Evaluation of Transcriptomic Regulations behind Metabolic Syndrome in Obese and Lean Subjects.

Multiple mechanisms have been suggested to confer to the pathophysiology of metabolic syndrome (MetS), however despite great interest from the scientific community, the exact contribution of each of MetS risk factors still remains unclear. The present study aimed to investigate molecular signatures in peripheral blood of individuals affected by MetS and different degrees of obesity. Metabolic health of 1204 individuals from 1000PLUS cohort was assessed, and 32 subjects were recruited to four study groups: MetS lean, MetS obese, "healthy obese", and healthy lean. Whole-blood transcriptome next generation sequencing with functional data analysis were carried out. MetS obese and MetS lean study participants showed the upregulation of genes involved in inflammation and coagulation processes: granulocyte adhesion and diapedesis (p < 0.0001, p = 0.0063), prothrombin activation pathway (p = 0.0032, p = 0.0091), coagulation system (p = 0.0010, p = 0.0155). The results for "healthy obese" indicate enrichment in molecules associated with protein synthesis (p < 0.0001), mitochondrial dysfunction (p < 0.0001), and oxidative phosphorylation (p < 0.0001). Our results suggest that MetS is related to the state of inflammation and vascular system changes independent of excess body weight. Furthermore, "healthy obese", despite not fulfilling the criteria for MetS diagnosis, seems to display an intermediate state with a lower degree of metabolic abnormalities, before they proceed to a full blown MetS.

Medulloblastoma with transitional features between Group 3 and Group 4 is associated with good prognosis.

Medulloblastoma, the most common malignant pediatric brain tumor, is a heterogeneous disease, with the existence of at least four molecular types: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4 tumors. The latter two groups, which can be identified by an application of multi-gene expression or methylation profiling, show sometimes ambiguous categorization and are still classified for diagnostic reason as non-SHH/non-WNT medulloblastomas in updated WHO 2016 classification. In order to better characterize non-SHH/non-WNT tumors, we applied the method based on the Nanostring nCounter Technology, using the 26 genes codeset in 68 uniformly treated medulloblastoma patients. This allowed for identification of tumors, which shared common Group 3 and Group 4 gene signatures. We recognized three transcriptional groups within non-WNT/non-SHH tumors: Group 3, Group 4 and the Intermediate 3/4 Group. Group 3, in line with previously published results, showed poor prognosis with survival rate < 40%, frequent metastases, large cell/anaplastic pathology and presence of tumors with MYCC amplification. This is in contrast to patients from the Intermediate 3/4 Group who showed the best survival rate (100%). Overall and progression free survival were better for this group than for Group 3 (p = 0.001, for both) and Group 4 (p = 0.064 and p = 0.066, respectively). Our work supports the view that within the non-WNT/non-SHH tumors different risk groups exist and that the current two groups classifier may be not sufficient for proper clinical categorization of individual patients.

Maternal plasma metabolic fingerprint indicative for fetal Down syndrome.

OBJECTIVE: The objective of the study was to perform maternal plasma metabolic fingerprinting to evaluate differences in plasma metabolites between healthy and Down syndrome (DS) pregnancies and to indicate novel non-invasive markers for DS prenatal diagnostics. METHODS: This was a case-control study of pregnancies between 15th and 18th gestational week. LC-MS-based metabolic fingerprinting of plasma samples was performed. RESULTS: Levels of five metabolites were significantly lower in the plasma of DS pregnancies. The majority of the statistically significant metabolites may be connected with fetal brain and central nervous system development (eg, fatty acid amides). According to the receiver operating characteristic (ROC), the combination of linoleamide and piperine has the highest diagnostic potential: area under the curve (AUC) = 0.878, sensitivity of 100%, and specificity of 73.3%. CONCLUSIONS: The study indicates disturbances in maternal metabolic pathways evoked by fetal DS. Novel potential maternal plasma metabolomic markers for non-invasive prenatal diagnostics of fetal DS are proposed.

Obesity, metabolic health and omics: Current status and future directions.

The growing obesity epidemic is becoming a major public health concern, and the associated costs represent a considerable burden on societies. Among the most common complications of severe obesity are the development of hypertension, dyslipidemia, type 2 diabetes, cardiovascular disease, and various types of cancer. Interestingly, some obese individuals have a favorable metabolic profile and appear to be somehow protected from the detrimental effects of excessive adipose tissue accumulation. These individuals remain normoglycemic, insulin sensitive, and hypotensive with proper blood lipid levels, despite their high body mass index and/or waist circumference. Multiple independent observations have led to the concept of the metabolically healthy obese (MHO) phenotype, yet no consensus has been reached to date regarding a universal definition or the main mechanism behind this phenomenon. Recent technological advances and the use of high-throughput analysis techniques have revolutionized different areas of biomedical research. A multi-omics approach, which is used to investigate changes at different molecular levels in an organism or tissue, may provide valuable insights into the interplay between the molecules or pathways and the roles of different factors involved in the mechanisms underlying metabolic health deterioration. The aim of this review is to present the current status regarding the use of omics technologies to investigate the MHO phenotype, as well as the results of targeted analyses conducted in MHO individuals.

Gas Chromatography-Mass Spectroscopy-Based Metabolomics Analysis Reveals Potential Biochemical Markers for Diagnosis of Gestational Diabetes Mellitus.

