Is Macronutrients Intake a Challenge for Cardiometabolic Risk in Obese Adolescents?

(1) Background: Pediatric obesity is an emerging public health issue, mainly related to western diet. A cross-sectional study was conducted to explore the association between macronutrients intake and cardiometabolic risk factors in obese adolescents. (2) Methods: Ninety-three Italian obese adolescents were recruited; anthropometric parameters, body composition, glucose and lipid metabolism profiles were measured. Macronutrients intake was estimated by a software-assisted analysis of a 120-item frequency questionnaire. The association between macronutrients and cardiometabolic risk factors was assessed by bivariate correlation, and multiple regression analysis was used to adjust for confounders such as age and sex. (3) Results: By multiple regression analysis, we found that higher energy and lower carbohydrate intakes predicted higher body mass index (BMI) z-score, p = 0.005, and higher saturated fats intake and higher age predicted higher HOmeostasis Model Assessment of insulin resistance (HOMA-IR) and lower QUantitative Insulin-sensitivity ChecK (QUICK) index, p = 0.001. In addition, a saturated fats intake <7% was associated with normal HOMA-IR, and a higher total fats intake predicted a higher HOMA of percent \u3b2-cell function (HOMA-\u3b2), p = 0.011. (4) Conclusions: Higher energy intake and lower carbohydrate dietary intake predicted higher BMI z-score after adjustment for age and sex. Higher total and saturated fats dietary intakes predicted insulin resistance, even after adjustment for confounding factors. A dietary pattern including appropriate high-quality carbohydrate and reduced saturated fat intakes could result in reduced cardiometabolic risk in obese adolescents

Further phenotypic heterogeneity of CoQ10 deficiency associated with Steroid Resistant Nephrotic Syndrome and novel COQ2 and COQ6 variants.

open16noWe descripe three patients with SRNS associated with pathogentic changes in two CoQ pathway genes: one novel homozygous COQ2 variant was identified in two cousins with adolescent-onset SRNS and mild neurological symptoms (Family 1); and one novel COQ6 variant was found in a child with early onset SRNS without deafness and neurological involvement (Family 2). (A, B) : families (C) : Sanger sequencing showing COQ2 change: NM_015697.7: c.1169G>C; NP_056512.5; p.Gly390Ala (c.1019G>C; p.Gly340Ala, according to KU877220 GenBank sequence) (D) : Sanger sequencing showing COQ6 change: NM_182476.2:c.782C>T; NP_872282.1:p.Pro261Leu. (E, F): Functional complementation in yeast. Serial dilutions of ΔCOQ2 and ΔCOQ6 yeast transformed with wild-type, the empty vector and the mutant alleles; complex II+III (C.II+C.III) and citrate synthase (CS) activities.embargoed_20180801Gigante, M; Diella, S; Santangelo, L; Trevisson, Eva; Acosta, Mj; Amatruda, M; Finzi, G; Caridi, G; Murer, L; Accetturo, M; Ranieri, E; Ghiggeri, Gm; Giordano, M; Grandaliano, G; Salviati, Leonardo; Gesualdo, L.Gigante, M; Diella, S; Santangelo, L; Trevisson, Eva; Acosta, Mj; Amatruda, M; Finzi, G; Caridi, G; Murer, L; Accetturo, M; Ranieri, E; Ghiggeri, Gm; Giordano, M; Grandaliano, G; Salviati, Leonardo; Gesualdo, L

Neutrophil C5a receptor and the outcome in a rat model of sepsis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154259/1/fsb2fj030009fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154259/2/fsb2fj030009fje-sup-0001.pd

Papillary thyroid cancer associated with syndrome of inappropriate antidiuresis: a case report

<p>Abstract</p> <p>Introduction</p> <p>The syndrome of inappropriate antidiuresis is the most common cause of euvolemic hypo-osmolality. This syndrome is associated with a wide variety of diseases. However, its most frequent causes are related to malignancies, especially lung cancer. In this case report, we describe an unknown association of the syndrome of inappropriate antidiuresis with papillary thyroid cancer.</p> <p>Case presentation</p> <p>We present the case of a 71-year-old Caucasian, German woman with marked hyponatremia and neurological symptoms. After a detailed clinical investigation, the common causes of syndrome of inappropriate antidiuresis and other malignancies were ruled out. A thyroid nodule was detected by ultrasound and magnetic resonance imaging. Although fine needle aspiration cytology showed negative results, our patient underwent surgery. Papillary thyroid cancer was later diagnosed. After total thyroidectomy, a complete remission of the clinical symptoms occurred and our patient subsequently had iodine-131 radioactive therapy. Hyponatremia was no longer observed during the follow-up investigations.</p> <p>Conclusion</p> <p>This is the first reported case of paraneoplastic syndrome of inappropriate antidiuresis caused by papillary thyroid carcinoma. Since its symptoms occurred before the development of local symptoms, total thyroidectomy may provide a timely and efficient treatment for the underlying malignancy.</p

Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma.

