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Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) is an enzyme that converts cholesterol to cholesteryl esters. A recent in vivo study reported that inhibiting ACAT1 enzyme activity upregulates the membrane cholesterol levels of T cells, enhancing their cytotoxic function. In the present study, we investigated whether the presence of the ACAT1 single nucleotide polymorphism rs11545566 in transplant donors affected the risk of graft-versus-host disease (GVHD) in 116 adult patients who underwent bone marrow transplantation from human leukocyte antigen-identical sibling donors, and who received GVHD prophylaxis with short-term methotrexate and cyclosporine. The frequencies of the AA, AG, and GG genotypes in the donors were 31%, 45%, and 24%, respectively. The cumulative incidences of grade II–IV acute GVHD on day 100 in patients whose donors had AA vs. non-AA genotypes were 6% and 18%, respectively, and those of extensive chronic GVHD at 2 years were 7% and 32%, respectively. Multivariate analyses demonstrated that donor rs11545566 non-AA genotypes showed a trend toward a higher incidence of grade II–IV acute GVHD (P = 0.079), and were significantly associated with a higher incidence of extensive chronic GVHD (P = 0.021). These results suggest that donor ACAT1 rs11545566 genotype may be predictive of GVHD., ファイル公開：2021/01/01

The oxidation mechanism of hafnium overlayers on an Si(111) substrate [Hf-Si(111), including the outermost metallic Hf overlayers and interfacial Hf silicides (HfSi and HfSi

Bendamustine-rituximab (BR) therapy has been established as a highly effective regimen for indolent non-Hodgkin lymphoma (NHL). However, patients who receive BR therapy exhibit persistent hypogammaglobulinemia and lymphopenia, resulting in an increased incidence of infections. As a sustained immunosuppressive state is a risk factor for infections, early predictive biomarkers for infections related to BR therapy need to be identified. We retrospectively analyzed 61 patients with indolent NHL who were followed up for 2 years after the end of BR therapy. Progression-free survival was significantly influenced by the incidence of infections. Patients with infections related to BR therapy exhibited persistent hypogammaglobulinemia and lymphopenia. In addition, we determined the cutoff values of serum IgG values and lymphocyte counts for infections using receiver operating characteristic curve analysis. Minimum serum IgG and lymphocyte counts at the first BR treatment cycle were significantly associated with the incidence of infections during and after BR treatment. Furthermore, the development of skin reactions during BR therapy was significantly associated with the incidence of infections after BR therapy. Our study suggested that these values and symptom are predictive biomarkers for infections related to BR therapy. Based on these findings, better management of indolent NHL patients will be possible.

We investigated the effects of a 1,2-dimyristoyl-sn-glycerol-3-phosphocholine (DMPC) molecular film surrounding microbubbles on their collapse under ultrasound irradiation. We defined the ejection of the internal gas from the microbubble (i.e. “daughter” bubbles) as bubble collapse. In particular, we measured the sound-pressure thresholds for microbubble collapse in water and a DMPC solution. Bubbles with the DMPC film had a smaller resonance size than naked bubbles. The measured contact angles of the bubbles were lower after collapse, implying that DMPC molecules on the bubble surface partially desorbed between the processes of vibration and collapse.

This paper investigates a thin sensor used to detect the position of an object in front of an ultrasonic transducer using changes in the radiation impedance. The sensor consists of a rectangular plate and a piezoelectric transducer, and the configuration is determined based on the results of a finite element analysis simulation. Stripe flexural vibration modes are generated on the plate, radiating sound waves into the air between the plate and the object. The radiation angle of these sound waves is dependent on the driving frequency, resulting in a change in the sound field and the electrical admittance characteristics. The sensing performance is examined using two resonant vibration modes. The sensor can determine the position of an object uniquely within a two-dimensional area, and the lower resonant mode gave a wider measurable range. The sensitivity is improved six-fold over that of our conventional sensor using the same sensing mechanism.

This paper proposed a board-mounted ultrasonic variable-focus liquid crystal (LC) lens. The lens controls the focus using the acoustic radiation force generated by the resonant flexural vibration mode. The LC lens was fixed to an aluminum substrate with a hole whose aperture corresponded to the inner diameter of the transducer. The part of the LC lens attached to the substrates functioned as a fixed condition, and the flexural vibration mode was successfully generated. The fixed lens exhibited a gradual focal change with current, confirming that fixing the condition affected the rate of focal change.

This paper investigates a method to detect the position of an object in front of an ultrasonic vibrator using changes in the radiation impedance. This acoustic touchless sensor is composed of a rectangular vibrating plate (width: 30 mm; length: 200 mm; thickness: 3 mm) and two bolt-clamped Langevin-type transducers with stepped horns. The sensor configuration was determined based on the results of a finite element analysis simulation. When a stripe flexural vibration mode excited on the plate was generated an acoustic standing-wave field in the air, the electrical impedance of the ultrasound transducers changed dramatically, thus indicating that the radiation impedance of the sensor was dependent on the object position. By measuring the amplitude of the input current to the transducers and the phase difference between the input current and the voltage applied to the sensor, the 40 mm long object’s position could be determined uniquely within a two-dimensional area of 160 × 7 mm2.

