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The purpose of this study was to investigate the optimal b values required for the generation of computed high-b-value DW images.Brain DWI was performed for eight subjects using 16 b values, ranging from 0 s/mm(2) to 5000 s/mm(2). The fractional value as the turning point between the fast and slow components was determined using a diffusion decay curve. Image contrast in the white matter, gray matter, thalamus, putamen, and lateral ventricle was compared between the acquired high-b-value images and the computed high-b-value images derived from various b value images. In addition, the signal-to-noise ratio of each computed image and acquired image was measured and compared.The fractional values obtained from the diffusion decay curve were between 1200 and 1800 s/mm(2). Image contrast in all regions was nearly equivalent between the acquired and computed high-b-value images when b values higher than the fractional value were used, whereas image contrast was significantly different between the two sets of images when b values lower than the fractional value were used (p0.05). The computed images derived from low-b-value images showed a higher signal-to-noise ratio, compared with the acquired images.Optimal b values should be considered when acquiring images for the derivation of computed DW images.

A movable optical lens array that uses acoustic radiation force was investigated. The lens array consists of a glass plate, two piezoelectric bimorph transducers, and a transparent viscoelastic gel film. A flexural vibration with a wavelength of approximately 9 mm was generated along the glass plate in the length direction at a frequency of 113 kHz. A cylindrical lens array with a lens pitch of 4.6 mm was fabricated using the acoustic radiation force that was generated by the flexural vibration of the glass plate. The focal point of the lens array can be changed by varying the input voltage. The flexural vibration distribution can be changed by varying the driving phase difference between the two transducers, and the positions of the lenses can be shifted along the length direction of the glass plate. The translation property of this lens array was applied in an optical scanner. The transmitted light could be swept and the maximum angle of refraction was 4.9°.

A method to estimate orientation direction of liquid crystal molecules three-dimensionally under ultrasound excitation was proposed and the relationship between the ultrasound vibration and the molecular orientation was discussed. Our group have reported a technique to control orientation direction of liquid crystal molecules using ultrasound vibration which could be applied to an optical variable-focus liquid crystal lens. The lens consisted of a liquid crystal layer sandwiched by two glass circular discs and a piezoelectric ring. Ultrasound vibration induces change in the refractive index of the lens, enabling the variable-focus function. The three-dimensional orientation direction of the liquid crystal molecules in the lens was predicted from the transmitted light distributions under the crossed Nicol conditions. The liquid crystal molecules were inclined from vertical alignment by the ultrasound vibration, and larger ultrasound vibration gave larger inclination of the molecules. There was a strong correlation between the distributions of ultrasound vibration and the liquid crystal molecular orientation; the molecular orientation was changed remarkably between the antinodal and nodal parts of the ultrasound flexural vibration on the glass plate and the molecules aligned towards the antinode.

This paper investigates acoustic levitation and noncontact transportation techniques for use with planar objects. An acoustic levitation system was developed which consists of a 1-mm-thick and 400-mm-long bending plate along with two bolt-clamped Langevin-type transducers (BLTs) that have stepped horns. A plane reflector was installed parallel to the vibrating plate to generate an ultrasound standing wave between the reflector and the plate. The sound pressure distribution in the ultrasound waveguide was calculated via finite-element analysis to investigate the effects of levitation of a planar object in the standing-wave field. A 1-mm-thick polystyrene plate was levitated along the nodal line of the acoustic standing wave in the waveguide. By controlling the driving phase difference between the two BLTs, the position at which flexural vibration occurs on the vibrating plate could be shifted along the length direction, and the trapped planar object could be moved by 9 mm along the same direction when the phase difference was varied from 0° to 360°.

This paper investigated an ultrasound vibration cell patterning technique. The ultrasound cell culture dish consisted of a culture dish with a glass bottom and a glass disc with a piezoelectric ring that generated a resonance flexural vibration mode on the bottom of the dish. The growth of HeLa cells on the dish was observed under ultrasound excitation for 24 h. Large ultrasound vibrations on the dish inhibited the cell growth. The acoustic field was predicted with finite element analysis and it was found that the cell growth depended strongly on both the acoustic field in the culture medium and the vibration distribution of the dish. The ultrasound vibrations did not affect the viability of the cells, and the cell growth could be controlled by the flexural vibration of the cultured dish.

