WT1 Trio Peptide-Based Cancer Vaccine for Rare Cancers Expressing Shared Target WT1.

No standard treatment has been established for most rare cancers. Here, we report a clinical trial of a biweekly WT1 tri-peptide-based vaccine for recurrent or advanced rare cancers. Due to the insufficient number of patients available for a traditional clinical trial, the trial was designed for rare cancers expressing shared target molecule WT1. The recruitment criteria included WT1-expressing tumors as well as HLA-A*24:02 or 02:01. The primary endpoints were immunoglobulin G (IgG) antibody (Ab) production against the WT1-235 cytotoxic T lymphocyte (CTL) epitope and delayed-type hypersensitivity (DTH) skin reactions to targeted WT1 CTL epitopes. The secondary endpoints were safety and clinical efficacy. Forty-five patients received WT1 Trio, and 25 (55.6%) completed the 3-month protocol treatment. WT1-235 IgG Ab was positive in 88.0% of patients treated with WT1 Trio at 3 months, significantly higher than 62.5% of the weekly WT1-235 CTL peptide vaccine. The DTH positivity rate in WT1 Trio was 62.9%, which was not significantly different from 60.7% in the WT1-235 CTL peptide vaccine. The WT1 Trio safety was confirmed without severe treatment-related adverse events, except grade 3 myasthenia gravis-like symptoms observed in a patient with thymic cancer. Fifteen (33.3%) patients achieved stable disease after 3 months of treatment. In conclusion, the biweekly WT1 Trio vaccine containing the WT1-332 helper T lymphocyte peptide induced more robust immune responses targeting WT1 than the weekly WT1-235 CTL peptide vaccine. Therefore, WT1-targeted immunotherapy may be a potential therapeutic strategy for rare cancers.

Comparison of the mechanical properties and mechanical damages to tendon tissue in three suspensory fixation techniques.

Background: Anterior cruciate ligament (ACL) injury is the most common traumatic injury to the knee joint. Suspensory fixation has become popular in ACL reconstruction because of its high primary stability, less invasiveness, and surgical convenience. There are two common types of suspensory fixation devices: those with fixed-length and those with adjustable-length loops. Owing to structural differences and differences in initial tensioning techniques, it is expected that mechanical property and damage to the tendons will vary from device to device; however, no literature has examined this so far. The main purpose of this study was to evaluate the damage caused to the tendon by three different suspensory fixation devices. An effective mechanical test was carried out as a prerequisite. Methods: First, the mechanical properties of simple loop device (SLD) as fixed-length loop device, first-generation, and second-generation adjustable devices (AD1 and AD2) as adjustable-length loop devices were tested (isolated device testing). Second, each device was tested using bovine extensor tendons (specimen testing). Cyclic testing included 2000 cycles; the devices were subsequently displaced until failure, and the ultimate tensile strength was determined using isolated device testing. Six samples of 3 devices were used in each testing experiment. After specimen testing, the surface structure of the tendon was evaluated quantitatively using optical coherence tomography (OCT) and our original histological scoring system. Results: During isolated device testing, SLD demonstrated the least cyclic displacement, followed by AD1 and AD2. The highest ultimate tensile strength was observed in AD2, followed by SLD and AD1. In specimen testing, the least cyclic displacement was observed in SLD, followed by AD1 and AD2. Histologically, AD1 demonstrated a significantly lower score, with damaged surface morphology, than SLD and AD2. OCT values were significantly higher, with a more disturbing tendon surface structure, in AD1 than in SLD and AD2. Conclusions: The first-generation adjustable loop device exhibited greatest graft tissue damage at the suspensory site in a clinically relevant setting. The thinner adjustable loop mechanism may have elevated graft damage by frictional stresses during loop adjustment or by repetitive tensioning stresses.

Comparison between gradient and spin-echo (GRASE) and compressed sensing sequences for single breath-hold three-dimensional magnetic resonance cholangiopancreatography in patients with T1 hyperintense bile.

