Fungal meningitis caused by Lomentospora prolificans after allogeneic hematopoietic stem cell transplantation.

Central nervous system lomentosporiosis is a rare pathological condition in immunocompromised patients. We describe a fatal case of meningitis caused by Lomentospora prolificans (which was previously named Scedosporium prolificans), after an allogeneic hematopoietic stem cell transplantation (allo-HSCT). To our knowledge, no cases of Lomentospora meningitis following allo-HSCT have been reported previously. Particularly in neutropenic patients, it is important to consider L. prolificans when a fungal infection is suspected and antifungal agents are ineffective.

Induction of programmed cell death in human hematopoietic cell lines by fibronectin via its interaction with very late antigen 5.

Extracellular matrix (ECM) molecules such as fibronectin (FN), collagens, and laminin have important roles in hematopoiesis. However, little is known about the precise mechanisms by which ECM molecules regulate proliferation of human hematopoietic progenitor cells. In this study, we have investigated the effects of ECM molecules, particularly of FN, on the proliferation of a myeloid leukemia cell line, M07E, which proliferates in response to either human granulocyte/macrophage colony-stimulating factor (GM-CSF) or stem cell factor (SCF). The [3H]thymidine incorporation and cell enumeration assays showed that FN strikingly inhibited GM-CSF- or SCF-induced proliferation of M07E cells in a dose-dependent manner, whereas little or no inhibition was induced by collagen types I and IV. The growth suppression of M07E cells was not due to the inhibitory effect of FN on ligand binding or very early events in the signal transduction pathways from the GM-CSF or SCF receptors. DNA content analysis using flow cytometry after staining with propidium iodide revealed that the treatment of M07E cells with FN did not block the entry of the cells into the cell cycle after stimulation with GM-CSF or SCF, whereas the treatment resulted in the appearance of subdiploid peak. Furthermore, FN was found to induce oligonucleosomal DNA fragmentation and chromatin condensation in the cells even in the presence of GM-CSF or SCF, suggesting the involvement of programmed cell death (apoptosis) in the FN-induced growth suppression. The growth suppression or apoptosis induced by FN was rescued by the addition of either anti-FN antibody, anti-very late antigen 5 monoclonal antibody (anti-VLA5 mAb), or GRGDSP peptide, but not by that of anti-VLA4 mAb or GRGESP peptide, suggesting that the FN effects on M07E cells were mediated through VLA5. In addition, the FN-induced apoptosis was detectable in VLA5-positive human hematopoietic cell lines other than M07E cells, but not in any of the VLA5-negative cell lines. These results suggest that FN is capable of inducing apoptosis via its interaction with VLA5, and also raise the possibility that the FN-VLA5 interaction may contribute, at least in part, to negative regulation of hematopoiesis.

Bifidobacterium infantis M-63 improves mental health in victims with irritable bowel syndrome developed after a major flood disaster.

Individuals in a community who developed irritable bowel syndrome (IBS) after major floods have significant mental health impairment. We aimed to determine if Bifidobacterium infantis M-63 was effective in improving symptoms, psychology and quality of life measures in flood-affected individuals with IBS and if the improvement was mediated by gut microbiota changes. Design was non-randomised, open-label, controlled before-and-after. Of 53 participants, 20 with IBS were given B. infantis M-63 (1×109 cfu/sachet/day) for three months and 33 were controls. IBS symptom severity scale, hospital anxiety and depression scale, SF-36 Questionnaire, hydrogen breath testing for small intestinal bacterial overgrowth and stools for 16S rRNA metagenomic analysis were performed before and after intervention. 11 of 20 who were given probiotics (M-63) and 20 of 33 controls completed study as per-protocol. Mental well-being was improved with M-63 vs controls for full analysis (P=0.03) and per-protocol (P=0.01) populations. Within-group differences were observed for anxiety and bodily pain (both P=0.04) in the M-63 per-protocol population. Lower ratio of Firmicutes/Bacteroidetes was observed with M-63 vs controls (P=0.01) and the lower ratio was correlated with higher post-intervention mental score (P=0.04). B. infantis M-63 is probably effective in improving mental health of victims who developed IBS after floods and this is maybe due to restoration of microbial balance and the gut-brain axis. However, our conclusion must be interpreted within the context of limited sample size. The study was retrospectively registered on 12 October 2017 and the Trial Registration Number (TRN) was NCT03318614.

