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Aims/hypothesis The small G-protein ras-related C3 botulinum toxin substrate 1 (RAC1) plays various roles in mammalian cells, such as in the regulation of cytoskeletal organisation, cell adhesion, migration and morphological changes. The present study examines the effects of RAC1 ablation on pancreatic beta cell function. Methods Isolated islets from pancreatic beta cell-specific Rac1 -knockout (beta Rac1 −/− ) mice and RAC1 knockdown INS-1 insulinoma cells treated with small interfering RNA were used to investigate insulin secretion and cytoskeletal organisation in pancreatic beta cells. Results Beta Rac1 −/− mice showed decreased glucose-stimulated insulin secretion, while there were no apparent differences in islet morphology. Isolated islets from the mice had blunted insulin secretion in response to high glucose levels. In RAC1 knockdown INS-1 cells, insulin secretion was also decreased in response to high glucose levels, consistent with the phenotype of beta Rac1 −/− mice. Even under high glucose levels, RAC1 knockdown INS-1 cells remained intact with F-actin, which inhibits the recruitment of the insulin granules, resulting in an inhibition of insulin secretion. Conclusions/interpretation In RAC1-deficient pancreatic beta cells, F-actin acts as a barrier for insulin granules and reduces glucose-stimulated insulin secretion.

Background: Brain-derived neutrophic factor (BDNF) is a member of the neutrophin family that is known to activate the high-affinity tropomyosin-related receptor kinase B (TrkB). This study aimed to clarify the clinical and biological significance of the BDNF/TrkB pathway in gastric cancer. Methods: We analysed BDNF and TrkB expression in gastric cancer samples by real-time reverse transcription PCR and immunohistochemistry. To investigate the biological role of BDNF/TrkB axis, recombinant human BDNF (rhBDNF) and the Trk antagonist K252a were used for in vitro and in vivo analysis. Results: The BDNF expression at the invasive front of primary tumours was significantly elevated compared with that in the tumour core and adjacent normal mucosa. Increased BDNF expression at the invasive front was significantly correlated with factors reflecting disease progression, and poor prognosis. Increased co-expression of the BDNF/TrkB axis was significantly correlated with poor prognosis. Gastric cancer cells expressed BDNF, and administration of rhBDNF promoted proliferation, migration, invasion, and inhibition of anoikis. These effects were generally inhibited by K252a. In an in vivo assay, BDNF(+)/TrkB(+) gastric cancer cells injected into nude mice established peritoneal dissemination, whereas K252a inhibited tumour growth. Conclusion: The BDNF/TrkB pathway might be deeply involved in gastric cancer disease progression.

LiteBIRD is a next-generation satellite mission to measure the polarization of the cosmic microwave background (CMB) radiation. On large angular scales the B-mode polarization of the CMB carries the imprint of primordial gravitational waves, and its precise measurement would provide a powerful probe of the epoch of inflation. The goal of LiteBIRD is to achieve a measurement of the characterizing tensor to scalar ratio r to an uncertainty of δ r = 0.001 . In order to achieve this goal we will employ a kilo-pixel superconducting detector array on a cryogenically cooled sub-Kelvin focal plane with an optical system at a temperature of 4 K. We are currently considering two detector array options; transition edge sensor (TES) bolometers and microwave kinetic inductance detectors. In this paper we give an overview of LiteBIRD and describe a TES-based polarimeter designed to achieve the target sensitivity of 2  μ K arcmin over the frequency range 50–320 GHz.

