Publications by authors named "Kyoko Miura"

58 Publications

Weight Gain After Heart Transplantation in Adults: Systematic Review and Meta-Analysis.

ASAIO J 2021 Sep 20. Epub 2021 Sep 20.

From the Population Health Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia Transplant Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom Advanced Heart Failure and Cardiac Transplant Unit, The Prince Charles Hospital, Chermside, Queensland, Australia CRUK Manchester Institute and University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.

Gain in weight is common after heart transplantation but the magnitude of usual weight gain and whether this varies by country is unknown. We systematically reviewed all relevant studies to quantify weight change among heart transplant recipients (HTRs) in the years after transplantation and assess variation with geographic location. We searched PubMed, Cumulative Index to Nursing and Allied Health Literature, and Excerpta Medica Database databases to September 2020. Eligible studies reported adult HTRs' mean/median weight and/or body mass index (BMI) up to time of transplantation (baseline) and posttransplantation in any language. Weighted mean differences (WMDs) (95% confidence intervals [CIs]) of weight/BMI from baseline to posttransplantation were estimated using a random-effects model. Ten studies met the inclusion criteria. Pooled analysis showed weight gain of 7.1 kg (95% CI, 4.4-9.8 kg) in HTRs 12 months posttransplant, with corresponding BMI increase of 1.69 kg/m2 (95% CI, 0.83-2.55 kg/m2). Greatest weight gain at 12 months posttransplant occurred in US HTRs (WMD weight 10.42 kg, BMI 3.25 kg/m2) and least, in European HTRs (WMD weight 3.10 kg, BMI 0.78 kg/m2). In conclusion, HTRs gain substantial weight in the years after transplantation, but varying widely by geographic location.
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http://dx.doi.org/10.1097/MAT.0000000000001566DOI Listing
September 2021

The naked truth: a comprehensive clarification and classification of current 'myths' in naked mole-rat biology.

Biol Rev Camb Philos Soc 2021 Sep 3. Epub 2021 Sep 3.

Department of Otolaryngology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, U.S.A.

The naked mole-rat (Heterocephalus glaber) has fascinated zoologists for at least half a century. It has also generated considerable biomedical interest not only because of its extraordinary longevity, but also because of unusual protective features (e.g. its tolerance of variable oxygen availability), which may be pertinent to several human disease states, including ischemia/reperfusion injury and neurodegeneration. A recent article entitled 'Surprisingly long survival of premature conclusions about naked mole-rat biology' described 28 'myths' which, those authors claimed, are a 'perpetuation of beautiful, but falsified, hypotheses' and impede our understanding of this enigmatic mammal. Here, we re-examine each of these 'myths' based on evidence published in the scientific literature. Following Braude et al., we argue that these 'myths' fall into four main categories: (i) 'myths' that would be better described as oversimplifications, some of which persist solely in the popular press; (ii) 'myths' that are based on incomplete understanding, where more evidence is clearly needed; (iii) 'myths' where the accumulation of evidence over the years has led to a revision in interpretation, but where there is no significant disagreement among scientists currently working in the field; (iv) 'myths' where there is a genuine difference in opinion among active researchers, based on alternative interpretations of the available evidence. The term 'myth' is particularly inappropriate when applied to competing, evidence-based hypotheses, which form part of the normal evolution of scientific knowledge. Here, we provide a comprehensive critical review of naked mole-rat biology and attempt to clarify some of these misconceptions.
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http://dx.doi.org/10.1111/brv.12791DOI Listing
September 2021

Induced Pluripotent Stem Cells from Cancer-Resistant Naked Mole-Rats.

Adv Exp Med Biol 2021 ;1319:329-339

Department of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Stem cells play essential roles in the development and tissue homeostasis of animals and are closely associated with carcinogenesis and aging. Also, the somatic cell reprogramming process to induced pluripotent stem (iPS) cells shares several characteristics with carcinogenesis. In this chapter, we focus on iPS cells and the reprogramming process of somatic cells in the naked mole-rat (NMR), the longest-living rodent with remarkable cancer resistance capabilities. NMR somatic cells show resistance to reprogramming induction, and generated NMR-iPS cells have a unique tumor-resistant phenotype. This phenotype is regulated by expressional activation of the tumor suppressor ARF gene and loss-of-function mutation in oncogene ERAS. Notably, it was also found that NMR somatic cells undergo senescence when ARF is suppressed during reprogramming, which would contribute to the resistance to both reprogramming and cancer in NMR somatic cells. Further studies on reprogramming resistance in NMR somatic cells and their concomitant tumor resistance in NMR-iPS cells would contribute to a better understanding of both cancer resistance and delayed aging in NMRs. In addition, NMR-iPS cells can be used as a new and important cell source for advancing research concerning several extraordinary physiological characteristics of NMR. Furthermore, study of NMR-iPS cells could lead to the development of safer regenerative therapies in the future.
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http://dx.doi.org/10.1007/978-3-030-65943-1_13DOI Listing
August 2021

Diversification of mineralocorticoid receptor genes in a subterranean rodent, the naked mole-rat.

J Mol Endocrinol 2021 05 11;66(4):299-311. Epub 2021 May 11.

