Melanogenic effect of dersimelagon (MT-7117), a novel oral melanocortin 1 receptor agonist.

Background: The activation of melanocortin 1 receptor (MC1R) on melanocytes stimulates the production of eumelanin. A tridecapeptide α melanocyte-stimulating hormone (αMSH) is known to induce skin pigmentation. Objectives: We characterised the properties of a novel oral MC1R agonist dersimelagon (MT-7117) with respect to its specific binding to MC1R, downstream signalling and eumelanin production in experimental models. Methods: The competitive binding and production of intracellular cyclic adenosine 3', 5'-monophosphate in cells expressing recombinant melanocortin receptors were examined. A mouse melanoma cell line B16F1 was used for the evaluation of in vitro melanin production. The in vitro activity of MT-7117 was determined with αMSH and [Nle4, D-Phe7]-αMSH (NDP-αMSH) as reference comparators. The change of coat colour and skin pigmentation were evaluated after repeat administration of MT-7117 by oral gavage to C57BL/6J-Ay/+ mice and cynomolgus monkeys, respectively. Results: MT-7117 showed the highest affinity for human MC1R compared to the other melanocortin receptors evaluated and agonistic activity for human, cynomolgus monkey and mouse MC1R, with EC50 values in the nanomolar range. In B16F1 cells, MT-7117 increased melanin production in a concentration-dependent manner. In vivo, MT-7117 (≥0.3 mg/kg/day p.o.) significantly induced coat colour darkening in mice. MT-7117 (≥1 mg/kg/day p.o.) induced significant skin pigmentation in monkeys and complete reversibility was observed after cessation of its administration. Conclusions: MT-7117 is a novel oral MC1R agonist that induces melanogenesis in vitro and in vivo, suggesting its potential application for the prevention of phototoxic reactions in patients with photodermatoses, such as erythropoietic protoporphyria and X-linked protoporphyria.

Assessment of the albumin-bilirubin grade as a prognostic factor in patients with non-small-cell lung cancer receiving anti-PD-1-based therapy.

INTRODUCTION: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. METHODS: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. RESULTS: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. CONCLUSION: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

Effect of Gum Chewing on PFC Activity During Discomfort Sound Stimulation.

The prefrontal cortex (PFC) is sensitive to the stress exposure and involved in stress coping. And the effects of gum chewing on the stress have been studied using NIRS. However, when measuring NIRS on PFC during gum chewing, blood flows in shallow tissues (scalp, skin, muscle) might be affected. A NIRS used in the present study first, which has a short distance (1 cm) and the usual (3 cm) source-detector (S-D) regression, can allow eliminating shallow tissues effect of gum chewing. The aim of this study was to investigate the hypothesis that gum chewing activates the right prefrontal cortex (PFC) in stress coping against negative sounds (NS) from the International Affective Digitized Sounds-2 (IADS) as a mental stress task. NS showed activation in the right PFC. There was a significant difference between NS, and NS with Gum, where NS with Gum showed an increased PFC activity, increased alpha wave appearance rate, a higher value in heart rate level, and a higher VAS score indicating 'pleasant'. Gum chewing activated right PFC activity while exposed to negative sounds from IADS as a mental stress task.

Influence of the trapeziometacarpal joint fusion on thumb muscles and thumb-tip movement: A cadaveric study.

BACKGROUND: Trapeziometacarpal (TMC) arthrodesis provides stability and strength of the thumb, whereas fixation of the TMC joint restricts motion of the thumb, which may consequently impair the activity of daily living. The objective of our study was to investigate how length and area of the thumb-tip trajectory were reduced after the TMC joint fusion. METHODS: Six fresh, frozen cadavers were used for this study. Tension was applied to the distal tendons of 4 extrinsic thumb muscles (extensor pollicis longus, flexor pollicis longus, abductor pollicis longus, and extensor pollicis brevis) by servomotor, whereas tension was applied to 4 intrinsic muscles (abductor pollicis brevis, opponens pollicis, flexor pollicis brevis, and adductor pollicis) using static weights. The thumb-tip trajectory was examined using a motion capture system without tension and with 5 different weights to induce intrinsic muscle tension before and after the TMC joint fusion. FINDINGS: When tension was applied to the intrinsic muscles, the length of the thumb-tip trajectory decreased in all conditions compared with that before the TMC joint fusion, whereas the trajectory decreased only when the abductor pollicis longus was pulled. The overall thumb-tip trajectory area was reduced to approximately 30% compared with that before the TMC joint fusion. INTERPRETATION: Thumb-tip trajectory was restricted by the TMC joint fusion to approximately 30%. However, the reduced area was found tolerable for performing daily activities. Thus, arthrodesis can be the first-line treatment in patients who wish to engage in activities of daily living without difficulties.

