New insights into the characteristic flavor components of traditional sour beers such as Lambic and Flanders Red Ale beers.

In recent years, the demand for beers with a variety of flavors has increased considerably owing to the diversification of consumer preferences. Sour beer is characterized by a sour taste unlike normal beer flavor, and previous studies on sour beer have been primarily focused on addressing issues, such as inconsistent product quality and long production time, and on the associated microorganisms. Scientific knowledge regarding the characteristic flavor of sour beer and flavor components is limited. Therefore, in this study, we aimed to clarify the characteristic sensory attributes of sour beer and the component profiles that explain these attributes. Component analysis was performed on 10 traditional sour beers (eight Flanders Red Ales and two Lambics), using untargeted gas chromatography-mass spectrometry with liquid-liquid extraction, liquid chromatography-mass spectrometry targeting amines and anionic compounds. Further, sensory evaluation was conducted by well-trained panelists via quantitative descriptive analysis. Orthogonal partial least squares regression analysis was also conducted to investigate candidate flavor components. Thus, 261 components were identified and our methods could explain the flavor attributes of the examined samples. Comprehensive component profiling data also showed that differences in fermentation method, barrel aging duration, and blending ratio affected beer flavor. Further, Lambics were found to be characterized by citrus and phenolic aroma, while Flanders Red Ales were characterized by solvent-like aroma, sourness complexity, full bodied, graininess, astringency, and bitterness. These findings may serve as a basis for addressing issues related to sour beer production and may facilitate process design for obtaining targeted sour beer flavors.

Treatment pattern and clinical outcomes in multiple myeloma patients in Japan using the Medical Data Vision claims database.

Multiple myeloma therapy has made remarkable progress with the advent of new drugs. We explored the treatment pattern and outcomes in Japanese patients with multiple myeloma using the Medical Data Vision database. Patients were categorized as per the initial diagnosis period (2003-2015 and 2016-2020), considering the adoption of these new agents and then based on stem cell transplantation. Overall, 6438 patient data were extracted as eligible for data analysis, and the median age at the index diagnosis date was 72.0 years. Bortezomib/dexamethasone was the most common regimen for induction therapy in patients requiring stem cell transplantation from 2003-2015, and the use of bortezomib/lenalidomide/dexamethasone increased from 2016-2020. Lenalidomide/dexamethasone was the most commonly used post-transplant therapy. In the non-stem cell transplantation group, bortezomib/dexamethasone was mainly used for both periods, while lenalidomide/dexamethasone was primarily used from 2016-2020. There was a trend toward shorter first-line treatment duration and a shift to additional treatment patterns with new drugs at the following lines. The time to inpatient death period suggested an improvement between the two periods. Thus, this study revealed that recent diversification of treatment options is preferred and contributes to improved outcomes in the clinical practice of multiple myeloma in Japan.

Profiling volatile compounds from culture supernatants of periodontal bacteria using gas chromatography/mass spectrometry/olfactometry analysis with a monolithic silica gel adsorption device.

Halitosis is formed mainly by the volatile compounds produced by periodontal bacteria. Three volatile sulfur compounds (VSCs), hydrogen sulfide, methanethiol, and dimethyl sulfide, have attracted attention as major components of halitosis. However, these compounds cannot account for all odors. In this study, we profiled volatile compounds from the culture supernatants of periodontal bacteria using gas chromatography/mass spectrometry/olfactometry analysis with a monolithic silica gel adsorption device to investigate the potential odorous compounds. Periodontal bacteria have been found to produce volatile compounds belonging to various classes, such as alcohols, ketones, fatty acids, and aromatic compounds, in addition to VSCs. In addition, VSCs different from hydrogen sulfide and methanethiol, which are considered important causative compounds, may also influence to halitosis.

The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells.

Extracellular adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, Entpd8-/- mice develop more severe dextran sodium sulfate-induced colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti-Gr-1 antibody or the introduction of P2rx4 deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of Entpd8-/- mice promotes glycolysis in neutrophils through P2x4 receptor-dependent Ca2+ influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward glycolysis via the P2X4 receptor in myeloid cells.

Influence of Protein Adsorption on Aggregation in Prefilled Syringes.