Department of Aging and Longevity Research, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Naked mole-rats (Heterocephalus glaber) inhabit subterranean burrows in savannas and are, thus, unable to access free water. To identify their mechanism of osmoregulation in xeric environments, we molecularly cloned and analyzed the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene encoding the mineralocorticoid receptor (MR), required for hormone-dependent regulation of genes contributing to body fluid homeostasis. Most vertebrates harbor a single MR homolog. In contrast, we discovered that MR is duplicated in naked mole-rats. The amino acid sequence of naked mole-rat MR1 is 90% identical to its mouse ortholog, and MR1 is abundantly expressed in the kidney and the nervous system. MR2 encodes a truncated protein lacking DNA- and ligand-binding domains of MR1 and is expressed in diverse tissues. Although MR2 did not directly transactivate gene expression, it increased corticosteroid-dependent transcriptional activity of MR1. Our results suggest that MR2 might function as a novel regulator of MR1 activity to fine-tune MR signaling in naked mole-rats.
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http://dx.doi.org/10.1530/JME-20-0325DOI Listing
May 2021

β-catenin-promoted cholesterol metabolism protects against cellular senescence in naked mole-rat cells.

Commun Biol 2021 03 19;4(1):357. Epub 2021 Mar 19.

Department of Oncogene Research, Research for Microbial Disease, Osaka University, Suita, Osaka, Japan.

The naked mole-rat (NMR; Heterocephalus glaber) exhibits cancer resistance and an exceptionally long lifespan of approximately 30 years, but the mechanism(s) underlying increased longevity in NMRs remains unclear. In the present study, we report unique mechanisms underlying cholesterol metabolism in NMR cells, which may be responsible for their anti-senescent properties. NMR fibroblasts expressed β-catenin abundantly; this high expression was linked to increased accumulation of cholesterol-enriched lipid droplets. Ablation of β-catenin or inhibition of cholesterol synthesis abolished lipid droplet formation and induced senescence-like phenotypes accompanied by increased oxidative stress. β-catenin ablation downregulated apolipoprotein F and the LXR/RXR pathway, which are involved in cholesterol transport and biogenesis. Apolipoprotein F ablation also suppressed lipid droplet accumulation and promoted cellular senescence, indicating that apolipoprotein F mediates β-catenin signaling in NMR cells. Thus, we suggest that β-catenin in NMRs functions to offset senescence by regulating cholesterol metabolism, which may contribute to increased longevity in NMRs.
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http://dx.doi.org/10.1038/s42003-021-01879-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979689PMC
March 2021

Characterization of an active LINE-1 in the naked mole-rat genome.

Sci Rep 2021 Mar 11;11(1):5725. Epub 2021 Mar 11.

Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Naked mole-rats (NMRs, Heterocephalus glaber) are the longest-living rodent species. A reason for their long lifespan is pronounced cancer resistance. Therefore, researchers believe that NMRs have unknown secrets of cancer resistance and seek to find them. Here, to reveal the secrets, we noticed a retrotransposon, long interspersed nuclear element 1 (L1). L1s can amplify themselves and are considered endogenous oncogenic mutagens. Since the NMR genome contains fewer L1-derived sequences than other mammalian genomes, we reasoned that the retrotransposition activity of L1s in the NMR genome is lower than those in other mammalian genomes. In this study, we successfully cloned an intact L1 from the NMR genome and named it NMR-L1. An L1 retrotransposition assay using the NMR-L1 reporter revealed that NMR-L1 was active retrotransposon, but its activity was lower than that of human and mouse L1s. Despite lower retrotrasposition activity, NMR-L1 was still capable of inducing cell senescence, a tumor-protective system. NMR-L1 required the 3' untranslated region (UTR) for retrotransposition, suggesting that NMR-L1 is a stringent-type of L1. We also confirmed the 5' UTR promoter activity of NMR-L1. Finally, we identified the G-quadruplex structure of the 3' UTR, which modulated the retrotransposition activity of NMR-L1. Taken together, the data indicate that NMR-L1 retrotranspose less efficiently, which may contribute to the cancer resistance of NMRs.
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http://dx.doi.org/10.1038/s41598-021-84962-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952902PMC
March 2021

Modifying dietary patterns in cardiothoracic transplant patients to reduce cardiovascular risk: The AMEND-IT Trial.

Clin Transplant 2021 02 26;35(2):e14186. Epub 2020 Dec 26.

The Ex-Vivo Lab, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.

Background: Cardiovascular disease (CVD) is common after cardiothoracic transplantation and causes substantial morbidity.

Aims: To assess feasibility and potential effectiveness of dietary interventions to reduce CVD risk.

Materials And Methods: In a pilot intervention, we recruited patients from a tertiary hospital and randomly allocated them to a Mediterranean or low-fat diet for 12 months. Feasibility was measured by patient participation, retention, and adherence. Changes in weight, body mass index (BMI), heart rate, blood pressure, glucose markers, and blood lipids were assessed using longitudinal generalized estimating equation regression models with 95% confidence intervals.

Results: Of 56 heart and 60 lung transplant recipients, 52 (45%) consented, 41 were randomized, and 39 (95%) completed the study with good adherence to randomized diets. After 12 months, changes in many risk factors were seen in the Mediterranean and low-fat-diet groups, respectively, including mean BMI (-0.5 vs. 0.0 kg/m ), systolic/diastolic blood pressure +0.5/+0.1 vs -4.4/-3.5 mmHg; fasting glucose -0.26 vs -0.27 mmol/L; total cholesterol -0.56 vs -0.40 mmol/L. Changes in BMI and systolic/diastolic blood pressure in 49 eligible patients who did not take part were +0.7 kg/m and +2.5/+1.8 mmHg.

Discussion: Dietary interventions in cardiothoracic transplant patients are feasible and potentially beneficial.

Conclusion: A definitive nutritional intervention study in these high-risk patients is warranted.
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http://dx.doi.org/10.1111/ctr.14186DOI Listing
February 2021

Clinical pathways and outcomes of patients with Barrett's esophagus in tertiary care settings: a prospective longitudinal cohort study in Australia, 2008-2016.

Dis Esophagus 2021 Aug;34(8)

Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

Background: Clinical services for Barrett's esophagus have been rising worldwide including Australia, but little is known of the long-term outcomes of such patients. Retrospective studies using data at baseline are prone to both selection and misclassification bias. We investigated the clinical characteristics and outcomes of Barrett's esophagus patients in a prospective cohort.

