ABSTRACT
Differentiation of pancreatic endocrine cells from human pluripotent stem cells (PSCs) has been thoroughly investigated for application in cell therapy against diabetes. In the context of induced pancreatic endocrine cell implantation, previous studies have reported graft enlargement resulting from off-target pancreatic lineage cells. However, there is currently no documented evidence of proliferative off-target cells beyond the pancreatic lineage in existing studies. Here, we show that the implantation of seven-stage induced PSC-derived pancreatic islet cells (s7-iPICs) leads to the emergence of unexpected off-target cells with proliferative capacity via in vivo maturation. These cells display characteristics of both mesenchymal stem cells (MSCs) and smooth muscle cells (SMCs), termed proliferative MSC- and SMC-like cells (PMSCs). The frequency of PMSC emergence was found to be high when 108 s7-iPICs were used. Given that clinical applications involve the use of a greater number of induced cells than 108, it is challenging to ensure the safety of clinical applications unless PMSCs are adequately addressed. Accordingly, we developed a detection system and removal methods for PMSCs. To detect PMSCs without implantation, we implemented a 4-wk-extended culture system and demonstrated that putative PMSCs could be reduced by compound treatment, particularly with the taxane docetaxel. When docetaxel-treated s7-iPICs were implanted, the PMSCs were no longer observed. This study provides useful insights into the identification and resolution of safety issues, which are particularly important in the field of cell-based medicine using PSCs.
Subject(s)
Induced Pluripotent Stem Cells , Islets of Langerhans , Humans , Docetaxel , Cell Differentiation , Embryo ImplantationABSTRACT
Metal nanoclusters (NCs) have unique properties because of their small size, which makes them useful as catalysts in reactions like cross-coupling. Pd-catalyzed oxidative amination, which involves dehydrogenative C-N bond formation, uses Pd complexes as the active species. It is known that the catalytic conditions involve the formation of Pd(0) species from Pd NCs, but the precise role of Pd NCs in the transformations has not been established. In this study, we investigated the characteristic properties of Pd NCs in oxidative amination of 1,3-dienes. The reaction achieved direct amination of commercially accessible 1,3-dienes with secondary aromatic amines, providing a variety of nitrogen containing 1,3-dienes. The compound was applicable to radical polymerization to provide the nitrogen-fabricated 1,3-diene-based polymer, which exhibited a different thermal stability compared to aliphatic nitrogen-fabricated diene polymers. In addition to the synthetic utility, by combining X-ray absorption fine structure and small-angle X-ray scattering analysis, we revealed amines and 1,3-dienes affected metal leaching from the Pd nanoparticles and stabilization of Pd NCs in the catalytic reaction. Additionally, DFT calculation suggested that the catalytic intermediate contained multiple adjacent Pd atoms and was responsible for formation of an σ-allylic intermediate that is difficult to form with the use of Pd complexes. These results could be used to understand the underlying phenomenon in the oxidative coupling reaction and develop Pd NCs-based dehydrogenation.
