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Nature Communications Jun 2020Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome. In mice,...
Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome. In mice, hematogenous F. nucleatum can colonize CRC tissue using its lectin Fap2, which attaches to tumor-displayed Gal-GalNAc. Here, we show that Gal-GalNAc levels increase as human breast cancer progresses, and that occurrence of F. nucleatum gDNA in breast cancer samples correlates with high Gal-GalNAc levels. We demonstrate Fap2-dependent binding of the bacterium to breast cancer samples, which is inhibited by GalNAc. Intravascularly inoculated Fap2-expressing F. nucleatum ATCC 23726 specifically colonize mice mammary tumors, whereas Fap2-deficient bacteria are impaired in tumor colonization. Inoculation with F. nucleatum suppresses accumulation of tumor infiltrating T cells and promotes tumor growth and metastatic progression, the latter two of which can be counteracted by antibiotic treatment. Thus, targeting F. nucleatum or Fap2 might be beneficial during treatment of breast cancer.
Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Colony Count, Microbial; DNA, Bacterial; Disease Models, Animal; Disease Progression; Female; Fusobacterium nucleatum; Galactosamine; Galactose; Genome, Bacterial; Humans; Immunity; Lung Neoplasms; Mice, Inbred BALB C; Neoplasm Metastasis
PubMed: 32591509
DOI: 10.1038/s41467-020-16967-2 -
JCI Insight Mar 2019The relation between the menopause transition (MT) and changes in body composition or weight remains uncertain. We hypothesized that, independent of chronological aging,...
BACKGROUND
The relation between the menopause transition (MT) and changes in body composition or weight remains uncertain. We hypothesized that, independent of chronological aging, the MT would have a detrimental influence on body composition.
METHODS
Participants were from the longitudinal Study of Women's Health Across the Nation (SWAN) cohort. We assessed body composition by dual energy x-ray absorptiometry. Multivariable mixed effects regressions fitted piece-wise linear models to repeated measures of outcomes as a function of time before or after the final menstrual period (FMP). Covariates were age at FMP, race, study site, and hormone therapy.
RESULTS
Fat and lean mass increased prior to the MT. At the start of the MT, rate of fat gain doubled, and lean mass declined; gains and losses continued until 2 years after the FMP. After that, the trajectories of fat and lean mass decelerated to zero slope. Weight climbed linearly during premenopause without acceleration at the MT. Its trajectory became flat after the MT.
CONCLUSION
Accelerated gains in fat mass and losses of lean mass are MT-related phenomena. The rate of increase in the sum of fat mass and lean mass does not differ between premenopause and the MT; thus, there is no discernable change in rate of weight gain at the start of the MT.
FUNDING
NIH, Department of Health and Human Services (DHHS), through the National Institute on Aging, National Institute of Nursing Research, and NIH Office of Research on Women's Health (U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495).
Topics: Adult; Aging; Body Composition; Body Mass Index; Body Weight; Female; Humans; Longitudinal Studies; Menopause; Middle Aged; Obesity; Premenopause; United States; Weight Gain
PubMed: 30843880
DOI: 10.1172/jci.insight.124865 -
The Lancet. Diabetes & Endocrinology Oct 2022Obesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased... (Observational Study)
Observational Study
Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study.
BACKGROUND
Obesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased among infants who had overweight or obesity at birth, but in low-resource settings one in five infants are born small for gestational age. We aimed to study the relationships between: (1) maternal metabolite signatures; (2) fetal abdominal growth; and (3) postnatal growth, adiposity, and neurodevelopment.
METHODS
In the prospective, multinational, observational INTERBIO-21st fetal study, conducted in maternity units in Pelotas (Brazil), Nairobi (Kenya), Karachi (Pakistan), Soweto (South Africa), Mae Sot (Thailand), and Oxford (UK), we enrolled women (≥18 years, with a BMI of less than 35 kg/m, natural conception, and a singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. Ultrasound scans were performed every 5±1 weeks until delivery to measure fetal growth and feto-placental blood flow, and we used finite mixture models to derive growth trajectories of abdominal circumference. The infants' health, growth, and development were monitored from birth to age 2 years. Early pregnancy maternal blood and umbilical cord venous blood samples were collected for untargeted metabolomic analysis.
