Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or ...resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.
Age-associated osteoporosis is widely accepted as involving the disruption of osteogenic stem cell populations and their functioning. Maintenance of the local bone marrow (BM) microenvironment is ...critical for regulating proliferation and differentiation of the multipotent BM mesenchymal stromal/stem cell (BMSC) population with age. The potential role of microRNAs (miRNAs) in modulating BMSCs and the BM microenvironment has recently gained attention. However, miRNAs expressed in rapidly isolated BMSCs that are naïve to the non-physiologic standard tissue culture conditions and reflect a more accurate in vivo profile have not yet been reported. Here we directly isolated CD271 positive (+) BMSCs within hours from human surgical BM aspirates without culturing and performed microarray analysis to identify the age-associated changes in BMSC miRNA expression. One hundred and two miRNAs showed differential expression with aging. Target prediction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the up-regulated miRNAs targeting genes in bone development pathways were considerably enriched. Among the differentially up-regulated miRNAs the novel passenger strand miR-29b-1-5p was abundantly expressed as a mature functional miRNA with aging. This suggests a critical arm-switching mechanism regulates the expression of the miR-29b-1-5p/3p pair shifting the normally degraded arm, miR-29b-1-5p, to be the dominantly expressed miRNA of the pair in aging. The normal guide strand miR-29b-1-3p is known to act as a pro-osteogenic miRNA. On the other hand, overexpression of the passenger strand miR-29b-1-5p in culture-expanded CD271+ BMSCs significantly down-regulated the expression of stromal cell-derived factor 1 (CXCL12)/ C-X-C chemokine receptor type 4 (SDF-1(CXCL12)/CXCR4) axis and other osteogenic genes including bone morphogenetic protein-2 (BMP-2) and runt-related transcription factor 2 (RUNX2). In contrast, blocking of miR-29b-1-5p function using an antagomir inhibitor up-regulated expression of BMP-2 and RUNX2 genes. Functional assays confirmed that miR-29b-1-5p negatively regulates BMSC osteogenesis in vitro. These novel findings provide evidence of a pathogenic anti-osteogenic role for miR-29b-1-5p and other miRNAs in age-related defects in osteogenesis and bone regeneration.
•Direct BMSC isolation without culturing allowed a more accurate in vivo profile of labile miRNAs than previously reported.•One hundred and two miRNAs, including 29b-1-5p showed differential expression with aging targeting bone development pathways.•miR-29b-1-5p is a passenger strand, suggesting a critical novel arm-switching mechanism regulates its expression with age.•Overexpression of miR-29b-1-5p decreased expression of CXCL12, CXCR4, BMP-2, RUNX2, other osteogenic genes and osteogenesis.•Targeting miR-29b-1-5p rescues osteogenic gene expression and function.
In solid tumors, cancer stem cells (CSCs) can arise independently of epithelial-mesenchymal transition (EMT). In spite of recent efforts, the metabolic reprogramming associated with CSC phenotypes ...uncoupled from EMT is poorly understood. Here, by using metabolomic and fluxomic approaches, we identify major metabolic profiles that differentiate metastatic prostate epithelial CSCs (e-CSCs) from non-CSCs expressing a stable EMT. We have found that the e-CSC program in our cellular model is characterized by a high plasticity in energy substrate metabolism, including an enhanced Warburg effect, a greater carbon and energy source flexibility driven by fatty acids and amino acid metabolism and an essential reliance on the proton buffering capacity conferred by glutamine metabolism. An analysis of transcriptomic data yielded a metabolic gene signature for our e-CSCs consistent with the metabolomics and fluxomics analyses that correlated with tumor progression and metastasis in prostate cancer and in 11 additional cancer types. Interestingly, an integrated metabolomics, fluxomics, and transcriptomics analysis allowed us to identify key metabolic players regulated at the post-transcriptional level, suggesting potential biomarkers and therapeutic targets to effectively forestall metastasis. Stem Cells 2016;34:1163-1176.
Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in ...patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.