PURPOSE: To compare image quality and the detectability of gallstones in patients with T1 hyperintense bile between single breath-hold three-dimensional (3D) magnetic resonance cholangiopancreatography (MRCP) with gradient and spin-echo (GRASE) and with compressed sensing (CS). METHODS: We retrospectively evaluated patients who underwent MRCP using GRASE and CS and had hyperintense bile on T1-weighted fat-suppressed images. The relative duct-to-periductal contrast ratios (RCs) of each bile duct segment were calculated. Pancreaticobiliary duct visibility, motion artifacts, background suppression, and overall image quality were scored on a 5-point scale. The Wilcoxon signed-rank test was used to analyze differences in qualitative and quantitative results. Diagnostic performance in detecting common bile duct (CBD) and gallbladder stones was assessed using receiver operating characteristic (ROC) curves. RESULTS: In total, 96 patients were included in the study. RCs of all bile duct segments in GRASE MRCP were significantly lower than those in CS MRCP (p < 0.001). All biliary duct visibility and overall image quality had significantly higher scores in GRASE MRCP than in CS MRCP (p < 0.001-0.003). Area under ROC curves of GRASE MRCP and CS MRCP were 1.00 and 0.88 for CBD stone (p = 0.14) and 0.93 and 0.82 for gallbladder stone (p = 0.08), respectively. CONCLUSIONS: GRASE MRCP provides better image quality than CS MRCP in patients with hyperintense bile on T1-weighted images. The detectability of biliary stones was also higher in GRASE MRCP than in CS MRCP, although not significantly.

The effects of massage velocity on heart rate and heart rate variability in healthy infants: A randomized crossover study.

BACKGROUND: Infant massage, in which mothers stroke their infant's skin slowly and gently, can cause pleasant sensations in the infant that can be affected by the velocity of massage. However, the massage velocity at which infants feel the most pleasant sensations remains unclear. OBJECTIVE: To investigate the effects of massage velocity on heart rate (HR) and HR variability (HRV) in healthy infants. METHOD: Twenty-two infant-mother dyads two to seven months of age were recruited. Mothers stroked their infant's skin at three massage velocities (5.0, 7.5, and 10.0 cm/s) in a randomized order for 15 min. The rhythm of massage velocity was calculated according to the length of three body areas. The massage velocity of the mothers was regulated using a metronome. HR and HRV (high frequency [HF] and low frequency [LF]) were measured at rest and during massage for each velocity. The effects on pleasantness were evaluated using percent change in median baseline value compared with median values for the three massage velocities. Statistical analysis was performed using analysis of variance mixed effect models to exclude "period" and "carryover" effects during massage. RESULTS: When measuring HF, massage (7.5 cm/s) caused a significant increase in pleasantness compared with 10.0 cm/s (p = 0.04). The HR and LF/HF ratio were not significantly changed between velocities. CONCLUSION: Results of this study suggested that a massage velocity of 7.5 cm/s was the most pleasant for infants. Future research should investigate the relationship between an infant massage by optimal velocity and infant development in longitudinal studies.

Analysis of sweating by optical coherence tomography in patients with palmoplantar hyperhidrosis.

Optical coherence tomography (OCT) is a high-resolution tomographic imaging technique that uses optical interference. OCT has enabled the non-invasive three-dimensional analysis of individual acrosyringia in the stratum corneum in human skin. However, no report on the measurement of sweating by OCT using clinical data from humans has been published to date. Twenty patients with hyperhidrosis and twenty healthy subjects were included in this study. Imaging of acrosyringia in the stratum corneum using OCT and measurement of the sweat rate using the ventilated capsule method were performed simultaneously. The hand grip exercise of the right hand was used as a load to induce sweating, and the left fingertip was measured before and after the exercise load. Five acrosyringia were extracted from each OCT image, and their volumes were calculated. The mean volume of each acrosyringium was divided by the thickness of the stratum corneum to calculate the mean cross-sectional area of the acrosyringium. Furthermore, the number of sweat droplets on the skin surface was measured. The mean cross-sectional area of acrosyringia after the load increased both in patients with hyperhidrosis and in healthy subjects (P < 0.001). The mean cross-sectional area of acrosyringia of patients with hyperhidrosis was larger than that of healthy subjects (P < 0.001). The mean cross-sectional area of acrosyringia and the sweat rate showed a positive correlation before and after the load (r = 0.88 to 0.91). The number of droplets also increased after the load (P < 0.001), and the number of droplets in patients with hyperhidrosis was higher than in healthy subjects (P < 0.001). Our study has shown that acrosyringia in the stratum corneum increase in proportion to the sweat rate. OCT is a rigorous and valuable method that can measure and quantify sweating in the body without being an invasive procedure.

