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A yacht often rolls very violently when it is sailing down-wind. This divergent oscillation may be dangerous enough to capsize the yacht. This study models a yacht as a sail-ballast system rolling in a wind. A mathematical model is presented to account for this phenomenon. Experiments have also been made for systems with triangular and elliptic sails. Analysis of the nonlinear governing equation implies that the instability occurs owing to coupling effects between aerodynamic and righting moments: in particular the large change in the side force under a small change in the angle of attack. The experimental results support this argument regarding interaction, as well as the existence of three distinctive types of rolling motion: divergence, divergent oscillation, and oscillation with weak damping. Estimated and measured periods of oscillation are in fairly good agreement. Evidence supports the idea that vortices behind the sails are not the main cause of the instability.

To overcome the low accuracy of acoustic velocity measurements based on Brillouin scattering from thermal phonons, we attempted to utilize induced coherent phonons, which cause intense Brillouin scattering. A ZnO piezoelectric film was used to induce gigahertz-range coherent phonons in a silica glass block sample. An evanescent electromagnetic wave leaked from a coaxial resonator was applied into the film to excite phonons. The scattered light obtained using this simple system was much more intense than that obtained from thermal phonons. This technique will improve the accuracy and reduce the measurement time.

This paper models sails as inextensible, flexible and slack surfaces. Some of these inextensible surfaces are known to be developable, and this fact simplifies the description of sails with cylindrical surfaces as well as the structural argument. The high aspect-ratio approximation also simplifies aerodynamic arguments: the lifting-line theory for three-dimensional effects and the thin-airfoil theory for sectional aerodynamic characteristics. The total problem consists of integrodifferential equations for unknown circulation distribution and unknown camber at the sail foot, accompanied by a nonlinear constraint on the arc length of a high aspect-ratio sail. Numerical calculations show that the slackness increases the magnitude of the zero lift angle and that the aspect ratio increases the slope of the lift curve. The results also show the existence of two equilibria in the region of small angles of attack. The theory agrees with the existing experimental data of parabolic sails, in cases where the slackness is small and the angle of attack is less than the stall angle.

We found a case of Ph-positive chronic myelogenous leukemia (CML) patient with an atypical BCR-ABL transcript that was undetectable by a routine reverse transcription polymerase chain reaction (RT-PCR) for major BCR-ABL. Additional RT-PCR and sequence analyses have demonstrated that the aberrant transcript consists of a fusion of BCR exon 8 (e8) and ABL exon 2 (a2) with an insertion of a 55-bp inverted sequence of intron 1b between them. The nucleotide sequences of the aberrant transcript were identical to those of a previously reported CML patient. These are the only two CML cases in the literature with identical aberrant BCR-ABL transcripts. Am. J. Hematol. 77:164–166, 2004. © 2004 Wiley-Liss, Inc.

Aerodynamics of sails in weakly sheared wind has been studied based on vortex mechanics. Assumptions of small disturbance simplify the basic equations, which show that the effective application of the rudder and coupled heeling and yawing motions give directional stability to sailing craft close to wind. Analysis has also revealed how heel-yaw motion and sheared wind affect the optimization of the thrust with constraints. The result has been compared with the present author's previous work that disregards the heel and the wind shear. While the optimum circulation is independent of the wind shear and the heel-yaw motion, the optimum geometry of sails is little affected by the wind shear. Closed-form solutions are given to represent the optimum design.

The aim of this study was to confirm the change in haemoglobin A1c consequent to pre-operative donation of autologous blood for elective surgery in patients with diabetes mellitus.For enrolment in this prospective study, patients had to be scheduled for multiple autologous blood donations at different times and have a haemoglobin A1c level more than 5.8% at the first donation. The values of four factors, haemoglobin, haemoglobin A1c, glycated albumin, and glycated albumin/haemoglobin A1c ratio were determined. Changes in the values of these four factors between before and after the blood donations were calculated.In all 24 patients studied, haemoglobin and haemoglobin A1c decreased as a result of the autologous blood donations. The group with a reduced glycated albumin/haemoglobin A1c ratio had short intervals between blood donations. Correlations were observed between donation interval and change in haemoglobin A1c (r=-0.63, P=0.003), and between donation interval and change in the glycated albumin/haemoglobin A1c ratio (r=0.489, P=0.045).Haemoglobin A1c levels are likely to be underestimated after autologous blood donation by patients with diabetes mellitus, so glycated albumin may be a better indicator of these patients' glycaemic control.

