Yanachkova M; Xu W-C; Dvoskin S; Dix E; Yanachkov I; Savi L; Focher F; Sanchez M; Foster T; Wright G
Prodrugs of herpes simplex thymidine kinase inhibitors. Journal Article
In: Antiviral Chemistry & Chemotherapy, 24 (2), pp. 47-55, 2015.
Background: Because guanine-based HSV thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent HSV-1 reactivation from latency in a mouse model. Methods: Organic synthesis was used to prepare compounds, HPLC to analyze hydrolytic conversion, MS to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug.
Results: Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovirTM (6-deoxy- mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N2-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of HSV-1 latent mice with sacrovirTM in 1 % Soluplus in drinking water significantly suppressed HSV-1 reactivation and viral genomic replication.Conclusions: Ad libitum oral delivery of sacrovirTM was effective in suppressing HSV-1 reactivation in ocularly-infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia (TG) positive for infectious virus, number of corneas that had detectable infectious virus, and HSV-1 genome copy numbers in TG following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing HSV-1 reactivation in vivo.
Bavelloni A; Piazzi M; Raffini M; Faenza I; Blalock WL
Prohibitin 2: At a communications crossroads. Journal Article
In: IUBMB Life, 67 (4), pp. 239-254, 2015.
Prohibitins (PHBs) are a highly conserved class of proteins first discovered as inhibitors of cellular proliferation. Since then PHBs have been found to have a significant role in transcription, nuclear signaling, mitochondrial structural integrity, cell division, and cellular membrane metabolism, placing these proteins among the key regulators of pathologies such as cancer, neuromuscular degeneration, and other metabolic diseases. The human genome encodes two PHB proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2), which function not only as a heterodimeric complex, but also independently. While many previous reviews have focused on the better characterized prohibitin, PHB1, this review focuses on PHB2 and new data concerning its cellular functions both in complex with PHB1 and independent of PHB1. 2015 International Union of Biochemistry and Molecular Biology.
Lanzafame M; Botta E; Teson M; Fortugno P; Zambruno G; Stefanini M; Orioli D
In: Experimental Dermatology, 24 (4), 2015.
Abnormalities in keratinocyte growth and differentiation have a pathogenic significance in many skin disorders and result in gene expression alterations detectable by quantitative real-time RT-PCR (qRT-PCR). Relative quantification based on endogenous control (EC) genes is the commonly adopted approach, and the use of multiple reference genes from independent pathways is considered a best practice guideline, unless fully validated EC genes are available. The literature on optimal reference genes during in vitro calcium-induced differentiation of normal human epidermal keratinocytes (NHEK) is inconsistent. In many studies, the expression of target genes is compared to that of housekeeping genes whose expression, however, significantly varies during keratinocyte differentiation. Here, we report the results of our investigations on the expression stability of 15 candidate EC genes, including those commonly used as reference in expression analysis by qRT-PCR, during NHEK calcium-induced differentiation. We demonstrate that YWHAZ and UBC are extremely stable genes, and therefore, they represent optimal EC genes for expression studies in proliferating and calcium-induced differentiating NHEK. Furthermore, we demonstrate that YWHAZ/14-3-3-zeta is a suitable reference for quantitative comparison of both transcript and protein levels. 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Brambati A; Colosio A; Zardoni L; Galanti L; Liberi G
In: Frontiers in Genetics, 6 , pp. 166, 2015.
DNA replication and transcription are vital cellular processes during which the genetic information is copied into complementary DNA and RNA molecules. Highly complex machineries required for DNA and RNA synthesis compete for the same DNA template, therefore being on a collision course. Unscheduled replication-transcription clashes alter the gene transcription program and generate replication stress, reducing fork speed. Molecular pathways and mechanisms that minimize the conflict between replication and transcription have been extensively characterized in prokaryotic cells and recently identified also in eukaryotes. A pathological outcome of replication-transcription collisions is the formation of stable RNA:DNA hybrids in molecular structures called R-loops. Growing evidence suggests that R-loop accumulation promotes both genetic and epigenetic instability, thus severely affecting genome functionality. In the present review, we summarize the current knowledge related to replication and transcription conflicts in eukaryotes, their consequences on genome stability and the pathways involved in their resolution. These findings are relevant to clarify the molecular basis of cancer and neurodegenerative diseases.
Cea V; Cipolla L; Sabbioneda S
In: Frontiers in Genetics, 6 , pp. 209, 2015.
