372 research outputs found
Mukai varieties as hyperplane sections
No full textLet (M,L) be a smooth (n+1)-dimensional variety polarized by an
ample and spanned line bundle L.
Let A be a smooth member of t the linear system defined by L. Assume that and that
(A,H_A) is a Mukai variety, i.e.,
-K_A=(n-2)H_A for some ample line bundle
H_A on A. Let H be the line bundle on
M which extends H_A. We show that M is a Fano variety and either
H is ample, in which case the cones
of effective 1-cycles
NE(A) and NE(M) on A and M coincide, or \grk(H)=n, H is
semiample and (M,L) has a structure
of a conic fibration.
Then most of the paper is devoted to classify the pair(M,L) in the
case whenL is very
ample
Pharmacological rationale for tapentadol therapy: a review of new evidence
No full textPatrizia Romualdi,1 Mariagrazia Grilli,2 Pier Luigi Canonico,3 Massimo Collino,4 Anthony H Dickenson5 1Department of Pharmacy and Biotechnologies Alma Mater Studiorum, University of Bologna, Bologna 40126, Italy; 2Laboratory of Neuroplasticity, Department Pharmaceutical Sciences, University of Piemonte Orientale, Novara 28100, Italy; 3Departiment of Pharmacological Sciences, University of Piemonte Orientale, Novara 28100, Italy; 4Department of Drug Science and Technology, University of Turin, Turin 10121, Italy; 5Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK Abstract: Chronic pain could be considered as a neurological disorder. Therefore, appropriate selection of the therapy, which should consider the pathophysiological mechanisms of pain, can result in a successful analgesic outcome. Tapentadol is an analgesic drug which acts both as a μ-opioid receptor (MOR) agonist and as a noradrenaline reuptake inhibitor (NRI), thereby generating a synergistic action in terms of analgesic efficacy, but not for the burden of adverse effects. Therefore, tapentadol can be defined as the first “MOR-NRI” drug. This molecule holds the potential to address at least some of the current limitations of analgesic therapy due to its unique mechanism of action and has shown to be safe and effective in the treatment of chronic pain of cancer and noncancer etiologies including nociceptive, neuropathic and mixed pain. In particular, the MOR component of tapentadol activity predominantly allows for analgesia in nociceptive pain; on the other hand, the NRI component contributes, now in a predominant manner, for analgesic efficacy in cases of neuropathic pain states. This paper will discuss recent pieces of evidence on the pathophysiology of pain, the background on tapentadol and then present some new studies on how the unique mechanism of action of tapentadol provides a key role in its analgesic efficacy in a number of pain states and with a favorable safety profile. Keywords: tapentadol, neuropathic pain, pain chronicizatio
Peroxisome Proliferator-Activated Receptors (PPARs) in Glucose Control
No full textThe peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. PPARs regulate gene expression by binding with retinoid X receptor as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated α, β/δ, and γ, have been identified. PPAR-γ was the first isoform demonstrated to affect carbohydrate metabolism and PPAR-γ agonists, the thiazolidinediones, are now in clinical use for the treatment of insulin resistance. Unexpectedly, later studies revealed that also the other two isoforms modulate glucose metabolism. Here we summarize our understanding on how these nuclear receptor isoforms are involved in the control of glucose metabolism, describing some of the novel regulatory mechanisms. In addition, this chapter reviews the evidence and recent developments relating to the role of some foods containing natural compounds as PPAR agonists
Tapentadol: an overview of the safety profile
No full textEnrico Polati,1 Pier Luigi Canonico,2 Vittorio Schweiger,1 Massimo Collino31Anesthesia and Intensive Care, Pain Relief Center, Ospedale Policlinico GB Rossi, Verona, Italy; 2Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara, Italy; 3Department of Drug Science and Technology, University of Turin, Turin, ItalyAbstract: Long-term opioid therapy may be associated with analgesic efficacy and also predictable adverse events, including cardiovascular and pulmonary events, gastrointestinal disorders, endocrinological harms, psychological problems, impairment of driving ability, and risk of abuse. These effects of opioids are mostly due to the wide expression of the mu receptor. Tapentadol, a centrally acting analgesic, is the first agent of a new class of drugs (MOR-NRI), since it combines two mechanisms of action, namely μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. Noteworthy, MOR activation with tapentadol is markedly lower compared with that exerted by classical opioids, thus likely resulting in fewer opioid-related adverse effects. In this review, we discuss current safety data on tapentadol, with a focus on some specific events, risk of abuse, and driving ability, a well-accepted proxy of the ability of taking critical decisions.Keywords: tapentadol, safety, pai
Reducing Cognitive Biases Through Digitally Enabled Training. A Conceptual Framework
No full textSince cognitive biases impair decision-making processes, organizations strive to reduce their effect. Training sustains such effort, especially when innovative learning approaches are adopted. The introduction of digital technologies, such as those related to Industry 4.0, challenges firms to upskill and reskill their employees. At the same time, these technologies offer a new set of tools for training. This paper proposes a conceptual model that disentangles the effect of the form of training and its reliance on digital technological tools, on the reduction of cognitive biases and performance in tasks related to digital transformations
D-Tagatose Feeding Reduces the Risk of Sugar-Induced Exacerbation of Myocardial I/R Injury When Compared to Its Isomer Fructose