Dynamic contrast enhancement (DCE)-MRI has high diagnostic performance of prostate cancer. However, it is preferable to avoid the use of MRI contrast media. A study reported that the diagnosability of the wash-in index of DCE-MRI was equivalent to the intravoxel incoherent motion of the diffusion weighted image. The purpose of this study was to examine the correlation between the slow component apparent diffusion coefficient (ADC) and the wash-out index of the DCE.Thirty-eight patients diagnosed with prostate cancer by biopsy were enrolled in this study. The fast and slow component ADCs of the DWI were calculated for 76 points of the tumor and the contralateral normal parts. Furthermore, the wash-in and wash-out indices of the DCE-MRI were calculated. The correlations for each calculated index were compared.There was a significant difference between the tumor and the contralateral normal parts for both fast (p = 0.03) and slow component (p 0.01) ADCs. In addition, the slow component ADC was correlated with the wash-out index (r = 0.64).The slow component ADC was correlated with the wash-out index, and may, therefore, be a suitable substitute for DCE-MRI.

This paper investigated a cell patterning technique using ultrasound vibration. The ultrasound cell culture dish consisted of a culture dish with a glass bottom and a glass disc with an ultrasound transducer that generated a resonance flexural vibration mode on the bottom of the dish. HeLa cells were used as adhesives cells, and the growth of cells on the dish was observed under ultrasound excitation for 24 hours. The vibration amplitude was largest at the center of the dish, and the axisymmetric resonance flexural vibration mode with three concentric nodal circles and no nodal line was generated on the bottom of the dish. Large vibrations inhibited the cell growth. The distributions of the sound pressure amplitude and the acoustic radiation force in the culture medium were calculated with finite element analysis and it was found that the cell growth depended strongly on both the acoustic field in the culture medium and the vibration distribution of the dish. The ultrasound vibrations did not affect the viability of the cells, and the cell growth could be controlled by the flexural vibration of the cultured dish.This paper investigated a cell patterning technique using ultrasound vibration. The ultrasound cell culture dish consisted of a culture dish with a glass bottom and a glass disc with an ultrasound transducer that generated a resonance flexural vibration mode on the bottom of the dish. HeLa cells were used as adhesives cells, and the growth of cells on the dish was observed under ultrasound excitation for 24 hours. The vibration amplitude was largest at the center of the dish, and the axisymmetric resonance flexural vibration mode with three concentric nodal circles and no nodal line was generated on the bottom of the dish. Large vibrations inhibited the cell growth. The distributions of the sound pressure amplitude and the acoustic radiation force in the culture medium were calculated with finite element analysis and it was found that the cell growth depended strongly on both the acoustic field in the culture medium and the vibration distribution of the dish. The ultrasound vibrations did not affect the v...

This paper investigates acoustic levitation and noncontact transportation techniques for use with planar objects. An acoustic levitation system was developed that consists of a 1-mm-thick and 400-mm-long bending plate along with two bolt-clamped Langevin-type transducers (BLTs) that have stepped horns. A plane reflector was installed parallel to the vibrating plate to generate an ultrasound standing wave between the reflector and the plate. A planar object was levitated along the nodal line of the acoustic standing wave in the waveguide, and that affected the sound pressure distribution around the plate. The sound pressure distribution in the ultrasound waveguide was calculated via finite element analysis to investigate the effects of levitation of a planar object in the standing wave field. The (3, 1) resonance mode with a wavelength of approximately 15 mm in the x direction was excited in the air layer above and below the planar object. The acoustic field in the waveguide was sensitive to the length of the planar object, and several peaks occurred in the sound pressure amplitude when the half-wavelength resonance mode in the z direction was generated in the waveguide, indicating that there were suitable lengths of the plate for the acoustic levitation.This paper investigates acoustic levitation and noncontact transportation techniques for use with planar objects. An acoustic levitation system was developed that consists of a 1-mm-thick and 400-mm-long bending plate along with two bolt-clamped Langevin-type transducers (BLTs) that have stepped horns. A plane reflector was installed parallel to the vibrating plate to generate an ultrasound standing wave between the reflector and the plate. A planar object was levitated along the nodal line of the acoustic standing wave in the waveguide, and that affected the sound pressure distribution around the plate. The sound pressure distribution in the ultrasound waveguide was calculated via finite element analysis to investigate the effects of levitation of a planar object in the standing wave field. The (3, 1) resonance mode with a wavelength of approximately 15 mm in the x direction was excited in the air layer above and below the planar object. The acoustic field in the waveguide was sensitive to the length of ...

BACKGROUND The serum level of eosinophil-derived neurotoxin (EDN), a protein present in eosinophil granules, correlates with the severity of childhood asthma. However, the relationship between the serum EDN level and the severity of adult asthma has not been sufficiently investigated. OBJECTIVE This study aimed to elucidate the correlation between the serum EDN level and markers of severity in adult asthma. METHODS The subjects comprised 83 adult patients who had asthma and who were undergoing treatment. Of these patients, 40 were positive for house-dust-specific immunoglobulin E (IgE) antibodies; 9 patients with severe adult asthma who were treated with omalizumab were included in the study. We measured the blood eosinophil count, serum EDN, and eosinophil cationic protein levels before investigating the correlations of these parameters with lung function and symptom score. RESULTS There were no significant correlations between the blood eosinophil count or serum EDN or eosinophil cationic protein level with lung function and the symptom score in patients with asthma. However, serum EDN level was inversely correlated with the decrease percentage forced expiratory volume in 1 second (%FEV1) in patients positive for house-dust-specific IgE antibody (R = -0.54; p < 0.05), whereas no such correlation was observed in patients with negative results for house-dust-specific IgE antibody (R = 0.11; p = 0.468). A significant correlation was observed between a decrease in serum EDN level from baseline and lung function improvement after 8 weeks of omalizumab therapy (R = -0.77; p = 0.015). CONCLUSION Serum EDN level may be a useful marker for monitoring persistent airflow limitation in adult patients with asthma who had positive results for house-dust-specific IgE antibodies.