Dynamic analysis of mental sweating of the sweat glands and peripheral vessels by optical coherence tomography.

The sweat gland and peripheral vessels underneath skin are a typical minute organ governed by the sympathetic nerve, and have important physiology functions to control of body temperature and maintenance. In this paper, we demonstrated the dynamic analysis of the mental sweating of the eccrine sweat glands and the dynamics of the small artery of human finger by optical coherence tomography (OCT). In the experiment of mental sweating, not only time variation of the amount of excess sweat can be evaluated simultaneously a few tens of sweat glands eccrine sweat glands but also the dynamics of peripheral vessels of a human finger were analyzed.

Claudin-3 Loss Causes Leakage of Sweat from the Sweat Gland to Contribute to the Pathogenesis of Atopic Dermatitis.

The transfer of sweat to the skin surface without leakage is important for the homeostatic regulation of skin and is impaired in atopic dermatitis. Although the precise composition of the leakage barrier remains obscure, there is a large contribution from claudins, the major components of tight junctions. In humans, claudin-1, -3, and -15 are expressed on sweat ducts, and claudin-3 and -10 are expressed on secretory coils. Although only two claudins are expressed in murine sweat glands, we found that the expression of claudin-3 is conserved. Atopic dermatitis lesional skin had decreased claudin-3 expression in sweat glands, which was accompanied by sweat leakage. This critical role in water barrier function was confirmed in Cldn3-/- and Cldn3+/- mice and those with experimentally decreased claudin-3. Our results show the crucial role of claudin-3 in preventing sweat gland leakage and suggest that the pathogenesis of dermatoses accompanied by hypohidrosis involves abnormally decreased claudin-3.

Dynamic analysis of mental sweating of eccrine sweat gland of human fingertip by time-sequential piled-up en face optical coherence tomography images.

In this paper, we demonstrate dynamic analysis of mental sweating for sound stimulus of a few tens of eccrine sweat glands by the time-sequential piled-up en face optical coherence tomography (OCT) images with the frame spacing of 3.3 sec. In the experiment, the amount of excess sweat can be evaluated simultaneously for a few tens of sweat glands by piling up of all the en face OCT images. Non-uniformity was observed in mental sweating where the amount of sweat in response to sound stimulus is different for each sweat gland. Furthermore, the amount of sweat is significantly increased in proportion to the strength of the stimulus.

Application to skin physiology using optical coherence tomography.

Background and aims: The sweat glands and peripheral vessels beneath the skin surface act as minute organs governed by the skin sympathetic nerves and have important physiological functions for body temperature control and nutrition support along with maintenance of a peripheral organization. Dynamics of the mental sweating of sweat glands and the peripheral vessels reflect the activity of a sympathetic nerve. The purpose of this paper is to study the dynamic observation and analysis of sweat glands and a peripheral vessels by optical coherence tomography (OCT). Materials and Methods: In the dynamic analysis of mental sweating of sweat glands, after confirmation of the resting state of the volunteer, mental stress was applied in the form of unpleasant sound for 0.5 sec; piled-up en-face OCT images of sweat glands were then obtained time-sequentially, with the frame-spacing of 3.3 sec. A swept-source (SS) OCT was used for in vivo en-face OCT of a group of sweat glands on the subject's fingertip. Furthermore, we conducted in vivo dynamic analysis in response to external mental stress of a peripheral vessel in the second joint of the subject's third finger using 1.3-µm SS OCT. Results: We analyzed time variation in the amount of excess sweat produced by a group of sweat glands and found a large difference in the amount of sweat stored by each sweat gland in the spiral lumen. Mental stress was also shown to cause the small artery of the finger to contract, reducing blood flow. In particular, the thickness of the tunica media of the small artery changed abruptly in response to the sound stress, increasing and then decreasing so that the artery contracted and expanded, respectively. Conclusions: Dynamic analysis of mental sweating in the eccrine sweat glands and changes in peripheral vessels was performed using time-sequential OCT imaging. For mental sweating, time variation in the amount of excess sweat produced could be simultaneously evaluated for a few tens of eccrine sweat glands. Furthermore, we performed the dynamic analysis of a peripheral vessel in a human finger in response to external mental stress and found that the small artery contracted and expanded in response to sound stress while continuing to pulse in synchronization with the heartbeat. These studies have the potential for establishing new knowledge about skin physiology.