FINDINGS
From Feb 8, 2012, to Nov 30, 2019, we enrolled 3598 pregnant women and followed up their infants to 2 years of age. We identified four ultrasound-derived trajectories of fetal abdominal circumference growth that accelerated or decelerated within a crucial 20-25 week gestational age window: faltering growth, early accelerating growth, late accelerating growth, and median growth tracking. These distinct phenotypes had matching feto-placental blood flow patterns throughout pregnancy, and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood. There were 709 maternal metabolites with positive effect for the faltering growth phenotype and 54 for the early accelerating growth phenotype; 31 maternal metabolites had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype. Metabolites associated with the faltering growth phenotype had statistically significant odds ratios close to 1·5 (ie, suggesting upregulation of metabolic pathways of impaired fetal growth). The metabolites had a reciprocal relationship with the early accelerating growth phenotype, with statistically significant odds ratios close to 0.6 (ie, suggesting downregulation of fetal growth acceleration). The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid, and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was highly abundant in the early accelerating growth phenotype group.
INTERPRETATION
Early pregnancy lipid biology associated with fetal abdominal growth trajectories is an indicator of patterns of growth, adiposity, vision, and neurodevelopment up to the age of 2 years. Our findings could contribute to the earlier identification of infants at risk of obesity.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Adiposity; Female; Fetal Development; Fungicides, Industrial; Humans; Kenya; Oxylipins; Pediatric Obesity; Phosphatidylcholines; Placenta; Pregnancy; Prenatal Care; Prospective Studies; South Africa; Ultrasonography, Prenatal
PubMed: 36030799
DOI: 10.1016/S2213-8587(22)00215-7 -
Irish Journal of Medical Science Feb 2017The participation of inflammation in the progression of cancer for many years have been the subject of research. (Review)
Review
BACKGROUND
The participation of inflammation in the progression of cancer for many years have been the subject of research.
METHODS
In the 19th century, there was evidence that an acute inflammation may inhibit the development of cancer. However, chronic inflammation affects the progression of the disease.
RESULTS
Today, it is known that inflammation and cancer use similar mechanisms of development such as severe cell proliferation or angiogenesis. It has been shown that prolonged presence of inflammatory cells and factors in the tumor microenvironment can accelerate its growth and inhibit apoptosis of transformed cells.
CONCLUSION
In this article we present a brief history of the discovery mechanisms and potential links between acute and chronic inflammation and cancer.
Topics: Apoptosis; Cell Proliferation; Disease Progression; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic
PubMed: 27156054
DOI: 10.1007/s11845-016-1464-0 -
PloS One 2019Skin aging is a complex process, and alterations in human skin due to aging have distinct characteristic as compared to other organs. The aging of dermal cells and the...
Skin aging is a complex process, and alterations in human skin due to aging have distinct characteristic as compared to other organs. The aging of dermal cells and the biological mechanisms involved in this process are key areas to understand skin aging. A large number of biological mechanisms, such as decreasing of protein synthesis of extracellular matrix or increasing of degradation, are known to be altered through skin aging. However, environmental influence can accelerate this characteristic phenotype. In this study, we analyzed primary human dermal fibroblasts in three different in-vitro aging models-UVB irradiation and accelerated proliferation of human dermal fibroblasts from young donors as well as from elderly donors-for the gene expression of COL1A1, COL1A2, COL3A1, COL4A1, COL7A1, MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12, MMP13, MMP14, TIMP1, TIMP2, TIMP3, TIMP4, IL1B, IL1A, IL6, IL8, IL10, PTGS2, TP53, CASP3, LMNA, SIRT1. We compared the gene expression levels with young control. Furthermore, the behavior of skin fibroblasts was also evaluated using cell growth rate. The findings reveal that the gene expression levels in skin fibroblasts was altered in the process of aging in all three in-vitro aging models, and the cell growth rate was reduced, suggesting that these methods can be employed to understand skin aging mechanisms as well as drug discovery screening method.
Topics: Cell Proliferation; Cells, Cultured; Cellular Senescence; Child; Female; Fibroblasts; Gene Expression; Humans; Male; Middle Aged; Models, Biological; Skin; Skin Aging; Ultraviolet Rays
PubMed: 31269075
DOI: 10.1371/journal.pone.0219165 -
The Cochrane Database of Systematic... Dec 2020The introduction and advancement of enteral feeds for preterm or low birth weight infants is often delayed because of concerns that early full enteral feeding will not... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The introduction and advancement of enteral feeds for preterm or low birth weight infants is often delayed because of concerns that early full enteral feeding will not be well tolerated or may increase the risk of necrotising enterocolitis. Early full enteral feeding, however, might increase nutrient intake and growth rates; accelerate intestinal physiological, metabolic, and microbiomic postnatal transition; and reduce the risk of complications associated with intravascular devices for fluid administration. OBJECTIVES: To determine how early full enteral feeding, compared with delayed or progressive introduction of enteral feeds, affects growth and adverse events such as necrotising enterocolitis, in preterm or low birth weight infants.