This paper is focused on the segregation of FGK dwarf and giant stars through narrow-band photometric data using the Spanish Virtual Observatory (SVO) Filter Profile Service and associated ...photometric tools. We selected spectra from the MILES, STELIB, and ELODIE stellar libraries, and used SVO photometric tools to derive the synthetic photometry in 15 J-PAS narrow filters, which were especially selected to cover spectral features sensitive to gravity changes. Using machine-learning techniques as the Gaussian mixture model and the support vector machine, we defined several criteria based on J-PAS colours to discriminate between dwarf and giant stars. We selected five colour-colour diagrams that presented the most promising separation between both samples. Our results show an overall accuracy in the studied sample of sim 0.97 for FGK stars, although a dependence on the luminosity type and the stellar effective temperature was found. We also defined a colour-temperature relation for dwarf stars with effective temperatures between 4\,000 and 7\,000\,K, which allows one to estimate the stellar effective temperature from four J-PAS filters ($J0450$, $J0510$, $J0550$, and $J0620$). Additionally, we extended the study to M-type giant and dwarf stars, achieving a similar accuracy to that for FGK stars.
Emotional exhaustion causes adverse effects in those who suffer from it. Housewives are not excluded. Domestic and care chores, which are considered to be sources of stress, increase when taking on ...the role of caregiver for a family member with Alzheimer's disease.
To analyse the influence of emotional exhaustion, somatic symptoms and social dysfunction, based on the activity they carry out.
Cross-sectional survey. 193 women participated, of which: housewives (HWs) (n = 97), and Alzheimer's patient caregiver-housewives (CHWs) (n = 96). The evaluation tools were: sociodemographic/working data questionnaire (ad hoc), Maslach Burnout Inventory (MBI) and Goldberg General Health Questionnaire (GHQ-28).
High rates of emotional exhaustion are observed, as well as an existing positive link between chronic diseases, somatic symptoms and social dysfunction. The structural model indicates that emotional exhaustion predicts the amount and extent of diseases, somatic symptoms and social dysfunction. The influence is higher in CHWs.
Sample procedure implemented at convenience; the variable of the grade of dependence of the Alzheimer's patient caregiver was not included in the study.
The domestic and care chores that HWs and CHWs carry out affect their health. Hence the need to develop psychoeducative programmes that are adapted to the particular needs of these women and focused on the different areas of their everyday lives.
Triatomine bugs, the vectors of Chagas disease, associate with vertebrate hosts in highly diverse ecotopes. It has been proposed that occupation of new microhabitats may trigger selection for ...distinct phenotypic variants in these blood-sucking bugs. Although understanding phenotypic variation is key to the study of adaptive evolution and central to phenotype-based taxonomy, the drivers of phenotypic change and diversity in triatomines remain poorly understood.
We combined a detailed phenotypic appraisal (including morphology and morphometrics) with mitochondrial cytb and nuclear ITS2 DNA sequence analyses to study Rhodnius ecuadoriensis populations from across the species' range. We found three major, naked-eye phenotypic variants. Southern-Andean bugs primarily from vertebrate-nest microhabitats (Ecuador/Peru) are typical, light-colored, small bugs with short heads/wings. Northern-Andean bugs from wet-forest palms (Ecuador) are dark, large bugs with long heads/wings. Finally, northern-lowland bugs primarily from dry-forest palms (Ecuador) are light-colored and medium-sized. Wing and (size-free) head shapes are similar across Ecuadorian populations, regardless of habitat or phenotype, but distinct in Peruvian bugs. Bayesian phylogenetic and multispecies-coalescent DNA sequence analyses strongly suggest that Ecuadorian and Peruvian populations are two independently evolving lineages, with little within-lineage phylogeographic structuring or differentiation.
We report sharp naked-eye phenotypic divergence of genetically similar Ecuadorian R. ecuadoriensis (nest-dwelling southern-Andean vs palm-dwelling northern bugs; and palm-dwelling Andean vs lowland), and sharp naked-eye phenotypic similarity of typical, yet genetically distinct, southern-Andean bugs primarily from vertebrate-nest (but not palm) microhabitats. This remarkable phenotypic diversity within a single nominal species likely stems from microhabitat adaptations possibly involving predator-driven selection (yielding substrate-matching camouflage coloration) and a shift from palm-crown to vertebrate-nest microhabitats (yielding smaller bodies and shorter and stouter heads). These findings shed new light on the origins of phenotypic diversity in triatomines, warn against excess reliance on phenotype-based triatomine-bug taxonomy, and confirm the Triatominae as an informative model system for the study of phenotypic change under ecological pressure .
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