Protein aggregate formation in prefilled syringes (PFSs) can be influenced by protein adsorption and desorption at the solid-liquid interface. Although inhibition of protein adsorption on the PFS surface can lead to a decrease in the amount of aggregation, the mechanism underlying protein adsorption-mediated aggregation in PFSs is unclear. This study investigated protein aggregation caused by protein adsorption on silicone oil-free PFS surfaces [borosilicate glass (GLS) and cycloolefin polymer (COP)] and the factors affecting the protein adsorption on the PFS surfaces. The adsorbed proteins formed multilayered structures that consisted of two distinct types of layers: proteins adsorbed on the surface of the material and proteins adsorbed on top of the proteins on the surface. A pH-dependent electrostatic interaction was the dominant force for protein adsorption on the GLS surface, while hydrophobic effects were dominant for protein adsorption on the COP surface. When the repulsion force between proteins was weak, protein adsorption on the adsorbed protein layer was increased for both materials and as a result, protein aggregation increased. Therefore, a formulation with high colloidal stability can minimize protein adsorption on the COP surface, leading to reduced protein aggregation.

Acral persistent papular mucinosis: A case report and summary of 24 Japanese cases.

Acral persistent papular mucinosis is a rare subtype of localized lichen myxedematosus. We report a case of a 41-year-old woman with acral persistent papular mucinosis. She had a 5-year history of multiple, scattered, whitish papules, on the back of both hands, of 2-5 mm in diameter. Histopathological examination revealed a focal, fairly circumscribed area with sparse collagen fibers in the upper and middle dermis. The circumscribed area was positively stained with Alcian blue. The papules were clinically and histologically diagnosed as acral persistent papular mucinosis. We also summarized 24 Japanese acral persistent papular mucinosis cases, including ours. Although acral persistent papular mucinosis occurs predominantly in women according to overseas reports, the male : female ratio is 5:7 in Japan. It has been reported that tranilast (N-[3,4-dimethoxycinnamoyl]-anthranilic acid) was effective in two Japanese cases. In our case, the patient had been treated with tranilast for 2 months without improvement. Further studies are required to confirm the efficacy of tranilast for acral persistent papular mucinosis.

Physicochemical Characterization of Sabin Inactivated Poliovirus Vaccine for Process Development.

Upscaling the production capacity of inactivated poliovirus vaccines (IPV) is urgently needed to eradicate polio worldwide. For the development of a robust manufacturing process for IPV, the impact of stresses on the properties of the poliovirus during manufacturing needs to be carefully evaluated. In this study, the physicochemical properties of Sabin poliovirus after low pH exposure were analyzed by asymmetrical flow field-flow fractionation coupled to multi-angle laser light scattering (AF4-MALS), sedimentation velocity analytical ultracentrifugation (SV-AUC), transmission electron microscopy (TEM), dynamic light scattering (DLS) and surface plasmon resonance (SPR). Low pH stress caused structural changes and aggregation of inactivated poliovirus virions, whereas degraded virion particles would not revert to native virions even after neutralization. Importantly, a complete loss of the D-antigenicity of IPV by low pH stress, followed by neutralization, was observed in SPR. These results suggest that the exposure of poliovirus particle to low pH stress would induce irreversible denaturation and aggregation of virus particles and lead to the loss of D-antigenicity; thus, low pH stress during the manufacturing of poliovirus vaccine should be minimized. The analytical methods above can be efficiently utilized in the development of high-integrity manufacturing processes and high-quality vaccines.

The correlation between metastasis-free survival and overall survival in non-metastatic castration resistant prostate cancer patients from the Medical Data Vision claims database in Japan.

