Search

Immune checkpoint inhibitors (ICIs) are widely used for the treatment of various cancers. However, paradoxical exacerbation of neoplasms, referred to as "hyperprogressive disease," has been reported in a proportion of patients treated with anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) blockade. We herein report a case of acute adult T-cell leukemia (ATL) that developed shortly after the administration of nivolumab, a PD-1 inhibitor, to treat non-small-cell lung cancer. There were no signs of ATL before the administration of nivolumab, and seropositivity for human T-cell leukemia virus type-1 (HTLV-1) was confirmed after the development of acute ATL. We speculate that nivolumab likely contributed to the development of acute ATL.

A varifocal concave-convex lens using ultrasound and transparent viscoelastic gel is reported. The configuration of the lens is simple and thin, consisting of four pieces of a piezoelectric ultrasound transducer, a glass disk, and a transparent silicone gel film. It uses a combination of the ultrasound resonant flexural standing- and traveling-wave modes excited by in-phase and four-phase drives so that the lens can change its shape to both concave and convex by switching the resonance mode with the same structure. The acoustic radiation force (ARF) originated from the resonant flexural vibration modes changed the surface profile of the gel. Convex and concave deformation were generated at the center of the lens at the resonance frequencies of 38 and 60 kHz, respectively, indicating that a varifocal concave-convex lens could be fabricated by controlling the driving frequency, voltage amplitude, and phase differences among the ultrasound transducers. The deformational displacement on the lens surface and the change in the focal length increased with the input voltage amplitude. The optical microscopic images observed through the lens were enlarged 1.28× (reduced 0.92× ) in the convex (concave) mode with 20 [Formula: see text]. The response time for focusing and the temperature stability under operation were evaluated. By switching the resonance vibration modes of the lens through the input signals to multiple ultrasound transducers, the variable-focus function with both concave and convex lenses was achieved in the same configuration.

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.

pRetroX-TetOne vector sequence with CD19CAR and tEGFR

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.

Sequence data of CD3zeta and ATAM

CAR expression and the subsequent function of Tet-CD19CAR T cells can be precisely regulated in a dose-dependent manner.

Safety profile of Tet-CD19CAR T cells against autologous B cells.

Sequence data of CD3 and ATAM

Supplementary Materials and Methods, Tables S1-5, and Figures S1-9

Rapid reperfusion therapy can reduce disability and death in patients with large vessel occlusion strokes (LVOS). It is crucial for emergency medical services to identify LVOS and transport patients directly to a comprehensive stroke center. Our ultimate goal is to develop a non-invasive, accurate, portable, inexpensive, and legally employable in vivo screening system for cerebral artery occlusion. As a first step towards this goal, we propose a method for detecting carotid artery occlusion using pulse wave measurements at the left and right carotid arteries, feature extraction from the pulse waves, and occlusion inference using these features. To meet all of these requirements, we use a piezoelectric sensor. We hypothesize that the difference in the left and right pulse waves caused by reflection is informative, as LVOS is typically caused by unilateral artery occlusion. Therefore, we extracted three features that only represented the physical effects of occlusion based on the difference. For inference, we considered that the logistic regression, a machine learning technique with no complex feature conversion, is a reasonable method for clarifying the contribution of each feature. We tested our hypothesis and conducted an experiment to evaluate the effectiveness and performance of the proposed method. The method achieved a diagnostic accuracy of 0.65, which is higher than the chance level of 0.43. The results indicate that the proposed method has potential for identifying carotid artery occlusions.

The oscillation of shelled microbubbles during exposure to ultrasound is influenced by the mechanical properties of the shell components. The oscillation behavior of bubbles coated with various phospholipids and other amphiphiles has been studied. However, there have been few investigations of how the adsorption conditions of the shell molecules relate to the viscoelastic properties of the shell and influence the oscillation behavior of the bubbles. In the present study, we investigated the oscillation characteristics of microbubbles coated with a poloxamer surfactant, that is, Pluronic F-68, at several concentrations after the adsorption kinetics of the surfactant at the gas-water interface had reached equilibrium. The dilatational viscoelasticity of the shell during exposure to ultrasound was analyzed in the frequency domain from the attenuation characteristics of the acoustic pulses propagated in the bubble suspension. At Pluronic F-68 concentrations lower than 2.0 × 10

Adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have led to impressive clinical outcomes in B cell malignancies. Beyond induction of remission, the persistence of CAR-T cells is required to prevent relapse and provide long-term disease control. To improve CAR-T cell function and persistence, we developed a composite co-stimulatory domain of a B cell signaling moiety, CD79A/CD40, to induce a nuclear translocating signal, NF-κB, to synergize with other T cell signals and improve CAR-T cell function. CD79A/CD40 incorporating CD19CAR-T cells (CD19.79a.40z) exhibited higher NF-κB and p38 activity upon CD19 antigen exposure compared with the CD28 or 4-1BB incorporating CD19CAR-T cells (CD19.28z and CD19.BBz). Notably, we found that CD19.79a.40z CAR-T cells continued to suppress CD19(+) target cells throughout the co-culture assay, whereas a tendency for tumor growth was observed with CD19.28z CAR-T cells. Moreover, CD19.79a.40z CAR-T cells exhibited robust T cell proliferation after culturing with CD19(+) target cells, regardless of exogenous interleukin-2. In terms of in vivo efficiency, CD19.79a.40z demonstrated superior anti-tumor activity and in vivo CAR-T cell proliferation compared with CD19.28z and CD19.BBz CD19CAR-T cells in Raji-inoculated mice. Our data demonstrate that the CD79A/CD40 co-stimulatory domain endows CAR-T cells with enhanced proliferative capacity and improved anti-tumor efficacy in a murine model.