SEARCH METHODS
We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials; MEDLINE Ovid, Embase Ovid, Maternity & Infant Care Database Ovid, the Cumulative Index to Nursing and Allied Health Literature, and clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials to October 2020.
SELECTION CRITERIA
Randomised controlled trials that compared early full enteral feeding with delayed or progressive introduction of enteral feeds in preterm or low birth weight infants.
DATA COLLECTION AND ANALYSIS
We used the standard methods of Cochrane Neonatal. Two review authors separately assessed trial eligibility, evaluated trial quality, extracted data, and synthesised effect estimates using risk ratios (RR), risk differences, and mean differences (MD) with 95% confidence intervals (CI). We used the GRADE approach to assess the certainty of evidence.
MAIN RESULTS
We included six trials. All were undertaken in the 2010s in neonatal care facilities in India. In total, 526 infants participated. Most were very preterm infants of birth weight between 1000 g and 1500 g. Trials were of good methodological quality, but a potential source of bias was that parents, clinicians, and investigators were not masked. The trials compared early full feeding (60 mL/kg to 80 mL/kg on day one after birth) with minimal enteral feeding (typically 20 mL/kg on day one) supplemented with intravenous fluids. Feed volumes were advanced daily as tolerated by 20 mL/kg to 30 mL/kg body weight to a target steady-state volume of 150 mL/kg to 180 mL/kg/day. All participating infants were fed preferentially with maternal expressed breast milk, with two trials supplementing insufficient volumes with donor breast milk and four supplementing with preterm formula. Few data were available to assess growth parameters. One trial (64 participants) reported a slower rate of weight gain (median difference -3.0 g/kg/day), and another (180 participants) reported a faster rate of weight gain in the early full enteral feeding group (MD 1.2 g/kg/day). We did not meta-analyse these data (very low-certainty evidence). None of the trials reported rate of head circumference growth. One trial reported that the mean z-score for weight at hospital discharge was higher in the early full enteral feeding group (MD 0.24, 95% CI 0.06 to 0.42; low-certainty evidence). Meta-analyses showed no evidence of an effect on necrotising enterocolitis (RR 0.98, 95% CI 0.38 to 2.54; 6 trials, 522 participants; I² = 51%; very low-certainty evidence).
AUTHORS' CONCLUSIONS
Trials provided insufficient data to determine with any certainty how early full enteral feeding, compared with delayed or progressive introduction of enteral feeds, affects growth in preterm or low birth weight infants. We are uncertain whether early full enteral feeding affects the risk of necrotising enterocolitis because of the risk of bias in the trials (due to lack of masking), inconsistency, and imprecision.
Topics: Body Weight; Enteral Nutrition; Enterocolitis, Necrotizing; Fluid Therapy; Humans; Infant Formula; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Milk, Human; Randomized Controlled Trials as Topic; Weight Gain
PubMed: 33368149
DOI: 10.1002/14651858.CD013542.pub2 -
Science (New York, N.Y.) Nov 2016Crop leaves in full sunlight dissipate damaging excess absorbed light energy as heat. When sunlit leaves are shaded by clouds or other leaves, this protective...
Crop leaves in full sunlight dissipate damaging excess absorbed light energy as heat. When sunlit leaves are shaded by clouds or other leaves, this protective dissipation continues for many minutes and reduces photosynthesis. Calculations have shown that this could cost field crops up to 20% of their potential yield. Here, we describe the bioengineering of an accelerated response to natural shading events in Nicotiana (tobacco), resulting in increased leaf carbon dioxide uptake and plant dry matter productivity by about 15% in fluctuating light. Because the photoprotective mechanism that has been altered is common to all flowering plants and crops, the findings provide proof of concept for a route to obtaining a sustainable increase in productivity for food crops and a much-needed yield jump.
Topics: Arabidopsis Proteins; Bioengineering; Carbon Dioxide; Crops, Agricultural; Darkness; Light-Harvesting Protein Complexes; Magnoliopsida; Oxidoreductases; Photosynthesis; Photosystem II Protein Complex; Plant Leaves; Plants, Genetically Modified; RNA, Messenger; Sunlight; Nicotiana
PubMed: 27856901
DOI: 10.1126/science.aai8878 -
Nature Communications Jan 2016The domestic dog is becoming an increasingly valuable model species in medical genetics, showing particular promise to advance our understanding of cancer and...