Brillouin scattering method is a nondestructive and noncontact technique to measure local longitudinal and shear acoustic velocities in the GHz range. However, the measurements of weak scattering from thermal phonons result in the lower measurement accuracy and longer measurement time. To overcome this problem, a technique with artificially induced acoustic phonons was developed using a polycrystalline ZnO film, with a coaxial resonator to apply electric field. In this study, we observed Brillouin scattering by induced longitudinal phonons from ZnO film deposited on the rear surface of a plate sample. We investigated the relationship between the intensity of induced acoustic phonons and the input microwave power of a coaxial resonator. The effect of incident angle of light was also investigated.

Transfusion-related acute lung injury (TRALI) is associated with vascular endothelial cell injury following neutrophil activation. Recently, it has been suggested that haem-related molecules induce activation of neutrophils and that erythrocyte-derived substances contained in blood preparations are involved in TRALI. We observed the morphological effects and reactive oxygen species (ROS) production of haem-related molecules and investigated the effects of signal transduction inhibitors on haem-induced neutrophil activation.The polymorphonuclear cell fraction was isolated and stimulated using a control stimulant, PMA or fMLP, or by haem-related molecules, haemin, ferric citrate, or protoporphyrin IX. After stimulation, neutrophil was analysed using electron microscopy, a flowcytometer (FCM) and confocal laser scanning microscope to determine the fluorescent intensity of aminophenyl fluorescein (to detect ROS).In FCM analysis, haemin and protoporphyrin IX, both of which have a porphyrin ring, induced ROS production in neutrophils. Ferric citrate, which has no porphyrin ring, did not induce neutrophil activation. Haemin alone induced ROS production at relatively high concentrations, whereas low-level fMLP acted as an agonist in the presence of low concentrations of haemin. Haem-related molecules induced ROS production in neutrophil granules through signal transduction in a way similar to PMA. However, in electron microscopy studies, haemin stimulated neutrophils showed minute process at their surface and did not show the vacuolation observable following stimulation with PMA or fMLP.We suggest that low concentrations of haem-related molecules with porphyrin rings in the presence of other stimulating agent are important for ROS production and possibly the onset of TRALI. The ROS production induced by these molecules is dependent on a signal transduction pathway in a way similar to PMA.

The optimum sail geometry is analytically obtained for the case of maximizing the thrust under equality and inequality constraints on the lift and the heeling moment. A single mainsail is assumed to be set close-hauled in uniform wind and upright on the flat sea surface. The governing parameters are the mast height and the gap between the sail foot and the sea surface. The lifting line theory is applied to analyze the aerodynamic forces acting on a sail. The design method consists of the variational principle and a feasibility study. Almost triangular sails are found to be optimum. Their advantages are discussed.

Rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) have been studied extensively as prognostic markers of rheumatoid arthritis (RA). However, despite the fact that matrix metalloproteinase-3 (MMP-3) is linked to RA activity, few studies have evaluated MMP-3 as prognostic marker.To evaluate the performance of MMP-3 as predictor of joint destruction in RA treated with non-biological disease modifying anti-rheumatic drugs.In a retrospective study of 58 early to moderate stage RA patients who consulted the Department of Clinical Pathology and Immunology, Kobe University Hospital between May 2002 and April 2009, we evaluated the performance of MMP-3 and other biomarkers as predictors of joint destruction, by comparing them between radiographically progressive and non-progressive group.Serum levels of RF at entry and ACPA, but not MMP-3 at entry, were significantly higher for the progressive group. Ratios of patients with MMP-3 levels higher than healthy control were not significantly different for the two groups. However, cutoff values determined through receiver operating characteristic analysis showed that the ratio of patients with elevated RF was significantly higher in the progressive group (p=0.001), while MMP-3 (p=0.092), ACPA (p=0.052), CRP (p=0.056), and ESR (p=0.069) tended to be more elevated in the progressive group. Multiple logistic regression analysis using the cutoff value identified MMP-3 positive and RF positive, but not ACPA, CRP or ESR, as significant factors for radiographic progression (OR 16.79 [95% CI: 1.34-414.19]).MMP-3 can be a useful marker for prediction of joint destruction.

