MicroRNAs (miRNAs) represent important regulators of gene expression besides transcriptional control. miRNA regulation can be involved in the cell developmental fate decisions, but can also have more ...subtle roles in buffering stochastic fluctuations in gene expression. They participate in pathways fundamental to B-cell development like B-cell receptor (BCR) signalling, B-cell migration/adhesion, cell-cell interactions in immune niches, and the production and class-switching of immunoglobulins. miRNAs influence B-cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells. In this review, we discuss miRNAs with essential functions in malignant B-cell development (such as miR-150, miR-155, miR-21, miR-34a, miR-17-92 and miR-15-16). We also put these miRNAs in the context of normal B-cell differentiation, as this is intimately connected to neoplastic B-cell development. We review miRNAs' role in the most common B-cell malignancies, including chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). We focus on miR-contribution to the regulation of important signalling pathways (such as NF-κB, PI3K/AKT and TGF-β), BCR signalling and its modulators (such as PTEN, SHIP-1, ZAP-70, GAB1 and BTK), anti- and pro-apoptotic proteins (such as BCL2, MCL1, TCL1, BIM, p53 and SIRT1) and transcription factors (such as MYC, MYB, PU.1, FOXP1 and BCL6). We also discuss the association of miRNAs' expression levels with the patients' survival and response to therapy, summarizing their potential use as predictive and prognostic markers. Importantly, the targeting of miRNAs (like use of anti-miR-155 or miR-34a mimic) could provide a novel therapeutic approach as evidenced by tumour regression in xenograft mouse models and initial promising data from clinical trials.
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•Microalgal biofuels may present a sustainable alternative to fossil fuels.•Microalgae convert solar energy to a variety of fuel precurseurs.•Many different types of biofuels, both ...gaseous and liquid, are possible.•Improved sustainability could come from combining production with wastewater treatment.•Further development is required before algal biofuels become practical.
With impending climate change and ever decreasing supplies of easily extractable fossil fuel, means to produce renewable and sustainable replacement fuels are being sought. Plants or algae appear ideal since they can use sunlight to fix CO2 into usable fuel or fuel feedstocks. However, as the world population approaches the 1010 (10 billion) mark, the use of agricultural land to produce fuel instead of food cannot be justified. Microalgal biofuel production is under intense investigation due to its promise as a sustainable, renewable biofuel that can be produced using non-arable land and brackish or non-potable water. Some species accumulate high levels of TAGs (triacylglycerols) that can be converted to fatty acid esters suitable as replacement diesel fuels. However, there are many technical barriers to the practical application of microalgae for biofuel production and thus a number of significant challenges need to be met before microalgal biodiesel production becomes a practical reality. These include developing cost-effective cultivation strategies, low energy requiring harvesting technologies, and energy efficient and sustainable lipid conversion technologies. The large culture volumes that will be necessary dictate that the necessary nutrients come from wastewaters, such as the effluents from secondary treatment of sewage. Economical and energy sparing harvesting will require the development of novel flocculation or floatation strategies and new methods of oil extraction/catalysis that avoid the extensive use of solvents. Recent advances in these critical areas are reviewed and some of the possible strategies for moving forward are outlined.
MicroRNAs (miRNAs) are small RNA molecules, which act as post-transcriptional regulators of a gene expression, with important functions within the cell physiology. Whilst many authors have focused on ...the study of miRNA expression in physiological and pathological processes, various technical variables related to miRNA isolation have simultaneously emerged and the stability of the stored miRNA samples has been questioned. A robust method for RNA isolation is essential for reproducible results and miRNAs instability in the stored samples would make for an alarming situation for most expression studies. Here these issues are discussed and we investigate the stability of miRNAs isolated from clinical samples of B lymphocytes (chronic lymphocytic leukemia) by the most commonly utilized method based on a Trizol/TRI-Reagent solution (RNAs stored at −80
°C). To assess the stability of miRNAs, a Real Time-PCR analysis was performed for a panel of 29 miRNAs from a freshly isolated RNA sample and after 14
days storage at −80
°C. Furthermore, a Real Time-PCR analysis was repeatedly performed for a stored RNA sample over a period of ∼10
months. We observed high stability of isolated miRNAs and respective cDNAs. The reproducibility and efficiency of the Trizol/TRI-Reagent isolation method was also tested and compared to the mirVana Isolation kit (Ambion) and RNeasy kit (Qiagen). In conclusion, Trizol/TRI-Reagent based isolation is a robust reproducible method, and obtained miRNA samples do not show any tendency to degradation when properly stored and handled.