The domestic dog is becoming an increasingly valuable model species in medical genetics, showing particular promise to advance our understanding of cancer and orthopaedic disease. Here we undertake the largest canine genome-wide association study to date, with a panel of over 4,200 dogs genotyped at 180,000 markers, to accelerate mapping efforts. For complex diseases, we identify loci significantly associated with hip dysplasia, elbow dysplasia, idiopathic epilepsy, lymphoma, mast cell tumour and granulomatous colitis; for morphological traits, we report three novel quantitative trait loci that influence body size and one that influences fur length and shedding. Using simulation studies, we show that modestly larger sample sizes and denser marker sets will be sufficient to identify most moderate- to large-effect complex disease loci. This proposed design will enable efficient mapping of canine complex diseases, most of which have human homologues, using far fewer samples than required in human studies.
Topics: Animals; Body Size; Dog Diseases; Dogs; Female; Genome-Wide Association Study; Genotype; Humans; Male; Phenotype; Quantitative Trait Loci
PubMed: 26795439
DOI: 10.1038/ncomms10460 -
Clinical Epigenetics Aug 2021In the first study of its kind, we examine the association between growth and development in early life and DNAm age biomarkers in mid-life. (Comparative Study)
Comparative Study
BACKGROUND
In the first study of its kind, we examine the association between growth and development in early life and DNAm age biomarkers in mid-life.
METHODS
Participants were from the Medical Research Council National Survey of Health and Development (n = 1376). Four DNAm age acceleration (AgeAccel) biomarkers were measured when participants were aged 53 years: AgeAccelHannum; AgeAccelHorvath; AgeAccelLevine; and AgeAccelGrim. Exposure variables included: relative weight gain (standardised residuals from models of current weight z-score on current height, and previous weight and height z-scores); and linear growth (standardised residuals from models of current height z-score on previous height and weight z-scores) during infancy (0-2 years, weight gain only), early childhood (2-4 years), middle childhood (4-7 years) and late childhood to adolescence (7-15 years); age at menarche; and pubertal stage for men at 14-15 years. The relationship between relative weight gain and linear growth and AgeAccel was investigated using conditional growth models. We replicated analyses from the late childhood to adolescence period and pubertal timing among 240 participants from The National Child and Development Study (NCDS).
RESULTS
A 1SD increase in relative weight gain in late childhood to adolescence was associated with 0.50 years (95% CI 0.20, 0.79) higher AgeAccelGrim. Although the CI includes the null, the estimate was similar in NCDS [0.57 years (95% CI - 0.01, 1.16)] There was no strong evidence that relative weight gain and linear growth in childhood was associated with any other AgeAccel biomarker. There was no relationship between pubertal timing in men and AgeAccel biomarkers. Women who reached menarche ≥ 12 years had 1.20 years (95% CI 0.15, 2.24) higher AgeAccelGrim on average than women who reached menarche < 12 years; however, this was not replicated in NCDS and was not statistically significant after Bonferroni correction.
CONCLUSIONS
Our findings generally do not support an association between growth and AgeAccel biomarkers in mid-life. However, we found rapid weight gain during pubertal development, previously related to higher cardiovascular disease risk, to be associated with older AgeAccelGrim. Given this is an exploratory study, this finding requires replication.
Topics: Adolescent; Adult; Age Factors; Aging; Biomarkers; Birth Weight; Body Height; Body Mass Index; Child; Child Development; Child, Preschool; DNA Methylation; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; United Kingdom; Weight Gain; Young Adult
PubMed: 34372922
DOI: 10.1186/s13148-021-01138-x -
Annual Review of Genomics and Human... 2015Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately... (Review)
Review
Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately 1/5,000 births, and some are lethal. Since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders, genetic causes of 56 skeletal disorders have been uncovered. This remarkable rate of discovery is largely due to the expanded use of high-throughput genomic technologies. In this review, we discuss these recent discoveries and our understanding of the molecular mechanisms behind these skeletal dysplasia phenotypes. We also cover potential therapies, unusual genetic mechanisms, and novel skeletal syndromes both with and without known genetic causes. The acceleration of skeletal dysplasia genetics is truly spectacular, and these advances hold great promise for diagnostics, risk prediction, and therapeutic design.
Topics: Animals; Body Height; Bone Diseases, Developmental; Disease Models, Animal; Dwarfism; Epigenesis, Genetic; High-Throughput Nucleotide Sequencing; Histone Acetyltransferases; Humans; Mice; MicroRNAs; Mutation; Osteochondrodysplasias; Proteus Syndrome
PubMed: 25939055
DOI: 10.1146/annurev-genom-090314-045904