Background In spite of its establishment from the peripheral blood of a case with acute myeloid leukemia (AML)-M1, HPB-AML-I shows plastic adherence with spindle-like morphology. In addition, lipid droplets can be induced in HPB-AML-I cells by methylisobutylxanthine, hydrocortisone, and indomethacin. These findings suggest that HPB-AML-I is similar to mesenchymal stem cells (MSCs) or mesenchymal stromal cells rather than to hematopoietic cells. Methods To examine this possibility, we characterized HPB-AML-I by performing cytochemical, cytogenetic, and phenotypic analyses, induction of differentiation toward mesenchymal lineage cells, and mixed lymphocyte culture analysis. Results HPB-AML-I proved to be negative for myeloperoxidase, while surface antigen analysis disclosed that it was positive for MSC-related antigens, such as CD29, CD44, CD55, CD59, and CD73, but not for CD14, CD19, CD34, CD45, CD90, CD105, CD117, and HLA-DR. Karyotypic analysis showed the presence of complicated abnormalities, but no reciprocal translocations typically detected in AML cases. Following the induction of differentiation toward adipocytes, chondrocytes, and osteocytes, HPB-AML-I cells showed, in conjunction with extracellular matrix formation, lipid accumulation, proteoglycan synthesis, and alkaline phosphatase expression. Mixed lymphocyte culture demonstrated that CD3+ T-cell proliferation was suppressed in the presence of HPB-AML-I cells. Conclusions We conclude that HPB-AML-I cells appear to be unique neoplastic cells, which may be derived from MSCs, but are not hematopoietic progenitor cells.

To develop the hydrogen sensor, the chemical potential due to the catalytic reaction of the metals are required to evaluate. The platinum and titanium layered electrode on the insulator/semiconductor layered device are fabricated as the test chip. The catalytic reaction of platinum and hydrogen gas were successfully visualized.

We discussed the usefulness of routine technologies of laboratory medicine in blood transfusion and transplantation medicine. New parameters that can be measured by automated hematology analyzers have been clinically evaluated and proven to be useful so far. Based on our experience, detection systems for fragmented red cells (FRC), immature platelets (immature platelet function, IPF), and hematopoietic progenitor cells (HPC) are useful for the diagnosis of thrombotic microangiopathy, differential diagnosis of thrombocytopenia, and decision regarding the optimal timing to collect peripheral stem cells, respectively. Moreover, IPF were suggested to be an indicator of the platelet transfusion requirement. The establishment of non invasive assaying technology has been eagerly anticipated. We evaluated a hemoglobin measurement tool, and revealed that it might be applicable in predeposited, autologous blood donation. Some adverse transfusion reactions are related to neutrophil activation. Thus, we investigated the effects of serum from patients and blood donors, in the context of adverse reactions, on adhesion molecule expressions of neutrophils from volunteers using flow-cytometry. This kind of simple technology is expected to be useful in future studies to clarify the mechanisms and prevent adverse reactions.

Cyclooxygenase-2 (Cox-2) is known to be associated with tumorigenesis in many cancers including endometrial cancer, while there is substantial evidence for the tumorigenicity of cyclooxygenase-1 (Cox-1). However, little is known about the involvement of Cox-1 in the development of endometrial cancer. The aim of this study was to determine whether cyclooxygenase-1 or -2 (Cox-1, Cox-2) is tumorigenetic, as well as whether these two cyclooxygenase isoforms correlate with the clinicopathological characteristics or with another two biomarkers, human epidermal growth factor receptor type-2 (Her-2) and vascular endothelial growth factor (VEGF), of endometrial cancer.At first, Cox-1 and Cox-2 levels in eight endometrial cancer cell lines were determined by means of real-time PCR. At second, the levels of four biomarkers (Cox-1, Cox-2, Her-2, and VEGF) in 70 endometrial cancer samples were determined by means of real-time PCR. Pairs of these biomarkers were subjected to correlation as each biomarker and clinical status or survival.In the eight cell lines, the expression of Cox-1 and Cox-2 showed major variations in their mRNA levels. Analysis of the patient samples showed that the mRNA expression of Cox-1 was elevated significantly in the G1 (P=0.021) and G2 (P=0.036) groups, as was the mRNA expression of Her-2 in the two groups (P=0.036 and P=0.0029, respectively). The mRNA expression of Cox-1 and Her-2 were correlated (CI=0.671). None of the three biomarkers, Cox-1, Cox-2, and Her-2, was correlated with clinical status such as FIGO classification, myometrial invasion, or clinical outcome.Cox-1, together with Her-2, may be involved in the early stage of endometrial cancer development.

