Transformation of Different Human Breast Epithelial Cell Types Leads to Distinct Tumor Phenotypes
Tan A. InceAndrea L. RichardsonGeorge W. BellMaki SaitohSamuel GodárAntoine E. KarnoubJ. Dirk IglehartRobert A. Weinberg
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Keywords:
Cell type
Neoplastic transformation
Objective
To classify the high-resolution CT (HRCT) phenotypes of COPD, and to investigate the clinical characteristics of various phenotypes and the relationship with airway inflammation.
Methods
Chest HRCT and pulmonary function tests were performed in 84 COPD patients. The patients were classified into 3 phenotypes according to the visual HRCT findings. Exhaled breath condensate was gathered from 30 patients and the interleukin (IL)-6 level was measured by ELISA.
Results
The COPD patients were classified into 3 phenotypes: Phenotype A, absence of emphysema, with or without bronchial wall thickening (n=34); Phenotype E, emphysema without bronchial wall thickening (n=23); and Phenotype M, emphysema with bronchial wall thickening (n=27). The 3 phenotypes of COPD showed different characteristics in several aspects. Patients with phenotype A showed a higher body mass index [(25.1±4.4) kg/m2vs phenotype E (22.5±4.1) kg/m2 and phenotype M (21.3±3.4) kg/m2,F=6.732, P<0.01]. The prevalence of patients with milder dyspnea was lower in phenotype A compared with others (15/34) vs phenotype E (2/23) and phenotype M (6/27), χ2 =9.097, P<0.05. The patients who complained of severe expectoration in phenotype E were fewer than those in other groups (0/23) vs phenotype A (2/34) and phenotype M (4/27), χ2=8.702, P<0.05. The FEV1/FVC and FEV1% in phenotype M [(53±14)% and (51±25)%] were significantly lower as compared with those in other phenotypes [ (67±11)% and (72±24)% in phenotype A, and (53±14)% and (52±26)% in phenotype E], F=10.252, F=6.508, P<0.01. The ratio of inspiratory capacity to total lung capacity (IC/TLC) in phenotype A was higher [phenotype A (41±17)%, phenotype E (33±13)%, phenotype M (28±13)%, F=5.964, P<0.01], while the ratio of residual volume to total lung capacity (RV/TLC) was lower [phenotype A (37±9)%, phenotype E (44±10)%, phenotype M (45±8)%, F=6.954, P<0.01]. Patients with different phenotypes showed various levels of IL-6 in exhaled breath condensate [phenotype A (19.9±6.3) ng/L, phenotype E (16.7±2.1) ng/L, phenotype M (25.6±4.4) ng/L, F=7.749, P<0.01].
Conclusion
Various morphological phenotypes of COPD based on HRCT showed different clinical characteristics and airway inflammation.
Key words:
Pulmonary disease, chronic obstructive; Tomography, X-ray computed; Respiratory function tests; Interleukin-6
Air trapping
Clinical phenotype
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Differences between individual phenotypes are due both to differences in genotype and to exposure to different environmental factors. A fundamental contribution to the definition of the individual phenotype for clinical and therapeutic applications would come from a deeper understanding of the metabolic phenotype. The existence of unique individual metabolic phenotypes has been hypothesized, but the experimental evidence has been only recently collected. Analysis of individual phenotypes over the timescale of years shows that the metabolic phenotypes are largely invariant. The present work also supports the idea that the individual metabolic phenotype can also be considered a metagenomic entity that is strongly affected by both gut microbiome and host metabolic phenotype, the latter defined by both genetic and environmental contributions.
Metabolic pathway
Clinical phenotype
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Three rice genetic transformation systems,PEG
Mediated,Biolistic Gun and Agrobacterium Mediated were compared.After due considering
transformation frequency,transformation period,transformation cost and transformation
difficulty,Agrobacterium Mediated system was selected as one more economical,more efficient
and more simple rice gene transformation system.
Gene gun
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In two brothers treated for severe pulmonary emphysema, was demonstrated an alpha-1-antitrypsin deficiency associated with a ZZ phenotype (Pi system). The authors carried out a genetic study of the family including 60 members spread over 4 generations. In all, were demonstrated 4 subjects of phenotype ZZ, 29 of phenotype MZ, 3 of phenotype MS ; one subject had a phenotype SZ and 23 members of this family had normal levels of alpha-1-antitrypsin and were of phenotype MM. The disease was transmitted in all cases as an autosomic codominant. The interest of a study of the phenotype in alpha-1-antitrypsin deficiency is emphasized together with the practical steps to be taken on discovery of a subject with the allele responsible for a reduction in serum levels of alpha-1-antitrypsin.