In the pharmaceutical field, a technique to level the surface of powdered medicines is important in the dispensing process because the flatness of the powder surface affects the packaging accuracy directly. This paper investigates a method for leveling of the surface profile of powder using ultrasound vibration on a plate. The system used comprises a V-shaped plate and two ultrasound transducers, and the plate configuration required was determined from the results of simulations performed by finite element analysis. The resonant longitudinal vibration of the transducers generated the resonant flexural vibration mode of the plate at 27.4 kHz, which resulted in transportation and leveling of the powder. The powder was aggregated at the nodal positions of the flexural standing wave, and a correlation was observed between the sound pressure distribution over the plate and the surface profile of the powder. The powder leveling accuracy was investigated by varying the driving phase difference between the transducers, and it was found that a smaller standing wave ratio for the flexural vibration produced higher leveling accuracy. When the input voltage to the transducers was increased, the leveling time decreased and the leveling accuracy improved; the highest leveling accuracy obtained was 2.2 mm at 130 V

In an acoustic standing wave generated in the air between a vibrator and a reflector, a small object is levitated near the nodal positions of the sound pressure where the acoustic radiation force and the gravity are balanced. By controlling the sound field spatially and temporally, the object can be transported without contact. In this report, we experimentally investigated the non-contact high-speed rotation of a small object using ultrasound, which can be applied to measurement techniques of the physical properties of liquids. The experimental system consists of a vibrating disc with four bolt-clamped Langevin-type transducers and a reflector, and an acoustic standing wave is generated between them. The effects of the tilt angle of the reflector with respect to the vibrator on the rotation speed of the object and the acoustic field were investigated. When the tilt angle was around 1.2°, the object was trapped in the air at 31.5 kHz by the standing-wave component in the vertical direction and rotated by the traveling-wave component propagating in the horizontal direction. The maximum sound pressure amplitude and the rotation speed of the object were changed with the tilt angle, and a larger sound pressure amplitude gave a larger rotation speed.

A non-contact acoustic sensing system using changes in the radiation impedance was proposed to detect the position of an object in front of an ultrasonic vibrator. The sensor is composed of a rectangular vibrating plate (20 × 100 × 1 mm3) and a PZT transducer (20 × 20 × 2 mm3). The sensor configuration was determined based on the results of a finite element analysis simulation. The flexural vibration modes were excited on the plate at two resonance frequencies, 29.7 and 46.2 kHz. The radiation angle of ultrasound from the sensor and the acoustic field between the object and the plate were compared at the two frequencies to investigate the detection characteristics. When an acoustic standing-wave field was generated in the air, the electrical impedance of the ultrasound transducers dramatically increased, indicating that the radiation impedance of the sensor was dependent on the object position. By measuring the amplitude of the input current to the transducers and the phase difference between the input current and the voltage applied to the sensor, the object position could be determined uniquely within a two-dimensional area.

Piezoelectric thin film transducers that can receive and transmit high-frequency and high-intensity ultrasound are powerful tools for future medical and industrial applications. Our group has developed acousto-optic devices where the refractive index can be controlled at high speed and high precision using ultrasound, but there are few reports on the interaction between high-frequency (tens to hundreds MHz) and high-intensity (MPa) ultrasound and visible light in liquids. In this study, we evaluated the acousto-optic interaction using polarized CW laser (532 nm) and a piezoelectric KNbO3 thin film transducer formed by hydrothermal method. The transducer was driven continuously at the fundamental or higher resonance frequencies (32, 96, 160, or 210 MHz) in a water cell, and the projection light of a laser beam penetrating perpendicularly to the sound axis was observed. The length of the projection light was elongated in the sound axis on the screen as the driving frequency increased. These results implies that the relationship between the wavelength of ultrasound and the laser beam width is the critical parameter for the acousto-optic phenomenon; the profile of the projection light is dependent on a ratio of the wavelength of ultrasound and the beam width of the laser beam.

Although ultrasonically controlled liquid crystal lens may play in important role in future optical systems, many optical properties in the liquid crystal layer are still unclear. Moreover, most of the previously conducted studies control the liquid crystal molecular orientation by an applied electric field using transparent electrodes. In this study, using multichannel piezoelectric transducer, standing wave and traveling wave actuation mechanism were applied to the liquid crystal lens and further reported about its optical characteristics using a Shack-Hartmann wavefront sensor. The surface data obtained from the sensor was analyzed and the optical aberrations measured. Traveling wave actuation showed small optical aberrations when compared to the standing wave.

The contemporary world faces shortage of human resources in face-to-face working environment. Collaborative robots are promising for that environment because these robots enable people to work keeping a distance. In the operative tasks, the robot required to precisely follow human moving so as not to cause uncomfortable feelings of the operator. As a solution to this problem, we consider a swipe gesture robotic system for operating a robot. The proposed robotic system captures human gestures in real time by image processing, and commands a mobile robot with servo compensation.

SLAMF7 is expressed mainly on multiple myeloma (MM) cells and considered an ideal target for immunotherapeutic approaches. Indeed, elotuzumab, an anti-SLAMF7 antibody, is used for the treatment of MM in combination with immunomodulatory drugs. SLAMF7 is cleaved via unknown mechanisms and detected as a soluble form (sSLAMF7) exclusively in the serum of MM patients; however, little is known about the role of sSLAMF7 in MM biology. In this study, we found that sSLAMF7 enhanced the growth of MM cells via homophilic interaction with surface SLAMF7 and subsequent activation of the SHP-2 and ERK signaling pathways. Elotuzumab suppressed sSLAMF7-induced MM cell growth both in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the SLAMF7 gene. Pharmacological targeting of Ikaros by lenalidomide and its analog pomalidomide downregulated SLAMF7 expression and ameliorated the response of MM cells to sSLAMF7. Elotuzumab blocked the growth-promoting function of sSLAMF7 when combined with lenalidomide in a murine xenograft model. Neutralization of sSLAMF7 is a novel antimyeloma mechanism of elotuzumab, which is enhanced by immunomodulatory drugs via downregulation of surface SLAMF7 expression on MM cells. These findings may provide important information for the optimal use of elotuzumab in MM treatment.