Different physiological properties of human-residential and non-human-residential bifidobacteria in human health.

Bifidobacteria have increasingly been shown to exert positive health benefits to humans, which are clearly reflected by their application in various commercialised dairy products and supplements. Bifidobacteria naturally inhabit a range of ecological niches and display substantial differences in their ecological adaptation among species. In general, bifidobacteria could be categorised into two major groups; bifidobacterial species of human origins as human-residential bifidobacteria (HRB) while other species which are the natural inhabitants of animals or environment as non-HRB. Current research has focused on the differential physiological features of HRB and non-HRB, such as metabolic capabilities, whilst comparative and functional genomic investigations have revealed the genetic attributes of bifidobacteria that may explain their colonisation affinities in human gut. It is becoming more apparent that distinct residential origins of bifidobacteria are likely contributed to their comparable adaptive health attributes on human host. Notably, debate still remains about the nature of bifidobacteria for use as human probiotics. Clinical evaluations involving supplementation of bifidobacteria of different origins point out the superiority of HRB in human host. Evidence also suggests that HRB especially infant-type HRB may exert better health-promoting effects and therefore serve as a better probiotic candidate for infant use. In this review, we aim to provide an overview of the genotypic and physiological differences of bifidobacteria associated with different residential origins and to shed light on the practical considerations for selection of bifidobacteria as probiotics in order to establish a healthy gut microbial community in humans.

Bifidobacterium longum BB536 alleviated upper respiratory illnesses and modulated gut microbiota profiles in Malaysian pre-school children.

This 10-months randomised, double-blind, parallel and placebo-controlled study evaluated the effects of Bifidobacterium longum BB536 on diarrhoea and/or upper respiratory illnesses in 520 healthy Malaysian pre-school children aged 2-6 years old. The subjects randomly received a one-gram sachet containing either BB536 (5×109 cfu) or placebo daily. Data analysis was performed on 219 subjects who fully complied over 10-months (placebo n=110, BB536 n=109). While BB536 did not exert significant effects against diarrhoea in children, Poisson regression with generalised estimating equations model indicated significant intergroup difference in the mean number of times of respiratory illnesses over 10 months. The duration of sore throat was reduced by 46% (P=0.018), with marginal reduction for duration of fever (reduced by 27%, P=0.084), runny nose (reduced by 15%, P=0.087) and cough (reduced by 16%, P=0.087) as compared to the placebo. Principal coordinate analysis at genus level of the gut microbiota revealed significant differences between 0 and 10 months in the BB536 group (P<0.01) but not in placebo group (P>0.05). The abundance of the genus Faecalibacterium which is associated with anti-inflammatory and immuno-modulatory properties was significantly higher in the BB536 group (P<0.05) compared to the placebo group. Altogether, our present study illustrated the potential protective effects of BB536 against upper respiratory illnesses in pre-school Malaysian children, with gut microbiota modulating properties.

Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product.

The c-kit proto-oncogene encodes a receptor tyrosine kinase. Binding of c-kit ligand, stem cell factor (SCF) to c-kit receptor (c-kitR) is known to activate c-kitR tyrosine kinase, thereby leading to autophosphorylation of c-kitR on tyrosine and to association of c-kitR with substrates such as phosphatidylinositol 3-kinase (PI3K). In a human mast cell leukemia cell line HMC-1, c-kitR was found to be constitutively phosphorylated on tyrosine, activated, and associated with PI3K without the addition of SCF. The expression of SCF mRNA transcript in HMC-1 cells was not detectable by means of PCR after reverse transcription (RT-PCR) analysis, suggesting that the constitutive activation of c-kitR was ligand independent. Sequencing of whole coding region of c-kit cDNA revealed that c-kit genes of HMC-1 cells were composed of a normal, wild-type allele and a mutant allele with two point mutations resulting in intracellular amino acid substitutions of Gly-560 for Val and Val-816 for Asp. Amino acid sequences in the regions of the two mutations are completely conserved in all of mouse, rat, and human c-kit. In order to determine the causal role of these mutations in the constitutive activation, murine c-kit mutants encoding Gly-559 and/or Val-814, corresponding to human Gly-560 and/or Val-816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line, 293T cells. In the transfected cells, both c-kitR (Gly-559, Val-814) and c-kitR (Val-814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of c-kitR (Gly-559) or wild-type c-kitR was modest or little, respectively. These results suggest that conversion of Asp-816 to Val in human c-kitR may be an activating mutation and responsible for the constitutive activation of c-kitR in HMC-1 cells.

