BMF
Bcl-2-modifying factor
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Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Animals
- Apoptosis
- Cell Cycle Proteins
- Cell Line, Tumor
- Cell Proliferation
- Cell Survival
- Cellular Senescence
- Drug Resistance, Neoplasm
- ErbB Receptors
- Female
- Gene Deletion
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Neoplasms
- MAP Kinase Kinase 1
- Male
- Mice
- Mice, Knockout
- Mutation
- Signal Transduction
- Transcription Factors
- Transcription, Genetic
Keywords
- YAP
- dormancy
- drug resistance
- drug tolerance
- epidermal growth factor receptor
- lung cancer
- senescence
Vascular calcification/aging is common in diabetes and is associated with increased morbidity and mortality of patients. MiR-34c-5p, not miR-34c-3p, was suppressed significantly in calcification/senescence of human aorta vascular smooth muscle cells (HA-VSMCs) induced by high glucose, which was proven by the formation of mineralized nodules and staining of senescence associated-β-galactosidase staining (SA β-gal) positive cells. Overexpression of miR-34c-5p alleviated calcification/senescence of HA-VSMCs, whereas inhibition of miR-34c-5p received the opposite results. Bcl-2 modifying factor (BMF) was a functional target of miR-34c-5p and it was involved in the process of calcification/senescence of HA-VSMCs. Besides, lncRNA-ES3 acted as a competing endogenous RNAs (ceRNA) of miR-34c-5p to enhance BMF expression. Further, lncRNA-ES3 inhibited miR-34c-5p expression by direct interaction and its knockdown suppressed the calcification/senescence of HA-VSMCs. Our results showed for the first time that the calcification/senescence of VSMCs was regulated by lncRNA-ES3 /miR-34c-5p/BMF axis.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Calcinosis
- Cellular Senescence
- Gene Expression Regulation
- Glucose
- Humans
- MicroRNAs
- Muscle, Smooth, Vascular
- Myocytes, Smooth Muscle
- RNA, Long Noncoding
Keywords
- BMF
- VSMCs calcification/senescence
- diabetes
- lncRNA-ES3
- miR-34c-5p
- vascular aging
The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.
MeSH Terms
- Aging
- Cellular Senescence
- Hematopoiesis
- Hematopoietic Stem Cells
- Humans
- Myelodysplastic Syndromes
Obesity increases bone marrow fat (BMF) content. The association between early obesity and bone marrow fatty acid composition is unknown. We measured BMF unsaturation index (UI) in normal-weight and overweight young adults with a known weight status in early childhood and tested the relationship between BMF UI and exercise history, glycemic state, and other clinical characteristics. The study included 18 normal-weight (BMI <25 kg/m(2); 2 males, 16 females) and 17 overweight (BMI ≥25 kg/m(2); 9 males, 8 females) young adults aged 15-27 years. BMF UI was assessed with magnetic resonance proton spectroscopy optimized to reduce water interference. Exercise information was obtained with a pedometer accompanied with the history of recent physical activity. Blood samples (insulin, glucose, HbA1c) and body characteristics (BMI, waist-to-hip ratio, body fat composition) were assessed. BMF UI was not affected by obesity at the time of study or before age 7 years. BMF UI increased with age in normal-weight and overweight subjects (R=0.408, p=0.015) but did not associate with gender, physical activity or body fat composition; a suggestive association was observed with glucose (R=-0.289, p=0.10). The association of BMF UI with age in early adulthood may represent normal maturation of bone marrow. There was a trend toward an association with blood glucose, warranting further studies.