Immature or reticulated platelets are known as a clinical marker of thrombopoiesis. Recently, an automatic method was established to detect reticulated platelets as immature platelet fraction (IPF) by means of hematology analyzer XE-2100. We assessed the effects of IPF detection after chemotherapy for various pediatric malignant disorders of 16 patients. Our results indicate that IPF should be considered a useful marker of imminent platelet recovery so that unnecessary platelet transfusion can be avoided.

Objective To determine how standard IVF vs. intracytoplasmic sperm injection (ICSI) fertilization influences early and late morphokinetic parameters during prolonged embryo culture. Design Five-hundred expanded blastocysts that were monitored in a time-lapse monitoring incubator were analysed retrospectively. Early (pronuclear fading [PNf], t2–t9) and late (start of blastulation, expanded blastocyst) morphokinetic variables were scored according to published consensus criteria. Setting Private infertility clinic. Patient(s) A total of 209 consecutive infertile patients (mean ± SD age, 38.4 ± 4 years; range, 28–47 years) undergoing 238 natural IVF/minimal ovarian stimulation cycles during 2012–2014. Intervention(s) Minimal ovarian stimulation, oocyte retrieval, fertilization with standard IVF or ICSI, prolonged embryo culture in a time-lapse monitoring incubator. Main Outcome Measure(s) Differences in morphokinetic parameters according to insemination techniques. Result(s) In total, 29% and 71% of the whole cohort was fertilized with standard IVF and ICSI, respectively. During early cleavage stages (PNf to t4) there was a statistically significant delay (+1.5 to +1.1 hours) among IVF-fertilized embryos. By contrast, at the expanded blastocyst stage IVF-fertilized embryos showed faster development (−3.3 to −4.1 hours). After normalizing to the time point of PNf, differences in cleavage-stage parameters disappeared, but those at all blastocyst stages increased even further in favor of IVF-fertilized embryos (−3.2 to −5.7 hours). Conclusion(s) The observed 1.5-hour time difference between standard IVF- and ICSI-fertilized embryos is an artificial phenomenon. At the blastocyst stages, however, genuine timing differences arise between IVF- and ICSI-fertilized embryos, possibly related to their different quality. Normalization to a common time point permits the joint analysis of IVF- and ICSI-fertilized embryos, thus increasing the size of studied cohorts.

A 29-year-old male was admitted because of thrombocytopenia. A diagnosis of acute lymphoblastic leukaemia was made on the basis of a 61.6% infiltration of leukemic cells in his bone marrow. Standard G-binding chromosome analysis of bone marrow cells revealed a normal karyotype. He received combination chemotherapy, and achieved hematological complete remission. However, chromosomal analysis of bone marrow cells after 2 courses of consolidation therapy showed the Philadelphia (Ph) chromosome in two cells out of 20 analysed. We retrospectively examined the sample of bone marrow cells before chemotherapy; It showed minor BCR/ABL positivity with FISH and RT-PCR methods. The Ph chromosome disappeared after consolidation chemotherapy and allogeneic bone marrow transplantation, but the Ph chromosome reappeared at relapse. We postulated that there were two clones, both a Ph-positive clone and Ph-negative clone. At the initial diagnosis, Ph chromosome was not detected because the G-banding method analyzed only metaphase cells, which contained few Ph-positive clones. In order to offer effective therapy with molecular targeting agents, in this poor prognostic disease, it is necessary to detect Ph chromosome before the first chemotherapy and BCR/ABL detection with FISH or RT-PCR methods appears more useful than G-banding chromosome analysis.