In chronic lymphocytic leukemia (CLL), the worst prognosis is associated with TP53 defects with the affected patients being potentially directed to alternative treatment. Therapy administration was ...shown to drive the selection of new TP53 mutations in CLL. Using ultra-deep next-generation sequencing (NGS), we performed a detailed analysis of TP53 mutations' clonal evolution. We retrospectively analyzed samples that were assessed as TP53-wild-type (wt) by FASAY from 20 patients with a new TP53 mutation detected in relapse and 40 patients remaining TP53-wt in relapse. Minor TP53-mutated subclones were disclosed in 18/20 patients experiencing later mutation selection, while only one minor-clone mutation was observed in those patients remaining TP53-wt (n=40). We documented that (i) minor TP53 mutations may be present before therapy and may occur in any relapse; (ii) the majority of TP53-mutated minor clones expand to dominant clone under the selective pressure of chemotherapy, while persistence of minor-clone mutations is rare; (iii) multiple minor-clone TP53 mutations are common and may simultaneously expand. In conclusion, patients with minor-clone TP53 mutations carry a high risk of mutation selection by therapy. Deep sequencing can shift TP53 mutation identification to a period before therapy administration, which might be of particular importance for clinical trials.
Summary
Objective Fibroblast growth factor‐21 (FGF21) is a novel endocrine and paracrine regulator of metabolic homeostasis. The aim of our study was to measure its serum concentrations in patients ...with obesity, obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C), and to assess the changes of its circulating levels and mRNA expression after dietary and pharmacological interventions.
Design We measured biochemical parameters, serum FGF21, adiponectin, leptin and insulin levels by commercial ELISA and RIA kits, and mRNA expression in the liver, subcutaneous and visceral fat by RT PCR in 26 obese patients, 11 T2DM patients and 32 control subjects. The interventions were acute hyperinsulinaemia during isoglycaemic–hyperinsulinaemic clamp, very low calorie diet (VLCD) and 3 months treatment with PPAR‐α agonist fenofibrate.
Results Baseline serum FGF21 levels were significantly higher in both obese and T2DM patients relative to healthy controls. FGF21 levels in obesity did not significantly differ from T2DM group. Both 3 weeks of VLCD and 3 months of fenofibrate treatment significantly increased FGF21 levels. FGF21 mRNA expression in visceral fat was twofold higher in obesity relative to C group, while it did not differ in subcutaneous fat. VLCD significantly increased FGF21 mRNA expression in subcutaneous fat of obesity. 3‐h hyperinsulinaemia during the clamp increased FGF21 levels in T2DM but not in C group.
Conclusion An increase in FGF21 levels after VLCD and fenofibrate treatment may contribute to positive metabolic effect of these interventions and suggests the possibility of direct positive metabolic effects of FGF21 in humans.
Three different noise moments of field strength, intensity, and their correlations are simultaneously measured. For this purpose a homodyne cross-correlation measurement 1 is implemented by ...superimposing the signal field and a weak local oscillator on an unbalanced beam splitter. The relevant information is obtained via the intensity noise correlation of the output modes. Detection details like quantum efficiencies or uncorrelated dark noise are meaningless for our technique. Yet unknown insight in the quantumness of a squeezed signal field is retrieved from the anomalous moment, correlating field strength with intensity noise. A classical inequality including this moment is violated for almost all signal phases. Precognition on quantum theory is superfluous, as our analysis is solely based on classical physics.
