S-1 (A2). Removal of the trimethyl group from the N-pep suppressed the above effect on the actin-S-1 interaction. Our findings suggest that the amino-terminal region of A1 binds to the actin molecule to affect the mechanism of actin-activated S-1 ATPase.

Chromosome 11 rearrangement at band 11q21 in a patient with essential thrombocythemia.

A case of essential thrombocythemia with a partial deletion of the long arm of chromosome 11, del(11)(q21) as a sole chromosomal anomaly is reported. Rearrangement of chromosome 11 at band 11q21 has been reported in six patients with chronic myeloproliferative disorders: four with post-polycythemic myelofibrosis, one with myelofibrosis with myeloid metaplasia, and one with Ph+ chronic myeloid leukemia in blastic phase. Except for the last patient, all patients had been treated with 32P and/or an alkylating agent prior to cytogenetic examination. This is the first report of the 11q21 abnormality in essential thrombocythemia seen at diagnosis.

Therapeutic and prognostic value of modal number of chromosomes at the blastic phase of Philadelphia-chromosome-positive chronic myeloid leukemia: comparison based on the same criteria between Nagasaki University and Roswell Park Memorial Institute.

In a comparison of 47 patients with Philadelphia-chromosome (Ph)-positive chronic myeloid leukemia (CML) in the Nagasaki University School of Medicine and 64 patients with the same disease in the Roswell Park Memorial Institute, the correlation between the modal number of chromosomes and the therapeutic response and/or survival after the onset of the blastic phase (BP) was evaluated. The patients were divided into four groups on the basis of the modal number of chromosomes of the cells in the bone marrow: those with hypodiploidy (group 1), those with pseudodiploidy carrying a Ph chromosome (group 2), those with 47 chromosomes (group 3), and those with 48 or more chromosomes (group 4). The results revealed similar trends in the two institutes. Namely, the therapeutic response and the survival after the onset of the BP in groups 1 and 4 were more unfavorable and shorter than those in groups 2 and 3, although the former (group 2) had a better prognosis than the latter (group 3). Thus, the statistical analysis revealed that the numerical chromosome findings at the BP are useful parameters for assessing the therapeutic response and survival after the onset of the BP of CML.

[Primary bilateral adrenal lymphomas in 3 cases].

This report describes three of primary bilateral adrenal lymphoma. Case 1 was an 87-year-old female. She was admitted to our hospital because of anemia. Masses in the bilateral adrenal glands were noted on abdominal computed tomography (CT). After combination chemotherapy, bilateral adrenal masses transiently showed a remarkable reduction, but they soon enlarged and she died. The pathological diagnosis at autopsy was non-Hodgkin lymphoma (diffuse medium sized cell type). Case 2 was a 77-year-old male. He visited our hospital complaining of general malaise. Masses in the bilateral adrenal glands were noted on abdominal CT and he was admitted. The left adrenal was biopsied under echo guidance. The pathological diagnosis was non-Hodgkin lymphoma (diffuse medium sized cell type). The bilateral adrenal masses transiently responded to combination chemotherapy, but soon enlarged again and he died. Case 3 was a 75-year-old male. He visited our hospital complaining of general malaise. Masses in the bilateral adrenal glands was noted on abdominal CT and he was admitted. The left adrenal was biopsied under echo guidance. The pathological diagnosis was non-Hodgkin lymphoma (diffuse medium sized cell type). Combination chemotherapy was followed by a complete remission and discharge of the patient.

[Basic examination of deoxythymidine kinase using Prolifigen TK kit "Daiichi"].

To clarify the clinical significance of serum deoxythymidine kinase in various hematological disorders, basic examination was performed of a newly developed radioenzyme assay kit for TK (Prolifigen TK kit "Daiichi") using 125I-iodo-deoxyuridine as a substrate. The assessment of the standard curve, and the results of recovery test, dilution test, and precision and reproducibility were satisfactory. Among several anticoagulant agents tested, heparin was the best one showing no influence on the measurement of TK level. Based on these results, serum TK level was measured in 140 healthy adults as a control group. There was no difference by age and sex. The serum TK level of normal control was 3.1 +/- 1.2 U/l, with an upper limit of 5.5 U/l.

Diaper area granuloma of the aged.

Nine women, aged 77 to 89 years, suffered from diaper dermatitis, and many granulomas were seen in the genital or gluteal region restricted to the lesion of dermatitis. Because these granulomas resembled granuloma gluteale infantum of Tappeiner and Pfleger, we propose to call this condition diaper area granuloma of the aged.