345 research outputs found
Accessory mitral valve tissue causing severe left ventricular outflow tract obstruction in a post-Senning patient with transposition of the great arteries
Accessory mitral valve tissue is a rare congenital anomaly associated with congenital cardiac defects and is usually detected in the first decade of life. We describe the case of an 18-year old post-Senning asymptomatic patient who was found to have accessory mitral valve tissue on transthoracic echocardiography producing severe left ventricular outflow tract obstruction
Specific gut microbiota features and metabolic markers in postmenopausal women with obesity
BACKGROUND: Gut microbial gene richness and specific bacterial species are associated with metabolic risk markers in humans, but the impact of host physiology and dietary habits on the link between the gut microbiota and metabolic markers remain unclear. The objective of this study was to identify gut metagenomic markers associated with estimates of insulin resistance, lipid metabolism and inflammation in obesity, and to explore whether the associations between metagenomic and metabolic markers persisted after adjustment for body fat, age and habitual dietary intake. METHODS: Faecal DNA from 53 women with obesity was analysed through quantitative metagenomic sequencing and analysis, and a systematic search was performed for bacterial genes associated with estimates of insulin resistance, inflammation and lipid metabolism. Subsequently, the correlations between metagenomic species and metabolic markers were tested by linear regression models, with and without covariate adjustment. RESULTS: One hundred and fourteen metagenomic species correlated with metabolic markers (P<0.001) including Akkermansia muciniphila, Bilophila wadsworthia, Bifidobacterium longum and Faecalibacterium prausnitzii, but also species not previously associated with metabolic markers including Bacteroides faecis and Dorea longicatena. The majority of the identified correlations between bacterial species and metabolic markers persisted after adjustment for differences in body fat, age and dietary macronutrient composition; however, the negative correlation with insulin resistance observed for B. longum and F. prausnitzii appeared to be modified by the intake of dietary fibre and fat, respectively. CONCLUSIONS: This study shows that several gut bacterial species are linked to metabolic risk markers in obesity, also after adjustment for potential confounders, such as long-term diet composition. The study supports the use of gut metagenomic markers for metabolic disease prediction and warrants further investigation of causality
Adipose tissue pathways involved in weight loss of cancer cachexia
White adipose tissue (WAT) constitutes our most expandable tissue and largest
endocrine organ secreting hundreds of polypeptides collectively termed adipokines.
Changes in WAT mass induce alterations in adipocyte secretion and function, which
are linked to disturbed whole-body metabolism. Although the mechanisms controlling
this are not clear they are dependent on changes in gene expression, a complex process
which is regulated at several levels. Results in recent years have highlighted the role of
small non-coding RNA molecules termed microRNAs (miRNAs), which regulate gene
expression via post-transcriptional mechanisms. The aim of this thesis was to
characterize global gene expression levels and describe novel miRNAs and adipokines
controlling the function of human WAT in conditions with pathological increases or
decreases in WAT mass. Obesity and cancer cachexia were selected as two models
since they are both clinically relevant and characterized by involuntary changes in
WAT mass.
In Study I, expressional analyses were performed in subcutaneous WAT from cancer
patients with or without cachexia and obese versus non-obese subjects. In total, 425
transcripts were found to be regulated in cancer cachexia. Pathway analyses based on
this set of genes revealed that processes involving extracellular matrix, actin
cytoskeleton and focal adhesion were significantly downregulated, whereas fatty acid
metabolism was upregulated comparing cachectic with weight-stable cancer subjects.
Furthermore, by overlapping these results with microarray data from an obesity study,
many transcripts were found to be reciprocally regulated comparing the two conditions.
This suggests that WAT gene expression in cancer cachexia and obesity are regulated
by similar, albeit opposing, mechanisms.
In Study II, the focus was on the family of
fibroblast growth factors (FGFs), members of which have recently been implicated in
the development of obesity and insulin resistance. A retrospective analysis of global
gene expression data identified several FGFs (FGF1/2/7/9/13/18) to be expressed in
WAT. However, only one, FGF1, was actively secreted from WAT and predominantly
so from the adipocyte fraction. Moreover, FGF1 release was increased in obese
compared to non-obese subjects, but was not normalized by weight loss. Although the
clinical significance of these findings is not yet clear, it can be hypothesized that FGF1
may play a role in WAT growth, possibly by promoting fat cell proliferation and/or
differentiation.
In Study III, we identified adipose miRNAs regulated in obesity. Out
of eleven miRNAs regulated by changes in body fat mass, ten controlled the production
of the pro-inflammatory chemoattractant chemokine (C-C motif) ligand 2 (CCL2)
when overexpressed in fat cells and for two, miR-126 and -193b, signaling circuits
were defined.
In Study IV, a novel adipokine, semaphorin 3C (SEMA3C), was
identified by combining transcriptome and secretome data. Detailed studies focusing on
SEMA3C revealed that this factor was secreted from adipocytes and induced the
expression of extracellular matrix and matricellular genes in preadipocytes.
Furthermore, SEMA3C mRNA levels correlated with interstitial fibrosis and insulin
resistance in WAT derived from subjects with a wide range in BMI.
In summary, the results presented in this thesis have delineated transcriptional
alterations in WAT in two clinically relevant conditions, obesity and cancer cachexia.
This has allowed the identification of novel adipokines and microRNAs with potential
pathophysiological importance. These findings form the basis for further studies aiming
at understanding the central role of WAT in disorders associated with metabolic
complications
Poly (A)+ Transcriptome Assessment of ERBB2-Induced Alterations in Breast Cell Lines
We report the first quantitative and qualitative analysis of the poly (A)+ transcriptome of two human mammary cell lines, differentially expressing (human epidermal growth factor receptor) an oncogene over-expressed in approximately 25% of human breast tumors. Full-length cDNA populations from the two cell lines were digested enzymatically, individually tagged according to a customized method for library construction, and simultaneously sequenced by the use of the Titanium 454-Roche-platform. Comprehensive bioinformatics analysis followed by experimental validation confirmed novel genes, splicing variants, single nucleotide polymorphisms, and gene fusions indicated by RNA-seq data from both samples. Moreover, comparative analysis showed enrichment in alternative events, especially in the exon usage category, in ERBB2 over-expressing cells, data indicating regulation of alternative splicing mediated by the oncogene. Alterations in expression levels of genes, such as LOX, ATP5L, GALNT3, and MME revealed by large-scale sequencing were confirmed between cell lines as well as in tumor specimens with different ERBB2 backgrounds. This approach was shown to be suitable for structural, quantitative, and qualitative assessment of complex transcriptomes and revealed new events mediated by ERBB2 overexpression, in addition to potential molecular targets for breast cancer that are driven by this oncogene
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