Nondestructive observation of teeth post core-space using optical coherence tomography: comparison with microcomputed tomography and live images.

No previous reports have observed inside the root canal using both optical coherence tomography (OCT) and x-ray microcomputed tomography (µCT) for the same sample. The purpose of this study was to clarify both OCT and µCT image properties from observations of the same root canal after resin core build-up treatment. As OCT allows real-time observation of samples, gap formation may be able to be shown in real time. A dual-cure, one-step, self-etch adhesive system bonding agent, and dual-cure resin composite core material were used in root canals in accordance with instructions from the manufacturer. The resulting OCT images were superior for identifying gap formation at the interface, while µCT images were better to grasp the tooth form. Continuous tomographic images from real-time OCT observation allowed successful construction of a video of the resin core build-up procedure. After 10 to 12 s of light curing, a gap with a clear new signal occurred at the root-core material interface, proceeding from the coronal side (6 mm from the cemento-enamel junction) to the apical side of the root.

Nondestructive observation of teeth post core space using optical coherence tomography: a pilot study.

Coronal tooth lesions, such as caries, enamel cracking, and composite resin restoration cavities, have been observed by optical coherence tomography (OCT). This pilot study was performed to verify whether OCT could reveal details of root canals filled with resin core build-up. A dual-cure, one-step, self-etch adhesive system-bonding agent (Clearfil Bond SE ONE, Kuraray Noritake Dental) and dual-cure resin composite core material (Clearfil DC Core Automix ONE, Kuraray Noritake Dental) were used according to the manufacturer's instructions in root canals. OCT was performed at three stages of the core build-up: after the post space preparation, after bonding application, and after resin core fabrication. The cementum was removed in the cementum absent group and the root was left untreated in the cementum present group. Bubbles were observed in the resin cores and gaps formed between the resin core and dentin. In the cementum absent group, the internal structure of the root could be visualized clearly compared with the cementum present group. The root internal structure could be observed by OCT and the image became clearer when cementum was removed.

Dynamic analysis of histamine-mediated attenuation of acetylcholine-induced sweating via GSK3ß activation.

Sweating has been associated with the exacerbation of atopic dermatitis (AD) in diverse ways. Acetylcholine (ACh)-mediated sweating is known to be attenuated in AD, but its cause remains obscure. To address this issue, the impact of histamine on ACh-induced sweating was evaluated. Sweating was measured by counting the number of active sweat pores by the starch-iodine reaction and dynamic optical coherence tomography; sweat was visualized using two-photon excitation fluorescence microscopy in mice and the quantitative sudomotor axon reflex test in humans. Both histamine receptor antagonists and H1 receptor (H1R)-knockout (KO) mice were used to determine methodological specificity. Histamine demonstrably inhibited ACh-induced sweating in both mice and humans via H1R-mediated signaling. In sweat glands, ACh inactivated glycogen synthase kinase 3ß (GSK3ß), a kinase involved in endocytosis and secretion, whereas simultaneous stimulation with histamine activated GSK3ß. Results of two-photon excitation fluorescence microscopy confirmed the dynamic motion of sweat and sweat glands after ACh treatment, showing that simultaneous stimulation with histamine altered their dynamic properties. These results indicate that histamine inhibits sweat gland secretions by blocking ACh-induced inactivation of GSK3ß. Histamine-mediated hypohidrosis might be involved in the mechanism of abnormal skin dryness in patients with AD.

Dynamic analysis for mental sweating of a group of eccrine sweat glands on a human fingertip by optical coherence tomography.