Transition of Spleen Volume Long After Pediatric Living Donor Liver Transplantation for Biliary Atresia.

PURPOSE: After undergoing the Kasai procedure for biliary atresia (BA), most patients develop severe splenomegaly that tends to be improved by liver transplantation. However, fluctuations in splenic volume long after transplantation remain to be elucidated. PATIENTS AND METHODS: Seventy-one consecutive patients who had undergone pediatric living donor liver transplantation (LDLT) for BA were followed up in our outpatient clinic for 5 years. They were classified into 3 groups according to their clinical outcomes: a good course group (GC, n = 41) who were maintained on only 1 or without an immunosuppressant, a liver dysfunction group (LD, n = 18) who were maintained on 2 or 3 types of immunosuppressants, and a vascular complication group (VC, n = 11). Splenic and hepatic volumes were calculated by computed tomography in 464 examinations and the values compared before and after the treatment, especially in the VC group. RESULTS: Splenic volume decreased exponentially in the GC group, with splenic volume to standard spleen volume ratio (SD) being 1.59 (0.33) 5 years after liver transplantation. Splenic volume to standard spleen volume ratios were greater in the VC and LD groups than in the GC group. Patients in the VC group with portal vein stenosis developed liver atrophy and splenomegaly, whereas those with hepatic vein stenosis developed hepatomegaly and splenomegaly. Interventional radiation therapy tended to improve the associated symptoms. CONCLUSIONS: Fluctuations in splenic volume long after pediatric LDLT for BA may reflect various clinical conditions. Evaluation of both splenic and hepatic volumes can facilitate understanding clinical conditions following pediatric LDLT.

Relationships Between Gum Chewing and Stroop Test: A Pilot Study.

Cognitive function tends to decrease with aging, therefore maintenance of this function in an aging society is an important issue. The role of chewing in nutrition is important. Although several studies indicate that gum chewing is thought to improve cognitive function, it remains debatable whether gum-chewing does in fact improve cognitive function. The Stroop test is a psychological tool used to measure cognition. A shorter reaction time indicates a mean higher behavioral performance and higher levels of oxy-Hb concentration. fNIRS is a powerful, non-invasive imaging technique offering many advantages, including compact size, no need for specially equipped facilities, and the potential for real-time measurement. The left dorsolateral prefrontal cortex (DLPFC) seems to be mainly involved in the Stroop task.The aim of the present study was to investigate the hypothesis that gum-chewing changes cerebral blood flow in the left DLPFC during the Stroop test, and also changes the reaction time. Fourteen healthy volunteers (mean age 26.9 years) participated in this study after providing written informed consent. A piece of tasteless gum weighing 1.0 g was used. Each session was designed in a block manner, i.e. 4 rests (30 s) and 3 blocks of task (30 s). A computerized Stroop test was used (including both congruent and incongruent Stroop tasks) which calculates a response time automatically. The Binominal test was used for comparisons (p < 0.05). The results show activation of the left DLPFC during the Stroop task and that gum chewing significantly increases responses/oxy-Hb concentration and significantly shortens the reaction time.

Note: Optimization of magnifying a polarization angle with Littrow layout blazed gratings.

Magnification of a polarization angle with Littrow layout gratings has been developed. High magnification with a factor of 7.7 using two gratings in Littrow layout was experimentally proved. The magnification range was investigated by calculation at a wavelength of 10.6 µm. The method can be applied for a high magnification factor >30. Larger groove numbers and smaller blaze angles are suitable for the large magnification. Statistical fluctuation of the diffracted polarization angle is compared with that of the incident polarization angle.