Owing to the difficulty in isolating T cells from human biopsy samples, the characteristics of T cells that are infiltratinghuman acute graft-versus-host disease (GVHD) tissues remain largely uninvestigated. In the present study, TCR-β deep sequencing of various GVHD tissue samples and concurrent peripheral blood obtained from transplant recipients was performed in combination with functional assays of tissue-infiltrating T cell clones. The T cell repertoire was more skewed in GVHD tissues than in the peripheral blood. The frequent clonotypes differed from tissue to tissue in the same patient, and the frequent clonotypes in the same tissue differed from patient to patient. Two T cell clones were successfully isolated from GVHD skin of a patient. In a cytotoxicity assay, both Tcell clones lysed patient peripheral blood mononuclear cells, but not donor-derived Epstein-Barr virus-transformed lymphoblastoid cells. Their clonotypes were identical to the most and second most frequent T cell clonotypes in the original GVHD skin and accounted for almost all of the skin-infiltrating T cells. These results suggest that human acute GVHD may result from only a few different alloreactive cytotoxic T cell clones, which differ from tissue to tissue and from patient to patient. The characterization of T cells infiltrating human GVHD tissues should be further investigated.

Purpose: Lysine-specific demethylase 1 (LSD1) regulates several biological processes via the bifunctional modulation of enhancer functions. Recently, we reported that LSD1 overexpression is a founder abnormality of T-cell leukemogenesis and is maintained in fully transformed T-cell acute lymphoblastic leukemia (T-ALL) cells. On the basis of this finding, we attempted to develop novel LSD1 inhibitors effective for T-ALL with central nervous system (CNS) involvement. Experimental Design: We chemically modified the prototype LSD inhibitor tranylcypromine (TCP) and screened for cytotoxicity against TCP-resistant T-ALL cell lines. In vivo efficacy of novel LSD1 inhibitors was examined in immunodeficient mice transplanted with luciferase-expressing T-ALL cell lines, which faithfully reproduce human T-ALL with CNS involvement. Results: We found robust cytotoxicity against T-ALL cells, but not normal bone marrow progenitors, for two N-alkylated TCP derivatives, S2116 and S2157. The two compounds induced apoptosis in TCP-resistant T-ALL cells in vitro and in vivo by repressing transcription of the NOTCH3 and TAL1 genes through increased H3K9 methylation and reciprocal H3K27 deacetylation at superenhancer regions. Both S2116 and S2157 significantly retarded the growth of T-ALL cells in xenotransplanted mice and prolonged the survival of recipients as monotherapy and in combination with dexamethasone. Notably, S2157 could almost completely eradicate CNS leukemia because of its ability to efficiently pass through the blood–brain barrier. Conclusions: These findings provide a molecular basis and rationale for the inclusion of a brain-permeable LSD1 inhibitor, S2157, in treatment strategies for T-ALL with CNS involvement.

In this paper, we consider a design method of the control system using double feedback control that provides low sensitivity with robust stability for single-input and singleoutput continuous time-invariant systems by independent design of the controllers. If the control system has low sensitivity characterinstics, then the steady state error for the reference input and influence of the disturbance for the output become small. However, It is said that the low sensitivity control has bad robust stability characteristics. Yu et al. propose a design method of the control system called the double feedback control system that provides low sensitivity characteristics and robust stability by using many controllers. However, Yu et al. does not considered how to design each controllers, independently. In this paper, we expand the result of Yu et al. and propose a design method of the double feedback control system that each controller is designed, independently.

The orientation angles of liquid crystal (LC) molecules were measured during ultrasound vibrations. Light transmitted through a fabricated LC lens was analyzed via the crossed Nicol condition and a crystal rotation method. The LC orientation angle was estimated with a theoretical model, and its distribution in the lens was determined. There was a strong correlation between the molecular angles and ultrasonic vibrational distributions, indicating that the angle was changed by the acoustic radiation force. The maximum tilt angle was 12° for a 50 V peak-to-peak input.

A method to improve the performance of an ultrasound liquid crystal lens is proposed. A double-layer-based lens model tailored based on the liquid crystal’s physical properties, e.g., its dielectric anisotropy and elastic constants, is presented as an alternative method to improve the lens’s optical performance while forming weak anchoring surfaces for nematic liquid crystals, thus promoting easier reorientation of the liquid crystal molecules. The lens configuration was simulated by finite-element analysis using Ansys software. The lens’s physical and optical characteristics were evaluated via comparison using two different liquid crystal materials: 5CB and RDP-85475. The birefringence distribution within the liquid crystal layer was investigated under ultrasound excitation, and the molecular angles of inclination were estimated. A higher birefringence distribution, greater molecular inclination, and a longer focal length were obtained for the double-layered liquid crystal lens using the 5CB material.