Methods: We recruited patients diagnosed with Barrett's esophagus in tertiary settings across Australia between 2008 and 2016. We compared baseline and follow-up epidemiological and clinical data between Barrett's patients with and without dysplasia. We calculated age-adjusted incidence rates and estimated minimally and fully adjusted hazard ratios (HR) to identify those clinical factors related to disease progression.

Results: The cohort comprised 268 patients with Barrett's esophagus (median follow-up 5 years). At recruitment, 224 (84%) had no dysplasia, 44 (16%) had low-grade or indefinite dysplasia (LGD/IND). The age-adjusted incidence of esophageal adenocarcinoma (EAC) was 0.5% per year in LGD/IND compared with 0.1% per year in those with no dysplasia. Risk of progression to high-grade dysplasia/EAC was associated with prior LGD/IND (fully adjusted HR 6.55, 95% confidence interval [CI] 1.96-21.8) but not long-segment disease (HR 1.03, 95%CI 0.29-3.58).

Conclusions: These prospective data suggest presence of dysplasia is a stronger predictor of progression to cancer than segment length in patients with Barrett's esophagus.
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http://dx.doi.org/10.1093/dote/doaa119DOI Listing
August 2021

Characterization of brown adipose tissue thermogenesis in the naked mole-rat (Heterocephalus glaber), a heterothermic mammal.

Sci Rep 2020 11 10;10(1):19488. Epub 2020 Nov 10.

Department of Aging and Longevity Research, Kumamoto University, Kumamoto, 860-0811, Japan.

The naked mole-rat (NMR) is a heterothermic mammal that forms eusocial colonies consisting of one reproductive female (queen), several reproductive males, and subordinates. Despite their heterothermy, NMRs possess brown adipose tissue (BAT), which generally induces thermogenesis in cold and some non-cold environments. Previous studies suggest that NMR-BAT induces thermogenesis by cold exposure. However, detailed NMR-BAT characteristics and whether NMR-BAT thermogenesis occurs in non-cold environments are unknown. Here, we show beta-3 adrenergic receptor (ADRB3)-dependent thermogenic potential of NMR-BAT, which contributes to thermogenesis in the isolated queen in non-cold environments (30 °C). NMR-BAT expressed several brown adipocyte marker genes and showed noradrenaline-dependent thermogenic activity in vitro and in vivo. Although our ADRB3 inhibition experiments revealed that NMR-BAT thermogenesis slightly delays the decrease in body temperature in a cold environment (20 °C), it was insufficient to prevent the decrease in the body temperatures. Even at 30 °C, NMRs are known to prevent the decrease of and maintain their body temperature by heat-sharing behaviors within the colony. However, isolated NMRs maintained their body temperature at the same level as when they are in the colony. Interestingly, we found that queens, but not subordinates, induce BAT thermogenesis in this condition. Our research provides novel insights into NMR thermoregulation.
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http://dx.doi.org/10.1038/s41598-020-74929-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656259PMC
November 2020

Inflammatory Dietary Patterns and Risk of Keratinocyte Cancers in Kidney Transplant Recipients: Prospective Cohort Study.

Dermatology 2020 Sep 23:1-6. Epub 2020 Sep 23.

QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Background: Kidney transplant recipients (KTRs) are at increased risk of cutaneous squamous (SCC) and basal cell carcinomas (BCC) due to immunosuppression and sun exposure. Skin carcinogenesis involves inflammation, and foods that promote inflammation may promote carcinogenesis.

Methods: We prospectively examined the association between pro-inflammatory diets and SCC and BCC incidence in KTRs in Queensland, Australia. We recruited KTRs at high risk of skin cancer (aged ≥18 years and previously affected; or aged ≥40; or immunosuppressed ≥10 years) between 2012 and 2014 and followed up until June 2016. A baseline dietary questionnaire was used to calculate modified-Empirical Dietary Inflammatory Pattern (EDIP) scores to indicate dietary inflammatory capacity; higher scores indicated pro-inflammatory diets. EDIP scores were ranked into 3 groups. Outcomes were histologically confirmed SCC and BCC. Adjusted relative risks (RRadj) and 95% CIs were estimated using negative binomial regression.

Results: Among 260 KTRs, 100 (38%) and 93 (36%) developed at least 1 new SCC and BCC, with 426 SCC and 343 BCC diagnosed in the follow-up period. The highest modified-EDIP score group (vs. lowest) were at increased risk of SCC (RRadj 1.79, 95% CI 1.01-3.16) but not BCC. Pro-inflammatory diets may increase SCC but not BCC risk among KTRs.

Conclusions: Inflammatory diets may increase the risk of SCC in KTRs.
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http://dx.doi.org/10.1159/000509875DOI Listing
September 2020

Omega-3 fatty acid intake and decreased risk of skin cancer in organ transplant recipients.

Eur J Nutr 2021 Jun 9;60(4):1897-1905. Epub 2020 Sep 9.

Population Health Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, Australia.

Purpose: Organ transplant recipients have over 100-fold higher risk of developing skin cancer than the general population and are in need of further preventive strategies. We assessed the possible preventive effects of omega-3 polyunsaturated fatty acid (PUFA) intake from food on the two main skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in kidney and liver transplant recipients.

Methods: Adult kidney or liver transplant recipients transplanted for at least 1 year and at high risk of skin cancer were recruited from the main transplant hospital in Queensland, 2012-2014 and followed until mid-2016. We estimated their dietary total long-chain omega-3 PUFAs and α-linolenic acid intakes at baseline using a food frequency questionnaire and ranked PUFA intakes as low, medium, or high. Relative risks (RRs) of skin cancer adjusted for confounding factors with 95% confidence intervals (CIs) were calculated.