Preventive effect of renin-angiotensin system inhibitors on new-onset atrial fibrillation in hypertensive patients: a propensity score matching analysis.

It is still controversial whether treatment with renin-angiotensin system (RAS) inhibitors reduces the risk of incident atrial fibrillation (AF). This longitudinal observational study was performed to investigate the confounder-independent effects of RAS inhibitors on new-onset AF in hypertensive patients. Among 1263 consecutive hypertensive patients who underwent echocardiography, 964 eligible patients (mean age, 63 years) were enrolled as the study population. Forty-nine patients developed new-onset AF during the follow-up period (mean: 4.6 years). Kaplan-Meier analysis showed that the cumulative AF event rate was lower in patients receiving RAS inhibitors than in patients without these drugs, but the difference between these two groups was not significant (P=0.057). Since the use of RAS inhibitors was influenced by concomitant diabetes, chronic kidney disease and left ventricular hypertrophy, propensity score matching (1:1) was employed to minimize the influence of selection bias for RAS inhibitors. Clinical and echocardiographic parameters showed no significant differences between the propensity score-matched groups with and without RAS inhibitor therapy (both n=326), but the cumulative AF event rate was significantly lower in the group receiving RAS inhibitors (P=0.013). Univariate and multivariate Cox regression analyses also revealed that RAS inhibitor therapy was associated with a significantly lower risk of new-onset AF during the follow-up period. In conclusion, this propensity score matching study demonstrated that the incidence of new-onset AF was lower in hypertensive patients receiving RAS inhibitor therapy.

Dietary Variety and Decline in Lean Mass and Physical Performance in Community-Dwelling Older Japanese: A 4-year Follow-Up Study.

OBJECTIVES: To examine associations of dietary variety with changes in lean mass and physical performance during a 4-year period in an elderly Japanese population. DESIGN: Four-year prospective study. SETTING: The Hatoyama Cohort Study and Kusatsu Longitudinal Study, Japan. PARTICIPANTS: 935 community-dwelling Japanese aged 65 years or older. MEASUREMENTS: Dietary variety was assessed using a 10-item food frequency questionnaire. Body composition was determined by multifrequency bioelectrical impedance analysis, and physical performance (grip strength and usual gait speed) was measured in surveys at baseline and 4 years later. Longitudinal analysis included only participants who were originally in the upper three quartiles of lean body mass, appendicular lean mass, grip strength, and usual gait speed. The outcome measures were decline in lean body mass, appendicular lean mass, grip strength, and usual gait speed, defined as a decrease to the lowest baseline quartile level at the 4-year follow-up survey. Associations of dietary variety with the outcome measures were examined by logistic regression analysis adjusted for potential confounders. RESULTS: In the fully adjusted model, the odds ratios for decline in grip strength and usual gait speed were 0.43 (95% confidence interval, 0.19-0.99) and 0.43 (confidence interval, 0.19-0.99), respectively, for participants in the highest category of dietary variety score as compared with those in the lowest category. Dietary variety was not significantly associated with changes in lean body mass or appendicular lean mass. CONCLUSION: Among older adults, greater dietary variety may help maintain physical performance, such as grip strength and usual gait speed, but not lean mass.

Design of tangential viewing phase contrast imaging for turbulence measurements in JT-60SA.

A tangential viewing phase contrast imaging system is being designed for the JT-60SA tokamak to investigate microturbulence. In order to obtain localized information on the turbulence, a spatial-filtering technique is applied, based on magnetic shearing. The tangential viewing geometry enhances the radial localization. The probing laser beam is injected tangentially and traverses the entire plasma region including both low and high field sides. The spatial resolution for an Internal Transport Barrier discharge is estimated at 30%-70% of the minor radius at k = 5 cm-1, which is the typical expected wave number of ion scale turbulence such as ion temperature gradient/trapped electron mode.

Analysis of circulating human and viral microRNAs in patients with congenital cytomegalovirus infection.