Background Recently, various blood cell lineages expressing the BCR-ABL fusion gene in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have been reported. However, the biological and clinical significance of these BCR-ABL lineages has not been established; therefore, we aimed to clarify the impacts of these different BCR-ABL-expressing lineages. Patients Multi-lineage BCR-ABL expression (multi-Ph) was defined as BCR-ABL expression outside of the B-lineage compartment, as determined by fluorescence in situ hybridization (FISH) in peripheral blood neutrophils and bone marrow clots, and flow cytometry-sorted polymerase chain reaction (PCR). We analyzed IKZF1 deletion patterns by PCR, examined gene expression profiles using RNA sequencing, and compared treatment outcomes across different BCR-ABL-expressing lineages. Results Among the 21 multi-Ph patients in our 59-patient cohort (36%), BCR-ABL expression was detected at the multipotential progenitor level. However, no IKZF1 deletion patterns or gene expression profiles were identified that were specific for multi-Ph. However, multi-Ph patients were found to have better survival rates than patients with uni-lineage BCR-ABL expression [event-free survival (EFS): 74 vs. 33%, P = 0.01; overall survival (OS): 79 vs. 44% at 4 years, P = 0.01]. In multivariate analyses, multi-Ph was identified as a good prognostic factor for both EFS and OS. Conclusion We confirmed that more than one-third of Ph+ALL patients could be classified as mutli-Ph. Although no specific molecular characteristics were identified for multi-Ph, this phenotype was associated with better treatment outcomes.

Introduction: Hairy cell leukemia variant (HCL-v) is a rare lymphoproliferative disorder regarded as a splenic B-cell lymphoma/leukemia, unclassifiable tumor in the 2017 World Health Organization classification of lymphoid tumors. The prognosis of HCL-v is much worse than that of classical hairy cell leukemia and there is no consensus regarding the optimal treatment strategy for HCL-v. For patients with indolent lymphoma, rituximab plus bendamustine (RB) has proven effective in several clinical trials. Thus, RB is expected to be a treatment option for patients with HCL-v, but there have been few reports of its use in these patients. Patient concerns: A 64-year-old man presented with leukocytosis and abnormal lymphocytes in peripheral blood in a medical examination. Computed tomography revealed mild splenomegaly, but no lymph node enlargement. Diagnosis: The patient was initially diagnosed with low-grade B-cell lymphoma. After he experienced a second relapse, his clinical data were reviewed again; subsequently, he was diagnosed with HCL-v on the basis of clinical presentation, flow cytometry findings, and cytogenetic abnormalities. Interventions: The patient was first treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen. After the regimen was ineffective, he received six cycles of RB. After relapse, the patients received an additional six cycles of RB. Outcomes: The patients exhibited a slight reduction of the abnormal lymphocyte level but insufficient therapeutic efficacy during CHOP therapy. After the first cycle of RB, the patient exhibited an immediate response with the absence of minimal residual disease. He remained relapse-free for approximately 67 months. After a second relapse, complete response was again achieved with the absence of minimal residual disease following RB re-administration. He remained relapse-free for approximately 29 months after the second RB. Conclusion: RB could be a treatment option for patients with relapsed or refractory HCL-v. Further research is needed to establish the optimal treatment regimen for patients of HCL-v.

A 56-year-old woman was referred to our hospital with symptoms of swelling, purpura, and pain in her limbs. Prior to referral, bleeding in her limbs had spontaneously appeared and disappeared several times. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged, and the factor II level was 17%. The plasma-mixing test indicated lupus anticoagulant (LA), which was confirmed using aPTT-LA and dilute Russell's viper venom time (dRVVT). Therefore, she was diagnosed with lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS). During screening for underlying disorders, chest computed tomography (CT) revealed a retrosternal mass. Biopsy was not performed because the administration of freshly frozen plasma failed to correct her coagulopathy. Prednisolone (PSL) treatment (1 mg/kg) was initiated, which normalized the coagulation tests. The retrosternal mass also disappeared. PSL was tapered without LAHPS recurrence; however, the follow-up CT revealed systemic lymphadenopathy. Follicular lymphoma was diagnosed using lymph-node biopsy. Considering the subsequent LAHPS recurrence, six cycles of bendamustine + rituximab were administered. Complete response with no LAHPS recurrence was observed at the time of drafting this report. LAHPS is rare and distinct from antiphospholipid syndrome because it can cause severe bleeding. Underlying disorders should be evaluated in cases of LAHPS.

Chronic myeloid leukemia is driven by the BCR‐ABL oncoprotein, a constitutively active protein tyrosine kinase. Although tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of CML patients, the emergence of TKI resistance is an important clinical problem, which deserves additional treatment options based on unique biological properties to CML cells. In this study, we show that metabolic homeostasis is critical for survival of CML cells, especially when the disease is in advanced stages. The BCR‐ABL protein activates AMP‐activated protein kinase (AMPK) for ATP production and the mTOR pathway to suppress autophagy. BCR‐ABL is detected in the nuclei of advanced‐stage CML cells, in which ATP is sufficiently supplied by enhanced glucose metabolism. AMP‐activated protein kinase is further activated under energy‐deprived conditions and triggers autophagy through ULK1 phosphorylation and mTOR inhibition. In addition, AMPK phosphorylates 14‐3‐3 and Beclin 1 to facilitate cytoplasmic translocation of nuclear BCR‐ABL in a BCR‐ABL/14‐3‐3τ/Beclin1/XPO1 complex. Cytoplasmic BCR‐ABL protein undergoes autophagic degradation when intracellular ATP is exhausted by disruption of the energy balance or forced autophagy flux with AMP mimetics, mTOR inhibitors, or arsenic trioxide, leading to apoptotic cell death. This pathway represents a novel therapeutic vulnerability that could be useful for treating TKI‐resistant CML., BCR‐ABL is translocated to the nucleus under energy‐inflated conditions and returns to the cytoplasm, coinciding with priming of autophagy. Cytoplasmic BCR‐ABL succumbs to autophagic degradation when intracellular ATP is exhausted, providing a novel therapeutic vulnerability.