PurposeWe examined whether eccrine sweat glands ion reabsorption rate declined with age in 35 adults aged 50–84 years. Aerobic fitness (VO2max) and salivary aldosterone were measured to see if they modulated ion reabsorption rates.MethodsDuring a passive heating protocol (lower leg 42 °C water submersion) the maximum ion reabsorption rates from the chest, forearm and thigh were measured, alongside other thermophysiological responses. The maximum ion reabsorption rate was defined as the inflection point in the slope of the relation between galvanic skin conductance and sweat rate.ResultsThe maximum ion reabsorption rate at the forearm, chest and thigh (0.29 ± 0.16, 0.33 ± 0.15, 0.18 ± 0.16 mg/cm2/min, respectively) were weakly correlated with age (r ≤  − 0.232, P ≥ 0.05) and salivary aldosterone concentrations (r ≤  − 0.180, P ≥ 0.179). A moderate positive correlation was observed between maximum ion reabsorption rate at the thigh and VO2max (r = 0.384, P = 0.015). Salivary aldosterone concentration moderately declined with age (r =  − 0.342, P = 0.021). Whole body sweat rate and pilocarpine-induced sudomotor responses to iontophoresis increased with VO2max (r ≥ 0.323, P ≤ 0.027) but only moderate (r =  − 0.326, P = 0.032) or no relations (r ≤  − 0.113, P ≥ 0.256) were observed with age.ConclusionThe eccrine sweat glands’ maximum ion reabsorption rate is not affected by age, spanning 50–84 years. Aldosterone concentration in an aged cohort does not appear to modulate the ion reabsorption rate. We provide further support for maintaining cardiorespiratory fitness to attenuate any decline in sudomotor function.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has curative potential against hematological malignancies. However, there are concerns about the associated risk of non-relapse mortality (NRM). We performed a retrospective single-center study to assess changes in outcomes after allo-HSCT and causes of NRM over three 5-year periods. The rates of 2-year NRM and overall survival (OS) were 16% and 59%, respectively. We found a significant decrease in NRM ( P< 0.001), with 2-year NRM of 26, 14 and 9%, and a significant increase in OS ( P =0.005), with 2-year OS of 52%, 58% and 65%, over the three periods (1998–2002, 2003–2007 and 2008–2012), respectively. Of note, a steady improvement was observed in NRM, period by period, among patients aged 50 years or older, patients who underwent HSCT from an unrelated bone marrow donor and patients who underwent HSCT with a reduced-intensity conditioning regimen. Our data showed that the improved NRM can mainly be attributed to a decreased mortality related to infection after starting systemic steroid as GVHD treatment, and a decreased mortality related to organ failure.

Background:Rituximab and tocilizumab exhibit potential as molecular targeted therapies for skin fibrosis in patients with systemic sclerosis. While rituximab has demonstrated improvement in skin fibrosis in a limited number of double-blind studies, tocilizumab has shown a favorable trend in a larger double-blind study. However, there is insufficient data on the real-world effectiveness of both drugs in daily clinical practice, and prognostic factors remain unclear.Objectives:To assess and compare the efficacy of rituximab and tocilizumab in treating skin fibrosis relative to standard of care (SoC), while also investigating the factors influencing the effectiveness of each treatment.Methods:In a comparative analysis, 32 patients treated with rituximab alongside SoC, 29 patients receiving tocilizumab with SoC, and 32 patients in the SoC-only group were examined. To mitigate potential selection bias in patient backgrounds across the three groups, propensity score-based inverse probability of treatment weighting was applied. The primary endpoint was the alteration in the modified Rodnan skin score (mRSS) after 24 weeks. Additionally, flow cytometric immune cell profiling, known as the “Human Immunology Project” by NIH/FOCIS, was conducted, and microvascular damages were assessed using nailfold video capillaroscopy. As an exploratory endpoint, we examined peripheral blood immunophenotypic characteristics and the extent of microvascular damages in cases exhibiting improved skin fibrosis.Results:The mRSS values were 14.0, 13.1, and 13.5 for the rituximab, tocilizumab, and SoC groups, respectively, with no significant differences among the three groups. Other parameters such as disease duration (7.2, 8.1, and 7.9 years) and age (59.9, 60.7, and 60.2 years) also exhibited no notable differences. After 6 months of treatment, the improvement in skin score was -3.6 points for rituximab, -2.1 points for tocilizumab, and +0.9 points for SoC. Both rituximab and tocilizumab demonstrated significant improvement compared to SoC (p < 0.001, p = 0.005), with no significant difference between rituximab and tocilizumab (p = 0.24) (Figure 1). The analysis of factors contributing to the effectiveness of each drug revealed that neither rituximab nor tocilizumab exhibited a clinical background predictive of efficacy. Peripheral blood immunophenotyping revealed associations between the percentages of effector memory CD4+ T cells, central memory CD4+ T cells, Th1, Th17, plasmablasts, and CD16+ NK cells and improved skin fibrosis at 24 weeks with rituximab. In multivariate analysis, only plasmablasts were inversely correlated with the efficacy of rituximab (p = 