A technique to form an optical lens array using an ultraviolet (UV)-curable resin and ultrasound was investigated. A UV-curable gel film was formed on a glass plate having four lead zirconate titanate (PZT) transducers. Excitation of the transducers generated a lattice flexural vibration mode on the glass plate. The acoustic radiation force acted to deform the surface of the gel film, so that a lens array could be fabricated on the gel film. The lens array was exposed to UV light under ultrasonication to cure the UV-curable film. The quality factor of the transducer resonance was decreased upon curing of the resin film because the cured resin dampened the vibration of the plate. The acoustic characteristics of the UV-curable gel film were measured by using an ultrasound pulse technique at the MHz range. The sound speed of the gel increased from 987 to 1006 m/s (increase of 1.9%) as the UV exposure time increased. The attenuation coefficient also increased and the larger attenuation of the resin caused the lens array to have a lower quality factor.

A bubble filter with no mesh structure for extracorporeal circulation using ultrasound was developed. Hemolysis was evaluated by measuring free hemoglobin (FHb). FHb in 120 mL of bovine blood was measured in acoustic standing-wave fields. With a sound pressure amplitude of 60 kPa at driving frequencies of 1 MHz, 500 kHz and 27 kHz for 15 min. FHb values were 641.6, 2575 and 8903 mg/dL, respectively. Thus, hemolysis was inhibited with higher driving frequencies when the same sound pressure amplitude was applied. An ultrasound bubble filter with a resonance frequency of 1 MHz was designed. The filtering characteristics of the flowing microbubbles were investigated with a circulation system using bovine blood with a flow rate of 5.0 L/min. Approximately 99.1% of microbubbles were filtered with 250 kPa and a flow of 5.0 L/min. Hemolysis decreased as the sound pressure decreased; FHb values were 225.8 and 490.7 mg/dL when using 150 and 200 kPa, respectively.

The diffusion weighted images (DWIs) are used widely in clinical practice. Recently, the gradient overplus imaging was developed in addition to orthogonal technique for the duration method of motion-probing gradient pulses. The gradient overplus technique can reduce the load of a gradient strength, and enables setting of the shortest TE compared with the orthogonal gradients, and moreover it has the information on diffusion tensor. The apparent diffusion coefficient (ADC) values, signal-to-noise ratio (SNR), and geometric distortion were compared for the two duration methods of DWI using four different phantoms of coefficient of viscosity. In the gradient overplus, the time of smallest TE became smaller than the orthogonal gradients according to the increase of the b value. As a result, SNR increased by shortening of TE, and thus the geometric distortion was improved. Moreover, the ADC value did not show any difference in the two duration methods of DWI. The gradient overplus technique is a more useful technique in a clinical study than the orthogonal gradients because the quality of image is improved, and the ADC value is the same as the orthogonal gradients.

The clinical efficacy of T-cell therapies based on T cells transduced with genes encoding tumor-specific T-cell receptors (TCR-T) is related to the in vivo persistence of the T cells. To improve persistence without modifying TCR affinity, we instead modified intracellular signaling, using artificial T cell–activating adapter molecules (ATAM), generated by inserting the intracellular domain (ICD) of activating T-cell signaling moieties into CD3ζ. ATAMs with the ICD of either CD28 or 4-1BB were generated, assembled into the TCR complex as a part of CD3ζ, and enhanced downstream signaling from the supramolecular activation cluster. ATAMs were retrovirally introduced into human CMV-specific or NY-ESO-1–specific TCR-transduced CD8+ T lymphocytes, and downstream functionality was then examined. ATAM-transduced NY-ESO-1 TCR-T cells were also investigated using the U266-xenograft mouse model. ATAMs were successfully transduced and localized to the cell membrane. ATAM-transduced CMV-specific T cells retained their cytotoxic activity and cytokine production against peptide-pulsed target cells without altering antigen-specificity and showed resistance to activation-induced cell death. Upon both single and repeated stimulation, CD3ζ/4-1BB–transduced T cells had superior proliferation to the CD3ζ-transduced T cells in both the CMV-specific and the NY-ESO-1 TCR-T models and significantly improved antitumor activity compared with untransduced T cells both in vitro and in a mouse xenograft model. ATAM-transduced TCR-T cells demonstrated improved proliferation and persistence in vitro and in vivo. This strategy to control the intracellular signaling of TCR-T cells by ATAM transduction in combination with various tumor-specific TCRs may improve the efficacy of TCR-T therapy. Cancer Immunol Res; 6(6); 733–44. ©2018 AACR.