ABSTRACT
This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35-69 years from the Japan Multi-Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and ≥7 hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure-time metabolic equivalents (METs), frequency of leisure-time physical activity, and daily walking time, were examined. During 315,189 person-years of follow-up, 554 incident cases of BC were identified. When compared to participants who spent <7 h/d sedentary, those who spent ≥7 h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07-1.71). The corresponding HRs among participants who spent ≥7 h/d sedentary with more physical activity, such as ≥1 h/d for leisure-time METs, ≥3 days/week of leisure-time physical activity, and ≥1 h/d of daily walking were 1.58 (95% CI, 1.11-2.25), 1.77 (95% CI, 1.20-2.61), and 1.42 (95% CI, 1.10-1.83), respectively, compared with those who spent <7 h/d sedentary. This study found that spending ≥7 h/d of sedentary time is associated with the risk of BC. Neither leisure-time physical activity nor walking had a BC-preventive effect in those with ≥7 h/d of sedentary time.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/epidemiology , Breast Neoplasms/etiology , Sedentary Behavior , Japan/epidemiology , Cohort Studies , Motor Activity , Risk FactorsABSTRACT
BACKGROUND AIMS: The administration of human cell-processed therapeutic products (hCTPs) is associated with a risk of tumorigenesis due to the transformed cellular contaminants. To mitigate this risk, these impurities should be detected using sensitive and validated assays. The digital soft agar colony formation (D-SAC) assay is an ultrasensitive in vitro test for detecting tumorigenic transformed cells in hCTPs. METHODS: In this study, we first evaluated the colony formation efficiency (CFE) precision of tumorigenic reference cells in positive control samples according to a previously reported D-SAC assay protocol (Protocol I) from multiple laboratories. However, the CFE varied widely among laboratories. Thus, we improved and optimized the test protocol as Protocol II to reduce variability in the CFE of tumorigenic reference cells. Subsequently, the improved protocol was validated at multiple sites. Human mesenchymal stromal cells (hMSCs) were used as model cells, and positive control samples were prepared by spiking them with HeLa cells. RESULTS: Based on the previously reported protocol, the CFE was estimated using an ultra-low concentration (0.0001%) of positive control samples in multiple plates. Next, we improved the protocol to reduce the CFE variability. Based on the CFE results, we estimated the sample size as the number of wells (Protocol II) and assessed the detectability of 0.0001% HeLa cells in hMSCs to validate the protocol at multiple sites. Using Protocol I yielded low CFEs (mean: 30%) and high variability between laboratories (reproducibility coefficient of variance [CV]: 72%). In contrast, Protocol II, which incorporated a relatively high concentration (0.002%) of HeLa cells in the positive control samples, resulted in higher CFE values (mean: 63%) and lower variability (reproducibility CV: 18%). Moreover, the sample sizes for testing were estimated as the number of wells per laboratory (314-570 wells) based on the laboratory-specific CFE (42-76%). Under these conditions, all laboratories achieved a detection limit of 0.0001% HeLa cells in hMSCs in a predetermined number of wells. Moreover, colony formation was not observed in the wells seeded with hMSCs alone. CONCLUSIONS: The D-SAC assay is a highly sensitive and robust test for detecting malignant cells as impurities in hCTPs. In addition, optimal assay conditions were established to test tumorigenic impurities in hCTPs with high sensitivity and an arbitrary false negative rate.
Subject(s)
Cell- and Tissue-Based Therapy , Mesenchymal Stem Cells , Humans , HeLa Cells , Cell- and Tissue-Based Therapy/methods , Mesenchymal Stem Cells/cytology , Cell Transformation, NeoplasticABSTRACT
Wetwood of living trees is a habitat of methanogenic archaea, but the ubiquity of methanogenic archaea in the trunk of various trees has not been revealed. The present study analysed methanogenic archaeal communities inside coniferous and broadleaved trees in a cold temperate mountain forest by culture-dependent or independent techniques. Heartwood and sapwood segments were obtained from the trunk of seven tree species, Cryptomeria japonica, Quercus crispula, Fraxinus mandshurica, Acer pictum, Aesculus turbinata, Magnolia obovata, and Populus tremula. Amplicon sequencing analysis of 16S rRNA genes showed that Methanobacteriaceae predominated the archaeal communities and Methanomassiliicoccaceae also inhabited some trees. Real-time PCR analysis detected methanogenic archaeal mcrA genes from all the tree species, with a maximum of 107 copies g-1 dry wood. Digital PCR analysis also detected mcrA genes derived from Methanobacterium spp. and Methanobrevibacter spp. from several samples, with a maximum of 105 and 104 copies g-1 dry wood. The enumeration by the most probable number method demonstrated the inhabitation of viable methanogenic archaea inside the trees; 106 cells g-1 dry wood was enumerated from a heartwood sample of C. japonica. Methanogenic archaea related to Methanobacterium beijingense were cultivated from a heartwood sample of Q. crispula and F. mandshurica. The present study demonstrated that the inside of various trees is a common habitat for methanogenic archaeal communities and a potential source of methane in forest ecosystems.