MeSH Terms
- Adipose Tissue
- Adult
- Aging
- Bone Marrow
- Case-Control Studies
- Child
- Female
- Humans
- Male
- Obesity
- Pilot Projects
- Young Adult
Keywords
- Bone marrow fat
- Fatty acid composition
- Obesity
- Spectroscopy
- Unsaturation
The duration of the female fertile life span is influenced by the number of oocytes stored in the ovary as primordial follicles. Cell death, both during ovarian development in the embryo and in the postnatal ovary, plays a critical role in determining how many primordial follicles are established and maintained within the ovary. However, the roles of individual apoptotic regulators in mediating cell death within the ovary have not yet been characterized. In this study, gene targeted mice were used to investigate the role of BCL-2-modifying factor (BMF), a proapoptotic protein belonging to the BH3-only subgroup of the BCL-2 family, in determining the number of primordial follicles maintained in the adult ovary and the length of the fertile life span. Stereological analysis of ovaries showed that Bmf(-/-) mice had significantly more primordial follicles than wild-type (WT) control animals at Postnatal Days 100, 200, 300, and 400 but not at Day 20. No differences were observed between WT and Bmf(-/-) mice in the number of ova shed following ovulatory stimulation with exogenous gonadotropins. Bmf(-/-) females were fertile and produced the same number pups/litter as WT females, but Bmf(-/-) females produced litters more frequently and consequently more offspring than WT females over a 6-mo period. Furthermore, the fertile life span of Bmf(-/-) females was significantly extended compared to WT females. Our findings support an important role for BMF in determining the number of primordial follicles maintained in the ovary throughout adult reproductive life and thus indicate that the length of female fertility may be extended by increasing the number of primordial follicles maintained within the ovary through inhibition of BMF.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aging
- Animals
- Apoptosis
- Apoptosis Regulatory Proteins
- Female
- Fertility
- Follicular Atresia
- Granulosa Cells
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Ovarian Follicle
- Ovulation
- Proto-Oncogene Proteins c-bcl-2
Keywords
- BCL-2
- BMF
- apoptosis
- fertility
- follicles
- ovary
- primordial follicles
Inphase and out-of-phase magnetic resonance imaging is a robust and fast method which can provide similar vertebral bone marrow fat estimation as (1)H proton magnetic resonance spectroscopy, indicating that this technique is a potentially useful tool in both research and clinical practice. The importance of evaluating bone marrow fat lies in the fact that osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Bone fat mass can be reliably assessed using proton magnetic resonance spectroscopy ((1)H MRS), but this method is technically demanding and needs advanced post-processing unlike inphase and out-of-phase magnetic resonance imaging (MRI), which is a robust and fast method. We compared vertebral bone marrow fat (BMF) content assessed by inphase and out-of-phase MRI and (1)H MRS using a 1.5-T MRI scanner in mothers (n = 34, aged 49.4 years), fathers (n = 31, aged 53.1 years) and their daughters (n = 40, aged 20.3 years) who participated in the CALEX family study. Signal intensity on the inphase and out-of-phase MRI was analyzed from the same location and size of the single-voxel (1)H MRS measurement. Positive correlations were found between (1)H MRS and inphase and out-of-phase MRI in the axial plane (r = 0.746, p < 0.001) and sagittal plane (r = 0.804, p < 0.001). The mean differences between (1)H MRS and inphase and out-of-phase MRI in the axial and sagittal planes were relatively small, at 4.13 and 2.67 %, and the agreement between techniques was 89.4 and 93.2 %, respectively. Girls had a significantly lower vertebral BMF than mothers and fathers with both methods (for all, p < 0.001). We conclude that inphase and out-of-phase MRI can provide similar vertebral BMF estimation as (1)H MRS, indicating that this technique is a potentially useful tool in both research and clinical practice.
MeSH Terms
- Absorptiometry, Photon
- Adipose Tissue
- Adult
- Aging
- Body Composition
- Body Mass Index
- Bone Density
- Bone Marrow
- Female
- Humans
- Lumbar Vertebrae
- Magnetic Resonance Imaging
- Magnetic Resonance Spectroscopy
- Male
- Middle Aged
- Reproducibility of Results
- Sex Characteristics
- Young Adult
Fanconi anemia (FA) is an inherited DNA repair deficiency syndrome. FA patients undergo progressive bone marrow failure (BMF) during childhood, which frequently requires allogeneic hematopoietic stem cell transplantation. The pathogenesis of this BMF has been elusive to date. Here we found that FA patients exhibit a profound defect in hematopoietic stem and progenitor cells (HSPCs) that is present before the onset of clinical BMF. In response to replicative stress and unresolved DNA damage, p53 is hyperactivated in FA cells and triggers a late p21(Cdkn1a)-dependent G0/G1 cell-cycle arrest. Knockdown of p53 rescued the HSPC defects observed in several in vitro and in vivo models, including human FA or FA-like cells. Taken together, our results identify an exacerbated p53/p21 "physiological" response to cellular stress and DNA damage accumulation as a central mechanism for progressive HSPC elimination in FA patients, and have implications for clinical care.