Nematic liquid crystal is widely used in optical devices such as liquid crystal displays. The optical characteristics of liquid crystal devices (ex, birefringence) can be controlled by applying an electric field because the liquid crystal molecules have electric dipoles. Although indium tin oxide (ITO) is generally employed as the transparent electrode material, ITO needs the rare metal indium and has problems of low electric conductivity and transparency. Our group has proposed a novel control technique of liquid crystal molecular orientation using ultrasound vibration without using ITO [1]. In this report, an optical variable-focus liquid crystal lens using ultrasound was discussed.

Contact manipulation using a micropipette is widely used for cell culture and evaluation. However, the operation efficiency and the damage on the cells depend on the individual skills. A technique for manipulating a micro biological material with high accuracy and selectivity is required. Our group has been investigating noncontact ultrasonic manipulation techniques using acoustic standing wave. In this report, ultrasonic manipulation, separation, and evaluation of HeLa cells in a microchannel are discussed.

Multiple myeloma (MM) cells acquire dormancy and drug resistance via interaction with bone marrow stroma cells (BMSC) in a hypoxic microenvironment. Elucidating the mechanisms underlying the regrowth of dormant clones may contribute to further improvement of the prognosis of MM patients. In this study, we find that the CD180/MD-1 complex, a noncanonical lipopolysaccharide (LPS) receptor, is expressed on MM cells but not on normal counterparts, and its abundance is markedly upregulated under adherent and hypoxic conditions. Bacterial LPS and anti-CD180 antibody, but not other Toll-like receptor ligands, enhanced the growth of MM cells via activation of MAP kinases ERK and JNK in positive correlation with expression levels of CD180. Administration of LPS significantly increased the number of CD180/CD138 double-positive cells in a murine xenograft model when MM cells were inoculated with direct attachment to BMSC. Knockdown of CD180 canceled the LPS response in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the CD180 gene. Both cell adhesion and hypoxia activated transcription of the CD180 gene by increasing Ikaros expression and its binding to the promoter region. Pharmacological targeting of Ikaros by the immunomodulatory drug lenalidomide ameliorated the response of MM cells to LPS in a CD180-dependent manner in vitro and in vivo. Thus, the CD180/MD-1 pathway may represent a novel mechanism of growth regulation of MM cells in a BM milieu and may be a therapeutic target of preventing the regrowth of dormant MM cells. Significance: This study describes a novel mechanism by which myeloma cells are regulated in the bone marrow, where drug resistance and dormancy can evolve after treatment, with potential therapeutic implications for treating this often untreatable blood cancer. Cancer Res; 78(7); 1766–78. ©2018 AACR.

In this paper, we examine a design method for low-sensitivity control with robust stability for multiple-input/multiple-output continuous time-invariant systems and minimum-phase systems using two-degree-of-freedom control system and multiplex feedback control. On Low-sensitivity control system the steady state error for the reference input and influence of the disturbance for the output became small. But the robust stability on low-sensitivity control became bad because the sum of the sensitive function and the complementary sensitivity function is equal to 1, the low-sensitivity and robust stability on the control system respectively depend on the sensitivity function and the complementary sensitive function. However According to Yamada, Low-sensitivity control system make the system robust stable with considering the class of uncertainty. And according to Yu et al. and Koyama et al. Using stratifled two-degree-of-freedom control, we can design more low-sensitivity characteristics than that of single two-degree-of-freedom control. In this paper, we expand the results of Yamada, Yu et al. and Koyama et al. and propose a design method of more low-sensitivity control system for multiple-input/multiple-output systems using two-degree-of-freedom control and multiplex feedback control system.

A hybrid version of the symmetric interior penalty (HSIP) method is considered for linear elasticity problems for nearly incompressible materials. When the P1 conforming finite element method is applied to such problems, volume locking phenomena occur. Discontinuous Galerkin (DG) methods are known as a remedy for the locking. The HSIP method has two unknowns which are approximations for the displacement and its trace on the skeleton. The latter is often called the numerical trace. The HSIP method with the discontinuous numerical trace is free from locking. On the other hand, it is numerically observed that the HSIP method with the continuous numerical trace causes volume locking phenomena when the P1 elements are employed for the two unknowns. The numerical fact is mathematically proved in this paper.