Subject(s)
Forests , Methane , Phylogeny , RNA, Ribosomal, 16S , RNA, Ribosomal, 16S/genetics , Methane/metabolism , Trees/microbiology , Archaea/classification , Archaea/genetics , Archaea/metabolism , Archaea/isolation & purification , Wood/microbiology , DNA, Archaeal/geneticsABSTRACT
To clarify whether changes in frequency of going out due to the COVID-19 pandemic affect ikigai (sense of purpose in life) and mental health in Japanese middle-aged and older adults. In a questionnaire survey mailed to 16,866 adults aged > 40 years in Japan in September 2020, 7,973 responses were received (response rate, 47.3%) in October 2020. Following exclusions, data from 6,978 individuals (50.6% female, mean age 67.8 ± 12.2 years) were available for analysis. Respondents were categorized based on changes in frequency of going out, reflecting changes in social and/or physical activity, during the pandemic compared with before it: the previously active group went out often before but less often during the pandemic; the remained active group continued going out often; and the inactive group continued not going out often. Whether these changes affected the respondents' ikigai and mental health was investigated. The previously active group had a significantly higher proportion of individuals with decreased ikigai during the pandemic than the other groups. Mental health score decreased in all groups during the pandemic, but more so in the previously active group (-3.21), followed by the inactive and then the remained active groups (-1.45 and -1.28, respectively). Previously active individuals showed the greatest decline in ikigai and mental health among the three groups. These findings suggest that continuing to engage in appropriate physical and social activities, including going out, while following appropriate infection control measures, even under restrictions, can help people maintain ikigai and mental health.
Subject(s)
COVID-19 , Mental Health , SARS-CoV-2 , Humans , COVID-19/epidemiology , COVID-19/psychology , Female , Male , Aged , Japan/epidemiology , Middle Aged , Surveys and Questionnaires , Pandemics , Exercise/psychology , Aged, 80 and over , Quality of Life , AdultABSTRACT
Serratia marcescens is an opportunistic pathogen that can utilize chitin as a carbon source, through its ability to produce chitin-degrading enzymes to digest chitin and membrane transporters to transport the degradation products (chitooligosaccharides) into the cells. Further characterization of these proteins is important to understand details of chitin metabolism. Here, we investigate the properties and function of the S. marcescens chitoporin, namely SmChiP, a chitooligosaccharide transporter. We show that SmChiP is a monomeric porin that forms a stable channel in artificial phospholipid membranes, with an average single-channel conductance of 0.5 ± 0.02 nS in 1 M KCl electrolyte. Additionally, we demonstrated that SmChiP allowed the passage of small molecules with a size exclusion limit of <300 Da and exhibited substrate specificity toward chitooligosaccharides, both in membrane and detergent-solubilized forms. We found that SmChiP interacted strongly with chitopentaose (Kd = 23 ± 2.0 µM) and chitohexaose (Kd = 17 ± 0.6 µM) but did not recognize nonchitose oligosaccharides (maltohexaose and cellohexaose). Given that S. marcescens can use chitin as a primary energy source, SmChiP may serve as a target for further development of nutrient-based antimicrobial therapies directed against multidrug antibiotic-resistant S. marcescens infections.
Subject(s)
Chitin , Porins , Serratia marcescens , Chitin/metabolism , Chitosan/metabolism , Porins/metabolism , Particle Size , Membranes, ArtificialABSTRACT
The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion.
Subject(s)
Environment , Regenerative Medicine , Asia , Genetic Therapy/adverse effectsABSTRACT
Direct numerical simulation and theoretical analyses showed that the probability density functions (PDFs) of the energy dissipation rate and enstrophy in turbulence are asymptotically stretched gamma distributions with the same stretching exponent, and both the left and right tails of the enstrophy PDF are longer than those of the energy dissipation rate regardless of the Reynolds number. The differences in PDF tails arise due to the kinematics, with differences in the number of terms contributing to the dissipation rate and enstrophy. Meanwhile, the stretching exponent is determined by the dynamics and likeliness of singularities.