BACKGROUND: An important function of skin physiology is mental sweating, where sweating is accelerated via the sympathetic nerve by mental or physical stress externally applied to a volunteer. AIM: Activity of the sympathetic nerve (ASN) is evaluated by quantitative measurement of mental sweating. MATERIAL AND METHODS: Optical coherence tomography (OCT) is highly potential for in vivo observation of human sweating dynamics which affects ASN. We demonstrate dynamic OCT analysis of mental sweating of a group of eccrine sweat glands. The sweating dynamics is tracked simultaneously for 19 sweat glands by time-sequential piled-up en-face OCT images with the frame spacing of 3.3 s. The en-face OCT images of the spiral lumen of the eccrine sweat gland are constructed by data acquisition of the 128 B-mode OCT images. RESULTS: It is thus found that the response to mental stress is different for each sweat gland even though the sweat glands are adjacent to each other. Such strong non-uniformity is observed in mental sweating where the amount of excess sweat is different for each sweat gland although the sweat glands are adjacent to each other. DISCUSSION: The non-uniformity should be necessary to adjust as precisely the total amount of excess sweat as possible through the sympathetic nerve in response to strength of the stress.

Dynamic analysis of internal and external mental sweating by optical coherence tomography.

Mental sweating is human sweating that is accelerated via the sympathetic nerve by application of mental or physical stress. In the neurosciences, there is keen interest in this type of sweating, because the amount of sweat in response to a stress applied to a volunteer directly reflects activity of the sympathetic nerve. It is therefore of particular value that optical coherence tomography (OCT) can provide clear in vivo imaging of the spiral lumen of an eccrin sweat gland in the epidermis with a spatial resolution around 10 mum. We demonstrate dynamic OCT of mental sweating of an eccrin sweat gland on a human fingertip, where the sweating dynamics can be tracked by time-sequential OCT images with a frame spacing of one second. An instantaneous amount of sweat stored in the spiral lumen is evaluated quantitatively in each OCT image, resulting in time variation measurements of excess sweat in response to mental or physical stress. In the dynamic OCT of mental sweating, as demonstrated here, we note for the first time internal sweating without ejection of excess sweat from the spiral lumen to the skin surface. Internal sweating has not been previously detected without the availability of our dynamic OCT technique. Until now, it has been commonly accepted that sweating is always accompanied with ejection of excess sweat to the skin surface. On the basis of our findings reported here, this type of sweating should now be referred to as external sweating. In this study, we demonstrate that internal sweating occurs more often in the case where mental stress is applied to a volunteer, and that it is more useful for evaluation of activity of the sympathetic nerve. The dynamic OCT for both external and internal sweating is demonstrated.

Imaging of in vitro chicken leg using time-resolved near-infrared optical tomography.

Near-infrared optical imaging gains much attention because of its noninvasiveness and deep penetration depths into tissue. Here, we report near-infrared optical tomographic imaging of an in vitro chicken leg from time-resolved measurements. The in vitro chicken leg, dipped in a cylindrical container filled with diluted Intralipid-10% solution, was imaged with a multichannel time-resolved imaging system. A two-dimensional reconstruction algorithm based on a modified generalized pulse spectrum technique has been developed to reconstruct the images of both the absorption and reduced scattering coefficients simultaneously and quickly. The results demonstrate that a simultaneous reconstruction of absorption and reduced scattering coefficients from time-resolved measurement has a potential to reveal the changes in the optical properties associated with not only the physiological information but also the anatomical structure of the organ.

Low-coherence interferometer system for the simultaneous measurement of refractive index and thickness.

We have developed a low-coherence interferometer system used for the simultaneous measurement of refractive index n and thickness t of transparent plates. Both the phase index n(p) and group index n(g) can be determined automatically in a wide thickness range of from 10 microm to a few millimeters. Two unique techniques are presented to measure n(p), n(g), and t simultaneously. One allows us to determine n(p), n(g), and t accurately by using a special sample holder, in which the measurement accuracy is 0.3% for the thickness t above 0.1 mm. In the other technique the chromatic dispersion delta n of index is approximately expressed as a function of (n(p) - 1) on the basis of measured values of n(p) and n(g) for a variety of materials, and then the simultaneous measurement is performed with a normal sample holder. In addition, a measurement accuracy of less than 1% is achieved even when the sample is as thin as 20 microm. The measurement time is also 3 min or more.