An optical lens array is used various field such as camera modules and liquid crystal displays. In this report, a new fabrication technique of a lens array was proposed using ultraviolet (UV)-curable resin and ultrasound vibration. The hardening characteristics of the gel were investigated. An UV-curable gel film was formed on a glass plate having four ultrasound transducers. By exciting the transducers, the lattice flexural vibration was generated on the glass plate. The acoustic radiation force was generated to the gel surface, so that the gel was statically deformed. The lens array could be formed for 20 minutes under UV-light irradiation with keeping the deformation. The quality factor of the transducer resonance was measured in order to investigate the curing of resin, and the quality factor decreased with time. It was found that the gel acts as the damper and additional mass as the lens array was formed.

The direct finite-difference fluid simulation of acoustic streaming on a fine-meshed three-dimensional model using a graphics processing unit (GPU)-based calculation array is discussed. Airflows are induced by an acoustic traveling wave when an intense sound field is generated in a gap between a bending transducer and a reflector. The calculation results showed good agreement with measurements in a pressure distribution. Several flow vortices were observed near the boundary layer of the reflector and the transducer, which have often been observed near the boundary of acoustic tubes, but have not been observed in previous calculations for this type of ultrasonic air pump.

Several clinical trials have demonstrated the effectiveness of bortezomib in combination with various anti-myeloma agents; however, no definitive information is available regarding drugs best suited for use in combination with bortezomib. Using isobologram analysis, we investigated the combined effects of bortezomib with four key anti-myeloma drugs (melphalan, cyclophosphamide, doxorubicin and lenalidomide), which represent components of major bortezomib-based regimens with corticosteroids, in three myeloma cell lines (U266, RPMI8226 and KMS-12BM) under various conditions. Melphalan showed the best performance with bortezomib under all culture conditions tested (liquid culture, on fibronectin-coated plates, and co-culture with bone marrow stromal cells), whereas cyclophosphamide was antagonistic with bortezomib especially in the presence of stromal cells. Doxorubicin showed additive effects under stroma-free conditions and in contact with fibronectin, but was rather antagonistic in the presence of stromal cells. In contrast, lenalidomide exerted the most favorable effect with bortezomib in contact with stromal cells. Consistent with these results, caspase-3 was activated more strongly by melphalan than by other agents in combination with bortezomib. Moreover, bortezomib-induced up-regulation of CHOP was readily enhanced by lenalidomide in contact with stromal cells. The present findings may provide fundamental information for the selection of bortezomib-based regimens for myeloma patients.

We developed a plate-shaped non-contact transporter based on ultrasonic vibration, exploiting a phenomenon that a plate can be statically levitated at the place where its gravity and the acoustic radiation force are balanced. In the experiment, four piezoelectric zirconate titanate elements were attached to aluminum plates, on which lattice flexural vibration was excited at 22.3 kHz. The vibrating plates were connected to a loading plate via flexible posts that can minimize the influence of the flexure induced by heavy loads. The distribution of the vibration displacement on the plate was predicted through finite-element analysis to find the appropriate positions of the posts. The maximum levitation height of this transporter was 256 μm with no load. When two vibrating plates were connected to a loading plate, the maximum transportable load was 4.0 kgf.

The Notch signaling pathway has been recognized as a key factor for the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), because of the high incidence of activating mutations of Notch1. Notch inhibition could serve as a new treatment strategy for T-ALL; however, the attempts to perturb Notch signaling pathways have been unsuccessful so far. In this study, we found that proteasome inhibitors exert cytotoxic effects on T-ALL cells with constitutive activation of Notch1 to a similar extent as myeloma cells. The proteasome inhibitor bortezomib repressed the transcription of Notch1 and downstream effectors including Hes1, GATA3, RUNX3 and nuclear factor-κB (NF-κB) (p65 and p50), coincided with downregulation of the major transactivator Sp1 and its dissociation from Notch1 promoter. Overexpression of the Notch1 intracellular domain (NICD) significantly ameliorated bortezomib-induced cytotoxicity against T-ALL cells. Drug combination studies revealed that bortezomib showed synergistic or additive effects with key drugs for the treatment of T-ALL such as dexamethasone (DEX), doxorubicin and cyclophosphamide, which were readily abolished by NICD overexpression. The synergy of bortezomib and DEX was confirmed in vivo using a murine xenograft model. Our findings provide a molecular basis and rationale for the inclusion of proteasome inhibitors in treatment strategies for T-ALL.

The multiple Dirichlet-to-Neumann (DtN) boundary condition has been derived by Grote and Kirsch (J Comput Phys 201:630–650, 2004) to numerically solve multiple scattering problems. An a priori error estimate is established for finite element methods applied to the Helmholtz problem with the multiple DtN boundary condition. The error estimates account for the effects of truncation of infinite Fourier series representing the multiple DtN boundary condition as well as of discretization of the finite element method.