Subject(s)
Biomechanical Phenomena , ProbabilityABSTRACT
BACKGROUND: Previous cohort studies have yielded contradictory findings regarding the associations of dietary carbohydrate and fat intakes with risks of mortality. OBJECTIVES: We examined long-term associations of carbohydrate and fat intakes with mortality. METHODS: In this cohort study, 34,893 men and 46,440 women aged 35-69 y (mean body mass index of 23.7 and 22.2 kg/m2, respectively) were followed up from the baseline survey (2004-2014) to the end of 2017 or 2018. Intakes of carbohydrate, fat, and total energy were estimated using a food frequency questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for all-cause and cause-specific mortality according to percentage of energy intakes of carbohydrate and fat. RESULTS: During a mean 8.9-y follow-up, we identified 2783 deaths (1838 men and 945 women). Compared with men who consumed 50% to <55% of energy from carbohydrate, those who consumed <40% carbohydrate energy experienced a significantly higher risk of all-cause mortality (the multivariable-adjusted HR: 1.59; 95% CI: 1.19-2.12; P-trend = 0.002). Among women with 5 y or longer of follow-up, women with high-carbohydrate intake recorded a higher risk of all-cause mortality; the multivariable-adjusted HR (95% CI) was 1.71 (0.93-3.13) for ≥65% of energy from carbohydrate compared with that for 50% to <55% (P-trend = 0.005). Men with high fat intake had a higher risk of cancer-related mortality; the multivariable-adjusted HR (95% CI) for ≥35% was 1.79 (1.11-2.90) compared with that for 20% to <25%. Fat intake was marginally inversely associated with risk of all-cause and cancer-related mortality in women (P-trend = 0.054 and 0.058, respectively). CONCLUSIONS: An unfavorable association with mortality is observed for low-carbohydrate intake in men and for high-carbohydrate intake in women. High fat intake can be associated with a lower mortality risk in women among Japanese adults with a relatively high-carbohydrate intake.
Subject(s)
Cardiovascular Diseases , Neoplasms , Adult , Female , Humans , Male , Cardiovascular Diseases/etiology , Cohort Studies , Dietary Carbohydrates , East Asian People , Japan/epidemiology , Prospective Studies , Risk Factors , Middle Aged , AgedABSTRACT
Metal-organic frameworks (MOFs)âcrystalline coordination polymersâwith unique characteristics such as structural designability accompanied by tunable electronic properties and intrinsic uniform nanopores have become the platform for applications in diverse scientific areas ranging from nanotechnology to energy/environmental sciences. To utilize the superior features of MOF in potential applications, the fabrication and integration of thin films are of importance and have been actively sought. Especially, downsized MOFs into nanosheets can act as ultimately thin functional components in nanodevices and potentially display unique chemical/physical properties rarely seen in bulk MOFs. Assembling nanosheets by aligning amphiphilic molecules at the air/liquid interface has been known as the Langmuir technique. By utilizing the air/liquid interface as a reaction field between metal ions and organic ligands, MOFs are readily formed into the nanosheet state. The expected features in MOF nanosheets including electrical conduction largely depend on the nanosheet characteristics such as lateral size, thickness, morphology, crystallinity, and orientation. However, their control has not been achieved as yet. Here, we demonstrate how changing the concentration of a ligand spread solution can modify the assembly of MOF nanosheets, composed of 2,3,6,7,10,11-hexaiminotriphenylene (HITP) and Ni2+ ions (HITP-Ni-NS), at the air/liquid interface. A systematic increase in the concentration of the ligand spread solution leads to the enlargement of both the lateral size and the thickness of the nanosheets while retaining their perfect alignment and preferred orientation. On the other hand, at much higher concentrations, we find that unreacted ligand molecules are included in HITP-Ni-NS, introducing disorder in HITP-Ni-NS. These findings can develop further sophisticated control of MOF nanosheet features, accelerating fundamental and applied studies on MOFs.