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy

Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy. Ewing sarcoma is characterized by the fusion of EWSR1 and FLI1. Here, the authors show that EWSR1-FLI1 increases the activity of the developmental transcription factor SOX6, which promotes tumor growth but also increases sensitivity to oxidative stress

CapZ-lipid membrane interactions: a computer analysis

BACKGROUND: CapZ is a calcium-insensitive and lipid-dependent actin filament capping protein, the main function of which is to regulate the assembly of the actin cytoskeleton. CapZ is associated with membranes in cells and it is generally assumed that this interaction is mediated by polyphosphoinositides (PPI) particularly PIP(2), which has been characterized in vitro. RESULTS: We propose that non-PPI lipids also bind CapZ. Data from computer-aided sequence and structure analyses further suggest that CapZ could become partially buried in the lipid bilayer probably under mildly acidic conditions, in a manner that is not only dependent on the presence of PPIs. We show that lipid binding could involve a number of sites that are spread throughout the CapZ molecule i.e., alpha- and beta-subunits. However, a beta-subunit segment between residues 134–151 is most likely to be involved in interacting with and inserting into lipid membrane due to a slighly higher ratio of positively to negatively charged residues and also due to the presence of a small hydrophobic helix. CONCLUSION: CapZ may therefore play an essential role in providing a stable membrane anchor for actin filaments

A Novel Xenograft Model in Zebrafish for High-Resolution Investigating Dynamics of Neovascularization in Tumors

Tumor neovascularization is a highly complex process including multiple steps. Understanding this process, especially the initial stage, has been limited by the difficulties of real-time visualizing the neovascularization embedded in tumor tissues in living animal models. In the present study, we have established a xenograft model in zebrafish by implanting mammalian tumor cells into the perivitelline space of 48 hours old Tg(Flk1:EGFP) transgenic zebrafish embryos. With this model, we dynamically visualized the process of tumor neovascularization, with unprecedented high-resolution, including new sprouts from the host vessels and the origination from VEGFR2+ individual endothelial cells. Moreover, we quantified their contributions during the formation of vascular network in tumor. Real-time observations revealed that angiogenic sprouts in tumors preferred to connect each other to form endothelial loops, and more and more endothelial loops accumulated into the irregular and chaotic vascular network. The over-expression of VEGF165 in tumor cells significantly affected the vascularization in xenografts, not only the number and size of neo-vessels but the abnormalities of tumor vascular architecture. The specific inhibitor of VEGFR2, SU5416, significantly inhibited the vascularization and the growth of melanoma xenografts, but had little affects to normal vessels in zebrafish. Thus, this zebrafish/tumor xenograft model not only provides a unique window to investigate the earliest events of tumoral neoangiogenesis, but is sensitive to be used as an experimental platform to rapidly and visually evaluate functions of angiogenic-related genes. Finally, it also offers an efficient and cost-effective means for the rapid evaluation of anti-angiogenic chemicals

Zebrafish usp39 Mutation Leads to rb1 mRNA Splicing Defect and Pituitary Lineage Expansion

Loss of retinoblastoma (Rb) tumor suppressor function is associated with human malignancies. Molecular and genetic mechanisms responsible for tumorigenic Rb downregulation are not fully defined. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish ubiquitin specific peptidase 39 (usp39) mutation, the yeast and human homolog of which encodes a component of RNA splicing machinery. Zebrafish usp39 mutants exhibit microcephaly and adenohypophyseal cell lineage expansion without apparent changes in major hypothalamic hormonal and regulatory signals. Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130), and cdkn1a (p21) expression. Rb1 mRNA overexpression, or antisense morpholino knockdown of e2f4, partially reversed embryonic pituitary expansion in usp39 mutants. Analysis of pre-mRNA splicing status of critical cell cycle regulators showed misspliced Rb1 pre-mRNA resulting in a premature stop codon. These studies unravel a novel mechanism for rb1 regulation by a neuronal mRNA splicing factor, usp39. Zebrafish usp39 regulates embryonic pituitary homeostasis by targeting rb1 and e2f4 expression, respectively, contributing to increased adenohypophyseal sensitivity to these altered cell cycle regulators. These results provide a mechanism for dysregulated rb1 and e2f4 pathways that may result in pituitary tumorigenesis

Signaling pathways downstream of P2 receptors in human neutrophils

Extracellular nucleotides stimulate human neutrophils by activating the purinergic P2Y2 receptor. However, it is not completely understood which types of G proteins are activated downstream of this P2 receptor subtype. We investigated the G-protein coupling to P2Y2 receptors and several subsequent signaling events. Treatment of neutrophils with pertussis toxin (PTX), a Gi protein inhibitor, caused only ∼75% loss of nucleotide-induced Ca2+ mobilization indicating that nucleotides cause Ca2+ mobilization both through Gi-dependent and Gi-independent pathways. However, the PLC inhibitor U73122 almost completely inhibited Ca2+ mobilization in both nucleotide- and fMLP-stimulated neutrophils, strongly supporting the view that both the PTX-sensitive and the PTX-insensitive mechanism of Ca2+ increase require activation of PLC. We investigated the dependence of ERK phosphorylation on the Gi pathway. Treatment of neutrophils with PTX caused almost complete inhibition of ERK phosphorylation in nucleotide or fMLP activated neutrophils. U73122 caused inhibition of nucleotide- or fMLP-stimulated ERK phosphorylation, suggesting that although pertussis toxin-insensitive pathways cause measurable Ca2+ mobilization, they are not sufficient for causing ERK phosphorylation. Since PLC activation leads to intracellular Ca2+ increase and PKC activation, we investigated if these intracellular events are necessary for ERK phosphorylation. Exposure of cells to the Ca2+ chelator BAPTA had no effect on nucleotide- or fMLP-induced ERK phosphorylation. However, the PKC inhibitor GF109203X was able to almost completely inhibit nucleotide- or fMLP-induced ERK phosphorylation. We conclude that the P2Y2 receptor can cause Ca2+ mobilization through a PTX-insensitive but PLC-dependent pathway and ERK phosphorylation is highly dependent on activation of the Gi proteins