Background and purpose: Several recent randomized controlled trials (RCTs) in non-metastatic castration resistant prostate cancer (nmCRPC) have demonstrated a significant improvement in metastasis-free survival (MFS); however, an improvement in overall survival (OS) is not reported yet. Since the surrogacy of MFS to OS has not been formally investigated in nmCRPC in Japan, this study evaluated the correlation between MFS and OS among a nmCRPC population in Japan. Methods: This is a retrospective longitudinal observational cohort study in patients with nmCRPC using the Japanese Medical Data Vision (MDV) database covering over 20 million patients. A total of 1236 patients with CRPC who had no prior medical history of cancer except prostate cancer and no distant metastasis, and who fulfilled PCWG2 criteria, were identified. Following the identification of nmCRPC, patients' medical records were investigated for subsequent events of metastasis and death. Results: The median follow-up time was 24 months. Median MFS was 28 months (95% CI: 24.0 to 33.0 months) and median OS could not be estimated (95% CI: not estimated). There was a statistically significant correlation between MFS and OS (Pearson's correlation coefficient = 0.62; 95% CI: 0.58-0.65; p < .0001, Spearman's correlation coefficient = 0.62; 95% CI: 0.58-0.65; p < .0001 and Kendall's τ statistic = 0.53; 95% CI: 0.49-0.56; p < .0001). Conclusions: The results of this study indicate a significant correlation between MFS and OS. It may justify the usefulness of MFS as surrogate for OS in nmCRPC.

Phase I, multicenter, open-label, dose-escalation study of sonidegib in Asian patients with advanced solid tumors.

Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose-limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, two-group, parallel, dose-escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with Clinicaltrials.gov: NCT01208831.).

[Everolimus plus exemestane in postmenopausal patients with estrogen-receptor-positive advanced breast cancer - Japanese subgroup analysis of BOLERO -2].

In a phase 3, double-blind, randomized, international study (the BOLERO-2), the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive (ER⁺) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor (NSAI). This report presents the safety and updated (18- month) efficacy results from the Japanese subset (n=106) of BOLERO-2. After a median follow-up of 18 months, the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane. The most common adverse events (AEs) with everolimus plus exemestane were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention. In conclusion, this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs.

Cost-utility analysis of antihypertensive combination therapy in Japan by a Monte Carlo simulation model.

The objective of the present study was to analyze the cost-effectiveness of lifetime antihypertensive therapy with angiotensin II receptor blocker (ARB) monotherapy, calcium channel blocker (CCB) monotherapy, or ARB plus CCB (ARB+CCB) combination therapy in Japan. Based on the results of large-scale clinical trials and epidemiological data, we constructed a Markov model for patients with essential hypertension. Our Markov model comprised coronary heart disease (CHD), stroke, and progression of diabetic nephropathy submodels. Based on this model, analysis of the prognosis of each patient was repeatedly conducted by Monte Carlo simulation. The three treatment strategies were compared in hypothetical 55-year-old patients with systolic blood pressure (SBP) of 160 mmHg in the absence and presence of comorbid diabetes. Olmesartan medoxomil 20 mg/d was the ARB and azelnidipine 16 mg/d the CCB in our model. On-treatment SBP was assumed to be 125, 140, and 140 mmHg in the ARB+CCB, ARB alone, and CCB alone groups, respectively. Costs and quality-adjusted life years (QALYs) were discounted by 3%/year. The ARB+CCB group was the most cost-effective both in male and female patients with or without diabetes. In conclusion, ARB plus CCB combination therapy may be a more cost-effective lifetime antihypertensive strategy than monotherapy with either agent alone.

Epigallocatechin gallate-induced apoptosis does not affect adipocyte conversion of preadipocytes.

In the present study, we examined the effect of epigallocatechin gallate (EGCG) on the growth and differentiation of human preadipocyte cells, AML-I. EGCG exhibited cytotoxic activity on AML-I cells, accompanied by the appearance of characteristics of apoptosis by Annexin V-FITC staining method. Among apoptosis-related proteins examined, loss of NF-kappaB and p-Akt, and accumulation of Bad were displayed in EGCG-treated cells by Western blot analysis. Among 6 structure-related catechins including catechin (C), epicatechin (EC), catechin gallate (CG), epigallocatechin (EGC), epicatechin gallate (ECG) and EGCG, the catechins containing galloyl moiety exhibited apoptotic capacity. Interestingly, exposure of AML-I to EGCG increased the amounts of cytoplasmic lipid droplets as well as the expression of fatty acid synthase and peroxisome proliferator activated receptor-gamma proteins. Our results suggest that EGCG induces growth arrest and apoptosis, but does not affect adipocyte conversion of preadipocytes.