MeSH Terms
- Adolescent
- Adult
- Adult Stem Cells
- Aging
- Animals
- Bone Marrow
- Child
- Child, Preschool
- Cyclin-Dependent Kinase Inhibitor p21
- DNA Damage
- Disease Models, Animal
- Embryonic Stem Cells
- Fanconi Anemia
- Fanconi Anemia Complementation Group C Protein
- Fanconi Anemia Complementation Group D2 Protein
- G1 Phase Cell Cycle Checkpoints
- G2 Phase Cell Cycle Checkpoints
- Gene Knockdown Techniques
- Gene Silencing
- Hematopoietic Stem Cells
- Humans
- Infant
- Mice
- Middle Aged
- S Phase
- Tumor Suppressor Protein p53
The maturation pattern of the envelope following response (EFR) was described using rats as an experimental model. EFRs were recorded in animals at different postnatal ages (15, 20, 25, 35, and 70 postnatal days) in response to broadband noise (BBN) and tones of 8000 and 4000 Hz modulated in amplitude using a continuous sweep of modulation frequencies. Responses were analysed in the 90-190 Hz modulation frequency (MF) range. Forty individuals (eight individuals for each age bracket) were included in the present study. During maturation, the MF at which the maximum amplitude was obtained (BMF, best modulation frequency) shifted to higher values when animals were stimulated with tones. At the same time, the amplitude of the response at the BMF increased. For every group of animals, the amplitude of the response continuously decreased for MFs higher than the BMF. However, less steep decreases of amplitude were obtained as animals became adults. These results provide normative data regarding the maturation of the EFR in rats. They provide information for the development of predictor models to estimate the temporal resolution of the auditory system during maturation.
MeSH Terms
- Acoustic Stimulation
- Age Factors
- Aging
- Animals
- Audiometry, Evoked Response
- Auditory Pathways
- Auditory Perception
- Evoked Potentials, Auditory
- Rats
- Rats, Wistar
- Signal Processing, Computer-Assisted
- Time Factors
- Time Perception
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p = 2.61 × 10(-19)), ARPC1A (rs740160; p = 1.56 × 10(-16)), TRIM4 (rs17277546; p = 4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p = 4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
MeSH Terms
- Actin-Related Protein 2-3 Complex
- Adaptor Proteins, Signal Transducing
- Adult
- Aged
- Aging
- Apoptosis Regulatory Proteins
- Aryl Hydrocarbon Hydroxylases
- Bcl-2-Like Protein 11
- Cytochrome P-450 CYP2C9
- DNA-Binding Proteins
- Dehydroepiandrosterone Sulfate
- European Continental Ancestry Group
- Female
- Gene Expression
- Genome-Wide Association Study
- Homeodomain Proteins
- Humans
- Kruppel-Like Transcription Factors
- Linkage Disequilibrium
- Liver
- Male
- Membrane Proteins
- Middle Aged
- Polymorphism, Single Nucleotide
- Proto-Oncogene Proteins
- Sulfotransferases
- Transcription Factors
- Young Adult
The protective effect of total fat mass on bone mineral density (BMD) has been challenged with studies showing no or negative association after adjusting for weight. Subsequently, more studies have evaluated the relationship of regional adiposity with BMD, and findings were inconsistent for central obesity. Advancements in imaging techniques enable us to directly and noninvasively study the role of adiposity on skeletal health. Visceral adiposity measured by computed tomography (CT) has consistently been shown to have negative effects on bone. Availability of magnetic resonance spectroscopy (MRS) also allows us to noninvasively quantify bone marrow fat (BMF), which has been known to be associated with osteoporosis from histomorphometric studies. Using MRS along with dual energy x-ray absorptiometry, studies have reported a detrimental role of BMF on BMD. With the increase in aging and obesity of the population, it is important to continue this effort in identifying the contribution of adipose tissues to bone quality and fracture.