ABSTRACT
BACKGROUND: Improving diets requires an awareness of the need to limit foods for which excessive consumption is a health problem. Since there are limited reports on the link between this awareness and mortality risk, we examined the association between awareness of limiting food intake (energy, fat, and sweets) and all-cause mortality in a Japanese cohort study. METHODS: Participants comprised 58,772 residents (27,294 men; 31,478 women) aged 35-69 years who completed baseline surveys of the Japan Multi-Institutional Collaborative Cohort Study from 2004 to 2014. Hazard ratios (HRs) for all-cause mortality and 95% confidence intervals (CIs) were estimated by sex using a Cox proportional hazard model, with adjustment for related factors. Mediation analysis with fat intake as a mediator was also conducted. RESULTS: The mean follow-up period was 11 years and 2,516 people died. Estimated energy and fat intakes according to the Food Frequency Questionnaire were lower in those with awareness of limiting food intake than in those without this awareness. Women with awareness of limiting fat intake showed a significant decrease in mortality risk (HR=0.73; 95% CI, 0.55 to 0.94). Mediation analysis revealed that this association was due to the direct effect of the awareness of limiting fat intake and that the total effect was not mediated by actual fat intake. Awareness of limiting energy or sweets intake was not related to mortality risk reduction. CONCLUSION: Awareness of limiting food intake had a limited effect on reducing all-cause mortality risk.
ABSTRACT
BACKGROUND AND AIMS: To date, the relationship between coffee consumption and metabolic phenotypes has hardly been investigated and remains controversial. Therefore, the aim of this cross-sectional study is to examine the associations between coffee consumption and metabolic phenotypes in a Japanese population. METHODS AND RESULTS: We analyzed the data of 26,363 subjects (aged 35-69 years) in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Coffee consumption was assessed using a questionnaire. Metabolic Syndrome (MetS) was defined according to the Joint Interim Statement Criteria of 2009, using body mass index (BMI) instead of waist circumference. Subjects stratified by the presence or absence of obesity (normal weight: BMI <25 kg/m2; obesity: BMI ≥25 kg/m2) were classified by the number of MetS components (metabolically healthy: no components; metabolically unhealthy: one or more components) other than BMI. In multiple logistic regression analyses adjusted for sex, age, and other potential confounders, high coffee consumption (≥3 cups/day) was associated with a lower prevalence of MetS and metabolically unhealthy phenotypes both in normal weight (OR 0.83, 95% CI 0.76-0.90) and obese subjects (OR 0.83, 95% CI 0.69-0.99). Filtered/instant coffee consumption was inversely associated with the prevalence of MetS and metabolically unhealthy phenotypes, whereas canned/bottled/packed coffee consumption was not. CONCLUSION: The present results suggest that high coffee consumption, particularly filtered/instant coffee, is inversely associated with the prevalence of metabolically unhealthy phenotypes in both normal weight and obese Japanese adults.