Bouin's or a 10% formalin solution has been used to fixate internal fetal observations for developmental toxicity studies in rats. However, these fixatives are known to cause contraction of the ventricle of the heart and arteries, which makes dissection and observation more difficult. Fetuses on day 20 of gestation from pregnant Crj:CD(SD)IGS rats were injected with 10 w/v% magnesium chloride/10 vol% neutral buffered formalin solution into the thoracic cavity, and then fixed in 10 vol% neutral buffered formalin. After fixation, the heart was dissected using a modified Staples technique. In treated fetuses, the membranous region of the ventricular septum and the valves were clearly observed in an expanded state. We conclude that this method increases the ability to detect heart anomalies and decreases the chance of a false-positive finding.

A 59-year-old woman, diagnosed with chronic myelogenous leukemia (chronic phase) and treated with interferon-α for 13 years, developed renal failure. Renal biopsy showed thrombotic thrombocytopenic purpura, but intensive therapy including plasma exchange and steroid administration was not effective. The activity of von Willebrand factor-cleaving protease was detectable at the intermediate level (15–46%) during the clinical course, suggesting that this case was not compatible with the previously reported pattern of idiopathic or drug-induced thrombotic thrombocytopenic purpura, but with the pattern associated with malignant disease or immunological disorders. Further studies to determine the effects of interferon-α on endothelial cells in chronic myelogenous leukemia patients are needed.

A 43-year-old man presented with gastrointestinal bleeding. A tumor with central ulceration was observed in the jejunum, with the use of a new enteroscopy system called “double-balloon enteroscopy”. Bleeding after biopsy sampling of the tumor was controlled endoscopically by using electrocoagulation. Histological findings of the biopsy specimens were consistent with gastrointestinal stromal tumor, and this was surgically resected. Double-balloon enteroscopy was useful for the diagnosis as well as the control of bleeding in this patient.

This study explores so-called Darwinian Daisyworlds mathematically rigorously in detail. The original Daisyworld was introduced by Watson & Lovelock (1983) to demonstrate how two species of daisies regulate the global temperature of their planet through competition among these species against the rising solar luminosity, i.e. the Gaia hypothesis. Its variants are Darwinian Daisyworlds in which daisies can adapt themselves to the local temperature. Robertson & Robinson (1998) insist their Darwinian daisies lose the ability for temperature regulation on the basis of their spreadsheet simulations. Lenton & Lovelock (2000) point out that the constraints on adaptation recovers Darwinian daisies' ability of temperature regulation on the basis of their Euler-code simulations. The present study shows there exist the exact and closed-form solutions to these two Daisyworlds. The results contradict the former studies: Robertson and Robinson's daisies do regulate the global temperature even longer than non-adaptive daisies; Lenton and Lovelock's daisies are less adaptive than Robertson and Robinson's daisies because of the constraints on adaptation; the introduction of weak adaptability drives species into a dead end of evolution. Thus, the present results confirm that the Gaia hypothesis and Darwinian evolution can coexist.

Peripheral blood and bone marrow analysis of a 79-year-old female led to a diagnosis of acute myeloblastic leukemia with differentiation (AML-M2). Chromosome analysis of the unstimulated bone marrow cells revealed 48, XX,+21,+21, and tetrasomy 21 was the sole cytogenetic abnormality in this constitutionally normal female patient.

t(8;21) is one of the common chromosomal translocations in acute myelogenous leukemia (AML). Using a recently developed real-time quantitative polymerase chain reaction (PCR) system, we analyzed the minimal residual disease (MRD) in bone marrow samples from seven AML patients with t(8;21) at different time points during the clinical courses of their disease. Four of these patients received chemotherapy and allogenic bone marrow transplantation (allo-BMT), and the other three were treated with chemotherapy alone. Two of the patients that received allo-BMT suffered a relapse. In these patients, the levels of AML1-MTG8 mRNA expression were shown to quantitatively increase. After re-induction chemotherapy and donor lymphocyte infusion therapy, AML went into remission and the expression levels decreased. In the other two patients receiving allo-BMT, the disease went into remission and the level of AML1-MTG8 mRNA expression remained under the detectable range. The other three patients received several courses of chemotherapy, without allo-BMT, and all of them clinically reached the hematological and cytogenetic remission state. However, there were low but detectable levels of MRD in their bone marrow samples. These results suggest that the real-time quantitative PCR assay is very useful for the monitoring of MRD and detecting an early relapse. This assay may also be useful in determining the quantitative difference in myelo-ablative activity between the chemotherapy alone and chemotherapy in conjunction with allo-BMT.