MeSH Terms
- Aging
- Bone Density
- Bone Marrow
- Bone and Bones
- Fractures, Bone
- Humans
- Intra-Abdominal Fat
- Metabolic Syndrome
- Obesity
- Osteoporosis
- Radiography
Dyskeratosis congenita (DC) was originally defined as a rare inherited bone marrow failure (BMF) syndrome associated with distinct mucocutaneous features. Today DC is defined by its pathogenetic mechanism and mutations in components of the telomere maintenance machinery resulting in excessively short telomeres in highly proliferating tissues. With this new definition the disease spectrum has broadened and ranges from intrauterine growth retardation, cerebellar hypoplasia, and death in early childhood to asymptomatic mutation carriers whose descendants are predisposed to malignancy, BMF, or pulmonary disease. The degree of telomere dysfunction is the major determinant of disease onset and manifestations.
MeSH Terms
- Adult
- Aged
- Aging
- Bone Marrow
- Cell Division
- Dyskeratosis Congenita
- Genetic Diseases, Inborn
- Humans
- Infant, Newborn
- Middle Aged
- Mutation
- Neoplasms
- Telomerase
- Telomere
- Telomere-Binding Proteins
Harbour porpoises (Phocoena phocoena) and harbour seals (Phoca vitulina) were found to differ in the ability to metabolize polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Biomagnification factors (BMFs), calculated between both predators and their prey (sole--Solea solea and whiting--Merlangius merlangus), had a large range of variation (between 0.5 and 91 for PCBs and between 0.6 and 53 for PBDEs). For the higher chlorinated PCBs and the highest brominated PBDEs, the BMF values in adult males were significantly higher than in the juvenile individuals of both species. BMF values of hexa- to octa-PCBs were the highest, suggesting reduced ability to degrade these congeners. Harbour porpoises had higher BMFs for lower chlorinated PCBs and for all PBDEs compared to harbour seals. Other factors, which may influence biomagnification, such as the octanol-water partition coefficients and the trophic level position measured through stable isotope (delta15N) analysis, were found to be of lesser importance to predict biomagnification in the studied food chain.
MeSH Terms
- Aging
- Animals
- Biotransformation
- Female
- Food Chain
- Halogenated Diphenyl Ethers
- Male
- North Sea
- Octanols
- Phoca
- Phocoena
- Polychlorinated Biphenyls
- Sex Factors
- Species Specificity
- Water Pollutants, Chemical
Loss of temporal processing is characteristic of age-related loss of speech understanding observed in the elderly. Inhibitory glycinergic circuits provide input onto dorsal cochlear nucleus (DCN) projection neurons which likely serve to modulate excitatory responses to time-varying complex acoustic signals. The present study sought to test the hypothesis that age-related loss of inhibition would compromise the ability of output neurons to encode sinusoidally amplitude modulated (SAM) tones. Extracellular recordings were obtained from young and aged FBN rat DCN putative fusiform cells. Stimuli were SAM tones at three modulation depths (100, 50, and 20%) at 30 dB hearing level with the carrier frequency set to the unit's characteristic frequency. Discharge rate and synchrony were calculated to describe SAM responses. There were significant age-related changes in the shape and peak vector strength [best modulation frequency (BMF)] of temporal modulation transfer functions (tMTFs), with no significant age-related changes in rate modulation transfer functions (rMTFs) at BMF. Young neurons exhibited band-pass tMTFs for most SAM conditions while aged fusiform cells exhibited significantly more low-pass or double-peaked tMTFs. There were significant differences in tMTFs between buildup, pauser-buildup, and wide-chopper temporal response types. Young and aged wide-choppers displayed significantly lower vector strength values than the other two temporal DCN response types. Age-related decreases in the number of pauser-buildup response types and increases in wide-chopper types reported previously, could account, in part, for the observed loss of temporal coding of the aged fusiform cell. Age-related changes in SAM coding were similar to changes observed with receptor blockade of glycinergic inhibition onto fusiform cells and consistent with previously observed age-related loss of endogenous glycine levels and changes in normal adult glycine receptor function. DCN changes in SAM coding could, in part, underpin temporal processing deficits observed in the elderly.