Subject(s)
Coffee , Metabolic Syndrome , Humans , Cross-Sectional Studies , Coffee/adverse effects , Cohort Studies , Japan/epidemiology , Metabolic Syndrome/diagnosis , Metabolic Syndrome/epidemiology , Metabolic Syndrome/prevention & control , Obesity/diagnosis , Obesity/epidemiology , Obesity/metabolism , Body Mass Index , Phenotype , Risk FactorsABSTRACT
BACKGROUND: The nocebo response refers to the phenomenon where non-specific factors, including negative verbal suggestion and treatment expectations, cause adverse events (AE) following a placebo treatment. Non-specific factors are also likely to influence AE occurrence following administration of active pharmacological treatments. OBJECTIVE: This meta-analysis aimed to estimate the nocebo response in dentistry by assessing the AEs prevalence in placebo- and active arms of randomised controlled trials (RCTs) assessing analgesic treatment following third molar (M3) surgery. METHODS: A systematic search was performed in PubMed, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials. Eligible studies had to report the number of patients experiencing at least one drug-related AE (patients with AE ≥ 1) separately for the active and placebo arms. The proportion of patients with AE ≥ 1 and drug-related dropouts were pooled, and risk differences (RDs) between patients in the placebo- and active arm were calculated. RESULTS: In 50 independent RCTs of 47 identified articles, the pooled rates of patients with AE ≥ 1 were 22.8% in the placebo arm and 20.6% in the active arm. The pooled rates of drug-related dropout were 0.24% in the placebo arm and 0.08% in the active arm. There were no significant RDs in patients with AE ≥ 1 and drug-related dropouts. CONCLUSION: These results show that patients in the placebo arm reported AEs to the same extent as patients receiving active treatment, suggesting that most AEs in analgesic medication following M3 surgery may be attributed to the nocebo phenomenon.
Subject(s)
Molar, Third , Nocebo Effect , Humans , Analgesics , DentistryABSTRACT
Determining the optimal timing for histopathological examination following exposure to a test article is crucial for assessing neurotoxicity. However, no study has focused on identifying an ideal dataset to define the optimal timing for histopathological examination of central nervous system (CNS) toxicity in monkeys. Therefore, this study aimed to define a predictive endpoint that would guide us in selecting the optimal timing for histopathological examination of CNS toxicity in monkeys. Four cynomolgus monkeys were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously at a dosage of 0.6 mg/kg twice at 1-week intervals. Necropsies were performed 1 week after the final dose. The Parkinsonian rating (PR) score and temporal changes in neurofilament light chain and glial fibrillary acidic protein concentrations in the cerebrospinal fluid (CSF) and serum were evaluated and compared with the histopathological findings in the brain. The PR score of all animals administered MPTP increased from days 10 to 11, with some degree of individual variability. Microscopically, all animals showed axonal swelling and vacuolation, with or without microgliosis in the nigrostriatal bundle. However, substantial neurodegenerative findings were observed only in animals with high PR scores at necropsy. A slight increase in CSF biomarker levels at necropsy was also observed in animals with high PR scores. However, their correlation with microscopic findings in these animals was unclear. These data suggest that comprehensive clinical observations, such as PR score alone or combined with other CSF biomarkers, could be further evaluated as potential indicators for triggering anatomic CNS evaluations in monkeys following toxic insults.
ABSTRACT
Neurofilament light chain (NfL) has recently been used as a biomarker of neurodegeneration. Although cerebrospinal fluid (CSF) NfL levels are hypothesized to affect blood NfL levels, whether blood NfL levels change independently of the CSF during peripheral nerve injury remains unclear. Thus, we evaluated the nervous tissues histopathology and serum and CSF NfL levels in partial sciatic nerve-ligated rats at 6 h and one, three, or seven days after the surgery. Sciatic and tibial nerve fiber damage was observed at 6 h after the surgery, and peaked at three days postoperatively. The serum NfL levels peaked 6 h to one day after ligation, but they tended to return to the normal seven days after ligation. However, the CSF NfL levels were unchanged throughout the study period. In conclusion, the comparative evaluation of serum and CSF NfL levels can provide useful information as biomarkers of nerve tissue damage and its distribution.