OBJECTIVE: Cytomegalovirus (CMV) is the most common cause of congenital infection and can cause neurodevelopmental disabilities, although a majority of patients are asymptomatic. Biomarkers associated with disease severity would be desirable to distinguish asymptomatic from mildly symptomatic patients who may benefit from antiviral treatment. MicroRNAs (miRNAs) are noncoding RNAs that may have the potential to serve as biomarkers. STUDY DESIGN: Thirteen infants with congenital CMV infection were enrolled, and plasma levels of 11 human- and 3 CMV-encoded miRNAs were quantitated by real-time PCR. Plasma levels of miRNAs and their associations with clinical features were evaluated. RESULTS: The levels of miR-183-5p and miR-210-3p were significantly higher in patients with congenital CMV infection than in control infants, whereas no significant associations between levels of miRNAs and clinical features of congenital CMV infection were observed. CONCLUSION: Plasma miRNAs could be associated with the pathogenesis of congenital CMV infection and could be used as disease biomarkers.

Association of Dietary Variety with Body Composition and Physical Function in Community-dwelling Elderly Japanese.

OBJECTIVES: To examine the associations of dietary variety with body composition and physical function in community-dwelling elderly Japanese. DESIGN: Cross-sectional study. SETTING: Community-based. PARTICIPANTS: A total of 1184 community-dwelling elderly adults aged 65 and over. MEASUREMENTS: Dietary variety was assessed with a food frequency questionnaire (maximum, 10 points) that encompassed the 10 main food components of Japanese meals (meat, fish/shellfish, eggs, milk, soybean products, green/yellow vegetables, potatoes, fruit, seaweed, and fats/oils). Body composition was determined by multifrequency bioelectrical impedance analysis. Physical function was assessed by measuring grip strength and usual walking speed. Multiple linear regression analysis was used to examine the associations of dietary variety with body composition and physical function. RESULTS: After adjusting for potential confounders, higher dietary variety scores were independently associated with higher lean mass (ß (SE): 0.176 (0.049), p<0.001) and appendicular lean mass (ß (SE): 0.114 (0.027), p<0.001) but not with body fat mass. Elders with a higher dietary variety score had greater grip strength and faster usual walking speed (ß (SE): 0.204 (0.071), p=0.004, and ß (SE): 0.008 (0.003), p=0.012, respectively). CONCLUSION: Greater dietary variety was significantly associated with greater lean mass and better physical function in Japanese elders. The causal relationship warrants investigation in a prospective study.

Complementary Indicators for Diagnosis of Hepatic Vein Stenosis After Pediatric Living-donor Liver Transplantation.

INTRODUCTION: Although hepatic vein stenosis after liver transplantation is a rare complication, the complication rate of 1% to 6% is higher in pediatric living-donor liver transplantation than that in other liver transplantation cases. Diagnosis is very important because this complication can cause hepatic congestion that develops to liver cirrhosis, graft loss, and patient loss. However, this is unlikely in cases where there are no ascites or hypoalbuminemia. OBJECTIVES: Eleven of 167 patients who had undergone pediatric living-donor liver transplantation were identified in the outpatient clinic at Jichi Medical University as having suffered from hepatic vein stenosis, and were enrolled in the study. METHODS: We conducted a retrospective study in which we reviewed historical patient records to investigate the parameters for diagnosis and examine treatment methods and outcomes. RESULTS: The 11 patients were treated with 16 episodes of balloon dilatation. Three among these received retransplantation and another 2 cases required the placement of a metallic stent at the stenosis. Histological examination revealed severe fibrosis in four of nine patients who had a liver biopsy, with mild fibrosis revealed in the other five grafts. Furthermore, hepatomegaly and splenomegaly diagnosed by computed tomography, elevated levels of hyarulonic acid, and/or a decrease in calcineurin inhibitor clearance were found to be pathognomonic at diagnosis, and tended to improve after treatment. CONCLUSIONS: Diagnosis of hepatic vein stenosis after liver transplantation can be difficult, so careful observation is crucial to avoid the risk of acute liver dysfunction. Comprehensive assessment using volumetry of the liver and spleen and monitoring of hyarulonic acid levels and/or calcineurin inhibitor clearance, in addition to some form of imaging examination, is important for diagnosis and evaluation of the effectiveness of therapy.

Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.

Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase-PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/µl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.

Targeting vasculogenesis to prevent progression in multiple myeloma.