0.003) (Table 1). Conversely, no immune cells contributed to predicting the effectiveness of tocilizumab. Nailfold capillaries analysis showed that tocilizumab tended to improve cases with normal or giant capillaries, while those with hemorrhage or loss of capillaries were less likely to improve (p = 0.20).Conclusion:Both rituximab and tocilizumab exhibited improvement in skin fibrosis compared to SoC. For rituximab, the immunophenotype may be useful in treatment selection. However, there is no identified indicator for tocilizumab, necessitating further biomarker studies.Table 1.Pearson correlation coefficientunivariate analysismultivariate analysisCD4+ T cellsNaive0.0240.895Central memory-0.4020.020.982Effector memory-0.3750.0310.207TEMRA0.1630.365Activated-0.1360.451CD8+ T cellsNaive0.2530.156Central memory-0.2180.224Effector memory0.0080.967TEMRA0.0360.841Activated0.0990.584CD4+ T cell subsetsTh1-0.3580.0410.352Activated Th1-0.130.471Th17-0.3920.0240.063Activated Th170.0490.785Tfh0.0180.923Activated Tfh-0.0190.916Naive Treg0.0850.637Memory Treg0.0020.991Activated Treg0.0940.601B cellsNaive-0.3170.073IgM memory0.0050.976Class-switched memory-0.1050.562Double negative-0.2980.092Plasmablasts0.5460.0010.003NK cellsCD16+ NK cell0.3580.0410.954CD16- NK cell-0.2760.119MonocytesClassical0.2740.122Non classical0.3260.064Dendritic cellsMyeloid0.1160.522Plasmacytoid0.0980.589Figure 1.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Satoshi Kubo has received speaking fees from Eli Lilly, GlaxoSmithKline, Bristol-Myers, Abbvie, Eisai, Pfizer, Astra-Zeneca., has received research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Yurie Satoh-Kanda: None declared, Yasuyuki Todoroki: None declared, Ryuichiro Kanda: None declared, Hiroaki Tanaka: None declared, Masanobu Ueno: None declared, Yoshino Inoue: None declared, Yusuke Miyazaki has received speaking fees from Eli Lilly and GlaxoSmithKline., Ippei Miyagawa: None declared, Kentaro Hanami: None declared, Shingo Nakayamada has received speaking fees from Bristol-Myers, UCB, Astellas, Abbvie, Eisai, Pfizer, and Takeda, has received research grants from Mitsubishi-Tanabe, Novartis, and MSD., Yoshiya Tanaka has received speaking fees from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho., has received research grants from Mitsubishi-Tanabe, Eisai, Chugai, Taisho.

Background:It is unclear as to which SLE patients respond favorably to belimumab (BEL), and the impact of such treatment on peripheral blood immunophenotype in this population remains unknown.Objectives:This study aimed to clarify peripheral immunophenotype of patients with SLE who successfully discontinued glucocorticoids (GC) by intervention with BEL in the maintenance phase.Methods:Patients with SLE (n=146), who were in the maintenance therapy phase with a SELENA-SLEDAI score of less than 10 and receiving glucocorticoid therapy at a prednisolone-equivalent dose of 0.2 mg/kg/day or less, were assessed. They were divided into the standard of care (SoC) group (46 patients who received hydroxychloroquine or mycophenolate mofetil) and the BEL group (100 patients who received BEL with SoC). The efficacy of BEL group was compared with SoC group after adjustment by propensity score-based inverse probability of treatment weighting (PS-IPTW). Based on the standard human immune cell subset classification protocol by NIH/FOCIS, peripheral immunophenotypes were analyzed in BEL group and SoC group, and were compared.Results:After PS-IPTW adjustment, no differences in patient characteristics were shown between the SoC and BEL groups. The retention rate of BEL at 52w was 98.0%. SELENA-SLEDAI scores improved after 52w in both groups. The BEL group also had significantly lower GC doses at 52w (p=0.0028) and 31.8% of the BEL group successfully discontinued GC, whereas on 2.1% of the SoC group did (p=0.0043). The incidence of infections was significantly lower in the BEL group compared to the SoC group before PS-IPTW (BEL, 4.0% vs. SoC, 17.5%, p=0.089). The baseline peripheral immunophenotypes were similar between the two groups. In the BEL group, the proportion of activated T follicular helper cells (p=0.0073), IgD-CD27-B (DNB) cells (p=0.0088) and plasmocytes (p=0.0092) decreased significantly at 26w. There were no significant changes in the SoC group. At 26 weeks, the proportion of DNB cells (p=0.0328) and plasmocytes (p=0.0415) was significantly lower in patients who discontinued glucocorticoids (GCs) compared to those who were unable to discontinue them. Multiple logistic regression analysis showed that GC discontinuation was associated with low GC doses, low SLEDAI scores at BEL initiation, decreased IgG levels at 52w, and a low percentage of DNB cells and plasmocytes at 26w.Of those who discontinued GCs in the BEL group, 81.3% (6/26) did not experience a flare-up of SLE one year after discontinuation. In peripheral blood immunophenotyping six months after discontinuation of GC, the proportion of DN Bcells and plasmocytes was increased in patients who relapsed after discontinuation of GC. On the other hand, the proportion of DN Bcells and plasmocytes did not change in those who did not relapse after discontinuation of GC.Conclusion:Intervention with BEL in patients with SLE reduced DNB cells and plasmocytes, thereby controlling the disease activity and enabling GC discontinuation. Among patients who received low GC doses and had low SLEDAI scores, those with decreased IgG levels at 52w successfully discontinued GCs.