An ultrasound bubble filter without a mesh structure was developed for extracorporeal circulation. The filter utilizes an ultrasound standing-wave field generated by flexural vibration and removes micro air bubbles from the circulation. The ultrasound filter consists of an aluminum cylinder, two annular ultrasound transducers, and three connectors to the flow path. The configuration of the filter was determined through finite element analysis computations. Flexural vibrations at 46 and 199 kHz were generated in prototypes with lengths of 69 and 130 mm. Two driving modes (both standing-wave and traveling-wave modes) were used to evaluate the filtering characteristics in a water circulation system. The bubble size decreased by increasing the input voltage to the filter; the average diameter changed from 60 to under 10 μm when the input voltage changed from 0 to 200 V. The total volume of air in the main flow estimated from the size distribution of the bubbles decreased to 1% for the 130-mm-long filter excited with the traveling-wave mode.

Bortezomib therapy is now indispensable for multiple myeloma, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. The development of orally active proteasome inhibitors with distinct mechanisms of action is therefore eagerly awaited. Previously, we identified homopiperazine derivatives as a novel class of proteasome inhibitors with a different mode of proteasome binding from bortezomib. In this study, we show that K-7174, one of proteasome inhibitory homopiperazine derivatives, exhibits a therapeutic effect, which is stronger when administered orally than intravenously, without obvious side effects in a murine myeloma model. Moreover, K-7174 kills bortezomib-resistant myeloma cells carrying a β5-subunit mutation in vivo and primary cells from a patient resistant to bortezomib. K-7174 induces transcriptional repression of class I histone deacetylases (HDAC1, -2, and -3) via caspase-8-dependent degradation of Sp1, the most potent transactivator of class I HDAC genes. HDAC1 overexpression ameliorates the cytotoxic effect of K-7174 and abrogates histone hyperacetylation without affecting the accumulation of ubiquitinated proteins in K-7174-treated myeloma cells. Conversely, HDAC inhibitors enhance the activity of K-7174 with an increase in histone acetylation. These results suggest that class I HDACs are critical targets of K-7174-induced cytotoxicity. It is highly anticipated that K-7174 increases the tolerability and convenience of patients by oral administration and has the clinical utility in overcoming bortezomib resistance as a single agent or in combination with HDAC inhibitors.

Objective Autologous stem cell transplantation is an important strategy for patients with relapsed or refractory lymphoma. Although various regimens for peripheral blood stem cell collection have been used, the optimal regimen has not yet been established. We aimed to evaluate the mobilization efficacy and safety of the regimen consisted of etoposide and cytarabine (EC regimen). Methods We retrospectively analyzed the clinical data of 46 lymphoma patients who received peripheral blood stem cell mobilization with the EC regimen [etoposide (100 mg/m2/day, days 1-4) and cytarabine (100 mg/m2/day, days 1-4)] at Toyohashi municipal hospital from 2004 to 2013. Results The median age of the patients was 55 years. The most common underlying diseases were diffuse large B-cell lymphoma (46%) and follicular lymphoma (26%). Three-quarters of patients were in their second complete or partial remission. The median total number of collected CD34+ cells was 10.6 × 106 kg-1. Forty-two patients (91%) yielded at least 2 × 106 kg-1 CD34+ cells within a median of 2 apheresis days, and 33 patients (72%) achieved it with only one apheresis. Successful mobilization was observed in five of six patients who failed to mobilize previously. Although febrile neutropenia occurred in 22 patients (48%), no fatal infection was observed. Conclusion The EC regimen was highly effective in lymphoma patients, including patients who mobilized poorly with other regimens.

The photochemical dynamics of the thione 2-mercaptobenzothiazole (MBT) initiated by absorption of 330-nm ultraviolet light are investigated by ultrafast transient absorption spectroscopy. The lowest energy triplet state (T1) has mixed 3ππ* / 3nπ* character and is populated with a quantum yield of 0.58 ± 0.01 from the photo-excited 1ππ* S2 state in methanol solution via rapid internal conversion to the 1nπ* S1 state (with time constant t1 < 150 fs). The spectroscopic evidence points to a mechanism involving intersystem crossing from S1 to the 3nπ* / 3ππ* T2 state (t2 = 400 ± 100 fs) and internal conversion to T1 (with time constant for growth t3 = 6.1 ± 0.4 ps). The remainder of the photoexcited molecules return to the ground state by S1 - S0 internal conversion. In methanol solution, the T1 state is long-lived but when the solvent is changed to styrene, triplet quenching is observed with a time constant of 107 ± 8 ps and assigned to the adduct-mediated energy transfer process MBT (T1) + Styrene (S0) -> 3[MBT-Styrene] ->  MBT (S0) + Styrene (T1). Transient vibrational absorption spectroscopy observes the 3[MBT-Styrene] biradical intermediate and determines its lifetime to be 700 ± 80 ps. Computational studies identify the mechanistic pathway for triplet quenching, which involves a curve crossing between two triplet states of the MBT-Styrene adduct. The quenching process occurs with high efficiency, and no long-lived isomers of the initial adduct are observed.