A 47-year-old man with acute myeloid leukemia and myelodysplastic-related changes relapsed after an allogenic bone marrow transplant and received a cord blood transplant as salvage therapy. The patient developed febrile neutropenia that was resistant to broad-spectrum antibiotics and multiple, painful, nodular skin lesions on his trunk and extremities before engraftment. A skin biopsy and blood culture found mold, and the subsequent microscopic examination, mass spectrometry, and DNA sequencing of the fungal colonies identified Fusarium solani. The patient's fever and skin lesions began to improve with the administration of liposomal amphotericin B at 5 mg/kg/day. Neutrophilic engraftment occurred on day 19. Stage 3 acute skin graft-versus-host disease was cured by the application of topical steroid. Unexpectedly, a change from liposomal amphotericin B to voriconazole on day 38 exacerbated the Fusarium infection. The Fusarium infection was finally cured by the administration of liposomal amphotericin B for a total of 19 weeks. Neutrophilic engraftment, an immediate definitive diagnosis, the sufficient and long-term administration of appropriate antifungal medication, and avoidance of the systemic administration of steroids might have contributed to the successful outcome of this patient.

The effect of the liquid crystal (LC) layer thickness on the optical characteristics of an ultrasound LC lens was explored. Three LC lenses with differing LC layer thicknesses (100, 200, and 300 μm) were fabricated, and the optical focal lengths were measured by an optical microscope with a varying driving voltage. For the lens with a 200 μm thick LC layer, a larger change in the focal length was observed for a smaller driving voltage compared with that of the other two lenses, indicating that the LC layer thickness is appropriate for a variable-focus lens.

Photoredox catalysis has driven a revolution in the field of organic chemistry, but direct mechanistic insights into reactions of genuine synthetic utility remain relatively scarce. Herein we report ultrafast time-resolved spectroscopic observation of a bimolecular organocatalyzed photoredox reaction, from catalyst photoexcitation through to photoinduced electron transfer (PET) and intermediate formation, using transient vibrational and electronic absorption spectroscopy with sub-picosecond time resolution. Specifically, the photochemical dynamics of initiation in organocatalyzed atom-transfer radical polymerization (O-ATRP) are elucidated for two complementary photoredox organocatalysts (N,N-diaryl-5,10-dihydrophenazines). Following photoexcitation, a dissociative bimolecular electron transfer is observed from the first excited singlet state of both photocatalysts to methyl 2-bromopropionate in dichloromethane, toluene, and dimethylformamide. The photocatalyst excited donor state, ground state, and radical cation are tracked in real time alongside the debrominated radical fragment. Our work challenges previously proposed mechanisms of initiation in O-ATRP and indicates that PET from short-lived excited singlet states can exert control of polymer molecular weight and dispersity by suppressing the steady-state concentration of the reactive debrominated radical. More broadly, we aim to demonstrate the potential of ultrafast absorption spectroscopy to observe directly transient, open-shell intermediates in mechanistic studies of photoredox catalysis.

Mantle cell lymphoma (MCL) is usually resistant to the current standard-of-care regimens and also to novel agents such as the proteasome inhibitor bortezomib. A better prognosis of leukemic variants of MCL suggests that MCL cells acquire drug resistance in nodal and/or bone marrow microenvironments via interaction with supporting cells. Bortezomib exerts cytotoxic action in MCL cells via stabilization of the pro-apoptotic BCL-2 family protein NOXA. Here we show that autophagic degradation of NOXA is a mechanism of bortezomib resistance in MCL cells in a tumor microenvironment. First, we demonstrated that interaction with bone marrow-derived or nodal stromal cells conferred bortezomib resistance to MCL cells in vitro and in a murine model. Co-culture of MCL cells with stromal cells enhanced bortezomib-induced ubiquitination and subsequent binding of NOXA to the p62 adaptor, which escorted NOXA to the lysosome for autophagic degradation. Finally, we found that not only direct contact with stromal cells but also stroma-derived humoral factors, especially interleukin-6, promoted selective autophagy and NOXA degradation in MCL cells. Targeting protective autophagy, for example, using the lysosome inhibitor chloroquine, might increase the efficacy of bortezomib-containing regimens in MCL.

Drug delivery systems (DDS) using ultrasound and microbubbles have been proposed to enhance drug efficacy and reduce undesirable side effects. While several researchers have reported the vibrational characteristics of lipid-coated microbubbles under ultrasound irradiation and the effects on cell damage, it is necessary to quantitatively evaluate the effects to establish the safety criteria of ultrasound DDS. In this paper, the effects of the microbubble behavior on adhesive HeLa cells under ultrasound irradiation were evaluated. Microbubbles coated with a phospholipid shell were fabricated and two size distributions of bubbles were prepared. The HeLa cells were exposed to pulsed ultrasound at 1 MHz with microbubbles in a water tank, and the cell mortality rate was measured quantitatively under fluorescent observation. The collapse of the microbubbles with a resonance size of approximately 2 μm enhanced the cell mortality rate. Greater sound pressure amplitude produced a higher collapsing rate of the microbubble and cell mortality rate, implying the destruction of microbubbles with resonance size generated a shock wave or microjet, inducing cell damage. While the cell mortality rate decreased exponentially with the increase in distance between cells and microbubbles, a smaller distance induced a higher cell mortality rate: 84% of the HeLa cells died within 2.5 μm of microbubbles produced by a pulsed ultrasound with 1.0 MPa at 1 MHz.