Due to many adverse effects of gestational diabetes mellitus (GDM) on the mother and fetus, its diagnosis is crucial. The presence of GDM can be confirmed by an abnormal fasting plasma glucose level (aFPG) and/or oral glucose tolerance test (OGTT) performed mostly between 24 and 28 gestational week. Both aFPG and abnormal glucose tolerance (aGT) are used to diagnose GDM. In comparison to measurement of FPG, OGTT is time-consuming, usually inconvenient for the patient, and very often needs to be repeated. Therefore, it is necessary to seek tests that will be helpful and convenient to diagnose GDM. For this reason, we investigated the differences in fasting serum metabolites between GDM women with abnGM and normal FPG (aGT-GDM group), with aFPG and normal glucose metabolism (aFPG-GDM group) as well as pregnant women with normal glucose tolerance (NGT) being a control group. Serum metabolites were measured by an untargeted approach using gas chromatography-mass spectrometry (GC-MS). In the discovery phase, fasting serum samples collected from 79 pregnant women (aFPG-GDM, n = 24; aGT-GDM, n = 26; NGT, n = 29) between 24 and 28 weeks of gestation (gwk) were fingerprinted. A set of metabolites (α-hydroxybutyric acid (α-HB), ß-hydroxybutyric acid (ß-HB), and several fatty acids) significant in aGT-GDM vs NGT but not significant in aFPG-GDM vs NGT comparison in the discovery phase was selected for validation. These metabolites were quantified by a targeted GC-MS method in a validation cohort consisted of 163 pregnant women (aFPG-GDM, n = 51; aGT-GDM, n = 44; and NGT, n = 68). Targeted analyses were also performed on the serum collected from 92 healthy women in the first trimester (8-14 gwk) who were NGT at this time, but in the second trimester (24-28 gwk) they were diagnosed with GDM. It was found that α-HB, ß-HB, and several fatty acids were associated with aGT-GDM. A combination of α-HB, ß-HB, and myristic acid was found highly specific and sensitive for the diagnosis of GDM manifested by aGT-GDM (AUC = 0.828) or to select women at a risk of aGT-GDM in the first trimester (AUC = 0.791). Our findings provide new potential markers of GDM and may have implications for its early diagnosis.

Prenatal circulating microRNA signatures of foetal Down syndrome.

The altered expression pattern of miRNAs might potentially reflect anomalies related to foetal chromosomal aberrations. The aim of the study was to determine the expression level of miRNAs in plasma of pregnant women with foetal Down syndrome (DS). Out of 198 amniocentesis performed at 15-18 weeks of gestation, within a group of 12 patients with foetal DS and 12 patients with uncomplicated pregnancies, who delivered healthy newborns at term, we examined the expression level of 800 miRNAs using the NanoString technology. Our study revealed that there are 6 miRNAs were upregulated (hsa-miR-15a, hsa-let-7d, hsa-miR-142, hsa-miR-23a, hsa-miR-199, hsa-miR-191) and 7 were downregulated (hsa-miR-1290, hsa-miR-1915, hsa-miR30e, hsa-miR-1260, hsa-miR-483, hsa-miR-548, hsa-miR-590) in plasma samples of women with foetal DS syndrome. The genes regulated by identified miRNAs are involved in central nervous system development, congenital abnormalities and heart defects. The results of the present study yielded information on DS-specific miRNA expression signature, which can further help to design a panel of miRNAs as a non-invasive test for DS diagnosis. We believe that identified miRNAs may attend in the pathogenesis of DS and would potentially make a significant role for the future preventive therapies.

Efficacy of family history, genetic risk score, and physical activity in assessing the prevalence of type 2 diabetes.

INTRODUCTION: Environmental and genetic factors play an important role in the development of type 2 diabetes (T2D). One of the most important lifestyle factors is a low level of physical activity (PA), but no studies have explicitly compared the amount of variation in diabetes prevalence explained by variation in PA compared with the amount explained by genetic variation. OBJECTIVES: We examined associations between PA and patients stratified by the levels of genetic susceptibility to T2D and the prevalence of the disease. PATIENTS AND METHODS: We assessed the level of PA and family history (FH) of T2D in first­degree relatives as well as calculated the genetic risk score (GRS). We examined associations of PA, GRS, and FH with the prevalence of T2D among 1195 individuals enrolled in the 1000 Polish Longitudinal University Study (1000­PLUS) by stratifying the sample according to GRS, FH, and PA. RESULTS: We found that FH, in contrast to GRS, was positively associated with a higher prevalence of T2D (23.4% in patients with positive FH [FH+], 11.6% in those with negative [FH-]; P <0.001), with the association being stronger in men than in women. The prevalence of T2D was slightly lower among physically active individuals in the FH- group (10.6% in high PA vs 14.7% in low PA) as well as in the FH+ group (19.2% in high PA vs 34.0% in low PA), but the differences were not significant. Similar results were found for high and low GRSs. CONCLUSIONS: We confirmed that PA is significantly associated with glucose homeostasis parameters and T2D prevalence, and that this association may be stronger in individuals who are more genetically predisposed to diabetes.

ALK Expression Is a Novel Marker for the WNT-activated Type of Pediatric Medulloblastoma and an Indicator of Good Prognosis for Patients.

ALK gene rearrangements were identified in a variety of cancers, including neuroblastoma, where the presence of ALK expression is associated with adverse prognosis. ALK mutations have recently been found in the pediatric brain tumor medulloblastoma, and microarray data indicate that ALK is highly expressed in a subset of these tumors. Therefore, we investigated whether ALK expression correlates with transcriptional profiles and clinical features of medulloblastoma. Tumors from 116 medulloblastoma patients were studied at diagnosis for the detection of ALK expression at the RNA level by an application of NanoString technology and at the protein level by immunohistochemistry using antibody ALK clone D5F3. The results indicate that ALK expression, at both the RNA and the protein levels, is strongly associated with the WNT-activated type of tumors and therefore may serve as a useful marker for the detection of this type of medulloblastoma. Importantly, ALK protein expression alone is also an indicator of good prognosis for medulloblastoma patients.