Involvement of prolonged ras activation in thrombopoietin-induced megakaryocytic differentiation of a human factor-dependent hematopoietic cell line.

Thrombopoietin (TPO) is a hematopoietic growth factor that plays fundamental roles is both megakaryopoiesis and thrombopoiesis through binding to its receptor, c-mpl. Although TPO has been shown to activate various types of intracellular signaling molecules, such as the Janus family of protein tyrosine kinases, signal transducers and activators of transcription (STATs), and ras, the precise mechanisms underlying TPO-induced proliferation and differentiation remain unknown. In an effort to clarify the mechanisms of TPO-induced proliferation and differentiation, c-mpl was introduced into F-36P, a human interleukin-3 (IL-3)-dependent erythroleukemia cell line, and the effects of TPO on the c-mpl-transfected F-36P (F-36P-mpl) cells were investigated. F-36P-mpl cells were found to proliferate and differentiate at a high rate into mature megakaryocytes in response to TPO. Dominant-negative (dn) forms of STAT1, STAT3, STAT5, and ras were inducibly expressed in F-36P-mpl cells, and their effects on TPO-induced proliferation and megakaryocytic differentiation were analyzed. Among these dn molecules, both dn ras and dn STAT5 reduced TPO- or IL-3-induced proliferation of F-36P-mpl cells by approximately 30%, and only dn ras could inhibit TPO-induced megakaryocytic differentiation. In accord with this result, overexpression of activated ras (H-rasG12V) for 5 days led to megakaryocytic differentiation of F-36P-mpl cells. In a time course analysis on H-rasG12V-induced differentiation, activation of the ras pathway for 24 to 28 h was required and sufficient to induce megakaryocytic differentiation. Consistent with this result, the treatment of F-36P-mpl cells with TPO was able to induce prolonged activation of ras for more than 24 h, whereas IL-3 had only a transient effect. These results suggest that prolonged ras activation may be involved in TPO-induced megakaryocytic differentiation.

Differences between live and heat-killed bifidobacteria in the regulation of immune function and the intestinal environment.

Probiotics are live microorganisms that confer a health benefit on the host, such as improvement of the intestinal environment, modulation of immune function and energy metabolism. Heat-killed probiotic strains have also been known to exhibit some physiological functions; however, the differences between live and heat-killed probiotics have not been well elucidated. In this study, we investigated the differences between live and heat-killed Bifidobacterium breve M-16V, a probiotic strain, in the regulation of immune function, intestinal metabolism and intestinal gene expression of the host using gnotobiotic mouse model and omics approaches. Both live and heat-killed cells of B. breve M-16V showed immune-modulating effects that suppressed pro-inflammatory cytokine production in spleen cells and affected intestinal metabolism; however, live cells exhibited a more remarkable effect in the regulation of intestinal metabolism and intestinal gene expression involved in nutrient metabolism. Our findings are valuable for considering the health benefits of live and heat-killed bacteria and the usefulness of different forms of probiotics.

Functional expression of interleukin 2 receptor in a human factor-dependent megakaryoblastic leukemia cell line: evidence that granulocyte-macrophage colony-stimulating factor inhibits interleukin 2 binding to its receptor.

Human interleukin 2 (IL-2) is a member of the class of crucial regulators of lymphocyte proliferation. The action of IL-2 is known to be mediated through binding to a specific IL-2 receptor (IL-2R) which comprises at least two distinct proteins: IL-2R alpha (p55) and IL-2R beta (p70-75). However, the expression and function of IL-2R are largely unknown in acute myeloblastic leukemia cells. In a human granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, or stem cell factor-dependent myeloid leukemia cell line (M07E), IL-2 was found to stimulate proliferation in a dose-dependent manner and to augment GM-CSF- and stem cell factor-induced proliferation of M07E cells. The expression of IL-2R beta on M07E cells was detectable with 125I-IL-2 binding and affinity cross-linking analyses and with a monoclonal antibody against IL-2R beta, Mik-beta 1. Although the expression of IL-2R beta was not down-regulated but somewhat up-regulated by treatment with GM-CSF in both mRNA and protein levels, GM-CSF was found to compete (75%) with radiolabeled IL-2 for binding to IL-2R on M07E cells, whereas no competition of GM-CSF binding was observed with IL-2 even at a 400-fold molar excess. These results suggest that IL-2R may be functionally expressed in some cases of acute myeloblastic leukemia cells and raise the possibility that IL-2 may have some effects on human myelopoiesis.

