334 research outputs found
Deformations of semi-smooth varieties
No full textFor a singular variety X, an essential step to determine its smoothability and study its deformations is the understanding of the tangent sheaf and of the sheaf T-X(1) := epsilon(l)(xt) (Omega(X), O-X). A variety is semi-smooth if its singularities are etale locally the product of a double crossing point (uv = 0) or a pinch point (u(2) - v(2)w = 0) with affine space; equivalently, if it can be obtained by gluing a smooth variety along a smooth divisor via an involution with smooth quotient. Our main result is the explicit computation of the tangent sheaf and the sheaf T(X)1 for a semi-smooth variety X in terms of the gluing data
On the Hilbert scheme of curves in higher-dimensional projective space
No full textIn this paper we prove that, for any n ≥ 3, there exist infinitely many r ∈ N and for each of them a smooth, connected curve Crin ℙrsuch that Crlies on exactly n irreducible components of the Hilbert scheme Hilb(ℙr). This is proven by reducing the problem to an analogous statement for the moduli of surfaces of general type
Automorphisms and moduli spaces of varieties with ample canonical class via deformations of abelian covers
No full textBy a recent result of Viehweg, protective manifolds with ample canonical class have a coarse moduli space, which is a union of quasiprojective varieties. In this paper, we prove that there are manifolds with ample canonical class that lie on arbitrarily many irreducible components of the moduli; moreover, for any finite abelian group G there exist infinitely many components M of the moduli of varieties with ample canonical class such that the generic automorphism group GMis equal to G. In order to construct the examples, we use abelian covers. Let Y be a smooth complex projective variety of dimension ≥ 2. A Galois cover f : X → y whose Galois group is finite and abelian is called an abelian cover of Y; by [Pa1], it is determined by its building data, i.e. by the branch divisors and by some line bundles on Y, satisfying appropriate compatibility conditions. Natural deformations of an abelian cover are also introduced in [Pa1]. In this paper we prove two results about abelian covers: first, that if the building data are sufficiently ample, then the natural deformations surject on the Kuranishi family of X; second, that if the building data are sufficiently ample and generic, then Aut(X) = G. Copyright © 1997 by Marcel Dekker, Inc
The Role of TNF-α in Alzheimer’s Disease: A Narrative Review
No full textThis review analyzes the role of TNF-α and its increase in biological fluids in mild cognitive impairment, and Alzheimer's disease (AD). The potential inhibition of TNF-α with pharmacological strategies paves the way for preventing AD and improving cognitive function in people at risk for dementia. We conducted a narrative review to characterize the evidence in relation to the involvement of TNF-α in AD and its possible therapeutic inhibition. Several studies report that patients with RA and systemic inflammatory diseases treated with TNF-α blocking agents reduce the probability of emerging dementia compared with the general population. Animal model studies also showed interesting results and are discussed. An increasing amount of basic scientific data and clinical studies underscore the importance of inflammatory processes and subsequent glial activation in the pathogenesis of AD. TNF-α targeted therapy is a biologically plausible approach for cognition preservation and further trials are necessary to investigate the potential benefits of therapy in populations at risk of developing AD
Abstract 4431: Urine microRNA profiling in bladder cancer by next-generation sequencing
No full textAbstract
Bladder cancer (BC) is one of the leading causes of cancer-related death worldwide. BC is among the most expensive cancer per patient because it requires frequent surveillance and repeated treatments over many years. The identification of new biomarkers for early BC detection, recurrence/progression is urgently needed to both improve patient outcomes and decrease health care costs. MicroRNAs (miRNAs) are aberrantly expressed in many cancers, including BC, and may be isolated from various biological specimens, including urine. To investigate miRNA signatures in surrogate tissues may be a useful alternative to reduce invasiveness of biopsies, allowing repetitive samplings during follow-up and reducing health care costs for detection, monitoring of progression and treatment. We aim to identify specific miRNA signatures in urine samples from 66 BC male patients (10 muscle invasive BC (MIBC) and 56 non-muscle invasive BC (NMIBC)) and 48 healthy controls using a Next Generation Sequencing (NGS) approach able to accurately distinguish BC patients and predict disease outcome. The measurement of miRNA levels in urine could allow to measure the levels of promising biomarkers in one of the best and closest surrogate tissue for BC, since it is in direct contact with the tissue of tumor origin. A specific miRNA signatures that could distinguish the different types of BC patients from healthy controls was found in urine. For MIBC, a 18-miRNAs signature had over 80% predictive power (PP) to recognize patients from controls (data are under validation). For NMIBC we were able to stratify cases according to grade. In particular, 23 miRNAs resulted differentially expressed among G1-G2 cases and controls (5 of them had PP>0.70), while several miRNAs resulted differentially expressed among G3 patients and controls (a 10-miRNAs signature with PP>0.97). Interestingly, we found several differentially expressed miRNAs in common among cases and some miRNAs that were differentially expressed only in specific subcategories of BC cases. NGS data were also used to search for the most constant miRNAs in the set of samples to be used as reference genes in a validation step. Twenty-three miRNAs (21 target and 2 reference miRNAs) were validated by qPCR on 177 urine samples from 113 BC case and 64 controls . Interestingly, miRNAs differentially expressed among cases and controls were able to discriminate not only BC cases from controls, but also its subcategories. This data provide evidences of the possibility to use miRNAs specifically within the urine of patients with BC as diagnostic, prognostic and predictive biomarkers. Acknowledgements Work supported by Fondazione Umberto Veronesi (FUV) “Post-doctoral fellowship Year 2014, 2015 and 2016” (B.P. recipient), a FUV Grant 2013 (G.M. recipient), and by a HuGeF grant.