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Yusuke Miyazaki Y. Miyazaki has received lecture fees from AstraZeneca, GlaxoSmithKline, Astellas, Eli Lilly., Shingo Nakayamada: None declared, Satoshi Kubo Satoshi Kubo has received speaking fees from Eli Lilly, GlaxoSmithKline, Bristol-Myers, Abbvie, Eisai, Pfizer, Astra-Zeneca and also research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Hiroaki Tanaka: None declared, Kentaro Hanami: None declared, Shunsuke Fukuyo: None declared, Ippei Miyagawa: None declared, Yasuyuki Todoroki: None declared, Yoshino Inoue: None declared, Yurie Satoh-Kanda: None declared, Masanobu Ueno: None declared, Yoshiya Tanaka Y. Tanaka has received Speakers bureau from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho., Y. Tanaka has received Grant/research support from Mitsubishi-Tanabe, Eisai, Chugai, Taisho.

Background:Achievement and maintenance of the Lupus Low Disease Activity State (LLDAS) are necessary for the long-term prevention of organ damage progression in patients with systemic lupus erythematosus (SLE); however, minor flares lower the achievement and maintenance rates, and consequent treatment changes such as glucocorticoid (GC) dose increase. Therefore, there is a demand for therapeutic strategies to control disease activity and achieve dose reduction or discontinuation of GCs using molecular targeted drugs.Objectives:This study aimed to analyze the safety and efficacy of anifrolumab in patients with SLE who experience minor flares after achieving LLDAS in real-world clinical practice.Methods:In this retrospective observational study, we assessed 65 SLE patients who experienced minor flares after achieving LLDAS. Of these, 30 were treated with the addition of glucocorticoids (GCs) or immunosuppressants, forming the standard of care (SoC) group. The remaining 35 patients were treated with the additon of only anifrolumab, constituting the anifrolumab group. Minor flare was defined as the revised Safety of Estrogens in Lupus Erythematosus National Assessment Flare Index. The LLDAS achievement rate at 26 weeks in the SoC and anifrolumab group were compared after adjusting with inverse probability of treatment weighting using propensity score (PS-IPTW).Results:The retention rate of anifrolumab was 97.1% (34/35 patients) at week 26. No significant difference was observed in the patient background between the two groups after adjustment by PS-IPTW. There was no difference between the two groups in either the LLDAS achievement rate or the DORIS remission rate at week 12 after the onset of minor flares followed by treatment intensification. At week 26, the anifrolumab group had a higher the rate of LLDAS achievement (SoC: anifrolumab=53.3:85.7%, p=0.0042) and DORIS remission (SoC: anifrolumab=6.7:25.7 %, p=0.0412). The SoC group did not exhibit a significant decrease in GC dose at 26 weeks, while the anifrolumab group exhibited a significant decrease. GC doses at week 26 were lower in the anifrolumab group (SoC: anifrolumab=6.9±3.5: 3.1±3.8mg/day, prednisolone equivalent, p<0.0001). The incidence of adverse events were fewer in the anifrolumab group (p=0.0012), especially infections (p=0.0169).Compared with patients treated for minor flares by GC dose increase (GC dose increase group, n=18) after adjustment by PS-IPTW, the anifrolumab group had a higher rate of LLDAS achievement (GC dose increase: anifrolumab=39.8:89.1%, p<0.0001) and DORIS remission (GC dose increase: anifrolumab=12.4:40.8%, p=0.0011). GC dose at week 26 was lower in the anifrolumab group (GC dose increase: anifrolumab=7.2±2.6:3.1±3.8 mg/day, prednisolone equivalent, p=0.0001). In anifrolumab group, three cases discontinued GC 26weeks after introduction of anifrolumab. The incidence of adverse events (p=0.0086) and infection (p=0.0442) were significant lower in the anifrolumab group.Conclusion:The current study demonstrated the safety and efficacy of anifrolumab in patients with minor flares who once achieved LLDAS but had difficulty maintaining LLDAS. These findings suggested that disease activity could be improved by initiating anifrolumab therapy alone without GC dose increase in patients with minor flares. Anifrolumab may prevent the accumulation of disease-induced organ damage caused by SLE and drug-induced organ damage caused by GCs, thereby improving long-term QOL and prognosis in patients with SLE.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Yusuke Miyazaki Y.Miyazaki has received speaking feesfrom Bristol-Myers, Pfizer, GlaxoSmithKline, Astellas, Asahi-Kasei, and Boehringer Ingelheim., Shingo Nakayamada: None declared, Satoshi Kubo Satoshi Kubo has received speaking fees from Eli Lilly, GlaxoSmithKline, Bristol-Myers, Abbvie, Eisai, Pfizer, Astra-Zeneca. research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Satoshi Kubo has received research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Satsuki Matsunaga: None declared, Hiroaki Tanaka: None declared, Kentaro Hanami: None declared, Shunsuke Fukuyo: None declared, Yurie Satoh-Kanda: None declared, Yoshino Inoue: None declared, Yasuyuki Todoroki: None declared, Masanobu Ueno: None declared, Yoshiya Tanaka Y. Tanaka has received Speakers bureau from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho, Y. Tanaka has received Grant/research support from Mitsubishi-Tanabe, Eisai, Chugai, Taisho.