A variable focus optical lens using a thixotropic gel and ultrasonic vibration is discussed. The surface profile of the gel could be deformed via acoustic radiation force generated by ultrasound. A thixotropic gel in which the viscosity was changed by shear stress was employed as a transparent lens material. The thixotropic gel allowed the lens to maintain shape deformation in the absence of continuous ultrasound excitation. The lens had a simple structure with no mechanical moving parts and included an annular piezoelectric transducer, a glass disk, and the thixotropic gel film. The axisymmetric concentric flexural vibration mode was generated on the lens at 71 kHz, which resulted in static surface deformation of the gel via the acoustic radiation force. The preservation rate was investigated after switching off the ultrasonic excitation. There was a trade-off between the preservation rate of the lens deformation and the response time for focusing. The focal length could be controlled via the input voltage to the lens, and a variable-focus convex lens could be realized; the change in the focal length with 4.0 Vpp was 0.54 mm. The optical transmittance of the lens was measured and the transmittance ranged 70%–80% in the visible spectral region.

To understand the in-plane elastic character of ultrasonic waves in the skull, longitudinal wave velocities were studied in the MHz range using a conventional pulse technique. Taking advantage of the thickness of swine skulls, anisotropic in-plane wave velocity changes in the outer and diploe layers were experimentally investigated using structural information measured by X-ray computer tomography (CT). The velocities in the thin inner layer were difficult to measure. The main trabecular alignment (MTA) in the thick swine diploe layer was almost perpendicular to the thickness direction and changed with position inside the skull. The degree of anisotropy of in-plane longitudinal wave velocity ranged 1.07-1.33 in both outer and diploe layers, depending on position and swine sample. The angle of the fastest velocity in the outer layer was different from that in most parts of the diploe layer. Anisotropic character in the diploe layer gradually changed with position in the thickness direction.

Piezoelectricity in bone is thought to be a mechanism by which ultrasound promotes the healing of bone fractures. However, a few studies have been conducted in the more clinically relevant megahertz range. To understand the piezoelectricity in bone, we fabricated ultrasound transducers using bone samples as piezoelectric materials and identified the longitudinal ultrasound radiation and reception in the megahertz range. The maximum transmitting sensitivity of the bone transducer was 140 mPa/V, which was nearly 1/1000 of a polyvinylidene difluoride (PVDF) transducer that has better electrical properties and piezoelectricity. The resonance frequencies of the transducer depend on the plate thickness and angle between the bone axis (alignment direction of the hydroxyapatite crystallites) and ultrasound propagation direction, reflecting the anisotropic character of the bone. The reception and transmission sensitivities of the bone transducers also depend on the plate thickness and angle, showing maximum values at off-axis angles. These results indicate the existence of both piezoelectricity and inverse piezoelectricity in bone, which may be key factors in understanding the bone healing by low-intensity biophysical (electrical or mechanical) stimulation.

Objective To prolong the health expectancy, it is important to prevent age-related diseases, such as osteoporosis and cerebrovascular disease, which are major causes of a bedridden state. Early predictable biomarkers for these diseases are urgently required in the clinical setting. Three members of the fibroblast growth factor (FGF) family - FGF19, FGF21, and FGF23 - are designated as endocrine FGFs and play crucial roles in various metabolic processes. We tried to clarify the clinical utility of endocrine FGFs as biomarkers for age-related diseases in elderly patients. Methods We examined the serum endocrine FGF levels and analyzed their association with various clinical parameters in 73 outpatients >60 years old as a single-center cross-sectional study. Results In a multivariable linear regression analysis, FGF19 was associated with ALT, a history of cardiovascular disease, and medication with active vitamin D3. FGF21 was associated with the estimated glomerular filtration rate (eGFR), triglyceride level, and hypertension. FGF23 was associated with the eGFR and the serum levels of 1,25-dihydroxy vitamin D3 and TRACP5b. In addition, a receiver operating characteristics analysis revealed that the measurement of FGF21 and FGF23 was useful for detecting chronic kidney disease (CKD) and its complications, including cardiovascular disease and metabolic bone disorder. Conclusion The measurement of FGF21 and FGF23 may be useful for evaluating CKD and its complications. Using serum endocrine FGFs as biomarkers for age-related conditions may help prevent elderly patients from entering a bedridden state.

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

This study investigated a method to control neurite outgrowth direction using ultrasound vibration. An ultrasound cell culture dish comprising a glass-bottom culture surface and a glass disc with an ultrasound transducer was fabricated, and undifferentiated neuron-like PC12 cells were grown on the dish as an adherent culture. The 78 kHz resonant concentric flexural vibration mode of the dish was used to quantitatively evaluate the neurite outgrowth direction and length. Time-lapse imaging of cells was performed for 72 h under ultrasound excitation. Unsonicated neurites grew in random directions, whereas neurite outgrowth was circumferentially oriented during ultrasonication in a power-dependent manner. The neurite orientation correlated with the spatial gradient of the ultrasound vibration, implying that neurites tend to grow in directions along which the vibrational amplitude does not change. Ultrasonication with 30 Vpp for 72 h increased the neurite length by 99.7% compared with that observed in unsonicated cells.

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.

In this paper, we consider a condition of the control system with low-sensitivity and robust stability and fault-tolerant using double feedback control. Several researchers study the robust stabilization problem. Yu et al. propose a double feedback control system. However, Yu et al. do not consider a problem of fault-tolerant control using double feedback control. In this paper, we consider a condition of the control system with low-sensitivity and robust stability and fault-tolerant using double feedback control.

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.