New technologies for adaptive optics are becoming increasingly important for miniature devices such as cell-phone cameras. In particular, motion-free autofocusing and optical image stabilization require sophisticated approaches for alternative lens architectures, materials, and processing to replace multiple solid elements. We discuss a new method, to the best of our knowledge, that provides image stabilization via an annular piezoelectric ceramic that uses ultrasound to drive a liquid crystal layer sandwiched between two circular glass substrates. The piezoelectric ceramic is divided into four quadrants that are independently driven with sinusoidal voltages at the resonant frequency of the lens. The technique is based on ultrasound vibrations with a suitable driving scheme. The lens configuration was modeled via finite-element analysis. Various combinations of the four-channel ultrasound transducer can be used to define the focal point of the liquid crystal lens. Clear optical images could be obtained with the lens. By using two-dimensional fast Fourier transforms, the focal point position was defined and shifted in the radial direction.

In this paper, we propose a ring-type grating in which grating vectors formed by periodic molecular alignments are superimposed radially. Depending on incident polarization states, the anisotropic gratings generate polarization dependencies for the ring-like first order diffraction. To determine the polarization states of incident light for both single and multi-wavelengths, we attempted to extract the optical intensity distribution on the ring-like diffraction from each single-shot diffraction image. In addition, a system that enables the detection of spatial modulation of optical birefringence is proposed. Finally, we concluded that the optical intensity distribution on the circumference of the ring-like diffraction has sufficient potential to be available.

To predict environmental changes and prevent disasters in rivers it is important to track how the size distributions of sand and stones in the riverbed change over time. In this paper, we used a passive piezoelectric sensor to measure the particle distribution of a simulated bed load. The sensor had a simple, robust structure consisting of a circular aluminum plate and an annular piezoelectric transducer. The detection characteristics were evaluated by measuring the impact of alumina spheres with diameters of 3–8 mm in air. When particles hit the sensor, the impact excited a flexural vibration in the circular plate, generating electric power through the piezoelectric effect. The electric output signal exhibited two main frequency peaks, at 16.3 and 66.7 kHz, whose amplitude ratio depended on particle size. These two frequencies correspond to the fundamental and third resonance vibration modes. When particles hit the sensor surface sequentially, we could determine their particle sizes from short-term frequency analysis of the observed voltage waveform.

The computationally predicted presence of two structurally distinct minima in the first triplet excited (T1) state of 2-thiouracil (2TU) is substantiated by sub-picosecond transient vibrational absorption spectroscopy (TVAS) in deuterated acetonitrile solution. Following 300-nm ultraviolet excitation to the second singlet excited state of 2TU, a transient infrared absorption band centered at 1643 cm-1 is observed within our minimum time resolution of 0.3 ps. It is assigned either to 2TU molecules in the S1 state, or to vibrationally hot T1 state molecules, with the latter assignment more consistent with recent computational and experimental studies. The 1643 cm-1 band decays with a time constant of 7.2 ± 0.8 ps, and there is corresponding growth of several further bands centered at 1234, 1410, 1424, 1443, 1511, 1626 and 1660 cm-1 which show no decline in intensity over the 1 ns time limit of our measurements. These spectral features are assigned to two different conformations of 2TU, corresponding to separate energy minima on the T1 state potential energy surface, on the basis of their extended lifetimes, computed infra-red frequencies, and the observed quenching of the bands by addition of styrene. Corresponding measurements for the 4-thiouracil (4TU) isomer show sub-picosecond population of the T1 state, which vibrationally cools with a time constant of 5.2 ± 0.6 ps. However, TVAS measurements in the carbonyl stretching region do not distinguish the two computed T1-state conformers of 4TU because of the similarity of their vibrational frequencies.

As biotechnology develops, techniques for manipulating and separating small particles such as cells and DNA are required in the life sciences. This paper investigates on-chip manipulation of microparticles in small channels by using ultrasonic vibration. The chip consists of a rectangular glass substrate with a cross-shaped channel (cross-section: 2.0×2.0mm2) and four lead zirconate titanate transducers attached to the substrate's four corners. To efficiently generate the flexural vibration mode on the chip, we used finite element analysis to optimize the configurations of the glass substrate and transducers. Silicon carbide microparticles with an average diameter of 50μm were immersed in the channels, which were filled with ethanol. By applying an in-phase input voltage of 75V at 225kHz to the four transducers, a flexural vibration mode with a wavelength of 13mm was excited on the glass substrate, and this flexural vibration generated an acoustic standing wave in the channel. The particles could be trapped at the nodal lines of the standing wave. By controlling the driving phase difference between the two pairs of transducers, the vibrational distribution of the substrate could be moved along the channels so that the acoustic standing wave moved in the same direction. The trapped particles could be manipulated by the two-phase drive, and the transport direction could be switched at the junction of the channels orthogonally by changing the combination of the driving condition to four transducers.