We measured serum soluble Fas ligand (sFasL) in a patient with natural killer cell lymphoma, and investigated relationship between sFasL and liver dysfunction. An elevated level of sFasL was decreased after local radiation therapy, and liver function improved. When lymphoma relapsed, liver dysfunction reappeared and the level of sFasL increased parallelly. Lymphoma cells expressed mRNA of FasL. This suggested that this liver dysfunction was induced by some remote effectors, and sFasL was one of candidates of these effectors. Am. J. Hematol. 62:253‐255, 1999. © 1999 Wiley-Liss, Inc.

Exchanging ideas and concepts among people can be handled with by so-called Synergetic Inter-Representation Network, which is described by n -dimensional ordinary differential equations with cubic nonlinearity. The novel find is the fact that the basic equation set is transformed to a set of n -dimensional Lotka-Volterra equations. This discovery allows us to scrutinize the existence and stability of the fixed points: (1) The origin is an unstable fixed point; (2) The single representation survival, for example (0, 0, …, λj/C, …, 0), is a stable fixed point; (3) The coexistence of several representations exists as a saddle point. If all of these exist, the number of the saddle points is 2n – n – 1. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

This study presents a concise mathematical model that accounts for sea-anchor soaring, a special flight technique used by sea birds, in particular storm petrels. Conventional wing theory is used to reveal the mechanics of sea-anchor soaring. The feasibility and existence of an equilibrium are summarized by formulae giving the wind velocity criteria. The stability of the equilibrium is also revealed: among two possible equilibria, the equilibrium at the very low velocity to water is shown to be stable. Numerical examples show the following: sea-anchor soaring is almost always stable; Wilson's storm petrel can soar at 0.256 ms-1 in wind with 4.79 ms-1 under the best conditions. Larger sea-birds like albatrosses need gusty winds to soar, but such strong winds make the sea choppy and hence prevent soaring. Foot-web size regulates the size of a bird utilizing sea-anchor soaring at low velocities to water.Copyright 1998 Academic Press Limited

Snipes are known to exhibit peculiar display flights. They generate sounds by flattering outer tail feathers as they dive. Most snipes are almost identical. But one can tell them in the hand, because the number of tail feathers differs among species. This means the sound made by tail feathers also differs among species. This study treats Latham's Snipe Gallinago hardwickii. Measurements and analysis reveals the geometry and configuration of outer tail feathers accounts for the feature in sound spectrum of their aerial drumming.

This is the first report of complex bifurcation and manyfold hysteresis phenomena in the physics behind a pair of sails set in a flow of two dimensions. The formalism is based on inviscid vorticity theory, and the basic equations consist of a pair of integro-differential equations subject to a pair of nonlinear integral constraints. The method of solution is built up with the boundary element method for the integro-differential equations as well as the Newton–Raphson method for parameter search by use of the nonlinear integral constraints. Three types of configurations are considered as case studies on effects due to overlapping of the jib sail upon the main sail. Numerical analyses predict three sets of solutions: The convex-convex sail shapes, the concave-convex sail shapes, and the concave-concave sail shapes as well as two- or threefold hysteresis in aerodynamic and structural characteristics. Experimental observations confirm the existence of all the three solution sets, and moreover another set, the...