Results: There were 449 transplant recipients (mean age, 55 years; 286 (64%) male). During follow-up, 149 (33%) patients developed SCC (median 2/person; range 1-40) and 134 (30%), BCC. Transplant recipients with high total long-chain omega-3 PUFA compared with low intakes showed substantially reduced SCC tumour risk (RR 0.33, 95% CI 0.18-0.60), and those with high α-linolenic acid intakes experienced significantly fewer BCCs (RR 0.40, 95% CI 0.22-0.74). No other significant associations were seen.

Conclusion: Among organ transplant recipients, relatively high intakes of long-chain omega-3 PUFAs and of α-linolenic acid may reduce risks of SCC and BCC, respectively.
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http://dx.doi.org/10.1007/s00394-020-02378-yDOI Listing
June 2021

Destructive and topical treatments of skin lesions in organ transplant recipients and relation to skin cancer.

Arch Dermatol Res 2020 Sep 5. Epub 2020 Sep 5.

Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Various treatments of keratotic skin lesions and early skin cancers are performed in organ transplant recipients (OTRs) at high risk of skin malignancies but the frequency of their use is unknown. We prospectively assessed the frequency of use of cryotherapy, diathermy, and topical therapies and also investigated their associations with background incidence of histologically-confirmed squamous-cell carcinoma (SCC) and basal cell carcinoma (BCC) in a cohort of OTRs in Queensland, Australia. Median follow-up ranged from 1.7 to 3.2 years across organ transplant groups. Among 285 kidney, 125 lung and 203 liver transplant recipients [382 (62%) male, 380 (62%) immunosuppressed > 5 years, 394 (64%) previously diagnosed with skin cancer], 306 (50%) reported treatment of skin lesions with major types of non-excision therapies during follow-up: 278 (45%) cryotherapy or diathermy; 121 (20%) topical treatments. Of these 306, 150 (49%) developed SCC at double the incidence of those who did not receive these treatments, as assessed by incidence rate ratio (IRR) adjusted for age, sex, type of organ transplant, skin color and history of skin cancer at baseline, calculated by multivariable Poisson regression (IRR = 2.1, 95% confidence interval (CI) 1.4-3.1). BCC incidence was not associated with these therapies. Skin lesions in OTRs that are treated with cryotherapy, diathermy, or topical treatment warrant judicious selection and careful follow-up.
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http://dx.doi.org/10.1007/s00403-020-02136-4DOI Listing
September 2020

Patterns of Omega-3 and Omega-6 Fatty Acid Dietary Intake and Melanoma Thickness at Diagnosis.

Cancer Epidemiol Biomarkers Prev 2020 08 19;29(8):1647-1653. Epub 2020 May 19.

Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Background: Experimental evidence suggests that dietary intakes of omega-3 and omega-6 polyunsaturated fatty acids have divergent effects on melanoma growth, but epidemiologic evidence on their combined effect is lacking.

Methods: In 634 Australian patients with primary melanoma, we assessed prediagnosis consumption of 39 food groups by food frequency questionnaires completed within 2 months of diagnosis. We derived, by reduced rank regression, dietary patterns that explained variability in selected omega-3 and omega-6 fatty acid intakes. Prevalence ratios (PR) and 95% confidence intervals (CI) for the association between tertiles of dietary patterns and melanoma thickness >2 mm versus ≤2 mm were estimated using Poisson regression.

Results: Overall omega-3 fatty acid intakes were low. Two major fatty acid dietary patterns were identified: "meat, fish, and fat," positively correlated with intakes of all fatty acids; and "fish, low-meat, and low-fat," positively correlated with long-chain omega-3 fatty acid intake, and inversely with medium-chain omega-3 and omega-6 fatty acid intakes. Prevalence of thick melanomas was significantly higher in those in the highest compared with lowest tertile of the "meat, fish, and fat" pattern (PR, 1.40; 95% CI, 1.01-1.94), especially those with serious comorbidity (PR, 1.83; 95% CI, 1.15-2.92) or a family history (PR, 2.32; 95% CI, 1.00-5.35). The "fish, low-meat, and low-fat" pattern was not associated with melanoma thickness.

Conclusions: People with high meat, fish, and fat intakes, who thus consumed relatively high levels of omega-3 and high omega-6 fatty acid intakes, are more likely to be diagnosed with thick than thin melanomas.

Impact: High omega-3 and omega-6 fatty acid intakes may contribute to patients' presentation with thick melanomas.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0319DOI Listing
August 2020

Oxidized Perilla and Linseed Oils Induce Neuronal Apoptosis by Caspase-Dependent and -Independent Pathways.

Foods 2020 Apr 26;9(5). Epub 2020 Apr 26.

Department of Health and Nutrition, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike Iwasaki-cho, Nisshin, Aichi 470-0195, Japan.

Alpha-linolenic acid (ALA), a polyunsaturated fatty acid, is involved in bioregulatory functions. In recent years, the health-promoting effects of vegetable-derived edible oils rich in ALA have attracted attention. ALA has a variety of physiological effects such as anti-arteriosclerotic and antiallergic properties, but is prone to oxidation. Therefore, safety concerns exist with regard to adverse effects on humans induced by its oxides. However, the effects on neuronal cells induced by oxidized ALA-rich oils, such as perilla and linseed oils, have not been fully investigated. This information is very important from the viewpoint of food safety. In this study, we investigated the effects of oxidized perilla and linseed oils, which are rich in ALA, on the toxicity of neuronal SH-SY5Y cells. Perilla and linseed oils were significantly oxidized compared with other edible vegetable oils. These oxidized oils induce neuronal cell death and apoptosis via caspase-dependent and -independent pathways through reactive oxygen species (ROS) generation. Furthermore, they suppressed neurite outgrowth. These results suggest that oxidized perilla and linseed oils have the potential to cause neuronal loss and ROS-mediated apoptosis, and thus may affect the onset and progression of neurodegenerative disorders and other diseases.
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http://dx.doi.org/10.3390/foods9050538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278870PMC
April 2020

Flow cytometric identification and cell-line establishment of macrophages in naked mole-rats.