Three dimensional image-based simulation of ultrasonic wave propagation in polycrystalline metal using phase-field modeling.

When modeling ultrasonic wave propagation in metals, it is important to introduce mesoscopic crystalline structures because the anisotropy of the crystal structure and the heterogeneity of grains disturb ultrasonic waves. In this paper, a three-dimensional (3D) polycrystalline structure generated by multiphase-field modeling was introduced to ultrasonic simulation for nondestructive testing. 3D finite-element simulations of ultrasonic waves were validated and compared with visualization results obtained from laser Doppler vibrometer measurements. The simulation results and measurements showed good agreement with respect to the velocity and front shape of the pressure wave, as well as multiple scattering due to grains. This paper discussed the applicability of a transversely isotropic approach to ultrasonic wave propagation in a polycrystalline metal with columnar structures.

Effect of probiotic yoghurt on animal-based diet-induced change in gut microbiota: an open, randomised, parallel-group study.

Diet has a significant influence on the intestinal environment. In this study, we assessed changes in the faecal microbiota induced by an animal-based diet and the effect of the ingestion of yoghurt supplemented with a probiotic strain on these changes. In total, 33 subjects were enrolled in an open, randomised, parallel-group study. After a seven-day pre-observation period, the subjects were allocated into three groups (11 subjects in each group). All of the subjects were provided with an animal-based diet for five days, followed by a balanced diet for 14 days. Subjects in the first group ingested dairy in the form of 200 g of yoghurt supplemented with Bifidobacterium longum during both the animal-based and balanced diet periods (YAB group). Subjects in the second group ingested yoghurt only during the balanced diet period (YB group). Subjects who did not ingest yoghurt throughout the intervention were used as the control (CTR) group. Faecal samples were collected before and after the animal-based diet was provided and after the balanced diet was provided, followed by analysis by high-throughput sequencing of amplicons derived from the V3-V4 region of the 16S rRNA gene. In the YB and CTR groups, the animal-based diet caused a significant increase in the relative abundance of Bilophila, Odoribacter, Dorea and Ruminococcus (belonging to Lachnospiraceae) and a significant decrease in the level of Bifidobacterium after five days of intake. With the exception of Ruminococcus, these changes were not observed in the YAB group. No significant effect was induced by yoghurt supplementation following an animal-based diet (YB group vs CTR group). These results suggest that the intake of yoghurt supplemented with bifidobacteria played a role in maintaining a normal microbiota composition during the ingestion of a meat-based diet. This study protocol was registered in the University Hospital Medical Information Network: UMIN000014164.

Changes in phenotype and proliferative potential of human acute myeloblastic leukemia cells in culture with stem cell factor.

The interaction of the proto-oncogene c-kit product with its ligand (stem cell factor or SCF) is considered to play crucial roles in hematopoiesis. In a series of human acute myeloblastic leukemia (AML) cells, the effects of recombinant human (rh) SCF on AML cells were examined in short-term and long-term cultures. c-kit expression was detected in 26 of 31 AML cases, and short-term treatment of AML cells with rhSCF led to proliferation in 13 of 18 AML cases that expressed the c-kit product. In seven of the 13 cases showing proliferative response to rhSCF, AML cells were exclusively composed of immature blast cells. We therefore used the seven AML cases for examining the effect of rhSCF on the differentiation and proliferation of AML cells in a long-term culture. Proliferation of AML cells was found to be maintained with rhSCF more than 2 weeks in five of seven cases and 4 weeks in two cases, whereas most of the AML cells died before 2 weeks in the absence of rhSCF. Further, in four of five AML cases, all of which expressed the CD34 antigen and showed a proliferative response to rhSCF in a long-term culture, rhSCF appeared to promote differentiation of blast cells toward lineages of various cell types, such as granulocytic and/or monocytic and mast-cell lineages. These results suggest that, at least in a fraction of AML cases, rhSCF can induce not only proliferation but also differentiation of AML cells, and also that phenotypic manifestation of AML cells may not mean definite cell commitment but can be changed by stimulation with rhSCF.