The aim of the present study was to evaluate the expression profile of genes potentially related to metabolic complications of obesity in the whole adipose tissue and isolated adipocytes from ...subcutaneous (SAT) and visceral adipose tissue (VAT) from 12 non-diabetic obese women and 12 lean women. Real-time polymerase chain reaction was used for expression analysis of 41 genes of interest and two housekeeping genes. We found increased expression of specific proinflammatory and adipogenic genes and reduced expression of specific lipogenic and insulin signaling pathway genes in obese relative to lean women with no preferable localization in SAT or VAT depot. The gene expression significantly differed between adipocytes and adipose tissue but both contributed to the proinflammatory profile in obesity. We conclude that both SAT and VAT exhibit alterations in the expression of specific genes possibly contributing to proinflammatory and insulin resistance state and consequently to metabolic complications of obesity.
•Subcutaneous fat of obese exerts a strong chemoattracting profile.•Peripheral monocytes complement this profile with corresponding receptors.•Laparoscopic sleeve gastrectomy reduced systemic ...low-grade inflammation.•LSG improved proinflammatory and chemotactic profile only in SCAT.
Low-grade inflammation links obesity, insulin resistance, and cardiovascular diseases. We investigated the effects of laparoscopic sleeve gastrectomy (LSG) on expression profile of genes involved in inflammatory pathways in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM). At baseline, obese group had significantly increased mRNA expression of proinflammatory chemokines (CCL-3, -17, -22), chemokine receptor CCR1 and cytokines (IL-10, IL-18) in SCAT and chemokine and other proinflammatory receptors (CCR-1, -2, -3, TLR-2, -4) in PM relative to control group. LSG decreased body weight, improved metabolic profile and reduced mRNA expression of up-regulated chemokine receptors, chemokines and cytokines in SCAT. In contrast, expression profiles in PM were largely unaffected by LSG. We conclude that LSG improved proinflammatory profile in subcutaneous fat but not in peripheral monocytes. The sustained proinflammatory and chemotactic profile in PM even 2years after LSG may contribute to partial persistence of metabolic complications in obese patients after metabolic surgery.
Subcutaneous adipose tissue and peripheral monocytes of obese type 2 diabetic patients exert a strong chemoattracting expression profile that is improved after short-term caloric restriction.
...Context:
Low-grade inflammation links obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases.
Objective:
To explore the expression profile of genes involved in inflammatory pathways in adipose tissue and peripheral monocytes (PM) of obese patients with and without T2DM at baseline and after dietary intervention.
Design:
Two-week intervention study with very-low-calorie diet (VLCD).
Setting:
University hospital.
Patients:
Twelve obese females with T2DM, 8 obese nondiabetic females (OB) and 15 healthy age-matched females.
Intervention:
Two weeks of VLCD (2500 kJ/d).
Main Outcome Measures:
Metabolic parameters, circulating cytokines, hormones, and mRNA expression of 39 genes in sc adipose tissue (SCAT) and PM.
Results:
Both T2DM and OB group had significantly increased serum concentrations of circulating proinflammatory factors (C-reactive protein, TNFα, IL-6, IL-8), mRNA expression of macrophage antigen CD68 and proinflammatory chemokines (CCL-2, -3, -7, -8, -17, -22) in SCAT and complementary chemokine receptors (CCR-1, -2, -3, -5) and other proinflammatory receptors (toll-like receptor 2 and 4, TNF receptor superfamily 1A and 1B, IL-6R) in PM, with OB group showing less pronounced chemoattracting and proinflammatory profile compared to T2DM group. In T2DM patients VLCD decreased body weight, improved metabolic profile, and decreased mRNA expression of up-regulated CCRs in PM and chemokines CCL 8, chemokine (C-X-C motif) ligand 10 in SCAT. VLCD markedly increased mRNA expression of T-lymphocyte attracting chemokine CCL-17 in SCAT.
Conclusion:
Obese patients with and without T2DM have increased mRNA expression of chemotactic and proinflammatory factors in SCAT and expression of corresponding receptors in PM. Two weeks of VLCD significantly improved this profile in T2DM patients.
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