Sci Rep 2019 11 29;9(1):17981. Epub 2019 Nov 29.

Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

Naked mole rats (NMRs) have extraordinarily long lifespans and anti-tumorigenic capability. Recent studies of humans and mice have shown that many age-related diseases, including cancer, are strongly correlated with immunity, and macrophages play particularly important roles in immune regulation. Therefore, NMR macrophages may contribute to their unique phenotypes. However, studies of the roles of macrophages are limited by material restrictions and the lack of an established experimental strategy. In this study, we developed a flow cytometric strategy to identify NMR macrophages. The NMR macrophages were extractable using an off-the-shelf anti-CD11b antibody, M1/70, and forward/side scatter data obtained by flow cytometry. NMR macrophages proliferated in response to human/mouse recombinant M-CSF and engulfed Escherichia coli particles. Interestingly, the majority of NMR macrophages exhibited co-staining with an anti-NK1.1 antibody, PK136. NK1.1 antigen crosslinking with PK136 results in mouse NK cell stimulation; similarly, NMR macrophages proliferated in response to NK1.1 antibody treatment. Furthermore, we successfully established an NMR macrophage cell line, NPM1, by transduction of Simian virus 40 early region that proliferated indefinitely without cytokines and retained its phagocytotic capacity. The NPM1 would contribute to further studies on the immunity of NMRs.
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http://dx.doi.org/10.1038/s41598-019-54442-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884578PMC
November 2019

Melanoma incidence in Australian commercial pilots, 2011-2016.

Occup Environ Med 2019 07 21;76(7):462-466. Epub 2019 May 21.

Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Objectives: Occupational exposure to cosmic and ultraviolet radiation may increase airline pilots' risk of cutaneous melanoma. Meta-analyses of available data show a higher than average incidence of melanoma in airline pilots, but the most recent systematic review revealed that few contemporary data are available. Moreover, all relevant studies have been conducted in Northern Hemisphere populations. We therefore aimed to examine if Australian commercial pilots have a raised incidence of melanoma compared with the general population.

Methods: We examined all melanoma histologically diagnosed among Australian-licensed commercial pilots in the period 2011-2016 by manually reviewing de-identified data in the medical records system of the Australian Civil Aviation Safety Authority. We estimated age-specific incidence rates and compared these with corresponding population rates using standardised incidence ratios (SIRs) as measures of relative risk. Expected numbers were calculated by multiplying age- and calendar period-specific person-years (PYs) with corresponding rates from the entire Australian population; 95% CI were calculated assuming a Poisson distribution of the observed cases.

Results: In this cohort of Australian-licensed commercial pilots observed for 91 370 PYs, 114 developed a melanoma (51 invasive, 63 in situ). More than 50% of melanomas occurred on the trunk, and the predominant subtype was superficial spreading melanoma. The SIR for invasive melanoma was 1.20 (95% CI 0.89 to 1.55) and for melanoma in situ, 1.39 (95% CI 1.08 to 1.78).

Conclusion: Australian-licensed commercial pilots have a modestly raised risk of in situ melanoma but no elevation of invasive melanoma compared with the general population.
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http://dx.doi.org/10.1136/oemed-2018-105676DOI Listing
July 2019

Gonadal steroid hormone secretion during the juvenile period depends on host-specific microbiota and contributes to the development of odor preference.

Dev Psychobiol 2019 07 24;61(5):670-678. Epub 2019 Jan 24.

Department of Animal Science and Biotechnology, Azabu University, Sagamihara, Japan.

The host microbial community is thought to have an important role in the host endocrine system and behavioral phenotype. We investigated chronological changes of levels of gonadal hormones and corticosterone in the feces of 4- to 8-week-old female germ-free (GF) mice, and conducted odor preference test at 8 weeks of age. We further evaluated the developmental impact of the microbial community by analyzing 4-week-old GF mice orally administered the fecal microbiota of specific pathogen-free (SPF) mice or guinea pigs (GF-SPF mice or GF-Guinea pig mice). The fecal estradiol, progesterone, and corticosterone levels of GF mice were lower than those of SPF mice. Furthermore, the increased levels in GF mice were suggested to be caused by colonization of microbiota of SPF mice or guinea pigs. However, the degree of recovery of progesterone and corticosterone by microbiota of guinea pigs was lower than that by SPF mice. In odor preference tests, interestingly, female GF mice preferred female odors to male odors, although this preference was not seen in other mice. These findings suggested that the microbial community plays an important role in the development of the host endocrine system for gonadal hormones and corticosterone, and odor preference in mice.
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http://dx.doi.org/10.1002/dev.21827DOI Listing
July 2019

Omega-3 fatty acid supplement skin cancer prophylaxis in lung transplant recipients: A randomized, controlled pilot trial.

J Heart Lung Transplant 2019 01 14;38(1):59-65. Epub 2018 Sep 14.

Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; CRUK Manchester Institute, University of Manchester, Manchester, UK.

Background: Lung transplant recipients (LTRs) are at very high risk of skin cancer. Omega-3 fatty acids (FAs) are anti-inflammatory and immune-modulating and could potentially reduce this risk. We assessed the feasibility of omega-3 FA supplementation to reduce skin cancer among these patients.

