Intentional gaze shift to neglected space: a compensatory strategy during recovery after unilateral spatial neglect.

Unilateral spatial neglect is a common neurological syndrome following predominantly right hemispheric stroke. While most patients lack insight into their neglect behaviour and do not initiate compensatory behaviours in the early recovery phase, some patients recognize it and start to pay attention towards the neglected space. We aimed to characterize visual attention capacity in patients with unilateral spatial neglect with specific focus on cortical processes underlying compensatory gaze shift towards the neglected space during the recovery process. Based on the Behavioural Inattention Test score and presence or absence of experience of neglect in their daily life from stroke onset to the enrolment date, participants were divided into USN+‰‰+ (do not compensate, n = 15), USN+ (compensate, n = 10), and right hemisphere damage groups (no neglect, n = 24). The patients participated in eye pursuit-based choice reaction tasks and were asked to pursue one of five horizontally located circular objects flashed on a computer display. The task consisted of 25 trials with 4-s intervals, and the order of highlighted objects was randomly determined. From the recorded eye tracking data, eye movement onset and gaze shift were calculated. To elucidate the cortical mechanism underlying behavioural results, electroencephalagram activities were recorded in three USN+‰‰+, 13 USN+ and eight patients with right hemisphere damage. We found that while lower Behavioural Inattention Test scoring patients (USN+‰‰+) showed gaze shift to non-neglected space, some higher scoring patients (USN+) showed clear leftward gaze shift at visual stimuli onset. Moreover, we found a significant correlation between Behavioural Inattention Test score and gaze shift extent in the unilateral spatial neglect group (r = -0.62, P < 0.01). Electroencephalography data clearly demonstrated that the extent of increase in theta power in the frontal cortex strongly correlated with the leftward gaze shift extent in the USN+‰‰+ and USN+ groups. Our results revealed a compensatory strategy (continuous attention to the neglected space) and its neural correlates in patients with unilateral spatial neglect. In conclusion, patients with unilateral spatial neglect who recognized their own neglect behaviour intentionally focused on the neglected space as a compensatory strategy to avoid careless oversight.

Interleukin enhancer-binding factor 3/NF110 is a target of YM155, a suppressant of survivin.

Survivin is responsible for cancer progression and drug resistance in many types of cancer. YM155 selectively suppresses the expression of survivin and induces apoptosis in cancer cells in vitro and in vivo. However, the mechanism underlying these effects of YM155 is unknown. Here, we show that a transcription factor, interleukin enhancer-binding factor 3 (ILF3)/NF110, is a direct binding target of YM155. The enhanced survivin promoter activity by overexpression of ILF3/NF110 was attenuated by YM155 in a concentration-dependent manner, suggesting that ILF3/NF110 is the physiological target through which YM155 mediates survivin suppression. The results also show that the unique C-terminal region of ILF3/NF110 is important for promoting survivin expression and for high affinity binding to YM155.

Synergistic antitumor activities of sepantronium bromide (YM155), a survivin suppressant, in combination with microtubule-targeting agents in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) has a poor prognosis compared to other subtypes, and effective treatment options are limited to cytotoxic agents, including microtubule-targeting agents, due to the lack of molecular targets. Here, we examined the combined effect of sepantronium bromide (YM155) and microtubule-targeting agents in TNBC models. The combination of YM155 with docetaxel showed synergistic antiproliferative and caspase 3/7-inducing effects in MRK-nu-1 and MDA-MB-453 human TNBC cell lines in vitro. YM155 also synergistically enhanced the efficacies of other microtubule-targeting agents, including paclitaxel and vinorelbine, which induced accumulation of survivin at the G2/M phase, whereas it did not affect the efficacy of doxorubicin. Combination treatment with YM155 and microtubule-targeting agents decreased the accumulation of survivin at the G2/M phase and induced greater apoptosis than either single agent alone. Further, combination treatment with YM155 and docetaxel also had a synergistic antitumor effect, achieving complete regression without exacerbation of body weight loss in all mice, in a MRK-nu-1 human TNBC xenograft model. These results suggest that survivin inhibition synergistically sensitize human TNBC cells to microtubule-targeting agents.