Whole-body hybrid PET with 18F-FDG in the staging of non-Hodgkin's lymphoma.

UNLABELLED: PET with a double-head gamma camera (hybrid PET) is a new approach to tumor imaging with 18F-FDG. This study was conducted to clarify the feasibility of whole-body FDG hybrid PET in the staging of non-Hodgkin's lymphoma (NHL) in comparison with PET with a dedicated camera (dedicated PET) and to compare the results of both FDG studies with those of CT and 67Ga scanning as conventional imaging studies (CIS). METHODS: Thirty patients with NHL were prospectively evaluated. The results of the imaging studies regarding detection of the sites involved and staging were compared with each other and with those of the reference standard based on the final overall clinical evaluation. RESULTS: Of the total of 206 sites, whole-body FDG hybrid PET and dedicated PET detected 159 sites (77.2%) and 179 sites (86.9%), respectively. Eighteen of the 20 sites missed by hybrid PET alone consisted of lesions < 1.5 cm. Both FDG studies provided concordant staging results in all but 2 patients. CIS, on the other hand, detected 164 (79.6%) of the 206 sites, 137 of which were also detected by hybrid PET. Hybrid PET detected an additional 22 sites not found by CIS, whereas CIS detected 27 additional sites. Hybrid PET and CIS provided concordant staging results in 19 patients. Hybrid PET correctly staged NHL in 5 additional patients, whereas CIS correctly staged NHL in only 1 additional patient. CONCLUSION: Whole-body FDG hybrid PET appeared to be an accurate method of staging NHL. Despite its poorer image quality compared with dedicated PET, hybrid PET provided NHL staging results comparable with those of dedicated PET. Hybrid PET also yielded results comparable with those of CIS. However, whole-body FDG hybrid PET is currently inadequate as a single modality for staging NHL and is complementary to CT.

Regulation of basophilic and erythroid-differentiation of a human chronic myelogenous leukemia-cell line, ku812f, by interleukin-3 and stem-cell factor.

We have investigated the effects of c-kit ligand (stem cell factor [SCF]) and interleukin-3 (IL-3) on proliferation and differentiation of a human chronic myelogenous leukemia cell line, KU812F, which can differentiate toward erythroid and basophilic lineages. When purified c-kit-positive cells (approximately 20% of KU812F cells) were used as a target, SCF induced not only proliferation but also augumented erythroid differentiation of the cells, while IL-3 did promote basophilic differentiation. Further, analyses of in situ hybridization and cell sorting with anti-c-kit antibody showed that the expression of c-kit decreased along with differentiation from immature to mature basophils and erythroid cells.

Expression, function and activation of the proto-oncogene c-kit product in human leukemia cells.

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is considered to play important roles in hematopoiesis. The proto-oncogene c-kit product is expressed on various types of human cell lines derived from leukemic cells of erythroid, megakaryocytic and mast-cell lineages. Also, the c-kit product is detectable in blast cells in most cases of acute myeloblastic leukemia (AML) and in some cases of chronic myelogenous leukemia (CML) in blastic crisis (BC). By contrast, little or no expression of c-kit is observed in human leukemia cell lines of lymphoid lineage and in blast cells in acute lymphoblastic leukemia (ALL). Tyrosine phosphorylation and activation of the c-kit product with the ligand for c-kit (stem cell factor: SCF) results in proliferation of some human leukemia cell lines, such as M07E, and blast cells in a substantial fraction of AML cases. In addition, SCF appears to have an activity in inducing differentiation of certain types of leukemic cells. In some cases, further, the c-kit product is found to be activated in leukemic cells even before the stimulation with SCF. These results suggest that c-kit may be involved in excessive proliferation and aberrant differentiation of human leukemia cells.

Effect of diltiazem on silent ischemic episodes, plasma bradykinin and prostaglandin metabolism.