OBJECTIVE. The purpose of this study is to examine how the fractional b value affects the calculation of apparent diffusion coefficient (ADC) using DWI. The fractional b value is the point of intersection between the fast and slow components of biexponential decay in DWI. SUBJECTS AND METHODS. Human brains were imaged using multiple b values on echo-planar DWI. The ADCs of white matter, gray matter, and thalamus were calculated using the combination of b values by two-point and multipoint methods, and the characteristics of each ADC value were compared. RESULTS. When the two selected points for calculation were smaller than the fractional b value (b = 1700 s/mm2), the ADC value was 0.0007–0.0008 mm2/s, but when the two points used for calculation were greater than the fractional b value, the ADC value was 0.0003–0.0004 mm2/s. When a range of b values was included in the fast and slow components by use of the multipoint method, the ADC value showed a statistically significant increase as the number of mult...

Autoimmune-like hepatitis after allogeneic hematopoietic stem cell transplantation: humoral hepatic GvHD

The numerous applications of microbubbles in food science and medicine call for a better understanding and control of the effects of the properties of their shells on their stability and ability to resonate at chosen frequencies when submitted to an ultrasound field. We have investigated both millimetric and micrometric bubbles stabilized by an amphiphilic block copolymer, Poloxamer 188 (e.g., Pluronic F-68). Although Pluronic F-68 is routinely being used as a dispersing and foaming agent to facilitate phospholipid-based microbubble preparation, it has never been studied as a shell component per se. First, we investigated the adsorption kinetics of Pluronic F-68 at the interface between water and air, or air saturated with vapors of perfluorohexane (F-hexane), using bubble profile tensiometry analysis. F-Hexane was found to strongly accelerate the adsorption of Pluronic F-68 (at low concentrations) and decrease the interfacial tension values at equilibrium (at all concentrations). We also found that relatively stable microbubbles could unexpectedly be prepared from Pluronic F-68 in the absence of any other surfactant, but only when F-hexane was present. These bubbles showed an only limited volume increase over ∼3 h, while a 10-fold increase in size occurred within 200 s in the absence of a fluorocarbon. Remarkably, their deflation rate decreased when the Pluronic F-68 concentration decreased, suggesting that bubbles with semidilute copolymer coverage are more stable than those more densely covered by copolymer brushes. Single-bubble experiments using laser Doppler vibratometry showed that, by contrast with other surfactant-coated microbubbles, the resonance radius of the Pluronic F-68-coated microbubbles was lower than that of naked microbubbles, meaning that they are less elastic. It was also found that the bubble's vibrational displacement amplitude decreased substantially when the microbubbles were covered with Pluronic F-68, an effect that was further amplified by F-hexane.

The photochemical reaction dynamics of the benzothiazole-2-thiyl (BS) radical, produced by 330 nm ultraviolet photolysis of 2,2′-dithiobis(benzothiazole) (BSSB), are examined on the picosecond time scale. The initial addition product of a thiol–ene reaction between the BS radical and styrene is directly observed by transient vibrational absorption spectroscopy (TVAS). Transient electronic absorption spectroscopy (TEAS) in the ultraviolet and visible spectral regions reveals rapid formation of the ground state BS radical with a time constant of ∼200 fs. The photolytically generated BS radical decays through geminate recombination to the parent molecule BSSB and competitive formation of a BS radical dimer with a rate coefficient of (3.7 ± 0.2) × 1010 M−1 s−1 in methanol, and thereafter (36 ± 1)% of the initially formed BS radicals survive at the longest time delay (1.3 ns). In styrene solution, in contrast to methanol and toluene solutions, kinetic traces of the BS radical show an additional decay with a time constant of 305 ± 13 ps, and a broad band at 345–500 nm grows with the same time constant, suggesting a bimolecular reaction of the BS radical with styrene. The TVAS measurements reveal an absorption band of the ground state BS radical at 1301 cm−1 in toluene solution, and the band decays with a time constant of 294 ± 32 ps in styrene solution. Two product bands grow at 1239 cm−1 and 1429 cm−1 with respective time constants of 312 ± 68 ps and 325 ± 33 ps, and are attributed to the addition product BS–St radical formed from the BS radical and styrene. A bimolecular reaction rate coefficient of kreact = (3.8 ± 0.2) × 108 M−1 s−1 is deduced and 22 ± 1% of the initially formed BS radicals are converted to the BS–St radical in neat styrene solution.