No full textIt is known that fructose may contribute to myocardial vulnerability to ischemia/reperfusion (I/R) injury. D-tagatose is a fructose isomer with less caloric value and used as low-calorie sweetener. Here we compared the metabolic impact of fructose or D-tagatose enriched diets on potential exacerbation of myocardial I/R injury. Wistar rats were randomizedly allocated in the experimental groups and fed with one of the following diets: control (CTRL), 30% fructose-enriched (FRU 30%) or 30% D-tagatose-enriched (TAG 30%). After 24 weeks of dietary manipulation, rats underwent myocardial injury caused by 30 min ligature of the left anterior descending (LAD) coronary artery followed by 24 h′ reperfusion. Fructose consumption resulted in body weight increase (49%) as well as altered glucose, insulin and lipid profiles. These effects were associated with increased I/R-induced myocardial damage, oxidative stress (36.5%) and inflammation marker expression. TAG 30%-fed rats showed lower oxidative stress (21%) and inflammation in comparison with FRU-fed rats. Besides, TAG diet significantly reduced plasmatic inflammatory cytokines and GDF8 expression (50%), while increased myocardial endothelial nitric oxide synthase (eNOS) expression (59%). Overall, we demonstrated that D-tagatose represents an interesting sugar alternative when compared to its isomer fructose with reduced deleterious impact not only on the metabolic profile but also on the related heart susceptibility to I/R injury. © Copyright © 2021 Durante, Sgambellone, Lucarini, Failli, Laurino, Collotta, Provensi, Masini and Collino
A Selective IκB Kinase Inhibitor (IKK16) Attenuates The Organ Injury / Dysfunction Associated With Haemorrhagic Shock In The Rat
No full textDUAL SECOND DIMENSION COLUMN-DUAL DETECTION IN TWO-DIMENSIONAL COMPREHENSIVE GAS CHROMATOGRAPHY (GC×2GC-MS/FID): INCREASED INFORMATION IN OPTIMIZED SEPARATION CONDITIONS IN METABOLOMICS
No full textTwo-dimensional comprehensive GC-MS (GC×GC-MS) is the most advanced GC platform, among other, presenting a great potential for metabolomic studies because of its uncomparable separation power, sensitivity and possibility to obtain structured 2D patterns that can be adopted for. GC×GC-MS profiles can successfully be used for samples cross-comparisons to provide more extensive information than with 1D-GC-MS enabling to run simultaneously sample profiling and fingerprinting. However, the great diversity of chemical properties and the wide concentration ranges of these compounds in tissues and biological fluids is a significant challenge since methods need to be robust, reproducible, accurate and informative to enable samples to be reliably compared. In this perspective, the system configuration is a critical but challenging aspect requiring a careful tuning of columns diameters to avoid 2D column overloading and to improve quantitation accuracy and response linearity over a wider range of concentration [1]. This study investigates the advantages of a GC×2GC system in the metabolite profiling of urine samples from murine models of diet-induced metabolic derangements, characterized by hyperlipidemia, impaired glucose tolerance and insulin resistance. [2]. The system consists of a conventional first dimension column (1D - 30 m x 0.25 mm ID) coupled to two second dimension columns of variable lengths (2D-FID 1.6 m x 0.1 mm ID and 2D-MS 1.8 m x 0.1 mm ID) and combined with parallel MS and FID detection. In particular, male C57BL/6J mice were maintained on control rodent diet or high-fat high-fructose diet (HFHF, 45 kcal% Fat and 24 kcal% Fructose) for 22 weeks and urine samples were collected at different steps of the study. Our preliminary results show that urine sample profiles offer pivotal and comparative data on the presence and on the relative distribution of early markers of metabolic disease.
Besides, samples collected at the end of the experiments provide information on the global impact of the dietary manipulation on the systemic metabolism. Experimental results emphasized the advantages of the adopted configuration in terms of quantitation accuracy and precision in targeted profiling, maximization of the informative potentials due to the increased 2D column loadability and selectivity, reliability of untargeted fingerprinting performed by template matching approaches [3] on dual patterns.
References
[1] M.F. Almstetter, P.J. Oefner, K. Dettmer Analytical and Bioanalytical Chemistry 2012;402 (6):1993-2013.
[2] M. Collino, M. Aragno , S. Castiglia, G. Miglio, C. Tomasinelli et al. Br J Pharmacol. 160, 1892-902 (2010)
[3] S.E. Reichenbach, X. Tian , A.A. Boateng, C.A. Mullen , C. Cordero, Q. Tao, Anal Chem
Oncogenic micro-RNAs and Renal Cell Carcinoma
No full textTumor formation is a complex process that occurs in different steps and involves many cell types, including tumor cells, endothelial cells, and inflammatory cells, which interact to promote growth of the tumor mass and metastasization. Epigenetic alterations occurring in transformed cells result in de-regulation of miRNA expression (a class of small non-coding RNA that regulates multiple functions) which contributes to tumorigenesis. The specific miRNAs, which have an aberrant expression in tumors, are defined as oncomiRNAs, and may be either over- or under-expressed, but down-regulation is most commonly observed.Renal cell carcinoma is a frequent form of urologic tumor, associated with an alteration of multiple signaling pathways. Many molecules involved in the progression of renal cell carcinomas, such as HIF, VEGF or mTOR, are possible targets of deregulated miRNAs. Within tumor mass, the cancer stem cell population is a fundamental component that promotes tumor growth. The cancer stem cell hypothesis postulates that cancer stem cells have the unique ability to self-renew and to maintain tumor growth and metastasis. Cancer stem cells present in renal cell carcinoma were shown to express the mesenchymal stem cell marker CD105 and to exhibit self-renewal and clonogenic properties, as well as the ability to generate serially transplantable tumors. The phenotype of cancer stem cell has been related to the potential to undergo the epithelial-mesenchymal transition, which has been linked to the expression pattern of tumorigenic miRNAs or down-regulation of anti-tumor miRNAs. In addition, the pattern of circulating miRNAs may allow discrimination between healthy and tumor patients. Therefore, a miRNA signature may be used as a tumor biomarker for cancer diagnosis, as well as to classify the risk of relapse and metastasis, and for a guide for therapy.<br/
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