ABSTRACT
The tumor microenvironment is one of the most important factors determining the efficacy of cancer immunotherapy. In particular, variability in efficacy has been linked to whether tumors are hot or cold, with hot tumors exhibiting greater T cell infiltration and responding better to immunotherapy. Z-100 extracted from Mycobacterium tuberculosis Aoyama B strain has been reported to increase cytokine production from immune cells. In this study, we examined its effect on the tumor microenvironment and its potential as a hot tumor inducer. The antitumor effect of Z-100 was confirmed in a mouse oral squamous cell carcinoma (Sq-1979) tumor model by starting administration before tumor injection. Treated tumors were collected to identify infiltrating CD8+ T cells. The antitumor effects of Z-100 were additionally examined in mice treated with anti-CD8 antibody and in IL-12p40 knockout (KO) mice. We found that Z-100 had strong antitumor effects and increased the proportion of CD8+ T cells in tumors. Moreover, the CD8+ T cells infiltrating tumors were identified as effector memory CD8+ T cells. Furthermore, the antitumor effects of Z-100 were abolished in mice treated with an anti-CD8 antibody and in IL-12p40 KO mice. Thus, Z-100 induces its antitumor effects by increasing tumor-infiltrating CD8+ T cells, suggesting that Z-100 may be a useful cancer therapy by acting as a hot tumor inducer.
ABSTRACT
The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future.
Subject(s)
Cell- and Tissue-Based Therapy , Regenerative Medicine , Asia , JapanABSTRACT
Liver ischemia and reperfusion injury (IRI) is a major challenge in liver surgery. Diet restriction reduces liver damage by increasing stress resistance; however, the underlying molecular mechanisms remain unclear. We investigated the preventive effect of 12-h fasting on mouse liver IRI. Partial warm hepatic IRI model in wild-type male C57BL/6 mice was used. The control ischemia and reperfusion (IR) group of mice was given food and water ad libitum, while the fasting IR group was given water but not food for 12 h before ischemic insult. In 12-h fasting mice, serum liver-derived enzyme level and tissue damages due to IR were strongly suppressed. Serum ß-hydroxybutyric acid (BHB) was significantly raised before ischemia and during reperfusion. Up-regulated BHB induced an increment in the expression of FOXO1 transcription factor by raising the level of acetylated histone. Antioxidative enzyme heme oxigenase 1 (HO-1), a target gene of FOXO1, then increased. Autophagy activity was also enhanced. Serum high-mobility group box 1 was remarkably lowered by the 12-h fasting, and activation of NF-κB and NLRP3 inflammasome was suppressed. Consequently, inflammatory cytokine production and liver injury were reduced. Exogenous BHB administration or histone deacetylase inhibitor administration into the control fed mice ameliorated liver IRI, while FOXO1 inhibitor administration to the 12-h fasting group exacerbated liver IRI. The 12-h fasting exerted beneficial effects on the prevention of liver IRI by increasing BHB, thus up-regulating FOXO1 and HO-1, and by reducing the inflammatory responses and apoptotic cell death via the down-regulation of NF-κB and NLRP3 inflammasome.
Subject(s)
3-Hydroxybutyric Acid/therapeutic use , Fasting , Forkhead Box Protein O1/metabolism , Liver Diseases/prevention & control , Reperfusion Injury/prevention & control , Animals , Inflammation/drug therapy , Liver/metabolism , Liver/surgery , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxidative Stress , Up-RegulationABSTRACT
BACKGROUND: Evidence for the nocebo effect, a phenomenon characterised by suboptimal treatment efficacy, worsening of symptoms, or the occurrence of adverse events caused by an individual's negative treatment expectations, is growing across a multitude of medical fields. However, little attention has been paid to patients' negative expectations and the nocebo effect within dentistry. AIM: This review summarises essential evidence of the nocebo phenomenon especially in relation to pain and drug administration. Subsequently, an overview of the current evidence of the nocebo phenomenon in the dental field is presented. METHODS: A PubMed search was performed using keywords related to "nocebo," "placebo," "expectations," and "dentistry." In addition to the articles selected from the search, placebo/nocebo researchers and dental researchers added important references from their respective fields. RESULTS: Although research on the nocebo effect in dentistry is limited, available current evidence suggests that the factors, which is related to the nocebo effect are likely to play a role in dental practice. CONCLUSION: Preliminary evidence from the review warrants further investigation into the nocebo effect in dentistry. Finally, based on the general knowledge of the nocebo effect, the review indicates fruitful arrays of research into the nocebo effect in dentistry.