Methods: LTRs aged 18 years, at least 1 year post-transplant, were recruited from the outpatient clinic of The Prince Charles Hospital, Brisbane. Participants were randomly allocated to 4-times-daily supplements containing either omega-3 FA (3.36 eicosapentaenoic acid [EPA] + docosahexaenoic acid) or placebo (4 g olive oil) for 12 months. Primary outcomes were rates of recruitment, retention, adherence (assessed by plasma omega-3 FA), and safety. Secondary outcomes were incident skin cancers.

Results: Among 106 eligible lung transplant recipients, 49 consented to take part (46%) with 25 allocated to omega-3 FA and 24 to placebo supplements. Of these, 22 (88%) and 20 (83%), respectively, completed the trial. After 12 months, median plasma EPA increased substantially in the intervention group (125.0 to 340.0 µmol/L), but not the placebo group (98.0 to 134.5 µmol/L). In the intervention group, 6 patients developed skin cancers compared with 11 in the placebo group, giving an odds ratio (95% confidence interval) of 0.34 (0.09 to 1.32). There were no serious, active intervention-related adverse events.

Conclusions: This pilot trial among LTRs showed acceptable recruitment and high retention and adherence. We demonstrated a signal for reduction of new skin cancer cases in those taking omega-3 FA supplements, which supports the notion that a larger, more definitive trial is warranted.
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http://dx.doi.org/10.1016/j.healun.2018.09.009DOI Listing
January 2019

Responses to pup vocalizations in subordinate naked mole-rats are induced by estradiol ingested through coprophagy of queen's feces.

Proc Natl Acad Sci U S A 2018 09 27;115(37):9264-9269. Epub 2018 Aug 27.

Companion Animal Research, School of Veterinary Medicine, Azabu University, 252-5201 Sagamihara, Japan.

Naked mole-rats form eusocial colonies consisting of a single breeding female (the queen), several breeding males, and sexually immature adults (subordinates). Subordinates are cooperative and provide alloparental care by huddling and retrieving pups to the nest. However, the physiological mechanism(s) underlying alloparental behavior of nonbreeders remains undetermined. Here, we examined the response of subordinates to pup voice and the fecal estradiol concentrations of subordinates during the three reproductive periods of the queen, including gestation, postpartum, and nonlactating. Subordinate response to pup voice was observed only during the queen's postpartum and was preceded by an incremental rise in subordinates' fecal estradiol concentrations during the queen's gestation period, which coincided with physiological changes in the queen. We hypothesized that the increased estradiol in the queen's feces was disseminated to subordinates through coprophagy, which stimulated subordinates' responses to pup vocalizations. To test this hypothesis, we fed subordinates either fecal pellets from pregnant queens or pellets from nonpregnant queens amended with estradiol for 9 days and examined their response to recorded pup voice. In both treatments, the subordinates exhibited a constant level of response to pup voice during the feeding period but became more responsive 4 days after the feeding period. Thus, we believe that we have identified a previously unknown system of communication in naked mole-rats, in which a hormone released by one individual controls the behavior of another individual and influences the level of responsiveness among subordinate adults to pup vocal signals, thereby contributing to the alloparental pup care by subordinates.
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http://dx.doi.org/10.1073/pnas.1720530115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140523PMC
September 2018

Adherence to Mediterranean and low-fat diets among heart and lung transplant recipients: a randomized feasibility study.

Nutr J 2018 02 14;17(1):22. Epub 2018 Feb 14.

Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.

Background: Heart and lung transplant recipients are at a substantially increased risk of cardiovascular disease (CVD). Since both low-fat and Mediterranean diets can reduce CVD in immunocompetent people at high risk, we assessed adherence among thoracic transplant recipients allocated to one or other of these diets for 12 months.

Methods: Forty-one transplant recipients (20 heart; 21 lung) randomized to a Mediterranean or a low-fat diet for 12 months received diet-specific education at baseline. Adherence was primarily assessed by questionnaire: 14-point Mediterranean diet (score 0-14) and 9-point low-fat diet (score 0-16) respectively, high scores indicating greater adherence. Median scores at baseline, 6 months, 12 months, and 6-weeks post-intervention were compared by dietary group. We further assessed changes in weight, body mass index (BMI) and serum triglycerides from baseline to 12 months as an additional indicator of adherence.

Results: In those randomized to a Mediterranean diet, median scores increased from 4 (range 1-9) at baseline, to 10 (range 6-14) at 6-months and were maintained at 12 months, and also at 6-weeks post-intervention (median 10, range 6-14). Body weight, BMI and serum triglycerides decreased over the 12-month intervention period (mean weight - 1.8 kg, BMI -0.5 kg/m, triglycerides - 0.17 mmol/L). In the low-fat diet group, median scores were 11 (range 9-14) at baseline; slightly increased to 12 (range 9-16) at 6 months, and maintained at 12 months and 6 weeks post-intervention (median 12, range 8-15). Mean changes in weight, BMI and triglycerides were - 0.2 kg, 0.0 kg/m and - 0.44 mmol/L, respectively.

Conclusions: Thoracic transplant recipients adhered to Mediterranean and low-fat dietary interventions. The change from baseline eating habits was notable at 6 months; and this change was maintained at 12 months and 6 weeks post-intervention in both Mediterranean diet and low-fat diet groups. Dietary interventions based on comprehensive, well-supported education sessions targeted to both patients and their family members are crucial to success. Such nutritional strategies can help in the management of their substantial CVD risk.

Trial Registration: The IRAS trial registry ( ISRCTN63500150 ). Date of registration 27 July 2016. Retrospectively registered.
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http://dx.doi.org/10.1186/s12937-018-0337-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813407PMC
February 2018

Leucine-Enriched Essential Amino Acids Augment Muscle Glycogen Content in Rats Seven Days after Eccentric Contraction.