PurposeChanges in mean skin temperature (Tsk) have been shown to modify the maximum rate of sweat ion reabsorption. This study aims to extend this knowledge by investigating if modifications could also be caused by local Tsk.MethodsThe influence of local Tsk on the sweat gland maximum ion reabsorption rates was investigated in ten healthy volunteers (three female and seven male; 20.8 ± 1.2 years, 60.4 ± 7.7 kg, 169.4 ± 10.4 cm) during passive heating (water-perfused suit and lower leg water immersion). In two separate trials, in a randomized order, one forearm was always manipulated to 33 °C (Neutral), whilst the other was manipulated to either 30 °C (Cool) or 36 °C (Warm) using water-perfused patches. Oesophageal temperature (Tes), forearm Tsk, sweat rate (SR), galvanic skin conductance (GSC) and salivary aldosterone concentrations were measured. The sweat gland maximum ion reabsorption rates were identified using the ∆SR threshold for an increasing ∆GSC.ResultsThermal [Tes and body temperature (Tb)] and non-thermal responses (aldosterone) were similar across all conditions (p > 0.05). A temperature-dependent response for the sweat gland maximum ion reabsorption rates was evident between 30 °C (0.18 ± 0.10 mg/cm2/min) and 36 °C (0.28 ± 0.14 mg/cm2/min, d = 0.88, p < 0.05), but not for 33 °C (0.22 ± 0.12 mg/cm2/min), d = 0.44 and d = 0.36, p > 0.05.ConclusionThe data indicate that small variations in local Tsk may not affect the sweat gland maximum ion reabsorption rates but when the local Tsk increases by > 6 °C, ion reabsorption rates also increase.

Permeable reactive barrier (PRB) systems containing effective and low-cost adsorbents for heavy metals are expected to function as in situ treatment methods for leachate from waste landfills and contaminated groundwater surrounding the landfills in developing countries. This study was conducted to characterize the adsorption of Cd 2+ and Pb 2+ onto coconut shell biochar (fine granules), a local soil from Sri Lanka (Entisol), and a biochar-mixed soil (1:1 mixture of biochar and soil) as potential adsorbents for PRB systems. Batch experiments were carried out to investigate the effects of solution pH, contact time, initial ion concentration, and competitive ions on the Cd 2+ and Pb 2+ adsorption. Results showed that the adsorption kinetics of Cd 2+ and Pb 2+ onto all adsorbents were well described by the pseudo second order kinetics model and that adsorption isotherms followed the Langmuir model. In the range of pH ≥3, the initial solution pH had a minor effect on efficiency of metal removal and the removal of metals mostly exceeded 80 % for all adsorbents. Measured maximum adsorptions onto soil and biochar-mixed soil were 30.1 mmol/g for Cd 2+ and 44.8–46.7 mmol/g for Pb 2+ . These adsorption capacities are similar to or higher than the values of biosorbents tested for wastewater treatment in previous studies, suggesting our tested materials would be useful as adsorbents of Cd 2+ and Pb 2+ in PRB systems. Additional analysis by scanning electron microscopy linked with energy dispersive X-ray revealed that both Cd 2+ and Pb 2+ exhibited high adsorption affinity towards soil particles while adsorbing randomly to biochar granules.