The role of endothelial progenitor cell (EPC)-mediated vasculogenesis in hematological malignancies is not well explored. Here, we showed that EPCs are mobilized from the bone marrow (BM) to the peripheral blood at early stages of multiple myeloma (MM); and recruited to MM cell-colonized BM niches. Using EPC-defective ID1+/- ID3-/- mice, we found that MM tumor progression is dependent on EPC trafficking. By performing RNA-sequencing studies, we confirmed that endothelial cells can enhance proliferation and favor cell-cycle progression only in MM clones that are smoldering-like and have dependency on endothelial cells for tumor growth. We further confirmed that angiogenic dependency occurs early and not late during tumor progression in MM. By using a VEGFR2 antibody with anti-vasculogenic activity, we demonstrated that early targeting of EPCs delays tumor progression, while using the same agent at late stages of tumor progression is ineffective. Thus, although there is significant angiogenesis in myeloma, the dependency of the tumor cells on EPCs and vasculogenesis may actually precede this step. Manipulating vasculogenesis at an early stage of disease may be examined in clinical trials in patients with smoldering MM, and other hematological malignancies with precursor conditions.

Development of real-time rotating waveplate Stokes polarimeter using multi-order retardation for ITER poloidal polarimeter.

The rotating waveplate Stokes polarimeter was developed for ITER (International Thermonuclear Experimental Reactor) poloidal polarimeter. The generalized model of the rotating waveplate Stokes polarimeter and the algorithm suitable for real-time field-programmable gate array (FPGA) processing were proposed. Since the generalized model takes into account each component associated with the rotation of the waveplate, the Stokes parameters can be accurately measured even in unideal condition such as non-uniformity of the waveplate retardation. Experiments using a He-Ne laser showed that the maximum error and the precision of the Stokes parameter were 3.5% and 1.2%, respectively. The rotation speed of waveplate was 20 000 rpm and time resolution of measuring the Stokes parameter was 3.3 ms. Software emulation showed that the real-time measurement of the Stokes parameter with time resolution of less than 10 ms is possible by using several FPGA boards. Evaluation of measurement capability using a far-infrared laser which ITER poloidal polarimeter will use concluded that measurement error will be reduced by a factor of nine.

Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia.

The outcome of 55 children with severe aplastic anemia (SAA) who received a second hematopoietic stem cell transplantation (HSCT) was retrospectively analyzed using the registration data of the Japanese Society for Hematopoietic Cell Transplantation. The 5-year overall survival (OS) and failure-free survival (FFS) after the second transplantation were 82.9% (95% confidence interval (CI), 69.7-90.8)) and 81.2% (95% CI, 67.8-89.4), respectively. FFS was significantly better when the interval between the first and second transplantation was >60 days (88.9%; 95% CI, 73.0-95.7) than when it was ⩽60 days (61.4%; 95% CI, 33.3-80.5; P=0.026). All 12 patients who were conditioned with regimens containing fludarabine and melphalan were alive with hematopoietic recovery. These findings justify the recommendation of a second HSCT for children with SAA who have experienced graft failure after first HSCT.

Copper-catalyzed α-selective hydrostannylation of alkynes for the synthesis of branched alkenylstannanes.

A variety of branched alkenylstannanes can directly be synthesized with excellent α-selectivity by the copper-catalyzed hydrostannylation using a distannane or a silylstannane, irrespective of the electronic and steric characteristics of terminal alkynes employed. Synthetic utility of the resulting branched alkenylstannane has been demonstrated by the total synthesis of bexarotene.

Accumulation of accident-derived radiocesium in lake and coastal sediments at 300-700 km distance from Fukushima area.

The accumulation of accident-derived radiocesium was investigated in nine water bodies located 300-700 km from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP). (134)Cs from the accident was detected in surface sediment of five water bodies. The (134)Cs concentration, corrected to the time of the accident in 2011, was generally lower than that of (137)Cs, and its spatial pattern does not fully correspond to that of (137)Cs. These results suggest that radiocesium derived from both FDNPP and past global fallout can be separately observed and that the contributions of both sources are non-uniform within these sites. The (134)Cs inventory in surface sediments is smaller than its deposition, suggesting that almost all deposited (134)Cs remains within the catchment and/or a part has been discharged from the saline and brackish water bodies.