Introduction Suppression of Bcl-2 expression can overcome cellular resistance to apoptosis induced by the adenovirus type 5 gene E1A in models of ovarian and breast cancer. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, is known to downregulate Bcl-2 expression. We hypothesized that celecoxib would enhance E1A-induced apoptosis by suppressing Bcl-2 through suppressing COX-2 expression. If successful, this strategy could represent a means of overcoming resistance to E1A gene therapy. Methods We first established the cytotoxicity of celecoxib in two COX-2-overexpressing E1A-transfected breast cancer cell lines (MDA-MB-231 and MDA-MB-435) and in two low-COX-2-expressing E1A-transfected cell lines (MCF-7 (breast cancer) and SKOV3.ip1 (ovarian cancer)). We next tested whether higher sensitivity to celecoxib among these cell lines resulted from increased apoptosis by flow cytometry and western blotting. We further investigated whether suppression of Bcl-2 by celecoxib was involved in the apoptosis resulting from celecoxib treatment, and we explored whether the celecoxib-induced apoptosis in these cells depends on a COX-2 downstream pathway. Results The two COX-2-overexpressing cell lines MDA-MB-231-E1A and MDA-MB-435-E1A were more sensitive to celecoxib than the corresponding control cells, but the two low-COX-2-expressing cell lines MCF-7-E1A and SKOV3.ip1-E1A were no more sensitive than control cells to celecoxib. Therefore, we used the MDA-MB-231-E1A and MDA-MB-435-E1A cells for all further experiments. In both cell lines, sub-G1 fraction was increased, or cleavage of PARP and caspase-9 were increased after 5 days of exposure to 40 μM celecoxib. However, Bcl-2 was suppressed only in the MDA-MB-435-E1A cells and not in the MDA-MB-231-E1A cells. Restoring Bcl-2 expression in the MDA-MB-435-E1A stable transfectants did not affect their sensitivity to celecoxib. However, adding prostaglandin E2 (PGE2) or PGF2α blunted the sensitivity to celecoxib of both E1A stable transfectants. Conclusion We speculate that one mechanism by which celecoxib enhances E1A-induced apoptosis in cells that express high levels of COX-2 is through blocking PGE2 or PGF2α.

In Ph+ leukemia, the breakpoints within BCR cluster in 3 distinct breakpoint cluster regions (bcr). Rearrangements in the minor (m−), major (M−) and micro (m−) breakpoint cluster region (bcr) give rise to e1a2, e13/14a2 and e19a2 BCR-ABL fusion proteins that are associated with Ph+ ALL, CML and chronic neutrophilic leukemia, respectively. Atypical BCR-ABL fusions have also been reported, mostly in isolated cases. Here, we describe eight patients with an unusual e8a2 BCR-ABL transcript and provide an overview of their common characteristics. The index case (#1) was a 56 year old man diagnosed with CML in 1993. Therapy with busulfan and hydrea induced a complete hematologic remission (CHR) that was maintained until March 2001, when accelerated disease developed. Treatment with imatinib and subsequently AML-type chemotherapy were only transiently effective and the patient died from myeloid blast crisis in March 2003. Cytogenetics demonstrated a standard t(9;22)(q34;q11). Unexpectedly, FISH was consistent with an m-bcr rearrangement and multiplex PCR showed an unusually large band. Sequencing identified a fusion between BCR exon e8 and ABL exon a2, with a 55 bp insert corresponding to an inverted segment of ABL intron Ib (corresponding to nt 29861–29915, Genbank U07561). Immunoblotting of bone marrow mononuclear cells with anti-ABL antibody identified a 200 kDa protein (p200BCR-ABL). Seven additional patients with an e8a2 BCR-ABL fusion have been identified (table 1). These patients tend to have relatively high platelet counts (median 569 x 109/L, range 216 – 1123) and relatively low white counts (median 42 x 109/L, range 4.7 – 146) but no other distinguishing characteristics at diagnosis. With a median follow-up of 36 months (range, 4 –97), two patients had progressed to blast crisis and died, one died from an unrelated cause, and five were alive, one after allogeneic BMT. Remarkably, none of the patients treated with interferon-a achieved even a minor cytogenetic remission, similar to patients with p190-positive CML. Two patients besides case #1 have received imatinib, one has achieved a CHR at four months, and information on the other is not available. Compared to P190 and P210, p200 lacks the pleckstrin homology (PH) domain but retains the Dbl-like and CDC24 homology domains of BCR. Deletion of the PH domain may disrupt the function of the Dbl-like domain to serve as a GTP exchange factor for Rac, Cdc42 and Rho. This may lead to disruption of the actin cytoskeleton and would be expected to cause a disease that is biologically closer to p190 than to p210.