Iron overload is a common complication in allogeneic hematopoietic cell transplantation (HCT). We studied the prevalence of iron overload using serum ferritin from 122 allogeneic HCT survivors who had survived a median of 1259 (range 134–4261) days. We also quantified iron overload by determining non-transferrin-bound iron (NTBI), which reflects iron overload more directly than ferritin, and compared the results with those of the ferritin assay. Fifty-two patients (43 %) showed hyperferritinemia (HF) (serum ferritin >1000 ng/mL), and there was a moderate correlation between serum ferritin and the number of transfused red blood cell units (ρ = 0.71). In multivariate analyses, HF was a significant risk factor for liver dysfunction (P = 0.0001) and diabetes (P = 0.02), and was related to a lesser extent with performance status (P = 0.08). There was a significant correlation between serum ferritin and NTBI (ρ = 0.59); however, the association of NTBI with these outcomes was weaker than that of serum ferritin. In conclusion, serum ferritin is a good surrogate marker of iron overload after allogeneic HCT, and reflects organ damage more accurately than NTBI.

Nematic liquid crystal is widely used in optical devices such as liquid crystal displays and controlled by electric fields through the liquid crystal layer. Our group has proposed a control technique of liquid crystal molecular orientation using ultrasound vibration without indium tin oxide electrodes [1]. In this study, using ultrasound and nematic liquid crystal, we realized a variable focus liquid crystal lens. The liquid crystal lens has no transparent electrodes and consists of a simple structure; a nematic liquid crystal layer with a thickness of 50 μm is formed between two circular grass plates. An annular PZT ultrasonic transducer was bonded on the glass plate. By exciting the transducer at the resonance frequencies (28 kHz), the flexural vibration modes were generated. The acoustic radiation force from the vibration changed the molecular orientation of the liquid crystals, which induced the distribution of the execution refractive indices. The liquid crystal layer then worked as a lens. The focal...

A liquid lens was fabricated with a focal point that can be varied in the axial and radial directions. We have been developing a variable-focus liquid lens that employs acoustic radiation force and does not contain any mechanical moving parts. Our liquid lens is more compact and has a faster response than conventional mechanical lenses. Rapid scanning of its focus at 1 kHz has been realized by excitation with an amplitude-modulation (AM) signal. The liquid lens consists of a cylindrical acrylic cell (inner diameter: 10 mm; thickness: 3 mm), two immiscible liquids with different refractive indices (water and silicone oil), and an annular piezoelectric lead zirconate titanate transducer with four electrodes. The oil-water interface functions as a lens surface and it can be deformed by the acoustic radiation force generated by the transducer; this enables the lens to act as a variable-focus lens. The variation of the oil-water interface was observed by optical coherence tomography. The laser beam path through the lens was calculated by ray-tracing simulations. The oil-water interface could be deformed and its focal point could be varied in three dimensions by controlling the input voltages of the PZT electrodes. The displacement angle in the radial direction was approximately 3° when two of the electrodes were excited by an input voltage of 45 V at a frequency of 1.9 MHz. The dynamic performance of the lens was investigated using a high-speed cam- era. Excitation by AM signals with a phase difference caused the hemispherical water droplet to oscillate, enabling the focus to be scanned in the axial and radial directions.

The effects of macrophage activation on the outcome of allogeneic hematopoietic SCT (allo-HSCT) have yet to be fully examined. A total of 70 adult patients who received a first allo-HSCT for hematological diseases were studied. We counted the number of hemophagocytic cells in BM clot sections on day +14±7, and analyzed its impact on subsequent outcome. In all, 23 patients were diagnosed as having increased numbers of hemophagocytic cells (HP group), whereas 47 were not (non-HP group). The HP group was not associated with an increased incidence of acute or chronic GVHD, but was associated with worse hematopoietic recovery than the non-HP group. The 2-year OS for the HP group and the non-HP group was 30 and 65% (P

A liquid lens is proposed that uses acoustic radiation force with no mechanical moving parts. It consists of a cylindrical acrylic cell filled with two immiscible liquids (degassed water and silicone oil) and a concave ultrasound transducer. The focal point of the transducer is located on the oil-water interface, which functions as a lens. The acoustic radiation force is generated when there is a difference in the acoustic energy densities of different media. An acoustic standing wave was generated in the axial direction of the lens and the variation of the shape of the oil-water interface was observed by optical coherence tomography (OCT). The lens profile can be rapidly changed by varying the acoustic radiation force from the transducer. The kinematic viscosity of silicone oil was optimized to minimize the response times of the lens. Response times of 40 and 80 ms when switching ultrasonic radiation on and off were obtained with a kinematic viscosity of 200 cSt. The path of a laser beam transmitted through the lens was calculated by ray-tracing simulations based on the experimental results obtained by OCT. The transmitted laser beam could be focused by applying an input voltage. The liquid lens could be operated as a variable-focus lens by varying the input voltage.