Citation Format: Barbara Pardini, Francesca Cordero, Alessio Naccarati, Giulio Ferrero, Clara Viberti, Marco Oderda, Maddalena Arigoni, Raffaele Calogero, Carlotta Sacerdote, Paolo Gontero, Paolo Vineis, Giuseppe Matullo. Urine microRNA profiling in bladder cancer by next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4431. doi:10.1158/1538-7445.AM2017-4431</jats:p
Polymorphisms in mirna-binding sites of nucleotide excision repair genes and colorectal cancer risk
No full textReduced DNA repair capacity and DNA damage accumulation may lead to cancer development. Regulation of and coordination between genes involved in DNA repair pathways is fundamental for maintaining genome stability, and post-transcriptional gene regulation by microRNAs (miRNAs) may therefore be of particular relevance. In this context, the presence of single nucleotide polymorphisms (SNPs) within the 3'untranslated regions of target DNA repair genes could alter the binding with specific miRNAs, modulating gene expression and ultimately affecting cancer susceptibility.In this study, we investigated the role of genetic variations in miRNA-binding sites of nucleotide excision repair (NER) genes in association with colorectal cancer (CRC) risk. From 28 NER genes, we screened among SNPs residing in their 3'untranslated regions and simultaneously located in miRNA-binding sites, with an in silico approach. Through the calculation of different binding free energy according to both alleles of identified SNPs, and with global binding free energies median providing a threshold, we selected nine NER gene variants. We tested those SNPs in 1098 colorectal cancer cases and 1469 healthy controls from the Czech Republic.Rs7356 in RPA2 and rs4596 in GTF2H1 were associated with colorectal cancer risk. After stratification for tumor location, the association of both SNPs was significant only for rectal cancer (rs7356: OR 1.52, 95% CI 1.02-2.26, P = 0.04 and rs4596: OR 0.69, 95% CI 0.50-0.94, P = 0.02; results not adjusted for multiple testing).Variation in miRNA target binding sites in the 3' untranslated region of NER genes may be important for modulating colorectal cancer risk, with a different relevance according to tumor location. © The Author 2012. Published by Oxford University Press. All rights reserved
Intake of Natural Compounds and Circulating microRNA Expression Levels: Their Relationship Investigated in Healthy Subjects With Different Dietary Habits
No full textDiet has a strong influence on many physiological processes, which in turn have important implications on a variety of pathological conditions. In this respect, microRNAs (miRNAs), a class of small non-coding RNAs playing a relevant epigenetic role in controlling gene expression, may represent mediators between the dietary intake and the healthy status. Despite great advances in the field of nutri-epigenomics, it remains unclear how miRNA expression is modulated by the diet and, specifically, the intake of specific nutrients. We investigated the whole circulating miRNome by small RNA-sequencing performed on plasma samples of 120 healthy volunteers with different dietary habits (vegans, vegetarians, and omnivores). Dietary intakes of specific nutrients were estimated for each subject from the information reported in the food-frequency questionnaire previously validated in the EPIC study. We focused hereby on the intake of 23 natural compounds (NCs) of the classes of lipids, micro-elements, and vitamins. We identified 78 significant correlations (rho > 0.300, p-value < 0.05) among the estimated daily intake of 13 NCs and the expression levels of 58 plasma miRNAs. Overall, vitamin D, sodium, and vitamin E correlated with the largest number of miRNAs. All the identified correlations were consistent among the three dietary groups and 22 of them were confirmed as significant (p-value < 0.05) by age-, gender-, and body-mass index-adjusted Generalized Linear regression Model analysis. miR-23a-3p expression levels were related with different NCs including a significant positive correlation with sodium (rho = 0.377) and significant negative correlations with lipid-related NCs and vitamin E. Conversely, the estimated intake of vitamin D was negatively correlated with the expression of the highest number of circulating miRNAs, particularly miR-1277-5p (rho = −0.393) and miR-144-3p (rho = −0.393). Functional analysis of the targets of sodium intake-correlated miRNAs highlighted terms related to cardiac development. A similar approach on targets of those miRNAs correlated with vitamin D intake showed an enrichment in genes involved in hormone metabolisms, while the response to chronic inflammation was among the top enriched processes involving targets of miRNAs negatively related with vitamin E intake. Our findings show that nutrients through the habitual diet influence circulating miRNA profiles and highlight that this aspect must be considered in the nutri-epigenomic research