Pre-exercise isomaltulose intake affects carbohydrate oxidation reduction during endurance exercise and maximal power output in the subsequent Wingate test.

BACKGROUND: Ingestion of low-glycemic index (GI) isomaltulose (ISO) not only suppresses subsequent carbohydrate (CHO) oxidation but also inversely retains more CHO after prolonged endurance exercise. Therefore, ISO intake may affect anaerobic power output after prolonged endurance exercise. This study aimed to clarify the time course of CHO utilization during endurance exercise after a single intake of ISO or sucrose (SUC) and the anaerobic power output at the end of endurance exercise. METHODS: After an intake of either ISO or SUC, 13 athletes were kept at rest for 60 min. Thereafter, they performed a 90-min of treadmill running at their individual target level of % [Formula: see text]max. During the experimental session, the expired gas was recorded, and the energy expenditure (EE) and CHO oxidation rate were estimated. Immediately after 90 min of running, a 30-s Wingate test was performed, and the maximal anaerobic power output was compared between the ISO and SUC conditions. RESULTS: The percentage of CHO-derived EE increased rapidly after CHO intake and then decreased gradually throughout the experiment. The slopes of the regression lines calculated from the time course in the CHO-derived EE were significantly (negatively) larger in the SUC condition (-19.4 ± 9.6 [%/h]) than in the ISO condition (-13.3 ± 7.5 [%/h]). Furthermore, the maximal power output in the Wingate test immediately after the endurance exercise was significantly higher in the ISO condition than in the SUC condition (peak power: 12.0 ± 0.6 vs. 11.5 ± 0.9 [W/kg]). CONCLUSION: Compared with SUC intake, ISO intake does not produce an abrupt decline in the percentage of CHO-derived EE during prolonged endurance exercise; it remains relatively high until the final exercise phase. Additionally, anaerobic power output at the end of the exercise, largely contributed by anaerobic glycolysis, was greater after ISO intake than after SUC intake.

Sepantronium bromide (YM155) induces disruption of the ILF3/p54(nrb) complex, which is required for survivin expression.

YM155, a small-molecule survivin suppressant, specifically binds to the transcription factor ILF3, which regulates the expression of survivin[1]. In this experiment we have demonstrated that p54(nrb) binds to the survivin promoter and regulates survivin expression. p54(nrb) forms a complex with ILF3, which directly binds to YM155. YM155 induces disruption of the ILF3/p54(nrb) complex, which results in a different subcellular localization between ILF3 and p54(nrb). Thus, identification of molecular targets of YM155 in suppression of the survivin pathway, might lead to development of its use as a novel potential target in cancers.

Sepantronium bromide (YM155) enhances response of human B-cell non-Hodgkin lymphoma to rituximab.

In the treatment of B-cell non-Hodgkin lymphoma (B-NHL) rituximab improves long-term survival in combination with conventional chemotherapy. However, because the majority of patients with B-NHL eventually relapse, the development of more effective therapies is needed. Here, we evaluated the antitumor effects of a combination treatment involving sepantronium bromide (YM155), a first-in-class survivin suppressant, and rituximab in B-NHL xenograft mice models. To determine the efficacy of the combination treatment, YM155- and rituximab-treated B-NHL cell xenografted mice were monitored for tumor size and survival and subjected to 2'-deoxy-2'-(18)F-fluoro-D-glucose ((18)F-FDG) and 3'-(18)F-fluoro-3'-deoxythymidine ((18)F-FLT) positron emission tomography (PET) imaging. In addition, the cell proliferation status of excised tumors was examined by Ki-67 immunohistochemistry. In DB, WSU-DLCL-2, and Mino xenograft-bearing mice, the combination treatment of YM155 and rituximab induced significant tumor growth inhibition and tumor regression compared with either single agent. On day 3 after the initiation of treatment a significant decrease in both (18)F-FDG and (18)F-FLT tumor uptake from pretreatment levels was observed in combination treatment groups. The Ki-67 proliferation index was significantly decreased on day 3 in the xenograft models treated with combination treatment, suggesting that the combination of YM155 and rituximab reduced cell proliferation and glucose metabolism. Furthermore, compared with monotherapy, combination treatment prolonged survival times of severe combined immunodeficient mice with disseminated WSU-FSCCL and Jeko B-NHL tumors. Our findings demonstrate that YM155 and rituximab combination treatment enhances antitumor activity in B-NHL xenografts, and (18)F-FLT and (18)F-FDG PET imaging may allow the early functional evaluation of treatment responses in patients with B-NHL.