Plasma bradykinin and prostaglandin metabolism are related to the anginal pain modulating system in patients with ischemic heart disease. We carried out a placebo controlled single blind test of diltiazem (30 mg three times a day) in 15 patients with chronic stable angina. The effect of diltiazem was evaluated by exercise treadmill testing and 48-h ambulatory electrocardiographic monitoring. Plasma bradykinin, thromboxane B2, and 6-keto-prostaglandin F1 alpha levels were determined by radioimmunoassay prior to and during diltiazem therapy. Diltiazem significantly increased the exercise time and reduced episodes of angina. Diltiazem, however, did not appreciably improve either the frequency of silent myocardial ischemic episodes or the total duration of the silent myocardial ischemic episodes. Diltiazem also tended to decrease plasma bradykinin, thromboxane B2, and 6-keto-prostaglandin F1 alpha levels. When ischemic episodes on ambulatory electrocardiographic monitoring are categorized according to heart rate change at the onset of episode (type A, preceded by heart rate increase > or = 5 beats/min; type B, no preceding heart rate increase), diltiazem was only effective on type A ischemic episodes as well as on symptomatic ischemia. Further, bradykinin was significantly decreased by diltiazem only in patients with exercise-induced silent ischemia or no exercise-induced ischemia, while the thromboxane B2/6-keto-prostaglandin F1 alpha ratio was unaffected by the administration of diltiazem. Thus, silent and symptomatic ischemia may be associated with different bradykinin and prostaglandin responses.

Painless myocardial ischemia in elderly patients compared with middle-aged patients and its relation to treadmill testing and coronary hemodynamics.

We compared painless ST-segment depression (1 mm greater than or equal to 80 ms and lasting greater than or equal to 60 s) in elderly patients with coronary artery disease (greater than or equal to 65 years, mean 67 years; n = 22) and that of middle-aged patients (less than 60 years, mean 54 years; n = 20) by Holter monitoring for 24 hours to determine the relationship between episodes of painless myocardial ischemia, findings of treadmill testing, and coronary hemodynamics. Coronary arteriographic findings (Gensini score) and ejection fraction (EF) did not differ between the two groups. Painless ST-segment depression was found to be 77% in the older age group versus 45% in the middle-aged group (p less than 0.05). However, treadmill exercise score, ST-segment depression, and ST-segment integral achieved did not differ significantly between the two groups. Within 2 weeks after the above testing, coronary hemodynamic study was performed. The increment of coronary sinus flow in the older age group was 1.4 +/- 0.3 versus 1.8 +/- 0.3 in the middle-aged group (p less than 0.05), and the change of lactate extraction ratio from the basal condition in the older age group was -50 +/- 40% versus -2 +/- 15% in the middle-aged group (p less than 0.05). We conclude that episodes of painless myocardial ischemia in elderly patients with aging may be associated with the impairment of the coronary vascular reserve and easier anaerobic myocardial metabolism by pacing stress despite similar findings of coronary artery disease and EF in both groups.

Physiological rationale of aggressive behavior: a brain blood perfusion hypothesis.

The physiological rationale of aggressive behavior is discussed. The potential importance of homeostatic reaction in brain blood perfusion is described. The author speculates that pathological aggressive behavior arises from urgent biological needs. Attacks of anger show increased regional cerebral blood flow in the temporal cortex or other paralimbic areas, which show hypoperfusion in inter-attack states. This hypoperfusion may also be related to psychological stress-induced cerebral vasoconstriction. Furious physical motion, accompanying the attack, would augment regional cerebral blood flow and maintain it longer. A brain blood perfusion hypothesis as the etiological role of aggressive behavior is presented.

[Induction of apoptosis by fibronectin via its interaction with VLA5].

Little is known how Extra cellular matrix (ECM) molecules regulate proliferation of human hematopoietic progenitor cells. Fibronectin (FN) strikingly inhibited a human growth factor dependent cell line, M07E, cell proliferation. DNA content analysis revealed that FN treatment resulted in the appearance of subdiploid peak. Furthermore, FN induced oligonucleosomal DNA fragmentation and chromatin condensation, suggesting the involvement of apoptosis in the FN induced growth suppression. The apoptosis was rescued by anti-VLA5 mAb and the FN-induced apoptosis was detectable only VLA5-positive human cell lines but not in any of the VLA5-negative cell lines. These results suggest that FN induces apoptosis via its interaction with VLA5, and also raise the possibility that the FN-VLA5 interaction may contribute to negative regulation of hematopoiesis.