DNA replication is an extremely risky process that cells have to endure in order to correctly duplicate and segregate their genome. This task is particularly sensitive to DNA damage and multiple mechanisms have evolved to protect DNA replication as a block to the replication fork could lead to genomic instability and possibly cell death. The DNA in the genome folds, for the most part, into the canonical B-form but in some instances can form complex secondary structures such as G-quadruplexes (G4). These G rich regions are thermodynamically stable and can constitute an obstacle to DNA and RNA metabolism. The human genome contains more than 350,000 sequences potentially capable to form G-quadruplexes and these structures are involved in a variety of cellular processes such as initiation of DNA replication, telomere maintenance and control of gene expression. Only recently, we started to understand how G4 DNA poses a problem to DNA replication and how its successful bypass requires the coordinated activity of ssDNA binding proteins, helicases and specialized DNA polymerases. Their role in the resolution and replication of structured DNA crucially prevents both genetic and epigenetic instability across the genome.
Manfrini N; Clerici M; Wery M; Colombo CV; Descrimes M; Morillon A; d'Adda di Fagagna F; Longhese MP
In: Elife, 4 , 2015.
Emerging evidence indicate that the mammalian checkpoint kinase ATM induces transcriptional silencing in cis to DNA double-strand breaks (DSBs) through a poorly understood mechanism. Here we show that in Saccharomyces cerevisiae a single DSB causes transcriptional inhibition of proximal genes independently of Tel1/ATM and Mec1/ATR. Since the DSB ends undergo nucleolytic degradation (resection) of their 5′-ending strands, we investigated the contribution of resection in this DSB-induced transcriptional inhibition. We discovered that resection-defective mutants fail to stop transcription around a DSB, and the extent of this failure correlates with the severity of the resection defect. Furthermore, Rad9 and generation of γH2A reduce this DSB-induced transcriptional inhibition by counteracting DSB resection. Therefore, the conversion of the DSB ends from double-stranded to single-stranded DNA, which is necessary to initiate DSB repair by homologous recombination, is responsible for loss of transcription around a DSB in S. cerevisiae.
Manfrini N; Trovesi C; Wery M; Martina M; Cesena D; Descrimes M; Morillon A; d'Adda di Fagagna F; Longhese MP
In: Embo Reports, 16 (2), pp. 221-231, 2015.
Eukaryotic cells respond to DNA double-strand breaks (DSBs) by activating a checkpoint that depends on the protein kinases Tel1/ATM and Mec1/ATR. Mec1/ATR is activated by RPA-coated single-stranded DNA (ssDNA), which arises upon nucleolytic degradation (resection) of the DSB. Emerging evidences indicate that RNA-processing factors play critical, yet poorly understood, roles in genomic stability. Here, we provide evidence that the Saccharomyces cerevisiae RNA decay factors Xrn1, Rrp6 and Trf4 regulate Mec1/ATR activation by promoting generation of RPA-coated ssDNA. The lack of Xrn1 inhibits ssDNA generation at the DSB by preventing the loading of the MRX complex. By contrast, DSB resection is not affected in the absence of Rrp6 or Trf4, but their lack impairs the recruitment of RPA, and therefore of Mec1, to the DSB. Rrp6 and Trf4 inactivation affects neither Rad51/Rad52 association nor DSB repair by homologous recombination (HR), suggesting that full Mec1 activation requires higher amount of RPA-coated ssDNA than HR-mediated repair. Noteworthy, deep transcriptome analyses do not identify common misregulated gene expression that could explain the observed phenotypes. Our results provide a novel link between RNA processing and genome stability. 2014 The Authors.
Frisone P; Pradella D; Di Matteo A; Belloni E; Ghigna C; Paronetto MP
SAM68: Signal Transduction and RNA Metabolism in Human Cancer. Journal Article
In: Biomed Research International, 2015 , pp. 528954, 2015.