Graft failure (GF) remains an obstacle to survival after allogeneic hematopoietic stem cell transplantation. However, differentiating GF from delayed engraftment (DE) can be difficult. Host CD8+ lymphocytes have been reported to mediate graft rejection, but the impact of macrophages on DE or GF is yet to be clarified. Peri-engraftment bone marrow (BM) specimens of 32 adult patients with normal engraftment, DE or GF were retrospectively evaluated to identify the potential associations of CD163+ macrophage and CD8+ lymphocyte infiltration into BM. The macrophage or CD8+ lymphocyte number/total nucleated cell number was defined as the Mac ratio and CD8 ratio, respectively. Both DE and GF groups had significantly higher Mac ratios at day 14 than the normal group (P

The mechanism of the thiol-ene reaction induced by 330-nm ultraviolet excitation of 1,2-di(quinolin-2-yl)disulfide (QSSQ) in the presence of methyl methacrylate (MMA) is investigated by sub-picosecond to microsecond transient absorption spectroscopy. The measurements, spanning more than seven orders of magnitude of time, directly reveal multiple radical reaction steps. The ground state quinoliene-2-thiyl radical (QS) is formed with a time constant of ~200 fs by photolysis of QSSQ, followed by (64 ± 1)% decay of the initially formed QS radical because of solvent cage induced geminate recombination and QS dimer formation with a rate coefficient of (3.4 ± 0.2) × 1010 M-1 s-1 in methanol solution. In MMA solution, the carbon centered radical QS-MMA forms with a bimolecular reaction rate coefficient of (2.8 ± 0.2) × 107 M-1 s-1. The distinct infrared band at 1653 cm-1 assigned to the C=O stretch mode of the QS-MMA radical decays rapidly in aerated solution, in contrast to observations in a solution purged of O2 by N2 bubbling. This decay is attributed to reaction of the QS-MMA radicals with molecular oxygen, producing peroxy radicals. Kinetic analysis of the intensity of the band at 1653 cm-1 reveals a bimolecular reaction rate coefficient of (3.3 ± 0.3) × 109 M-1 s-1 for the reaction of the QS-MMA radicals with molecular oxygen, and indicates that this reaction step is reversible.

The viscosity and the surface profile of a thixotropic gel were controlled via ultrasound vibrations. The ultrasound device consisted of two piezoelectric lead zirconate titanate transducers glued to each end of a 60-mm-long rectangular glass substrate. It generated a 71-kHz flexural standing wave along the length. A 0.9-mm-thick thixotropic gel film made from silicone oil and hydrophobic fumed silica was formed on the glass substrate. The ultrasound vibration decreased the film viscosity, and its surface profile could be changed by the acoustic radiation force acting from the gel to the surrounding air, generated by the flexural vibration of the substrate. The transient response of the surface profile was observed by switching the ultrasound excitation ON and OFF. When the excitation was switched OFF, the gel displacement gradually decreased, but the surface profile did not return to that of the initial steady state, indicating that the viscosity recovered in time to preserve the surface profile. When a pulsed megahertz (MHz) signal was used to control the gel deformation, the surface profile rapidly approached the initial steady-state profile after the excitation.

Microbubbles shelled with soft materials are expected to find applications as ultrasound-sensitive drug delivery systems, including through sonoporation. Microbubbles with specific vibrational characteristics and long intravascular persistence are required for clinical uses. To achieve this aim, the kinetics of the microbubble shell components at the gas/liquid interface while being subjected to ultrasound need to be better understood. This paper investigates the vibration characteristics and lifetime of single microbubbles coated with a poloxamer surfactant, Pluronic F-68, and 1,2-dimyristoyl

In this paper, we consider a robust stability condition of the double feedback control system with low-sensitivity for single-input/single-output time-delay system having an uncertainty in which has a varying number of the closed right half plane. The robust stability problem is to stabilize the control system for the uncertainty. The control system is made robust stability if the complementary sensitivity function of the control system is made small value. On other hands, the control system has the low-sensitivity characteritics such as reducing the influence of uncertaity, the disturbance and etc. if the sensitivity function of the control system is made small value. However, it is difficult that the control system with robust stability has the low-sensitivity characteristics because the sum of the sensitivity function and the complementary sensitivity function is equal to 1. According to Yamada and Yu et al., we can construct the high-performance control system such as having the robust stability and low-sensitivity. The aim of this paper is to expand the result of Yamada and Yu et al. and propose the design method of the control system with robust stablity and low-sensitivity by reducing the influence of uncertainty.

International audience; Microbubbles have potential for applications as drug and gene delivery systems in which the release of a substance is triggered by an ultrasonic pulse. In this paper, we discuss the adsorption and desorption of a film of phospholipid on the surface of a single microbubble under ultrasound irradiation. Our optical observation system consisted of a high-speed camera, a laser Doppler vibrometer, and an ultrasound cell; 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) was used as the surfactant. The adsorption of the DMPC molecules onto the surface of the bubble was evaluated by measuring the contact angle between the bubble and a glass plate. A decrease of the contact angle of the bubble indicates desorption of the DMPC molecules from the bubble surface into the surrounding aqueous solution. The amount of DMPC molecules adsorbed on the bubble’s surface is shown to decrease over time after bubble generation. The type and intensity of the pulsed ultrasound waves were varied so as mimic ultrasound triggered drug release. Increasing the number of cycles and the amplitude of the sound pressure of the pulsed ultrasound yielded a greater increase of the contact angle. We also measured the radial vibrations of the microbubbles in the ultrasound field. The vibrational characteristics of the microbubbles and the desorption characteristics of the DMPC molecules showed the same variation; namely, a greater sound pressure amplitude induced greater vibrational displacement and a larger amount of molecular desorption under resonance conditions. These results support the possibility of controlling drug release with pulsed ultrasound in a microbubble-based drug delivery system.