Alpha 1-antitrypsin deficiency
Alpha (finance)
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Summary 1. Many organisms respond to threats such as stress and predation by expressing a defended phenotype (phenotypic plasticity) or inducing the expression of a defended phenotype in offspring (transgenerational phenotypic plasticity). While defended phenotypes can increase resistance to a predator or stress, in the absence of the inducing agent defended phenotypes often have poorer performance. Producing a defended phenotype unnecessarily has been termed a phenotype‐environment mismatch. 2. Most studies have focused on the benefits of a defended phenotype along a single environmental gradient (i.e. the presence/absence of the inducing agent) but in nature, organisms must face conditions that vary across a number of environmental gradients simultaneously. By focusing on the costs and benefits of a defended phenotype in a single dimension alone we risk underestimating the strength and likelihood of phenotype‐environment mismatches. 3. For the marine bryozoan Bugula neritina , we examined the performance of individuals with an induced, defended phenotype (pollution resistance) relative to individuals with an undefended phenotype across a number of different environments. We found that individuals with the defended phenotype were more sensitive to osmotic stress, but surprisingly, were less susceptible to predation than individuals with the undefended phenotype. 4. Our findings suggest that the costs and benefits associated with expressing a defended phenotype are more complex than previously realized because the full consequences of induced phenotypes are only unmasked when performance in multiple environments is examined.
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Abstract Disease phenotypes, serving as valuable descriptors for delineating the spectrum of human pathologies, play a critical role in understanding disease mechanisms. Integration of these phenotypes with single-cell RNA sequencing (scRNA-seq) data facilitates the elucidation of potential associations between phenotypes and specific cell types underlying them, which sheds light on the underlying physiological processes related to these phenotypes. In this study, we utilized scRNA-seq data to infer potential associations between rare disease phenotypes and cell types. Differential expression and co-expression analyses of genes linked to abnormal phenotypes were employed as metrics to identify the involved cell types. Comparative assessments were made against existing phenotype-cell type associations documented in the literature. Our findings underscore the utility of differential expression and co-expression analyses in identifying significant relationships. Moreover, co-expression analysis unveils cell types potentially linked to abnormal phenotypes not extensively characterized in prior studies. Key points - Cell types underling rare disease phenotypes remain largely unknown - Single-cell RNA-seq data from healthy tissues can be analyzed to reveal these cell types - We employed differential expression and co-expression analysis to identify cell types associated with rare disease phenotypes - We validated our results with known relations described in the literature
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RNA-Seq
Expression (computer science)
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Summary There is growing evidence that the metastatic spread of melanoma is driven not by a linear increase in tumorigenic aggressiveness, but rather by switching back and forth between two different phenotypes of metastatic potential. In vitro these phenotypes are respectively defined by the characteristics of strong proliferation/weak invasiveness and weak proliferation/strong invasiveness. Melanoma cell phenotype is tightly linked to gene expression. Taking advantage of this, we have developed a gene expression–based tool for predicting phenotype called Heuristic Online Phenotype Prediction. We demonstrate the predictive utility of this tool by comparing phenotype‐specific signatures with measurements of characteristics of melanoma phenotype‐specific biology in different melanoma cell lines and short‐term cultures. We further show that 86% of 536 tested melanoma lines and short‐term cultures are significantly associated with the phenotypes we describe. These findings reinforce the concept that a two‐state system, as described by the phenotype switching model, underlies melanoma progression.
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The C3H/10T1/2 cell system has been widely used as a quantitative assay for neoplastic transformation. Following exposure to chemical or physical carcinogens, there is a dose-dependent induction of neoplastic transformation in a small percentage of surviving cells. The ability of carcinogen-initiated cells to undergo transformation is highly dependent upon the effects of cell population density and is also inhibited by cancer chemopreventive retinoids. It is proposed that these observations are functionally related. Inhibition of transformation by retinoids correlates strongly with their ability to up-regulate intercellular gap junctional communication in normal and carcinogen-initiated cells while inhibition due to density effects correlates with the proximity of initiated cells to normal cells. It is hypothesized that junctional communication allows the transfer of signal molecules which suppress neoplastic transformation.
Neoplastic transformation
Neoplastic cell
Malignant Transformation
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We describe the second patient with the de novo p.Arg377Trp variant in ACTL6A (Actin-like 6A) (MIM#604958) and a phenotype reminiscent a disorder of the BRG1-associated factor (BAF) complex, including dysmorphic facies and acral malformations. So far, only three patients with ACTL6A variants and neurodevelopmental delay have been reported but the specific p.Arg377Trp mutation seems to correlate with a distinctive phenotype well-fitting a BAFopathy, which lacks in individuals carrying different mutations. This could suggest an emergent genotype-phenotype correlation among the ACTL6A-related phenotype.
Genotype-phenotype distinction
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