Broad spectrum and potent antitumor activities of YM155, a novel small-molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models.

Antitumor activities of YM155, a novel small-molecule survivin suppressant, were investigated in a wide variety of human cancer cell lines and xenograft models. YM155 inhibited the growth of 119 human cancer cell lines, with the greatest activity in lines derived from non-Hodgkin's lymphoma, hormone-refractory prostate cancer, ovarian cancer, sarcoma, non-small-cell lung cancer, breast cancer, leukemia and melanoma. The mean log growth inhibition of 50% (GI(50) ) value was 15 nM. The mean GI(50) values of YM155 were 11 nM for p53 mut/null cell lines and 16 nM for p53 WT cell lines, suggesting that YM155 inhibits the growth of human tumor cell lines regardless of their p53 status. In non-small-cell lung cancer (Calu 6, NCI-H358), melanoma (A375), breast cancer (MDA-MB-231) and bladder cancer (UM-UC-3) xenograft models, 3- or 7-day continuous infusions of YM155 (1-10 mg/kg) demonstrated significant antitumor activity without showing significant bodyweight loss. Tumor regressions induced by YM155 were associated with reduced intratumoral survivin expression levels, increased apoptosis and decreased mitotic indices. The broad and potent antitumor activity presented in the present study is indicative of the therapeutic potential of YM155 in the clinical setting.

YM155, a novel survivin suppressant, enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model.

Survivin, an apoptotic inhibitor, is overexpressed in the majority of human tumor types and represents a novel target for anticancer therapy. Taxanes induce a mitotic cell-cycle block through the inhibition of microtubule depolymerization, with subsequent elevated expression/stabilization of survivin. We investigated the administration of survivin suppressant YM155 monobromide (YM155), in combination with docetaxel, in a human non-small-cell lung cancer (NSCLC) xenograft model. Animals received a 7-day continuous infusion of YM155, 2 mg/kg, and/or three bolus doses of docetaxel, 20 mg/kg, according to three dosing schedules: YM155 administered concomitantly with docetaxel, before docetaxel, and after docetaxel. YM155 administered either concomitantly with or before docetaxel showed significant antitumor activity (tumor regression ≥ 99%), with complete regression of the established human NSCLC-derived tumors in mice (eight of eight and seven of eight animals, respectively). Significantly fewer complete responses (three of eight animals) were achieved when YM155 was administered after docetaxel. No statistically significant decreases in body weight were observed in the combination versus docetaxel groups. YM155 administered concomitantly with docetaxel resulted in significant decreases in mitotic and proliferative indices, and in a significant increase in the apoptosis index. Elevated survivin expression was seen in tumors from mice treated with docetaxel alone; a significant reduction in survivin expression was seen in tumors from mice treated with YM155 alone or in combination with docetaxel, but not in the control group. These results indicate that in a human NSCLC xenograft model YM155 in combination with docetaxel diminished the accumulation of survivin by docetaxel and induced more intense apoptosis and enhanced antitumor activity, compared with single-agent YM155 or docetaxel.

Acquisition of novel ball-related skills associated with sports experience.