A new type of ultrasonically controlled concave liquid crystal lens based on traveling waves (TWs) with a divided electrode structure and an appropriate driving scheme is proposed in this Letter. The lens uses an annular piezoelectric ceramic divided into four parts for four-phase driving and consists of a liquid crystal layer in a sandwich structure between two circular glass substrates. The lens configuration was simulated by finite element analysis using the Ansys software. Here we discuss the use of TWs to expand the lens aperture and clarify the lens’ optical characteristics using a Shack–Hartmann wavefront sensor. The effective lens aperture using TWs was 4.4 mm, and the focal length was 3.8 m.

The success rate of low-intensity pulsed ultrasound (LIPUS) therapy depends on the bone site. However, the initial mechanism of physical stimulation by ultrasound and bone cellular response remains unclear. One possible physical stimulation is the induced electrical potentials due to the piezoelectricity. In this study, the output electrical potentials of ultrasound transducers made from bovine bones were investigated. Transducers made from the radius bone showed the largest electric potentials, followed by tibia, femur, and humerus. There was clear site dependence of the induced electric potentials of bone, in good accordance with the success rate of LIPUS therapy.

Programmed death-ligand 1 (PD-L1) binds to programmed death-1 (PD-1) on activated T cells and contributes to T-cell exhaustion. PD-L1 expressed on antigen-presenting cells (APCs) could be thought to inhibit the induction of Ag-specific cytotoxic T lymphocytes (CTLs) by transducing negative signal into T cells; however, the roles of PD-L1 on APCs have not yet been well examined. Therefore, we evaluated the roles of PD-L1 on APCs in the induction of Ag-specific CTLs. CD3 T cells isolated from cytomegalovirus (CMV)-seropositive healthy donors were stimulated with mature dendritic cells pulsed with CMV pp65-derived HLA-restricted peptides in the presence of anti-PD-L1 blocking antibody. Unexpectedly, PD-L1 blockade resulted in a less efficient induction of CMV-specific CTLs, suggesting that PD-L1 play a positive role in the induction of Ag-specific CTLs. For further evaluations and application to adoptive immunotherapy, we generated K562-based artificial APCs, which were retrovirally transduced with HLA class I molecules and various combinations of CD80/86 and PD-L1. K562/HLA+CD80/86+PD-L1 cells produced significantly higher induction of CMV-specific CTLs than K562/HLA or K562/HLA+CD80/86 cells without causing excessive differentiation or functional exhaustion of the induced CTLs, whereas PD-L1 itself did not have a stimulatory effect. Furthermore, only K562/HLA+CD80/86+PD-L1 cells pulsed with HLA-A*24:02-restricted Wilms tumor 1 (WT1) peptide clearly expanded WT1-specific CTLs from healthy donors. Our findings presumed that PD-L1 expressed on APCs along with CD80/86 enhanced the induction of Ag-specific CTLs probably depending on fine-tuning excessive stimulation of CD80/86, and that K562/HLA+CD80/86+PD-L1 cells has therapeutic potential as a novel type of artificial APCs for adoptive immunotherapy.

T cells genetically modified with a CD19 chimeric antigen receptor (CD19CAR) are remarkably effective against B-cell malignancies in clinical trials. However, major concerns remain regarding toxicities, such as hypogammaglobulinemia, due to B-cell aplasia or severe cytokine release syndrome after overactivation of CAR T cells. To resolve these adverse events, we aimed to develop an inducible CAR system by using a tetracycline regulation system that would be activated only in the presence of doxycycline (Dox). In this study, the second-generation CD19CAR was fused into the third-generation Tet-On vector (Tet-CD19CAR) and was retrovirally transduced into primary CD8+ T cells. Tet-CD19CAR T cells were successfully generated and had minimal background CD19CAR expression without Dox. Tet-CD19CAR T cells in the presence of Dox were equivalently cytotoxic against CD19+ cell lines and had equivalent cytokine production and proliferation upon CD19 stimulation, compared with conventional CD19CAR T cells. The Dox(+) Tet-CD19CAR T cells also had significant antitumor activity in a xenograft model. However, without Dox, Tet-CD19CAR T cells lost CAR expression and CAR T-cell functions in vitro and in vivo, clearly segregating the “On” and “Off” status of Tet-CD19CAR cells by Dox administration. In addition to suicide-gene technology, controlling the expression and the functions of CAR with an inducible vector is a potential solution for CAR T-cell therapy–related toxicities, and may improve the safety profile of CAR T-cell therapy. This strategy might also open the way to treat other malignancies in combination with other CAR or TCR gene–modified T cells. Cancer Immunol Res; 4(8); 658–68. ©2016 AACR. See related Spotlight by June, p. 643.

The experimental investigation of an optical fiber Bragg grating (FBG) sensor for biomedical application is described. The FBG sensor can be used to measure sound pressure and temperature rise simultaneously in biological tissues exposed to ultrasound. The theoretical maximum values that can be measured with the FBG sensor are 73.0 MPa and 30 °C. In this study, measurement of sound pressure up to 5 MPa was performed at an ultrasound frequency of 2 MHz. A maximum temperature change of 6 °C was measured in a tissue-mimicking material. Values yielded by the FBG sensor agreed with those measured using a thermocouple and a hydrophone. Since this sensor is used to monitor the sound pressure and temperature simultaneously, it can also be used for industrial applications, such as ultrasonic cleaning of semiconductors under controlled temperatures.