Alterations in expression and/or activity of splicing factors as well as mutations in cis-acting splicing regulatory sequences contribute to cancer phenotypes. Genome-wide studies have revealed more than 15,000 tumor-associated splice variants derived from genes involved in almost every aspect of cancer cell biology, including proliferation, differentiation, cell cycle control, metabolism, apoptosis, motility, invasion, and angiogenesis. In the past decades, several RNA binding proteins (RBPs) have been implicated in tumorigenesis. SAM68 (SRC associated in mitosis of 68 kDa) belongs to the STAR (signal transduction and activation of RNA metabolism) family of RBPs. SAM68 is involved in several steps of mRNA metabolism, from transcription to alternative splicing and then to nuclear export. Moreover, SAM68 participates in signaling pathways associated with cell response to stimuli, cell cycle transitions, and viral infections. Recent evidence has linked this RBP to the onset and progression of different tumors, highlighting misregulation of SAM68-regulated splicing events as a key step in neoplastic transformation and tumor progression. Here we review recent studies on the role of SAM68 in splicing regulation and we discuss its contribution to aberrant pre-mRNA processing in cancer.
Magrassi L; Aromataris G; Cabrini A; Annovazzi-Lodi V; Moro A
In: Proceedings of the National Academy of Sciences of the United States of America, 112 (6), pp. 1868-1873, 2015.
How language is encoded by neural activity in the higher-level language areas of humans is still largely unknown. We investigated whether the electrophysiological activity of Broca’s area correlates with the sound of the utterances produced. During speech perception, the electric cortical activity of the auditory areas correlates with the sound envelope of the utterances. In our experiment, we compared the electrocorticogram recorded during awake neurosurgical operations in Broca’s area and in the dominant temporal lobe with the sound envelope of single words versus sentences read aloud or mentally by the patients. Our results indicate that the electrocorticogram correlates with the sound envelope of the utterances, starting before any sound is produced and even in the absence of speech, when the patient is reading mentally. No correlations were found when the electrocorticogram was recorded in the superior parietal gyrus, an area not directly involved in language generation, or in Broca’s area when the participants were executing a repetitive motor task, which did not include any linguistic content, with their dominant hand. The distribution of suprathreshold correlations across frequencies of cortical activities varied whether the sound envelope derived from words or sentences. Our results suggest the activity of language areas is organized by sound when language is generated before any utterance is produced or heard.
Meena JK; Cerutti A; Beichler C; Morita Y; Bruhn C; Kumar M; Kraus JM; Speicher MR; Wang ZQ; Kestler HA; d'Adda di Fagagna F; Günes C; Rudolph KL
In: Embo Journal, 34 (10), pp. 1371-1384, 2015.
The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb-dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase-deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy-induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction. 2015 The Authors.
Arseni L; Lanzafame M; Compe E; Fortugno P; Afonso-Barroso A; Peverali FA; Lehmann AR; Zambruno G; Egly JM; Stefanini M; Orioli D
In: Proceedings of the National Academy of Sciences of the United States of America, 112 (5), pp. 1499-1504, 2015.
Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in distinct clinical entities, including the cancer-prone xeroderma pigmentosum (XP) and the multisystem disorder trichothiodystrophy (TTD), which share only cutaneous photosensitivity. Gene-expression profiles of primary dermal fibroblasts revealed overexpression of matrix metalloproteinase 1 (MMP-1), the gene encoding the metalloproteinase that degrades the interstitial collagens of the extracellular matrix (ECM), in TTD patients mutated in XPD compared with their healthy parents. The defect is observed in TTD and not in XP and is specific for fibroblasts, which are the main producers of dermal ECM. MMP-1 transcriptional up-regulation in TTD is caused by an erroneous signaling mediated by retinoic acid receptors on the MMP-1 promoter and leads to hypersecretion of active MMP-1 enzyme and degradation of collagen type I in the ECM of cell/tissue systems and TTD patient skin. In agreement with the well-known role of ECM in eliciting signaling events controlling cell behavior and tissue homeostasis, ECM alterations in TTD were shown to impact on the migration and wound-healing properties of patient dermal fibroblasts. The presence of a specific inhibitor of MMP activity was sufficient to restore normal cell migration, thus providing a potential approach for therapeutic strategies. This study highlights the relevance of ECM anomalies in TTD pathogenesis and in the phenotypic differences between TTD and XP.
Giampietro C; Deflorian G; Gallo S; Di Matteo A; Pradella D; Bonomi S; Belloni E; Nyqvist D; Quaranta V; Confalonieri S; Bertalot G; Orsenigo F; Pisati F; Ferrero E; Biamonti G; Fredrickx E; Taveggia C; Wyatt CD; Irimia M; Di Fiore PP; Blencowe BJ; Dejana E; Ghigna C
In: Nature communications, 6 , pp. 8479, 2015.