Set-up experiments for microRNAs characterization in plasma and circulating tumor cells derived from patients with cutaneous melanoma
No full textMalignant melanoma is among the most lethal of the cutaneous neoplasms with a 5-year survival of 6% and a median
survival of 7.5 months for patients in the later stage of the disease (Luke and Ott, 2014). Acquired resistance may limit the
therapeutic potential of currently used drugs (Tronnier et al., 2013, Shtivelman et al., 2014) and novel biomarkers may help
clinicians tailor cancer treatments. The present study was aimed at the isolation and characterization of microRNAs
(miRNAs) derived from plasma and circulating tumor cells (CTCs) as a non-invasive approach to investigate the changing
patterns of drug susceptibility in individual patients. Twenty candidate biomarker miRNAs were selected among those that
play a role in cell cycle, survival, proliferation and invasion (Segura et al., 2014). The study received the approval of the
local Ethics Committee. Blood samples were collected from healthy volunteers and patients with melanoma at different
disease stages (I-IV). Plasma miRNAs were isolated by miRNeasy Serum/Plasma Kit (Qiagen). Before isolating
disseminated circulating tumor cells from melanoma patients, set-up experiments were preliminary carried out in samples
enriched with cells derived from the A375 human melanoma cell line. We tested an immunomagnetic technique using the
antibody mouse anti-MCSP (Melanoma Chonidroitin Sulfate Proteoglycane) conjugated to magnetic beads (CELLection
Pan Mouse IgG Kita, Invitrogen) and a system based on the cell separation by density gradient centrifugation (OncoQuick,
Greiner Bio-One, Germany). Although immunomagnetic method is commonly used for CTC isolation, we demonstrated by
confocal microscopy that seeding dilutions of A375 into normal blood (10 cells per ml) resulted in consistent loss of cells
during the immunobead procedure. This was probably due to a scarcity of tumor cells associated to an excessive cell stress
during erythrocyte lysis and magnetic separation. At variance with this, cell separation by density gradient centrifugation
allowed us to obtain a detectable A375 cells in samples containing only 4 cells per ml of blood (30 cells total).
Quantification by Real-Time PCR of the expression levels of selected plasma-derived and CTC-associated miRNAs in
patients with metastatic melanoma before and after drug treatment is in progress.
REFERENCES
Luke J.J. and Ott. P.A. (2014) Drug, healthcare and patient safety 6: 77–88.
Tronnier M., Semkova K., Wollina U. et al. (2013) Wien Med Wochenschr 163: 354-8
Shtivelman E., M.A., Hwu P., et al. (2014) Oncotarget 5: 1701–1752.
Segura M.F., Greenwald H.S., Hanniford D., et al. (2014) Carcinogenesis 33: 1823–32.
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Birational geometry and moduli spaces
No full textThis volume collects contributions from speakers at the INdAM Workshop “Birational Geometry and Moduli Spaces”, which was held in Rome on 11–15 June 2018. The workshop was devoted to the interplay between birational geometry and moduli spaces and the contributions of the volume reflect the same idea, focusing on both these areas and their interaction. In particular, the book includes both surveys and original papers on irreducible holomorphic symplectic manifolds, Severi varieties, degenerations of Calabi-Yau varieties, uniruled threefolds, toric Fano threefolds, mirror symmetry, canonical bundle formula, the Lefschetz principle, birational transformations, and deformations of diagrams of algebras. The intention is to disseminate the knowledge of advanced results and key techniques used to solve open problems. The book is intended for all advanced graduate students and researchers interested in the new research frontiers of birational geometry and moduli spaces
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