MeSH Terms
- Acoustic Stimulation
- Action Potentials
- Aging
- Analysis of Variance
- Animals
- Auditory Pathways
- Auditory Perception
- Auditory Threshold
- Cell Count
- Cochlear Nucleus
- Neural Inhibition
- Neurons
- Rats
- Rats, Inbred F344
- Reaction Time
Juvenile rainbow trout (Oncorhynchus mykiss) were exposed to three diastereoisomers (alpha, beta, gamma) of hexabromocyclododecane (C12H18Br6) via their diet for 56 d followed by 112 d of untreated food to examine bioaccumulation parameters and test the hypothesis of in vivo bioisomerization. Four groups of 70 fish were used in the study. Three groups were exposed to food fortified with known concentrations of an individual diastereoisomer, while a fourth group were fed unfortified food. Bioaccumulation of the gamma-diastereoisomer was linear during the uptake phase, while the alpha- and beta-diastereoisomers were found to increase exponentially with respective doubling times of 8.2 and 17.1 d. Both the beta- and the gamma-diastereoisomers followed a first-order depuration kinetics with calculated half-lives of 157 /- 71 and 144 /- 60 d ( /-1 x standard error), respectively. The biomagnification factor (BMF) for the alpha-diastereoisomer (BMF = 9.2) was two times greater than the beta-diastereoisomer (BMF = 4.3); the large BMF for the beta-diastereoisomer is consistent with this diastereoisomer dominating higher-trophic-level organisms. Although the BMF of the beta-diastereoisomer suggests that it will biomagnify, it is rarely detected in environmental samples because it is present in small quantities in commercial mixtures. Results from these studies also provide evidence of bioisomerization of the beta- and gamma-diastereoisomers. Most importantly, the alpha-diastereoisomer that was recalcitrant to bioisomerization by juvenile rainbow trout in this study and known to be the dominant diastereosiomer in fish was bioformed from both the beta- and the gamma-diastereoisomers. To our knowledge, this is the first report of bioisomerization of a halogenated organic pollutant in biota.
MeSH Terms
- Aging
- Animals
- Diet
- Hydrocarbons, Brominated
- Stereoisomerism
- Trout
Recordings were made from 185 neurons in the primary auditory cortex of cats in the age range of 15 to 297 days. A comparison was made between the tuning for click repetition-rate and for amplitude modulation-frequency of a noise burst on the basis of temporal Modulation Transfer Functions (tMTF). 90 of the 185 units had a clear band-pass type tMTF for both repetition rate and modulation frequency, there was, however, no correlation between the respective Best Modulation Frequencies (BMF). Amplitude modulated noise (AMnoise) was the more effective stimulus in young kittens while click-train stimulation was more effective in adult cats. For all neurons with significant synchronization, BMFs for both click-train and AMnoise increased with age from about 4 Hz in kittens younger than 30 days to about 10 Hz in adult cats. In the approximately 50% of the neurons that were tuned both to click rate and modulation frequency, however, the BMF to AMnoise was consistently and significantly higher than that for clicks. In this group the mean BMF for kittens younger than 30 days were 7.94 Hz for AMnoise and 3.29 Hz for clicks and in the adults 10.91 Hz for AMnoise and 7.71 Hz for clicks.
MeSH Terms
- Acoustic Stimulation
- Aging
- Animals
- Auditory Cortex
- Auditory Perception
- Auditory Threshold
- Cats