Some individuals can quickly acquire novel motor skills, while others take longer. This study aimed to investigate the relationships between neurophysiological state, sports experience, and novel ball-related skill acquisition. We enrolled 28 healthy collegiate participants. The participants' neurophysiological data (input-output curve of the corticospinal tract) were recorded through transcranial magnetic stimulation. Subsequently, the participants performed a novel motor task (unilateral two-ball juggling) on a different day, after which they reported their previous sports experience (types and years). We found that individuals with more years of experience in ball sports showed faster acquisition of novel ball-related skills. Further, this result was not limited to any single ball sport. Therefore, the acquisition of novel ball-related skills is associated with familiarity with a ball's nature. Furthermore, gain of the corticospinal tract was negatively and positively correlated with the years of experience in primary ball and non-ball sports (implemented for the longest time in individuals), respectively. These results could be associated with the extent of proficiency in their primary sport. The chosen type of sports (e.g., ball or non-ball) could critically influence the future acquisition of novel motor skills. This study provides important insights regarding how to approach sports and physical activities.

Helical springs as a color indicator for determining chirality and enantiomeric excess.

Chirality plays a key role in the physiological system, because molecular functionalities may drastically alter due to a change in chirality. We report herein a unique color indicator with a static helicity memory, which exhibits visible color changes in response to the chirality of chiral amines. A difference of less than 2% in the enantiomeric excess (ee) values causes a change in the absorption that is visible to the naked eyes. This was further quantified by digital photography by converting to RGB values. This system relies on the change in the tunable helical pitch of the π-conjugated polymer backbone in specific solvents and allows rapid on-site monitoring of chirality of nonracemic amines, including drugs, and the simultaneous quantitative determination of their ee values.

Single-trial EEG power and phase dynamics associated with voluntary response inhibition.

Human voluntary response inhibition has frequently been investigated using go/no-go RT tasks. Recent studies have indicated that not only the traditional averaging waveforms of EEG activities (ERPs) but also the power and phase dynamics of single-trial EEG are important in studying the neural correlates of various human cognitive functions. Therefore, here, we aimed to undertake a detailed study of the time/frequency power and phase dynamics of single-trial EEG during go/no-go RT tasks, with focus particularly on the no-go-specific power and phase dynamics, which are presumed to involve the voluntary response inhibition processes. Thus, we demonstrated no-go-specific theta band EEG power increases and intertrial phase-locking in the midline-frontal areas, which are related to no-go-specific midline-frontal negative-positive ERP waveforms (no-go N2/no-go P3). In addition, we observed no-go-specific alpha band EEG intertrial phase-locking with an adjacent dephasing phenomenon, which is mainly associated with the early part of no-go N2. The estimated time point when the no-go-specific midline-frontal dephasing phenomenon occurred corresponded to the initial part of the voluntary response inhibition process (decision to withhold). Moreover, the no-go-specific phase dynamics in the midline-frontal areas just before and around the no-go N2 peak latency, unlike the power modulations, were affected by changes in the no-go stimulus probability, suggesting the dependence of only phase dynamics on no-go stimulus probability. From these results, we conclude that the complex power and phase dynamics of the theta and alpha band EEG in the midline-frontal areas are specific to no-go trials, being the underlying bases of the no-go-specific ERP waveforms, and suggest that the phase dynamics just before and around the no-go N2 peak latency may involve, at least, the initial part of the voluntary response inhibition process (decision to withhold).

A generalized method to estimate waveforms common across trials from EEGs.

We propose a generalized method to estimate waveforms common across trials from electroencephalographic (EEG) data. From single/multi-channel EEGs, the proposed method estimates the number of waveforms common across trials, their delays in individual trials, and all of the waveforms. After verifying the performance of this method by a number of simulation tests with artificial EEGs, we apply it to EEGs during a Go/NoGo task. This method can be used in general situations where the number and the delays of EEG waveforms common across trials are unknown.

Radiosensitizing effect of YM155, a novel small-molecule survivin suppressant, in non-small cell lung cancer cell lines.

PURPOSE: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effect of YM155, a small-molecule inhibitor of survivin expression, on the sensitivity of human non-small cell lung cancer (NSCLC) cell lines to gamma-radiation. EXPERIMENTAL DESIGN: The radiosensitizing effect of YM155 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced DNA damage was evaluated on the basis of histone H2AX phosphorylation and foci formation. RESULTS: YM155 induced down-regulation of survivin expression in NSCLC cells in a concentration- and time-dependent manner. A clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to gamma-radiation in vitro. The combination of YM155 and gamma-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone gamma-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and gamma-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone. CONCLUSIONS: These results suggest that YM155 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of YM155 is likely attributable, at least in part, to the inhibition of DNA repair and enhancement of apoptosis that result from the down-regulation of survivin expression. Combined treatment with YM155 and radiation warrants investigation in clinical trials as a potential anticancer strategy.

YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts.

Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2-related proteins. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations approximately 20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach.

Predicting response to sepantronium bromide (YM155), a survivin suppressant, by PET imaging with [11C]YM155.

INTRODUCTION: Sepantronium bromide (YM155) is a survivin suppressant that induces apoptosis in tumor cells. Although YM155 induces tumor regression in various tumor types in vivo, phase I and II studies demonstrated responding and non-responding patient populations. We investigated 11C-labeled YM155 ([11C]YM155) used as a positron emission tomography (PET) tracer to assess whether tumor uptake of [11C]YM155 correlated with its anti-tumor effect, thereby allowing identification of patients who would respond to YM155 treatment. METHODS: (1) Uptake of YM155 was measured in 39 human cancer cell lines in vitro using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). (2) In vivo tumor uptake was assessed in xenografted mice and total body distribution was evaluated in a cynomolgus monkey using [11C]YM155 with PET/computed tomography (CT) (mice) and PET (monkey) imaging. RESULTS: Intracellular uptake of YM155 in human cancer cell lines correlated well with its in vitro efficacy measured by GI50 (Pearson's r = -0.5709). Similarly, in vivo studies using tumor xenografted mice showed that tumors sensitive to YM155 demonstrated robust uptake of [11C]YM155, whereas insensitive tumors demonstrated low uptake. In the monkey, the biodistribution of [11C]YM155 indicated low accumulation in lung, breast, head, and neck and was only significant in organs involved with drug clearance: i.e. liver, kidneys, and bladder. CONCLUSIONS: Robust uptake of [11C]YM155 by a tumor appears to be a positive predictive marker for a good response to YM155. The findings suggest the potential utility of PET/CT imaging with [11C]YM155 for selection of patients whose tumors are likely to respond to YM155. ADVANCES IN KNOWLEDGE: YM155 efficacy correlated closely with its in vitro intracellular uptake and uptake on [11C]YM155 PET imaging. [11C]YM155 PET may predict tumor sensitivity to YM155. IMPLICATIONS FOR PATIENT CARE: The concept that tumor response can be accurately predicted prior to chemotherapy should be exploited to improve cancer treatment outcomes through judicious patient selection. The small molecule sepantronium bromide (YM155), a survivin suppressant, has been developed for the treatment of several cancers, including non-Hodgkin lymphoma, lung cancer, and breast cancer. The preferentially high in vitro uptake of YM155 by YM155-sensitive cancer cells and the high in vivo uptake of [11C]YM155 in YM155-sensitive tumors demonstrated by PET imaging suggest the potential utility of performing [11C]YM155 PET to allow the identification of patients with YM155-sensitive tumors.

Relationships between Psychophysiological Responses to Cycling Exercise and Post-Exercise Self-Efficacy.

Although self-efficacy (SE) is an important determinant of regular exercise, it is unclear how subjective and physiological states before, during, and after the exercise session affects post-exercise SE. The aim of this study was to clarify subjective and physiological factors affecting post-exercise SE assessed after a single exercise session at a physiologically equivalent level. Forty-three healthy volunteers (28 women, 15 men) completed an 82-min experimental session, comprising a 22-min pre-exercise rest, a 30-min steady-state cycling exercise at moderate intensity [40% of heart rate (HR) reserve], and a 30-min post-exercise rest. We measured physiological (HR) and subjective [Rating of Perceived Exertion (RPE), Feeling Scale (FS)] states during the experimental session. Autonomic states were assessed by power spectral analysis of heart rate variability (HRV) during pre- and post-exercise rest. Post-exercise SE, which was the participants' confidence in their ability to perform the 30-min exercise that they had just performed, was assessed at 30-min post-exercise. A stepwise multiple regression analysis, with post-exercise SE as the dependent variable and physiological and subjective measures of the exercise as candidate explanatory variables, showed that post-exercise SE was negatively correlated with RPE and positively correlated with FS at the end of the 30-min exercise. In addition, post-exercise SE was negatively correlated with high-frequency power of the post-exercise HRV, an index of parasympathetic function. These results indicate that post-exercise SE is related not only to subjective responses to the exercise but also to autonomic response after the exercise.