Vascular lumen formation is a fundamental step during angiogenesis; yet, the molecular mechanisms underlying this process are poorly understood. Recent studies have shown that neural and vascular systems share common anatomical, functional and molecular similarities. Here we show that the organization of endothelial lumen is controlled at the post-transcriptional level by the alternative splicing (AS) regulator Nova2, which was previously considered to be neural cell-specific. Nova2 is expressed during angiogenesis and its depletion disrupts vascular lumen formation in vivo. Similarly, Nova2 depletion in cultured endothelial cells (ECs) impairs the apical distribution and the downstream signalling of the Par polarity complex, resulting in altered EC polarity, a process required for vascular lumen formation. These defects are linked to AS changes of Nova2 target exons affecting the Par complex and its regulators. Collectively, our results reveal that Nova2 functions as an AS regulator in angiogenesis and is a novel member of the 'angioneurins' family.
Casey SC; Vaccari M; Al-Mulla F; Al-Temaimi R; Amedei A; Barcellos-Hoff MH; Brown DG; Chapellier M; Christopher J; Curran C; Forte S; Hamid RA; Heneberg P; Koch DC; Krishnakumar PK; Laconi E; Maguer-Satta V; Marongiu F; Memeo L; Mondello C; Raju J; Roman J; Roy R; Ryan EP; Ryeom S; Salem HK; Scovassi AI; Singh N; Soucek L; Vermeulen L; Whitfield JR; Woodrick J; Colacci A; Bisson WH; Felsher DW
In: Carcinogenesis, 36 (Suppl. 1), pp. S160-183, 2015.
Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis. The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Ochieng J; Nangami GN; Ogunkua O; Miousse IR; Koturbash I; Odero-Marah V; McCawley L; Nangia-Makker P; Ahmed N; Luqmani Y; Chen Z; Papagerakis S; Wolf GT; Dong C; Zhou BP; Brown DG; Colacci A; Hamid RA; Mondello C; Raju J; Ryan EP; Woodrick J; Scovassi I; Singh N; Vaccari M; Roy R; Forte S; Memeo L; Salem HK; Amedei A; Al-Temaimi R; Al-Mulla F; Bisson WH; Eltom SE
In: Carcinogenesis, 36 (Suppl. 1), pp. S128-159, 2015.
The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis. The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.
Bavagnoli L; Cucuzza S; Campanini G; Rovida F; Paolucci S; Baldanti F; Maga G
In: Nucleic Acids Research, 43 (19), pp. 9405-9417, 2015.
The PA protein of Influenza A virus (IAV) encoded by segment 3 acts as a specialized RNA endonuclease in the transcription of the viral genome. The same genomic segment encodes for a second shorter protein, termed PA-X, with the first 191 N-terminal aminoacids (aa) identical to PA, but with a completely different C-ter domain of 61 aa, due to a ribosomal frameshifting. In addition, it has been shown that several IAV isolates encode for a naturally truncated PA-X variant, PAXΔC20, missing the last 20 aa. The biochemical properties of PA-X and PAXΔC20 have been poorly investigated so far. Here, we have carried out an enzymatic characterization of PA-X and its naturally deleted form, in comparison with PA from the human IAV strain A/WSN/33 (H1N1). Our results showed, to the best of our knowledge for the first time, that PA-X possesses an endonucleolytic activity. Both PA and PA-X preferentially cut single stranded RNA regions, but with some differences. In addition, we showed that PAXΔC20 has severely reduced nuclease activity. These results point to a previously undetected role of the last C-ter 20 aa for the catalytic activity of PA-X and support distinct roles for these proteins in the viral life cycle. The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
Engstrom W; Darbre P; Eriksson S; Gulliver L; Hultman T; Karamouzis MV; Klaunig JE; Mehta R; Moorwood K; Sanderson T; Sone H; Vadgama P; Wagemaker G; Ward A; Singh N; Al-Mulla F; Al-Temaimi R; Amedei A; Colacci AM; Vaccari M; Mondello C; Scovassi AI; Raju J; Hamid RA; Memeo L; Forte S; Roy R; Woodrick J; Salem HK; Ryan E; Brown DG; Bisson WH
In: Carcinogenesis, 36 (Suppl. 1), pp. S38-60, 2015.
The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.
Kato N; Loh M; et al
In: Nature Genetics, 47 (11), 2015.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10-11 to 5.0 × 10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
D'Auria F; Centurione L; Centurione MA; Angelini A; Di Pietro R
In: Journal of Cellular Biochemistry, 116 (11), pp. 2427-2434, 2015.
"Shear stress is determined by three physical components described in a famous triad: blood flow, blood viscosity and vessel geometry. Through the direct action on endothelium, shear stress is able to radically interfere with endothelial properties and the physiology of the vascular wall. Endothelial cells (ECs) have also to sustain biochemical stresses represented by chemokines, growth factors, cytokines, complement, hormones, nitric oxide (NO), oxygen and reactive oxygen species (ROS). Many growth factors, cytokines, chemokines, hormones, and chemical substances, like NO, act and regulate endothelium functions and homeostasis. Among these cytokines Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) has been assigned a regulatory role in ECs physiology and physiopathology. Thus, the aim of this review is to provide a general overview of the endothelial response pathways after different types of biomechanical and biochemical stress in in vitro models and to analyze the crucial role of TRAIL under pathological conditions of the cardiocirculatory system like atherosclerosis, coronary artery disease, and diabetes. 2015 Wiley Periodicals, Inc.
Spallarossa A; Caneva C; Caviglia M; Alfei S; Butini S; Campiani G; Gemma S; Brindisi M; Zisterer DM; Bright SA; Williams CD; Crespan E; Maga G; Sanna G; Delogu I; Collu G; Loddo R
In: European Journal of Medicinal Chemistry, 102 , pp. 648-660, 2015.
A new series of indole-based analogues were recently identified as potential anticancer agents. The Knoevenagel-type indoles herein presented were prepared via a one-pot condensation of iminium salts with active methylene reagents and were isolated as single geometric isomers. Biological evaluation in different cell-based assays revealed an antiproliferative activity for some analogues already in the nanomolar range against leukaemia, breast and renal cancer cell lines. To explain these effects, the most promising analogues of the series were engaged in further cell-based studies. Compounds 5e, l, p and 6a, b highlighted a pro-apoptotic potential being able to induce apoptosis in HL60, K562 and MCF-7 cell lines in a dose and time-dependent manner. The ability of these compounds to arrest cell cycle at the G2/M phase inspired the immunofluorescence studies which allowed us to identify tubulin as a potential target for compounds 5l and 6b. Copyright 2015 Elsevier Masson SAS. All rights reserved.
Taylor PN; Porcu E; Chew S; et al
Whole-genome sequence-based analysis of thyroid function. Journal Article
In: Nature Communications, 6 , pp. 5681, 2015.
Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.
Tintori C; La Sala G; Vignaroli G; Botta L; Fallacara AL; Falchi F; Radi M; Zamperini C; Dreassi E; Dello Iacono L; Orioli D; Biamonti G; Garbelli M; Lossani A; Gasparrini F; Tuccinardi T; Laurenzana I; Angelucci A; Maga G; Schenone S; Brullo C; Musumeci F; Desogus A; Crespan E; Botta M
In: Journal of Medicinal Chemistry, 58 (11), pp. 4590-4609, 2015.
Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K(i) of about 2 μM, while derivative 4a, derived from our internal library, showed a K(i) of 0.9 μM. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 4d having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines.
Il Pensiero Scientifico Editore, 2014, ISBN: 978-8849004809, (Vincitore del primo premio categoria saggi del Premio Letterario Nazionale Fanz Kafka - 2014).
Ancora oggi esiste una corrente di opinione, tutt’altro che secondaria e sempre vitale, che afferma che l’AIDS non esiste e che l’HIV è un innocuo parassita. Ma negare l’AIDS significa sottovalutare la pericolosità dell’infezione da HIV e indurre i pazienti a rifiutare terapie in grado di salvare loro la vita. Quando l’opinione errata di alcuni compromette la salute e la sicurezza di altri, è necessario correggerla. Giovanni Maga dimostra, con un linguaggio comprensibile a tutti e attraverso la narrazione appassionata di tante storie di pazienti, medici e ricercatori, che respingere la relazione tra HIV e AIDS è un errore dalle drammatiche conseguenze. Documentando, inoltre, gli straordinari progressi fatti nel combattere questa malattia, il libro vuole essere un invito all’ottimismo e alla speranza. La difficoltà nell’accettare l’AIDS e, di conseguenza, la disponibilità a credere che non esista nascono spesso dalla disperazione di chi vive la sieropositività come una condanna senza appello. Ma la scienza arriverà inevitabilmente a sconfiggere l’HIV e questo libro ci spiega come e perché.
Due atei, un prete e un agnostico. Pranzo a casa Darwin Book
Il Prato, Saonara, 2012, ISSN: 2037-9234.
Di Pietro R; Centurione MA
Elementi di Istologia Book
Edises, Napoli, 2012, ISBN: 978 88 7959 743 2.
Alexander von Humboldt. Schizzo biografico dal vivo Book
Il Prato, Saonara, 2009, ISBN: 9788863360677.
Multiple Pathways in cancer development. Book
Transworld Research Network, Trivandrum, 2008, ISBN: 9788178953625.
Bollati Boringhieri, Torino, 2006, ISBN: 9788833916705.
Alfred Russel Wallace (1823-1913) fu uno dei massimi naturalisti vittoriani. I suoi interessi scientifici spaziavano dall’entomologia all’antropologia, dalla geologia alla glaciologia, dal mimetismo alla biogeografia evolutiva. Tuttavia, nonostante la sua vastissima produzione scientifica, egli viene generalmente ricordato solo per esser stato l’altro uomo che scopri la selezione naturale.
Pochi in realtà conoscono i suoi anni avventurosi trascorsi nelle foreste tropicali, l'eccellente lavoro di divulgazione del darwinismo, il sincero impegno sociale in difesa dei deboli e la sua fede nello spiritualismo, che lo portava a credere ottimisticamente in un continuo progresso morale e sociale dell’umanità.
La presente opera propone, inseriti in una sintetica cornice critica, i più famosi saggi evoluzionistici e antropologici di Wallace e alcuni significativi passi tratti dall'autobiografia e dagli scritti sociali.
Da queste pagine Wallace emerge non solo come un grande naturalista, ma anche, e sopratutto, come un grande uomo.
Cavalli-Sforza LL; Moroni A; Zei G
2004, ISBN: 9780691089928.
In 1951, the geneticist Luigi Luca Cavalli-Sforza was teaching in Parma when a student — a priest named Antonio Moroni — told him about rich church records of demography and marriages between relatives. After convincing the Church to open its records, Cavalli-Sforza, Moroni, and Gianna Zei embarked on a landmark study that would last fifty years and cover all of Italy. This book assembles and analyzes the team’s research for the first time.
Using blood testing as well as church records, the team investigated the frequency of consanguineous marriages and its use for estimating inbreeding and studying the relations between inbreeding and drift. They tested the importance of random genetic drift by studying population structure through demography of the last three centuries, using it to predict the spatial variation of frequencies of genetic markers. The authors find that drift-related genetic variation, including its stabilization by migration, is best predicted by computer simulation. They also analyze the usefulness and limits of the concept of deme for defining Mendelian populations. The genetic effect of consanguineous marriage on recessive genetic diseases and for the detection of dominance in metric characters are also studied.
Ultimately bringing together the many strands of their massive project, Cavalli-Sforza, Moroni, and Zei are able to map genetic drift in all of Italy’s approximately 8,000 communes and to demonstrate the relationship between each locality’s drift and various ecological and demographic factors. In terms of both methods and findings, their accomplishment is tremendously important for understanding human social structure and the genetic effects of drift and inbreeding.
Carano F; Teti G; Ruggeri A; Chiarini F; Giorgetti A; Mazzotti MC; Fais P; Falconi M
In: Scientific Reports, 11 (1), pp. 19248, 0000.
The discovery of the expression of opioid receptors in the skin and their role in orchestrating the process of tissue repair gave rise to questions regarding the potential effects of clinical morphine treatment in wound healing. Although short term treatment was reported to improve tissue regeneration, in vivo chronic administration was associated to an impairment of the physiological healing process and systemic fibrosis. Human mesenchymal stem cells (hMSCs) play a fundamental role in tissue regeneration. In this regard, acute morphine exposition was recently reported to impact negatively on the functional characteristics of hMSCs, but little is currently known about its long-term effects. To determine how a prolonged treatment could impair their functional characteristics, we exposed hMSCs to increasing morphine concentrations respectively for nine and eighteen days, evaluating in particular the fibrogenic potential exerted by the long-term exposition. Our results showed a time dependent cell viability decline, and conditions compatible with a cellular senescent state. Ultrastructural and protein expression analysis were indicative of increased autophagy, suggesting a relation to a detoxification activity. In addition, the enhanced transcription observed for the genes involved in the synthesis and regulation of type I collagen suggested the possibility that a prolonged morphine treatment might exert its fibrotic potential risk, even involving the hMSCs.