Nutrients 2017 Oct 23;9(10). Epub 2017 Oct 23.

Frontier Research Laboratories, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa 210-8681, Japan.

Eccentric contractions induce muscle damage, which impairs recovery of glycogen and adenosine tri-phosphate (ATP) content over several days. Leucine-enriched essential amino acids (LEAAs) enhance the recovery in muscles that are damaged after eccentric contractions. However, the role of LEAAs in this process remains unclear. We evaluated the content in glycogen and high energy phosphates molecules (phosphocreatine (PCr), adenosine di-phosphate (ADP) and ATP) in rats that were following electrically stimulated eccentric contractions. Muscle glycogen content decreased immediately after the contraction and remained low for the first three days after the stimulation, but increased seven days after the eccentric contraction. LEAAs administration did not change muscle glycogen content during the first three days after the contraction. Interestingly, however, it induced a further increase in muscle glycogen seven days after the stimulation. Contrarily, ATP content decreased immediately after the eccentric contraction, and remained lower for up to seven days after. Additionally, LEAAs administration did not affect the ATP content over the experimental period. Finally, ADP and PCr levels did not significantly change after the contractions or LEAA administration. LEAAs modulate the recovery of glycogen content in muscle after damage-inducing exercise.
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http://dx.doi.org/10.3390/nu9101159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691775PMC
October 2017

Teratoma Formation Assay for Assessing Pluripotency and Tumorigenicity of Pluripotent Stem Cells.

Bio Protoc 2017 Aug 20;7(16):e2518. Epub 2017 Aug 20.

Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Hokkaido, Japan.

Pluripotent stem cells such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) form teratomas when transplanted into immunodeficient mice. As teratomas contain all three germ layers (endoderm, mesoderm, ectoderm), teratoma formation assay is widely used as an index of pluripotency (Evans and Kaufman, 1981; Hentze , 2009 ; Gropp , 2012 ). On the other hand, teratoma-forming tumorigenicity also represents a major risk factor impeding potential clinical applications of pluripotent stem cells ( Miura , 2009 ; Okano , 2013 ). Recently, we reported that iPSCs derived from naked mole-rat lack teratoma-forming tumorigenicity when engrafted into the testes of non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice due to an ES cell-expressed Ras (ERAS) and Alternative reading frame (ARF)-dependent tumor-suppression mechanism specific to this species ( Miyawaki , 2016 ). Here, we describe a method for transplanting pluripotent stem cells into the testes of NOD/SCID mice to generate teratomas for assessing the pluripotency and tumorigenicity.
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http://dx.doi.org/10.21769/BioProtoc.2518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413610PMC
August 2017

Absolute versus relative measures of plasma fatty acids and health outcomes: example of phospholipid omega-3 and omega-6 fatty acids and all-cause mortality in women.

Eur J Nutr 2018 Mar 19;57(2):713-722. Epub 2016 Dec 19.

Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Brisbane, QLD, 4006, Australia.

Purpose: In a well-characterised community-based prospective study, we aimed to systematically assess the differences in associations of plasma omega-3 and omega-6 fatty acid (FA) status with all-cause mortality when plasma FA status is expressed in absolute concentrations versus relative levels.

Methods: In a community sample of 564 women aged 25-75 years in Queensland, Australia, baseline plasma phospholipid FA levels were measured using gas chromatography. Specific FAs analysed were eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, total long-chain omega-3 FAs, linoleic acid, arachidonic acid, and total omega-6 FAs. Levels of each FA were expressed in absolute amounts (µg/mL) and relative levels (% of total FAs) and divided into thirds. Deaths were monitored for 17 years and hazard ratios and 95% confidence intervals calculated to assess risk of death according to absolute versus relative plasma FA levels.

Result: In total 81 (14%) women died during follow-up. Agreement between absolute and relative measures of plasma FAs was higher in omega-3 than omega-6 FAs. The results of multivariate analyses for risk of all-cause mortality were generally similar with risk tending to inverse associations with plasma phospholipid omega-3 FAs and no association with omega-6 FAs. Sensitivity analyses examining effects of age and presence of serious medical conditions on risk of mortality did not alter findings.

Conclusions: The directions and magnitude of associations with mortality of absolute versus relative FA levels were comparable. However, plasma FA expressed as absolute concentrations may be preferred for ease of comparison and since relative units can be deduced from absolute units.
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http://dx.doi.org/10.1007/s00394-016-1358-yDOI Listing
March 2018

Plasma eicosapentaenoic acid is negatively associated with all-cause mortality among men and women in a population-based prospective study.

Nutr Res 2016 11 13;36(11):1202-1209. Epub 2016 Sep 13.

QIMR Berghofer Medical Research Institute, Cancer and Population Studies Group, 300 Herston Rd, Herston, Brisbane, Queensland 4006, Australia; CRUK Manchester Institute, University of Manchester, Wilmslow Rd, Manchester, UK.

Omega-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties, whereas omega-6 PUFAs appear to have proinflammatory properties. We aimed to assess plasma omega-3 and omega-6 PUFA status in relation to all-cause mortality in an Australian community-based study. We hypothesized that omega-3 PUFA would be inversely associated, and omega-6 PUFA positively associated with all-cause mortality. Plasma phospholipid omega-3 (eicosapentaenoic acid [EPA], docosapentaenoic acid [DPA], docosahexaenoic acid, α-linolenic acid, and total) and omega-6 PUFAs (linoleic acid, arachidonic acid, and total) were measured among 1008 adults (44% men) in 1996. Plasma PUFA composition was quantified using gas chromatography. During 17-year follow-up, 98 men and 81 women died. After adjustment for potential confounding factors, plasma EPA was inversely associated with all-cause mortality overall (adjusted hazard ratio [HR] per 1-SD increase, 0.81; 95% confidence interval [CI], 0.68-0.95), in men (HR, 0.78; 95% CI, 0.62-0.98), and in women (HR, 0.78; 95% CI, 0.65-0.94), separately. Inverse associations with mortality among men were also seen for DPA (HR, 0.76; 95% CI, 0.60-0.97) and α-linolenic acid (HR, 0.73; 95% CI, 0.57-0.94). No omega-6 PUFAs were significantly associated with mortality. Our findings of reduced all-cause mortality in men and women who have high EPA in plasma, and in men with high plasma DPA and α-linolenic acid, partially support our hypothesis that omega-3 PUFAs help reduce mortality but provide no evidence that omega-6 PUFAs may increase mortality.
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http://dx.doi.org/10.1016/j.nutres.2016.09.006DOI Listing
November 2016

Greater Amino Acid Intake Is Required to Maximize Whole-Body Protein Synthesis Immediately after Endurance Exercise Than at Rest in Endurance-Trained Rats, as Determined by an Indicator Amino Acid Oxidation Method.

J Nutr 2016 08 29;146(8):1546-51. Epub 2016 Jun 29.

Frontier Research Laboratories, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa, Japan.

Background: The indicator amino acid oxidation (IAAO) method has contributed to establishing protein and amino acid (AA) requirements by determining the optimal protein and AA intake that maximizes whole-body protein synthesis. However, it has not been used with endurance-trained subjects.

Objective: This study aimed to determine the optimal AA intake immediately after endurance exercise and at rest in endurance-trained rats by using the IAAO method.

Methods: Four-week-old male Fischer rats were divided into a sedentary (SED) group and a trained (TR) group, which underwent treadmill training 5 d/wk for 6 wk at 26 m/min for 60 min/d. On the metabolic trial day, half of the TR group was provided with test diets after daily treadmill running (TR-PostEx). The other half of the TR group (TR-Rest) and all of the SED group were provided with test diets while at rest. The test diets contained different amounts of AAs (3.3-37.3 g ⋅ kg(-1) ⋅ d(-1)). Phenylalanine in the test diet was replaced with L-[1-(13)C]phenylalanine. The phenylalanine oxidation rate (PheOx) was determined with (13)CO2 enrichment in breath, CO2 excretion rate, and enrichment of phenylalanine in blood during the feeding period. The optimal AA intake was determined with biphasic mixed linear regression crossover analysis for PheOx, which identified a breakpoint at the minimal PheOx in response to graded amounts of AA intake.

Results: The optimal AA intake in the TR-PostEx group (26.8 g ⋅ kg(-1) ⋅ d(-1); 95% CI: 21.5, 32.1 g ⋅ kg(-1) ⋅ d(-1)) was significantly higher than in the SED (15.1 g ⋅ kg(-1) ⋅ d(-1); 95% CI: 11.1, 19.1 g ⋅ kg(-1) ⋅ d(-1)) and TR-Rest (13.3 g ⋅ kg(-1) ⋅ d(-1); 95% CI: 10.9, 15.7 g ⋅ kg(-1) ⋅ d(-1)) groups, which did not differ.

Conclusions: Greater AA intake is required to maximize whole-body protein synthesis immediately after endurance exercise than at rest, but not at rest in endurance-trained rats.
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http://dx.doi.org/10.3945/jn.115.226373DOI Listing
August 2016

Leucine-enriched essential amino acids attenuate inflammation in rat muscle and enhance muscle repair after eccentric contraction.

Amino Acids 2016 09 11;48(9):2145-55. Epub 2016 May 11.

Frontier Research Laboratories, Institute for Innovation, Ajinomoto Co., Inc., Kawasaki, Kanagawa, Japan.

Eccentric exercise results in prolonged muscle damage that may lead to muscle dysfunction. Although inflammation is essential to recover from muscle damage, excessive inflammation may also induce secondary damage, and should thus be suppressed. In this study, we investigated the effect of leucine-enriched essential amino acids on muscle inflammation and recovery after eccentric contraction. These amino acids are known to stimulate muscle protein synthesis via mammalian target of rapamycin (mTOR), which, is also considered to alleviate inflammation. Five sets of 10 eccentric contractions were induced by electrical stimulation in the tibialis anterior muscle of male SpragueDawley rats (8-9 weeks old) under anesthesia. Animals received a 1 g/kg dose of a mixture containing 40 % leucine and 60 % other essential amino acids or distilled water once a day throughout the experiment. Muscle dysfunction was assessed based on isometric dorsiflexion torque, while inflammation was evaluated by histochemistry. Gene expression of inflammatory cytokines and myogenic regulatory factors was also measured. We found that leucine-enriched essential amino acids restored full muscle function within 14 days, at which point rats treated with distilled water had not fully recovered. Indeed, muscle function was stronger 3 days after eccentric contraction in rats treated with amino acids than in those treated with distilled water. The amino acid mix also alleviated expression of interleukin-6 and impeded infiltration of inflammatory cells into muscle, but did not suppress expression of myogenic regulatory factors. These results suggest that leucine-enriched amino acids accelerate recovery from muscle damage by preventing excessive inflammation.
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http://dx.doi.org/10.1007/s00726-016-2240-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989025PMC
September 2016

Tumour resistance in induced pluripotent stem cells derived from naked mole-rats.

Nat Commun 2016 05 10;7:11471. Epub 2016 May 10.

Biomedical Animal Research Laboratory, Institute for Genetic Medicine, Hokkaido University, Hokkaido 060-0815, Japan.

The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype-ARF suppression-induced senescence (ASIS)-that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR.
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http://dx.doi.org/10.1038/ncomms11471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866046PMC
May 2016
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