Facilitation of both stretch reflex and corticospinal pathways of the tibialis anterior muscle during standing in humans.

Excitability of both stretch reflex (SR) and motor evoked potential (MEP) elicited in the tibialis anterior (TA) muscle by transcranial magnetic stimulation were tested in standing humans. The results demonstrated significantly greater values for both SR and MEP in the TA while standing than while in the supine posture, although background electromyographic activity was silent in the two conditions. Taken together with previous reports that both pathways are facilitated in the TA at the early stance phase of human walking, our findings suggest that a common neural mechanism underlies both observations, one that might be functionally relevant for securing ankle joint stabilization during upright standing.

Revealing time-unlocked brain activity from MEG measurements by common waveform estimation.

Brain activities related to cognitive functions, such as attention, occur with unknown and variable delays after stimulus onsets. Recently, we proposed a method (Common Waveform Estimation, CWE) that could extract such brain activities from magnetoencephalography (MEG) or electroencephalography (EEG) measurements. CWE estimates spatiotemporal MEG/EEG patterns occurring with unknown and variable delays, referred to here as unlocked waveforms, without hypotheses about their shapes. The purpose of this study is to demonstrate the usefulness of CWE for cognitive neuroscience. For this purpose, we show procedures to estimate unlocked waveforms using CWE and to examine their role. We applied CWE to the MEG epochs during Go trials of a visual Go/NoGo task. This revealed unlocked waveforms with interesting properties, specifically large alpha oscillations around the temporal areas. To examine the role of the unlocked waveform, we attempted to estimate the strength of the brain activity of the unlocked waveform in various conditions. We made a spatial filter to extract the component reflecting the brain activity of the unlocked waveform, applied this spatial filter to MEG data under different conditions (a passive viewing, a simple reaction time, and Go/NoGo tasks), and calculated the powers of the extracted components. Comparing the powers across these conditions suggests that the unlocked waveforms may reflect the inhibition of the task-irrelevant activities in the temporal regions while the subject attends to the visual stimulus. Our results demonstrate that CWE is a potential tool for revealing new findings of cognitive brain functions without any hypothesis in advance.

Combination of YM155, a survivin suppressant, with bendamustine and rituximab: a new combination therapy to treat relapsed/refractory diffuse large B-cell lymphoma.

PURPOSE: There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to evaluate the therapeutic potential of sepantronium bromide (YM155), a survivin suppressant, in combination with either bendamustine or both bendamustine and rituximab using DLBCL models. EXPERIMENTAL DESIGN: Human DLBCL cell lines, DB, SU-DHL-8, and WSU-DLCL2, were treated with YM155 in combination with bendamustine. Cell viability, apoptosis induction, protein expression, and cell-cycle distribution were evaluated. Furthermore, antitumor activities of YM155, in combination with bendamustine or both bendamustine and rituximab, were evaluated in mice bearing human DLBCL xenografts. RESULTS: The combination of YM155 with bendamustine showed greater cell growth inhibition and sub-G1 population than either agent alone. YM155 inhibited bendamustine-induced activation of the ATM pathway and accumulation of survivin at G2-M phase, with greater DNA damage and apoptosis than either single agent alone. In a DLBCL DB murine xenograft model, YM155 enhanced the antitumor activity of bendamustine, resulting in complete tumor regression without affecting body weight. Furthermore, YM155 combined with bendamustine and rituximab, decreased FLT-PET signals in lymph nodes and prolonged overall survival of mice bearing disseminated SU-DHL-8, an activated B-cell-like (ABC)-DLBCL xenografts when compared with the combination of either rituximab and bendamustine or YM155 with rituximab. CONCLUSIONS: These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL.